U.S. patent application number 12/914101 was filed with the patent office on 2011-06-02 for substituted 3-phenylpropionic acids and the use thereof.
This patent application is currently assigned to Bayer Schering Pharma Aktiengesellschaft. Invention is credited to Eva-Maria BECKER, Sherif EL SHEIKH, Michael HAHN, Andreas KNORR, Thomas LAMPE, Volkhart Min-Jian LI, Karl-Heinz SCHLEMMER, Johannes-Peter STASCH, Friederike STOLL, Frank WUNDER.
Application Number | 20110130445 12/914101 |
Document ID | / |
Family ID | 43232960 |
Filed Date | 2011-06-02 |
United States Patent
Application |
20110130445 |
Kind Code |
A1 |
LAMPE; Thomas ; et
al. |
June 2, 2011 |
SUBSTITUTED 3-PHENYLPROPIONIC ACIDS AND THE USE THEREOF
Abstract
The present application relates to novel 3-phenylpropionic acid
derivatives, to processes for their preparation, to their use for
the treatment and/or prevention of diseases and to their use for
preparing medicaments for the treatment and/or prevention of
diseases, in particular for the treatment and/or prevention of
cardiovascular disorders.
Inventors: |
LAMPE; Thomas; (Dusseldorf,
DE) ; HAHN; Michael; (Langenfeld, DE) ;
STASCH; Johannes-Peter; (Solingen, DE) ; SCHLEMMER;
Karl-Heinz; (Wuppertal, DE) ; WUNDER; Frank;
(Wuppertal, DE) ; EL SHEIKH; Sherif; (Essen,
DE) ; LI; Volkhart Min-Jian; (Velbert, DE) ;
BECKER; Eva-Maria; (Wuppertal, DE) ; STOLL;
Friederike; (Dusseldorf, DE) ; KNORR; Andreas;
(Erkrath, DE) |
Assignee: |
Bayer Schering Pharma
Aktiengesellschaft
Berlin
DE
|
Family ID: |
43232960 |
Appl. No.: |
12/914101 |
Filed: |
October 28, 2010 |
Current U.S.
Class: |
514/449 ;
514/563; 549/510; 562/401; 562/441; 562/455; 562/456 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
1/04 20180101; A61P 7/06 20180101; C07C 2601/02 20170501; A61P
25/16 20180101; C07C 2601/04 20170501; A61P 7/02 20180101; C07C
233/88 20130101; C07C 205/38 20130101; A61P 3/14 20180101; A61P
25/00 20180101; A61P 25/14 20180101; A61P 1/18 20180101; C07C
233/45 20130101; A61P 37/02 20180101; C07C 2601/08 20170501; A61P
9/10 20180101; A61P 13/02 20180101; A61P 31/10 20180101; A61P 11/06
20180101; A61P 19/02 20180101; A61P 25/28 20180101; A61P 27/02
20180101; A61P 13/12 20180101; C07C 231/02 20130101; C07C 233/55
20130101; A61P 9/00 20180101; A61P 25/30 20180101; A61P 27/06
20180101; A61P 31/04 20180101; A61K 31/196 20130101; A61P 25/20
20180101; A61P 21/02 20180101; A61P 13/08 20180101; A61P 25/22
20180101; A61P 11/00 20180101; A61P 15/10 20180101; A61P 9/08
20180101; A61P 19/10 20180101; A61P 29/00 20180101; A61P 7/00
20180101; A61P 11/16 20180101; A61P 43/00 20180101; A61P 9/04
20180101; A61P 17/00 20180101; C07C 255/60 20130101; C07D 305/06
20130101; A61K 31/655 20130101 |
Class at
Publication: |
514/449 ;
562/456; 562/441; 549/510; 562/455; 562/401; 514/563 |
International
Class: |
A61K 31/196 20060101
A61K031/196; C07C 233/55 20060101 C07C233/55; C07D 305/06 20060101
C07D305/06; C07C 235/38 20060101 C07C235/38; C07C 231/24 20060101
C07C231/24; A61K 31/337 20060101 A61K031/337; A61P 9/04 20060101
A61P009/04; A61P 9/12 20060101 A61P009/12; A61P 9/10 20060101
A61P009/10; A61P 9/00 20060101 A61P009/00; A61P 7/00 20060101
A61P007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 28, 2009 |
DE |
102009046115.9 |
Claims
1. A compound of the formula (I) ##STR00418## in which R.sup.1A
represents hydrogen, fluorine, methyl, trifluoromethyl, ethyl,
1,1-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, cyclopropyl or
cyclobutyl, R.sup.1B represents hydrogen or methyl, R.sup.2A
represents hydrogen, methyl, trifluoromethyl, ethyl,
1,1-difluoroethyl, 2,2,2-tri-fluoroethyl or n-propyl, and R.sup.2B
represents hydrogen or methyl, or R.sup.1A and R.sup.2A are
attached to one another and together with the carbon atoms to which
they are attached form a cyclopropyl ring of the formula
##STR00419## in which R.sup.1B and R.sup.2B have the meanings
mentioned above, or R.sup.2A and R.sup.2B are attached to one
another and together with the carbon atom to which they are
attached form a cyclic group of the formula ##STR00420## in which n
represents the number 1, 2 or 3, and R.sup.1A and R.sup.1B have the
meanings mentioned above, R.sup.3 represents hydrogen, fluorine,
methyl or trifluoromethyl, R.sup.4 represents hydrogen, fluorine,
chlorine, cyano, methyl, trifluoromethyl or ethyl, R.sup.5A
represents methyl, trifluoromethyl or ethyl, and R.sup.5B
represents trifluoromethyl, or R.sup.5A and R.sup.5B are attached
to one another and together with the carbon atom to which they are
attached form a difluoro-substituted cycloalkyl ring of the formula
##STR00421## R.sup.6 represents hydrogen, fluorine, chlorine,
bromine, cyano, (C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.4)-alkenyl,
cyclopropyl or cyclobutyl, where (C.sub.1-C.sub.4)-alkyl and
(C.sub.2-C.sub.4)-alkenyl may be substituted up to three times by
fluorine and cyclopropyl and cyclobutyl may be substituted up to
two times by fluorine, and R.sup.7 represents hydrogen, fluorine,
chlorine, cyano, methyl, trifluoromethyl, ethyl, methoxy or
trifluoromethoxy, or a salt, solvate or solvate of a salt
thereof.
2. The compound according to claim 1 in which R.sup.1A represents
hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, cyclopropyl or
cyclobutyl, R.sup.1B represents hydrogen or methyl, R.sup.2A
represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
R.sup.2B represents hydrogen or methyl, or R.sup.2A and R.sup.2B
are attached to one another and together with the carbon atom to
which they are attached form a cyclic group of the formula
##STR00422## in which n represents the number 1 or 2, and R.sup.1A
and R.sup.1B have the meanings mentioned above, R.sup.3 represents
hydrogen, fluorine or methyl, R.sup.4 represents hydrogen,
fluorine, chlorine, cyano, methyl or trifluoromethyl, R.sup.5A
represents methyl or ethyl, R.sup.5B represents trifluoromethyl, or
R.sup.5A and R.sup.5B are attached to one another and together with
the carbon atom to which they are attached form a
difluoro-substituted cycloalkyl ring of the formula ##STR00423##
R.sup.6 represents fluorine, chlorine, (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.3)-alkenyl, cyclopropyl or cyclobutyl, where
(C.sub.1-C.sub.4)-alkyl and (C.sub.2-C.sub.3)-alkenyl may be
substituted up to three times by fluorine and cyclopropyl and
cyclobutyl may be substituted up to two times by fluorine, and
R.sup.7 represents hydrogen, fluorine, chlorine, methyl or methoxy,
or a salt, solvate or solvate of a salt thereof.
3. The compound according to claim 1 in which R.sup.1A represents
hydrogen, methyl or ethyl, R.sup.1B represents hydrogen, R.sup.2A
represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
R.sup.2B represents hydrogen or methyl, or R.sup.2A and R.sup.2B
are attached to one another and together with the carbon atom to
which they are attached form a cyclic group of the formula
##STR00424## in which n represents the number 1 or 2, and R.sup.1A
and R.sup.1B have the meanings mentioned above, R.sup.3 represents
hydrogen, R.sup.4 represents fluorine, chlorine or methyl, R.sup.5A
represents methyl, R.sup.5B represents trifluoromethyl, or R.sup.5A
and R.sup.5B are attached to one another and together with the
carbon atom to which they are attached form a difluoro-substituted
cyclopentyl ring of the formula ##STR00425## R.sup.6 represents
fluorine, chlorine, methyl, trifluoromethyl, ethyl,
1,1-difluoroethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl,
1,1,1-trifluoro-2-methylpropan-2-yl, vinyl, 1-fluorovinyl,
cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl or
3,3-difluorocyclobutyl, and R.sup.7 represents hydrogen, fluorine,
chlorine or methyl, or a salt, solvate or solvate of a salt
thereof.
4. The compound according to claim 1, wherein the compound is
(+)-3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-chlorophenyl)propanoic acid;
3-[4-Chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)pheny-
l]butanoyl}amino)phenyl]propanoic acid;
3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}phenyl)butanoic acid;
(3S)-3-(4-chloro-3-{[(4-chlorophenyl)(2,2-difluoro-cyclopentyl)acetyl]ami-
no}phenyl)butanoic acid;
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}phenyl)propanoic acid;
(+)-(2S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-met-
hylbutanoyl]amino}phenyl)-2-methylpropanoic acid;
(+)-[1-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]a-
mino}-4-fluorophenyl)-cyclopropyl]acetic acid;
[1-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl-
]amino}phenyl)cyclobutyl]acetic acid;
(+)-(2S)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-met-
hylbutanoyl]amino}benzyl)butanoic acid;
3-(3-{[(3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4--
fluorophenyl)-2-methylpropanoic acid;
threo-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}-4-fluorophenyl)-2-methylbutanoic acid;
2-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
-4-fluorophenyl)-trans-cyclopropanecarboxylic acid;
(+)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}benzyl)-2-methylbutanoic acid;
3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)hexanoic acid;
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}phenyl)hexanoic acid;
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}phenyl)-4,4,4-trifluorobutanoic acid;
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}phenyl)pentanoic acid;
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)-2,2-dimethylpropanoic acid;
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutan-
oyl]amino}-phenyl)cyclobutyl]acetic acid;
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutan-
oyl]amino}-phenyl)cyclopropyl]acetic acid;
(2S)-3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)-
phenyl]butanoyl}amino)phenyl]-2-methylpropanoic acid;
(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-difluorocyclobutyl)phenyl]-4,4,4-t-
rifluoro-3-methylbutanoyl}amino)phenyl]-2-methylpropanoic acid;
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutan-
oyl]amino}phenyl)-3,3-difluorocyclobutyl]acetic acid; or
(2S)-3-(4-Chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amin-
o}phenyl)-2-methylpropanoic acid.
5. A process for preparing a compound according to claim 1, wherein
(a) a carboxylic acid of the formula (II) ##STR00426## in which
R.sup.5A, R.sup.4B, R.sup.6 and R.sup.7 have the meanings given in
claim 1 is coupled with an amine of the formula (III) ##STR00427##
in which R.sup.1A, R.sup.1B, R.sup.2A, R.sup.3B, R.sup.1 and
R.sup.4 have the meanings given in claim 1 and T.sup.1 represents
(C.sub.1-C.sub.4)-alkyl or benzyl, to give a carboxamide of the
formula (IV) ##STR00428## in which R.sup.1A, R.sup.1B, R.sup.2A,
R.sup.2B, R.sup.3, R.sup.4, R.sup.5A, R.sup.5B, R.sup.6, R.sup.7
and T.sup.1 have the meanings given above, (b) the ester radical
T.sup.1 is removed to give the compound of formula (I), and (c) the
compound of formula (I) is optionally separated into its
enantiomers and/or diastereomers, and/or optionally reacted with
one or more (i) solvents and/or (ii) bases to give a solvate, salt
and/or solvate of a salt thereof.
6. The process according to claim 5, wherein step (a) is performed
via a carbonyl chloride intermediate in the presence of a base.
7. The process according to claim 5, wherein in step (b) the ester
radical T.sup.1 is removed by basic or acidic solvolysis and, if
T.sup.1 represents benzyl, also by hydrogenolysis.
8. A pharmaceutical composition comprising a compound according to
claim 1 and an inert, non-toxic, pharmaceutically suitable
excipient.
9. A pharmaceutical composition comprising a compound according to
claim 2 and an inert, non-toxic, pharmaceutically suitable
excipient.
10. A pharmaceutical composition comprising a compound according to
claim 3 and an inert, non-toxic, pharmaceutically suitable
excipient.
11. A pharmaceutical composition comprising a compound according to
claim 4 and an inert, non-toxic, pharmaceutically suitable
excipient.
12. A pharmaceutical composition comprising a compound according to
claim 1 in combination with one or more further active compounds
selected from the group consisting of organic nitrates, NO donors,
cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents
having antithrombotic activity, agents lowering blood pressure, and
agents altering lipid metabolism.
13. A pharmaceutical composition comprising a compound according to
claim 2 in combination with one or more further active compounds
selected from the group consisting of organic nitrates, NO donors,
cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents
having antithrombotic activity, agents lowering blood pressure, and
agents altering lipid metabolism.
14. A pharmaceutical composition comprising a compound according to
claim 3 in combination with one or more further active compounds
selected from the group consisting of organic nitrates, NO donors,
cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents
having antithrombotic activity, agents lowering blood pressure, and
agents altering lipid metabolism.
15. A pharmaceutical composition comprising a compound according to
claim 4 in combination with one or more further active compounds
selected from the group consisting of organic nitrates, NO donors,
cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents
having antithrombotic activity, agents lowering blood pressure, and
agents altering lipid metabolism.
16. A method for the treatment and/or prevention of heart failure,
angina pectoris, hypertension, pulmonary hypertension, ischemias,
vascular disorders, impaired microcirculation, thromboembolic
disorders or arteriosclerosis comprising administering to a human
or animal in need thereof an effective amount of a compound
according to claim 1.
17. A method for the treatment and/or prevention of heart failure,
angina pectoris, hypertension, pulmonary hypertension, ischemias,
vascular disorders, impaired microcirculation, thromboembolic
disorders or arteriosclerosis comprising administering to a human
or animal in need thereof an effective amount of a compound
according to claim 2.
18. A method for the treatment and/or prevention of heart failure,
angina pectoris, hypertension, pulmonary hypertension, ischemias,
vascular disorders, impaired microcirculation, thromboembolic
disorders or arteriosclerosis comprising administering to a human
or animal in need thereof an effective amount of a compound
according to claim 3.
19. A method for the treatment and/or prevention of heart failure,
angina pectoris, hypertension, pulmonary hypertension, ischemias,
vascular disorders, impaired microcirculation, thromboembolic
disorders or arteriosclerosis comprising administering to a human
or animal in need thereof an effective amount of a compound
according to claim 4.
20. The process according to claim 5, wherein step (a) is performed
in the presence of an inert solvent with the aid of a condensing
agent.
Description
[0001] The present application relates to novel 3-phenylpropionic
acid derivatives, to processes for their preparation, to their use
for the treatment and/or prevention of diseases and to their use
for preparing medicaments for the treatment and/or prevention of
diseases, in particular for the treatment and/or prevention of
cardiovascular disorders.
[0002] One of the most important cellular transmission systems in
mammalian cells is cyclic guanosine monophosphate (cGMP). Together
with nitric oxide (NO), which is released from the endothelium and
transmits hormonal and mechanical signals, it forms the NO/cGMP
system. Guanylate cyclases catalyze the biosynthesis of cGMP from
guanosine triphosphate (GTP). The representatives of this family
disclosed to date can be divided both according to structural
features and according to the type of ligands into two groups: the
particulate guanylate cyclases which can be stimulated by
natriuretic peptides, and the soluble guanylate cyclases which can
be stimulated by NO. The soluble guanylate cyclases consist of two
subunits and very probably contain one haem per heterodimer, which
is part of the regulatory site. The latter is of central importance
for the mechanism of activation. NO is able to bind to the iron
atom of haem and thus markedly increase the activity of the enzyme.
Haem-free preparations cannot, by contrast, be stimulated by NO.
Carbon monoxide (CO) is also able to attach to the central iron
atom of haem, but the stimulation by CO is distinctly less than
that by NO.
[0003] Through the production of cGMP and the regulation, resulting
therefrom, of phosphodiesterases, ion channels and protein kinases,
guanylate cyclase plays a crucial part in various physiological
processes, in particular in the relaxation and proliferation of
smooth muscle cells, in platelet aggregation and adhesion and in
neuronal signal transmission, and in disorders caused by an
impairment of the aforementioned processes. Under
pathophysiological conditions, the NO/cGMP system may be
suppressed, which may lead for example to high blood pressure,
platelet activation, increased cellular proliferation, endothelial
dysfunction, atherosclerosis, angina pectoris, heart failure,
thromboses, stroke and myocardial infarction.
[0004] A possible way of treating such disorders which is
independent of NO and aims at influencing the cGMP signaling
pathway in organisms is a promising approach because of the high
efficiency and few side effects which are to be expected.
[0005] Compounds, such as organic nitrates, whose effect is based
on NO have to date been exclusively used for the therapeutic
stimulation of soluble guanylate cyclase. NO is produced by
bioconversion and activates soluble guanylate cyclase by attaching
to the central iron atom of haem. Besides the side effects, the
development of tolerance is one of the crucial disadvantages of
this mode of treatment [O. V. Evgenov et al., Nature Rev. Drug
Disc. 5 (2006), 755].
[0006] Substances which directly stimulate soluble guanylate
cyclase, i.e. without previous release of NO, have been identified
in recent years. The indazole derivative YC-1 was the first
NO-independent but haem-dependent sGC stimulator described [Evgenov
et al., ibid.]. Based on YC-1, further substances were discovered
which are more potent than YC-1 and show no relevant inhibition of
phosphodiesterases (PDE). This led to the identification of the
pyrazolopyridine derivatives BAY 41-2272, BAY 41-8543 and BAY
63-2521. Together with the recently published structurally
different substances CMF-1571 and A-350619, these compounds form
the new class of the sGC stimulators [Evgenov et al., ibid.]. A
common characteristic of this substance class is an NO-independent
and selective activation of the haem-containing sGC. In addition,
the sGC stimulators in combination with NO have a synergistic
effect on sGC activation based on a stabilization of the
nitrosyl-haem complex. The exact binding site of the sGC
stimulators at the sGC is still being debated. If the haem group is
removed from the soluble guanylate cyclase, the enzyme still has a
detectable catalytic basal activity, i.e. cGMP is still being
formed. The remaining catalytic basal activity of the haem-free
enzyme cannot be stimulated by any of the stimulators mentioned
above [Evgenov et al., ibid.].
[0007] In addition, NO- and haem-independent sGC activators, with
BAY 58-2667 as prototype of this class, have been identified.
Common characteristics of these substances are that in combination
with NO they only have an additive effect on enzyme activation, and
that the activation of the oxidized or haem-free enzyme is markedly
higher than that of the haem-containing enzyme [Evgenov et al.,
ibid.; J. P. Stasch et al., Br. J. Pharmacol. 136 (2002), 773; J.
P. Stasch et al., J. Clin. Invest. 116 (2006), 2552]. Spectroscopic
studies show that BAY 58-2667 displaces the oxidized haem group
which, as a result of the weakening of the iron-histidine bond, is
attached only weakly to the sGC. It has also been shown that the
characteristic sGC haem binding motif Tyr-x-Ser-x-Arg is absolutely
essential both for the interaction of the negatively charged
propionic acids of the haem group and for the action of BAY
58-2667. Against this background, it is assumed that the binding
site of BAY 58-2667 at the sGC is identical to the binding site of
the haem group [J. P. Stasch et al., J. Clin. Invest. 116 (2006),
2552].
[0008] The compounds described in the present invention are now
likewise capable of activating the haem-free form of soluble
guanylate cyclase. This is also confirmed by the fact that these
novel activators firstly have no synergistic action with NO at the
haem-containing enzyme and that secondly their action cannot be
blocked by the haem-dependent inhibitor of soluble guanylate
cyclase, 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but is
even potentiated by this inhibitor [cf. O. V. Evgenov et al.,
Nature Rev. Drug Disc. 5 (2006), 755; J. P. Stasch et al., J. Clin.
Invest. 116 (2006), 2552].
[0009] Accordingly, it was an object of the present invention to
provide novel compounds which act as activators of soluble
guanylate cyclase in the manner described above and can be used as
such in particular for the treatment and prevention of
cardiovascular disorders.
[0010] WO 00/64888-A1, EP 1 216 980-A1, EP 1 375 472-A1, EP 1 452
521-A1, US 2005/0187266-A1 and US 2005/0234066-A1 describe various
arylalkanecarboxylic acid derivatives as PPAR agonists for the
treatment of diabetes, dyslipidemia, arteriosclerosis, obesity and
other disorders. EP 1 312 601-A1 and EP 1 431 267-A1 disclose
substituted arylalkanecarboxylic acids as PGE.sub.2 receptor
antagonists for the treatment of, for example, pain, urological
disorders, Alzheimer's disease and cancer. Furthermore,
arylalkanecarboxylic acids are claimed in WO 2005/086661-A2 as
GPR40 modulators for the treatment of diabetes and dyslipidemias,
and WO 2004/099170-A2, WO 2006/050097-A1 and WO 2006/055625-A2
describe phenyl-substituted carboxylic acids as PTP-1B inhibitors
for the treatment of diabetes, cancer and neurodegenerative
disorders. Furthermore, individual phenylacetamido-substituted
phenylalkanecarboxylic acids which, in the form of non-covalent
mixtures, improve the provision of active peptide compounds within
the body are known from WO 96/12473-A1 and WO 96/30036-A1.
Recently, oxoheterocyclically substituted carboxylic acid
derivatives which act as activators of soluble guanylate cyclase
have been disclosed in WO 2009/127338-A1.
[0011] The present invention provides compounds of the general
formula (I)
##STR00001##
in which [0012] R.sup.1A represents hydrogen, fluorine, methyl,
trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,
n-propyl, cyclopropyl or cyclobutyl, [0013] R.sup.1B represents
hydrogen or methyl, [0014] R.sup.2A represents hydrogen, methyl,
trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl or
n-propyl, [0015] R.sup.2B represents hydrogen or methyl, or [0016]
R.sup.1A and R.sup.2A are attached to one another and together with
the carbon atoms to which they are attached form a cyclopropyl ring
of the formula
[0016] ##STR00002## [0017] in which R.sup.1B and R.sup.2B have the
meanings mentioned above, or [0018] R.sup.2A and R.sup.2B are
attached to one another and together with the carbon atom to which
they are attached form a cyclic group of the formula
##STR00003##
[0018] in which [0019] n represents the number 1, 2 or 3, and
[0020] R.sup.1A and R.sup.1B have the meanings mentioned above,
[0021] R.sup.3 represents hydrogen, fluorine, methyl or
trifluoromethyl, [0022] R.sup.4 represents hydrogen, fluorine,
chlorine, cyano, methyl, trifluoromethyl or ethyl, [0023] R.sup.5A
represents methyl, trifluoromethyl or ethyl, [0024] R.sup.5B
represents trifluoromethyl, or [0025] R.sup.5A and R.sup.5B are
attached to one another and together with the carbon atom to which
they are attached form a difluoro-substituted cycloalkyl ring of
the formula
[0025] ##STR00004## [0026] R.sup.6 represents hydrogen, fluorine,
chlorine, bromine, cyano, (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.4)-alkenyl, cyclopropyl or cyclobutyl, where [0027]
(C.sub.1-C.sub.4)-alkyl and (C.sub.2-C.sub.4)-alkenyl may be
substituted up to three times by fluorine [0028] and [0029]
cyclopropyl and cyclobutyl may be substituted up to two times by
fluorine, and
[0030] R.sup.7 represents hydrogen, fluorine, chlorine, cyano,
methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy,
and the salts, solvates and solvates of the salts thereof.
[0031] Compounds according to the invention are the compounds of
the formula (I) and their salts, solvates and solvates of the
salts; the compounds, encompassed by formula (I), of the formulae
specified below and their salts, solvates and solvates of the
salts; and the compounds, encompassed by formula (I), specified
below as examples and their salts, solvates and solvates of the
salts, where the compounds, encompassed by formula (I), specified
below are not already salts, solvates and solvates of the
salts.
[0032] The compounds according to the invention can exist in
various stereoisomeric forms, i.e. in the form of configurational
isomers or, if appropriate, also as conformational isomers
(enantiomers and/or diastereomers, including those in the case of
atrop isomers), depending on their structure. The present invention
therefore includes the enantiomers and diastereomers and their
particular mixtures. The stereoisomerically uniform constituents
can be isolated from such mixtures of enantiomers and/or
diastereomers in a known manner; chromatographical processes are
preferably used for this, in particular HPLC chromatography on an
achiral or chiral phase.
[0033] Where the compounds according to the invention can occur in
tautomeric forms, the present invention includes all the tautomeric
forms.
[0034] Preferred salts in the context of the present invention are
physiologically acceptable salts of the compounds according to the
invention. Salts which are not themselves suitable for
pharmaceutical uses but can be used, for example, for isolation or
purification of the compounds according to the invention are also
included.
[0035] Physiologically acceptable salts of the compounds according
to the invention also include in particular the salts of
conventional bases, such as, by way of example and preferably,
alkali metal salts (e.g. sodium and potassium salts), alkaline
earth metal salts (e.g. calcium and magnesium salts) and ammonium
salts derived from ammonia or organic amines having 1 to 16 C
atoms, such as, by way of example and preferably, ethylamine,
diethylamine, triethylamine, ethyldiisopropyl-amine,
monoethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine,
N-methylmorpholine, N-methylpiperidine, arginine, lysine and
ethylenediamine.
[0036] Solvates in the context of the invention are designated as
those forms of the compounds according to the invention which form
a complex in the solid or liquid state by coordination with solvent
molecules. Hydrates are a specific form of solvates, in which the
coordination takes place with water. Hydrates are preferred
solvates in the context of the present invention.
[0037] The present invention moreover also includes prodrugs of the
compounds according to the invention. The term "prodrugs" here
designates compounds which themselves can be biologically active or
inactive, but are converted (for example metabolically or
hydrolytically) into compounds according to the invention during
their dwell time in the body.
[0038] The present invention comprises in particular hydrolyzable
ester derivatives of the carboxylic acids of the formula (I)
according to the invention. These are to be understood as meaning
esters which can be hydrolyzed to the free carboxylic acids, as the
compounds that are mainly active biologically, in physiological
media, under the conditions of the biological tests described later
and in particular in vivo by enzymatic or chemical routes.
(C.sub.1-C.sub.4)-alkyl esters, in which the alkyl group can be
straight-chain or branched, are preferred as such esters.
Particular preference is given to methyl, ethyl or tert-butyl
esters.
[0039] In the context of the present invention, the substituents
have the following meaning, unless specified otherwise:
[0040] (C.sub.1-C.sub.4)-Alkyl in the context of the invention
represents a straight-chain or branched alkyl radical having 1 to 4
carbon atoms. There may be mentioned by way of example and
preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl.
[0041] (C.sub.2-C.sub.4)-Alkenyl and (C.sub.2-C.sub.3)-Alkenyl in
the context of the invention represent a straight-chain or branched
alkenyl radical having a double bond and 2 to 4 or, respectively, 2
or 3 carbon atoms. Preference is given to a straight-chain or
branched alkenyl radical having 2 or 3 carbon atoms. There may be
mentioned by way of example and preferably: vinyl, allyl,
n-prop-1-en-1-yl, iso-propenyl, n-but-1-en-1-yl, n-but-2-en-1-yl,
n-but-3-en-1-yl, 2-methylprop-1-en-1-yl and
2-methylprop-2-en-1-yl.
[0042] In the context of the present invention, for all the
radicals which occur more than once, the meaning thereof is
independent of each other. If radicals in the compounds according
to the invention are substituted, the radicals can be mono- or
polysubstituted, unless specified otherwise. Substitution by one or
by two or by three individual or different substituents is
preferred. Substitution by one or by two identical or different
substituents is particularly preferred.
[0043] In a certain embodiment, the present invention embraces
compounds of the formula (I) in which [0044] R.sup.1A represents
hydrogen, fluorine, methyl, trifluoromethyl, ethyl,
1,1-difluoroethyl, 2,2,2-trifluoroethyl or n-propyl, [0045]
R.sup.1B represents hydrogen or methyl, [0046] R.sup.2A represents
hydrogen, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl,
2,2,2-trifluoroethyl or n-propyl, [0047] R.sup.2B represents
hydrogen or methyl, or [0048] R.sup.1A and R.sup.2A are attached to
one another and together with the carbon atoms to which they are
attached form a cyclopropyl ring of the formula
##STR00005##
[0048] in which R.sup.1B and R.sup.2B have the meanings mentioned
above, or [0049] R.sup.2A and R.sup.2B are attached to one another
and together with the carbon atom to which they are attached form a
cyclic group of the formula
##STR00006##
[0049] in which [0050] n represents the number 1, 2 or 3, and
[0051] R.sup.1A and R.sup.1B have the meanings mentioned above,
[0052] R.sup.3 represents hydrogen, fluorine, methyl or
trifluoromethyl, [0053] R.sup.4 represents hydrogen, fluorine,
chlorine, cyano, methyl, trifluoromethyl or ethyl, [0054] R.sup.5A
represents methyl, trifluoromethyl or ethyl, [0055] R.sup.5B
represents trifluoromethyl, or [0056] R.sup.5A and R.sup.5B are
attached to one another and together with the carbon atom to which
they are attached form a difluoro-substituted cycloalkyl ring of
the formula
[0056] ##STR00007## [0057] R.sup.6 represents hydrogen, fluorine,
chlorine, bromine, cyano, (C.sub.1-C.sub.4)-alkyl or
(C.sub.2-C.sub.4)-alkenyl, where (C.sub.1-C.sub.4)-alkyl and
(C.sub.2-C.sub.4)-alkenyl for their part may be substituted up to
three times by fluorine, and [0058] R.sup.7 represents hydrogen,
fluorine, chlorine or methyl, and the salts, solvates, and solvates
of the salts thereof.
[0059] In the context of the present invention, preference is given
to compounds of the formula (I) in which [0060] R.sup.1A represents
hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, cyclopropyl or
cyclobutyl, [0061] R.sup.1B represents hydrogen or methyl, [0062]
R.sup.2A represents hydrogen, methyl, trifluoromethyl, ethyl or
n-propyl, [0063] R.sup.2B represents hydrogen or methyl, or [0064]
R.sup.2A and R.sup.2B are attached to one another and together with
the carbon atom to which they are attached form a cyclic group of
the formula
##STR00008##
[0064] in which [0065] n represents the number 1 or 2, and [0066]
R.sup.1A and R.sup.1B have the meanings mentioned above, [0067]
R.sup.3 represents hydrogen, fluorine or methyl, [0068] R.sup.4
represents hydrogen, fluorine, chlorine, cyano, methyl or
trifluoromethyl, [0069] R.sup.5A represents methyl or ethyl, [0070]
R.sup.5B represents trifluoromethyl, or [0071] R.sup.5A and
R.sup.5B are attached to one another and together wtih the carbon
atom to which they are attached form a difluoro-substituted
cycloalkyl ring of the formula
[0071] ##STR00009## [0072] R.sup.6 represents fluorine, chlorine,
(C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.3)-alkenyl, cyclopropyl or
cyclobutyl, where [0073] (C.sub.1-C.sub.4)-alkyl and
(C.sub.2-C.sub.3)-alkenyl may be substituted up to three times by
fluorine [0074] and [0075] cyclopropyl and cyclobutyl may be
substituted up to two times by fluorine, and [0076] R.sup.7
represents hydrogen, fluorine, chlorine, methyl or methoxy, and the
salts, solvates, and solvates of the salts thereof.
[0077] A further preferred embodiment of the present invention
embraces compounds of the formula (I) in which [0078] R.sup.1A
represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
[0079] R.sup.1B represents hydrogen or methyl, [0080] R.sup.2A
represents hydrogen, methyl, trifluoromethyl or ethyl, [0081]
R.sup.2B represents hydrogen or methyl, or [0082] R.sup.2A and
R.sup.2B are attached to one another and together with the carbon
atom to which they are attached form a cyclic group of the
formula
##STR00010##
[0082] in which [0083] n represents the number 1 or 2, and [0084]
R.sup.1A and R.sup.1B have the meanings mentioned above, [0085]
R.sup.3 represents hydrogen or fluorine, [0086] R.sup.4 represents
hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl,
[0087] R.sup.5A represents methyl or ethyl, [0088] R.sup.5B
represents trifluoromethyl, or [0089] R.sup.5A and R.sup.5B are
attached to one another and together with the carbon atom to which
they are attached form a difluoro-substituted cycloalkyl ring of
the formula
[0089] ##STR00011## [0090] R.sup.6 represents fluorine, chlorine,
(C.sub.1-C.sub.4)-alkyl or (C.sub.2-C.sub.3)-alkenyl, where
(C.sub.1-C.sub.4)-alkyl and (C.sub.2-C.sub.3)-alkenyl for their
part may be substituted up to three times by fluorine, and [0091]
R.sup.7 represents hydrogen, fluorine or chlorine, and the salts,
solvates, and solvates of the salts thereof.
[0092] In the context of the present invention, particular
preference is given to compounds of the formula (I) in which [0093]
R.sup.1A represents hydrogen, methyl or ethyl, [0094] R.sup.1B
represents hydrogen, [0095] R.sup.2A represents hydrogen, methyl,
trifluoromethyl, ethyl or n-Propyl, [0096] R.sup.2B represents
hydrogen or methyl, or [0097] R.sup.2A and R.sup.2B are attached to
one another and together with the carbon atom to which they are
attached form a cyclic group of the formula
##STR00012##
[0097] in which [0098] n represents the number 1 or 2, and [0099]
R.sup.1A and R.sup.1B have the meanings mentioned above, [0100]
R.sup.3 represents hydrogen, [0101] R.sup.4 represents fluorine,
chlorine or methyl, [0102] R.sup.5A represents methyl, [0103]
R.sup.5B represents trifluoromethyl, or [0104] R.sup.5A and
R.sup.5B are attached to one another and together with the carbon
atom to which they are attached form a difluoro-substituted
cyclopentyl ring of the formula
[0104] ##STR00013## [0105] R.sup.6 represents fluorine, chlorine,
methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl,
2,2,2-trifluoroethyl, isopropyl, tert-butyl,
1,1,1-trifluoro-2-methylpropan-2-yl, vinyl, 1-fluorovinyl,
cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl or
3,3-difluorocyclobutyl, and [0106] R.sup.7 represents hydrogen,
fluorine, chlorine or methyl, and the salts, solvates, and solvates
of the salts thereof.
[0107] A further particularly preferred embodiment of the present
invention embraces compounds of the formula (I) in which [0108]
R.sup.1A represents hydrogen, methyl or ethyl, [0109] R.sup.1B
represents hydrogen, [0110] R.sup.2A represents hydrogen or methyl,
[0111] R.sup.2B represents hydrogen, or [0112] R.sup.2A and
R.sup.2B are attached to one another and together with the carbon
atom to which they are attached form a cyclic group of the
formula
##STR00014##
[0112] in which [0113] n represents the number 1 or 2, and [0114]
R.sup.1A and R.sup.1B have the meanings mentioned above, [0115]
R.sup.3 represents hydrogen, [0116] R.sup.4 represents fluorine,
chlorine or methyl, [0117] R.sup.5A represents methyl, [0118]
R.sup.5B represents trifluoromethyl, or [0119] R.sup.5A and
R.sup.5B are attached to one another and together with the carbon
atom to which they are attached form a difluoro-substituted
cyclopentyl ring of the formula
[0119] ##STR00015## [0120] R.sup.6 represents chlorine, methyl,
trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,
isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, vinyl
or 1-fluorovinyl, and [0121] R.sup.7 represents hydrogen or
fluorine, and the salts, solvates, and solvates of the salts
thereof.
[0122] A particular embodiment of the present invention embraces
compounds of the formula (I) in which [0123] R.sup.1A represents
hydrogen, methyl or ethyl and [0124] R.sup.1B, R.sup.2A and
R.sup.2B each represent hydrogen, and the salts, solvates, and
solvates of the salts thereof.
[0125] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0126] R.sup.2A A
represents methyl, trifluoromethyl, ethyl or n-propyl and [0127]
R.sup.1A, R.sup.1B and R.sup.2B each represent hydrogen, and the
salts, solvates, and solvates of the salts thereof.
[0128] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0129] R.sup.1A and
R.sup.1B each represent hydrogen and [0130] R.sup.2A and R.sup.2B
each represent methyl, and the salts, solvates, and solvates of the
salts thereof.
[0131] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0132] R.sup.1A and
R.sup.1B each represent hydrogen and [0133] R.sup.2A and R.sup.2B
are attached to one another and together with the carbon atom to
which they are attached form a cyclopropyl or cyclobutyl ring of
the formula
##STR00016##
[0133] and the salts, solvates, and solvates of the salts
thereof.
[0134] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0135] R.sup.3
represents hydrogen and [0136] R.sup.4 represents fluorine or
chlorine, and the salts, solvates, and solvates of the salts
thereof.
[0137] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0138] R.sup.5A
represents methyl and [0139] R.sup.5B represents trifluoromethyl,
or a salt, solvate or solvates of the salt thereof.
[0140] A further particular embodiment of the present invention
embraces compounds of the formula (I) in which [0141] R.sup.5A and
R.sup.5B are attached to one another and together with the carbon
atom to which they are attached form a difluoro-substituted
cyclopentyl ring of the formula
##STR00017##
[0141] and the salts, solvates, and solvates of the salts
thereof.
[0142] A further particular embodiment of the present invention
embraces compounds of the formula (I-A)
##STR00018##
in which the carbon atom marked by an * sign of the phenylacetamide
grouping has the S configuration shown and the radicals R.sup.1A,
R.sup.1B, R.sup.2A, R.sup.2B, R.sup.3, R.sup.4, R.sup.5A, R.sup.5B,
R.sup.6 and R.sup.7 each have the meanings given above, and the
salts, solvates, and solvates of the salts thereof.
[0143] The definitions of radicals indicated specifically in the
respective combinations or preferred combinations of radicals are
replaced as desired irrespective of the particular combinations
indicated for the radicals also by definitions of radicals of other
combinations.
[0144] Another embodiment of the present invention encompases
combinations of two or more of the abovementioned preferred
definitions of substituents.
[0145] The invention furthermore provides a process for preparing
the compounds of the formula (I) according to the invention,
characterized in that a carboxylic acid of the formula (H)
##STR00019##
in which R.sup.5A, R.sup.5B, R.sup.6 and R.sup.7 have the meanings
given above are coupled in an inert solvent with the aid of a
condensing agent or via the intermediate of the corresponding
carbonyl chloride in the presence of a base with an amine of the
formula (III)
##STR00020##
in which R.sup.1A, R.sup.1B, R.sup.2A, R.sup.2B, R.sup.3 and
R.sup.4 have the meanings given above and T.sup.1 represents
(C.sub.1-C.sub.4)-alkyl or benzyl, to give a carboxamide of the
formula (IV)
##STR00021##
in which R.sup.1A, R.sup.1B, R.sup.2A, R.sup.2B, R.sup.3, R.sup.4,
R.sup.5A, R.sup.5B, R.sup.6, R.sup.7 and T.sup.1 have the meanings
given above, the ester radical T.sup.1 is then removed by basic or
acidic solvolysis or, if T.sup.1 represents benzyl, also by
hydrogenolysis, giving the carboxylic acid of the formula (I), and
the compounds of the formula (I) are optionally separated by
methods known to the person skilled in the art into their
enantiomers and/or diastereomers, and/or optionally reacted with
the appropriate (i) solvents and/or (ii) bases to give the
solvates, salts and/or solvates of the salts thereof.
[0146] Inert solvents for the process step (II)+(III).fwdarw.(IV)
[amide coupling] are, for example, ethers such as diethyl ether,
tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, glycol
dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons
such as benzene, toluene, xylene, hexane, cyclohexane or mineral
oil fractions, halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethylene or chlorobenzene, or other solvents such as
acetone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide
(DMSO), N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea
(DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use
mixtures of the solvents mentioned. Preference is given to using
dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of
these solvents.
[0147] Suitable condensing agents for this coupling reaction are,
for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-,
N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) or
N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride
(EDC), phosgene derivatives such as N,N'-carbonyldiimidazole (CDI),
1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium
3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate,
acylamino compounds such as
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl
chloroformate, 1-chloro-2-methyl-1-dimethylamino-1-propene,
propanephosphonic anhydride, diethyl cyanophosphonate,
bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate,
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (Py-BOP),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
O-(benzo-triazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TPTU),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) or
O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TCTU), if appropriate in combination with
further auxiliaries such as 1-hydroxybenzotriazole (HOBt) or
N-hydroxysuccinimide (HOSu), and, as bases, alkali metal
carbonates, for example sodium carbonate or potassium carbonate, or
organic bases such as triethylamine, N-methylmorpholine,
N-methylpiperidine, N,N-diisopropylethylamine, pyridine or
4-N,N-dimethylaminopyridine. Preference is given to using
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) or
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), in each case in combination with pyridine
or N,N-diisopropylethylamine, or
N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride
(EDC) in combination with 1-hydroxybenzotriazole (HOBt) and
triethylamine, or 1-chloro-2-methyl-1-dimethylamino-1-propene
together with pyridine.
[0148] The reaction (II)+(III).fwdarw.(IV) is generally carried out
in a temperature range of from 0.degree. C. to +60.degree. C.,
preferably at from +10.degree. C. to +40.degree. C.
[0149] When a carbonyl chloride corresponding to the compound (II)
is used, the coupling with the amine component (III) is carried out
in the presence of a customary organic auxiliary base such as
triethylamine, N-methylmorpholine, N-methylpiperidine,
N,N-diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or
1,5-diazabicyclo-[4.3.0]non-5-ene (DBN). Preference is given to
using triethylamine or N,N-diisopropylethylamine.
[0150] The reaction of the amine (III) with the carbonyl chloride
is generally carried out in a temperature range of from -20.degree.
C. to +60.degree. C., preferably in the range from -10.degree. C.
to +30.degree. C.
[0151] The carbonyl chlorides may be prepared in a customary manner
by treating the carboxylic acid (II) with thionyl chloride or
oxalyl chloride.
[0152] The removal of the ester group T.sup.1 in process step
(IV).fwdarw.(I) may be carried out by customary methods by treating
the ester in inert solvents with acids or bases, where in the
latter variant the salt initially formed is converted by treatment
with acid into the free carboxylic acid. In the case of the
tert-butyl esters, the ester cleavage is preferably carried out
using acids. Benzyl esters are preferably cleaved by hydrogenolysis
(hydrogenation) in the presence of a suitable catalyst, such as,
for example, palladium on activated carbon.
[0153] Suitable inert solvents for these reactions are water or the
organic solvents customary for ester cleavage. These preferably
include alcohols such as methanol, ethanol, n-propanol,
isopropanol, n-butanol or tert-butanol, or ethers such as diethyl
ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other
solvents such as acetone, dichloromethane, dimethylformamide or
dimethyl sulphoxide. It is also possible to use mixtures of the
solvents mentioned. In the case of a basic ester hydrolysis,
preference is given to using mixtures of water with dioxane,
tetrahydrofuran, methanol and/or ethanol. In the case of the
reaction with trifluoroacetic acid, preference is given to using
dichloromethane, and in the case of the reaction with hydrogen
chloride, preference is given to using tetrahydrofuran, diethyl
ether, dioxane or water.
[0154] Suitable bases are the customary inorganic bases. These
include in particular alkali metal or alkaline earth metal
hydroxides such as, for example, lithium hydroxide, sodium
hydroxide, potassium hydroxide or barium hydroxide, or alkali metal
or alkaline earth metal carbonates such as sodium carbonate,
potassium carbonate or calcium carbonate. Preference is given to
lithium hydroxide, sodium hydroxide or potassium hydroxide.
[0155] Suitable acids for the ester cleavage are, in general,
sulphuric acid, hydrogen chloride/hydrochloric acid, hydrogen
bromide/hydrobromic acid, phosphoric acid, acetic acid,
trifluoroacetic acid, toluenesulphonic acid, methanesulphonic acid
or trifluoromethanesulphonic acid or mixtures thereof, if
appropriate with addition of water. Preference is given to hydrogen
chloride or trifluoroacetic acid in the case of the tert-butyl
esters and to hydrochloric acid in the case of the methyl
esters.
[0156] The ester cleavage is generally carried out in a temperature
range of from -20.degree. C. to +100.degree. C., preferably at from
0.degree. C. to +60.degree. C.
[0157] The intermediates of the formula (H) can be prepared, for
example, by initially deprotonating a carboxylic ester of the
formula (V)
##STR00022##
in which R.sup.5A and R.sup.5B have the meanings given above and
T.sup.2 represents (C.sub.1-C.sub.4)-alkyl or benzyl, in an inert
solvent with the aid of a base, then arylating it in the presence
of a suitable palladium catalyst with a phenyl bromide of the
formula (VI)
##STR00023##
in which R.sup.6 and R.sup.7 have the meanings given above, to give
a compound of the formula (VII)
##STR00024##
in which R.sup.5A, R.sup.5B, R.sup.6, R.sup.7 and T.sup.2 have the
meanings given above, and subsequently removing the ester radical
T.sup.2 by basic or acidic solvolysis or, in the case that T.sup.2
represents benzyl, also by hydrogenolysis, giving the carboxylic
acid (II).
[0158] The arylation reaction in process step (V)+(VI).fwdarw.(VII)
is preferably carried out in toluene or toluene/tetrahydrofuran
mixtures in a temperature range of from +20.degree. C. to
+100.degree. C. Here, the base used for deprotonating the ester (V)
is preferably lithium bis(trimethylsilyl)amide. Suitable palladium
catalysts are, for example, palladium(II) acetate or
tris(dibenzylideneacetone)di-palladium, in each case in combination
with an electron-rich, sterically demanding phosphine ligand such
as 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl or
2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl [cf., for
example, W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 123,
7996-8002 (2001)].
[0159] The removal of the ester group T.sup.2 in process setp
(VII).fwdarw.(II) may be carried out in a manner analogous to that
described above for the ester radical T.sup.1.
[0160] Alternatively, intermediates of the formula (II-A)
##STR00025##
in which R.sup.6 and R.sup.7 have the meanings given above, can
also be prepared by initially converting a phenylacetic ester of
the formula (VIII)
##STR00026##
in which R.sup.6, R.sup.7 and T.sup.2 have the meanings given above
by base-induced addition to 2-cyclopenten-1-one into a compound of
the formula (IX)
##STR00027##
in which R.sup.6, R.sup.7 and T.sup.2 have the meanings given
above, then fluorinating this compound with
1,1'-[(trifluoro-.lamda..sup.4-sulphanyl)imino]bis(2-methoxyethane)
under boron trifluoride catalysis to give a compound of the formula
(VII-A)
##STR00028##
in which R.sup.6, R.sup.7 and T.sup.2 have the meanings given
above, and subsequently again removing the ester group T.sup.2
giving the carboxylic acid (II-A).
[0161] In process step (VIII).fwdarw.(IX), for deprotonating the
ester (VIII), preference is given to using an amide base such as
lithium diisopropylamide or lithium bis(trimethylsilyl)amide. For
the deoxy-fluorination in the transformation (IX).fwdarw.(VII-A),
instead of the
1,1'-[(trifluoro-.lamda..sup.4-sulphanyl)-imino]bis(2-methoxyethane)
("Desoxofluor") mentioned above, it is also possible, if
appropriate, to employ other known fluorinating agents, such as
diethylaminosulphur trifluoride (DAST) or morpholinosulphur
trifluoride (morpho-DAST) [for the reaction sequence
(VIII).fwdarw.(IX).fwdarw.(VII-A), cf., for example, T. Mase et
al., J. Org. Chem. 66 (20), 6775-6786 (2001)].
[0162] The intermediates of the formula (III) can be prepared, for
example, either
[A] by reacting a phosphonoacetic ester of the formula (X)
##STR00029## [0163] in which R.sup.1A and T.sup.1 have the meanings
given above [0164] and [0165] R.sup.8 represents
(C.sub.1-C.sub.4)-alkyl, [0166] in an inert solvent in a
base-induced olefination reaction with a 3-nitrobenzoyl compound of
the formula (XI)
[0166] ##STR00030## [0167] in which R.sup.2A, R.sup.3 and R.sup.4
have the meanings given above, [0168] to give a compound of the
formula (XII)
[0168] ##STR00031## [0169] in which R.sup.1A, R.sup.2A, R.sup.3,
R.sup.4 and T.sup.1 have the meanings given above, [0170] and then
hydrogenating these in the presence of a suitable palladium or
platinum catalyst to give a 3-(3-aminophenyl)propionic ester of the
formula (III-A)
[0170] ##STR00032## [0171] in which R.sup.1A, R.sup.2A, R.sup.3,
R.sup.4 and T.sup.1 have the meanings given above, or [B] by
reacting an acrylic ester of the formula (XIII)
[0171] ##STR00033## [0172] in which R.sup.1A, R.sup.2A, R.sup.3B
and T.sup.1 have the meanings given above [0173] in an inert
solvent either (i) under rhodium(I) catalysis with a phenylboronic
acid of the formula (XIV)
[0173] ##STR00034## [0174] in which R.sup.3 and R.sup.4 have the
meanings given above [0175] and [0176] PG represents benzyl or
p-methoxybenzyl as inert aminoprotective group, [0177] or (ii)
under copper(I) catalysis with a phenylmagnesium reagent of the
formula (XV)
[0177] ##STR00035## [0178] in which R.sup.3, R.sup.4 and PG have
the meanings given above and [0179] Hal.sup.1 represents chlorine
or bromine, [0180] to give a compound of the formula (XVI)
[0180] ##STR00036## [0181] in which R.sup.1A, R.sup.2A, R.sup.2B,
R.sup.3, R.sup.4, PG and T.sup.1 have the meanings given above,
[0182] and subsequently removing the aminoprotective groups PG
according to customary methods by hydrogenolysis or oxidatively,
giving a 3-(3-aminophenyl)propionic ester of the formula
(III-B)
[0182] ##STR00037## [0183] in which R.sup.1A, R.sup.2A, R.sup.2B,
R.sup.3, R.sup.4 and T.sup.1 have the meanings given above, or [C]
by coupling an acrylic eseter of the formula (XVII)
[0183] ##STR00038## [0184] in which R.sup.1A, R.sup.2A and T.sup.1
have the meanings given above [0185] in an inert solvent under
palladium catalysis with a 3-amino- or 3-nitrophenyl bromide of the
formula (XVIII)
[0185] ##STR00039## [0186] in which R.sup.3 and R.sup.4 have the
meanings given above [0187] and [0188] R.sup.9 represents amino or
nitro, [0189] to give a compound of the formula (XIX)
[0189] ##STR00040## [0190] in which R.sup.1A, R.sup.2A, R.sup.3,
R.sup.4, R.sup.9 and T.sup.1 have the meanings given above, [0191]
and hydrogenating these in the presence of a suitable palladium or
platinum catalyst to give the 3-(3-aminophenyl)propionic ester of
the formula (III-C)
[0191] ##STR00041## [0192] in which R.sup.1A, R.sup.2A, R.sup.3,
R.sup.4 and T.sup.1 have the meanings given above, or [D] by
alkylating an ester of the formula (XX)
[0192] ##STR00042## [0193] in which R.sup.1A, R.sup.1B and T.sup.1
have the meanings given above [0194] in an inert solvent after
.alpha.-deprotonation with a 3-bromobenzyl halide of the formula
(XXI)
[0194] ##STR00043## [0195] in which R.sup.3 and R.sup.4 have the
meanings given above [0196] and [0197] Hal.sup.2 represents
chlorine, bromine or iodine, [0198] to give a compound of the
formula (XXII)
[0198] ##STR00044## [0199] in which R.sup.1A, R.sup.1B, R.sup.3,
R.sup.4 and T.sup.1 have the meanings given above, [0200] then
reacting it with benzylamine in the presence of a base and a
palladium catalyst to give a compound of the formula (XXIII)
[0200] ##STR00045## [0201] in which R.sup.1A, RIB, R.sup.3, R.sup.4
and T.sup.1 have the meanings given above, [0202] and then removing
the N-benzyl group by hydrogenolysis, giving a
3-(3-aminophenyl)-propionic ester of the formula (III-D)
[0202] ##STR00046## [0203] in which R.sup.1A, R.sup.1B, R.sup.3,
R.sup.4 and T.sup.1 have the meanings given above.
[0204] Suitable for deprotonating the phosphonic ester (X) in the
olefination reaction (X)+(XI).fwdarw.(XII) are in particular
non-nucleophilic strong bases such as, for example, sodium hydride
or potassium hydride, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide or potassium bis(tri-methylsilyl)amide or
lithium diisopropylamide; preference is given to using sodium
hydride.
[0205] The hydrogenation in the process step (XII).fwdarw.(III-A)
or (XIX).fwdarw.(III-C) is generally carried out under a stationary
hydrogen atmosphere at atmospheric pressure. Here, the catalyst
used is preferably palladium on activated carbon (as support). The
removal of the aminoprotective group(s) in the transformations
(XVI).fwdarw.(III-B) and (XXIII).fwdarw.(III-D) is usually carried
out by hydrogenolysis following the same procedure; in the case
that PG in (XVI) represents p-methoxy-benzyl, this may
alternatively also take place oxidatively, for example with the aid
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ammonium
cerium(IV) nitrate.
[0206] A preferred palladium catalyst for the reaction
(XVII)+(XVIII).fwdarw.(XIX) [Heck reaction] is palladium(II)
acetate in combination with a phosphine ligand such as, for
example, triphenyl- or tri-2-tolylphosphine [for the reaction
(XIII)+(XIV).fwdarw.(XVI), cf., for example, N. Miyaura et al.,
Organometallics 16, 4229 (1997) and also T. Hayashi, Synlett,
Special Issue 2001, 879-887; for the reaction
(XIII)+(XV).fwdarw.(XVI), cf., for example, P. Knochel et al.,
Tetrahedron 56, 2727-2731 (2000), Angew. Chem. 120, 6907-6911
(2008)].
[0207] Particularly suitable for the .alpha.-deprotonation of the
ester (XX) in the alkylation reaction (XX)+(XXI).fwdarw.(XXII) are
likewise non-nucleophilic strong bases such as, for example, sodium
hydride or potassium hydride, lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide or potassium
bis(trimethylsilyl)amide or lithium diisopropylamide; here,
preference is given to using lithium diisopropylamide.
[0208] For the reaction (XXII)+benzylamine.fwdarw.(XXIII)
[Buchwald-Hartwig coupling], preference is given to using
tris(dibenzylideneacetone)dipalladium(0) as palladium catalyst in
combination with (.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
as phosphine ligand and sodium tert-butoxide or potassium
tert-butoxide as base [cf., for example, J. P. Wolfe and S. L.
Buchwald, Organic Syntheses, Coll. Vol. 10, 423 (2004), Vol. 78, 23
(2002)].
[0209] The process steps described above can be carried out at
atmospheric pressure, at elevated pressure or at reduced pressure
(for example in the range of from 0.5 to 5 bar); in general, they
are in each case carried out at atmospheric pressure.
[0210] Separation of the compounds according to the invention into
the corresponding enantiomers and/or diastereomers can take place
where appropriate, depending on expediency, even at the stage of
the compounds (II), (III), (IV), (VII), (XVI), (XXII) or (XXIII),
which are then reacted further in separated form in accordance with
the above-described process sequences. Such a separation of the
stereoisomers can be carried out by conventional methods known to
the person skilled in the art. Preference is given to using
chromatographic methods on achiral or chiral separation phases; in
the case of carboxylic acids as intermediates or end products,
separation may alternatively also be via diastereomeric salts.
[0211] The compounds of the formulae (V), (VI), (VIII), (X), (XI),
(XIII), (XIV), (XV), (XVII), (XVIII), (XX) and (XXI) are either
commercially available or described as such in the literature, or
they can be prepared in a manner obvious to the person skilled in
the art analogously to the methods published in the literature.
Numerous detailed procedures and literature references for
preparing the starting materials can also be found in the
Experimental Part in the section on the preparation of the starting
materials and intermediates.
[0212] The preparation of the compounds according to the invention
can be illustrated in an exemplary manner by the reaction schemes
below:
##STR00047##
##STR00048##
##STR00049##
##STR00050##
##STR00051##
##STR00052##
##STR00053##
##STR00054##
##STR00055##
[0213] The compounds according to the invention have valuable
pharmacological properties and can be used for the prevention and
treatment of disorders in humans and animals.
[0214] The compounds according to the invention are potent
activators of soluble guanylate cyclase. They lead to
vasorelaxation, inhibition of platelet aggregation and lowering of
blood pressure and increase of coronary blood flow. These effects
are mediated by direct haem-independent activation of soluble
guanylate cyclase and an increase of intracellular cGMP.
[0215] In addition, the compounds according to the invention have
good pharmacokinetic properties, in particular with respect to
their bioavailability and their half-life in the body.
[0216] The compounds according to the invention can therefore be
employed in medicaments for the treatment and/or prevention of
cardiovascular disorders such as, for example, of high blood
pressure (hypertension) and heart failure, stable and unstable
angina pectoris, pulmonary arterial hypertension (PAH) and other
forms of pulmonary hypertension (PH), renal hypertension,
peripheral and cardiac vascular disorders, and also of arrhythmias,
for the treatment of thromboembolic disorders and ischemias such as
myocardial infarction, stroke, transitory and ischemic attacks and
also disturbances of peripheral blood flow, prevention of
restenoses as after thrombolysis therapies, percutaneous
transluminal angioplasties (PTAs), percutaneous transluminal
coronary angioplasties (PTCAs) and bypass, for the treatment of
arteriosclerosis, for promoting wound healing and for the treatment
of osteoporosis, glaucoma and gastroparesis.
[0217] In the context of the present invention, the term heart
failure includes both acute and chronic manifestations of heart
failure, as well as more specific or related types of disease, such
as acute decompensated heart failure, right heart failure, left
heart failure, global failure, ischemic cardiomyopathy, dilated
cardiomyopathy, hypertrophic cardiomyopathy, idiopathic
cardiomyopathy, congenital heart defects, heart valve defects,
heart failure associated with heart valve defects, mitral stenosis,
mitral insufficiency, aortic stenosis, aortic insufficiency,
tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis,
pulmonary valve insufficiency, combined heart valve defects,
myocardial inflammation (myocarditis), chronic myocarditis, acute
myocarditis, viral myocarditis, diabetic heart failure, alcoholic
cardiomyopathy, cardiac storage disorders, and also diastolic and
systolic heart failure.
[0218] The compounds according to the invention can additionally be
used for the treatment and/or prevention of primary and secondary
Raynaud's phenomenon, of microcirculation impairments,
claudication, tinnitus, peripheral and autonomic neuropathies,
diabetic microangiopathies, diabetic retinopathy, diabetic ulcers
on the extremities, Crest syndrome, erythematosis, onchomycosis and
rheumatic disorders.
[0219] In addition, the compounds according to the invention can be
used for preventing ischemia- and/or reperfusion-related damage to
organs or tissues and also as additives for perfusion and
preservation solutions of organs, organ parts, tissues or tissue
parts of human or animal origin, in particular for surgical
interventions or in the field of transplantation medicine.
[0220] Furthermore, the compounds according to the invention are
suitable for the treatment and/or prevention of kidney diseases, in
particular of renal insufficiency and kidney failure. In the
context of the present invention, the terms renal insufficiency and
kidney failure comprise both acute and chronic manifestations
thereof, as well as underlying or related kidney diseases such as
renal hyperfusion, intradialytic hypertension, obstructive
uropathy, glomerulopathies, glomerulonephritis, acute
glomerulonephritis, glomerulosclerosis, tubulointerstitial
diseases, nephropathic diseases such as primary and congenital
kidney disease, nephritis, immunological kidney diseases such as
kidney graft rejection and immunocomplex-induced kidney diseases,
nephropathy induced by toxic substances, nephropathy induced by
contrast agents, diabetic and non-diabetic nephropathy,
pyelonephritis, renal cysts, nephrosclerosis, hypertensive
nephrosclerosis and nephrotic syndrome, which can be characterized
diagnostically for example by abnormally reduced creatinine and/or
water excretion, abnormally raised blood concentrations of urea,
nitrogen, potassium and/or creatinine, altered activity of renal
enzymes such as, for example, glutamyl synthetase, altered urine
osmolarity or urine volume, increased microalbuminurea,
macroalbuminurea, lesions on glomerulae and arterioles, tubular
dilatation, hyperphosphatemia and/or need for dialysis. The present
invention also comprises the use of the compounds according to the
invention for the treatment and/or prevention of sequelae of renal
insufficiency, for example hypertension, pulmonary oedema, heart
failure, uremia, anaemia, electrolyte disturbances (for example
hypercalemia, hyponatremia) and disturbances in bone and
carbohydrate mechanism.
[0221] In addition, the compounds according to the invention are
suitable for the treatment and/or prevention of disorders of the
urogenital system such as, for example, hyperactive bladder,
disturbance of micturition, lower urinary tract syndrome (LUTS),
incontinence, benign prostate hyperplasia (BPH), erectile
dysfunction and female sexual dysfunction.
[0222] The compounds according to the invention can furthermore be
used for the treatment of asthmatic disorders, chronic obstructive
pulmonary disorders (COPD) and respiratory distress syndromes.
[0223] The compounds described in the present invention also
represent active compounds for controlling central nervous system
diseases characterized by disturbances of the NO/cGMP system. They
are suitable in particular for improving perception, concentration,
learning or memory after cognitive impairments like those occurring
in particular in association with situations/diseases/syndromes
such as mild cognitive impairment, age-associated learning and
memory impairments, age-associated memory loss, vascular dementia,
craniocerebral trauma, stroke, dementia occurring after strokes
(post-stroke dementia), post-traumatic craniocerebral trauma,
general concentration impairments, concentration impairments in
children with learning and memory problems, Alzheimer's disease,
Lewy body dementia, dementia with degeneration of the frontal lobes
including Pick's syndrome, Parkinson's disease, progressive nuclear
palsy, dementia with corticobasal degeneration, amyolateral
sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic
degeneration, Creutzfeld-Jacob dementia, HIV dementia,
schizophrenia with dementia or Korsakoff's psychosis. They are also
suitable for the treatment of central nervous system disorders such
as states of anxiety, tension and depression, CNS-related sexual
dysfunctions and sleep disturbances, and for controlling
pathological disturbances of the intake of food, stimulants and
addictive substances.
[0224] The compounds according to the invention are furthermore
also suitable for controlling cerebral blood flow and thus
represent effective agents for controlling migraine. They are also
suitable for the prophylaxis and control of the sequelae of
cerebral infarctions (Apoplexia cerebri) such as stroke, cerebral
ischemias and craniocerebral trauma. The compounds according to the
invention can likewise be employed for controlling states of
pain.
[0225] In addition, the compounds according to the invention have
antiinflammatory action and can therefore be used as
antiinflammatory agents for the treatment and/or prevention of
sepsis, multiple organ failure, inflammatory disorders of the
kidney, chronic intestinal inflammations such as Colitis ulcerosa
and Crohn's disease, pancreatitis, peritonitis, rheumatoid
disorders, inflammatory skin diseases and inflammatory eye
diseases.
[0226] By virtue of their activity profile, the compounds according
to the invention are particularly suitable for the treatment and/or
prevention of cardiovascular disorders such as heart failure,
angina pectoris, hypertension, pulmonary hypertension, ischemias,
vascular disorders, disturbances of microcirculation,
thromboembolic disorders and arteriosclerosis.
[0227] The present invention further relates to the use of the
compounds according to the invention for the treatment and/or
prevention of disorders, especially of the aforementioned
disorders.
[0228] The present invention further relates to the use of the
compounds according to the invention for producing a medicament for
the treatment and/or prevention of disorders, especially of the
aforementioned disorders.
[0229] The present invention further relates to the use of the
compounds according to the invention in a method for the treatment
and/or prevention of disorders, especially of the aforementioned
disorders.
[0230] The present invention further relates to a method for the
treatment and/or prevention of disorders, especially of the
aforementioned disorders, by using an effective amount of at least
one of the compounds according to the invention.
[0231] The compounds according to the invention can be employed
alone or, if required, in combination with other active compounds.
The present invention further relates to medicaments comprising at
least one of the compounds according to the invention and one or
more further active compounds, in particular for the treatment
and/or prevention of the aforementioned disorders. Examples of
suitable combination active compounds which may be preferably
mentioned are: [0232] organic nitrates and NO donors such as, for
example, sodium nitroprusside, nitroglycerin, isosorbide
mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and
inhaled NO; [0233] compounds which inhibit the breakdown of cyclic
guanosine monophosphate (cGMP), such as, for example, inhibitors of
phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5
inhibitors such as sildenafil, vardenafil and tadalafil; [0234]
NO-independent but haem-dependent stimulators of guanylate cyclase,
such as, in particular, the compounds described in WO 00/06568, WO
00/06569, WO 02/42301 and WO 03/095451; [0235] agents having
antithrombotic activity, for example and preferably from the group
of platelet aggregation inhibitors, of anticoagulants or of
profibrinolytic substances; [0236] active compounds which lower
blood pressure, for example and preferably from the group of
calcium antagonists, angiotensin AII antagonists, ACE inhibitors,
endothelin antagonists, renin inhibitors, alpha-receptor blockers,
beta-receptor blockers, mineralocorticoid receptor antagonists, and
of diuretics; and/or [0237] active compounds which modify lipid
metabolism, for example and preferably from the group of thyroid
receptor agonists, cholesterol synthesis inhibitors such as, for
example and preferably, HMG-CoA reductase inhibitors or squalene
synthesis inhibitors, of ACAT inhibitors, CETP inhibitors, MTP
inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,
cholesterol absorption inhibitors, lipase inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors and
lipoprotein (a) antagonists.
[0238] Agents having antithrombotic activity preferably mean
compounds from the group of platelet aggregation inhibitors, of
anticoagulants or of profibrinolytic substances.
[0239] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
platelet aggregation inhibitor such as, for example and preferably,
aspirin, clopidogrel, ticlopidin or dipyridamole.
[0240] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
thrombin inhibitor such as, for example and preferably,
ximelagatran, melagatran, bivalirudin or clexane.
[0241] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
GPIIb/IIIa antagonist such as, for example and preferably,
tirofiban or abciximab.
[0242] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
factor Xa inhibitor such as, for example and preferably,
rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux,
idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982,
MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or
SSR-128428.
[0243] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with
heparin or with a low molecular weight (LMW) heparin
derivative.
[0244] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
vitamin K antagonist such as, for example and preferably,
coumarin.
[0245] Agents which lower blood pressure preferably mean compounds
from the group of calcium antagonists, angiotensin AII antagonists,
ACE inhibitors, endothelin antagonists, renin inhibitors,
alpha-receptor blockers, beta-receptor blockers, mineralocorticoid
receptor antagonists, and of diuretics.
[0246] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
calcium antagonist such as, for example and preferably, nifedipine,
amlodipine, verapamil or diltiazem.
[0247] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
alpha-1-receptor blocker such as, for example and preferably,
prazosin.
[0248] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
beta-receptor blocker such as, for example and preferably,
propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol,
penbutolol, bupranolol, metipranolol, nadolol, mepindolol,
carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol,
carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol,
nebivolol, epanolol or bucindolol.
[0249] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
angiotensin AII antagonist such as, for example and preferably,
losartan, candesartan, valsartan, telmisartan or embursatan.
[0250] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
ACE inhibitor such as, for example and preferably, enalapril,
captopril, lisinopril, ramipril, delapril, fosinopril, quinopril,
perindopril or trandopril.
[0251] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
endothelin antagonist such as, for example and preferably,
bosentan, darusentan, ambrisentan or sitaxsentan.
[0252] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
renin inhibitor such as, for example and preferably, aliskiren,
SPP-600 or SPP-800.
[0253] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
mineralocorticoid receptor antagonist such as, for example and
preferably, spironolactone or eplerenone.
[0254] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
diuretic such as, for example and preferably, furosemide.
[0255] Agents which modify lipid metabolism preferably mean
compounds from the group of CETP inhibitors, thyroid receptor
agonists, cholesterol synthesis inhibitors such as HMG-CoA
reductase inhibitors or squalene synthesis inhibitors, of ACAT
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-delta agonists, cholesterol absorption inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors, lipase
inhibitors and of lipoprotein (a) antagonists.
[0256] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
CETP inhibitor such as, for example and preferably, torcetrapib
(CP-529 414), JJT-705 or CETP vaccine (Avant).
[0257] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
thyroid receptor agonist such as, for example and preferably,
D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome
(CGS 26214).
[0258] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
HMG-CoA reductase inhibitor from the class of statins such as, for
example and preferably, lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
[0259] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
squalene synthesis inhibitor such as, for example and preferably,
BMS-188494 or TAK-475.
[0260] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
ACAT inhibitor such as, for example and preferably, avasimibe,
melinamide, pactimibe, eflucimibe or SMP-797.
[0261] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
MTP inhibitor such as, for example and preferably, implitapide,
BMS-201038, R-103757 or ITT-130.
[0262] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
PPAR-gamma agonist such as, for example and preferably,
pioglitazone or rosiglitazone.
[0263] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
PPAR-delta agonist such as, for example and preferably, GW 501516
or BAY 68-5042.
[0264] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
cholesterol absorption inhibitor such as, for example and
preferably, ezetimibe, tiqueside or pamaqueside.
[0265] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
lipase inhibitor such as, for example and preferably, orlistat.
[0266] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
polymeric bile acid adsorbent such as, for example and preferably,
cholestyramine, colestipol, colesolvam, CholestaGel or
colestimide.
[0267] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
bile acid reabsorption inhibitor such as, for example and
preferably, ASBT (=IBAT) inhibitors such as, for example, AZD-7806,
S-8921, AK-105, BARI-1741, SC-435 or SC-635.
[0268] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
lipoprotein (a) antagonist such as, for example and preferably,
gemcabene calcium (CI-1027) or nicotinic acid.
[0269] The present invention further relates to medicaments which
comprise at least one compound according to the invention, normally
together with one or more inert, non-toxic, pharmaceutically
suitable excipients, and to the use thereof for the aforementioned
purposes.
[0270] The compounds according to the invention can act
systemically and/or locally. For this purpose, they can be
administered in a suitable way such as, for example, by the oral,
parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal,
dermal, transdermal, conjunctival, otic routes or as implant or
stent.
[0271] The compounds according to the invention can be administered
in administration forms suitable for these administration
routes.
[0272] Suitable for oral administration are administration forms
which function according to the prior art and deliver the compounds
according to the invention rapidly and/or in modified fashion, and
which contain the compounds according to the invention in
crystalline and/or amorphized and/or dissolved form, such as, for
example, tablets (uncoated or coated tablets, for example having
enteric coatings or coatings which are insoluble or dissolve with a
delay and control the release of the compound according to the
invention), tablets which disintegrate rapidly in the mouth, or
films/wafers, films/lyophilisates, capsules (for example hard or
soft gelatin capsules), sugar-coated tablets, granules, pellets,
powders, emulsions, suspensions, aerosols or solutions.
[0273] Parenteral administration can take place with avoidance of
an absorption step (e.g. intravenous, intraarterial, intracardiac,
intraspinal or intralumbar) or with inclusion of an absorption
(e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or
intraperitoneal). Administration forms suitable for parenteral
administration are, inter alia, preparations for injection and
infusion in the form of solutions, suspensions, emulsions,
lyophilisates or sterile powders.
[0274] Suitable for the other administration routes are, for
example, pharmaceutical forms for inhalation (inter alia powder
inhalers, nebulizers), nasal drops, solutions or sprays; tablets
for lingual, sublingual or buccal administration, films/wafers or
capsules, suppositories, preparations for the ears or eyes, vaginal
capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (e.g. patches), milk, pastes, foams, dusting powders,
implants or stents.
[0275] Oral or parenteral administration is preferred, especially
oral and intravenous administration.
[0276] The compounds according to the invention can be converted
into the stated administration forms. This can take place in a
manner known per se by mixing with inert, non-toxic,
pharmaceutically suitable excipients. These excipients include,
inter alia, carriers (for example microcrystalline cellulose,
lactose, mannitol), solvents (e.g. liquid polyethylene glycols),
emulsifiers and dispersants or wetting agents (for example sodium
dodecyl sulphate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example
albumin), stabilizers (e.g. antioxidants such as, for example,
ascorbic acid), colorants (e.g. inorganic pigments such as, for
example, iron oxides) and masking flavours and/or odours.
[0277] It has generally proved advantageous to administer on
parenteral administration amounts of about 0.001 to 1 mg/kg,
preferably about 0.01 to 0.5 mg/kg, of body weight to achieve
effective results, and on oral administration the dosage is about
0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and very
particularly preferably 0.1 to 10 mg/kg, of body weight.
[0278] It may nevertheless be necessary where appropriate to
deviate from the stated amounts, in particular as a function of the
body weight, route of administration, individual response to the
active ingredient, nature of the preparation and time or interval
over which administration takes place. Thus, it may be sufficient
in some cases to make do with less than the aforementioned minimum
amount, whereas in other cases the stated upper limit must be
exceeded. It may in the event of administration of larger amounts
be advisable to divide these into a plurality of individual doses
over the day.
[0279] The following exemplary embodiments illustrate the
invention. The invention is not restricted to the examples.
[0280] The percentage data in the following tests and examples are,
unless indicated otherwise, percentages by weight; parts are parts
by weight. Solvent ratios, dilution ratios and concentration data
for the liquid/liquid solutions are in each case based on
volume.
A. EXAMPLES
Abbreviations and Acronyms
[0281] abs. absolute [0282] Ac acetyl [0283] AIBN
2,2'-azobis(2-methylpropionitrile) [0284] aq. aqueous, aqueous
solution [0285] ATP adenosine 5'-triphosphate [0286] Bn benzyl
[0287] Brij.RTM. polyethylene glycol dodecyl ether [0288] BSA
bovine serum albumin [0289] Ex. Example [0290] Bu butyl [0291] c
concentration [0292] cat. catalytic [0293] CI chemical ionization
(in MS) [0294] d day(s) [0295] DAST diethylaminosulphur trifluoride
[0296] TLC thin-layer chromatography [0297] DCI direct chemical
ionization (in MS) [0298] DDQ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone [0299] de diastereomeric
excess [0300] DIBAH diisobutylaluminium hydride [0301] DMF
dimethylformamide [0302] DMSO dimethyl sulphoxide [0303] DTT
dithiothreitol [0304] EDC
N(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride [0305]
ee enantiomeric excess [0306] EI electron impact ionization (in MS)
[0307] ent enantiomerically pure, enantiomer [0308] eq.
equivalent(s) [0309] ESI electrospray ionization (in MS) [0310] Et
ethyl [0311] GC gas chromatography [0312] sat. saturated [0313] GTP
guanosine 5'-triphosphate [0314] h hour(s) [0315] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0316] HOBt 1-hydroxy-/H-benzotriazole hydrate
[0317] HPLC high-pressure, high-performance liquid chromatography
[0318] iPr isopropyl [0319] conc. concentrated [0320] LC-MS liquid
chromatography-coupled mass spectroscopy [0321] LDA lithium
diisopropylamide [0322] LiHMDS lithium hexamethyldisilazide
[lithium bis(trimethylsilyl)amide] [0323] Me methyl [0324] min
minute(s) [0325] MS mass spectroscopy [0326] NBS N-bromosuccinimide
[0327] NMR nuclear magnetic resonance spectroscopy [0328] p para
[0329] Pd/C palladium on carbon Ph phenyl [0330] PMB
p-methoxybenzyl [0331] Pr propyl [0332] rac racemic, racematee
[0333] R.sub.f retention index (in TLC) [0334] RP reversed phase
(in HPLC) [0335] RT room temperature [0336] R.sub.t retention time
(in HPLC) [0337] tBu tert-butyl [0338] TEA triethanolamine [0339]
TFA trifluoroacetic acid [0340] THF tetrahydrofuran [0341] UV
ultraviolet spectroscopy [0342] v/v volume:volume ratio (of a
solution) GC-MS and LC-MS methods:
Method 1 (GC-MS):
[0343] Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35,
15 m.times.200 .mu.m.times.0.33 .mu.m; constant helium flow: 0.88
ml/min; Oven: 70.degree. C.; inlet: 250.degree. C.; gradient:
70.degree. C., 30.degree. C./min.fwdarw.310.degree. C. (maintain
for 3 min)
Method 2 (LC-MS):
[0344] MS instrument type: Micromass ZQ; HPLC instrument type: HP
1100 Series; UV DAD; Column: Phenomenex Gemini 3.mu. 30
mm.times.3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50%
strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of
50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.2.5 min
30% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; flow rate: 0.0 min 1
ml/min.fwdarw.2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50.degree.
C.; UV detection: 210 nm.
Method 3 (LC-MS):
[0345] MS instrument type: Micromass ZQ; HPLC instrument type:
Waters Alliance 2795; Column: Phenomenex Synergi 2.5.mu. MAX-RP
100A Mercury 20 mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml
of 50% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min
90% A.fwdarw.0.1 min 90% A.fwdarw.3.0 min 5% A.fwdarw.4.0 min 5%
A.fwdarw.4.01 min 90% A; flow rate: 2 ml/min; oven: 50.degree. C.;
UV detection: 210 nm.
Method 4 (LC-MS):
[0346] Instrument: Micromass Quattro Premier with Waters HPLC
Acquity; Column: Thermo Hypersil GOLD 1.9.mu. 50 mm.times.1 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min
10% A.fwdarw.2.2 min 10% A; flow rate: 0.33 ml/min; oven:50.degree.
C.; UV detection: 210 nm.
Method 5 (LC-MS):
[0347] MS instrument type: Waters Micromass Quattro Micro; HPLC
instrument type: Agilent 1100 Serie; Column: Thermo Hypersil GOLD
3.mu. 20 mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml of 50%
strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of
50% strength formic acid; gradient: 0.0 min 100% A.fwdarw.3.0 min
10% A.fwdarw.4.0 min 10% A.fwdarw.4.01 min 100% A (flow rate 2.5
ml/min).fwdarw.5.00 min 100% A; oven: 50.degree. C.; flow rate: 2
ml/min; UV detection: 210 nm.
Method 6 (LC-MS):
[0348] Instrument: Waters Acquity SQD HPLC System; Column: Waters
Acquity HPLC HSS T3 1.8.mu., 50 mm.times.1 mm; mobile phase A: 1 l
of water+0.25 ml 99% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.25 ml 99% strength formic acid; gradient: 0.0 min
90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; flow rate: 0.40
ml/min; oven: 50.degree. C.; UV detection: 210-400 nm.
Method 7 (LC-MS):
[0349] MS instrument type: Waters ZQ; HPLC instrument type: Agilent
1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3.mu. 20
mm.times.4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength
formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%
strength formic acid; gradient: 0.0 min 100% A.fwdarw.3.0 min 10%
A.fwdarw.4.0 min 10% A.fwdarw.4.1 min 100% A (Flow rate 2.5
ml/min); oven: 55.degree. C.; flow rate: 2 ml/min; UV detection:
210 nm.
Method 8 (GC-MS):
[0350] Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35,
15 m.times.200 .mu.m.times.0.33 .mu.m; constant helium flow: 0.88
ml/min; oven: 70.degree. C.; inlet: 250.degree. C.; gradient:
70.degree. C., 30.degree. C./min.fwdarw.310.degree. C. (maintain
for 12 min)
Method 9 (LC-MS):
[0351] Instrument: Micromass Quattro Premier with Waters HPLC
Acquity; Column: Thermo Hypersil GOLD 1.9.mu. 50 mm.times.1 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.3.0 min
10% A.fwdarw.4.8 min 10% A; flow rate: 0.33 ml/min; oven:
50.degree. C.; UV detection: 210 nm.
Method 10 (GC-MS):
[0352] Instrument: Thermo DFS, Trace GC Ultra; Column: Restek
RTX-35, 15 m.times.200 .mu.m.times.0.33 .mu.m; constant helium
flow: 1.20 ml/min; Oven: 60.degree. C.; Inlet: 220.degree. C.;
Gradient: 60.degree. C., 30.degree. C./min.fwdarw.300.degree. C.
(maintain for 3.33 min).
Starting Materials and Intermediates:
Example 1A
tert-Butyl 3-(3-amino-2-methylphenyl)propanoate
##STR00056##
[0354] Under argon, 201 ml (1.39 mol) of tert-butyl-prop-2-enoate
were added dropwise to a solution of 100 g (463 mmol) of
1-bromo-2-methyl-3-nitrobenzene, 322 ml (2.31 mol) of
triethylamine, 28.18 g (92.58 mmol) of tri-2-tolylphosphine and
10.39 g (46.29 mmol) of palladium(II) acetate in 2 litres of DMF,
and the mixture was then stirred at 125.degree. C. for 36 h. After
cooling to room temperature, the reaction mixture was stirred with
saturated aqueous ammonium chloride solution and the organic phase
was separated off. The aqueous phase was extracted three times with
tert-butyl methyl ether, and the combined organic phases were
washed with saturated sodium chloride solution and dried over
sodium sulphate. After filtration, the solvent was removed to
dryness under reduced pressure. The residue obtained was purified
by flash chromatography on silica gel (mobile phase petroleum
ether/ethyl acetate 9:1). This gave 89 g (338 mmol, 73% of theory)
of the intermediate
tert-butyl-(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a
colourless solid. 88 g (334 mmol) of this solid were dissolved in 2
litres of ethanol, 7 g of palladium on carbon (10%) were added at
room temperature and the mixture was hydrogenated under atmospheric
pressure for 18 h. After complete conversion, the reaction solution
was filtered through kieselguhr and the filtrate obtained was
concentrated under reduced pressure. This gave 61.3 g (260.5 mmol,
78% of theory) of the title compound as a colourless solid.
[0355] LC-MS (Method 2): R.sub.t=1.84 min; m/z=236 (M+H).sup.+.
[0356] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 6.77 (1H,
t), 6.47 (1H, d), 6.36 (1H, d), 4.72 (2H, s), 2.14 (2H, t), 2.36
(2H, t), 1.95 (3H, s), 1.39 (9H, s).
Example 2A
Ethyl 3-(3-amino-2-methylphenyl)propanoate
##STR00057##
[0358] Under argon, 10.844 g (108 mmol) of ethyl prop-2-enoate were
added dropwise to a solution of 7.8 g (36.1 mmol) of
1-bromo-2-methyl-3-nitrobenzene, 25 ml (180.5 mmol) of
triethylamine, 2.197 g (7.22 mmol) of tri-2-tolylphosphine and 810
mg (3.6 mmol) of palladium(II) acetate in 200 ml of DMF, and the
mixture was then stirred at 125.degree. C. for 36 h. After cooling
to room temperature, the reaction mixture was stirred with
saturated aqueous ammonium chloride solution and the organic phase
was separated off. The aqueous phase was extracted three times with
tert-butyl methyl ether, and the combined organic phases were
washed with saturated sodium chloride solution and dried over
sodium sulphate. After filtration, the solvent was removed to
dryness under reduced pressure. The residue obtained was purified
by flash chromatography on silica gel (mobile phase petroleum
ether/ethyl acetate 3:1). This gave 6.6 g (27.2 mmol, content 97%,
75% of theory) of the intermediate
ethyl(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a colourless
solid. 6.6 g (27.2 mmol, content 97%) of this solid were dissolved
in 200 ml of ethanol, 500 mg of palladium on carbon (10%) were
added at room temperature and the mixture was hydrogenated under
atmospheric pressure overnight. After the reaction had gone to
completion, the reaction solution was filtered through kieselguhr
and the filtrate obtained was concentrated under reduced pressure.
This gave 5.47 g (26.38 mmol, content 97%, 97% of theory) of the
title compound as a colourless solid.
[0359] LC-MS (Method 3): R.sub.t=1.07 min; m/z=208 (M+H).sup.+.
Example 3A
tert-Butyl(2E)-3-(4-fluoro-3-nitrophenyl)acrylate
##STR00058##
[0361] Under argon, 0.65 g (16.3 mmol) of sodium hydride (as a 60%
suspension in mineral oil) was initially charged in 25 ml of THF
and cooled to 0.degree. C. 4.29 g (17 mmol) of tert-butyl
diethyl-phosphonoacetate were then slowly added dropwise. After 30
min, 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde were added.
The reaction mixture was stirred at RT for 3 h and then poured into
100 ml of water and extracted three times with in each case 100 ml
of ethyl acetate. The combined organic phases were dried over
magnesium sulphate and concentrated. The residue was purified by
flash chromatography (silica gel, mobile phase cyclohexane/ethyl
acetate 50:1). This gave 3.37 g (85% of theory) of the title
compound.
[0362] GC-MS (Method 1): R.sub.t=6.45 min; m/z=211
(M-.sup.tBu).sup.+.
[0363] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.49 (s,
9H), 6.69 (d, 1H), 7.59-7.76 (m, 2H), 8.19 (ddd, 1H), 8.50 (dd,
1H).
Example 4A
tert-Butyl 3-(3-amino-4-fluorophenyl)propanoate
##STR00059##
[0365] 535 mg (2.00 mmol)of
tert-butyl(2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate were
dissolved in 1 ml of ethanol and 1 ml of THF, and 21.3 mg of
palladium on carbon (10%) were added. At RT, the mixture was
hydrogenated under an atmosphere of hydrogen at atmospheric
pressure overnight. The reaction mixture was then filtered off with
suction through kieselguhr, the residue was washed with THF and the
filtrate was concentrated. This gave 479 mg (100% of theory) of the
title compound.
[0366] LC-MS (Method 6): R.sub.t=1.06 min; m/z=184
(M--C.sub.4H.sub.8).sup.+.
[0367] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=6.84 (dd, 1H),
6.58 (dd, 1H), 6.36-6.29 (m, 1H), 5.00 (s, 2H), 2.64 (t, 2H), 2.42
(t, 2H), 1.36 (s, 9H).
Example 5A
tert-Butyl(2E)-3-(4-chloro-3-nitrophenyl)prop-2-enoate
##STR00060##
[0369] Under argon, 1.19 g (29.64 mmol, 60%) of sodium hydride were
suspended in 25 ml of toluene and 25 ml of THF, and the mixture was
cooled to 0.degree. C. 7.28 ml (30.99 mmol) of tert-butyl
(diethoxyphosphoryl)acetate were then slowly added dropwise, and
the mixture was stirred at 0.degree. C. for 30 min 5 g (26.94 mmol)
of 4-chloro-3-nitrobenzaldehyde were then added to the reaction
mixture, and the mixture was subsequently warmed to room
temperature. The mixture was stirred at room temperature for 2 h,
and 50 ml of water were then added. The organic phase was separated
off, and the aqueous phase was then extracted three more times with
ethyl acetate. The combined organic phases were dried over sodium
sulphate. After filtration, the solvent was removed under reduced
pressure. The crude product was purified chromatographically on
silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave
6.77 g (23.86 mmol, 77% of theory) of the title compound.
[0370] MS (DCI): m/z=301 (M+NH.sub.4).sup.+.
[0371] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.46 (d, 1H),
8.07 (dd, 1H), 7.71 (d, 1H), 7.51 (d, 1H), 6.75 (d, 1H), 1.49 (s,
9H).
Example 6A
tert-Butyl-3-(3-amino-4-chlorophenyl)propanoate
##STR00061##
[0373] At room temperature, 500 mg of palladium on carbon (10%)
were added to a solution of 6.74 g (23.76 mmol) of
tert-butyl(2E)-3-(4-chloro-3-nitrophenyl)prop-2-enoate in 200 ml of
ethanol and 20 ml of THF, and the mixture was hydrogenated under
atmospheric pressure for 12 h. After the reaction had gone to
completion (monitored by TLC; mobile phase cyclohexane/ethyl
acetate 1:1), the reaction solution was filtered through kieselguhr
and the filtrate was concentrated under reduced pressure. The crude
product was purified chromatographically on silica gel (mobile
phase cyclohexane/ethyl acetate 4:1.fwdarw.2:1). This gave 1.40 g
(5.47 mmol, 23% of theory) of the title compound.
[0374] LC-MS (Method 6): R.sub.t=1.14 min; m/z=256 (M+H).sup.+.
[0375] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.08 (d, 1H),
6.62 (s, 1H), 6.39 (dd, 1H), 5.22 (s, 2H), 2.66 (t, 2H), 2.45 (t,
2H), 1.37 (s, 9H).
Example 7A
Methyl 3-(3-amino-4-chlorophenyl)propanoate
##STR00062##
[0377] Under reflux, 0.86 ml (11.7 mmol) of thionyl chloride was
added dropwise to a solution of 1.0 g (3.91 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)propanoate in 20 ml of methanol The
mixture was stirred under reflux for 1.5 h and then, after cooling,
diluted with dichloromethane The solution was added to water, and
after phase separation the organic phase was washed with saturated
sodium bicarbonate solution and saturated sodium chloride solution,
dried over sodium sulphate and concentrated under reduced pressure.
The residue was dried under high vacuum. This gave 745 mg (90.3% of
theory) of the target compound.
[0378] LC-MS (Method 6): R.sub.t=0.91 min; m/z=213/215
(M+H).sup.+.
[0379] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.52-2.60
(m, 2H), 2.62-2.77 (m, 2H), 5.22 (s, 2H), 6.39 (dd, 1H), 6.62 (d,
1H), 7.06 (d, 1H).
Example 8A
Methyl{1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate
##STR00063##
[0381] Preparation of solution A: Under argon, 688 mg (16.2 mmol)
of lithium chloride were dissolved in 50 ml of THF, and 789 mg
(32.5 mmol) of magnesium turnings and 23 .mu.l (0.023 mmol) of a 1
M solution of diisobutylaluminium hydride in THF were then added.
The reaction solution was stirred at room temperature for 10 min
and then cooled to -10.degree. C. 5 g (13.5 mmol) of
N,N-dibenzyl-5-bromo-2-fluoroaniline (CAS Reg.-No. 869529-97-5)
were then added, and the solution was stirred at -10.degree. C. for
about 1 h.
[0382] Preparation of solution B: Under argon, 110 mg (2.6 mmol) of
lithium chloride and 128 mg (1.3 mmol) of copper(1) chloride were
suspended at room temperature in 10 ml of THF, and 1.65 ml (12.98
mmol) of chloro(trimethyl)silane and 1.46 g (12.98 mmol) of methyl
cyclo-propylidene acetate (CAS Reg.-No. 110793-87-8) were then
added. Subsequently, the solution was stirred at RT for another 1
h.
[0383] Solution A obtained above was cooled to -40.degree. C.
Solution B was then slowly added dropwise. The combined solutions
were slowly warmed to -20.degree. C. and stirred at this
temperature for 1 h. 50 ml of an ice-cold semi-saturated ammonium
chloride solution were then added to the reaction mixture. The
phases were separated, the aqueous phase was then extracted three
more times with ethyl acetate and the combined organic phases were
dried over magnesium sulphate and concentrated to dryness. The
crude product obtained was purified chromatographically on silica
gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.1 g
(5.2 mmol, 39% of theory) of the title compound.
[0384] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.33-7.25
(8H, m), 7.25-7.18 (2H, m), 7.02-6.94 (1H, m), 6.78-6.69 (2H, m),
4.27 (4H, s), 3.43 (3H, s), 2.48 (2H, s), 0.78-0.73 (2H, m),
0.63-0.58 (2H, m).
[0385] LC-MS (Method 5): R.sub.t=2.99 min; m/z=404 (M+H).sup.+.
Example 9A
Methyl[1-(3-amino-4-fluorophenyl)cyclopropyl]acetate
##STR00064##
[0387] At room temperature, 200 mg of palladium on carbon (10%)
were added to a solution of 2.1 g (5.2 mmol) of
methyl{1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate in
100 ml of ethanol, and the mixture was hydrogenated at atmospheric
pressure for 12 h. After the reaction had gone to completion
(monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the
reaction solution was filtered through kieselguhr and the filtrate
was concentrated under reduced pressure. The crude product was
purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 10:1). This gave 647 mg (2.9 mmol, 56% of
theory) of the title compound.
[0388] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 6.88-6.78
(1H, m), 6.70-6.62 (1H, m), 6.44-6.35 (1H, m), 4.98 (2H, br. s),
3.51 (3H, s), 2.55 (2H, s), 0.84-0.79 (2H, m), 0.78-0.73 (2H,
m).
[0389] GC-MS (Method 1): R.sub.t=5.67 min; m/z=224 (M+H).sup.+.
Example 10A
5-Bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline
##STR00065##
[0391] Under argon, 5.07 g (126.93 mmol, 60%) of sodium hydride
were suspended in 150 ml of THF, and the mixture was cooled to
0.degree. C. 10.70 g (51.81 mmol) of 5-bromo-2-chloroaniline
dissolved in 10 ml of THF were then slowly added dropwise, and the
mixture was stirred at 0.degree. C. for 30 min. 25 g (124.34 mmol)
of 4-methoxybenzyl chloride were then added to the reaction
mixture, and the mixture was subsequently warmed to room
temperature. The mixture was stirred at RT for 2 h and then slowly
poured onto 150 ml of ice-water. The organic phase was separated
off, and the aqueous phase was extracted three more times with
ethyl acetate. The combined organic phases were dried over sodium
sulphate. After filtration, the solvent was removed under reduced
pressure. The crude product was purified chromatographically
[column: Kromasil Si 6012, 350 mm.times.30 mm; mobile phase A:
isohexane, mobile phase B: ethyl acetate; gradient: 0 min 98%
A.fwdarw.4.65 min 98% A.fwdarw.13 min 87% A.fwdarw.13.01 min 98%
A.fwdarw.13.28 min 98% A; flow rate: 70 ml/min; temperature:
20.degree. C.; UV detection: 265 nm]. This gave 12.37 g (27.69
mmol, 57% of theory) of the title compound.
[0392] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.37 (1H,
d), 7.26-7.19 (5H, m), 7.19-7.14 (1H, m), 6.86 (4H, d), 4.11 (4H,
s), 3.71 (6H, s).
[0393] LC-MS (Method 4): R.sub.t=1.68 min; m/z=446 (M).sup.+.
Example 11A
{3-[Bis(4-methoxybenzyflamino]-4-chlorophenyl}boronic acid
##STR00066##
[0395] Under argon and at -78.degree. C., 6.1 ml (15.25 mmol) of a
2.5 M solution of n-butyllithium in hexane were slowly added
dropwise to a solution of 5.2 g (11.64 mmol) of
5-bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline in 100 ml of
THF/diethyl ether (1:1). The reaction solution was stirred at
-78.degree. C. for 60 min, and 4.3 ml (18.62 mmol) of triisopropyl
borate were then added slowly. The reaction solution was then
stirred at -78.degree. C. for another 15 min, then slowly warmed to
room temperature and stirred at this temperature for another 3 h.
150 ml of ice-water were then metered in. The organic phase was
separated off, and the aqueous phase was then extracted three more
times with ethyl acetate. The combined organic phases were dried
over sodium sulphate. After filtration, the solvent was removed
under reduced pressure. The crude product was purified
chromatographically on silica gel (mobile phase: initially
cyclohexane/ethyl acetate 10:1.fwdarw.9:1.fwdarw.4:1, then
dichloromethane/methanol 95:5). This gave 2.54 g (6.17 mmol, 53% of
theory) of the title compound.
[0396] LC-MS (Method 6): R.sub.t=1.20 min; m/z=412 (M+H).sup.+.
Example 12A
Benzyl oxetan-3-ylideneacetate
##STR00067##
[0398] Under argon and at 0.degree. C., 3.0 g (41.63 mmol) of
oxetan-3-one (CAS Reg.-No. 6704-31-0) were dissolved in 50 ml of
dichloromethane, and 18.8 g (45.79 mmol) of
benzyl(triphenyl-X.sup.5-phos-phanylidene)acetate were then added.
The reaction mixture was then slowly warmed to room temperature and
stirred for another 15 minutes. The reaction solution was then
concentrated to dryness. The residue was taken up in 25 ml of
diethyl ether and stirred, and the mixture was kept at 4.degree. C.
for 12 h. The precipitated triphenylphosphine oxide was filtered
off and the filtrate was concentrated to dryness. The crude product
obtained was purified chromatographically on silica gel (mobile
phase cyclohexane/ethyl acetate 4:1.fwdarw.1:1). This gave 4.2 g
(20.57 mmol, 49% of theory) of the title compound.
[0399] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.42-7.30
(5H, m), 5.85-5.80 (1H, m), 5.39-5.34 (2H, m), 5.27-5.22 (2H, m),
5.13 (2H, s).
[0400] MS (DCI): m/z=205 (M+H).sup.+.
Example 13A
Benzyl(3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}oxetan-3-yl)acetate
##STR00068##
[0402] Under argon and at room temperature, 1.6 ml (2.37 mmol) of a
1.5 M aqueous potassium hydroxide solution, 272 mg (1.82 mmol) of
benzyl oxetan-3-ylideneacetate and 750 mg (1.82 mmol) of
{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}boronic acid were
added successively to a solution of 45 mg (0.09 mmol) of
(1Z,5Z)-cycloocta-1,5-diene/rhodium(I) chloride dimer in 25 ml of
dioxane. The reaction solution was then stirred at room temperature
for 4 h. After the reaction had gone to completion, the solution
was concentrated to dryness and the residue was taken up in 25 ml
of water and 25 ml of ethyl acetate. The phases were separated and
the aqueous phase was extracted three more times with ethyl
acetate, and the combined organic phases were dried over magnesium
sulphate and concentrated to dryness. The crude product obtained
was purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 4:1.fwdarw.1:1). This gave 669 mg (1.17
mmol, 64% of theory) of the title compound.
[0403] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.34-7.26
(4H, m), 7.18-7.13 (4H, m), 7.12-7.07 (2H, m), 6.86-6.76 (6H, m),
4.90 (2H, s), 4.72 (2H, d), 4.57 (2H, d), 4.01 (6H, s), 3.08 (2H,
s).
[0404] LC-MS (Method 6): R.sub.t=1.45 min; m/z=572 (M).sup.+.
[0405] The following compound was obtained analogously to synthesis
Example 13A:
TABLE-US-00001 Example Name/Structure/Starting Materials Analytical
Data 14A ##STR00069## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
.delta./ppm): 7.29 (1H, d), 7.19 (4H, d), 6.83 (4H, d), 6.79-6.74
(2H, m), 4.04 (4H, s), 3.70 (6H, s), 3.35 (3H, s), 2.69 (2H, s),
2.26- 2.17 (2H, m), 2.16-2.06 (2H, m), 2.03-1.89 (1H, m), 1.71-
1.58 (1H, m). LC-MS (Method 6): R.sub.t = 1.50 min; m/z = 494
(M).sup.+.
Example 15A
Benzyl[3-(3-amino-4-chlorophenyl)oxetan-3-yl]acetate
##STR00070##
[0407] At room temperature, 576 mg (2.54 mmol) of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were added to a
solution of 660 mg (1.15 mmol) of
benzyl(3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}oxetan-3-yl)acetat-
e in 30 ml of dichloromethane and 6 ml of water, and the mixture
was stirred for 2 h. After the reaction had gone to completion
(monitored by TLC; mobile phase cyclohexane/ethyl acetate 2:1), 25
ml of saturated sodium bicarbonate solution were added to the
reaction solution. The phases were separated and the aqueous phase
was then extracted three more times with dichloromethane, and the
combined organic phases were dried over magnesium sulphate and
concentrated to dryness. The crude product obtained was purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl
acetate 5:1). This gave 360 mg (0.98 mmol, content 90%, 85% of
theory) of the title compound.
[0408] LC-MS (Method 4): R.sub.t=1.18 min; m/z=332 (M+H).sup.+.
[0409] The following compound was obtained analogously to synthesis
Example 15A:
TABLE-US-00002 Example Name/Structure/Starting Materials Analytical
Data 16A ##STR00071## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
.delta./ppm): 7.06 (1H, d), 6.59 (1H, s), 6.32 (1H, d), 5.21 (2H,
br. s), 3.43 (3H, s), 2.73 (2H, s), 2.31-2.19 (4H, m), 2.09-1.94
(1H, m), 1.82- 1.67 (1H, m). LC-MS (Method 4): R.sub.t = 1.20 min;
m/z = 254 (M + H).sup.+.
Example 17A
3-Bromo-2-fluoroaniline
##STR00072##
[0411] 2.0 g (9.09 mmol) of 3-bromo-2-fluoronitrobenzene were
dissolved in 10 ml of dioxane, and 8.62 g (45.45 mmol) of tin(II)
chloride were added at RT. After addition of a few drops of 1 N
hydrochloric acid, the mixture was heated at 70.degree. C. for 2 h.
After cooling, the reaction mixture was concentrated under reduced
pressure and the residue was taken up in ethyl acetate. The
solution was washed successively twice with 1 N aqueous sodium
hydroxide solution, water and saturated sodium chloride solution,
dried over magnesium sulphate and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave
997 mg (57.7% of theory) of the target compound.
[0412] LC-MS (Method 6): R.sub.t=0.88 min; m/z=189/191
(M+H).sup.+.
[0413] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=5.43 (s,
2H), 6.66-6.85 (m, 3H).
Example 18A
tert-Butyl(2E)-3-(3-amino-2-fluorophenyl)acrylate
##STR00073##
[0415] 5.2 ml (37.1 mmol) of triethylamine were added to a solution
of 1.41 g (7.42 mmol)of 3-bromo-2-fluoroaniline and 2.85 g (22.3
mmol) of tert-butyl acrylate in 8 ml of DMF. Three times, the flask
was evacuated and vented with argon, and 451 mg (1.48 mmol) of
tri-2-tolylphosphine and 166.6 mg (0.74 mmol) of palladium(II)
acetate were then added. Once more, the reaction vessel was twice
evacuated and vented with argon, and the mixture was then heated to
about 140.degree. C. After 2 h of vigorous stirring, the reaction
mixture was cooled and added to saturated sodium bicarbonate
solution. The mixture was extracted three times with ethyl acetate,
and the combined organic phases were dried over magnesium sulphate
and concentrated under reduced pressure. The residue was purified
by chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 10:1). This gave 1660 mg of the target product (94.3% of
theory).
[0416] LC-MS (Method 6): R.sub.t=1.12 min; m/z=279
(M-Pfl-PCH.sub.3CN).sup.+.
[0417] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.48 (s,
9H), 5.27 (s, 2H), 6.45 (d, 1H), 6.73-7.02 (m, 3H), 7.59 (d,
1H).
Example 19A
tert-Butyl 3-(3-amino-2-fluorophenyl)propanoate
##STR00074##
[0419] Palladium on carbon (10%) was added to a solution of 1660 mg
(7.0 mmol) of tert-butyl(2E)-3-(3-amino-2-fluorophenyl)acrylate in
a mixture of 5 ml of ethanol and 3 ml of THF, and the mixture was
stirred vigorously at atmospheric pressure under an atmosphere of
hydrogen overnight. The reaction mixture was then filtered through
kieselguhr and the filter residue was washed repeatedly with
ethanol/THF. The combined filtrates were concentrated under reduced
pressure and the residue was purified by chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 20:1.fwdarw.10:1). This
gave 1350 mg of the target product (80.6% of theory).
[0420] LC-MS (Method 6): R.sub.t=1.07 min; m/z=225.
[0421] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
9H), 2.45 (t, 2H), 2.74 (t, 2H), 5.00 (s, 2H), 6.24-6.46 (m, 1H),
6.51-6.66 (m, 1H), 6.66-6.82 (m, 1H).
Example 20A
Ethyl(E/Z)-3-(4-fluoro-3-nitrophenyl)-2-methylprop-2-enoate
##STR00075##
[0423] 3.17 g of sodium hydride (60% suspension in mineral oil,
79.36 mmol) were suspended in 90 ml of a THF/DMF mixture (2:1). The
mixture was cooled to 0.degree. C., and a solution of 19.76 g
(82.96 mmol) of triethyl 2-phosphonopropionate in 60 ml of THF/DMF
(2:1) was added dropwise. After 30 min, a solution of 12.2 g (72.14
mmol) of 4-fluoro-3-nitrobenzaldehyde in 60 ml of THF/DMF (2:1) was
added dropwise at 0.degree. C. After the addition had ended, the
reaction mixture was slowly warmed to RT and stirred at this
temperature for 2 h. The reaction mixture was then added to water.
The mixture was extracted three times with ethyl acetate, and the
combined organic phases were concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 20:1). This gave 15.2 g (83.2% of
theory) of the target product as an E/Z isomer mixture (E/Z
91:9).
[0424] LC-MS (Method 6): Z isomer: R.sub.t=1.11 min; m/z=254
(M+H).sup.+; E isomer: R.sub.t=1.14 min; m/z=254 (M+H).sup.+.
[0425] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): E isomer: .delta.
[ppm]=1.28 (t, 3H), 4.22 (q, 2H), 7.59-7.73 (m, 2H), 7.92 (ddd,
1H), 8.24 (dd, 1H).
Example 21A
Ethyl(+/-)-3-(3-amino-4-fluorophenyl)-2-methylpropanoate
##STR00076##
[0427] Palladium on carbon (10%) was added to 15.2 g (60.02 mmol)
of ethyl(E/Z)-3-(4-fluoro-3-nitrophenyl)-2-methylprop-2-enoate (E/Z
91:9) in a mixture of 100 ml of ethanol and 100 ml of THF, and the
mixture was stirred vigorously at atmospheric pressure under an
atmosphere of hydrogen overnight. The reaction mixture was then
filtered through celite, the residue was washed with
ethanol/dichloromethane and the combined filtrates were
concentrated under reduced pressure. The product was dried under
high vacuum. This gave 13.34 g of the target product (98.7% of
theory).
[0428] LC-MS (Method 6): R.sub.t=0.98 min; m/z=226 (M+H).sup.+.
[0429] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.04 (d,
3H), 1.12 (t, 3H), 2.46-2.50 (m, 1H), 2.55-2.66 (m, 1H), 2.66-2.78
(m, 1H), 4.01 (q, 2H), 5.00 (s, 2H), 6.18-6.35 (m, 1H), 6.55 (dd,
1H), 6.84 (dd, 1H).
[0430] The racematee obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.15
ml; temperature: 30.degree. C.; mobile phase: 90% isohexane/10%
ethanol; flow rate: 15 ml/min; detection: 220 nm]. 7.25 g of
racematee gave 3.43 g of enantiomer 1 (Example 22A) and 3.35 g of
enantiomer 2 (Example 23A):
Example 22A
Ethyl(+)-(2S)-3-(3-amino-4-fluorophenyl)-2-methylpropanoate
##STR00077##
[0432] Yield: 3.43 g
[0433] LC-MS (Method 6): R.sub.t=0.97 min; m/z=226 (M+H).sup.+.
[0434] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.04 (d,
3H), 1.12 (t, 3H), 2.46-2.50 (m, 1H), 2.55-2.66 (m, 1H), 2.66-2.78
(m, 1H), 4.01 (q, 2H), 5.00 (s, 2H), 6.18-6.35 (m, 1H), 6.55 (dd,
1H), 6.84 (dd, 1H).
[0435] [.alpha.].sub.D.sup.20=+18.3.degree., c=0.465,
chloroform.
Example 23A
Ethyl(-)-(2R)-3-(3-amino-4-fluorophenyl)-2-methylpropanoate
##STR00078##
[0437] Yield: 3.35 g
[0438] LC-MS (Method 6): R.sub.t=0.97 min; m/z=226 (M+H).sup.+.
[0439] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.04 (d,
3H), 1.12 (t, 3H), 2.46-2.50 (m, 1H), 2.55-2.66 (m, 1H), 2.68-2.79
(m, 1H), 4.01 (q, 2H), 5.00 (br. s, 2H), 6.30 (dd, 1H), 6.55 (dd,
1H), 6.84 (dd, 1H).
[0440] [.alpha.].sub.D.sup.20=-31.4.degree., c=0.520,
chloroform.
Example 24A
Ethyl(E/Z)-3-(4-chloro-3-nitrophenyl)-2-methylprop-2-enoate
##STR00079##
[0442] 4.74 g of sodium hydride (60% suspension in mineral oil,
118.56 mmol) were suspended in 93 ml of a THF/DMF mixture (1:1).
The mixture was cooled to 0.degree. C., and 26.6 ml (123.95 mmol)
of triethyl 2-phosphonopropionate were added dropwise. After 30
min, 20.0 g (107.78 mmol) of 4-chloro-3-nitrobenzaldehyde were
added at 0.degree. C. After the additon had ended, the reaction
mixture was slowly warmed to RT and stirred at this temperature for
another 3 h. The reaction mixture was then added to water. The
mixture was extracted three times with ethyl acetate, and the
combined organic phases were concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 70:1.fwdarw.50:1). This gave 26.7 g
(91.9% of theory) of the target product as an E/Z isomer mixture
(E/Z 91:9).
[0443] LC-MS (Method 4): Z isomer: R.sub.t=1.32 min; m/z=255; E
isomer: R.sub.t=1.36 min; m/z=270 (M+H).sup.+.
[0444] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): E isomer: .delta.
[ppm]=1.28 (t, 3H), 2.06 (d, 3H), 4.22 (q, 2H), 7.56-7.67 (m, 1H),
7.75-7.87 (m, 2H), 8.17 (d, 1H).
Example 25A
Ethyl(+/-)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate
##STR00080##
[0446] 10.0 g (37.08 mmol) of
ethyl(E/Z)-3-(4-chloro-3-nitrophenyl)-2-methylprop-2-enoate (E/Z
91:9) were dissolved in 25 ml of ethyl acetate and 25 ml of acetic
acid, and palladium on carbon (10%) was added. The reaction mixture
was stirred vigorously at atmospheric pressure under an atmosphere
of hydrogen for a total of 6 h, with another 25 ml of acetic acid
and further portions of 10% palladium on carbon being added after 2
h. The mixture was then filtered through celite and the residue was
washed with ethanol/dichloromethane. The combined filtrates were
washed with saturated sodium bicarbonate solution, dried over
sodium sulphate and concentrated under reduced pressure. The crude
product was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 30:1.fwdarw.10:1). This gave 4.01 g of
the target product (44.7% of theory).
[0447] LC-MS (Method 6): R.sub.t=1.06 min; m/z=242 (M+H).sup.+.
[0448] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.05 (d,
3H), 1.12 (t, 3H), 2.47-2.50 (m, 1H), 2.56-2.67 (m, 1H), 2.67-2.78
(m, 1H), 4.02 (q, 2H), 5.23 (s, 2H), 6.35 (dd, 1H), 6.58 (d, 1H),
7.05 (d, 1H).
[0449] The racematee obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.15
ml; temperature: 35.degree. C.; mobile phase: 50% isohexane/50%
isopropanol; flow rate: 15 ml/min; detection: 220 nm]. 10.3 g of
racematee gave 4.0 g of enantiomer 1 (Example 26A) and 3.7 g of
enantiomer 2 (Example 27A):
Example 26A
Ethyl(-)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate
##STR00081##
[0451] Yield: 4.0 g
[0452] LC-MS (Method 7): R.sub.t=2.27 min; m/z=196/198.
[0453] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.05 (d,
3H), 1.12 (t, 3H), 2.47-2.50 (m, 1H), 2.54-2.66 (m, 2H), 2.68-2.80
(m, 1H), 4.02 (q, 2H), 5.23 (s, 2H), 6.35 (dd, 1H), 6.58 (d, 1H),
7.05 (d, 1H).
[0454] [.alpha.].sub.D.sup.20=-35.8.degree., c=0.560,
chloroform.
Example 27A
Ethyl(+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate
##STR00082##
[0456] Yield: 3.7 g
[0457] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.05 (d,
3H), 1.12 (t, 3H), 2.47-2.50 (m, 1H), 2.56-2.67 (m, 1H), 2.67-2.81
(m, 1H), 4.02 (q, 2H), 5.23 (br. s, 2H), 6.35 (dd, 1H), 6.58 (d,
1H), 7.05 (d, 1H).
[0458] [.alpha.].sub.D.sup.20=+35.1.degree., c=0.525,
chloroform.
Example 28A
Ethyl(2E/Z)-2-(4-chloro-3-nitrobenzylidene)butanoate
##STR00083##
[0460] 1.19 g of sodium hydride (60% suspension in mineral oil,
29.64 mmol) were suspended in 50 ml of a THF/DMF mixture (1:1). The
mixture was cooled to 0.degree. C., and 7.3 ml (30.99 mmol) of
triethyl 2-phosphonobutyrate were added dropwise. After 30 min, 5.0
g (26.94 mmol) of 4-chloro-3-nitrobenzaldehyde were added a little
at a time at -10.degree. C. After the addition had ended, the
reaction mixture was stirred at 0.degree. C. for 5 h and then
slowly warmed to RT overnight. The reaction mixture was then added
to water. The mixture was extracted three times with ethyl acetate,
and the combined organic phases were concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 6:1). This gave 7.05 g
(92.1% of theory) of the target product as an E/Z isomer
mixture.
[0461] LC-MS (Method 6): R.sub.t=1.24 min and 1.26 min; no
ionization.
Example 29A
(+/-)-Ethyl 2-(3-amino-4-chlorobenzyl)butanoate
##STR00084##
[0463] 7.05 g (24.84 mmol) of
ethyl(2E/Z)-2-(4-chloro-3-nitrobenzylidene)butanoate were dissolved
in 35 ml of ethyl acetate and 35 ml of acetic acid, and palladium
on carbon (10%) was added. The reaction mixture was stirred
vigorously at atmospheric pressure under an atmosphere of hydrogen
for a total of 6 h, with further portions of 10% palladium on
carbon being added after 4 h. The mixture was then filtered through
celite and the residue was washed with ethyl acetate/THF. The
combined filtrates were washed with saturated sodium bicarbonate
solution, dried over sodium sulphate and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate
30:1.fwdarw.10:1). This gave 4.12 g of the target product (64.9% of
theory).
[0464] LC-MS (Method 6): R.sub.t=1.14 min; m/z=210.
[0465] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.84 (t,
3H), 1.10 (t, 3H), 1.42-1.59 (m, 2H), 2.40-2.80 (m, 4H), 4.01 (q,
2H), 5.23 (s, 2H), 6.34 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H).
[0466] The racematee obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.43
ml; temperature: 30.degree. C.; mobile phase: ethanol; flow rate:
15 ml/min; detection: 220 nm]. 3.22 g of racematee gave 1.22 g of
enantiomer 1 (Example 30A) and 1.27 g of enantiomer 2 (Example
31A):
Example 30A
(-)-Ethyl(2R)-2-(3-amino-4-chlorobenzyl)butanoate
##STR00085##
[0468] Yield: 1.22 g
[0469] LC-MS (Method 6): R.sub.t=1.14 min; m/z=210.
[0470] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.84 (t,
3H), 1.10 (t, 3H), 1.42-1.56 (m, 2H), 2.39-2.48 (m, 1H), 2.56-2.73
(m, 3H), 4.01 (q, 2H), 5.11-5.27 (m, 2H), 6.34 (dd, 1H), 6.58 (d,
1H), 7.05 (d, 1H).
[0471] [.alpha.].sub.D.sup.20=-28.1.degree., c=0.510,
chloroform.
Example 31A
(+)-Ethyl(2S)-2-(3-amino-4-chlorobenzyl)butanoate
##STR00086##
[0473] Yield: 1.27 g
[0474] LC-MS (Method 6): R.sub.t=1.15 min; m/z=210.
[0475] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.84 (t,
3H), 1.10 (t, 3H), 1.46-1.55 (m, 2H), 2.42-2.49 (m, 1H), 2.54-2.69
(m, 3H), 4.01 (q, 2H), 5.22 (s, 2H), 6.34 (dd, 1H), 6.57 (d, 1H),
7.05 (d, 1H).
[0476] [.alpha.].sub.D.sup.20=+34.1.degree., c=0.550,
chloroform.
Example 32A
tert-Butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)but-2-enoate
##STR00087##
[0478] 2.87 g of sodium hydride (60% suspension in mineral oil,
71.65 mmol) were suspended in 80 ml of THF. The mixture was cooled
to 0.degree. C., and 17.6 ml (749 mmol) of tert-butyl
(diethoxyphosphoryl)acetate were added dropwise. After 30 min at
0.degree. C., 13.0 g (65.1 mmol) of 4-chloro-3-nitroacetophenone
were added. After the addition had ended, the reaction mixture was
slowly warmed to RT and stirred at RT for another 1.5 h, and the
mixture was then added to water.
[0479] The mixture was extracted three times with ethyl acetate,
and the combined organic phases were concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 20:1.fwdarw.10:1). This
gave 17.03 g (87.8% of theory) of the target product as an E/Z
isomer mixture (E/Z about 1:1).
[0480] LC-MS (Method 5): isomer 1: R.sub.t=2.61 min; m/z=255;
isomer 2: R.sub.t=2.77 min; m/z=224.
Example 33A
tert-Butyl(+/-)-3-(3-amino-4-chlorophenyl)butanoate
##STR00088##
[0482] 11.5 g (38.62 mmol) of
tert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)but-2-enoate (E/Z about
1:1) were dissolved in 60 ml of ethyl acetate and 60 ml of acetic
acid, and palladium on carbon (10%) was added. The reaction mixture
was stirred vigorously at atmospheric pressure under an atmosphere
of hydrogen for 6 h. The mixture was then filtered through celite
and the residue was washed with ethyl acetate. The combined
filtrates were washed with saturated sodium bicarbonate solution,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 30:1). This gave 3.90 g
(37.4% of theory) of the target product.
[0483] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14 (d,
3H), 1.31 (s, 9H), 2.38 (dd, 2H), 2.95 (q, 1H), 5.21 (br. s, 2H),
6.42 (dd, 1H), 6.65 (d, 1H), 7.06 (d, 1H).
[0484] The racematee obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.15
ml; temperature: 30.degree. C.; mobile phase: 90% isohexane/10%
ethanol; flow rate: 15 ml/min; detection: 220 nm]. 5.0 g of
racematee gave 2.1 g of enantiomer 1 (Example 34A) and 1.8 g of
enantiomer 2 (Example 35A):
Example 34A
tert-Butyl(+)-(3S)-3-(3-amino-4-chlorophenyl)butanoate
##STR00089##
[0486] LC-MS (Method 4): R.sub.t=1.34 min; m/z=270 (M+H).sup.+.
[0487] .sup.1H-1-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14
(d, 3H), 1.31 (s, 9H), 2.19-2.45 (m, 2H), 2.95 (q, 1H), 5.20 (s,
2H), 6.42 (dd, 1H), 6.65 (d, 1H), 7.06 (d, 1H).
[0488] [.alpha.].sub.D.sup.20=+20.9.degree., c=0.670,
chloroform.
Example 35A
tert-Butyl(-)-(3R)-3-(3-amino-4-chlorophenyl)butanoate
##STR00090##
[0490] LC-MS (Method 4): R.sub.t=1.34 min; m/z=214
(M+H--C.sub.4H.sub.8).sup.+.
[0491] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14 (d,
3H), 1.31 (s, 9H), 2.38 (dd, 2H), 2.95 (q, 1H), 5.20 (br. s, 2H),
6.42 (dd, 1H), 6.65 (d, 1H), 7.06 (d, 1H).
[0492] [.alpha.].sub.D.sup.20=-24.1.degree., c=0.570,
chloroform.
Example 36A
tert-Butyl(2E/Z)-3-(4-fluoro-3-nitrophenyl)but-2-enoate
##STR00091##
[0494] 4.81 g of sodium hydride (60% suspension in mineral oil,
120.13 mmol) were suspended in a mixture of 120 ml of THF and 120
ml of DMF. The mixture was cooled to 0.degree. C., and 29.5 ml
(125.59 mmol) of tert-butyl(diethoxyphosphoryl)acetate were added
dropwise. After 30 min, 20.0 g (109.21 mmol) of
4-fluoro-3-nitroacetophenone were added at 0.degree. C. After the
addition had ended, the reaction mixture was slowly warmed to RT
and stirred at RT for another 3.5 h, after which the mixture was
added to water. The mixture was extracted three times with ethyl
acetate, and the combined organic phases were concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave
7.24 g (23.6% of theory) of the target product as an E/Z isomer
mixture (E/Z about 1.2:1).
[0495] LC-MS (Method 4): isomer 1: R.sub.t=1.34 min; m/z=208;
isomer 2: 12, =1.42 min; m/z=208.
Example 37A
tert-Butyl(+/-)-3-(3-amino-4-fluorophenyl)butanoate
##STR00092##
[0497] 7.24 g (25.74 mmol) of
tert-butyl(2E/Z)-3-(4-fluoro-3-nitrophenyl)but-2-enoate (E/Z about
1.2:1) were dissolved in 200 ml of ethanol, and palladium on carbon
(10%) was added. The reaction mixture was stirred vigorously at
atmospheric pressure under an atmosphere of hydrogen overnight. The
mixture was then filtered through celite, and the residue was
washed twice with ethyl acetate. The combined filtrates were
concentrated under reduced pressure and the residue was dried under
high vacuum. This gave 6.02 g of the target product (92.4% of
theory).
[0498] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14 (d,
3H), 1.31 (s, 9H), 2.37 (dd, 2H), 2.95 (q, 1H), 4.98 (s, 2H), 6.36
(ddd, 1H), 6.62 (dd, 1H), 6.85 (dd, 1H).
[0499] The racematee obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.15
ml; temperature: 35.degree. C.; mobile phase: 65% isohexane/35%
ethanol; flow rate: 15 ml/min; detection: 220 nm]. 6.0 g of
racematee gave 2.44 g of enantiomer 1 (Example 38A) and 1.92 g of
enantiomer 2 (Example 39A):
Example 38A
tert-Butyl(+)-(3S)-3-(3-amino-4-fluorophenyl)butanoate
##STR00093##
[0501] LC-MS (Method 6): R.sub.t=1.11 min; m/z=254 (M+H).sup.+.
[0502] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14 (d,
3H), 1.31 (s, 9H), 2.18-2.46 (m, 2H), 2.95 (q, 1H), 4.99 (br. s,
2H), 6.36 (ddd, 1H), 6.61 (dd, 1H), 6.85 (dd, 1H).
[0503] [.alpha.].sub.D.sup.20=+22.5.degree., c=0.570,
chloroform.
Example 39A
tert-Butyl(-)-(3R)-3-(3-amino-4-fluorophenyl)butanoate
##STR00094##
[0505] LC-MS (Method 6): R.sub.t=1.11 min; m/z=254 (M+H).sup.+.
[0506] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.14 (d,
3H), 1.31 (s, 9H), 2.26-2.45 (m, 2H), 2.95 (q, 1H), 4.99 (br. s,
2H), 6.36 (ddd, 1H), 6.62 (dd, 1H), 6.85 (dd, 1H).
[0507] [.alpha.].sub.D.sup.20=-23.2.degree., c=0.510,
chloroform.
Example 40A
Ethyl 3-(3-bromo-4-fluorophenyl)acrylate
##STR00095##
[0509] 9.65 g (111 mmol) of manganese dioxide were added to a
solution of 6.5 g (31.7 mmol) of 3-bromo-4-fluorobenzyl alcohol and
13.25 g (38 mmol) of ethoxycarbonylmethylenephosphorane in 390 ml
of toluene. The reaction mixture was heated at reflux, a further
9.65 g of manganese dioxide were added after 1 h and heating under
reflux was continued overnight. After cooling, the mixture was
filtered through celite and the filtrate was concentrated. The
residue was purified by flash chromatography on silica gel (mobile
phase cylclohexane/ethyl acetate 5:1). This gave 7.05 g (81% of
theory) of the target product in the form of an E/Z isomer
mixture.
[0510] LC-MS (Method 4): R.sub.t=1.33 min and 1.35 min; m/z=273/275
(M+H).sup.+.
Example 41A
rac-Ethyl
2-(3-bromo-4-fluorophenyl)-trans-cyclopropanecarboxylate
##STR00096##
[0512] Under argon, 381 mg (9.52 mmol) of sodium hydride (60% in
paraffin oil) were initially charged in 20 ml of DMSO, and 2.1 g
(9.52 mmol) of trimethylsulphoxonium iodide were added in one
portion at RT. After the evolution of gas had ceased, 2.0 g (7.3
mmol) of ethyl 3-(3-bromo-4-fluorophenyl)acrylate, dissolved in 10
ml of DMSO, were slowly added dropwise. The reaction mixture was
heated at 50.degree. C. overnight, then cooled to RT and, without
further work-up, purified by flash chromatography on silica gel
(mobile phase isohexane/ethyl acetate 100:1). This gave 907 mg (43%
of theory) of the target product.
[0513] LC-MS (Method 6): R.sub.t=1.20 min; m/z=289 (M+H).sup.+.
[0514] GC-MS (Method 1): R.sub.t=5.85 min; m/z=287/289
(M+14).sup.+.
[0515] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. [ppm]=1.20-1.33
(m, 4H), 1.56-1.63 (m, 1H), 1.80-1.88 (m, 1H), 2.43-2.52 (m, 1H),
4.17 (q, 2H), 7.00-7.06 (m, 2H), 7.28 (d, 1H).
Example 42A
rac-Ethyl
2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate
##STR00097##
[0517] Under argon, 361.5 m (3.8 mmol) of sodium tert-butoxide were
suspended in 12.9 ml of toluene, and 900 mg (3.1 mmol) of
(+1-)-trans-ethyl
2-(3-bromo-4-fluorophenyl)cyclopropanecarboxylate, 403 mg (3.8
mmol) of benzylamine, 28.7 mg (0.03 mmol) of
tris(dibenzylideneacetone)di-palladium and 19.5 mg (0.03 mmol) of
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were added
successively. The mixture was heated at 110.degree. C. for 4 h. The
reaction mixture was then cooled to RT, 100 ml of ethyl acetate and
50 ml of saturated ammonium chloride solution were added and the
mixture was filtered through celite. The organic phase was
separated off, washed with in each case 50 ml of saturated ammonium
chloride solution and saturated sodium chloride solution, dried
over magnesium sulphate and concentrated. The crude product was
purified by preparative HPLC. This gave 262 mg of the target
compound of a purity of 66% (18% of theory).
[0518] LC-MS (Method 6): R.sub.t=1.28 min; m/z=314 (M+H).sup.+.
Example 43A
rac-Ethyl
2-[3-amino-4-fluorophenyl]-trans-cyclopropanecarboxylate
##STR00098##
[0520] 262 mg (purity 66%, 0.55 mmol) of (+/-)-ethyl
2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclo-propanecarboxylate
were dissolved in 5 ml of ethanol/THF (1:1), 26 mg of palladium on
carbon (10%) were added and the mixture was hydrogenated at RT
using a hydrogen pressure of 1 bar for 24 h. The reaction mixture
was then filtered through celite, the residue was washed with
ethanol and the filtrate was concentrated. The crude product
obtained in this manner was purified by preparative HPLC. This gave
87 mg (69% of theory) of the target compound.
[0521] LC-MS (Method 6): R.sub.t=0.96 min; m/z=224 (M+H).sup.+.
[0522] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.17-1.23
(m, 3H), 1.23-1.28 (m, 1H), 1.39 (dt, 1H), 1.67-1.81 (m, 1H),
2.21-2.31 (m, 1H), 4.09 (q, 2H), 6.31 (ddd, 1H), 6.55 (dd, 1H),
6.86 (dd, 1H).
Example 44A
3-Amino-4-fluoroacetophenone
##STR00099##
[0524] At 0.degree. C., a solution of 11.1 g (89 mmol) of tin
chloride dihydrate in 12 ml of water was added dropwise over a
period of 15 min to a solution of 3 g (16.4 mmol) of
4-fluoro-3-nitroacetophenone in 7.8 ml of 12 N hydrochloric acid.
The reaction mixture was then heated at reflux for 15 min and
subsequently stirred at RT overnight. The reaction mixture was then
poured on ice, adjusted to pH 12 using 50% strength aqueous sodium
hydroxide solution and extracted with ethyl acetate. The organic
phase was washed with saturated sodium chloride solution, dried
over magnesium sulphate and concentrated. This gave 2.47 g (purity
90%, 87% of theory) of the target compound.
[0525] LC-MS (Method 5): R.sub.t=1.32 min; m/z=154 (M+H).sup.+.
Example 45A and Example 46A
Ethyl(2E)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate and
Ethyl(2Z)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate
##STR00100##
[0527] At 0.degree. C., 6.92 ml (7.68 g, 32.3 mmol) of triethyl
2-phosphonopropionate were slowly added dropwise to a suspension of
1.29 g of sodium hydride (60% in paraffin oil; 32.3 mmol) in 24.7
ml of THF. The reaction mixture was stirred for 30 min, and 2.47 g
(purity 90%, 14.5 mmol) of 3-amino-4-fluoroacetophenone were then
added. The reaction mixture was stirred initially at RT for 1 h and
then under reflux for 2 h, then cooled back to RT and stirred
overnight. The mixture was then poured into water and extracted
three times with in each case 100 ml of ethyl acetate. The combined
organic phases were dried over magnesium sulphate and concentrated
and the residue was purified by flash chromatography on silica gel
(mobile phase toluene/ethyl acetate 5:1). This gave, in separated
form, 612 mg (15% of theory) of the 2E isomer (Example 45A) and 529
mg (13% of theory) of the 2Z isomer (Example 46A).
2E Isomer (Example 45A):
[0528] LC-MS (Method 6): R.sub.t=1.05 min; m/z=238 (M+H).sup.+.
[0529] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22-1.29
(m, 3H), 1.69 (d, 3H), 2.11 (d, 3H), 4.17 (d, 2H), 6.30 (ddd, 1H),
6.56 (dd, 1H), 6.97 (dd, 1H).
2Z Isomer (Example 46A):
[0530] LC-MS (Method 6): R.sub.t=0.99 min; m/z=238 (M+H).sup.+.
[0531] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.85 (t,
3H), 1.86-1.92 (m, 3H), 1.94-2.01 (m, 3H), 3.82 (q, 2H), 6.24 (ddd,
1H), 6.51 (dd, 1H), 6.87 (dd, 1H).
Example 47A
rac-threo-Ethyl 3-(3-amino-4-fluorophenyl)-2-methylbutanoate
##STR00101##
[0533] 4.8 mg of palladium on carbon (10%) were added to a solution
of 48 mg (0.2 mmol) of
ethyl(2E)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate in 5 ml
of methanol. The reaction mixture was hydrogenated at a hydrogen
pressure of 1 bar overnight. The mixture was then filtered through
celite and the filtrate was concentrated. This gave 35.8 mg (74% of
theory) of the title compound which contained about 20% of the
erythro isomer.
[0534] LC-MS (Method 6): R.sub.t=1.02 min; m/z=240 (M+H).sup.+.
Example 48A
rac-erythro-Ethyl 3-(3-amino-4-fluorophenyl)-2-methylbutanoate
##STR00102##
[0536] 3 mg of palladium on carbon (10%) were added to a solution
of 30 mg (0.13 mmol) of
ethyl(2Z)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate in 3.1 ml
of methanol. The reaction mixture was hydrogenated at a hydrogen
pressure of 1 bar overnight. The mixture was then filtered through
celite and the filtrate was concentrated. This gave 22.5 mg (74% of
theory) of the title compound which contained about 5% of the threo
isomer.
[0537] LC-MS (Method 6): R.sub.t=1.04 min; m/z=240 (M+H).sup.+.
Example 49A
tert-Butyl(2E)-3-(4-fluoro-3-nitrophenyl)acrylate
##STR00103##
[0539] Under argon, 0.65 g of sodium hydride (60% in paraffin oil;
16.3 mmol) was initially charged in 25 ml of THF, and the mixture
was cooled to 0.degree. C. 4.29 g (17 mmol) of tert-butyl
diethyl-phosphonoacetate were then slowly added dropwise. After 30
min of stirring, 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde
were added. The reaction mixture was stirred at RT for 3 h, then
poured into 100 ml of water and extracted three times with in each
case 100 ml of ethyl acetate. The combined organic phases were
dried over magnesium sulphate and concentrated. The residue was
purified by flash chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1). This gave 3.37 g (85% of theory)
of the target product.
[0540] GC-MS (Method 1): R.sub.t=6.45 min; m/z=211
(M-.sup.tBu).sup.+.
[0541] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.49 (s,
9H), 6.69 (d, 1H), 7.59-7.76 (m, 2H), 8.19 (ddd, 1H), 8.50 (dd,
1H).
Example 50A
tert-Butyl(2E)-3-(4-cyano-3-nitrophenyl)acrylate
##STR00104##
[0543] 134 mg (2.06 mmol) of potassium cyanide were added to a
solution of 500 mg (1.87 mmol) of tert-butyl
(2E)-3-(4-fluoro-3-nitrophenyl)acrylate in 5.4 ml of DMF. The
reaction mixture was stirred at RT overnight and then purified
directly by flash chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate mixture). This gave 57 mg (11% of theory)
of the title compound.
[0544] LC-MS (Method 5): R.sub.t=2.40 min; m/z=292
(M+NH.sub.4).sup.+.
[0545] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.39-1.58
(m, 9H), 6.91 (d, 1H), 7.73 (d, 1H), 8.19 (d, 1H), 8.26-8.38 (m,
1H), 8.72 (d, 1H).
Example 51A
tert-Butyl 3-(3-amino-4-cyanophenyl)propanoate
##STR00105##
[0547] 4.9 mg of palladium on carbon (10%) were added to a solution
of 48.9 mg (0.18 mmol) of tert-butyl
(2E)-3-(4-cyano-3-nitrophenyl)acrylate in 4.4 ml of ethanol. The
reaction mixture was hydrogenated using a hydrogen pressure of 1
bar at RT overnight. The mixture was then filtered through celite
and the filtrate was concentrated. This gave 43.5 mg (99% of
theory) of the target compound of a purity of 85%.
[0548] LC-MS (Method 6): R.sub.t=1.06 min; m/z=247 (M+H).sup.+.
Example 52A
Ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate
##STR00106##
[0550] At room temperature, 133 ml (1.82 mmol) of thionyl chloride
were added slowly to 287 g (1.65 mol) of
(3R)-4,4,4-trifluoro-3-methylbutanoic acid [A. Gerlach and U.
Schulz, Speciality Chemicals Magazine 24 (4), 37-38 (2004); CAS
Acc.-No. 142:179196] in 580 ml of ethanol The reaction solution was
then heated to 80.degree. C. and stirred at this temperature for 2
h. The mixture was then cooled to room temperature, 250 ml of water
were added slowly and the mixture was extracted three times with in
each case 150 ml of tert-butyl methyl ether. The combined organic
phases were dried over sodium sulphate. After filtration, the
solvent was removed under a reduced pressure of 300 mbar at
30.degree. C. The crude product was then distilled at 100 mbar and
a head temperature of 65.degree. C. This gave 225.8 g (113 mol, 74%
of theory) of the title compound as a colourless liquid.
[0551] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 4.10 (2H,
q), 2.88-2.72 (1H, m), 2.66-2.57 (1H, m), 2.46-2.36 (1H, m), 1.19
(3H, t), 1.11 (3H, d).
[0552] GC-MS (Method 1): R.sub.t=1.19 min; m/z=184 (M).sup.+.
[0553] [.alpha.].sub.D.sup.20=+16.1.degree., c=0.41, methanol
Example 53A
Ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate
(Diastereomer Mixture)
##STR00107##
[0555] Under argon, 196.9 mg (0.88 mmol) of palladium(II) acetate
and 724.8 mg (1.84 mmol) of
2-di-cyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl were
initially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8
mmol) of a 1 M solution of lithium hexamethyldisilazide in THF were
then added slowly, and the reaction solution was stirred at RT for
10 min The reaction solution was then cooled to -10.degree. C., 7 g
(38.0 mmol) of (+/-)-ethyl 4,4,4-trifluoro-3-methylbutanoate were
added slowly and the mixture was stirred at -10.degree. C. for 10
min 5 g (29.2 mmol) of 4-bromotoluene, dissolved in 50 ml of
toluene, were then added dropwise, and the reaction solution was
warmed initially to RT and then to 80.degree. C. The mixture was
stirred at this temperature for 2 h, then cooled to RT and stirred
overnight. After the reaction had gone to completion (monitored by
TLC; mobile phase cyclohexane/dichloromethane 2:1), the reaction
mixture was filtered through kieselguhr, the residue was washed
repeatedly with ethyl acetate and dichloromethane and the combined
filtrates were concentrated under reduced pressure. The crude
product obtained was purified chromatographically on silica gel
(mobile phase petroleum ether/dichloromethane 4:1.fwdarw.3:1). This
gave 3.91 g (14.3 mmol, 48.8% of theory) of the title compound as a
colourless liquid.
[0556] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.26 (2H,
d), 7.20-7.12 (2H, m), 4.17-3.95 (2H, m), 3.74 (0.25H, d), 3.66
(0.75H, d), 3.35-3.07 (1H, m), 2.29 (2.25H, s), 2.28 (0.75H, s),
1.17 (0.75H, d), 1.11 (3H, t), 0.76 (2.25H, d).
[0557] GC-MS (Method 1): R.sub.t=4.20 min; m/z=275
(M+H).sup.+(diastereomer 1); R.sub.t=4.23 min; m/z=275
(M+H).sup.+(diastereomer 2).
Example 54A
Ethyl(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate
##STR00108##
[0558] Preparation of solution A: Under argon, 163.9 ml of a 1 M
solution of lithium hexamethyldi-silazide in toluene were cooled to
from -10.degree. C. to -20.degree. C. (cooling with acetone/dry
ice), and 20 g (108.6 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 150 ml of
toluene, were added slowly, where care was being taken not to
exceed a temperature of -10.degree. C. The solution was then
stirred at not more than -10.degree. C. for 10 min
Preparation of solution B: Under argon, 27.03 g (141.2 mmol) of
1-bromo-4-chlorobenzene were dissolved in 100 ml of toluene at RT,
and 731 mg (3.26 mmol) of palladium(II) acetate and 2.693 g (6.84
mmol) of 2'-(dicyclohexylphosphanyl)-N,N-dimethylbiphenyl-2-amine
were added. The solution was stirred at RT for 10 min
[0559] Initially, the cooling bath was removed from solution A.
Solution B was then slowly added dropwise to solution A, which was
still cold. The combined solutions were slowly warmed to RT and
stirred at this temperature for 1 h. The reaction solution was then
warmed to 80.degree. C. (internal temperature) and stirred at this
temperature for 3 h. The reaction solution was then slowly cooled
to RT and stirred for another 12 h. The reaction mixture was then
filtered through kieselguhr, the residue was washed repeatedly with
toluene and the combined filtrates were concentrated under reduced
pressure. The crude product obtained was purified
chromatographically on silica gel (mobile phase
cyclohexane/dichloromethane 4:1). This gave 27.4 g (92.98 mmol, 86%
of theory) of the title compound as a yellow oil in a diastereomer
ratio of 3:1.
[0560] GC-MS (Method 1): R.sub.t=4.45 min; m/z=294 (M).sup.+
(diastereomer 1); R.sub.t=4.48 min; m/z=294 (M).sup.+ (diastereomer
2).
[0561] The following compounds were obtained analogously to
synthesis Examples 53A and 54A:
TABLE-US-00003 Example Name/Structure/Starting Materials Analytical
Data 55A ##STR00109## GC-MS (Method 1): R.sub.t = 4.61 min; m/z =
302 (M).sup.+ (diastereomer 1); R.sub.t = 4.64 min; m/z = 302
(M).sup.+ (diastereomer 2). 56A ##STR00110## GC-MS (Method 1):
R.sub.t = 4.83 min; m/z = 317 (M + H).sup.+ (diastereomer 1);
R.sub.t = 4.85 min; m/z = 317 (M + H).sup.+ (diastereomer 2). MS
(DCI): m/z = 334 (M + NH.sub.4).sup.+. 57A ##STR00111## GC-MS
(Method 1): R.sub.t = 3.38 min; m/z = 328 (M).sup.+ (diastereomer
1); R.sub.t = 3.42 min; m/z = 328 (M).sup.+ (diastereomer 2). 58A
##STR00112## GC-MS (Method 1): R.sub.t = 4.68 min; m/z = 370
(M).sup.+.
Example 59A
Ethyl
2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate
##STR00113##
[0563] 2.25 g (8.2 mmol) of ethyl
4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6
mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of
2,2'-azobis-2-methylpropanenitrile in 36 ml of trichloromethane
were stirred under reflux overnight. After the reaction had gone to
completion, the succinimide was filtered off, the filter residue
was washed with dichloromethane and the filtrate was concentrated
under reduced pressure. The crude product was purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl
acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a
yellowish oil.
[0564] GC-MS (Method 1): R.sub.t=5.72 min; m/z=373
(M-Br).sup.+(diastereomer 1); R.sub.t=5.74 min; m/z=373
(M-Br).sup.+ (diastereomer 2).
Example 60A
Ethyl
4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate
##STR00114##
[0566] 529 mg (2.78 mmol) of copper(I) iodide and 4 g (20.82 mmol)
of methyl 2,2-difluoro-2-(fluorosulphonyl)acetate were added to
3.77 g (10.67 mmol) of ethyl
2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate in 40
ml of 1-methylpyrrolidin-2-one, and the mixture was stirred at
80.degree. C. overnight. After the reaction had gone to completion,
the reaction solution was slowly poured onto 100 ml of ice-water.
The mixture obtained was then extracted three times with diethyl
ether. The combined organic phases were dried over magnesium
sulphate. After filtration, the solvent was removed under reduced
pressure. The crude product obtained was purified
chromatographically on silica gel (mobile phase
cyclohexane/dichloromethane 4:1). This gave 1.48 g (4.32 mmol, 41%
of theory) of the title compound as a yellowish oil.
[0567] GC-MS (Method 1): R.sub.t=4.06 min; m/z=342 (M).sup.+
(diastereomer 1); R.sub.t=4.09 min; m/z=342 (M).sup.+ (diastereomer
2).
[0568] MS (DCI): m/z=360 (M+NH.sub.4).sup.+.
Example 61A
1-Bromo-4-(2-bromo-1-fluoroethyl)benzene
##STR00115##
[0570] 5.0 g (27.31 mmol) of 4-bromostyrene were dissolved in 40 ml
of dichloromethane and cooled to 0.degree. C., and 13.21 g (81.94
mmol) of triethylamine trihydrofluoride were added. 5.83 g (32.78
mmol) of N-bromosuccinimide were then added in three portions. The
mixture was stirred at RT overnight. After dilution with
dichloromethane, the reaction mixture was poured onto ice-water.
The organic phase was washed successively with 1 N hydrochloric
acid, water and saturated sodium bicarbonate solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (mobile phase
pentane). This gave 4.14 g (53.8% of theory) of the title
compound.
[0571] GC-MS (Method 1): R.sub.t=4.94 min; m/z=277/281/283
(M+H).sup.+
[0572] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.75-4.04
(m, 2H), 5.84 (dt, 1H), 7.31-7.51 (m, 2H), 7.55-7.78 (m, 2H).
Example 62A
1-Bromo-4-(1-fluorovinyl)benzene
##STR00116##
[0574] 796 mg (7.09 mmol) of potassium tert-butoxide were added in
several portions to a solution, cooled to 0.degree. C., of 1.0 g
(3.55 mmol) of 1-bromo-4-(2-bromo-1-fluoroethyl)benzene in 10 ml of
pentane. The resulting suspension was stirred at 0.degree. C. for
30 min and then at RT for 1 h. The solid was filtered off, and the
filtrate was washed with saturated ammonium chloride solution,
dried over magnesium sulphate and carefully concentrated under
reduced pressure. This gave 0.61 g (85.6% of theory) of the title
compound.
[0575] GC-MS (Method 1): R.sub.t=3.14 min; m/z=200/202
(M+H).sup.+
[0576] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=5.10 (dd,
1H), 5.47 (dd, 1H), 7.48-7.61 (m, 2H), 7.62-7.72 (m, 2H).
Example 63A
Ethyl(3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00117##
[0578] 24.4 ml (24.4 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -10.degree. C., and
a solution of 3.0 g (16.29 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate in 15 ml of abs.
toluene was added dropwise. The mixture was stirred for 10 min. At
-10.degree. C., a solution, prepared beforehand, of 3.92 g (21.18
mmol) of 1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of
palladium(II) acetate and 404 mg (1.03 mmol) of
2'-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of
abs. toluene was then added dropwise. The resulting reaction
mixture was stirred initially at RT for 1 h, then at 80.degree. C.
for 3 h. The mixture was then concentrated under reduced pressure
and the residue was taken up in ethyl acetate and added to water.
The aqueous phase was back-extracted with ethyl acetate, and the
combined organic phases were washed with saturated ammonium
chloride solution and saturated sodium chloride solution, dried
over magnesium sulphate and concentrated under reduced pressure.
The residue gave, after chromatography on silica gel (mobile phase:
initially cyclohexane, then gradient cyclohexane/ethyl acetate
200:1.fwdarw.50:1), 3.051 g of the title compound (64.9% of theory,
diastereomer ratio about 3:1).
[0579] LC-MS (Method 4): R.sub.t=1.52 min; m/z=289
(M+H).sup.+(minor diastereomer); R.sub.t=1.54 min; m/z=289
(M+H).sup.+(major diastereomer).
[0580] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.76 (d, 3H), 1.13 (t, 3H), 1.17 (t, 3H), 2.55-2.63
(m, 2H), 3.21-3.31 (m, 1H), 3.67 (d, 1H), 3.95-4.16 (m, 2H),
7.15-7.23 (m, 2H), 7.25-7.31 (m, 2H).
[0581] The two compounds below were prepared in an analogous manner
from ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate and the
appropriate phenyl bromide:
Example 64A
Ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate
(Diastereomer Mixture)
##STR00118##
[0583] GC-MS (Method 1): R.sub.t=4.64 min and 4.66 min; m/z=286
(M).sup.+.
[0584] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.79 (d, 3H), 1.12 (t, 3H), 3.22-3.32 (m, 1H), 3.73
(d, 1H), 3.99-4.17 (m, 2H), 5.28 (d, 1H), 5.84 (d, 1H), 6.72 (dd,
1H), 7.34-7.40 (m, 2H), 7.45-7.51 (m, 2H).
Example 65A
Ethyl(3R)-4,4,4-trifluoro-2-[4-(1-fluorovinyl)phenyl]-3-methylbutanoate
##STR00119##
[0586] GC-MS (Method 1): R.sub.t=4.60 min and 4.63 min; m/z=304
(M).sup.+.
[0587] LC-MS (Method 6): R.sub.t=1.29 min and 1.30 min;
m/z=279.
[0588] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.79 (d, 3H), 1.12 (t, 3H), 3.34-3.38 (m, 1H), 3.81
(d, 1H), 3.99-4.17 (m, 2H), 4.97 (dd, 1H), 5.42 (dd, 1H), 7.46-7.49
(m, 2H), 7.63 (d, 2H).
Example 66A
Methyl(4-chlorophenyl)(3-oxocyclopentyl)acetate
##STR00120##
[0590] Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were
initially charged in 150 ml of THF, the mixture was cooled to
-30.degree. C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of
n-butyllithium in hexane were added slowly. The reaction solution
was then warmed to -20.degree. C., 15 g (81.25 mmol) of
methyl(4-chlorophenyl)acetate, dissolved in 90 ml of THF, were
added slowly and the mixture was stirred at this temperature for 2
h. The reaction solution was then cooled to -78.degree. C., and 7.2
ml (86.1 mmol) of 2-cyclopentene-1-one, dissolved in 60 ml of THF,
were added slowly. After the addition had ended, the solution was
stirred at this temperature for 1 h. After TLC check (mobile phase
cyclohexane/ethyl acetate 9:1), saturated ammonium chloride
solution was added and the mixture was taken up in ethyl acetate.
The aqueous phase was extracted twice with ethyl acetate. The
combined organic phases were dried over magnesium sulphate. After
filtration, the solvent was removed under reduced pressure. The
crude product was purified chromatographically on silica gel
(mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g
(58.67 mmol, 72% of theory) of the title compound as a yellowish
oil.
[0591] GC-MS (Method 1): R.sub.t=7.02 min; m/z=266 (M).sup.+
(diastereomer 1); R.sub.t=7.04 min; m/z=266 (M).sup.+ (diastereomer
2).
[0592] MS (DCI): m/z=284 (M+NH.sub.4).sup.+.
Example 67A
Methyl(4-chlorophenyl)(3,3-difluorocyclopentyl)acetate
##STR00121##
[0594] Under argon, 82.5 ml (82.14 mmol) of a 50% strength solution
of 1,1'-[(trifluoro-X.sup.4-sulphanyl)-imino]bis(2-methoxyethane)
(Desoxofluor) in THF, diluted with 200 ml of toluene, were
initially charged and cooled to 5.degree. C., and 744 .mu.l (5.87
mmol) of a 1 M solution of boron trifluoride/diethyl ether complex
were added slowly. The mixture was stirred at 5.degree. C. for 2 h.
15.65 g (58.67 mmol) of
methyl(4-chlorophenyl)(3-oxocyclopentyl)acetate, dissolved in 200
ml of toluene, were then added slowly, and the mixture was
subsequently warmed to 55.degree. C. and stirred at this
temperature for 60 h. The reaction mixture was then added to a
mixture, cooled to 0.degree. C., consisting of 100 ml of toluene
and 100 ml of 2 M aqueous sodium hydroxide solution. The organic
phase was separated off, and the aqueous phase was extracted three
more times with ethyl acetate. The combined organic phases were
dried over sodium sulphate. After filtration, the solvent was
removed under reduced pressure. The crude product was purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl
acetate 7:1). This gave 13.24 g (45.86 mmol, 78% of theory) of the
title compound as a colourless oil.
[0595] MS (DCI): m/z=306 (M+NH.sub.4).sup.+.
[0596] GC-MS (Method 1): R.sub.t=5.83 min; m/z=288 (M).sup.+
(diastereomer 1); R.sub.t=5.86 min; m/z=288 (M).sup.+ (diastereomer
2).
Example 68A (+/-)-Ethyl(2,2-difluorocyclopentyl)acetate
##STR00122##
[0598] At RT, 17.0 g (99.88 mmol) of (+/-)-ethyl
2-oxocyclopentylacetate were added dropwise to a solution of 52.8
ml (399.5 mmol) of diethylaminosulphur trifluoride (DAST) in 150 ml
of abs. dichloromethane The mixture was heated under reflux
overnight. After cooling, a further 13.2 ml (99.88 mmol) of
diethylaminosulphur trifluoride (DAST) were added, and the mixture
was once more stirred under reflux for 36 h. After cooling, the
mixture was diluted with dichloromethane, saturated sodium
bicarbonate solution was added carefully and the mixture was then
stirred vigorously. The organic phase was washed successively with
saturated sodium bicarbonate solution, twice with 1 N hydrochloric
acid and with saturated sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. From
the dark brown residue, the product was isolated by column
chromatography on silica gel (mobile phase pentane/dichloromethane
10:1.fwdarw.1:1). This gave 7.52 g (39% of theory) of the title
compound.
[0599] GC-MS (Method 1): R.sub.t=2.88 min; m/z=172.
[0600] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.18 (t,
3H), 1.33-1.48 (m, 1H), 1.61-1.77 (m, 2H), 1.92-2.20 (m, 3H),
2.24-2.38 (m, 1H), 2.43-2.60 (m, 2H), 4.07 (q, 2H).
Example 69A
Ethyl(4-chlorophenyl)(2,2-difluorocyclopentyl)acetate (Diastereomer
Mixture)
##STR00123##
[0602] 22.6 ml (22.6 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -20.degree. C., and
a solution of 2.90 g (15.09 mmol) of
(+/-)-ethyl(2,2-difluorocyclopentyl)acetate in 20 ml of abs.
toluene was added dropwise. The mixture was stirred at -20.degree.
C. for 10 min Cooling was removed, and a solution, prepared
beforehand, of 3.75 g (19.61 mmol) of 4-bromo-chlorobenzene, 110 mg
(0.49 mmol) of palladium(II) acetate and 374 mg (0.95 mmol) of
2'-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of
abs. toluene was then added dropwise. The resulting reaction
mixture was stirred initially at RT for 1 h, and then at 90.degree.
C. for 2 h. After cooling, the reaction mixture was added to water.
The aqueous phase was extracted three times with ethyl acetate, and
the combined organic phases were dried over magnesium sulphate and
concentrated under reduced pressure. The residue gave, after
chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 50:1), 2.70 g of the title compound (59.1% of theory,
diastereomer ratio about 1:4.3).
[0603] GC-MS (Method 1): R.sub.t=6.09 min and 6.20 min
[0604] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.01-1.27
(m, 3H), 1.37-1.50 (m, 1H), 1.51-1.75 (m, 3H), 1.94-2.23 (m, 3H),
2.84-3.07 (m, 1H), 3.55-3.79 (m, 1H), 3.93-4.20 (m, 2H), 7.29-7.53
(m, 4H).
Example 70A
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
Acid
##STR00124##
[0606] 5.086 g (17.26 mmol) of
ethyl(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were
dissolved in 68 ml of dioxane, and 34 ml of 1 N aqueous sodium
hydroxide solution were added. The mixture was stirred at
50.degree. C. for 2 h. The reaction mixture was then acidified to
pH 1 with 1 N hydrochloric acid and extracted repeatedly with
dichloromethane. The combined organic phases were washed with
saturated sodium chloride solution, dried over sodium sulphate and
concentrated under reduced pressure. This gave 3.9 g (14.63 mmol,
85% of theory, 83% de) of the target compound.
[0607] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm):
12.95-12.73 (1H, br. s), 7.49-7.34 (4H, m), 3.68 (1H, d), 3.31-3.18
(1H, m), 1.20 (0.25H, d), 0.78 (2.75H, d).
[0608] GC-MS (Method 1): R.sub.t=4.85 min; m/z=266 (M).+-..
[0609] [.alpha.].sub.D.sup.20=+57.2.degree., c=0.41, methanol
[0610] The compounds listed in the table below were prepared
analogously to synthesis Example 70A:
TABLE-US-00004 Example Name/Structure/Starting materials Analytical
data 71A ##STR00125## GC-MS (Method 1): R.sub.t = 4.48 min; m/z =
246 (M).sup.+. 72A ##STR00126## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
.delta./ppm): 12.56 (1H, br. s), 7.25 (4H, q), 3.56 (1H, d),
3.28-3.16 (1H, m), 2.94-2.81 (1H, m), 1.19 (6H, d), 0.75 (3H, d).
GC-MS (Method 1): R.sub.t = 4.93 min; m/z = 274 (M).sup.+. 73A
##STR00127## GC-MS (Method 1): R.sub.t = 5.15 min; m/z = 288
(M).sup.+. 74A ##STR00128## GC-MS (Method 1): R.sub.t = 3.85 min;
m/z = 300 (M).sup.+. 75A ##STR00129## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6, .delta./ppm): 12.90-12.40 (1H, br. s), 7.53 (2H, d),
7.40 (2H, d), 3.69 (0.11H, d), 3.64 (0.89H, d), 3.30- 3.20 (1H, m),
1.55 (6H, s), 1.21 (0.33H, d), 0.76 (2.67H, d). LC-MS (Method 6):
R.sub.t = 1.19 min; m/z = 341 (M - H).sup.-. 76A ##STR00130##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 12.95-12.59 (1H,
br. s), 7.37 (4H, q), 3.70-3.57 (3H, m), 3.30-3.18 (1H, m), 0.76
(3H, d). GC-MS (Method 8): R.sub.t = 4.45 min; m/z = 315 (M +
H).sup.+. 77A ##STR00131## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
.delta./ppm): 12.59 (1H, br. s), 7.38 (4H, q), 3.51 (0.5H, d), 3.48
(0.5H, d), 2.77-2.60 (1H, m), 2.42-2.27 (0.5H, m), 2.26-1.20 (5.5H,
m). GC-MS (Method 1): R.sub.t = 6.33 min; m/z = 274 (M).sup.+
(diastereomer 1); R.sub.t = 6.38 min; m/z = 274 (M).sup.+
(diastereomer 2).
Example 78A
(3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoic acid
(Diastereomer Mixture)
##STR00132##
[0612] 3.0 g of
ethyl(3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate
(purity about 88%, about 9.16 mmol; diastereomer mixture) were
dissolved in a mixture of in each case 12.4 ml of methanol, THF and
water, and 5.49 g (137.35 mmol) of sodium hydroxide were added a
little at a time. The reaction mixture was stirred at 40.degree. C.
for 9 h. After cooling, most of the volatile solvents were removed
under reduced pressure and the residue was diluted with water. The
mixture was acidified by addition of hydrochloric acid, and the
aqueous phase was extracted three times with ethyl acetate. The
combined organic phases were dried over sodium sulphate and
concentrated under reduced pressure, and the residue was dried
under high vacuum. This gave 2.61 g of the title compound as a
crude product which was not purified any further (diastereomer
ratio about 9:1).
[0613] LC-MS (Method 6): R.sub.t=1.08 min; m/z=259 (M-H).sup.-
(minor diastereomer); R.sub.t=1.11 min; m/z=259 (M-H).sup.- (major
diastereomer).
[0614] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.76 (d, 3H), 1.17 (t, 3H), 2.54-2.66 (m, 4H),
3.10-3.29 (m, 1H), 3.56 (d, 1H), 7.14-7.22 (m, 2H), 7.22-7.32 (m,
2H), 12.58 (br. s, 1H).
[0615] In a similar manner (reaction temperature: RT to 40.degree.
C.; reaction time: 9-12 h), the two carboxylic acid derivatives
below were prepared from the corresponding esters:
Example 79A
(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoic Acid
(Diastereomer Mixture)
##STR00133##
[0617] Diastereomer ratio about 10:1.
[0618] LC-MS (Method 6): R.sub.t=1.04 min; m/z=257 (M-H).sup.-
(minor diastereomer); R.sub.t=1.06 min; m/z=257 (M-H).sup.- (major
diastereomer).
[0619] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.78 (d, 3H), 3.18-3.31 (m, 1H), 3.62 (d, 1H), 5.28
(d, 1H), 5.84 (d, 1H), 6.73 (dd, 1H), 7.31-7.39 (m, 2H), 7.40-7.54
(m, 2H), 12.74 (br. s, 1H).
Example 80A
(3R)-4,4,4-trifluoro-2-[4-(1-fluorovinyl)phenyl]-3-methylbutanoic
Acid (Diastereomer Mixture)
##STR00134##
[0621] Diastereomer ratio about 9:1.
[0622] GC-MS (Method 1): R.sub.t=4.97 min; m/z=276.
[0623] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer:
.delta. [ppm]=0.78 (d, 3H), 3.16-3.29 (m, 1H), 3.70 (d, 1H), 4.96
(dd, 1H), 5.34 (d, 1H), 5.47 (d, 1H), 7.39-7.51 (m, 2H), 7.58-7.69
(m, 2H), 12.83 (br. s, 1H).
Example 81A
(4-chlorophenyl)(2,2-difluorocyclopentyl)acetic Acid (Diastereomer
Mixture)
##STR00135##
[0625] 2.70 g (8.92 mmol) of
ethyl(4-chlorophenyl)(2,2-difluorocyclopentyl)acetate (diastereomer
mixture) were dissolved in 10 ml of methanol, 10 ml of THF and 5 ml
of water, and 7.13 g (89.18 mmol) of 50% strength aqueous sodium
hydroxide solution were added at RT. The reaction mixture was
stirred at RT overnight. The mixture was then diluted with water
and acidified with hydrochloric acid. The aqueous phase was
extracted three times with ethyl acetate, the combined organic
phases were dried over magnesium sulphate and concentrated under
reduced pressure and the residue was dried under high vacuum. This
gave 2.39 g of the title compound (97.6% of theory, diastereomer
ratio about 1:1).
[0626] LC-MS (Method 6): R.sub.t=1.05 min and 1.07 min; m/z=273
(M-H).sup.-.
Example 82A
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
Chloride
##STR00136##
[0628] 19.5 g (73.13 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
were dissolved in 860 ml of dichloromethane, and 0.5 ml of DMF was
added. At from -5.degree. C. to -10.degree. C. (ice/acetone cooling
bath), 73 ml (146.26 mmol) of a 2 M solution of oxalyl chloride in
dichloromethane were then slowly added dropwise, and the mixture
was stirred at this temperature for 1 h. After the reaction had
gone to completion, the reaction solution was evaporated under
reduced pressure and the residue obtained was taken up in 200 ml
dichloromethane and then once more concentrated to dryness. This
gave 20.1 g (70.5 mmol, 96% of theory) of the title compound as a
colourless oil. Without further purification and without further
spectroscopic characterization, the product obtained in this manner
was used for subsequent reactions.
[0629] The compounds listed in the table below were prepared in an
analogous manner
TABLE-US-00005 Example Name/Structure Starting material 83A
##STR00137## (2S,3R)-4,4,4-trifluoro- 2-(4-isopropylphenyl)-
3-methylbutanoic acid 84A ##STR00138## (2S,3R)-2-(4-tert-butyl-
phenyl)-4,4,4-trifluoro- 3-methylbutanoic acid 85A ##STR00139##
(2S,3R)-4,4,4-trifluoro- 3-methyl-2-[4-(trifluoro-
methyl)phenyl]butanoic acid 86A ##STR00140##
(2S,3R)-4,4,4-trifluoro- 3-methyl-2-[4-(1,1,1-tri-
fluoro-2-methylpropan- 2-yl)phenyl]butanoic acid 87A ##STR00141##
4,4,4-trifluoro-3-methyl- 2-[4-(2,2,2-trifluoroethyl)-
phenyl]butanoic acid 88A ##STR00142## (4-chlorophenyl)-
(3,3-difluorocyclopentyl)- acetic acid
Example 89A
tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-me-
thylbutanoyl]amino}-phenyl)propanoate
##STR00143##
[0631] 18 g (70.38 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride were dissolved in 500 ml of THF, 18.4 ml (105.57 mmol) of
N,N-diisopropylethylamine were added and the mixture was cooled to
-10.degree. C. 20.07 g (70.38 mmol) of
tert-butyl-3-(3-amino-4-chlorophenyl)-propanoate, dissolved in 500
ml of THF, were then added slowly, while care was being taken not
to exceed a reaction temperature of 0.degree. C. during the
addition. The mixture was then stirred for another 1 h. Water and
ethyl acetate were then added to the reaction solution, the organic
phase was separated off and the aqueous phase was extracted three
more times with ethyl acetate. The combined organic phases were
dried over sodium sulphate and concentrated on a rotary evaporator.
The residue was purified by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 20:1). This gave 30.13 g (59.74
mmol, 85% of theory) of the title compound.
[0632] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 9.82 (1H,
s), 7.50-7.42 (4H, m), 7.39-7.32 (2H, m), 7.07-7.01 (1H, m), 4.12
(1H, d), 3.42-3.29 (1H, m), 2.75 (2H, t), 2.46 (2H, t), 1.31 (9H,
s), 0.80 (3H, d).
[0633] LC-MS (Method 7): R.sub.t=3.03 min; m/z=502/504
(M-H).sup.-.
[0634] The compounds listed in the table below were obtained in an
analogous manner
TABLE-US-00006 Example Name/Structure/Starting materials Analytical
data 90A ##STR00144## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 9.70 (1H, s), 7.47- 7.42 (1H, m), 7.34 (3H, t), 7.23
(2H, d), 7.04-6.99 (1H, m), 4.07 (1H, d), 3.40-3.26 (1H, m),
2.94-2.81 (1H, m), 2.75 (2H, t), 2.45 (2H, t), 1.31 (9H, s), 1.19
(6H, d), 0.78 (3H, d). LC-MS (Method 4): R.sub.t = 1.72 min; m/z =
510/512 (M - H).sup.-. 91A ##STR00145## .sup.1H-NMR (400 MHz, DMSO-
d.sub.6, .delta./ppm): 9.71 (1H, s), 7.49- 7.43 (1H, m), 7.41-7.35
(4H, m), 7.34 (1H, d), 7.04-6.98 (1H, m), 4.08 (1H, d), 3.39- 3.25
(1H, m), 2.75 (2H, t), 2.45 (2H, t), 1.31 (9H, s), 1.27 (9H, s),
0.78 (3H, d). LC-MS (Method 6): R.sub.t = 1.52 min; m/z = 524/526
(M - H).sup.-. 92A ##STR00146## .sup.1H-NMR (400 MHz, DMSO-
d.sub.6, .delta./ppm): 9.89 (1H, s), 7.76 (2H, d), 7.69 (2H, d),
7.37 (1H, d), 7.35 (1H, d), 7.04 (1H, dd), 4.24 (1H, d), 3.48-3.36
(1H, m), 2.75 (2H, t), 2.45 (2H, t), 1.29 (9H, s), 0.80 (3H, d).
LC-MS (Method 6): R.sub.t = 1.43 min; m/z = 536 (M - H).sup.-. 93A
##STR00147## LC-MS (Method 6): R.sub.t = 1.48 min; m/z = 579 (M -
H).sup.-. 94A ##STR00148## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 9.78 (1H, s), 7.46 (2H, d), 7.41 (1H, d), 7.35 (3H,
t), 7.02 (1H, dd), 4.11 (1H, d), 3.63 (2H, q), 3.42-3.28 (1H, m),
2.75 (2H, t), 2.45 (2H, t), 1.30 (9H, s), 0.79 (3H, d). LC-MS
(Method 6): R.sub.t = 1.41 min; m/z = 550 (M - H).sup.-. 95A
##STR00149## LC-MS (Method 5): R.sub.t = 3.01 min; m/z = 510/512 (M
- H).sup.-. 96A ##STR00150## LC-MS (Method 7): R.sub.t = 2.94 min;
m/z = 498 (M).sup.+. 97A ##STR00151## LC-MS (Method 7): R.sub.t =
2.94 min; m/z = 498 (M).sup.+. 98A ##STR00152## .sup.1H-NMR (400
MHz, DMSO- d.sub.6, .delta./ppm): 9.95 (0.33H, s), 9.81 (0.66H, s),
7.54-7.30 (6H, m), 7.02-6.93 (1H, m), 4.14 (1H, d), 3.41-3.28 (1H,
m), 3.37 (3H, s), 2.80-2.74 (2H, m), 2.35-2.19 (4H, m), 2.11- 1.97
(1H, m), 1.82-1.69 (1H, m), 1.25 (1H, d), 0.80 (2H, d). LC-MS
(Method 7): R.sub.t = 2.96 min; m/z = 500/502 (M - H).sup.-. 99A
##STR00153## .sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm):
9.88 (1H, s), 7.51 (1H, d), 7.45 (4H, q), 7.38 (1H, d), 7.33-7.23
(3H, m), 7.17- 7.10 (2H, m), 7.03 (1H, dd), 4.92 (2H, s), 4.78-4.67
(4H, m), 4.17 (1H, d), 3.42-3.28 (1H, m), 3.18 (2H, s), 0.80 (3H,
d). LC-MS (Method 7): R.sub.t = 2.87 min; m/z = 578 (M -
H).sup.-.
Example 100A
Methyl[1-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}-4-fluorophenyl)cyclopropyl]acetate
##STR00154##
[0636] A solution of 70 mg (0.31 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid,
84 mg (0.31 mmol) of
methyl[1-(3-amino-4-fluorophenyflcyclopropyl]acetate, 179 mg (0.47
mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) and 0.6 ml of pyridine in 2.4 ml of DMF
was stirred at room temperature overnight. After the reaction had
ended, the mixture was separated directly, without further work-up,
by preparative HPLC. This gave 106 mg (0.22 mmol, 72% of theory) of
the title compound as a colourless oil.
[0637] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 10.02 (1H,
s), 7.71 (1H, dd), 7.52-7.38 (4H, m), 7.15-7.06 (1H, m), 7.05-6.98
(1H, m), 4.11 (1H, d), 3.48 (3H, s), 3.42-3.25 (1H, m), 2.57 (2H,
s), 0.90-0.84 (2H, m), 0.81-0.74 (5H, m).
[0638] LC-MS (Method 6): R.sub.t=1.33 min; m/z=472 (M+H).sup.+.
[0639] The following compound was obtained in an analogous
manner
TABLE-US-00007 Example Name/Structure/Starting materials Analytical
data 101A Methyl[1-(3-{[(2S,3R)-2-(4-ethylphenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-
4-fluorophenyl)cyclopropyl]acetate ##STR00155##
(from(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro- 3-methylbutanoic
acid and methyl[1-(3-amino- 4-fluorophenyl)cyclopropyl]acetate)
.sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 9.96 (1H, s),
7.74 (1H, dd), 7.34 (2H, d), 7.20 (2H, d), 7.12-7.05 (1H, m),
7.03-6.96 (1H, m), 4.04 (1H, d), 3.47 (3H, s), 3.41-3.25 (1H, m),
2.63-2.52 (4H, m), 1.17 (3H, t), 0.89-0.84 (2H, m), 0.81-0.73 (5H,
m). LC-MS (Method 4): R.sub.t = 1.53 min; m/z = 466 (M +
H).sup.+.
[0640] General procedure 1: HATU-mediated amide coupling of
4,4,4-trifluoro-3-methyl-2-phenyl-butanoic acid derivatives with
anilines
[0641] At RT, HATU (1.0 to 2.0 eq.) is added to a solution of the
4,4,4-trifluoro-3-methyl-2-phenylbutanoic acid derivative in
question (about 0.8 to 1.5 eq., 0.15 to 1.5 mol/l) and an aniline
(about 0.8 to 1.5 eq., 0.15 to 1.5 mol/l) in a mixture of DMF and
pyridine (mixing ratio about 3:1 to 1.5:1). Alternatively, instead
of pyridine, it is also possible to use N,N-diisopropylethylamine
(2.0 to 5.0 eq.). The resulting mixture is stirred at a temperature
of from RT to 60.degree. C. for 4 h to 48 h. If appropriate, a
further portion of aniline or of carboxylic acid and HATU is added
after 24 h. After the reaction has ended, the crude product can be
purified, after removal of the solvent under reduced pressure, by
preparative RP-HPLC (mobile phase: acetonitrile/water gradient) or
alternatively, after aqueous work-up of the reaction mixture, by
chromatography on silica gel (mobile phase: cyclohexane/ethyl
acetate or dichloromethane/methanol mixtures).
[0642] The following examples were prepared in accordance with the
General Procedure 1:
TABLE-US-00008 Example Name/Structure Analytical data 102A
tert-butyl (+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl)amino)-2- fluorophenyl)propanoate
(diastereomer 1) ##STR00156## LC-MS (Method 4): R.sub.t = 1.64 min;
m/z = 487 (M - H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 0.79 (d, 3H), 1.32 (s, 9H), 2.48 (t, 2H), 2.81 (t,
2H), 3.34-3.45 (m, 1H), 4.12 (d, 1H), 6.88-7.12 (m, 2H), 7.36-7.52
(m, 4H), 7.63 (td, 1H), 10.03 (s, 1H). 103A tert-butyl
(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoy]amino}-2- fluorophenyl)propanoate
(diastereomer 2) ##STR00157## .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 1.22 (d, 3H), 1.32 (s, 9H), 2.49 (t, 2H), 2.82 (t,
2H), 3.21 (dd, 1H), 4.15 (d, 1H), 6.93- 7.12 (m, 2H), 7.35-7.43 (m,
2H), 7.43-7.52 (m, 2H), 7.54-7.74 (m, 1H), 10.12 (s, 1H). 104A
tert-butyl(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4- fluorophenyl)propanoate
(diastereomer 1) ##STR00158## LC-MS (Method 4): R.sub.t = 1.63 min:
m/z = 486 (M - H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 0.78 (d, 3H), 1.31 (m, 9H), 2.44 (t, 2H), 2.74 (t,
2H), 3.33-3.48 (m, 1H), 4.11 (d, 1H), 6.92-7.04 (m, 1H), 7.12 (dd,
1H), 7.35-7.52 (m, 4H), 7.65 (dd, 1H), 10.02 (s, 1H). 105A
tert-butyl(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4- fluorophenyl)propanoate
(diastereomer 2) ##STR00159## LC-MS (Method 4): R.sub.t = 1.63 min;
m/z = 486 (M - H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 1.21 (d, 3H), 1.31 (s, 9H), 2.45 (t, 2H), 2.74 (t,
2H), 3.21 (dd, 1H), 4.13 (d, 1H), 6.89- 7.06 (m, 1H), 7.14 (dd,
1H), 7.36-7.44 (m, 2H), 7.45-7.55 (m, 2H), 7.62 (dd, 1H), 10.12 (s,
1H). 106A tert-butyl(+)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluoro- phenyl)propanoate
##STR00160## LC-MS (Method 6): R.sub.t = 1.43 min: m/z = 486 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.78
(d, 3H), 1.31 (s, 9H), 2.44 (t, 2H), 2.74 (t, 2H), 3.34-3.43 (m,
1H), 4.11 (d, 1H), 6.87-7.02 (m, 1H), 7.12 (dd, 1H), 7.36-7.51 (m,
4H), 7.65 (dd, 1H), 10.03 (s, 1H). [.alpha.].sub.D.sup.20 =
+127.degree., c = 0.52, Chloroform. 107A
tert-butyl(+)-3-(4-fluoro-3-{[(2S,3R)-4,4,4-
trifluoro-3-methyl-2-(4-
vinylphenyl)butanoyl]amino}phenyl)propanoate ##STR00161## LC-MS
(Method 6): R.sub.t = 1.39 min; m/z = 478 (M - H).sup.-.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.79 (d, 3H),
1.31 (s, 9H), 2.44 (t, 2H), 2.74 (t, 2H), 3.35-3.43 (m, 1H), 4.08
(d, 1H), 5.26 (d, 1H), 5.83 (d, 1H), 6.72 (dd, 1H), 6.97 (td, 1H),
7.11 (dd, 1H), 7.32-7.51 (m, 4H), 7.66 (dd, 1H), 9.99 (s, 1H).
[.alpha.].sub.D.sup.20 = +119.4.degree., c = 0.455, Chloroform.
108A Ethyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino)-4-fluoro-
phenyl)-2-methylpropanoate (diastereomer mixture) ##STR00162##
LC-MS (Method 6): R.sub.t = 1.35 min; m/z = 474 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.78 (d, 3H),
1.01-1.11 (m, 6H), 2.56-2.69 (m, 2H), 2.69- 2.83 (m, 1H), 3.34-3.44
(m, 1H), 3.87- 3.99 (m, 2H), 4.11 (d, 1H), 6.88-7.00 (m, 1H), 7.12
(dd, 1H), 7.39-7.48 (m, 4H), 7.55-7.66 (m, 1H), 10.03 (s, 1H). 109A
tert-butyl (+)-3-(4-chloro-3-{[(2S,3R)-4,4,4-
trifluoro-3-methyl-2-(4-
vinylphenyl)butanoyl]amino}phenyl)propanoate ##STR00163## LC-MS
(Method 6): R.sub.t = 1.43 min; m/z = 496 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.80 (d, 3H),
1.31 (s, 9H), 2.45 (t, 2H), 2.75 (t, 2H), 3.34-3.43 (m, 1H), 4.09
(d, 1H), 5.27 (d, 1H), 5.84 (d, 1H), 6.72 (dd, 1H), 7.03 (dd, 1H),
7.29- 7.53 (m, 6H), 9.78 (s, 1H). [.alpha.].sub.D.sup.20 =
+105.2.degree., c = 0.315, chloroform. 110A
tert-butyl(+)-3-(3-{[(2S,3R)-2-(4-ethylphenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluoro- phenyl)propanoate
##STR00164## LC-MS (Method 6): R.sub.t = 1.46 min; m/z = 480 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.77
(d, 3H), 1.17 (t, 3H), 1.31 (s, 9H), 2.44 (t, 2H), 2.60 (q, 2H),
2.74 (t, 2H), 3.29- 3.34 (m, 1H), 4.05 (d, 1H), 6.86- 7.00 (m, 1H),
7.11 (dd, 1H), 7.16-7.26 (m, 2H), 7.28-7.41 (m, 2H), 7.69 (dd, 1H),
9.96 (s, 1H). [.alpha.].sub.D.sup.20 = +108.7.degree., c = 0.500,
Chloroform. 111A tert-butyl(+)-3-(4-chloro-3-{[(2S,3R)-2-(4-
ethylphenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)propanoate ##STR00165## LC-MS (Method
6): R.sub.t = 1.51 min; m/z = 496 (M - H).sup.-. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. [ppm] = 0.78 (d, 3H), 1.17 (t, 3H),
1.31 (s, 9H), 2.45 (t, 2H), 2.59 (q, 2H), 2.75 (t, 2H), 3.34- 3.40
(m, 1H), 4.06 (d, 1H), 7.02 (dd, 1H), 7.20 (d, 2H), 7.34 (dd, 3H),
7.42 (d, 1H), 9.73 (s, 1H). [.alpha.].sub.D.sup.20 = +62.7.degree.,
c = 0.475, Chloroform. 112A Ethyl
3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 2-methylpropanoate
(diastereomer mixture) ##STR00166## LC-MS (Method 4): R.sub.t =
1.61 min; m/z = 484 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.78 (d, 3H), 1.03-1.07 (m, 5H),
1.17 (t, 3H), 2.55-2.69 (m, 4H), 2.74-2.83 (m, 1H), 3.27- 3.40 (m,
2H), 3.96 (qd, 2H), 4.03-4.12 (m, 1H), 6.97 (dd, 1H), 7.20 (d, 2H),
7.33-7.41 (d, 4H), 9.73 (s, 1H). 113A Ethyl
3-(3-{[(2S,3R)-2-(4-ethylphenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-4-
fluorophenyl)-2-methylpropanoate (diastereomer mixture)
##STR00167## LC-MS (Method 4): R.sub.t = 1.57 min; m/z = 468 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.77
(d, 3H), 0.99-1.11 (m, 6H), 1.11-1.23 (m, 3H), 2.52- 2.68 (m, about
5H), 2.70-2.85 (m, 1H), 3.28-3.32 (m, about 1H), 3.90-4.00 (m, 2H),
4.00- 4.08 (m, 1H), 6.82-6.96 (m, 1H), 7.11 (dd, 1H), 7.16-7.25 (m,
2H), 7.27-7.41 (m, 2H), 7.65 (dd, 1H), 9.96 (s, 1H). 114A Ethyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoyl]mino}pheny)- 2-methylpropanoate
(diastereamer mixture) ##STR00168## LC-MS (Method 5): R.sub.t =
2.95 min; m/z = 490/492 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.80 (d, 3H), 1.00-1.12 (m, 6H),
2.59-2.72 (m, 2H), 2.74- 2.86 (m, 1H), 3.34-3.42 (m, 1H), 3.96 (qd,
2H), 4.12 (d, 1H), 6.99 (dd, 1H), 7.26-7.39 (m, 2H), 7.39-7.54 (m,
4H), 9.81 (s, 1H). 115A tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
ethylphenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)butanoate (diastereomer mixture)
##STR00169## LC-MS (Method 6): R.sub.t = 1.55 min; m/z = 510 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.79
(d, 3H), 1.10-1.19 (m, 6H), 1.24/1.26 (2s, together 9H), 2.32-2.46
(m, 2H), 2.59 (q, 2H), 2.97-3.11 (m, 1H), 3.33- 3.40 (m, 1H),
4.02-4.14 (m, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.35 (d, 3H), 7.48
(dd, 1H), 9.72 (s, 1H). 116A Methyl
(+)-3-[4-chloro-3-({(2S,3R)-4,4,4-trifluoro-
2-[4-(1-fluorovinyl)phenyl]-3-
methylbutanoyl}amino)phenyl]propanoate ##STR00170## LC-MS (Method
6): R.sub.t = 1.30 min; m/z = 472/474 (M + H).sup.+. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.80 (d, 3H), 2.54-2.60
(m, 2H), 2.73-2.88 (m, 2H), 3.35- 3.45 (m, 1H), 4.15 (d, 1H), 4.96
(dd, 1H), 5.40 (dd, 1H), 7.04 (dd, 1H), 7.28-7.40 (m, 2H), 7.45-
7.55 (m, 2H), 7.59-7.71 (m, 2H), 9.84 (s, 1H).
[.alpha.].sub.D.sup.20 = +66.3.degree., c = 0.455, Chloroform. 117A
tert-butyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4- chlorophenyl)butanoate
(diastereomer mixture) ##STR00171## LC-MS (Method 4): R.sub.t =
1.66 min; m/z = 516/517 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.80 (d, 3H), 1.16 (d, 3H),
1.24/1.26 (2s, together 9H), 2.34-2.47 (m, 2H), 3.01-3.14 (m, 1H),
3.33-3.42 (m, 1H), 4.10- 4.18 (m, 1H), 7.08 (d, 1H), 7.36 (d, 1H),
7.40-7.51 (m, 5H), 9.80 (s, 1H). 118A
tert-butyl(3S)-3-(4-chloro-3-{[(4- chlorophenyl)(2,2-difluoro-
cyclopentyl)acetyl]amino}phenyl)butanoate (diastereomer mixture)
##STR00172## LC-MS (Method 6): R.sub.t = 1.45 min; m/z = 524/526 (M
- H).sup.-. and R.sub.t = 1.46 min; m/z = 524/526 (M - H).sup.-.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 1.16 (d, 3H),
1.24/1.26 (2s, together 9H), 1.48-1.78 (m, 3H), 1.96-2.25 (m, 3H),
2.33- 2.47 (m, 2H), 2.89-3.18 (m, 2H), 4.06 (ddd, 1H), 7.07 (ddd,
1H), 7.30-7.50 (m, 6H), 9.60/9.81 (2s, together 1H). 119A
tert-butyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4- fluorophenyl)butanoate
(diastereomer mixture) ##STR00173## LC-MS (Method 6): R.sub.t =
1.45 min; m/z = 500 (M - H).sup.-. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.79 (d, 3H), 1.16 (d, 3H),
1.23/1.24 (2s, together 9H), 1.58-1.72 (m, 1H), 2.30-2.47 (m, 2H),
2.99-3.10 (m, 1H), 3.32- 3.43 (m, 1H), 4.12 (d, 1H), 6.97- 7.06 (m,
1H), 7.13 (dd, 1H), 7.38-7.54 (m, 4H), 7.62-7.79 (m, 1H), 10.02 (s,
1H). 120A tert-butyl 3-(4-chloro-3-{[(4-chlorophenyl)(2,2-
difluorocyclopentyl)-acetyl]amino) phenyl)propanoate (diastereomer
mixture) ##STR00174## LC-MS (Method 6): R.sub.t = 1.44 min; m/z =
510/512 (M - H).sup.- and R.sub.t = 1.45 min; m/z = 510/512 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] =
1.07-1.25 (m, 1H), 1.31 (s, 9H), 1.46-1.75 (m, 3H), 1.95-2.25 (m,
2H), 2.42-2.47 (m, 2H), 2.70-2.81 (m, 2H), 2.87- 3.20 (m, 1H),
4.03/4.06 (2d, together 1H), 6.97-7.12 (m, 1H), 7.29-7.54 (m, 6H),
9.63/9.84 (2s, together 1H). 121A
Ethyl(2S)-3-(4-chloro-3-{[(4-chlorophenyl)(2,2-
difluorocyclopentyl)acetyl]amino}phenyl)-2- methylpropanoate
(diastereomer mixture) ##STR00175## LC-MS (Method 6): R.sub.t =
1.40 min; m/z = 498/500 (M + H).sup.+ and R.sub.t = 1.41 min; m/z =
498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
[ppm] = 0.98-1.08 (m, 6H), 1.10-1.24 (m, 1H), 1.48-1.80 (m, 3H),
1.96-2.26 (m, 2H), 2.57- 2.70 (m, 2H), 2.70-2.86 (m, 1H), 2.90-3.22
(m, 1H), 3.90-4.10 (m, 3H), 6.98 (ddd, 1H), 7.30-7.51 (m, 6H),
9.63/9.83 (2s, together 1H). 122A Ethyl
2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)- butanoate
(diastereomer mixture) ##STR00176## LC-MS (Method 6): R.sub.t =
1.45 min; m/z = 504 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.77-0.88 (m, about 6H), 0.98-1.07
(m, about 3H), 1.44-1.56 (m, 2H), 2.42-2.48 (m, 1H), 2.72 (d, 2H),
3.33-3.43 (m, 1H), 3.88-4.01 (m, 2H), 4.12 (d, 1H), 6.98 (dd, 1H),
7.30-7.37 (m, 2H), 7.40-7.51 (m, 4H), 9.81 (s, 1H).
Example 123A
Ethyl(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-met-
hylbutanoyl]amino}-phenyl)-2-methylpropanoate
##STR00177##
[0644] 500 mg (2.07 mmol) of
ethyl(-)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and 607
mg (2.28 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
were dissolved in a mixture of 2.0 ml of DMF and 1.0 ml of
pyridine, and 1022 mg (2.69 mmol) of HATU were added at room
temperature. The reaction mixture was stirred at RT overnight. The
mixture was diluted with ethyl acetate, and the solution was washed
successively with 1 N hydrochloric acid, water, saturated sodium
bicarbonate solution and saturated sodium chloride solution. The
organic phase was dried over magnesium sulphate and concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This
gave 998 mg (98.4% of theory) of the target compound.
[0645] LC-MS (Method 6): R.sub.t=1.41 min; m/z=490/492
(M+H).sup.+.
[0646] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 0.99-1.09 (m, 6H), 1.54-1.74 (m, 1H), 2.59-2.73 (m, 2H),
2.74-2.88 (m, 1H), 3.97 (q, 2H), 4.12 (d, 1H), 6.99 (dd, 1H),
7.25-7.37 (m, 2H), 7.40-7.55 (m, 4H), 9.81 (s, 1H).
Example 124A
(+)-Ethyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-
-methylbutanoyl]amino}phenyl)-2-methylpropanoate
##STR00178##
[0647] Method A:
[0648] 1.50 g (6.21 mmol) of
ethyl(+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and
1.82 g (6.83 mmol) of
(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (as
an about 9:1 diastereomer mixture) were dissolved in a mixture of
6.3 ml of DMF and 3.2 ml of pyridine, and 2.83 g (7.45 mmol) of
HATU were added at RT. The reaction mixture was stirred at RT
overnight. The mixture was then diluted with ethyl acetate, and the
solution was washed successively with saturated ammonium chloride
solution and saturated sodium chloride solution. The organic phase
was dried over magnesium sulphate and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 50:1.fwdarw.40:1). A mixed
fraction (which contained the minor diastereomer) obtained during
the purification was separated by another chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave a
total of 2.46 g (80.8% of theory) of the target compound.
Method B:
[0649] 30 ml of dichloromethane and one drop of DMF were added to
7.60 g (28.50 mmol) of
(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
(about 9:1-diastereomer mixture). 4.48 ml (51.3 mmol) of oxalyl
chloride were added dropwise to the solution, which had been cooled
to -10.degree. C., such that the temperature did not exceed
-5.degree. C. The reaction mixture was stirred at from -5.degree.
C. to 0.degree. C. for 1 h and then for about 30 min without
cooling with warming to RT and subsequently concentrated under
reduced pressure. The residue was taken up in dichloromethane and
the solution was once more concentrated under reduced pressure.
This procedure was repeated once more, and the acid chloride
obtained was then briefly dried under high vacuum and directly,
without further purification, reacted further.
[0650] 6.1 ml (35.04 mmol) of N,N-diisopropylethylamine were added
to a solution of 6.05 g (25.03 mmol) of
ethyl(+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate in 25
ml of abs. THF. The resulting solution was cooled to -10.degree.
C., and a solution of the acid chloride prepared above (7.85 g,
27.5 mmol) in about 10 ml of abs. THF was added dropwise, the
temperature being kept below 0.degree. C. The reaction mixture was
then stirred at from -10.degree. C. to 0.degree. C. for 1 h, and
ethyl acetate and three drops of water were then added. After 10
min, the mixture, which had been diluted further with ethyl
acetate, was washed successively with 1 N hydrochloric acid,
saturated sodium bicarbonate solution and saturated sodium chloride
solution, dried over magnesium sulphate and concentrated under
reduced pressure. The crude product was triturated with 50 ml of
diisopropyl ether for 4 h. After filtration, the solid obtained was
once more triturated with 40 ml of diisopropyl ether. The solid
obtained was dried thoroughly under high vacuum. This gave 8.32 g
of the target compound. The filtrates obtained above were combined
and concentrated under reduced pressure. The residue gave, after
chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 50:1), a further 1.75 g of product. In this manner, a total
of 10.07 g (82.1% of theory) of the title compound were
obtained.
[0651] LC-MS (Method 7): R.sub.t=2.95 min; m/z=490 (M+H).sup.+.
[0652] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.00-1.10 (m, 6H), 2.58-2.72 (m, 2H), 2.72-2.83 (m, 1H),
3.34-3.44 (m, 1H), 3.96 (q, 2H), 4.12 (d, 1H), 6.99 (dd, 1H),
7.27-7.38 (m, 2H), 7.42-7.51 (m, 4H), 9.82 (s, 1H).
[0653] [.alpha.].sub.D.sup.20=+94.degree., c=0.58, chloroform.
Example 125A
Ethyl(+)-(2S)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-
-methylbutanoyl]amino}benzyl)butanoate
##STR00179##
[0655] 13 ml of dichloromethane and one drop of DMF were added to
3.3 g (12.38 mmol) of
(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (as
an about 9:1 diastereomer mixture). 1.94 ml (22.28 mmol) of oxalyl
chloride were added dropwise to the solution, which had been cooled
to -10.degree. C., such that the temperature did not exceed
-5.degree. C. The reaction mixture was then stirred at from
-5.degree. C. to 0.degree. C. for 1 h and subsequently concentrated
under reduced pressure. The residue was taken up in
dichloromethane, and the solution was once more concentrated under
reduced pressure. This procedure was repeated once more, and the
acid chloride obtained was then briefly dried under high vacuum and
directly, without further purification, reacted further.
[0656] 1.2 ml (6.68 mmol) of N,N-diisopropylethylamine were added
to a solution of 1.22 g (4.77 mmol) of
(+)-ethyl(2S)-2-(3-amino-4-chlorobenzyl)butanoate in 4.8 ml of abs.
THF. The resulting solution was cooled to -10.degree. C., and a
solution of the acid chloride prepared above (1.5 g, 5.25 mmol) in
2 ml of abs. THF was added dropwise, the temperature being kept
below 0.degree. C. The reaction mixture was then stirred at from
-10.degree. C. to 0.degree. C. for 1 h and ethyl acetate and three
drops of water were then added. After 10 min, the mixture, which
had been diluted further with ethyl acetate, was washed
successively with 1 N hydrochloric acid, saturated sodium
bicarbonate solution and saturated sodium chloride solution, dried
over magnesium sulphate and concentrated under reduced pressure.
The desired product was isolated by chromatography of the residue
on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This
gave 2.13 g (88.5% of theory) of the title compound.
[0657] LC-MS (Method 6): R.sub.t=1.46 min; m/z=504 (M+H).sup.+.
[0658] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.76-0.88
(m, 6H), 1.02 (t, 3H), 1.45-1.56 (m, 2H), 2.47 (d, 1H), 2.72 (d,
2H), 3.34-3.43 (m, 1H), 3.93 (qd, 2H), 4.12 (d, 1H), 6.98 (dd, 1H),
7.29-7.38 (m, 2H), 7.40-7.52 (m, 4H), 9.81 (s, 1H).
[0659] [.alpha.].sub.D.sup.20=+62.6.degree., c=0.515,
chloroform.
[0660] The following compound was prepared according to an
analogous procedure:
Example 126A
Ethyl(+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-
-methylbutanoyl]amino}benzyl)butanoate
##STR00180##
[0662] LC-MS (Method 6): R.sub.t=1.46 min; m/z=504/506
(M+H).sup.+.
[0663] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 0.84 (t, 3H), 1.04 (t, 3H), 1.46-1.56 (m, 2H), 2.45-2.49 (m,
1H), 2.70-2.74 (m, 2H), 3.34-3.42 (m, 1H), 3.95 (q, 2H), 4.12 (d,
1H), 6.98 (dd, 1H), 7.30-7.37 (m, 2H), 7.42-7.50 (m, 4H), 9.81 (s,
1H).
[0664] [.alpha.].sub.D.sup.20=+52.3.degree., c=0.485,
chloroform.
Example 127A
Ethyl
2-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoor-3-methylbutanoyl]a-
mino}-4-fluorophenyl)-trans-cyclopropanecarboxylate
##STR00181##
[0666] 167 mg (0.44 mmol) of HATU were added to a solution of 90 mg
(0.34 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in
1.5 ml of a 4:1 mixture of DMF and pyridine. After 30 min of
stirring at RT, 83 mg (0.37 mmol) of rac-ethyl
2-[3-amino-4-fluoro-phenyl]-trans-cyclopropanecarboxylate were
added. The reaction mixture was stirred at RT overnight, then
diluted with ethyl acetate (about 50 ml) and washed with saturated
sodium chloride solution. The organic phase was dried over
magnesium sulphate and concentrated and the residue was purified by
preparative HPLC. This gave 123 mg (77% of theory) of the title
compound.
[0667] LC-MS (Method 6): R.sub.t=1.35 min; m/z=472 (M+H).sup.+.
[0668] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.19 (t, 3H), 1.25-1.34 (m, 1H), 1.42 (dt, 1H), 1.73-1.91 (m,
1H), 2.31-2.45 (m, 1H), 3.96-4.20 (m, 3H), 6.83-7.00 (m, 1H), 7.13
(dd, 1H), 7.45 (s, 4H), 7.57-7.68 (m, 1H), 10.06 (s, 1H).
Example 128A
Ethyl
threo-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbuta-
noyl]amino}-4-fluoro-phenyl)-2-methylbutanoate
##STR00182##
[0670] 15 .mu.l (0.19 mmol) of pyridine and 75.8 mg (0.2 mmol) of
HATU were added to a solution of 35.5 mg (0.13 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in
0.98 ml of DMF. The reaction mixture was stirred at RT for 30 min,
and 35 mg (0.15 mmol) of rac-threo-ethyl
3-(3-amino-4-fluorophenyl)-2-methylbutanoate were then added. The
reaction mixture was stirred overnight and then purified directly
by preparative HPLC. This gave 34 mg (52% of theory) of the title
compound.
[0671] LC-MS (Method 5): R.sub.t=2.89 min; m/z=488 (M+H).sup.+.
Example 129A
Ethyl
elythro-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}-4-fluorophenyl)-2-methylbutanoate
##STR00183##
[0673] 9.5 .mu.l (117 .mu.mol) of pyridine and 47.7 mg (125
.mu.mol) of HATU were added to a solution of 22.3 mg (84 .mu.mol)
of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
in 0.62 ml of DMF. The reaction mixture was stirred at RT for 30
min, and 22 mg (92 .mu.mol) of rac-erythro-ethyl
3-(3-amino-4-fluorophenyl)-2-methylbutanoate were then added. The
reaction mixture was stirred overnight and then purified directly
by preparative HPLC. This gave 10.7 mg (24% of theory) of the title
compound.
[0674] LC-MS (Method 4): R.sub.t=1.57 min; m/z=488 (M+H).sup.+.
Example 130A
tert-butyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutan-
oyl]amino}-4-cyano-phenyl)propanoate
##STR00184##
[0676] At 0.degree. C., 155 .mu.l (0.31 mmol) of a 2 M solution of
oxalyl chloride in dichloromethane and one drop of DMF were added
to a solution of 41.3 mg (0.16 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in
1.16 ml of dichloromethane. After 1 h of stirring at 0.degree. C.,
the mixture was concentrated, the residue that remained was
dissolved in 1 ml of THF, 32 .mu.l (0.19 mmol) of
N,N-diisopropylethylamine were added, the mixture was cooled to
0.degree. C. and a solution of 42 mg (0.17 mmol) of tert-butyl
3-(3-amino-4-cyanophenyl)propanoate in 2 ml of THF was added. The
reaction mixture was stirred at RT overnight. The mixture was then
poured into 10 ml of water and extracted with ethyl acetate. The
combined organic phases were dried over magnesium sulphate and
concentrated. The residue was purified by preparative HPLC. This
gave 16.5 mg (22% of theory) of the title compound.
[0677] LC-MS (Method 7): R.sub.t=2.86 min; m/z=439
(M-Bu).sup.+.
[0678] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.81 (d,
3H), 1.27-1.35 (m, 9H), 2.83 (t, 2H), 4.01 (d, 1H), 7.21 (dd, 1H),
7.30 (s, 1H), 7.40-7.52 (m, 4H), 7.69 (d, 1H), 10.47 (s, 1H).
Example 131A
Methyl(2E)-3-(2-methyl-3-nitrophenyl)acrylate
##STR00185##
[0680] Under argon, 119.5 g (1.39 mol) of methyl acrylate were
added dropwise to a mixture of 100 g (0.463 mol) of
2-bromo-6-nitrotoluene, 323 ml (2.31 mol) of triethylamine, 28.2 g
(92.6 mmol) of tri-2-tolylphosphine and 10.4 g (46.3 mmol) of
palladium(II) acetate in 2.0 litres of DMF, and the mixture was
then stirred at 125.degree. C. for 36 h. After cooling to room
temperature, the reaction mixture was stirred with 4 litres of
saturated aqueous ammonium chloride solution and extracted three
times with a total of 5 litres of diethyl ether. The combined
organic phases were washed with water and saturated sodium chloride
solution and dried over sodium sulphate. After filtration, the
solvent was removed to dryness under reduced pressure. The residue
obtained was purified by flash chromatography on silica gel (mobile
phase petroleum ether/ethyl acetate 6:1). The product was
triturated with heptane, and the solid obtained was filtered off
with suction and dried under high vacuum. This gave 48.7 g of the
title compound (46.6% of theory).
[0681] MS: m/z=162 (M-C.sub.2H.sub.3O.sub.2).sup.+.
[0682] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.41 (s,
3H), 3.76 (s, 3H), 6.63 (d, 1H), 7.48 (t, 1H), 7.84-7.95 (m, 2H),
8.00 (d, 1H).
Example 132A
Methyl 3-(3-amino-2-methylphenyl)propanoate
##STR00186##
[0684] 48.7 g (220.1 mmol) of
methyl(2E)-3-(2-methyl-3-nitrophenyl)acrylate were dissolved in 2.2
litres of methanol, and the solution was hydrogenated in a
continuous-flow hydrogenation reactor ("H-Cube midi" from Thales
Nano, Budapest) at a flow rate of 6-10 ml/min and at a reaction
temperature of 35-40.degree. C. and at maximum hydrogen pressure.
After the reaction had ended, the product-containing solution was
concentrated under reduced pressure. This gave 40.0 g of the target
product as a solid (92.1% of theory).
[0685] MS: m/z=194 (M+H).sup.+.
[0686] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.97 (s,
3H), 2.45 (t, 2H), 2.78 (t, 2H), 3.58 (s, 3H), 4.75 (s, 2H), 6.37
(d, 1H), 6.50 (d, 1H), 6.79 (t, 1H).
Example 133A
Methyl 3-(3-amino-4-chloro-2-methylphenyl)propanoate
##STR00187##
[0688] At RT, 1.38 g (10.3 mmol) of N-chlorosuccinimide were added
to a solution of 2.0 g (10.3 mmol) of methyl
3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile. The
reaction mixture was stirred for 30 min and then diluted with ethyl
acetate. The mixture was washed successively with sat. sodium
bicarbonate solution and sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product gave, after chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 10:1), 279 mg of the target product
(11.8% of theory).
[0689] LC-MS (Method 4): R.sub.t=1.11 min; m/z=228 (M+H).sup.+.
[0690] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. [ppm]=2.06 (s,
3H), 2.46 (t, 2H), 2.78 (t, 2H), 3.58 (s, 3H), 4.94 (s, 2H), 6.42
(d, 1H), 6.98 (d, 1H).
Example 134A
3-bromo-6-chloro-2-methylaniline
##STR00188##
[0692] At RT, 8.61 g (64.5 mmol) of N-chlorosuccinimide were added
to a solution of 12.0 g (64.5 mmol) of 3-bromo-2-methylaniline in
150 ml of acetonitrile. The reaction mixture was stirred at
60.degree. C. for 7 h and, after cooling, concentrated under
reduced pressure. The residue was taken up in dichloromethane, and
the mixture was washed successively with sat. sodium bicarbonate
solution and sat. sodium chloride solution, dried over sodium
sulphate and concentrated under reduced pressure. The crude product
gave, after chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 40:1 to 20:1), 3.78 g of the target
product (26.6% of theory).
[0693] GC-MS (Method 1): R.sub.t=5.07 min; m/z=218/220
(M+H).sup.+.
[0694] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.24 (s,
3H), 5.39 (s, 2H), 6.80 (d, 1H), 7.03 (d, 1H).
Example 135A
tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylacrylate
and tert-butyl 2-(3-amino-4-chloro-2-methylbenzyl)acrylate
##STR00189##
[0696] 1.50 g (6.80 mmol) of 3-bromo-6-chloro-2-methylaniline, 2.90
g (20.4 mmol) of tert-butyl methacrylate and 4.74 ml (34.0 mmol) of
triethylamine were dissolved in 10.0 ml of DMF. Three times, the
reaction solution was evacuated and in each case vented again with
argon. After addition of 152.7 mg (0.68 mmol) of palladium(H)
acetate and 414.1 mg (1.36 mmol) of tri-2-tolylphosphine, the
mixture was once more evacuated twice and in each case vented with
argon. The reaction mixture was then stirred at 150.degree. C. for
2 h. After cooling, the mixture was filtered through celite and the
residue was washed with DMF. The filtrate was concentrated under
reduced pressure and the residue was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This
gave 1.59 g of a mixture of the two title compounds (ratio about
2:1, 83% of theory).
[0697] LC-MS (Method 4): R.sub.t=1.45 min; m/z=226
(M-C.sub.4H.sub.8).sup.+and R.sub.t=1.49 min; m/z=282
(M+H).sup.+.
[0698] .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methyl-acrylate:
.delta. [ppm]=1.49 (s, 9H), 1.75 (d, 3H), 2.02 (s, 3H), 5.12 (s,
2H), 6.44 (d, 1H), 7.11 (d, 1H), 7.51 (s, 1H).
[0699] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): tert-butyl
2-(3-amino-4-chloro-2-methylbenzyl)acrylate: .delta. [ppm]=1.42 (s,
9H), 1.98 (s, 3H), 3.45 (s, 2H), 4.97 (s, 2H), 5.15 (d, 1H), 6.01
(d, 1H), 6.38 (d, 1H), 7.02 (d, 1H).
Example 136A
(+/-)-tert-butyl
3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate
##STR00190##
[0701] A solution of 1.58 g (5.61 mmol) of a mixture of
tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylacrylate
and tert-butyl 2-(3-amino-4-chloro-2-methylbenzyl)acrylate (Example
135A) in 5.0 ml of methanol was added to 354 mg (14.6 mmol) of
magnesium turnings and a few grains of iodine. The mixture was
stirred at RT (initially with cooling) overnight. 50 ml of 1 N
hydrochloric acid were then added with ice-cooling. By addition of
10% strength aqueous sodium hydroxide solution, the pH of the
mixture was then adjusted to about 10. The mixture was extracted
three times with ethyl acetate. The combined organic phases were
dried over magnesium sulphate and concentrated under reduced
pressure. The crude product gave, after chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 50:1 to 40:1), 962 mg
of the target product (60.5% of theory).
[0702] LC-MS (Method 9): R.sub.t=2.30 min; m/z=284 (M+H).sup.+.
[0703] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.02 (d,
3H), 1.32 (s, 9H), 2.06 (s, 3H), 2.46 (dd, 1H), 2.80 (dd, 1H), 4.94
(br. s, 2H), 6.38 (d, 1H), 6.97 (d, 1H).
[0704] The racemate obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 20 ml/min;
detection: 220 nm; injection volume: 0.28 ml; temperature:
22.degree. C.; mobile phase: 93% isohexane/7% isopropanol]. 962 mg
of racemate gave 434 mg of enantiomer 1 (Example 137A) and 325 mg
of enantiomer 2 (Example 138A):
Example 137A
(-)-tert-butyl(2R)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate
##STR00191##
[0706] Yield: 434 mg
[0707] LC-MS (Method 4): R.sub.t=1.44 min; m/z=284 (M+H).sup.+.
[0708] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.03 (d,
3H), 1.32 (s, 9H), 2.06 (s, 3H), 2.46 (dd, 1H), 2.80 (dd, 1H), 4.93
(s, 2H), 6.38 (d, 1H), 6.97 (d, 1H).
[0709] [.alpha.].sub.D.sup.20=-37.3.degree., c=0.455,
chloroform.
Example 138A
(+)-tert-butyl(2S)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate
##STR00192##
[0711] Yield: 325 mg
[0712] LC-MS (Method 4): R.sub.t=1.44 min; m/z=284 (M+H).sup.+.
[0713] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.03 (d,
3H), 1.32 (s, 9H), 2.06 (s, 3H), 2.46 (dd, 1H), 2.80 (dd, 1H), 4.93
(s, 2H), 6.38 (d, 1H), 6.97 (d, 1H).
[0714] [.alpha.].sub.D.sup.20=+35.0.degree., c=0.455,
chloroform.
Example 139A
Ethyl 4,4,4-trifluoro-3-(4-fluoro-3-nitrophenyl)but-2-enoate
##STR00193##
[0716] 10.9 g (48.5 mmol) of ethyl diethylphosphonoacetate were
slowly added dropwise to an ice-cooled suspension of 1.86 g (60% in
mineral oil, 46.4 mmol) of sodium hydride in a mixture of 70 ml of
THF and 20 ml of DMF. After the addition had ended, the mixture was
stirred at 0.degree. C. for another 30 min, and 10.0 g (42.2 mmol)
of 2,2,2-trifluoro-1-(4-fluoro-3-nitrophenyl)ethanone were then
added. The reaction mixture was stirred at RT overnight and then
added to water. The mixture was extracted three times with ethyl
acetate, and the combined organic phases were concentrated under
reduced pressure. The crude product gave, after chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 20:1 to 10:1),
9.23 g of the target product (71.2% of theory).
[0717] GC-MS (Method 1): R.sub.t=4.51 min; m/z=262
(M-C.sub.2H.sub.SO).sup.+.
[0718] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.04 (t,
3H), 4.03 (q, 2H), 6.96 (d, 1H), 7.67-7.76 (m, 1H), 7.78-7.86 (m,
1H), 8.16 (dd, 1H).
Example 140A
(+/-)-Ethyl 3-(3-amino-4-fluorophenyl)-4,4,4-trifluorobutanoate
##STR00194##
[0720] 5.0 g (16.3 mmol) of ethyl
4,4,4-trifluoro-3-(4-fluoro-3-nitrophenyl)but-2-enoate were
dissolved in 133 ml of ethanol, and 866 mg of palladium on carbon
(10%) were added under argon. At RT, the reaction mixture was
stirred vigorously under an atmosphere of hydrogen (atmospheric
pressure) overnight. The mixture was then filtered off through
celite and the residue was washed with ethyl acetate. The filtrate
was concentrated under reduced pressure and the residue obtained
was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1). This gave 3.91 g of the target
product (85.9% of theory).
[0721] LC-MS (Method 6): R.sub.t=0.97 min; m/z=280 (M+H).sup.+.
[0722] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.08 (t,
3H), 2.85 (dd, 1H), 2.99 (dd, 1H), 3.81-3.92 (m, 1H), 3.94-4.07 (m,
2H), 5.21 (s, 2H), 6.40-6.58 (m, 1H), 6.77 (dd, 1H), 6.96 (dd,
1H).
Example 141A
tert-butyl 2-methylbutanoate
##STR00195##
[0724] 15.0 g (124.4 mmol) of 2-methylbutyryl chloride were
dissolved in 150 ml of abs. THF and cooled to 0.degree. C., and 114
ml (114 mmol) of a 1 M solution of potassium tert-butylate in THF
were added dropwise. After the addition had ended, the mixture was
stirred at 0.degree. C. for 1 h and then at RT for h, and about
half of the solvent was then removed under reduced pressure. After
addition of diethyl ether, sat. sodium bicarbonate solution was
added dropwise with vigorous stirring. After phase separation, the
aqueous phase was extracted with diethyl ether, and the combined
organic phases were washed with sat. sodium carbonate solution,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by vacuum distillation (19 nun Hg,
40-45.degree. C.). This gave a total of 6.35 g of the target
product (32.3% of theory).
[0725] GC-MS (Method 1): R.sub.t=1.53 min; m/z=85.
[0726] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.84 (m,
3H), 1.01 (d, 3H), 1.33-1.41 (m, 1H), 1.39 (s, 9H), 1.48-1.55 (m,
1H), 2.13-2.26 (m, 1H).
Example 142A
2-bromo-4-(bromomethyl)-1-chlorobenzene
##STR00196##
[0727] Step 1:
[0728] 199.0 g (0.845 mol) of 3-bromo-4-chlorobenzoic acid were
dissolved in 2.5 litres of THF, the mixture was cooled to
-10.degree. C. and 1.69 litres (1.69 mol) of a 1 M solution of
borane in THF were added at this temperature. The reaction mixture
was warmed to RT overnight, and saturated aqueous ammonium chloride
solution was then added. After the addition of water, the mixture
was extracted twice with ethyl acetate and the combined organic
phases were dried over magnesium sulphate and concentrated under
reduced pressure. This gave, as a crude product, 206 g of
(3-bromo-4-chlorophenyl)methanol which were used in the subsequent
step without further purification.
Step 2:
[0729] 260 g (about 1.05 mol) of crude
(3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 litres of
dichloromethane, the mixture was cooled to -5.degree. C. and 127.1
g (44.6 ml, 460 mmol) of phosphorous tribromide were added slowly.
After the addition had ended, stirring at -5.degree. C. was
continued for 1 h, and the mixture was then diluted with
dichloromethane and water. The organic phase was separated off,
dried over magnesium sulphate and concentrated under reduced
pressure. This gave, as a crude product, 280.5 g (about 84% of
theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene.
[0730] GC-MS (Method 1): R.sub.t=5.36 min; m/z=281/283/285
(M+H).sup.+.
[0731] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.71 (s,
2H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.89 (d, 1H).
Example 143A
(+/-)-tert-butyl 2-(3-bromo-4-chlorobenzyl)-2-methylbutanoate
##STR00197##
[0733] Under argon, 5.8 ml (41.6 mmol) of diisopropylamine were
dissolved in 50 ml of dry THF, and the mixture was cooled to
-30.degree. C. 16.6 ml (41.6 mmol) of n-butyllithium solution (2.5
M in hexane) were added dropwise, and the resulting mixture was
warmed to 0.degree. C. and then cooled to -70.degree. C. A solution
of 5.06 g (32.0 mmol) of tert-butyl 2-methylbutanoate in 20 ml of
THF was added, the reaction temperature being kept below
-60.degree. C. After 4 h of stirring at -60.degree. C., a solution
of 10.0 g (35.2 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in
30 ml of THF was added, and the temperature was once more kept
below -60.degree. C. The reaction mixture was then slowly warmed
to
[0734] RT overnight, and saturated aqueous ammonium chloride
solution and ethyl acetate were then added. After phase separation,
the aqueous phase was extracted twice with ethyl acetate. The
combined organic phases were dried over magnesium sulphate and
concentrated under reduced pressure. The crude product was purified
by chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 100:1). This gave 7.62 g (65.9% of theory) of the title
compound.
[0735] GC-MS (Method 1): R.sub.t=6.52 min; m/z=306
(M-C.sub.4H.sub.7).sup.+.
[0736] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.83 (t,
3H), 0.93 (s, 3H), 1.32-1.45 (m, 10H), 1.60-1.73 (m, 1H), 2.62 (d,
1H), 2.91 (d, 1H), 7.18 (dd, 1H), 7.47-7.56 (m, 2H).
Example 144A
(+/-)-tert-butyl
2-[3-(benzylamino)-4-chlorobenzyl]-2-methylbutanoate
##STR00198##
[0738] Under argon, 1.59 g (16.6 mmol) of sodium tert-butoxide were
weighed out into a dry flask, and 34.6 ml of abs. toluene were
added. 5.0 g (13.8 mmol) of
(+/-)-tert-butyl-2-(3-bromo-4-chlorobenzyl)-2-methylbutanoate, 1.8
ml (16.6 mmol) of benzylamine, 633 mg (0.69 mmol) of
tris(dibenzylidenacetone)dipalladium and 344 mg (0.55 mmol) of
(+/-)-2,2'-bis(diphenylphos-phino)-1,1'-binaphthyl were added in
succession. The reaction mixture was then stirred at 110.degree. C.
for 2.0 h. After cooling, saturated aqueous ammonium chloride
solution and ethyl acetate were added and the reaction mixture was
filtered off with suction through kieselguhr. After phase
separation, the organic phase was washed with sat ammonium chloride
solution and sat. sodium chloride solution, dried over magnesium
sulphate and concentrated under reduced pressure. The crude product
was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 80:1). This gave 4.44 g of the title
compound in still slightly contaminated form (about 83% of
theory).
[0739] LC-MS (Method 6): R.sub.t=1.57 min; m/z=388 (M+H).sup.+.
[0740] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.70 (t,
3H), 1.13-1.22 (m, 1H), 1.35 (s, 9H), 1.39 (s, 3H), 1.39-1.50 (m,
1H), 2.42 (d, 1H), 2.66 (d, 1H), 4.26-4.46 (m, 2H), 6.00 (t, 1H),
6.26-6.35 (m, 1H), 7.11 (d, 1H), 7.16-7.23 (m, 1H), 7.28-7.34 (m,
4H), 7.45-7.55 (m, 1H).
Example 145A
(+/-)-tert-butyl 2-(3-amino-4-chlorobenzyl)-2-methylbutanoate
##STR00199##
[0742] 2.20 g (about 5.67 mmol) of (+/-)-tert-butyl
2-[3-(benzylamino)-4-chlorobenzyl]-2-methylbutanoate were dissolved
in 130 ml of ethyl acetate, and 100 mg of palladium on carbon (10%)
were added. At RT, the reaction mixture was stirred under an
atmosphere of hydrogen at atmospheric pressure overnight. The
reaction mixture was then filtered off with suction through
kieselguhr, the residue was washed thoroughly with ethyl acetate
and the combined filtrate was concentrated. The crude product was
purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1 to 30:1). This gave 924 mg (54.7% of
theory) of the target compound.
[0743] LC-MS (Method 6): R.sub.t=1.34 min; m/z=298 (M+H).sup.+.
[0744] The racemate obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 20 ml/min;
detection: 220 nm; injection volume: 0.30 ml; temperature:
35.degree. C.; mobile phase: 70% isohexane/30% ethanol]. 924 mg of
racemate gave 405 mg of enantiomer 1 (Example 146A) and 403 mg of
enantiomer 2 (Example 147A):
Example 146A
(-)-tert-butyl 2-(3-amino-4-chlorobenzyl)-2-methylbutanoate
(Enantiomer 1)
##STR00200##
[0746] Yield: 405 mg
[0747] LC-MS (Method 6): R.sub.t=1.32 min; m/z=298 (M+H).sup.+.
[0748] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.81 (t,
3H), 0.93 (s, 3H), 1.28-1.37 (m, 1H), 1.38 (s, 9H), 1.59-1.71 (m,
1H), 2.45 (d, 1H), 2.74 (d, 1H), 5.14-5.22 (m, 2H), 6.31 (dd, 1H),
6.57 (d, 1H), 7.04 (d, 1H).
[0749] [.alpha.].sub.D.sup.20=-11.8.degree., c=0.50,
chloroform.
Example 147A
(+)-tert-butyl-2-(3-amino-4-chlorobenzyl)-2-methylbutanoate
(Enantiomer 2)
##STR00201##
[0751] Yield: 403 mg
[0752] LC-MS (Method 6): R.sub.t=1.32 min; m/z=298 (M+H).sup.+.
[0753] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.75-0.85
(m, 3H), 0.93 (s, 3H), 1.30-1.37 (m, 1H), 1.39 (s, 9H), 1.58-1.70
(m, 1H), 2.45 (d, 1H), 2.74 (d, 1H), 5.09-5.23 (m, 2H), 6.31 (dd,
1H), 6.57 (d, 1H), 7.04 (d, 1H).
[0754] [.alpha.].sub.D.sup.20=+12.0.degree., c=0.420,
chloroform.
Example 148A
2,2,2-trifluoro-1-(3-nitrophenyl)ethanone
##STR00202##
[0756] 20.0 g (114.9 mmol) of 2,2,2-trifluoroacetophenone were
initially charged in 80 ml of conc. sulphuric acid, and the mixture
was cooled to -10.degree. C. A solution, prepared beforehand at
-10.degree. C., of 4.8 ml (114.8 mmol) of nitric acid in 20 ml of
conc. sulphuric acid was added dropwise to this mixture such that
the reaction temperature did not exceed -5.degree. C. After the
addition had ended, the reaction mixture was stirred between
-10.degree. C. and 0.degree. C. for 1 h and then added carefully to
ice-water. By addition of 50% strength aqueous sodium hydroxide
solution, the pH of the mixture was adjusted to about 9-10. The
mixture was extracted three times with ethyl acetate, and the
combined organic phases were dried over magnesium sulphate and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (mobile phase initially
cyclohexane/dichloromethane 2:1 to 1:1, finally pure
dichloromethane) This gave 19.2 g of the target product (76.2% of
theory).
[0757] LC-MS (Method 6): R.sub.t=0.81 min; m/z=236.
[0758] GC-MS (Method 1): R.sub.t=3.19 min; m/z=150
(M-CF.sub.3).sup.+.
Example 149A
tert-butyl(2E/Z)-4,4,4-trifluoro-3-(3-nitrophenyl)but-2-enoate
##STR00203##
[0760] 25.9 ml (110.4 mmol) of
tert-butyl(diethoxyphosphoryl)acetate were added dropwise to a
suspension, cooled to 0.degree. C., of 4.41 g (60% in mineral oil,
110.4 mmol) of sodium hydride in a mixture of 37.2 ml of THF and
37.2 ml of DMF. After 30 min, 18.6 g (84.9 mmol) of
2,2,2-trifluoro-1-(3-nitrophenyl)ethanone were added, the cooling
bath was removed and the reaction mixture was stirred at RT for 2
h. The reaction mixture was then added to water and, after
saturation with sodium chloride, extracted three times with ethyl
acetate. The combined organic phases were dried over magnesium
sulphate and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 100:1 to 20:1). This gave 18.0 g of the
target product as an E/Z isomer mixture (66.8% of theory).
[0761] LC-MS (Method 6): R.sub.t=1.25 min; no ionization.
[0762] MS (DCI): m/z=335 (M+H.sub.2O).sup.+.
[0763] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.17/1.50
(2s, together 9H), 6.93/7.14 (2d, together 1H), 7.74-7.94 (m, 2H),
8.16/8.23 (2s, together 1H), 8.30-8.42 (m, 1H).
Example 150A
(+/-)-tert-butyl 3-(3-aminophenyl)-4,4,4-trifluorobutanoate
##STR00204##
[0765] 18.0 g (56.7 mmol) of
tert-butyl(2E/Z)-4,4,4-trifluoro-3-(3-nitrophenyl)but-2-enoate were
dissolved in 100 ml of ethanol and deoxygenated with argon. After
addition of 1.21 g of palladium on carbon (10%), the mixture was
stirred vigorously at RT under an atmosphere of hydrogen at
atmospheric pressure overnight. The reaction mixture was then
filtered through celite, the residue was washed thoroughly with
ethanol, the filtrate was concentrated under reduced pressure and
the product obtained was dried under high vacuum overnight. This
gave 13.7 g of the target product (83.7% of theory).
[0766] LC-MS (Method 6): R.sub.t=1.02 min; m/z=290 (M+H).sup.+.
[0767] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.27 (s,
9H), 2.70 (dd, 1H), 2.89 (dd, 1H), 3.62-3.79 (m, 1H), 5.11-5.17 (m,
2H), 6.43-6.56 (m, 3H), 6.99 (t, 1H).
Example 151A
(+/-)-tert-butyl
3-(3-amino-4-chlorophenyl)-4,4,4-trifluorobutanoate
##STR00205##
[0769] 13.6 g (47.0 mmol) of
(+/-)-tert-butyl-3-(3-aminophenyl)-4,4,4-trifluorobutanoate were
initially charged in 100 ml of acetonitrile, and 6.28 g (47.0 mmol)
of N-chlorosuccinimide were added at RT. The reaction mixture was
initially stirred at 60.degree. C. for 12 h and then allowed to
stand at RT for 3 days. After concentration under reduced pressure,
the residue was separated by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 100:1), and the desired target
product was isolated. This gave 4.49 g of the title compound (29.5%
of theory).
[0770] LC-MS (Method 6): R.sub.t=1.17 min; m/z=324 (M+H).sup.+.
[0771] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.27 (s,
9H), 2.72 (dd, 1H), 2.91 (dd, 1H), 3.74-3.86 (m, 1H), 5.43 (s, 2H),
6.55 (dd, 1H), 6.79 (d, 1H), 7.17 (d, 1H).
[0772] The racemate obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak OJ-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 15 ml/min;
detection: 220 nm; injection volume: 0.20 ml; temperature:
35.degree. C.; mobile phase: 70% isohexane/30% isopropanol]. 4.49 g
of racemate gave 2.02 g of enantiomer 1 (Example 152A) and 2.04 g
of enantiomer 2 (Example 153A):
Example 152A
(-)-tert-butyl(3R)-3-(3-amino-4-chlorophenyl)-4,4,4-trifluorobutanoate
##STR00206##
[0774] Yield: 2.02 g
[0775] LC-MS (Method 6): R.sub.t=1.17 min; m/z=324 (M+H).sup.+.
[0776] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.27 (s,
9H), 2.72 (dd, 1H), 2.91 (dd, 1H), 3.75-3.85 (m, 1H), 5.40-5.46 (m,
2H), 6.55 (dd, 1H), 6.79 (d, 1H), 7.17 (d, 1H).
[0777] [.alpha.].sub.D.sup.20=-69.4.degree., c=0.520,
chloroform.
Example 153A
(+)-tert-butyl(3S)-3-(3-amino-4-chlorophenyl)-4,4,4-trifluorobutanoate
##STR00207##
[0779] Yield: 2.04 g
[0780] LC-MS (Method 6): R.sub.t=1.17 min; m/z=324 (M+H).sup.+.
[0781] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.27 (s,
9H), 2.71 (dd, 1H), 2.91 (dd, 1H), 3.74-3.86 (m, 1H), 5.38-5.46 (m,
2H), 6.55 (dd, 1H), 6.73-6.80 (m, 1H), 7.17 (d, 1H).
[0782] [.alpha.].sub.D.sup.20=+66.3.degree., c=0.495,
chloroform.
Example 154A
tert-butyl Cyclobutylacetate
##STR00208##
[0784] 4.0 g (35.0 mmol) of cyclobutylacetic acid were dissolved in
20 ml of dichloromethane, a drop of DMF was added and 4.0 ml (45.6
mmol) of oxalyl chloride were added dropwise after cooling to
0.degree. C. The reaction mixture was stirred between 0.degree. C.
and 10.degree. C. for 2 h and then concentrated in the cold under
reduced pressure. The residue was taken up in abs. dichloromethane
and once more concentrated in the cold under reduced pressure. This
procedure was repeated once more, and the acid chloride obtained
was then briefly dried under high vacuum for 5 min The residue was
then taken up in 20 ml of abs. THF and cooled to 0.degree. C., and
28 ml (28 mmol) of a 1 M solution of potassium tert-butoxide in THF
were added dropwise. After the addition had ended, cooling was
removed and the mixture was stirred at RT for 1 h and then added to
water. The mixture was extracted three times with dichloromethane,
and the combined organic phases were dried over magnesium sulphate
and concentrated under reduced pressure. This gave 3.88 g of the
crude target product (about 65% of theory).
[0785] GC-MS (Method 1): R.sub.t=2.29 min; m/z=97
(M-C.sub.3H.sub.5O.sub.2).sup.+.
[0786] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.38 (s,
9H), 1.60-1.89 (m, 5H), 1.95-2.11 (m, 2H), 2.28 (d, 2H).
Example 155A
tert-butyl Cyclopropylacetate
##STR00209##
[0788] 10.0 g (99.9 mmol) of cyclopropylacetic acid were dissolved
in 50 ml of dichloromethane, a drop of DMF was added and 9.6 ml
(109.9 mmol) of oxalyl chloride were added dropwise after cooling
to 0.degree. C. The reaction mixture was stirred between 0.degree.
C. and 10.degree. C. for 2 h and then concentrated in the cold
under reduced pressure. The residue was briefly (about 5 min) dried
under high vacuum and then taken up in 20 ml of abs. THF and cooled
to 0.degree. C., and 89.9 ml (89.9 mmol) of a 1 M solution of
potassium tert-butoxide in THF were added dropwise. After the
addition had ended, cooling was removed and the mixture was stirred
at RT for 2 h, before most of the THF was removed under reduced
pressure (up to 150 mm Hg, water bath about 30.degree. C.). Diethyl
ether and 0.5 N aqueous sodium hydroxide solution were added to the
residue. After phase separation, the organic phase was dried over
magnesium sulphate and concentrated under reduced pressure and the
residue was briefly dried under high vacuum. This gave 8.38 g of
the crude target product (about 53% of theory).
[0789] GC-MS (Method 1): R.sub.t=1.80 min; m/z=100
(M-C.sub.4H.sub.8).sup.+.
[0790] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.05-0.14
(m, 2H), 0.38-0.51 (m, 2H), 0.81-0.99 (m, 1H), 1.40 (s, 9H), 2.10
(d, 2H).
Example 156A
(+/-)-tert-butyl
3-(3-bromo-4-chlorophenyl)-2-cyclobutylpropanoate
##STR00210##
[0792] Under argon, 2.9 ml (20.8 mmol) of diisopropylamine were
dissolved in 30 ml of dry THF, and the mixture was cooled to
-20.degree. C. 8.3 ml (20.8 mmol) of n-butyllithium solution (2.5 M
in hexane) were added dropwise, and the resulting mixture was
stirred to -20.degree. C. for 30 min and then cooled to -78.degree.
C. At this temperature, a solution of 2.60 g (about 15.3 mmol,
crude) of tert-butyl cyclobutylacetate in 10 ml of THF was added.
After 4 h of stirring at -78.degree. C., a solution of 3.95 g (13.9
mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 10 ml of THF
was added. The reaction mixture was slowly warmed to RT overnight,
and saturated aqueous ammonium chloride solution was then added.
The mixture was extracted three times with ethyl acetate. The
combined organic phases were dried over magnesium sulphate and
concentrated under reduced pressure. The solid that remained was
triturated with 30 ml of cyclohexane/dichloromethane (1:1) and
filtered off. The solid was once more triturated with 10 ml of
cyclohexane/dichloromethane (1:1) and again filtered off; this
procedure was repeated once more. All filtrates were collected,
combined and concentrated under reduced pressure. This residue was
then purified further by chromatography on silica gel (mobile phase
from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1).
This gave 2.24 g of the title compound (43.2% of theory).
[0793] GC-MS (Method 1): R.sub.t=6.92 min; m/z=318
(M-C.sub.4H.sub.7).sup.+.
[0794] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.27 (s,
9H), 1.71-1.84 (m, 4H), 1.90-1.94 (m, 1H), 1.96-2.04 (m, 1H),
2.33-2.44 (m, 1H), 2.53-2.60 (m, 1H), 2.61-2.71 (m, 1H), 7.22 (dd,
1H), 7.52 (d, 1H), 7.57 (d, 1H).
[0795] The example below was obtained in an analogous manner
Example 157A
tert-butyl 3-(3-bromo-4-chlorophenyl)-2-cyclopropylpropanoate
##STR00211##
[0797] From tert-butyl cyclopropylacetate and
2-bromo-4-(bromomethyl)-1-chlorobenzene, 3.13 g of the title
compound were obtained (45% of theory).
[0798] GC-MS (Method 1): R.sub.t=6.41 min; m/z=301/304
(M-C.sub.4H.sub.8).sup.+.
[0799] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.22 (tt,
2H), 0.40-0.50 (m, 2H), 0.82-0.93 (m, 1H), 1.28 (s, 9H), 1.82-1.88
(m, 1H), 2.81-2.89 (m, 2H), 7.24 (dd, 1H), 7.52 (d, 1H), 7.60 (d,
1H).
Example 158A
(+/-)-tert-butyl
3-[3-(benzylamino)-4-chlorophenyl]-2-cyclobutylpropanoate
##STR00212##
[0801] Under argon, 848.6 mg (8.83 mmol) of sodium tert-butoxide,
337 mg (0.39 mmol) of tris(dibenzylidenacetone)dipalladium and 183
mg (0.29 mmol) of rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
were weighed out into a dry flask, kept under high vacuum for 10
min and then vented with argon. 5 ml of abs. toluene, 0.96 ml (8.83
mmol) of benzylamine and a solution of 2.75 g (7.36 mmol) of
(+/-)-tert-butyl 3-(3-bromo-4-chlorophenyl)-2-cyclobutylpropanoate
in 5 ml of abs. toluene were added in succession. Three more times,
the reaction mixture was evacuated and in each case vented with
argon, and the mixture was then stirred at 110.degree. C. for 3 h.
After cooling, the reaction mixture was added to saturated aqueous
ammonium chloride solution. The mixture was extracted three times
with ethyl acetate. The organic phases were combined, dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel (mobile
phase cyclohexane/dichloromethane 4:1 to 2:1, then pure
dichloromethane) This gave 1.95 g of the title compound (65.1% of
theory).
[0802] LC-MS (Method 4): R.sub.t=1.90 min; m/z=400 (M+H).sup.+.
[0803] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.26 (s,
9H), 1.54-1.76 (m, 4H), 1.78-1.86 (m, 2H), 2.19-2.38 (m, 2H),
2.38-2.45 (m, 2H), 4.33-4.44 (m, 2H), 5.95 (t, 1H), 6.25-6.40 (m,
2H), 7.11 (d, 1H), 7.23 (td, 1H), 7.27-7.37 (m, 4H).
[0804] The example below was obtained in an analogous manner
Example 159A
tert-butyl
3-[3-(benzylamino)-4-chlorophenyl]-2-cyclopropylpropanoate
##STR00213##
[0806] From tert-butyl
3-(3-bromo-4-chlorophenyl)-2-cyclopropylpropanoate and benzylamine,
2.51 g of the title compound were obtained (74.7% of theory).
[0807] LC-MS (Method 6): R.sub.t=1.55 min; m/z=386 (M+H).sup.+.
Example 160A
(+/-)-tert-butyl
3-(3-amino-4-chlorophenyl)-2-cyclobutylpropanoate
##STR00214##
[0809] 1.85 g (4.63 mmol) of (+/-)-tert-butyl
3-[3-(benzylamino)-4-chlorophenyl]-2-cyclobutylpropanoate were
dissolved in 10 ml of ethyl acetate and deoxygenated with argon,
and 98 mg (0.093 mmol) of palladium on carbon (10%) were added. The
reaction mixture was stirred at RT under an atmosphere of hydrogen
at atmospheric pressure for 4 h and then allowed to stand over the
weekend. The mixture was filtered through celite, the residue was
washed with ethyl acetate, the filtrate was concentrated under
reduced pressure and the residue of the filtrate was dried under
high vacuum. This residue (about 1:1 mixture of starting material
and target product) was once more dissolved in about 10 ml of ethyl
acetate and deoxygenated with argon, and once more 98 mg (0.093
mmol) of palladium on carbon (10%) were added. Again, the reaction
mixture was stirred at RT under an atmosphere of hydrogen at
atmospheric pressure for 4 h. The mixture was then filtered through
celite, the residue was washed with ethyl acetate, the filtrate was
concentrated under reduced pressure and the residue was dried under
high vacuum. Chromatographic purification on silica gel (mobile
phase cyclohexane/ethyl acetate 20:1) gave 1.12 g of the target
product (78.2% of theory).
[0810] LC-MS (Method 6): R.sub.t=1.34 min; m/z=310 (M+H).sup.+, 254
(M-C.sub.4H.sub.7).+-..
[0811] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (s,
9H), 1.68-1.86 (m, 4H), 1.87-1.95 (m, 1H), 1.96-2.07 (m, 1H),
2.32-2.48 (m, 4H), 5.21 (s, 2H), 6.33 (dd, 1H), 6.57 (d, 1H), 7.04
(d, 1H).
[0812] The racemate obtained above was separated into the
enantiomers by preparative HPLC on a chiral phase [column: Daicel
Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 20 ml/min;
detection: 230 nm; injection volume: 0.80 ml; temperature:
25.degree. C.; mobile phase: 95% isohexane/5% ethanol]. 790 mg of
racemate gave 318 mg of enantiomer 1 (Example 161A) and 339 mg of
enantiomer 2 (Example 162A):
Example 161A
tert-butyl 3-(3-amino-4-chlorophenyl)-2-cyclobutylpropanoate
(Enantiomer 1)
##STR00215##
[0814] Yield: 318 mg
[0815] LC-MS (Method 4): R.sub.t=1.70 min; m/z=254
(M-C.sub.4H.sub.7).sup.+.
[0816] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (s,
9H), 1.68-1.85 (m, 4H), 1.87-1.94 (m, 1H), 1.96-2.06 (m, 1H),
2.31-2.48 (m, 4H), 5.21 (s, 2H), 6.33 (dd, 1H), 6.57 (d, 1H), 7.04
(d, 1H).
Example 162A
tert-butyl 3-(3-amino-4-chlorophenyl)-2-cyclobutylpropanoate
(Enantiomer 2)
##STR00216##
[0818] Yield: 339 mg
[0819] LC-MS (Method 4): R.sub.t=1.71 min; m/z=254
(M-C.sub.4H.sub.7).+-..
[0820] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (s,
9H), 1.67-1.84 (m, 4H), 1.87-1.94 (m, 1H), 1.95-2.05 (m, 1H),
2.32-2.48 (m, 4H), 5.22 (s, 2H), 6.33 (dd, 1H), 6.57 (d, 1H), 7.04
(d, 1H).
Example 163A
(+/-)-tert-butyl
3-(3-amino-4-chlorophenyl)-2-cyclopropylpropanoate
##STR00217##
[0822] 2.50 g (4.63 mmol) of (+1-)-tert-butyl
3-[3-(benzylamino)-4-chlorophenyl]-2-cyclopropylpropanoate were
dissolved in 160 ml of ethyl acetate, the mixture was deoxygenated
with argon and 150 mg of palladium on carbon (10%) were added. The
reaction mixture was stirred at RT under an atmosphere of hydrogen
at atmospheric pressure for 8 h. The mixture was then filtered
through celite, the residue was washed with ethyl acetate, the
filtrate was concentrated under reduced pressure and the residue
was dried under high vacuum. The residue was purified by
chromatography on silica gel (mobile phase pure cyclohexane to
cyclohexane/ethyl acetate 20:1). This gave 1.41 g of the target
product (73.6% of theory).
[0823] LC-MS (Method 6): R.sub.t=1.28 min; m/z=240
(M-C.sub.4H.sub.7).sup.+.
[0824] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.10-0.18
(m, 1H), 0.19-0.26 (m, 1H), 0.37-0.52 (m, 2H), 0.79-0.92 (m, 1H),
1.30 (s, 9H), 1.73 (td, 1H), 2.65-2.74 (m, 2H), 5.10-5.25 (m, 2H),
6.35 (dd, 1H), 6.59 (d, 1H), 6.99-7.06 (m, 1H).
Example 164A
Methyl 3-(3-amino-4-chlorophenyl)hex-2-enoate and methyl
3-(3-amino-4-chlorophenyl)hex-3-enoate
##STR00218##
[0826] 33.8 ml (242.2 mmol) of triethylamine were added to a
mixture of 10.0 g (48.4 mmol) of 5-bromo-2-chloraniline and 8.69 g
(67.8 mmol) of methyl(2E)-hex-2-enoate in 100 ml of DMF. Three
times, the mixture was evacuated and in each case vented with
argon. After addition of 1.09 g (4.84 mmol) of palladium(11)
acetate and 2.95 g (9.69 mmol) of tri-2-tolylphosphine, the mixture
was evacuated two more times and in each case vented with argon,
and the reaction mixture was then stirred at 150.degree. C. for 4
h. After cooling, the mixture was added to water, saturated with
sodium chloride and extracted three times with ethyl acetate. The
combined organic phases were dried over magnesium sulphate and
concentrated under reduced pressure, finally under high vacuum. The
residue was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1). This gave 7.70 g of a mixture of
the two title compounds (62.7% of theory, ratio about 1.5:1 in
favour of the .alpha.,.beta.-unsaturated isomer).
[0827] LC-MS (Method 6): Methyl
3-(3-amino-4-chlorophenyl)hex-2-enoate: R.sub.t=1.04 min, m/z=254
(M+H).sup.+; methyl 3-(3-amino-4-chlorophenyl)hex-3-enoate:
R.sub.t=1.12 min, m/z=254 (M+H).sup.+.
[0828] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): Methyl
3-(3-amino-4-chlorophenyl)hex-2-enoate: .delta. [ppm]=0.85 (t, 3H),
1.29-1.41 (m, 2H), 2.92-3.00 (m, 2H), 3.46 (s, 3H), 5.45 (s, 2H),
5.98 (s, 1H), 6.69 (dd, 1H), 6.94 (d, 1H), 7.20 (d, 1H).
[0829] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): Methyl
3-(3-amino-4-chlorophenyl)hex-3-enoate: .delta. [ppm]=1.00 (t, 3H),
2.15 (quin, 2H), 3.56 (s, 3H), 3.66 (s, 2H), 5.26-5.31 (m, 2H),
5.84 (t, 1H), 6.54 (dd, 1H), 6.79 (d, 1H), 7.09 (d, 1H).
Example 165A
(+/-)-Methyl 3-(3-amino-4-chlorophenyl)hexanoate
##STR00219##
[0831] 7.70 g (30.3 mmol) of the mixture of methyl
3-(3-amino-4-chlorophenyl)hex-2-enoate and methyl
3-(3-amino-4-chlorophenyl)hex-3-enoate (about 1.5:1, Example 164A)
were dissolved in 45 ml of ethyl acetate, 646 mg (0.303 mmol) of
palladium on carbon (5%) were added and the mixture was stirred
under an atmosphere of hydrogen at atmospheric pressure and RT.
After 10 h, the reaction mixture was filtered off through celite,
the residue was washed with ethyl acetate and the filtrate was
concentrated. The residue was taken up in about 50 ml of ethyl
acetate, another about 650 mg of palladium on carbon (5%) were
added and the mixture was stirred under an atmosphere of hydrogen
at atmospheric pressure and RT. After a further 36 h, the reaction
mixture was once more filtered off through celite, the residue was
washed with ethyl acetate and the filtrate was concentrated. The
residue was taken up in 800 ml of ethyl acetate, once more about
650 mg of palladium on carbon (5%) were added and the mixture was
stirred under an atmosphere of hydrogen at atmospheric pressure and
RT for 24 h. Again, the reaction mixture was filtered off through
celite, the residue was washed with ethyl acetate and the filtrate
was concentrated. The residue was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 50:1 to 10:1).
This gave a total of 4.79 g of a mixture of target product and
starting material. This mixture was dissolved in 180 ml of ethyl
acetate, another 603 mg (0.566 mmol) of palladium on carbon (10%)
were added and the mixture was stirred under an atmosphere of
hydrogen at atmospheric pressure and RT overnight. The reaction
mixture was filtered off through celite, the residue was washed
with ethyl acetate, the filtrate was concentrated and the residue
was dried under high vacuum. This gave 4.45 g (about 57% of theory)
of the target product.
[0832] LC-MS (Method 4): R.sub.t=1.50 min; m/z=256 (M+H).sup.+.
[0833] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (t,
3H), 1.03-1.15 (m, 2H), 1.39-1.56 (m, 2H), 2.46 (dd, 1H), 2.59 (dd,
1H), 2.78-2.89 (m, 1H), 3.50 (s, 3H), 5.22 (br. s, 2H), 6.39 (dd,
1H), 6.61 (d, 1H), 7.06 (d, 1H).
Example 166A and Example 167A
Methyl 3-(3-amino-4-chlorophenyl)pent-2-enoate and methyl
3-(3-amino-4-chlorophenyl)pent-3-enoate
##STR00220##
[0835] 16.9 ml (121 mmol) of triethylamine were added to a mixture
of 5.0 g (24.2 mmol) of 5-bromo-2-chloraniline and 5.53 g (48.4
mmol) of methyl 2-pentenoate in 50 ml of DMF. Three times, the
mixture was evacuated and in each case vented with argon. After
addition of 544 mg (2.42 mmol) of palladium(II) acetate and 1.47 g
(4.84 mmol) of tri-2-tolylphosphine, the mixture was evacuated two
more times and in each case vented with argon, and the reaction
mixture was then stirred at 150.degree. C. for 6 h. After cooling,
the mixture was kept at RT overnight and then added to water. The
mixture was extracted three times with ethyl acetate. The organic
phases were combnied, dried over magnesium sulphate, concentrated
under reduced pressure and the residue was dried under high vacuum.
The residue gave, by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1 to 10:1), the two isomeric target
products in separated form. This gave 0.85 g of methyl
3-(3-amino-4-chlorophenyl)pent-2-enoate (14.6% of theory) and 3.05
g of methyl 3-(3-amino-4-chlorophenyl)pent-3-enoate (52.5% of
theory).
Methyl 3-(3-amino-4-chlorophenyl)pent-2-enoate (Example 166A)
[0836] LC-MS (Method 6): R.sub.t=1.09 min; m/z=240 (M+H).sup.+.
[0837] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.97 (t,
3H), 2.98 (q, 2H), 3.66 (s, 3H), 5.45 (s, 2H), 5.96 (s, 1H), 6.70
(dd, 1H), 6.95 (d, 1H), 7.21 (d, 1H).
Methyl 3-(3-amino-4-chlorophenyl)pent-3-enoate (Example 167A)
[0838] LC-MS (Method 6): R.sub.t=1.00 min; m/z=240 (M+H).sup.+.
[0839] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.75 (d,
3H), 3.47 (s, 2H), 3.56 (s, 3H), 5.28 (s, 2H), 5.94 (q, 1H), 6.54
(dd, 1H), 6.77 (d, 1H), 7.09 (d, 1H).
Example 168A
(+/-)-Methyl 3-(3-amino-4-chlorophenyl)pentanoate
##STR00221##
[0841] 3.05 g (12.7 mmol) of methyl
3-(3-amino-4-chlorophenyl)pent-3-enoate and 0.85 g (3.55 mmol) of
methyl 3-(3-amino-4-chlorophenyl)pent-2-enoate were dissolved
together in 500 ml of ethyl acetate, 346 mg (0.325 mmol) of
palladium on carbon (10%) were added and the mixture was stirred at
RT under an atmosphere of hydrogen at atmospheric pressure
overnight. The reaction mixture was then filtered off through
celite, the residue was washed with ethyl acetate and the filtrate
was concentrated. Drying of the residue under high vacuum gave 3.73
g of the target product (94.8% of theory).
[0842] GC-MS (Method 1): R.sub.t=6.07 min; m/z=242 (M).sup.+.
[0843] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.71 (t,
3H), 1.42-1.49 (m, 1H), 1.55-1.61 (m, 1H), 2.42-2.48 (m, 1H), 2.60
(dd, 1H), 2.68-2.78 (m, 1H), 3.50 (s, 3H), 5.22 (s, 2H), 6.39 (dd,
1H), 6.61 (d, 1H), 7.05-7.08 (m, 1H).
Example 169A
Ethyl(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00222##
[0845] 81.5 ml (81.5 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -20.degree. C., and
a solution of 10.0 g (50.3 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate in 50 ml of abs.
toluene was added dropwise. The mixture was stirred for 10 min At
-20.degree. C., a solution, prepared beforehand, of 14.8 g (70.6
mmol) of 1-bromo-4-chloro-2-fluorobenzene, 366 mg (1.63 mmol) of
palladium(11) acetate and 1.35 g (3.42 mmol) of
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl in 50 ml of
abs. toluene was then added dropwise. After the addition had ended,
cooling was removed and the resulting reaction mixture was
initially stirred at RT for 1 h and then at 80.degree. C.
overnight. After cooling, the mixture was filtered through celite,
the residue was washed repeatedly with toluene and the filtrate
obtained was concentrated under reduced pressure. The residue gave,
after chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 100:1.fwdarw.100:4), 4.26 g of the title compound (25.1% of
theory).
[0846] GC-MS (Method 1): R.sub.t=4.21 min; m/z=312 (M).sup.+.
[0847] The example below was obtained in an analogous manner
Example 170A
Ethyl(3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00223##
[0849] From 2.0 g of ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate
and 2.96 g of 1-bromo-4-chloro-3-fluorobenzene, 2.47 g of the
target compound were obtained.
[0850] GC-MS (Method 1): R.sub.t=4.33 min+4.36 min; both m/z=312
(M).sup.+.
[0851] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer
.delta. [ppm]=0.80 (d, 3H), 1.08-1.19 (m, 3H), 3.34-3.41 (m, 1H),
3.88 (d, 1H), 4.01-4.18 (m, 2H), 7.28-7.34 (m, 1H), 7.51-7.64 (m,
2H).
Example 171A
Ethyl(3R)-2-(4-chloro-2-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00224##
[0853] 22.5 ml (22.5 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -20.degree. C., and
a solution of 2.76 g (50.3 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate in 15 ml of abs.
toluene was added dropwise. The mixture was stirred for 10 min. At
-20.degree. C., a solution, prepared beforehand, of 4.0 g (19.5
mmol) of 2-bromo-5-chlorotoluene, 101 mg (0.45 mmol) of
palladium(II) acetate and 371 mg (0.94 mmol) of
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl in 15 ml of
abs. toluene was then added dropwise. After the addition had ended,
cooling was removed and the resulting reaction mixture was stirred
initially at RT for 1 h and then at 100.degree. C. overnight. After
cooling, the mixture was filtered through celite, the residue was
washed repeatedly with toluene and the filtrate obtained was
concentrated under reduced pressure. This gave 3.10 g of the title
compound as a crude product which was directly reacted further.
[0854] GC-MS (Method 1): R.sub.t=4.72 min; m/z=308 (M).sup.+.
Example 172A
Ethyl(3R)-2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00225##
[0856] 29.2 ml (29.2 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -10.degree. C., and
a solution of 4.30 g (23.4 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate in 26 ml of abs.
toluene was added dropwise. The mixture was stirred for 10 min At
-10.degree. C., a solution, prepared beforehand, of 5.0 g (19.5
mmol, 80% pure) of 5-bromo-2-chlorotoluene, 131 mg (0.58 mmol) of
palladium(II) acetate and 483 mg (1.23 mmol) of
2-dicyclohexyl-phosphino-2'-(N,N-dimethylamino)biphenyl in 26 ml of
abs. toluene was then added dropwise. The resulting reaction
mixture was initially stirred at RT for 1 h and then at 80.degree.
C. for 4 h. After cooling, the mixture was diluted with ethyl
acetate, washed twice with sat. aqueous sodium bicarbonate solution
and once with sat. sodium chloride solution, dried over sodium
sulphate and concentrated under reduced pressure. This gave 7.80 g
of the title compound as a crude product which was directly reacted
further.
[0857] LC-MS (Method 4): R.sub.t=1.55 min; m/z=309 (M+H).sup.+.
[0858] The example below was obtained in an analogous manner
Example 173A
Ethyl(3R)-2-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture)
##STR00226##
[0860] From 3.91 g of ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate
and 5.0 g of 4-bromo-1,2-dichloro-benzene, 7.54 g of the target
compound were obtained as a crude product.
[0861] LC-MS (Method 4): R.sub.t=1.54 min; m/z=329 (M+H).sup.+.
[0862] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.80/1.17 (2d, together 3H), 1.10-1.15 (m, 3H),
3.30-3.41 (m, 1H), 3.89/3.94 (2d, together 1H), 4.01-4.18 (m, 2H),
7.38-7.48 (m, about 1H), 7.59-7.68 (m, about 1H), 7.74/7.75 (2d,
together 1H).
Example 174A
(3R)-2-(4-Chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (Diastereomer Mixture)
##STR00227##
[0864] 4.26 g (13.6 mmol) of
ethyl(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture) were dissolved in a mixture of 22 ml of
methanol, 22 ml of THF and 11 ml of water, and 10.9 g of 50%
strength aqueous sodium hydroxide solution were added at 0.degree.
C. The reaction mixture was stirred at RT overnight. Most of the
organic solvents were then removed under reduced pressure. The
mixture that remained was diluted with water and extracted with
diethyl ether. After phase separation, the organic phase was
discarded and the aqueous phase was acidified with semiconcentrated
hydrochloric acid (pH about 2) and extracted repeatedly with ethyl
acetate. The combined ethyl acetate phases were dried over sodium
sulphate and concentrated under reduced pressure. This gave 3.38 g
(76.7% of theory) of the target product as a mixture of
diastereomers which could be used without further purification for
subsequent reactions.
[0865] LC-MS (Method 4): R.sub.t=1.25 min; m/z=283 (M-H).sup.-.
[0866] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer
.delta. [ppm]=0.87 (d, 3H), 3.27-3.37 (m, 1H), 4.02 (d, 1H), 7.35
(dd, 1H), 7.45-7.52 (m, 2H), 13.02 (br. s, 1H).
[0867] The two carboxylic acids below were obtained in an analogous
manner
Example 175A
(3R)-2-(4-Chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (Diastereomer Mixture)
##STR00228##
[0869] Diastereomer ratio about 1:1.
[0870] GC-MS (Method 1): R.sub.t=4.79 min; m/z=284 (M).sup.+.
[0871] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.80/1.19 (2d, together 3H), 3.18-3.29 (m, 1H),
3.74/3.77 (2 dd, together 1H), 7.28 (d, 1H), 7.43-7.65 (m, 2H),
12.91/13.24 (2 br. s, together 1H).
Example 176A
(3R)-2-(4-Chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (Diastereomer Mixture)
##STR00229##
[0873] Diastereomer ratio about 5:1.
[0874] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.78/1.11 (2d, together 3H), 2.31/2.32 (2s, together
3H), 3.24-3.30 (m, 1H), 3.61/3.64 (2d, together 1H), 7.20-7.50 (m,
5H), 12.80 (br. s, 1H).
Example 177A
(3R)-2-(4-Chloro-2-methylphenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (Diastereomer Mixture)
##STR00230##
[0876] 3.10 g (crude, about 10.04 mmol) of
ethyl(3R)-2-(4-chloro-2-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture) were dissolved in a mixture of 10 ml of
methanol, 10 ml of THF and 5 ml of water, and 8.03 g of 50%
strength aqueous sodium hydroxide solution were added at 0.degree.
C. The reaction mixture was stirred at RT overnight. The mixture
was then acidified with 1 N hydrochloric acid (pH about 2) and
extracted three times with ethyl acetate. The combined organic
phases were washed with sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 50:1 to 4:1). This gave 1.46 g (51.8% of
theory) of the target product as a mixture of diastereomers (about
5:1).
[0877] GC-MS (Method 1): R.sub.t=5.14 min; m/z=280 (M).sup.+.
[0878] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.76/1.11 (2d, together 3H), 2.34/2.36 (2s, together
3H), 3.33-3.38 (m, about 1H, obscured), 3.81/3.88 (2d, together
1H), 7.27-7.41 (m, 3H), 12.81 (br. s, 1H).
Example 178A
(3R)-2-(3,4-Dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
(Diastereomer Mixture)
##STR00231##
[0880] 3.77 g (crude, about 11.5 mmol) of
ethyl(3R)-2-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoate
(Diastereomer Mixture) were dissolved in a mixture of 14 ml of
methanol, 14 ml of THF and 5 ml of water, and 9.16 g of 50%
strength aqueous sodium hydroxide solution were added at 0.degree.
C. The reaction mixture was stirred at 40.degree. C. for about 6 h.
The mixture was then acidified with 1 N hydrochloric acid (pH about
2) and extracted three times with ethyl acetate. The combined
organic phases were washed with sat. sodium chloride solution,
dried over sodium sulphate and concentrated under reduced pressure.
This gave 3.94 g of the target compound as a crude product which
could be used without further purification for subsequent
reactions.
[0881] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.80/1.19 (2d, together 3H), 3.21-3.30 (m, 1H),
3.69-3.82 (m, 1H), 7.42 (dd, 1H), 7.63-7.67 (m, 1H), 7.70-7.73 (m,
1H), 12.97 (br. s, 1H).
Example 179A
(3R)-2-(4-Chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride (diastereomer mixture)
##STR00232##
[0883] 660 mg (2.32 mmol) of
(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (Diastereomer Mixture) were dissolved in 2 ml of
dichloromethane After addition of a small drop of DMF, the reaction
solution was cooled to from -5.degree. C. to 0.degree. C., and 0.4
ml (4.64 mmol) of oxalyl chloride was added dropwise. Cooling was
removed and the reaction mixture was stirred at RT for 1 h until
the evolution of gas had ceased. The mixture was then concentrated
under reduced pressure. The residue was twice taken up in abs.
dichloromethane, in each case reconcentrated under reduced pressure
and the residue was finally dried under high vacuum. This gave 640
mg of the target product which was directly, without further
purification, reacted further.
[0884] The examples below were prepared according to General
Procedure 1 (HATU-mediated amide coupling of
4,4,4-trifluoro-3-methyl-2-phenylbutanoic acid derivatives with
anilines in DMF using pyridine or N,N-diisopropylethylamine as
base):
TABLE-US-00009 Example Name/Structure/Starting Materials Analytical
Data 180A (+)-tert-Butyl 3-(4-chloro-3-{[((2S,3R)-2-(4-chloro-3-
fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)propanoate ##STR00233## (from tert-butyl
3-(3-amino-4-chloro- phenyl)propanoate and (3R)-2-(4-chloro-3-
fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (diastereomer
mixture)) LC-MS (Method 6): R.sub.t = 1.44 min; m/z = 520 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.83
(d, 3H), 1.30 (s, 9H), 2.42-2.48 (m, 2H), 2.76 (t, 2H), 3.35-3.46
(m, 1H), 4.09-4.19 (m, 1H), 7.05 (dd, 1H), 7.26-7.41 (m, 3H), 7.49
(dd, 1H), 7.62 (t, 1H), 9.86 (s, 1H). [.alpha.].sub.D.sup.20 =
+66.9.degree., c = 0.46, chloroform. 181A (+)-Ethyl
(2S,)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-
fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-methylpropanoate ##STR00234## (from ethyl
(+)-(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate and
(3R)-2-(4-chloro-3-fluoro- phenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (diastereomer mixture)) LC-MS (Method 6): R.sub.t = 1.40 min;
m/z = 508 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 0.83 (d, 3H), 1.01-1.10 (m, 6H), 2.60-2.71 (m, 2H),
2.74-2.84 (m, 1H), 3.35-3.49 (m, 1H), 3.96 (q, 2H), 4.15 (d, 1H),
7.00 (dd, 1H), 7.24-7.39 (m, 3H), 7.49 (dd, 1H), 7.62 (t, 1H), 9.87
(s, 1H). [.alpha.].sub.D.sup.20 = +98.6.degree., c = 0.45,
chloroform. 182A (+)-Ethyl
(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-
methylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-methylpropanoate ##STR00235## (from ethyl
(+)-(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate and
(3R)-2-(4-chloro-2-methyl- phenyl)-4,4,4-trifluoro-3-methylbutanoic
acid (diastereomer mixture)) LC-MS( Method 6): R.sub.t = 1.46 min;
m/z = 504 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. [ppm] = 0.75 (d, 3H), 1.02-1.12 (m, 6H), 2.61-2.72 (m, 2H),
2.77-2.84 (m, 1H), 3.33-3.42 (m, 1H), 3.98 (q, 2H), 4.15 (d, 1H),
7.02 (dd, 1H), 7.24-7.30 (m, 2H), 7.32- 7.38 (m, 2H), 7.52 (d, 1H),
9.88 (s, 1H). [.alpha.].sub.D.sup.20 = +112.3.degree., c = 0.40,
chloroform. 183A tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-
methylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)propanoate ##STR00236## (from tert-butyl
3-(3-amino-4-chlorophenyl)- propanoate and
(3R)-2-(4-chloro-3-methylphenyl)- 4,4,4-trifluoro-3-methylbutanoic
acid) LC-MS (Method 4): R.sub.t = 1.69 min; m/z = 516/518 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.80
(d, 3H), 1.31 (s, 9H), 2.33 (s, 3H), 2.46 (t, 2H), 2.75 (t, 2H),
3.34-3.41 (m, 1H), 4.07 (d, 1H), 7.03 (dd, 1H), 7.27-7.45 (m, 5H),
9.80 (s, 1H). 184A Ethyl
(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-
methylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-methylpropanoate ##STR00237## (from ethyl
(+)-(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate and
(3R)-2-(4-chloro-3-methyl- phenyl)-4,4,4-trifluoro-3-methylbutanoic
acid) LC-MS (Method 4): R.sub.t = 1.64 min; m/z = 502/504 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.80
(d, 3H), 1.02-1.09 (m, 6H), 2.33 (s, 3H), 2.59-2.72 (m, 2H), 2.74-
2.85 (m, 1H), 3.34-3.44 (m, 1H), 3.96 (q, 2H), 4.04-4.11 (m, 1H),
6.99 (dd, 1H), 7.26- 7.38 (m, 3H), 7.39-7.44 (m, 2H), 9.80 (s, 1H).
185A Ethyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-
dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-methylpropanoate ##STR00238## (from ethyl
(+)-(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate and
(3R)-2-(3,4-dichlorophenyl)- 4,4,4-trifluoro-3-methylbutanoic acid)
LC-MS (Method 6): R.sub.t = 1.44 min; m/z = 524/526 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.83 (d, 3H),
1.01-1.08 (m, 6H), 2.60-2.70 (m, 2H), 2.75-2.83 (m, 1H), 3.35-3.48
(m, 1H), 3.96 (q, 2H), 4.09-4.16 (m, 1H), 7.01 (dd, 1H), 7.30-7.38
(m, 2H), 7.45 (dd, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 9.87 (s, 1H).
186A tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]- amino}phenyl)propanoate
##STR00239## (from tert-butyl-3-(3-amino-4-chlorophenyl)-
propanoate and (3R)-2-(3,4-dichlorophenyl)-4,4,4-
trifluoro-3-methylbutanoic acid) LC-MS (Method 6): R.sub.t = 1.48
min; m/z = 536/538 (M - H).sup.-. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.83 (d, 5H), 1.30 (s, 9H),
2.42-2.48 (m, 2H), 2.72-2.80 (m, 2H), 3.34- 3.48 (m, 1H), 4.07-4.17
(m, 1H), 7.05 (dd, 1H), 7.31-7.39 (m, 2H), 7.45 (dd, 1H), 7.67 (d,
1H), 7.72 (d, 1H), 9.87 (s, 1H). 187A tert-Butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-
methylphenyl)-2-methylpropanoate (diastereomer mixture)
##STR00240## (from (+/-)-tert-butyl 3-(3-amino-4-chloro-2-methyl-
phenyl)-2-methylpropanoate and (+)-(2S,3R)-2-(4-
chlorophenyl)-4,4.4-trifluoro-3-methylbutanoic acid) LC-MS (Method
6): R.sub.t = 1.45 min; m/z = 530/532 (M - H).sup.-. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.80 (d, 3H), 1.03 (br. s,
about 3H), 1.29 (s, about 9H), 1.51 (br. s, about 1H), 1.56 (br. s,
about 1H), 2.15 (br. s, 1H), 2.77 (br. s, 1H), 3.34-3.43 (m, 1H),
3.86- 4.02 (m, 1H), 6.97-7.08 (m, 1H), 7.15 (br. s, 1H), 7.23 (br.
s, 1H),7.38-7.53 (m, 5H), 9.87 (br. s, 1H) [because of rotamers,
the signals are very broad]. 188A Ethyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-
4,4,4-trifluorobutanoate ##STR00241## (from (+/-)-ethyl
3-(3-amino-4-fluorophenyl)-4,4,4- trifluorobutanoate and
(+)-(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid) LC-MS (Method 4): R.sub.t = 1.65 min; m/z = 526 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm] = 0.79 (d, 3H), 1.03 (t, 3H), 2.91 (dd, 1H), 3.03
(dd, 1H), 3.34-3.46 (m, 1H), 3.89-4.00 (m, 2H), 4.04-4.18 (m, 2H),
7.15-7.32 (m, 2H), 7.42-7.55 (m, 4H), 7.85-8.06 (m, 1H), 10.17 (s,
1H). 189A tert-Butyl 2-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}benzyl)-2-methylbutanoate (diastereomer mixture) ##STR00242##
(from (+/-)-tert-butyl-2-(3-amino-4-chlorobenzyl)-2-
methylbutanoate and (+)-(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoic acid) LC-MS (Method 6): R.sub.t =
1.64 min; m/z = 544/546 (M - H).sup.-. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): both diastereomers .delta. [ppm] = 0.74-0.84 (m,
6H), 0.88/0.91 (2d, together 3H), 1.22/1.32 (2s, together 9H),
1.32-1.40 (m, 1H), 1.58-1.68 (m, 1H), 2.57 (d, 1H), 2.84/2.85 (2d,
together 1H), 3.35-3.43 (m, 1H), 4.03- 4.08/4.10 (2d, together 1H),
6.95 (dd, 1H), 7.26-7.38 (m, 2H), 7.39-7.52 (m, 4H). 9.81/9.83 (2s,
together 1H). 190A tert-Butyl 2-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}benzyl)-2-methylbutanoate (diasteromer B) ##STR00243## (from
(+)-tert-butyl-2-(3-amino-4-chlorobenzyl)-2- methylbutanoate
(enantiomer 2) and (+)-(2S,3R)-2-
(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid) LC-MS
(Method 6): R.sub.t = 1.57 min; m/z = 544/546 (M - H).sup.-.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm] = 0.75-0.82 (m,
6H), 0.88 (s, 3H), 1.22 (s, 9H), 1.27-1.38 (m, 1H), 1.56-1.70 (m,
1H), 2.54 (d, about 1H, obscured), 2.84 (d, 1H), 3.35- 3.43 (m,
1H), 4.01-4.14 (m, 1H), 6.95 (d, 1H), 7.17-7.32 (m, 1H), 7.35 (d,
1H), 7.41- 7.57 (m, 4H), 9.83 (s, 1H). [.alpha.].sub.D.sup.20 =
+68.0.degree., c = 0.280, chloroform. 191A tert-Butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-4,4,4-trifluorobutanoate (diastereomer mixture)
##STR00244## (from (+/-)-tert-butyl 3-(3-amino-4-chlorophenyl)-
4,4,4-trifluorobutanoate and (+)-(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid) LC-MS (Method
6): R.sub.t = 1.50 min; m/z = 570/572 (M - H).sup.-. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): both diastereomers .delta. [ppm] = 0.80
(d, 3H), 1.21 (s, 9H), 2.74-2.81 (m, 1H), 2.88-2.99 (m, 1H),
3.34-3.46 (m, 1H), 3.95-4.10 (m, 1H), 4.11-4.19 (m, 1H), 7.25 (dd,
1H), 7.40-7.54 (m, 5H), 7.58- 7.72 (m, 1H), 9.93/9.94 (2s, together
1H). 192A tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-2-cyclobutylpropanoate (diastereomer
mixture) ##STR00245## (from (+/-)-tert-butyl
3-(3-amino-4-chlorophenyl)-2- cyclobutylpropanoate and
(+)-(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid) LC-MS (Method 4): R.sub.t = 1.97 min; m/z = 556 (M -
H).sup.-. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm] = 0.79 (d, 3H), 1.18/1.22 (2s, together 9H),
1.66-1.85 (m, 4H), 1.86-2.02 (m, 2H), 2.28-2.45 (m, 2H), 255-2.64
(m, 1H), 3.34-3.42 (m, 1H), 4.11/4.12 (2d, together 1H), 6.97/6.99
(2d, together 1H), 7.30-7.37 (m, 2H), 7.40-7.51 (m, 4H), 9.80/9.81
(2d, together 1H). 193A (+)-tert-Butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
phenyl)-2-cyclobutylpropanoate (diastereomer A) ##STR00246## (from
tert-butyl 3-(3-amino-4-chlorophenyl)-2-cyclo- butylpropanoate
(enantiomer 1) and (+)-(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid) LC-MS (Method
6): R.sub.t = 1.67 min; m/z = 556 (M - H).sup.-. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. [ppm] = 0.79 (d, 3H), 1.22 (s, 9H),
1.68-1.82 (m, 4H), 1.86-1.93 (m, 1H), 1.94- 2.03 (m, 1H), 2.31-2.47
(m, 2H), 2.56-2.63 (m, 2H), 3.36- 3.43 (m, 1H), 4.12 (d, 1H), 6.98
(dd, 1H), 7.31-7.37 (m, 2H), 7.41-7.51 (m, 4H), 9.81 (s, 1H).
[.alpha.].sub.D.sup.20 = +51.3.degree., c = 0.445, chloroform. 194A
(+)-tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
phenyl)-2-cyclobutylpropanoate (diastereomer B) ##STR00247## (from
tert-butyl 3-(3-amino-4-chlorophenyl)-2-cyclo- butylpropanoate
(enantiomer 2) and (+)-(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid) LC-MS (Method
6): R.sub.t = 1.58 min; m/z = 556 (M - H).sup.-. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. [ppm] = 0.79 (d, 3H), 1.18 (s, 9H),
1.67-1.83 (m, 4H), 1.84-1.93 (m, 1H), 1.94- 2.02 (m, 1H), 2.31-2.44
(m, 2H), 2.57-2.64 (m, 1H), 3.35- 3.42 (m, 1H), 4.08-4.14 (m, 1H),
6.98 (dd, 1H), 7.29-7.37 (m, 2H), 7.42-7.49 (m, 4H), 9.81 (s, 1H).
[.alpha.].sub.D.sup.20 = +81.8.degree., c = 0.475, chloroform. 195A
tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-cyclopropylpropanoate (diastereomer mixture)
##STR00248## (from (+/-)-tert-Butyl 3-(3-amino-4-chlorophenyl)-2-
cyclopropylpropanoate and (+)-(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid) LC-MS (Method
4): R.sub.t = 1.80 min; m/z = 542 (M - H).sup.-. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): both diastereomers .delta. [ppm] = 0.12-0.26
(m, 2H), 0.43 (q, 2H), 0.79 (d, 3H), 0.81-0.90 (m, 1H), 1.20/1.24
(2s, together 9H), 1.67-1.81 (m, 1H), 2.76-2.83 (m, 2H), 3.36-3.43
(m, 1H), 4.11/4.12 (2d, together 1H), 7.01 (dd, 1H), 7.30-7.39 (m,
2H), 7.41- 7.51 (m, 4H), 9.78-9.85 (m, 1H).
Example 196A
(+)-Ethyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-tr-
ifluoro-3-methyl-butanoyl]amino}phenyl)-2-methylpropanoate
##STR00249##
[0886] 280.7 mg (1.16 mmol) of
ethyl(+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate were
dissolved in 1.5 ml of abs. THF, 0.26 ml (1.48 mmol) of
N,N-diisopropylethylamine was added and, after cooling to
-10.degree. C., a solution of 320 mg (crude, about 1.06 mmol) of
(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride, prepared in situ, in 0.5 ml of abs. THF was added
dropwise. After the addition had ended, the reaction mixture was
stirred between -10.degree. C. and 0.degree. C. for 30 min After
addition of a few drops of water, the mixture was then diluted with
dichloromethane The mixture was washed with 1 N hydrochloric acid
and sat. sodium chloride solution, dried over magnesium sulphate
and concentrated under reduced pressure. The crude product was
purified initially by preparative RP-HPLC (mobile phase
methanol/water) and then by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 40:1). This gave 144 mg of the
target compound (26.9% of theory).
[0887] LC-MS (Method 6): R.sub.t=1.42 min; m/z=508 (M+H).sup.+.
[0888] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.86 (d,
3H), 1.02-1.12 (m, 6H), 2.63-2.72 (m, 2H), 2.76-2.86 (m, 1H),
3.34-3.44 (m, 1H), 3.93-4.02 (m, 2H), 4.36 (d, 1H), 7.03 (dd, 1H),
7.25-7.29 (m, 1H), 7.32-7.38 (m, 2H), 7.51 (dd, 1H), 7.61 (t, 1H),
10.02 (s, 1H).
[0889] [.alpha.].sub.D.sup.20=+90.degree., c=0.30, chloroform.
Example 197A
Methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}-2-methylphenyl)propanoate
##STR00250##
[0891] 265 mg (1.16 mmol) of methyl
3-(3-amino-4-chloro-2-methylphenyl)propanoate were dissolved in 1.5
ml of abs. THF, 0.28 ml (1.63 mmol) of N,N-diisopropylethylamine
was added and, after cooling to -10.degree. C., a solution of 398
mg (crude, about 1.40 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride, prepared in situ, in 0.5 ml of abs. THF was added
dropwise. After the addition had ended, the reaction mixture was
warmed from -10.degree. C. to RT over 1 h and then diluted with
ethyl acetate. The mixture was washed with 1 N hydrochloric acid
and sat. sodium chloride solution, dried over magnesium sulphate
and concentrated under reduced pressure. The crude product was
purified by preparative RP-HPLC (mobile phase methanol/water). This
gave 485 mg of the target compound (87.5% of theory).
[0892] LC-MS (Method 6): R.sub.t=1.25 min; m/z=476 (M+H).sup.+.
Example 198A
(+)-tert-Butyl(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-triflu-
oro-3-methyl-butanoyl]amino}-2-methylphenyl)-2-methylpropanoate
##STR00251##
[0894] 200 mg (0.705 mmol) of
(-)-tert-Butyl(2R)-3-(3-amino-4-chloro-2-methylphenyl)-2-methyl-propanoat-
e were dissolved in 1 ml of abs. THF, 0.17 ml (0.987 mmol) of
N,N-diisopropylethylamine was added and, after cooling to
-10.degree. C., a solution of 241 mg (crude, about 0.846 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride, prepared in situ, in 0.2 ml of abs. THF was added
dropwise. After the addition had ended, the reaction mixture was
warmed from -10.degree. C. to RT over 2 h and then added to water.
The aqueous phase was extracted three times with ethyl acetate, and
the combined organic phases were washed with 1 N hydrochloric acid
and sat. sodium chloride solution, dried over magnesium sulphate
and concentrated under reduced pressure, and the residue was dried
under high vacuum. This gave 282 mg of the target compound (75.2%
of theory).
[0895] LC-MS (Method 6): R.sub.t=1.45 min; m/z=530 (M-H).sup.-.
[0896] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.03 (br. s, 3H), 1.30 (s, 9H), 1.50 (br. s, 1H), 2.15 (br. s,
1H), 2.42 (br. s, 1H), 2.69-2.92 (m, 1H), 3.34-3.45 (m, 1H), 3.94
(d, 1H), 7.03 (d, 1H), 7.23 (br. s, 1H), 7.45 (s, 4H), 9.83/9.91 (2
br. s, together 1H) [because of rotamers, the signals are very
broad].
[0897] [.alpha.].sub.D.sup.20=+68.9.degree.c=0.50, chloroform.
[0898] The example below was obtained in an analogous manner
Example 199A
(+)-tert-Butyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-triflu-
oro-3-methylbutanoyl]-amino}-2-methylphenyl)-2-methylpropanoate
##STR00252##
[0900] From 200 mg of
(+)-tert-butyl(2S)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate
and 241 mg of freshly prepared
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl
chloride, 287 mg of the target product were obtained (75.2% of
theory).
[0901] LC-MS (Method 6): R.sub.t=1.51 min; m/z=530 (M-H).sup.-.
[0902] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.04 (br. s, 3H), 1.29 (s, 9H), 1.51 (br. s, 1H), 2.15 (br. s,
1H), 2.56-2.68 (m, 1H), 2.79 (br. s, 1H), 3.34-3.45 (m, 1H), 3.94
(br. d, 1H), 7.03 (d, 1H), 7.15 (br. s, 1H), 7.23 (br. s, 1H), 7.45
(s, 4H), 9.87 (br. s, 1H) [because of rotamers, the signals are
very broad].
[0903] [.alpha.].sub.D.sup.20=+116.1.degree., c=0.520,
chloroform.
Example 200A
(+)-tert-Butyl
2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]-amino}benzyl)-2-methylbutanoate (diastereomer A)
##STR00253##
[0905] 225 mg (0.756 mmol) of (-)-tert-butyl
2-(3-amino-4-chlorobenzyl)-2-methylbutanoate (enantiomer 1) and 231
mg (0.907 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid were dissolved in 0.9 ml of pyridine and 2.7 ml of DMF, and
345 mg (0.907 mmol) of HATU were added at RT. The reaction mixture
was stirred at 45.degree. C. overnight, and a further 0.5 eq. of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid and 0.6 eq. of HATU were then added. The reaction mixture was
stirred at 45.degree. C. for another 3 h and then, after cooling,
diluted with ethyl acetate. The mixture was washed with 1 N
hydrochloric acid and sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product was purified by preparative RP-HPLC (mobile phase
acetonitrile/water) and subsequent chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 40:1). This gave 177 mg of
the target product (35.6% of theory).
[0906] LC-MS (Method 4): R.sub.t=1.97 min; m/z=544 (M-H).sup.-.
[0907] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.76-0.83
(m, 6H), 0.91 (s, 3H), 1.31 (s, 9H), 1.33-1.40 (m, 1H), 1.57-1.67
(m, 1H), 2.57 (d, 1H), 2.85 (d, 1H), 3.35-3.43 (m, 1H), 4.07-4.13
(m, 1H), 6.95 (dd, 1H), 7.30-7.36 (m, 2H), 7.41-7.48 (m, 4H), 9.82
(s, 1H).
[0908] [.alpha.].sub.D.sup.20=+63.2.degree., c=0.365,
chloroform.
Example 201A
Methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}-phenyl)hexanoate (Diastereomer Mixture)
##STR00254##
[0910] 1.45 g (5.67 mmol) of (+/-)-methyl
3-(3-amino-4-chlorophenyl)hexanoate and 1.81 g (6.80 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid were dissolved in 5.0 ml of pyridine and 10.0 ml of DMF, and
2.80 g (7.37 mmol) of HATU were added at RT. The reaction mixture
was stirred at RT overnight and then diluted with ethyl acetate.
The mixture was washed with 1 N hydrochloric acid and sat. sodium
chloride solution, dried over magnesium sulphate and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel (mobile phase initially cyclohexane,
then cyclohexane/ethyl acetate 50:1). In two fractions, in total
2.02 g of the target product were obtained (70.6% of theory).
[0911] LC-MS (Method 6): R.sub.t=1.43 min; m/z=504 (M+H).sup.+.
[0912] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.74-0.85 (m, 6H), 0.98-1.16 (m, 2H), 1.42-1.61 (m,
2H), 2.49 (dd, about 1H, obscured), 2.64 (dd, 1H), 2.84-3.02 (m,
1H), 3.37-3.42 (m, 1H), 3.47/3.48 (2s, together 3H), 4.12 (d, 1H),
7.05 (dd, 1H), 7.31-7.38 (m, 2H), 7.41-7.55 (m, 4H), 9.83 (s,
1H).
Example 202A
Methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}-phenyl)pentanoate (Diastereomer Mixture)
##STR00255##
[0914] 500 mg (2.07 mmol) of (+/-)-methyl
3-(3-amino-4-chlorophenyl)pentanoate and 668.9 mg (2.48 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid were dissolved in 1.7 ml of pyridine and 3.3 ml of DMF, and
1.02 g (2.69 mmol) of HATU were added at RT. The reaction mixture
was stirred at RT overnight and then diluted with ethyl acetate.
The mixture was washed with 1 N hydrochloric acid and sat. sodium
chloride solution, dried over magnesium sulphate and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel (mobile phase initially cyclohexane,
then cyclohexane/ethyl acetate 50:1). This gave 675 mg of the
target product (66.6% of theory).
[0915] LC-MS (Method 6): R.sub.t=1.39 min; m/z=490 (M-H).sup.-.
[0916] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.65-0.74 (m, 3H), 0.80 (d, 3H), 1.43-1.67 (m, 2H),
2.49 (dd, about 1H, obscured), 2.65 (dd, 1H), 2.80-2.92 (m, 1H),
3.35-3.43 (m, 1H), 3.47/3.48 (2s, together 3H), 4.13 (d, 1H), 7.05
(dd, 1H), 7.36 (dd, 2H), 7.43-7.51 (m, 4H), 9.84 (s, 1H).
Example 203A
(+)-tert-Butyl(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-triflu-
oro-3-methylbutanoyl]-amino}phenyl)-4,4,4-trifluorobutanoate
##STR00256##
[0918] 2.0 g (6.18 mmol) of
(+)-tert-butyl(3S)-3-(3-amino-4-chlorophenyl)-4,4,4-trifluorobutanoate
and 1.98 g (7.41 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid were dissolved in 5.0 ml of pyridine and 10.0 ml of DMF, and
3.05 g (8.03 mmol) of HATU were added at RT. The reaction mixture
was stirred at RT overnight, and a further 1.98 g (7.41 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid and 3.05 g (8.03 mmol) of HATU were then added. The reaction
mixture was stirred at 40.degree. C. for another 8 h and then,
after cooling, diluted with ethyl acetate. The mixture was washed
with 1 N hydrochloric acid and sat. sodium chloride solution, dried
over magnesium sulphate and concentrated under reduced pressure.
The crude product was purified by chromatography on silica gel
(mobile phase initially cyclohexane, then cyclohexane/ethyl acetate
50:1). The product obtained in this manner (2.7 g) was repurified
again by another chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 100:1). This gave 1.80 g of the target
product (50.9% of theory).
[0919] LC-MS (Method 4): R.sub.t=1.74 min; m/z=570 (M-H).sup.-.
[0920] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.21 (s, 9H), 2.77 (dd, 1H), 2.94 (dd, 1H), 3.36-3.46 (m, 1H),
3.99-4.09 (m, 1H), 4.15 (d, 1H), 7.17-7.29 (m, 1H), 7.42-7.52 (m,
5H), 7.59-7.65 (m, 1H), 9.94 (s, 1H).
[0921] [.alpha.].sub.D.sup.20=+84.0.degree., c=0.48,
chloroform.
[0922] The example below was prepared in an analogous manner
Example 204A
(+)-tert-Butyl(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-triflu-
oro-3-methylbutanoyl]-amino}phenyl)-4,4,4-trifluorobutanoate
##STR00257##
[0924] From 1.0 g (3.09 mmol) of
(-)-tert-butyl(3R)-3-(3-amino-4-chlorophenyl)-4,4,4-trifluorobutanoate
and 988 mg (3.71 mmol) of
(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic
acid 1.2 g (68% of theory) of the target product were obtained.
[0925] LC-MS (Method 4): R.sub.t=1.75 min; m/z=570 (M-H).sup.-.
[0926] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.21 (s, 9H), 2.78 (dd, 1H), 2.93 (dd, 1H), 3.35-3.47 (m, 1H),
3.99-4.10 (m, 1H), 4.15 (d, 1H), 7.19-7.28 (m, 1H), 7.40-7.52 (m,
5H), 7.60-7.66 (m, 1H), 9.93 (s, 1H).
[0927] [.alpha.].sub.D.sup.20=+42.7.degree., c=0.48,
chloroform.
Example 205A
tert-Butyl 3-(3-amino-2-methylphenyl)propanoate
##STR00258##
[0929] Under argon, 201 ml (1.39 mol) of tert-butyl prop-2-enoate
were added dropwise to a solution of 100 g (463 mmol) of
1-bromo-2-methyl-3-nitrobenzene, 322 ml (2.31 mol) of
triethylamine, 28.18 g (92.58 mmol) of tri-2-tolylphosphine and
10.39 g (46.29 mmol) of palladium(II) acetate in 2 litres of DMF,
and the mixture was then stirred at 125.degree. C. for 36 h. After
cooling to room temperature, the reaction mixture was stirred with
saturated aqueous ammonium chloride solution, and the organic phase
was separated off. The aqueous phase was extracted three times with
tert-butyl methyl ether, and the combined organic phases were
washed with saturated sodium chloride solution and dried over
sodium sulphate. After filtration, the solvent was removed to
dryness under reduced pressure. The residue obtained was purified
by flash chromatography on silica gel (mobile phase petroleum
ether/ethyl acetate 9:1). This gave 89 g (338 mmol, 73% of theory)
of the intermediate
tert-butyl(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a
colourless solid.
[0930] 88 g (334 mmol) of this solid were dissolved in 2 litres of
ethanol, 7 g of palladium on carbon (10%) were added at room
temperature and the mixture was hydrogenated under atmospheric
pressure for 18 h. After the reaction had gone to completion, the
reaction solution was filtered through kieselguhr and the filtrate
obtained was concentrated under reduced pressure. This gave 61.3 g
(260.5 mmol, 78% of theory) of the title compound as a colourless
solid.
[0931] LC-MS (Method 2): R.sub.t=1.84 min; m/z=236 (M+H).sup.+.
[0932] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 6.77 (1H,
t), 6.47 (1H, d), 6.36 (1H, d), 4.72 (2H, s), 2.14 (2H, t), 2.36
(2H, t), 1.95 (3H, s), 1.39 (9H, s).
Example 206A
tert-Butyl 3-(3-bromo-4-chlorophenyl)-2,2-dimethylpropanoate
##STR00259##
[0934] Under argon, 4.0 ml (28.8 mmol) of diisopropylamine were
dissolved in 50 ml of dry THF, and the mixture was cooled to
-30.degree. C. 11.5 ml (28.8 mmol) of n-butyllithium solution (2.5
M in hexane) were added dropwise. The resulting mixture was warmed
to 0.degree. C. and then cooled to -70.degree. C. A solution of
2.77 g (19.2 mmol) of tert-butyl-2-methylpropanoate in 20 ml of THF
was then added, the temperature being kept below -60.degree. C.
After 4 h of stirring at -60.degree. C., a solution of 6.0 g (21.1
mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF
was added, the reaction temperature once more being kept below
-60.degree. C. The reaction mixture was stirred overnight slowly
warming to RT, and saturated aqueous ammonium chloride solution and
ethyl acetate were then added. After phase separation, the aqueous
phase was extracted twice with ethyl acetate. The combined organic
phases were dried over magnesium sulphate and concentrated under
reduced pressure. The crude product was purified by chromatography
on silica gel (mobile phase cyclohexane/ethyl acetate
10:1.fwdarw.4:1). This gave 5.6 g (84% of theory) of the title
compound.
[0935] GC-MS (Method 1): R.sub.t=6.16 min; m/z=290/292
(M-C.sub.4H.sub.8).sup.+.
Example 207A
tert-Butyl
3-[3-(benzylamino)-4-chlorophenyl]-2,2-dimethylpropanoate
##STR00260##
[0937] Under argon, 1.73 g (17.95 mmol) of sodium tert-butoxide
were weighed out into a dry flask, and 40 ml of abs. toluene were
added. 5.2 g (14.96 mmol) of tert-butyl
3-(3-bromo-4-chlorophenyl)-2,2-dimethylpropanoate, 1.96 ml (17.95
mmol) of benzylamine, 685 mg (0.75 mmol) of
tris(dibenzylideneacetone)dipalladium and 373 mg (0.60 mmol) of
(+/-)-2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl were added in
succession. The reaction mixture was stirred at 110.degree. C. for
2.0 h, then cooled to RT and stirred at this temperature overnight.
Saturated aqueous ammonium chloride solution and ethyl acetate were
then added, and the reaction mixture was filtered off with suction
through kieselguhr. After phase separation, the organic phase was
washed with saturated ammonium chloride solution and saturated
sodium chloride solution, dried over magnesium sulphate and
concentrated under reduced pressure. The crude product was purified
by preparative HPLC (mobile phase acetonitrile/water). This gave
2.78 g of the title compound (50% of theory).
[0938] LC-MS (Method 6): R.sub.t=1.53 min; m/z=374/376
(M+H).sup.+.
Example 208A
tert-Butyl 3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate
##STR00261##
[0940] 2.7 g (about 7.22 mmol) of tert-butyl
3-[3-(benzylamino)-4-chlorophenyl]-2,2-dimethylpropanoate were
dissolved in 150 ml of ethyl acetate, and 100 ml of palladium on
carbon (10%) were added. The reaction mixture was stirred at RT
under an atmosphere of hydrogen at atmospheric pressure overnight.
The mixture was then filtered off with suction through kieselguhr,
the residue was washed thoroughly with ethyl acetate and the
combined filtrate was concentrated. The crude product was purified
by chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 10:1.fwdarw.7:1). This gave 1.49 g (72.7% of theory) of the
target compound.
[0941] LC-MS (Method 4): R.sub.t=1.46 min; m/z=284/286
(M+H).sup.+.
[0942] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 7.05 (1H,
d), 6.57 (1H, d), 6.32 (1H, dd), 5.20 (2H, s), 2.60 (2H, s), 1.38
(9H, s), 1.05 (6H, s).
Example 209A
N,N-Dibenzyl-5-bromo-2-chloroaniline
##STR00262##
[0944] Under argon, 9.69 g (242.16 mmol, 60% in mineral oil) of
sodium hydride were suspended in 100 ml of THF, and the mixture was
cooled to 0.degree. C. 20.0 g (96.86 mmol) of
5-bromo-2-chloro-aniline, dissolved in 50 ml of THF, were then
slowly added dropwise, and the mixture was stirred at 0.degree. C.
for 30 min 39.76 g (232.47 mmol) of benzyl bromide, dissolved in
150 ml of THF, were then slowly added to the reaction mixture, and
the mixture was then warmed to room temperature. The mixture was
stirred at RT overnight and then carefully poured onto 150 ml of
ice-water. The organic phase was separated off, and the aqueous
phase was then extracted three more times with ethyl acetate. The
combined organic phases were dried over sodium sulphate. After
filtration, the solvent was removed under reduced pressure.
Isopropanol was added to the crude product obtained, and the
crystals formed were filtered off with suction and dried at
40.degree. C. under high vacuum. This gave 14 g of the title
compound. The filtrate was evaporated and the residue obtained was
purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave a further 7.57 g of the
title compound (total yield: 21.57 g, 58% of theory).
[0945] LC-MS (Method 6): R.sub.t=1.53 min; m/z=386/388
(M+H).sup.+.
[0946] The following compound was obtained analogously to Example
209A:
TABLE-US-00010 Example Name/Structure/Starting Materials Analytical
Data 210A N,N-Dibenzyl-2-chloro-5-iodoaniline ##STR00263## (from
2-chloro-5-iodoaniline and benzyl bromide) LC-MS (Method 4):
R.sub.t = 1.86 min; m/z = 433/435 (M + H).sup.+.
Example 211A
[4-Chloro-3-(dibenzylamino)phenyl]boronic acid
##STR00264##
[0948] Under argon and at -78.degree. C., 20.2 ml (50.42 mmol) of a
2.5 M solution of n-butyllithium in hexane were slowly added
dropwise to a solution of 15 g (38.79 mmol) of
N,N-dibenzyl-5-bromo-2-chloroaniline in 350 ml of THF/diethyl ether
(1:1). The reaction solution was stirred at -78.degree. C. for 60
min, and 14.3 ml (62.1 mmol) of triisopropyl borate were then added
slowly. The reaction solution was subsequently stirred at
-78.degree. C. for another 15 min, then slowly warmed to room
temperature, and stirring at this temperature was continued
overnight. 150 ml of ice-water were then metered in. The organic
phase was separated off, and the aqueous phase was then extracted
three more times with ethyl acetate. The combined organic phases
were dried over sodium sulphate. After filtration, the solvent was
removed under reduced pressure. The crude product was purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl
acetate 10:1.fwdarw.4:1). This gave 9 g (66% of theory) of the
title compound.
[0949] LC-MS (Method 6): R.sub.t=1.21 min; m/z=352 (M+H).sup.+.
Example 212A
tert-Butyl Cyclobutylideneacetate
##STR00265##
[0951] Under argon and at room temperature, 3.0 g (42.8 mmol) of
cyclobutanone were dissolved in 160 ml of dichloromethane, and
20.95 g (55.64 mmol) of
tert-butyl(triphenyl-X.sup.5-phosphanylidene) acetate and 0.68 g
(5.56 mmol) of benzoic acid were then added. The reaction mixture
was stirred at room temperature overnight and then concentrated to
dryness. The residue was triturated with 25 ml of diethyl ether,
and the mixture was stored at 4.degree. C. for 12 h. The
precipitated triphenyl-phosphane oxide was filtered off and the
filtrate was concentrated to dryness. The crude product obtained
was purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 9.3 g (99% of theory) of
the title compound.
[0952] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 5.47-5.41
(1H, m), 3.05-2.95 (2H, m), 2.82-2.74 (2H, m), 2.06-1.95 (2H, m),
1.50 (9H, s).
[0953] GC-MS (Method 1): R.sub.t=3.01 min; m/z=112
(M-C.sub.4H.sub.8).+-..
Example 213A
tert-Butyl Cyclopropylideneacetate
##STR00266##
[0955] At room temperature, 55 ml (55 mmol) of a 1 M solution of
tetra-n-butylammonium fluoride in THF were added dropwise to a
solution of 9.65 g (55.34 mmol) of
[(1-ethoxycyclo-propyl)oxy](trimethyl)silane, 25 g (66.41 mmol) of
tert-butyl(triphenyl-X.sup.5-phosphanylidene)-acetate and 8.11 g
(66.41 mmol) of benzoic acid in 240 ml of THF. After 1 h of
stirring, the reaction mixture was heated to 80.degree. C. and
stirred at this temperature for 2 h. Using a rotary evaporator, the
solvent was then distilled off (200 mbar, bath temperature
40.degree. C.). The residue obtained was taken up in diethyl ether
and the mixture was cooled to 4.degree. C. and allowed to stand at
this temperature for 1 h. The resulting precipitate
(triphenylphosphane oxide) was filtered off. Using a rotary
evaporator, the filtrate was then freed from the solvent. The crude
product obtained was purified chromatographically on silica gel
(mobile phase cyclohexane/ethyl acetate 20:1). This gave 3.58 g
(42% of theory) of the title compound.
[0956] GC-MS (Method 1): R.sub.t=2.45 min; m/z=98
(M-C.sub.4H.sub.8).sup.+.
[0957] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 1.18-1.26
(m, 2H), 1.34-1.41 (m, 3H), 1.44 (s, 9H), 6.06-6.13 (m, 1H).
Example 214A
Ethyl(3,3-dimethoxycyclobutylidene)acetate
##STR00267##
[0959] A solution of 3.93 g (44.59 mmol) of 1,1-dimethoxyethene and
5 g (44.59 mmol) of ethyl buta-2,3-dienoate in 50 ml of toluene was
heated at reflux and stirred for 24 h. After cooling to room
temperature, the reaction mixture was freed from the solvent, and
the crude product obtained was purified chromatographically on
silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave
1.9 g (21% of theory) of the title compound as a colourless liquid
which was used without further characterization for subsequent
reactions.
Example 215A
tert-Butyl{1-[4-chloro-3-(dibenzylamino)phenyl]cyclopropyl}acetate
##STR00268##
[0961] Preparation of solution A: under argon, 300 mg (0.69 mmol)
of N,N-dibenzyl-2-chloro-5-iodoaniline were dissolved in 3 ml of
THF, and the solution was cooled to -78.degree. C. 0.4 ml (0.80
mmol) of a 2M solution of isopropylmagnesium chloride in THF was
then slowly added dropwise. The reaction solution was then slowly
warmed to -40.degree. C. and stirred at this temperature for 30
min.
[0962] Preparation of solution B: under argon and at room
temperature, 6 mg (0.14 mmol) of lithium chloride and 13 mg (0.07
mmol) of copper(I) chloride were suspended in 12 ml of THF, and 84
.mu.l (0.66 mmol) of chloro(trimethyl)silane and 102 mg (0.66 mmol)
of tert-butyl cyclopropylidene acetate were then added. The
solution was then stirred at RT for another 1 h.
[0963] Solution B was cooled to -40.degree. C. and slowly added
dropwise to solution A. The reaction mixture obtained was then
stirred at -40.degree. C. for another 1 h. 20 ml of an ice-cold
semisaturated aqueous ammonium chloride solution were then added to
the reaction mixture. The phases were separated, the aqueous phase
was extracted three more times with ethyl acetate and the combined
organic phases were dried over magnesium sulphate, filtered and
concentrated to dryness. The crude product obtained was purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl
acetate 20:1). This gave 135 mg (42% of theory) of the title
compound.
[0964] LC-MS (Method 6): R.sub.t=1.73 min; m/z=462/464
(M+H).sup.+.
[0965] The following compounds were obtained analogously to Example
13A:
TABLE-US-00011 Example Name/Structure/Starting materials Analytical
data 216A tert-Buty {1-[4-chloro-3-(dibenzylamino)-
phenyl]cyclobutyl}acetate ##STR00269## (from
[4-chloro-3-(dibenzylamino)phenyl]boronic acid and tert-butyl
cyclobutylidene acetate) LC-MS (Method 4): R.sub.t = 1.96 min; m/z
= 476/478 (M + H).sup.+. 217A Ethyl
{1-[4-chloro-3-(dibenzylamino)phenyl]-
3,3-dimethoxycyclobutyl}acetate ##STR00270## (from
[4-chloro-3-(dibenzylamino)phenyl]boronic acid and ethyl
(3,3-dimethoxycyclobutylidene)- acetate) LC-MS (Method 6): R.sub.t
= 1.53 min; m/z = 508/510 (M + H).sup.+.
Example 218A
Ethyl{1-[4-chloro-3-(dibenzylamino)phenyl]-3-oxocyclobutyl}acetate
##STR00271##
[0967] 770 mg (1.52 mmol) of
ethyl{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-dimethoxycyclobutyl}-aceta-
te were dissolved in 10 ml of THF, 2 ml of 1 M hydrochloric acid
were added and the mixture was stirred at 50.degree. C. for 1 h.
The reaction solution was then diluted with 10 ml of water and 10
ml of ethyl acetate. The phases were separated, and the organic
phase was then dried over magnesium sulphate, filtered and
concentrated to dryness using a rotary evaporator. This gave 607 mg
of the title compound (87% of theory).
[0968] LC-MS (Method 6): R.sub.t=1.44 min; m/z=462/464
(M+H).sup.+.
Example 219A
Ethyl{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-difluorocyclobutyl}acetate
##STR00272##
[0970] Under argon, 0.3 ml (2.27 mmol) of
[ethyl(trifluoro-.lamda..sup.4-sulphanyl)amino]ethane was added to
2 ml of dichloromethane The reaction solution was cooled to
0.degree. C., and 175 mg (0.38 mmol) of
ethyl{1-[4-chloro-3-(dibenzylamino)phenyl]-3-oxocyclobutyl}acetate
in 3 ml of dichloromethane were then added slowly. The solution was
then slowly warmed to room temperature and stirred at this
temperature overnight. The reaction mixture was then poured into 50
ml of ice-water, and the organic phase was separated off. The
aqueous phase was extracted three more times with dichloromethane
The combined organic phases were dried over magnesium sulphate.
After filtration, the solvent was removed under reduced pressure
and the crude product obtained was purified by preparative HPLC
(mobile phase methanol/water 8:2). This gave 59 mg of the title
compound (32% of theory).
[0971] LC-MS (Method 6): R.sub.t=1.53 min; m/z=484/486
(M+H).sup.+.
Example 220A
tert-Butyl[1-(3-amino-4-chlorophenyl)cyclopropyl]acetate
##STR00273##
[0973] 135 mg (0.29 mmol) of
tert-butyl{1-[4-chloro-3-(dibenzylamino)phenyl]cyclopropyl}acetate
were dissolved in 10 ml of ethyl acetate, 15 mg of palladium on
carbon (10%) were added and the mixture was stirred at RT under an
atmosphere of hydrogen at atmospheric pressure for 2 h. The
reaction mixture was then filtered off through celite, the residue
was washed with ethyl acetate and the filtrate was concentrated.
This gave 73 mg of the title compound (89% of theory).
[0974] LC-MS (Method 6): R.sub.t=1.15 min; m/z=282/284
(M+H).sup.+.
[0975] The following compounds were obtained analogously to Example
220A:
TABLE-US-00012 Example Name/Structure/Starting material Analytical
Data 221A ##STR00274## LC-MS (Method 6): R.sub.t = 1.24 min; m/z =
296 (M + H).sup.+. (from tert-butyl {1-(4-chloro-3-(dibenzylamino)-
phenyl]cyclobutyl}acetate) 222A ##STR00275## LC-MS (Method 4):
R.sub.t = 1.36 min; m/z = 304/306 (M + H).sup.+. (from ethyl
{1-[4-chloro-3-(dibenzylamino)-
phenyl]-3,3-difluorocyclobutyl}acetate)
Example 223A
tert-Butyl(2E)-3-(3-amino-4-cyanophenyl)-2-methylacrylate
##STR00276##
[0977] Under argon, a mixture of 2.0 g (10.15 mmol) of
2-amino-4-bromobenzonitrile, 2.165 g (2.5 ml, 15.23 mmol) of
tert-butyl 2-methylacrylate, 93 mg (0.10 mmol) of
tris(dibenzylideneacetone)-dipalladium, 41 mg (0.20 mmol) of
tri-tert-butylphosphine and 2.4 ml (11.17 mmol) of
N,N-di-cyclohexylmethylamine in 20 ml of dioxane was heated to
120.degree. C. and stirred at this temperature overnight. The
reaction was checked (TLC, mobile phase cyclohexane/ethyl acetate
9:1), and another 10 mg of tris(dibenzylideneacetone)dipalladium,
10 mg of tri-tert-butylphosphine and 500 .mu.l of tert-butyl
2-methylacrylate were then added and the mixture was stirred at
120.degree. C. for a further 4 h. The reaction mixture was then
filtered through celite, and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel (mobile phase cyclohexane/ethylacetate 9:1.fwdarw.4:1).
This gave 1.375 g of the title compound (52% of theory).
[0978] LC-MS (Method 4): R.sub.t=1.33 min; m/z=259 (M+H).sup.+.
Example 224A
tert-Butyl 3-(3-amino-4-cyanophenyl)-2-methylpropanoate
##STR00277##
[0980] 1370 mg (5.3 mmol) of
tert-butyl(2E)-3-(3-amino-4-cyanophenyl)-2-methylacrylate were
dissolved in 30 ml of ethyl acetate, 282 mg of palladium on carbon
(10%) were added and the mixture was stirred at RT under an
atmosphere of hydrogen at atmospheric pressure for three days. The
reaction mixture was then filtered off through celite, the filter
residue was washed with ethyl acetate and the combined filtrate was
concentrated. The crude product was purified by preparative HPLC
(mobile phase acetonitrile/water). This gave 870 mg of the title
compound (63% of theory).
[0981] LC-MS (Method 6): R.sub.t=1.04 min; m/z=261 (M+H).sup.+.
[0982] The compound below was obtained analogously to Example
54A:
TABLE-US-00013 Example Name/Structure/Starting materials Analytical
Data 225A ##STR00278## GC-MS (Method 1): R.sub.t = 5.34 min; m/z =
324/326 (M).sup.+. (from 4-bromo-1-chloro-2-methoxybenzene and
ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate)
Example 226A
Ethyl(3R)-2-[4-(2,2-dichloro-3-oxocyclobutyflphenyl]-4,4,4-trifluoro-3-met-
hylbutanoate
##STR00279##
[0984] 3.83 g (13.38 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate were
dissolved in 50 ml of diethyl ether, and 2.67 g (20.74 mmol) of
zinc-copper couple and 6.5 ml of 1,2-dimethoxyethane were added in
succession. 4 ml (36.1 mmol) of trichloroacetyl chloride were then
slowly added dropwise to the suspension obtained. The reaction
solution was then heated under reflux and stirred overnight. After
addition of dichloromethane, the reaction mixture was washed
successively with water and saturated sodium chloride solution. The
organic phase was dried over magnesium sulphate, filtered and
concentrated under reduced pressure. The crude product obtained was
purified chromatographically on silica gel (mobile phase:
cyclohexane/ethyl acetate 4:1). This gave 4.57 g (86% of theory) of
the title compound in the form of a yellowish oil which was used
without further characterization in subsequent reactions.
Example 227A
Ethyl(3R)-4,4,4-trifluoro-3-methyl-2-[4-(3-oxocyclobutyl)phenyl]butanoate
##STR00280##
[0986] 100 ml of saturated aqueous ammonium chloride solution were
added to 4.57 g (11.51 mmol) of
ethyl(3R)-2-[4-(2,2-dichloro-3-oxocyclobutyl)phenyl]-4,4,4-trifluoro-3-me-
thylbutanoate and 3.76 g (57.5 mmol) of zinc dust in 100 ml of THF,
and the mixture was then stirred at 75.degree. C. for 5 h. After
cooling to room temperature and addition of dichloromethane, the
reaction mixture was washed with water. After separation of the
phases, the aqueous phase was back-extracted three times with
dichloromethane The combined organic phases were then dried over
magnesium sulphate, filtered and concentrated under reduced
pressure. This gave 1.21 g of the title compound (32% of
theory).
[0987] GC-MS (Method 1): R.sub.t=6.52 min, m/z=286
(M-C.sub.2H.sub.2O).sup.+(diastereomer 1); R.sub.t=6.55 min,
m/z=286 (M-C.sub.2H.sub.2O).sup.+ (diastereomer 2).
[0988] MS (DCI): m/z=346 (M+NH.sub.4).sup.+.
Example 228A
Ethyl(3R)-2-[4-(3,3-difluorocyclobutyl)phenyl]-4,4,4-trifluoro-3-methylbut-
anoate
##STR00281##
[0990] Under argon, 7.3 ml (5.16 mmol) of a 50% strength solution
of 1, F-Rtrifluoro-X.sup.4-sulphanyl)-iminoThis(2-methoxyethane)
(Desoxofluor) in THF, diluted with 20 ml of toluene, were initially
charged, the mixture was cooled to 5.degree. C. and 47 .mu.l (0.37
mmol) of a 1 M boron trifluoride diethyl ether complex solution
were added slowly. The mixture was stirred at 5.degree. C. for 2 h.
1.21 g (3.69 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methyl-2-[4-(3-oxocyclobutyflphenyl]butanoate-
, dissolved in 20 ml of toluene, were then added slowly to the
reaction solution, and the mixture was then warmed to 55.degree. C.
and stirred at this temperature for 48 h. The reaction mixture was
then added to a mixture, cooled to 0.degree. C., consisting of 20
ml of toluene and 20 ml of 2 M aqueous sodium hydroxide solution.
The organic phase was separated off, and the aqueous phase was
extracted three more times with ethyl acetate. The combined organic
phases were dried over sodium sulphate. After filtration, the
solvent was removed under reduced pressure. The crude product was
purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 10:1). This gave 558 mg (43% of theory)
of the title compound as a yellowish liquid.
[0991] GC-MS (Method 1): R.sub.t=5.40 min, m/z=350
(M).sup.+(Diastereomer 1); R.sub.t=5.44 min, m/z=350 (M).sup.+
(Diastereomer 2).
[0992] MS (DCI): m/z=368 (M+NH.sub.4).sup.+.
Example 229A
Ethyl(3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbu-
tanoate
##STR00282##
[0994] 1.58 g (5.52 mmol) of
ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate, 23
mg (0.55 mmol) of sodium fluoride and 24 mg (0.11 mmol) of
2,6-di-tert-butyl 4-methylphenol were heated to 110.degree. C. and
stirred for 5 minutes. 1.9 ml (9.38 mmol) of trimethylsilyl
difluoro(fluorosulphonyl)acetate were then slowly added dropwise,
and the mixture was stirred at 110.degree. C. for 60 min (caution:
evolution of gas after about 30 min) After cooling to room
temperature and addition of ethyl acetate and saturated aqueous
sodium hydrocarbonate solution, the organic phase was separated
off, dried over magnesium sulphate, filtered and concentrated to
dryness. The crude product was purified chromatographically on
silica gel (mobile phase cyclohexane/dichloromethane 4:1). This
gave 1.5 g of the title compound (81% of theory).
[0995] GC-MS (Method 1): R.sub.t=4.99 min, m/z=336 (M).sup.+
(Diastereomer 1); R.sub.t=5.01 min, m/z=336 (M).sup.+ (Diastereomer
2).
[0996] MS (DCI): m/z=354 (M+NH.sub.4).sup.+.
[0997] The compounds listed in the table below were prepared
analogously to Example 70A:
TABLE-US-00014 Example Name/Structure/Starting material Analytical
Data 230A ##STR00283## GC-MS (Method 1): R.sub.t = 5.76 min: m/z =
322 (M).sup.+. MS (EI): m/z = 322 (M).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. [ppm] = 0.76 (d, 3H), 2.58-2.76 (m, 2H),
2.91-3.05 (m, 2H), 3.17- 3.28 (m, 1H), 3,34-3,45 (m, 1H), 3.60 (d,
1H), 7.27-7.36 (m, 4H), 12.63-12.81 (br. s, 1H). (from ethyl
(3R)-2-[4-(3,3-difluorocyclobutyl)-
phenyl]-4,4,4-trifluoro-3-methylbutanoate) 231A ##STR00284##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 12.91-12.71 (1H,
br. s), 7.41 (1H, d), 7.18 (1H, d), 6.98 (1H, dd), 3.86 (3H, s),
3.66 (1H, d), 3.40-3.19 (1H, m, partially obscured by H.sub.2O
signal), 0.79 (3H, d). LC-MS (Method 5): R.sub.t = 2.20 min; m/z =
295/297 (M - H).sup.-. (from ethyl
(3R)-2-(4-chloro-3-methoxyphenyl)-
4,4,4-trifluoro-3-methylbutanoate) 232A ##STR00285## LC-MS (Method
6): R.sub.t = 1.09 min; m/z = 307 (M - H).sup.-. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. [ppm] = 0.76 (d, 3H), 1.86-2.04 (m,
2H), 2.92-3.06 (m, 1H), 3.18- 3.29 (m, 1H), 3.61 (d, 1H), 7.27 (d,
2H), 7.34 (d, 2H), 12.72 (br. s, 1H). (from ethyl
(2S,3R)-2-[4-(2,2-difluorocyclo-
propyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate)
[0998] The compounds listed in the table below were prepared
analogously to Example 82A:
TABLE-US-00015 Example Name/Structure Analytical Data 233A
##STR00286## (2S,3R)-2-[4-(3,3-Difluoro- cyclobutyl)phenyl]-4,4,4-
trifluoro-3-methylbutanoic acid 234A ##STR00287##
(2S,3R)-2-[4-(2,2-Difluoro- cyclopropyl)phenyl]-4,4,4-
trifluoro-3-methylbutanoic acid
Example 235A
tert-Butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-me-
thylbutanoyl]amino}-phenyl)-2,2-dimethylpropanoate
##STR00288##
[1000] 400 mg (1.50 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid
were dissolved in 24 ml of dichloromethane, 320 mg (2.40 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the
mixture was stirred at room temperature for 30 min. 364 .mu.l (4.5
mmol) of pyridine and 510 mg (1.80 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate were then added,
and the mixture was stirred at room temperature for 2 h. The
reaction mixture was then concentrated under reduced pressure, and
the crude product obtained was purified by chromatography on silica
gel (mobile phase cyclohexane/ethylacetate 20:1). This gave 462 mg
of the target compound (58% of theory).
[1001] LC-MS (Method 6): R.sub.t=1.53 min; m/z=530/532
(M-H).sup.-.
[1002] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.02 (s, 3H), 1.05 (s, 3H), 1.26 (s, 9H), 2.65-2.78 (m, 2H),
3.27-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.10 (d,
1H), 6.96 (dd, 1H), 7.31 (d, 1H), 7.35 (d, 1H), 7.41-7.51 (m, 4H),
9.83 (s, 1H).
[1003] The compounds listed in the table below were prepared in an
analogous manner
TABLE-US-00016 Example Name/Structure/Starting materials Analytical
Data 236A ##STR00289## LC-MS (Method 6): R.sub.t = 1.52 min; m/z =
542/544 (M - H).sup.-. (from tert-butyl
[1-(3-amino-4-chlorophenyl)- cyclobutyl]acetate and
(2S,3R)-2-(4-chlorophenyl)- 4,4,4-trifluoro-3-methylbutanoic acid)
237A ##STR00290## LC-MS (Method 6): R.sub.t = 1.46 min; m/z = 564
(M - H).sup.-. (from ethyl (2S)-3-(3-amino-4-chlorophenyl)-2-
methylpropanoate and (2S,3R)-4,4,4-trifluoro-3-
methyl-2-[4-(1,1,1-trifluoro-2-methylpropan-2- yl)phenyl]butanoic
acid) 238A ##STR00291## LC-MS (Method 6): R.sub.t = 1.37 min; m/z =
536/538 (M - H).sup.-. (from ethyl
(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate and
4,4,4-trifluoro-3-methyl-2-
[4-(2,2,2-trifluoroethyl)phenyl]butanoic acid) 239A ##STR00292##
LC-MS (Method 6): R.sub.t = 1.37 min; m/z = 520/522 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm): 9.80 (1H, s),
7.42 (1H, d), 7.35 (2H, d), 7.25- 7.20 (1H, m), 7.06-6.96 (2H, m),
4.10 (1H, d), 3.95 (2H, q), 3.87 (3H, s), 3.49-3.34 (1H, m),
2.84-2.74 (1H, m), 2.72- 2.58 (2H, m), 1.11-1.00 (6H, m), 0.83 (3H,
d). (from ethyl (2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate
and (2S,3R)-2-(4-chloro-3-
methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoic acid) 240A
##STR00293## LC-MS (Method 6): R.sub.t = 1.43 min; m/z = 532/534 (M
+ H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm): 9.80
(1H, s), 7.42 (1H, d), 7.38 (1H, d), 7.36 (1H, d), 7.23 (1H, d),
7.07- 6.99 (2H, m), 4.09 (1H, d), 3.87 (3H, s), 3.50-3.34 (1H, m),
2.76 (2H, t), 2.46 (2H, t), 1.30 (9H, s), 0.83 (3H, d). (from
tert-butyl 3-(3-amino-4-chlorophenyl)- propanoate and
(2S,3R)-2-(4-chloro-3-
methoxyphenyl)-4,4,4-(trifluoro-3-methylbutanoic acid) 241A
##STR00294## LC-MS (Method 6): R.sub.t = 1.48 min; m/z = 528/530 (M
- H).sup.-. (from tert-butyl [1-(3-amino-4-chlorophenyl)-
cyclopropyl]acetate and (2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoic acid) 242A ##STR00295## LC-MS
(Method 6): R.sub.t = 1.39 min; m/z = 550/552 (M - H).sup.-. (from
ethyl [1-(3-amino-4-chlorophenyl)-3,3-difluoro- cyclobutyl]acetate
and (2S,3R)-2-(4-chlorophenyl)- 4,4,4-trifluoro-3-methylbutanoic
acid) 243A ##STR00296## LC-MS (Method 6): R.sub.t = 1.39 min; m/z =
507/509 (M - H).sup.-. (from tert-butyl
3-(3-amino-4-cyanophenyl)-2-methyl- propanoate and
(2S,3R)-2-(4-chlorophenyl)- 4,4,4-trifluoro-3-methylbutanoic
acid)
[1004] The compounds listed in the table below were prepared
analogously to Example 89A:
TABLE-US-00017 Example Name/Structure/Starting materials Analytical
Data 244A ##STR00297## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 9.75 (1H, s), 7.44- 7.37 (3H, m), 7.36-7.27 (3H, m),
7.02 (1H, dd), 4.10 (1H, d), 3.46-3.27 (2H, m, partially obscured
by H.sub.2O signal), 3.06-2.91 (2H, m), 2.75 (2H, t), 2.71-2.59
(2H, m), 2.45 (2H, t), 1.31 (9H, s), 0.79 (3H, d). LC-MS (Method
4): R.sub.t = 1.64 min; m/z = 558/560 (M - H).sup.-. (from
(2S,3R)-2-[4-(3,3-difluorocyclobutyl)phenyl]-
4,4,4-trifluoro-3-methylbutanoyl chloride and tert-
butyl-3-(3-amino-4-chlorophenyl)propanoate) 245A ##STR00298##
.sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm): 9.75 (1H, s),
7.40 (3H, t), 7.32 (3H, t), 6.97 (1H, dd), 4.10 (1H, d), 3.96 (2H,
q), 3.46-3.28 (2H, m, partially obscured by H.sub.2O signal).
3.06-2.91 (2H, m), 2.84-2.58 (5H, m), 1.10-1.01 (6H, m), 0.79 (3H,
d). LC-MS (Method 6): R.sub.t = 1.43 min; m/z = 544/546 (M -
H).sup.-. (from (2S,3R)-2-[4-(3,3-difluorocyclobutyl)phenyl]-
4,4,4-trifluoro-3-methylbutanoyl chloride and ethyl-
(2S)-3-(3-amino-4-chlorophenyl)-2- methylpropanoate) 246A
##STR00299## .sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm):
9.77 (1H, s), 7.42 (3H, d), 7.34 (1H, d), 7.27 (2H, d), 7.02 (1H,
dd), 4.09 (1H, d), 3.43-3.28 (1H, m, partially obscured by H.sub.2O
signal), 3.05-2.94 (1H, m), 2.75 (2H, t), 2.45 (2H, t), 2.04-1.86
(1H, m), 1.31 (9H, s), 0.78 (3H, d). LC-MS (Method 7): R.sub.t =
2.99 min; m/z = 544/546 (M - H).sup.-. (from
(2S,3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-
4,4,4-trifluoro-3-methylbutanoyl chloride and tert-
butyl-3-(3-amino-4-chlorophenyl)propanoate)
Example 247A
tert-Butyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutan-
oyl]amino}-2-methyl-phenyl)propanoate
##STR00300##
[1006] A mixture of 100 mg (0.38 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid,
88 mg (0.38 mmol) of tert-butyl
3-(3-amino-2-methylphenyl)propanoate, 213 mg (0.56 mmol) of
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) and 1 ml of pyridine in 4 ml of DMF was
stirred at room temperature overnight. After the reaction had
ended, the reaction mixture was directly, without further work-up,
separated into its components by preparative HPLC (mobile phase
acetonitrile/water). This gave 151 mg (83% of theory) of the title
compound as a colourless oil.
[1007] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 9.68 (1H,
s), 7.46 (4H, s), 7.09-6.93 (3H, m), 3.94 (1H, d), 3.43-3.28 (1H,
m, partially obscured by H.sub.2O signal), 2.78 (2H, t), 2.41 (2H,
t), 1.91 (3H, s), 1.35 (9H, s), 0.80 (3H, d).
[1008] LC-MS (Method 4): R.sub.t=1.57 min; m/z=482 (M-H).sup.-.
[1009] The following compound was obtained in an analogous
manner
TABLE-US-00018 Example Name/Structure/Starting Materials Analytical
Data 248A ##STR00301## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 10.00 (1H, s), 7.64 (1H, d), 7.41 (1H, d), 7.20 (1H,
s), 7.13 (1H, t), 7.03-6.94 (2H, m), 4.07 (1H, d), 3.87 (3H, s),
3.48-3.34 (1H, m), 2.74 (2H, t), 2.45 (2H, t), 1.30 (9H, s), 0.82
(3H, d). LC-MS (Method 6): R.sub.t = 1.38 min; m/z = 516/518 (M -
H).sup.-. (from (2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-
trifluoro-3-methylbutanoic acid and tert-butyl
3-(3-amino-4-fluorophenyl)propanoate)
Example 249A
Diethyl[2-(4-chlorophenyl)propan-2-yl]malonate
##STR00302##
[1011] Under argon, 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in
2.5 ml of diethyl ether was added slowly to 254 mg (10.45 mmol) of
magnesium turnings in 5 ml of diethyl ether. After the reaction had
started, a further 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in
2.5 ml of diethyl ether was metered into the reaction mixture. The
reaction mixture was stirred at room temperature for 30 min, 103 mg
(1.05 mmol) of copper(I) chloride were added and the mixture was
then cooled to -10.degree. C. 2.09 g (10.45 mmol) of diethyl
propan-2-ylidenemalonate were then slowly added dropwise. The
reaction mixture was subsequently heated to reflux and stirred at
this temperature for 3 h. 20 ml of ice-cold 1 M hydrochloric acid
were then added very slowly. After separation of the phases, the
aqueous phase was extracted three more times with diethyl ether.
The combined organic phases were dried over magnesium sulphate and
then concentrated to dryness. The crude product was purified by
preparative HPLC (mobile phase methanol/water 70:30). This gave 800
mg of the title compound (25% of theory).
[1012] MS (DCI): m/z=330 (M+NH.sub.4).sup.+.
[1013] GC-MS (Method 1): R.sub.t=6.19 min; m/z=312 (M).sup.+.
Example 250A
Ethyl 3-(4-chlorophenyl)-3-methylbutanoate
##STR00303##
[1015] A solution of 796 mg (2.55 mmol) of
diethyl[2-(4-chlorophenyl)propan-2-yl]malonate, 216 mg (5.10 mmol)
of lithium chloride and 46 .mu.l (2.55 mmol) of water in 5 ml of
DMSO was heated to reflux and stirred at this temperature for 4 h.
After cooling to room temperature, 20 ml of diethyl ether and 20 ml
of water were added to the reaction mixture. After separation of
the phases, the organic phase was washed three more times with
water, and the organic phase was dried over magnesium sulphate and
then concentrated to dryness. The crude product was purified by
preparative HPLC (mobile phase methanol/water 70:30). This gave 276
mg of the title compound (45% of theory).
[1016] MS (DCI): m/z=258 (M+NH.sub.4).sup.+.
[1017] GC-MS (Method 1): R.sub.t=4.99 min; m/z=240/242
(M).sup.+.
Example 251A
Ethyl 3-(4-chloro-3-nitrophenyl)-3-methylbutanoate
##STR00304##
[1019] 276 mg (1.45 mmol) of ethyl
3-(4-chlorophenyl)-3-methylbutanoate were dissolved in 10 ml of
dichloromethane, and the mixture was cooled to 0.degree. C. A
little at a time, 278 mg (1.38 mmol) of nitronium tetrafluoroborate
were then added, and the mixture was stirred at a temperature
between 0.degree. C. and 10.degree. C. for 4 h. 10 ml of water and
10 ml of dichloromethane were then added, and the phases were
separated. The organic phase was dried over magnesium sulphate and
concentrated to dryness. The residue was purified by chromatography
on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This
gave 223 mg of the title compound (68% of theory).
[1020] MS (DCI): m/z=303 (M+NH.sub.4).sup.+.
[1021] GC-MS (Method 1): R.sub.t=6.39 min; m/z=285 (M).sup.+.
[1022] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.00 (t,
3H), 1.38 (s, 6H), 2.74 (s, 2H), 3.89 (q, 2H), 7.66-7.76 (m, 2H),
8.03 (d, 1H).
Example 252A
Ethyl 3-(3-amino-4-chlorophenyl)-3-methylbutanoate
##STR00305##
[1024] 40 mg of palladium on carbon (10%) were added to a solution
of 213 mg (0.75 mmol) of ethyl
3-(4-chloro-3-nitrophenyl)-3-methylbutanoate in 10 ml of ethyl
acetate. The reaction mixture was hydrogenated at RT using a
hydrogen pressure of 1 bar overnight. The mixture was then filtered
through celite, and the filtrate was concentrated. This gave 166 mg
(87% of theory) of the target compound as a yellowish oil.
[1025] LC-MS (Method 6): R.sub.t=1.05 min; m/z=256/258
(M+H).sup.+.
[1026] The following compound was obtained analogously to Example
235A:
TABLE-US-00019 Example Name/Structure/Starting Materials Analytical
Data 253A ##STR00306## LC-MS (Method 6): R.sub.t = 1.42 min; m/z =
504/506 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6):
.delta. [ppm] = 0.80 (d, 3H), 0.98 (t, 3H), 1.32 (s, 6H), 2.58 (s,
2H), 3.30-3.43 (m, 1H, partially obscured by H.sub.2O signal), 3.86
(q, 2H), 4.14 (d, 1H), 7.20 (dd, 1H), 7.35 (d, 1H), 7.43-7.50 (m,
4H), 7.55 (d, 1H), 9.82 (s, 1H). (from ethyl
3-(3-amino-4-chlorophenyl)- 3-methylbutanoate and
(2S,3R)-2-(4-chlorophenyl)- 4,4,4-trifluoro-3-methylbutanoic
acid)
Exemplary Embodiments
[1027] General Procedure 2: Cleavage of tert-butyl esters to the
corresponding carboxylic acids using trifluoroacetic acid
[1028] At from 0.degree. C. to RT, trifluoroacetic acid (TFA) is
added dropwise to a solution of the tert-butyl ester in question in
dichloromethane (concentration about 0.1 to 2.0 mol/l; additionally
optionally a drop of water) until a dichloromethane/TFA ratio of
about 2:1 to 1:2 (v/v) is reached. The mixture is stirred at RT for
1-24 h; if required, the mixture is warmed to 40.degree. C. until
complete conversion is achieved. The reaction mixture is then
concentrated under reduced pressure. The crude product can be
purified by chromatography on silica gel (elution with
dichloromethane/ethyl acetate or cyclohexane/ethyl acetate
mixtures, if appropriate with addition of small amounts of acetic
acid, or with dichloromethane/methanol mixtures), by
crystallization from acetonitrile or water/acetonitrile mixtures or
by preparative RP-HPLC (mobile phase: acetonitrile/water
gradient).
[1029] The following examples were prepared according to General
Procedure 2:
TABLE-US-00020 Example Name/Structure/Starting Material Analytical
Data 1 ##STR00307## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 12.65-11.44 (1H, br. s), 9.72 (1H, s), 7.45 (1H, d),
7.35 (3H, t), 7.24 (2H, d), 7.03 (1H, dd), 4.07 (1H, d), 3.39-3.24
(1H, m), 2.94-2.81 (1H, m), 2.76 (2H, t), 2.48 (2H, t), 1.19 (6H,
d), 0.79 (3H, d). LC-MS (Method 5): R.sub.t = 2.69 min; m/z = 456
(M + H).sup.+. [.alpha.].sub.D.sup.20 = +102.5.degree., c = 0.44,
methanol. (from tert-butyl 3-(4-chloro-3-{[(2S,3R)-4,4,4-
trifluoro-2-(4-isopropylphenyl)-3-methylbutanoyl]-
amino}phenyl)propanoate) 2 ##STR00308## .sup.1H-NMR (400 MHz, DMSO-
d.sub.6, .delta./ppm): 12.11 (1H, s), 9.72 (1H, s), 7.47 (1H, d),
7.41-7.35 (4H, m), 7.33 (1H, d), 7.03 (1H, dd), 4.08 (1H, d), 3.39-
3.24 (1H, m), 2.76 (2H, t), 2.48 (2H, t), 1.27 (9H, s), 0.79 (3H,
d). LC-MS (Method 4): R.sub.t = 1.47 min; m/z = 470 (M + H).sup.+.
[.alpha.].sub.D.sup.20 = +94.9.degree., c = 0.42, methanol. (from
tert-butyl-3-(3-{[(2S,3R)-2-(4-tert-butyl-
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
4-chlorophenyl)propanoate) 3 ##STR00309## .sup.1H-NMR (400 MHz,
DMSO- d.sub.6, .delta./ppm): 12.49-11.83 (1H, br. s), 9.89 (1H, s),
7.77 (2H, d), 7.69 (2H, d), 7.39 (1H, d), 7.35 (1H, d), 7.05 (1H,
dd), 4.24 (1H, d), 3.59-3.26 (1H, m), 2.76 (2H, t), 2.48 (2H, t),
0.80 (3H, d). LC-MS (Method 4): R.sub.t = 1.34 min; m/z = 482 (M +
H).sup.+. (from tert-butyl 3-[4-chloro-3-({(2S,3R)-4,4,4-
trifluoro-3-methyl-2-[4-(trifluoromethyl)phenyl]-
butanoyl}amino)phenyl]propanoate) 4 ##STR00310## .sup.1H-NMR (400
MHz, DMSO- d.sub.6, .delta./ppm): 12.11 (1H, s), 9.78 (1H, s), 7.54
(2H, d), 7.51-7.42 (3H, m), 7.34 (1H, d), 7.03 (1H, dd), 4.14 (1H,
d), 3.42- 3.26 (1H, m), 2.76 (2H, t), 2.48 (2H, t), 1.55 (6H, s),
0.79 (3H, d). LC-MS (Method 6): R.sub.t = 1.24 min; m/z = 524 (M +
H).sup.+. [.alpha.].sub.D.sup.20 = +72.1.degree., c = 0.43,
methanol. (from tert-butyl 3-[4-chloro-3-({(2S,3R)-4,4,4-
trifluoro-3-methyl-2-[4-(1,1,1-trifluoro-2-
methylpropan-2-yl)phenyl]butanoyl}- amino)phenyl]propanoate) 5
##STR00311## .sup.1H-NMR (400 MHz, DMSO- d.sub.6, .delta./ppm):
12.11 (1H, s), 9.79 (1H, s), 7.46 (2H, d), 7.41 (1H, d), 7.35 (3H,
t), 7.04 (1H. dd), 4.11 (1H, d), 3.64 (2H, q), 3.44-3.26 (1H, m),
2.76 (2H, t), 2.48 (2H, t), 0.79 (3H, d). LC-MS (Method 4): R.sub.t
= 1.33 min; m/z = 496 (M + H).sup.+. (from tert-butyl
3-[4-chloro-3-({4,4,4-trifluoro-
3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-
butanoyl}amino)phenyl]propanoate) 6 ##STR00312## .sup.1H-NMR (400
MHz, DMSO- d.sub.6, .delta./ppm): 12.13 (1H.s), 9.79 (0.5H, s),
9.75 (0.5H, s), 7.48- 7.34 (6H, m), 7.07 (1H, d), 3.78 (0.5H, d),
3.75 (0.5H, d), 3.58-3.45 (0.5H, m), 3.43-3.26 (0.5H, m), 2.92-2.81
(1H, m), 2.77 (2H, t), 2.57-2.45 (2H, t), 2.44-1.80 (3H, m),
1.71-1.45 (1.5H, m), 1.35-1.20 (0.5H, m). LC-MS (Method 6): R.sub.t
= 1.15 min; m/z = 456/458 (M + H).sup.+. (from tert-butyl
3-(4-chloro-3-{[(4-chlorophenyl)-
(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- propanoate) 7
##STR00313## LC-MS (Method 6): R.sub.t = 1.24 min; m/z = 456 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.79 (d, 3H), 1.12-1.21 (m, 6H), 2.45 (d, 2H), 2.59 (q, 2H),
3.03-3.13 (m, 1H), 3.32 (d, 1H), 4.07 (d, 1H), 7.06 (d, 1H), 7.20
(d, 2H), 7.31-7.38 (m, 3H), 7.47 (d, 1H), 9.69 (s, 1H), 12.03 (br.
s, 1H). 8 ##STR00314## LC-MS (Method 4): R.sub.t = 1.45 min; m/z =
462 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta.
[ppm] = 0.80 (d, 3H), 1.16 (d, 3H), 2.45 (d, 2H), 3.01-3.14 (m,
1H), 3.34-3.42 (m, 1H), 4.13 (d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H),
7.40- 7.50 (m, 5H), 9.81 (s, 1H), 12.06 (s, 1H). 9 ##STR00315##
LC-MS (Method 5): R.sub.t = 2.47 min; m/z = 446 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.79 (d, 3H),
1.15/1.16 (2d, together 3H), 2.44 (d, 2H), 3.02-3.13 (m, 1H),
3.34-3.42 (m, 1H), 4.12 (d, 1H), 6.97-7.06 (m, 1H), 7.13 (dd, 1H),
7.40-7.49 (m, 4H), 7.67 (d, 1H), 10.03 (s, 1H), 12.05 (br. s, 1H).
10 ##STR00316## LC-MS (Method 6): R.sub.t = 1.17 min; m/z = 470 (M
+ H).sup.+ and R.sub.t = 1.19 min; m/z = 470 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 1.11-1.19 (m,
3H), 1.45-1.78 (m, 3H), 2.00- 2.26 (m, 2H), 2.45/2.46 (2d, together
2H), 2.88-3.17 (m, 2H), 4.04/4.07 (2d, together 1H), 6.99-7.13 (m,
1H), 7.30- 7.44 (m, 3H), 7.44-7.52 (m, 2H), 9.64/9.84 (2s, together
1H), 12.07 (br. s, 1H). 11 ##STR00317## LC-MS (Method 6): R.sub.t =
1.16 min; m/z = 456 (M + H).sup.+ and R.sub.t = 1.18 min; m/z = 456
(M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm]
= 1.11-1.81 (m, 3H), 1.96-2.26 (m, 2H), 2.48 (t, 2H), 2.76 (t, 2H),
2.86-3.20 (m, 1H), 4.03/4.07 (2d, together 1H), 6.98-7.09 (m, 1H),
7.29-7.54 (m, 6H), 9.64/9.85 (2s, together 1H), 12.09 (br. s,
1H).
Example 12
(+)-3-(4-Fluoro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)buta-
noyl]amino}phenyl)-propanoic acid
##STR00318##
[1031] 283 mg (0.590 mmol) of
tert-butyl(+)-3-(4-fluoro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-vinyl-
phenyl)butanoyl]amino}phenyl)propanoate were dissolved in 5.9 ml of
a 4 N solution of hydrogen chloride in dioxane, and the mixture was
stirred at RT for 24 h. The volatile components were then removed
under reduced pressure. The residue was purified by two preparative
R.sup.P-HPLCs (mobile phase: acetonitrile/water gradient). This
gave 48 mg (19.2% of theory) of the title compound.
[1032] LC-MS (Method 6): R.sub.t=1.14 min; m/z=424 (M+H).sup.+.
[1033] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 2.63-2.82 (m, 4H), 3.58-3.66 (m, 1H), 4.08 (d, 1H), 5.27 (d,
1H), 5.83 (d, 1H), 6.72 (dd, 1H), 6.89-7.03 (m, 1H), 7.12 (dd, 1H),
7.41 (d, 2H), 7.47 (d, 2H), 7.65 (dd, 1H), 10.00 (s, 1H), 12.12
(br. s, 1H).
[1034] [.alpha.].sub.D.sup.20=+149.5.degree., c=0.310,
chloroform.
Example 13
(+)-3-(4-Chloro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)buta-
noyl]amino}phenyl)-propanoic acid
##STR00319##
[1036] 249.0 mg (0.502 mmol) of
tert-butyl(+)-3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-vinyl-
phenyl)butanoyl]amino}phenyl)propanoate were dissolved in 3.8 ml of
a 4 N solution of hydrogen chloride in dioxane, and the mixture was
stirred at RT for 24 h. The reaction mixture was then frozen
(-78.degree. C.) and subsequently lyophilized under high vacuum.
The residue was purified by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient). This gave 167.4 mg (75.8% of theory)
of the title compound.
[1037] LC-MS (Method 6): R.sub.t=1.16 min; m/z=440 (M+H).sup.+.
[1038] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 2.48 (t, 2H), 2.76 (t, 2H), 3.35-3.42 (m, 1H), 4.09 (d, 1H),
5.27 (d, 1H), 5.84 (d, 1H), 6.73 (dd, 1H), 7.04 (dd, 1H), 7.34 (d,
1H), 7.39-7.52 (m, 5H), 9.79 (s, 1H), 12.14 (br. s, 1H).
[1039] [.alpha.].sub.D.sup.20=+88.8.degree., c=0.325,
chloroform.
Example 14
(+)-3-[4-Chloro-3-({(2S,3R)-4,4,4-trifluoro-2-[4-(1-fluorovinyflphenyl]-3--
methylbutanoyl}amino)-phenyl]propanoic acid
##STR00320##
[1041] 16.1 mg (0.674 mmol) of lithium hydroxide were added to a
solution, cooled to 0.degree. C., of 212 mg (0.449 mmol) of
(+)-3-[4-chloro-3-({2S,3R)-4,4,4-trifluoro-2-[4-(1-fluorovinyl)phenyl]-3--
methylbutanoyl}amino)phenyl]propanoate in a mixture of in each case
1.0 ml of methanol, of THF and of water. The mixture was then
warmed to RT and stirred at RT for 3 h, then diluted with water and
acidified with 1 N hydrochloric acid (pH about 2). The mixture was
extracted three times with ethyl acetate. The organic phases were
combined and concentrated under reduced pressure. The crude product
was initially pre-purified by RP-HPLC (mobile phase:
acetonitrile/water gradient). The 2R diastereomer formed during
basic hydrolysis was then removed by preparative HPLC on a chiral
phase [column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm;
injection volume: 0.25 ml; temperature: 35.degree. C.; mobile
phase: 90% isohexane/10% ethanol; flow rate: 15 ml/min; detection:
220 nm]. This gave 74.0 mg (36.0% of theory) of the title
compound.
[1042] LC-MS (Method 4): R.sub.t=1.33 min; m/z=458 (M+H).sup.+.
[1043] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.81 (d,
3H), 2.47 (t, 2H), 2.76 (t, 2H), 3.35-3.43 (m, 1H), 4.15 (d, 1H),
4.95 (dd, 1H), 5.39 (dd, 1H), 7.04 (dd, 1H), 7.26-7.44 (m, 2H),
7.44-7.59 (m, 2H), 7.59-7.68 (m, 2H), 9.82 (s, 1H), 12.11 (br. s,
1H).
[1044] [.alpha.].sub.D.sup.20=+69.2.degree., c=0.405,
chloroform.
Example 15
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-
anoyl]amino}phenyl)-propanoic acid
##STR00321##
[1046] 30.13 g (59.74 mmol) of tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)propanoate were dissolved in 1000 ml of
dichloromethane, and 92 ml of trifluoroacetic acid were added at
RT. The reaction mixture was stirred at RT for 3.5 h.
Dichloromethane and water were then added. The organic phase was
separated off, dried over magnesium sulphate and concentrated under
reduced pressure. The residue was dried thoroughly under high
vacuum. This gave 26.31 g (98.3% of theory) of the target
compound.
[1047] LC-MS (Method 7): R.sub.t=2.51 min; m/z=446/448
(M-H).sup.-.
[1048] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 12.14 (1H,
s), 9.83 (1H, s), 7.50-7.43 (4H, m), 7.39 (1H, d), 7.35 (1H, d),
7.05 (1H, dd), 4.12 (1H, d), 3.43-3.28 (1H, m), 2.76 (2H, t), 2.48
(2H, t), 0.80 (3H, d).
[1049] [.alpha.].sub.D.sup.20=+100.1.degree., c=0.42, methanol.
Example 16
(+)-(2R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)-2-methylpropanoic acid
##STR00322##
[1051] 990 mg (2.02 mmol) of
ethyl(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-me-
thylbutanoyl]amino}phenyl)-2-methylpropanoate were dissolved in 5.7
ml of acetic acid, and 2.7 ml of concentrated hydrochloric acid
were added. The mixture was stirred at 100.degree. C. for 1 h.
After cooling, the mixture was concentrated under reduced pressure.
The residue was taken up in ethyl acetate and washed repeatedly
with water with addition of a few drops of saturated sodium
bicarbonate solution. The organic phase was dried over magnesium
sulphate and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (mobile phase: initially
dichloromethane, then dichloromethane/ethyl acetate 10:1). This
gave 652 mg (69.9% of theory) of the title compound.
[1052] LC-MS (Method 6): R.sub.t=1.21 min; m/z=462 (M+H).sup.+.
[1053] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.02 (d, 3H), 2.55-2.62 (m, 2H), 2.78-2.88 (m, 1H), 3.35-3.43
(m, 1H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.32-7.39 (m, 2H), 7.42-7.50
(m, 4H), 9.83 (s, 1H), 12.16 (br. s, 1H).
[1054] [.alpha.].sub.D.sup.20=+60.56.degree., c=0.530,
chloroform.
Example 17
(+)-(2S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)-2-methylpropanoic acid
##STR00323##
[1055] Method A:
[1056] A mixture of 2.45 g (5.0 mmol) of
ethyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-me-
thylbutanoyl]amino}phenyl)-2-methylpropanoate, 6.0 ml of acetic
acid and 20 ml of 20% strength aqueous sulphuric acid was stirred
under reflux for 7 h. After cooling, the reaction mixture was added
to water. The aqueous phase was extracted three times with ethyl
acetate, and the combined organic phases were concentrated under
reduced pressure. The residue was once more taken up in ethyl
acetate and washed repeatedly with water with addition of a few
drops of saturated sodium bicarbonate solution. The organic phase
was dried over magnesium sulphate and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate
10:1.fwdarw.4:1). This gave 1.88 g (81.4% of theory) of the title
compound.
[1057] LC-MS (Method 6): R.sub.t=1.22 min; m/z=462 (M+H).sup.+.
[1058] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.02 (d, 3H), 2.55-2.61 (m, 2H), 2.78-2.88 (m, 1H), 3.35-3.43
(m, 1H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.32-7.39 (m, 2H), 7.43-7.50
(m, 4H), 9.83 (s, 1H), 12.16 (br. s, 1H).
[1059] [.alpha.].sub.D.sup.20=+101.2.degree., c=0.590,
chloroform.
Method B:
[1060] A mixture of 12.99 g (26.49 mmol) of
(+)-ethyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro--
3-methylbutanoyl]amino}phenyl)-2-methylpropanoate, 60 ml of acetic
acid and 60 ml of 30% strength aqueous sulphuric acid was stirred
under reflux for 3 h (bath temperature 140.degree. C.). After
cooling, the reaction mixture was added to water. The aqueous phase
was extracted three times with ethyl acetate, and the combined
organic phases were washed with saturated sodium chloride solution,
dried over sodium sulphate and concentrated under reduced pressure.
The residue was dried under high vacuum overnight. The crude
product obtained in this manner was stirred with 90 ml of
diisopropyl ether, initially at 50.degree. C. for 1 h and then at
RT for 4 h. After filtration, the solid was dried under high
vacuum. This gave 7.84 g (64% of theory) of the target compound
(fraction 1). A further charge was isolated from the filtrate after
concentration and renewed treatment with 30 ml of diisopropyl
ether. Drying under high vacuum gave 1.65 g (13.5% of theory) of
slightly contaminated target compound (fraction 2).
[1061] LC-MS (Method 4): R.sub.t=1.39 min; m/z=461/463
(M+H).sup.+.
[1062] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.02 (d, 3H), 2.55-2.61 (m, 2H), 2.77-2.88 (m, 1H), 3.34-3.43
(m, 1H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.31-7.39 (m, 2H), 7.41-7.51
(m, 4H), 9.83 (s, 1H), 12.15 (s, 1H).
[1063] [.alpha.].sub.D.sup.20=+127.6.degree., c=0.575,
chloroform.
Example 18
(+)-[1-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]am-
ino}-4-fluorophenyl)-cyclopropyl]acetic acid
##STR00324##
[1065] 106 mg (0.23 mmol) of
methyl[1-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butanoy-
l]amino}-4-fluorophenyl)cyclopropyl]acetate were dissolved in 4 ml
of glacial acetic acid and 2 ml of concentrated hydrochloric acid,
and the mixture was stirred at 100.degree. C. for 1 h. The reaction
mixture was then diluted with 10 ml of water and the aqueous
solution was subsequently extracted three times with in each case
10 ml of ethyl acetate. The combined organic phases were dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product obtained was purified by preparative RP-HPLC (mobile
phase: acetonitrile/water gradient). This gave 64 mg of the title
compound (0.14 mmol, 89% of theory).
[1066] LC-MS (Method 4): R.sub.t=1.34 min; m/z=458 (M+H).sup.+.
[1067] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 10.03 (1H,
s), 7.69-7.59 (1H, m), 7.52-7.34 (4H, m), 7.11-7.00 (2H, m), 4.11
(1H, d), 3.43-3.27 (1H, m), 2.36 (2H, s), 0.88-0.82 (2H, m), 0.78
(3H, d), 0.72-0.64 (2H, m).
[1068] [.alpha.].sub.D.sup.20=108.7.degree., c=0.36, methanol.
[1069] General Procedure 3: Cleavage of ethyl or methyl esters to
the corresponding carboxylic acids using a mixture of hydrochloric
acid or sulphuric acid with acetic acid
[1070] A solution of the ethyl or methyl ester in question in a
mixture of acetic acid and concentrated hydrochloric acid or of
acetic acid and 10% strength or semi-concentrated sulphuric acid is
stirred at temperatures of from 80.degree. C. to 130.degree. C. (if
appropriate under reflux) for 30 min to 12 h. After cooling, the
reaction mixture is either concentrated directly under reduced
pressure or added to water, the aqueous phase is extracted with
ethyl acetate or dichloromethane and the combined organic phases
are concentrated under reduced pressure. The crude product can be
purified by chromatography on silica gel (elution with
dichloromethane/ethyl acetate or cyclohexane/ethyl acetate
mixtures, if appropriate with addition of small amounts of acetic
acid, or with dichloromethane/methanol mixtures), by
crystallization from acetonitrile or water/acetonitrile mixtures or
by preparative RP-HPLC (mobile phase: acetonitrile/water
gradient).
[1071] The examples below were prepared according to General
Procedure 3:
TABLE-US-00021 Example Name/Structure/Starting Material Analytical
Data 19 ##STR00325## .sup.1H-NMR (400 MHz, DMSO- d.sub.6,
.delta./ppm): 11.97 (1H, s), 9.96 (1H, s), 7.75 (1H, dd), 7.34 (2H,
d), 7.20 (2H, d), 7.09 (1H, t), 7.05-6.99 (1H, m), 4.05 (1H, d),
3.40-3.27 (1H, m), 2.59 (2H, q), 2.55-2.48 (2H, m), 1.17 (3H, t),
0.88- 0.82 (2H, m), 0.79-0.74 (5H, m). LC-MS (Method 5): R.sub.t =
2.58 min; m/z = 452 (M + H).sup.+. [.alpha.].sub.D.sup.20 =
+125.2.degree., c = 0.35, methanol. (from methyl
[1-(3-{[(2S,3R)-2-(4-ethylphenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-
4-fluorophenyl)cyclopropyl]acetate) 20 ##STR00326## LC-MS (Method
6): R.sub.t = 1.21 min; m/z = 470/472 (M).sup.+. (from ethyl
(2S)-3-(4-chloro-3-{[(4-chlorophcnyl)-
(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 2-methylpropanoate)
21 ##STR00327## I.C-MS (Method 6): R.sub.t = 1.21 min; m/z =
470/472 (M).sup.+. (from ethyl
(2R)-3-(4-chloro-3-{[(4-chlorophenyl)-
(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 2-methylpropanoate)
22 ##STR00328## LC-MS (Method 5): R.sub.t = 2.57 min; m/z = 462 (M
+ H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.80 (d, 3H), 1.02 (d, 3H), 2.55-2.61 (m, 2H), 2.77-2.89 (m, 1H).
3.33- 3.42 (m, 1H), 4.12 (d, 1H), 7.01 (dd. 1H), 7.30-7.40 (m, 2H),
7.41-7.51 (m, 4H), 9.82 (s, 1H), 12.14 (br. s, 1H). 23 ##STR00329##
LC-MS (Method 6): R.sub.t = 1.22 min; m/z = 440 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.77 (d, 3H),
1.01 (d, 3H), 1.17 (t, 3H), 2.53-2.62 (m, about 4H), 2.77- 2.87 (m,
1H), 3.27-3.38 (m, about 1H), 4.05 (d, 1H), 6.86- 6.98 (m, 1H),
7.11 (dd, 1H), 7.16-7.23 (m, 2H), 7.29-7.37 (m, 2H), 7.66 (dt, 1H),
9.97 (s, 1H), 12.14 (br. s, 1H). 24 ##STR00330## LC-MS (Method 6):
R.sub.t = 1.27 min; m/z = 456 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO- d.sub.6): .delta. [ppm] = 0.79 (d, 3H), 1.02 (d, 3H), 1.17
(t, 3H), 2.55-2.64 (m, about 4H), 2.77- 2.88 (m, 1H), 3.27-3.38 (m,
about 1H) 4.06 (d. 1H), 6.99 (dd, 1H), 7.21 (d, 2H), 7.34 (dd, 3H),
7.41 (d, 1H), 9.74 (s, 1H), 12.20 (br. s, 1H). 25 ##STR00331##
LC-MS (Method 6): R.sub.t = 1.17 min; m/z = 470 (M + H).sup.+ and
R.sub.t = 1.19 min; m/z = 470 (M + H).sup.+. .sup.1H-NMR (400 MHz,
DMSO- d.sub.6): .delta. [ppm] = 1.02 (d, 3H), 1.11-1.26 (m, 1H),
1.48-1.78 (m, 3H), 1.99-2.24 (m, 2H), 2.55-2.62 (m, about 2H),
2.77- 2.86 (m, 1H), 2.87-3.20 (m, 1H), 4.02/4.06 (2d, together 1H),
6.99/7.01 (2dd, together 1H), 7.30-7.45 (m, 4H), 7.45- 7.51 (m,
2H), 9.64 (s, 1H), 12.14 (br. s, 1H). 26 ##STR00332## LC-MS (Method
6): R.sub.t = 1.26 min; m/z = 476 (M + H).sup.+. .sup.1H-NMR (400
MHz, DMSO- d.sub.6): .delta. [ppm] = 0.74-0.89 (m, 6H), 1.40-1.53
(m, 2H), 2.30- 2.45 (m, 1H), 2.46-2.55 (m, about 1H), 2.57-2.68 (m,
1H), 2.68-2.81 (m, 1H), 3.36-3.44 (m, about 1H), 4.12 (d, 1H), 7.00
(dd, 1H), 7.29-7.40 (m, 2H), 7.41-7.51 (m, 4H), 9.82 (s, 1H), 12.15
(br. s, 1H).
Example 27
(+)-[3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbu-
tanoyl]amino}phenyl)-oxetan-3-yl]acetic acid
##STR00333##
[1073] 25 mg of palladium on carbon (10%) were added to a solution
of 120 mg (0.21 mmol) of
benzyl[3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methy-
lbutanoyl]amino}-phenyl)oxetan-3-yl]acetate in 15 ml of ethyl
acetate. Under an atmosphere of hydrogen, the mixture was
hydrogenated at atmospheric pressure for 2 h. The reaction mixture
was then filtered through Tonsil, the filter residue was washed
with ethyl acetate and the combined filtrates were concentrated on
a rotary evaporator. This gave 98 mg (0.2 mmol, 97% of theory) of
the title compound.
[1074] LC-MS (Method 4): R.sub.t=1.28 min; m/z=488/490
(M-H).sup.-.
[1075] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm):
12.76-11.52 (1H, br. s), 9.88 (1H, s), 7.52 (1H, d), 7.50-7.39 (5H,
m), 7.10 (1H, dd), 4.79-4.71 (2H, m), 4.71-4.64 (2H, m), 4.14 (1H,
d), 3.42-3.28 (1H, m), 3.03 (2H, s), 0.80 (3H, d).
[1076] [.alpha.].sub.D.sup.20=+88.4.degree., c=0.355, methanol.
Example 28
[1-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino }-phenyl)cyclo-butyl]acetic acid
##STR00334##
[1078] 38 mg (0.08 mmol) of
methyl-[1-(4-chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl--
butanoyl]amino}phenyl)cyclobutyl]acetate were dissolved in 9.5 ml
of dioxane, and 0.15 ml of 1 N aqueous sodium hydroxide solution
was added. The mixture was stirred at 80.degree. C. overnight. The
reaction mixture was then acidified with 1 N hydrochloric acid to
pH 1 and extracted repeatedly with ethyl acetate. The combined
organic phases were washed with saturated sodium chloride solution,
dried over sodium sulphate and concentrated under reduced pressure.
The crude product was purified by preferative HPLC. This gave 22 mg
(0.05 mmol, 60% of theory) of the target compound.
[1079] LC-MS (Method 6): R.sub.t=1.28 min; m/z=488/490
(M+H).sup.+.
[1080] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm): 11.88 (1H,
br. s), 9.95 (0.5H, s), 9.81 (0.5H, s), 7.54-7.31 (6H, m),
7.06-6.96 (1H, m), 4.14 (1H, d), 3.43-3.27 (0.5H, m), 3.27-3.14
(0.5H, m), 2.70 (1H, s), 2.69 (1H, s), 2.34-2.17 (4H, m), 2.10-1.95
(1H, m), 1.81-1.66 (1H, m), 1.25 (1.5H, d), 0.80 (1.5H, d).
Example 29
(+)-(2R)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-benzyl)butanoic acid
##STR00335##
[1082] 15.2 ml of acetic acid and 7.6 ml of concentrated
hydrochloric acid were added to 1.96 g (3.89 mmol) of
ethyl(+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro--
3-methylbutanoyl]amino}benzyl)butanoate. The reaction mixture was
stirred under reflux for 5 h (bath temperature 140.degree. C.).
After cooling, water was added. The mixture was extracted
repeatedly with dichloromethane, and the combined organic phases
were washed with saturated sodium chloride solution, dried over
sodium sulphate and concentrated under reduced pressure.
Chromatography of the residue on silica gel (mobile phase
cyclohexane/ethyl acetate 10:1.fwdarw.2:1) gave 1.46 g (78.6% of
theory) of the title compound.
[1083] LC-MS (Method 6): R.sub.t=1.25 min; m/z=476 (M+H).sup.+.
[1084] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 0.82-0.89 (m, 3H), 1.42-1.54 (m, 2H), 2.41 (t, 1H), 2.64 (dd,
1H), 2.75 (dd, 1H), 4.12 (d, 1H), 7.00 (dd, 1H), 7.31-7.39 (m, 1H),
7.42-7.50 (m, 3H), 9.82 (s, 1H), 12.16 (br. s, 1H).
[1085] [.alpha.].sub.D.sup.20=92.7.degree., c=0.380, methanol.
[1086] The compound below was prepared according to an analogous
procedure:
Example 30
(+)-(2S)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-benzyl)butanoic acid
##STR00336##
[1088] LC-MS (Method 5): R.sub.t=2.66 min; m/z=476 (M+H).sup.+.
[1089] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 0.85 (t, 3H), 1.43-1.52 (m, 2H), 2.26-2.47 (m, 1H), 2.59-2.69
(m, 1H), 2.70-2.82 (m, 1H), 3.34-3.44 (m, 1H), 4.12 (d, 1H), 7.00
(dd, 1H), 7.30-7.39 (m, 2H), 7.40-7.52 (m, 4H), 9.82 (s, 1H), 12.13
(br. s, 1H).
[1090] [.alpha.].sub.D.sup.20=+143.1.degree., c=0.380,
chloroform.
Example 31 and Example 32
3-[4-Chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl-
]butanoyl}amino)-phenyl]propanoic acid (enantiomers 1 and 2)
##STR00337##
[1092] 120 mg (0.24 mmol) of the racemic
3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoro-ethyl]phen-
yEbutanoyl}amino)phenyl]propanoic acid (Example 5) were separated
into the enantiomers by preparative HPLC on a chiral phase [column:
Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol 85:15 (v/v); flow rate: 15 ml/min; UV detection:
220 nm; temperature: 35.degree. C.]:
Example 31
(+)-3-[4-Chloro-3-({(2S,3R)-4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoro-
ethyl)phenyl]butanoyl}-amino)phenyl]propanoic acid (enantiomer
1)
##STR00338##
[1094] Yield: 48 mg
[1095] R.sub.t=5.75 min; chemical purity >99%; >99% ee
[1096] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/(ethanol+0.2% TFA+1% water) 85:15
(v/v); flow rate: 1 ml/min; temperature: 35.degree. C.; UV
detection: 220 nm].
[1097] [.alpha.].sub.D.sup.20=+91.8.degree., c=0.405, methanol.
[1098] LC-MS (Method 4): R.sub.t=1.33 min; m/z=496 (M+H).sup.+.
[1099] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta./ppm):
12.24-12.02 (1H, br. s), 9.80 (1H, s), 7.46 (2H, d), 7.43-7.39 (1H,
m), 7.35 (3H, t), 7.04 (1H, dd), 4.11 (1H, d), 3.64 (2H, q),
3.44-3.27 (1H, m), 2.76 (2H, t), 2.48 (2H, t), 0.79 (3H, d).
Example 32
(-)-3-[4-Chloro-3-({(2R,3S)-4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoro-
ethyl)phenyl]butanoyl}-amino)phenyl]propanoic acid (enantiomer
2)
##STR00339##
[1101] Yield: 52 mg
[1102] R.sub.t=6.85 min; chemical purity >97.4%; >99% ee
[1103] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/(ethanol+0.2% TFA+1% water) 85:15
(v/v); flow rate: 1 ml/min; temperature: 35.degree. C.; UV
detection: 220 nm].
[1104] [.alpha.].sub.D.sup.20=-94.3.degree., c=0.40, methanol
[1105] LC-MS (Method 4): R.sub.t=1.33 min; m/z=496 (M+H).sup.+.
Examples 33-36
3-(4-Chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amino}phen-
yl)propanoic acid (isomers 1-4)
##STR00340##
[1107] 44 mg (0.096 mmol) of the diastereomer mixture of
3-(4-chloro-3-{[(4-chlorophenyl)(3,3-difluoro-cyclopentyl)acetyl]amino}ph-
enyl)propanoic acid (Example 6) were separated further by
preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H,
5 .mu.m, 250 mm.times.20 mm; mobile phase: isohexane/ethanol 70:30
(v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature:
35.degree. C.]. This gave four different fractions each consisting
of a mixture of two isomers. By repeat preparative HPLC on a chiral
phase, these fractions were separated into the individual isomers
[fractions 1 and 2: column: Daicel Chiralpak AS-H, 5 .mu.m, 250
mm.times.20 mm; mobile phase: isohexane/isopropanol 75:25 (v/v);
flow rate: 15 ml/min; UV detection: 220 nm; temperature: 35.degree.
C. Fractions 3 and 4: column: Daicel Chiralpak AD-H, 5 .mu.m, 250
mm.times.20 mm; mobile phase: isohexane/ethanol 80:20 (v/v); flow
rate: 15 ml/min; UV detection: 220 nm; temperature: 35.degree.
C.]:
Example 33
Isomer 1
[1108] Yield: 8 mg
[1109] R.sub.t=6.49 min; chemical purity >99%
[1110] [Column: Daicel Chiralpak AS-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/isopropanol 75:25 (v/v); flow rate: 1
ml/min; UV detection: 220 nm; temperature: 35.degree. C.].
Example 34
Isomer 2
[1111] Yield: 11 mg
[1112] R.sub.t=9.08 min; chemical purity >98.5%
[1113] [Column: Daicel Chiralpak AS-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/isopropanol 75:25 (v/v); flow rate: 1
ml/min; UV detection: 220 nm; temperature: 35.degree. C.].
Example 35
Isomer 3
[1114] Yield: 12 mg
[1115] R.sub.t=7.19 min; chemical purity >99%
[1116] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/ethanol 80:20 (v/v); flow rate: 1
ml/min; UV detection: 220 nm; temperature: 30.degree. C.].
Example 36
Isomer 4
[1117] Yield: 9 mg
[1118] R.sub.t=8.58 min; chemical purity >97.5%
[1119] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4.6
mm; mobile phase: isohexane/ethanol 80:20 (v/v); flow rate: 1
ml/min; UV detection: 220 nm; temperature: 30.degree. C.].
Example 37
3-(3-{[(3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-f-
luorophenyl)-2-methylpropanoic acid (Diastereomer Mixture)
##STR00341##
[1121] 300 mg (0.633 mmol) of ethyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
-4-fluorophenyl)-2-methylpropanoate (Diastereomer Mixture) were
dissolved in a mixture of in each case 1.0 ml of methanol, THF and
water, and 265.5 mg (6.33 mmol) of lithium hydroxide were added at
0.degree. C. The mixture was stirred initially at 0.degree. C. for
1 h and then at RT for 1 h. The solution was then diluted with
water and acidified with 1 N hydrochloric acid (pH about 2). The
aqueous phase was extracted three times with diethyl ether and once
with ethyl acetate. The combined organic phases were dried over
sodium sulphate and concentrated under reduced pressure. This gave
294 mg (99.7% of theory) of the title compound as a mixture of four
diastereomers.
[1122] LC-MS (Method 6): R.sub.t=1.18 min; m/z=446 (M+H).sup.+.
Example 38 and Example 39
3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-fluorophenyl)-2-methylpropanoic acid (diastereomers 1 and 2)
##STR00342##
[1124] The mixture obtained above of the diastereomeric
3-(3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4--
fluorophenyl)-2-methylpropanoic acids (Example 37) was separated
further by preparative HPLC on a chiral phase [column: Daicel
Chiralpak AS-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.25
ml; temperature: 40.degree. C.; mobile phase: 90% isohexane/10%
(ethanol+0.2% TFA+1% water); flow rate: 15 ml/min; detection: 220
nm]. 260 mg of diastereomer mixture gave, in addition to two
further isomers, 52 mg of isomer 1 (Example 38) and 54 mg of isomer
2 (Example 39):
Example 38
Diastereomer 1
(+)-(2S)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-fluoro-phenyl)-2-methylpropanoic acid
##STR00343##
[1126] Isomer 1 was repurified again by preparative RP-HPLC (mobile
phase acetonitrile/water). This gave 32 mg.
[1127] LC-MS (Method 6): R.sub.t=1.18 min; m/z=446 (M+H).+-..
[1128] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.01 (d, 3H), 2.51-2.58 (m, 2H), 2.76-2.86 (m, 1H), 3.35 (dd,
1H), 4.11 (d, 1H), 6.87-7.00 (m, 1H), 7.12 (dd, 1H), 7.41-7.49 (m,
4H), 7.63 (dd, 1H), 10.04 (s, 1H), 12.11 (br. s, 1H).
[1129] [.alpha.].sub.D.sup.20=+150.4.degree., c=0.50,
chloroform.
Example 39
Diastereomer 2
(+)-(2R)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-fluoro-phenyl)-2-methylpropanoic acid
##STR00344##
[1131] Isomer 2 was repurified again by preparative RP-HPLC (mobile
phase acetonitrile/water). This gave 21 mg.
[1132] LC-MS (Method 6): R.sub.t=1.18 min; m/z=446 (M+H).sup.+.
[1133] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.02 (d, 3H), 2.53-2.58 (m, 2H), 2.77-2.87 (m, 1H), 3.30-3.41
(m, 1H), 4.11 (d, 1H), 6.89-7.00 (m, 1H), 7.12 (dd, 1H), 7.41-7.48
(m, 4H), 7.63 (dd, 1H), 10.04 (s, 1H), 12.12 (br. s, 1H).
[1134] [.alpha.].sub.D.sup.20=+131.6.degree., c=0.530,
chloroform.
Example 40 and Example 41
3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl-
]amino}phenyl)-2-methylpropanoic acid (diastereomers 1 and 2)
##STR00345##
[1136] The mixture obtained above of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}phenyl)-2-methylpropanoic acids (Example 24) was separated
further by preparative HPLC on a chiral phase [column: chiral
silica gel phase based on the selector
poly(N-methacryloyl-L-isoleucin-3-pentylamide), 430 mm.times.40 mm;
injection volume: 2.0 ml; temperature: 24.degree. C.; mobile phase:
40% isohexane/60% ethyl acetate; flow rate: 80 ml/min; detection:
265 nm]. 514 mg of diastereomer mixture gave 178 mg of diastereomer
1 (Example 40) and 218 mg of diastereomer 2 (Example 41):
Example 40
Diastereomer 1
(+)-(2R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methy-
lbutanoyl]amino}-phenyl)-2-methylpropanoic acid
##STR00346##
[1138] LC-MS (Method 6): R.sub.t=1.25 min; m/z=456 (M+H).sup.+.
[1139] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 0.98-1.05 (m, 3H), 1.17 (t, 3H), 2.55-2.63 (m, 4H), 2.78-2.88
(m, 1H), 3.28-3.37 (m, 1H), 4.06 (d, 1H), 6.99 (dd, 1H), 7.20 (d,
2H), 7.34 (dd, 3H), 7.41 (d, 1H), 9.73 (s, 1H), 12.15 (s, 1H).
[1140] [.alpha.]D.sup.20=+52.degree., c=0.500, chloroform.
Example 41
Diastereomer 2
(+)-(2S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methy-
lbutanoyl]amino}-phenyl)-2-methylpropanoic acid
##STR00347##
[1142] LC-MS (Method 6): R.sub.t=1.27 min; m/z=456 (M+H).sup.+.
[1143] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.78 (d,
3H), 1.02 (d, 3H), 1.17 (t, 3H), 2.54-2.64 (m, 4H), 2.77-2.87 (m,
1H), 3.28-3.37 (m, 1H), 4.06 (d, 1H), 6.99 (dd, 1H), 7.21 (d, 2H),
7.34 (dd, 3H), 7.41 (d, 1H), 9.74 (s, 1H), 12.16 (br. s, 1H).
[1144] [.alpha.].sub.D.sup.20=+75.0.degree., c=0.640,
chloroform.
Example 42 and Example 43
3-(3-{[(2S,3R)-2-(4-Ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-
-fluorophenyl)-2-methylpropanoic acid (diastereomers 1 and 2)
##STR00348##
[1146] The mixture obtained above of the diastereomeric
3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-fluorophenyl)-2-methylpropanoic acids (Example 23) was separated
further by preparative HPLC on a chiral phase [column: Daicel
Chiralpak AS-H, 5 .mu.m, 250 mm.times.20 mm; injection volume: 0.30
ml; temperature: 30.degree. C.; mobile phase: 92% isohexane/8%
(ethanol+0.2% TFA+1% water); flow rate: 15 ml/min; detection: 220
nm]. 509 mg of diastereomer mixture gave 209 mg of diastereomer 1
(Example 42) and 220 mg of diastereomer 2 (Example 43):
Example 42
Diastereomer 1
(+)-(2S)-3-(3-{[(2S,3R)-2-(4-Ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl-
]amino}-4-fluoro-phenyl)-2-methylpropanoic acid
##STR00349##
[1148] LC-MS (Method 6): R.sub.t=1.22 min; m/z=440 (M+H).sup.+.
[1149] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.77 (d,
3H), 1.01 (d, 3H), 1.17 (t, 3H), 2.55-2.63 (m, 4H), 2.76-2.86 (m,
1H), 3.25-3.39 (m, 1H), 4.05 (d, 1H), 6.88-6.98 (m, 1H), 7.11 (dd,
1H), 7.17-7.24 (m, 2H), 7.29-7.38 (m, 2H), 7.66 (dd, 1H), 9.97 (s,
1H), 12.13 (br. s, 1H).
[1150] [.alpha.].sub.D.sup.20=+162.1.degree., c=0.500,
chloroform.
Example 43
Diastereomer 2
(+)-(2R)-3-(3-{[(2S,3R)-2-(4-Ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl-
]amino}-4-fluoro-phenyl)-2-methylpropanoic acid
##STR00350##
[1152] LC-MS (Method 6): R.sub.t=1.22 min; m/z=440 (M+H).sup.+.
[1153] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.77 (d,
3H), 1.01 (d, 3H), 1.17 (t, 3H), 2.53-2.64 (m, 4H), 2.76-2.87 (m,
1H), 3.26-3.38 (m, 1H), 4.04 (d, 1H), 6.87-6.97 (m, 1H), 7.11 (dd,
1H), 7.17-7.23 (m, 2H), 7.28-7.38 (m, 2H), 7.65 (dd, 1H), 9.97 (s,
1H), 12.12 (br. s, 1H).
[1154] [.alpha.].sub.D.sup.20=+94.0.degree., c=0.620,
chloroform.
Example 44 and Example 45
3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl-
]amino}phenyl)-butanoic acid (diastereomers 1 and 2)
##STR00351##
[1156] The mixture obtained above of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}phenyl)butanoic acids (Example 7) was separated further by
preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H,
5 .mu.m, 250 mm.times.20 mm; injection volume: 0.20 ml;
temperature: 30.degree. C.; mobile phase: 90% isohexane/10%
(isopropanol+0.2% TFA+1% water); flow rate: 15 ml/min; detection:
220 nm]. 210 mg of diastereomer mixture gave 110 mg of diastereomer
1 (Example 44) and 99 mg of diastereomer 2 (Example 45):
Example 44
Diastereomer 1
(+)-(3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methy-
lbutanoyl]amino}-phenyl)butanoic acid
##STR00352##
[1158] LC-MS (Method 6): R.sub.t=1.26 min; m/z=456 (M+H).sup.+.
[1159] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.13-1.21 (m, 6H), 2.45 (d, 2H), 2.59 (q, 2H), 3.08 (q, 1H),
3.27-3.38 (m, 1H), 4.07 (d, 1H), 7.06 (dd, 1H), 7.21 (d, 2H), 7.35
(dd, 3H), 7.46 (d, 1H), 9.72 (s, 1H), 12.05 (br. s, 1H).
[1160] [.alpha.].sub.D20=+86.8.degree., c=0.440, chloroform.
Example 45
Diastereomer 2
(+)-(3R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methy-
lbutanoyl]amino}-phenyl)butanoic Acid
##STR00353##
[1162] LC-MS (Method 6): R.sub.t=1.26 min; m/z=456 (M+H).sup.+.
[1163] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.11-1.22 (m, 6H), 2.45 (d, 2H), 2.55-2.63 (m, 2H), 3.08 (q,
1H), 3.28-3.38 (m, 1H), 4.08 (d, 1H), 7.06 (dd, 1H), 7.20 (d, 2H),
7.35 (dd, 3H), 7.47 (d, 1H), 9.72 (s, 1H), 12.05 (br. s, 1H).
[1164] [.alpha.].sub.D.sup.20=+68.0.degree., c=0.415,
chloroform.
Example 46 and Example 47
3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-chlorophenyl)butanoic acid (diastereomers 1 and 2)
##STR00354##
[1166] The mixture obtained above of the diastereomeric
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyflamino}-
-4-chlorophenyl]butanoic acids (Example 8) was separated further by
preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H,
5 .mu.m, 250 mm.times.20 mm; injection volume: 0.30 ml;
temperature: 30.degree. C.; mobile phase: 90% isohexane/10%
isopropanol; flow rate: 15 ml/min; detection: 220 nm]. 250 mg of
diastereomer mixture gave 116 mg of diastereomer 1 (Example 46) and
113 mg of diastereomer 2 (Example 47):
Example 46
Diastereomer 1
(+)-(3S)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-chloro-phenyl)butanoic acid
##STR00355##
[1168] LC-MS (Method 4): R.sub.t=1.36 min; m/z=462 (M+H).sup.+.
[1169] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.16 (d, 3H), 2.45 (d, 2H), 3.03-3.14 (m, 1H), 3.33-3.42 (m,
1H), 4.13 (d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H), 7.41 (d, 1H),
7.43-7.51 (m, 4H), 9.81 (s, 1H), 12.05 (s, 1H).
[1170] [.alpha.].sub.D.sup.20=+88.6.degree., c=0.435,
chloroform.
Example 47
Diastereomer 2
(+)-(3R)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-chloro-phenyl)butanoic acid
##STR00356##
[1172] LC-MS (Method 4): R.sub.t=1.36 min; m/z=462 (M+H).sup.+.
[1173] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 1.16 (d, 3H), 2.45 (d, 2H), 3.09 (q, 1H), 3.33-3.42 (m, 1H),
4.13 (d, 1H), 7.08 (dd, 1H), 7.35 (d, 1H), 7.42 (d, 1H), 7.43-7.51
(m, 4H), 9.81 (s, 1H), 12.05 (s, 1H).
[1174] [.alpha.].sub.D.sup.20=+57.9.degree., c=0.365,
chloroform.
Example 48 and Example 49
3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-fluorophenyl)-butanoic acid (diastereomers 1 and 2)
##STR00357##
[1176] The mixture obtained above of the diastereomeric
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyflamino}-
-4-fluorophenyl]butanoic acids (Example 9) was separated further by
preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H,
5 .mu.m, 250 mm.times.20 mm; injection volume: 0.25 ml;
temperature: 30.degree. C.; mobile phase: 85% isohexane/15%
isopropanol; flow rate: 15 ml/min; detection: 220 nm]. 295 mg of
diastereomer mixture gave 121 mg of diastereomer 1 (Example 48) and
111 mg of diastereomer 2 (Example 49):
Example 48
Diastereomer 1
(+)-(3S)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-fluoro-phenyl)butanoic acid
##STR00358##
[1178] LC-MS (Method 6): R.sub.t=1.14 min; m/z=446 (M+H).sup.+.
[1179] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.16 (d, 3H), 2.44 (d, 2H), 3.02-3.12 (m, 1H), 3.33-3.42 (m,
1H), 4.12 (d, 1H), 7.00-7.04 (m, 1H), 7.13 (dd, 1H), 7.43-7.48 (m,
4H), 7.68 (dd, 1H), 10.04 (s, 1H), 12.03 (s, 1H).
[1180] [.alpha.].sub.D.sup.20=+142.0.degree., c=0.350,
chloroform.
Example 49
Diastereomer 2
(+)-(3R)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-4-fluoro-phenyl)butanoic Acid
##STR00359##
[1182] LC-MS (Method 6): R.sub.t=1.14 min; m/z=446 (M+H).sup.+.
[1183] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.15 (d, 3H), 2.44 (d, 2H), 3.08 (q, 1H), 3.30-3.42 (m, 1H),
4.12 (d, 1H), 6.94-7.06 (m, 1H), 7.13 (dd, 1H), 7.40-7.50 (m, 4H),
7.68 (dd, 1H), 10.04 (s, 1H), 12.04 (br. s, 1H).
[1184] [.alpha.].sub.D.sup.20=+139.8.degree., c=0.405,
chloroform.
[1185] General Procedure 4: Acidic hydrolysis of ethyl esters
[1186] The ethyl ester in question is dissolved in a 7:2 mixture of
glacial acetic acid and concentrated hydrochloric acid (about 10
ml/mmol of substrate) and heated at 100.degree. C. until the
reaction has gone to completion (in general between 1 h and 8 h).
The mixture is then cooled, poured into water and extracted
repeatedly with dichloromethane The combined organic phases are
washed three times with saturated sodium chloride solution, dried
over magnesium sulphate and concentrated. If required, the residue
is purified by flash chromatography or preparative HPLC.
[1187] The exemplary compounds below were prepared according to
General Procedure 4:
TABLE-US-00022 Example Name/Structure Analytical data 50
##STR00360## LC-MS (Method 6): R.sub.t = 1.21 min; m/z = 460 (M +
H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.75-0.95 (m, 3H), 1.00-1.06 (m, 2H), 1.07- 1.17 (m, 3H), 1.24 (s,
1H), 1.91 (s, 1H), 2.93 (t, 1H), 3.35- 3.45 (m, 1H), 4.06-4.20 (m,
1H), 6.93-7.04 (m, 1H), 7.07- 7.19 (m, 1H), 7.39-7.54 (m, 4H), 7.66
(dt, 1H), 9.98-10.09 (m, 1H), 11.96 (br.s, 1H). 51 ##STR00361##
LC-MS (Method 5): R.sub.t = 2.52 min; m/z = 460 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.71-0.91 (m,
4H), 1.00-1.11 (m, 1H), 1.14 (d, 3H), 1.23 (br. s, 2H), 1.91 (s,
1H), 3.37-3.45 (m, 1H), 4.12 (d, 1H), 6.90-7.05 (m, 1H), 7.14 (t,
1H), 7.33-7.56 (m, 4H), 7.65 (d, 1H), 10.05 (s 1H). 52 ##STR00362##
LC-MS (Method 5): R.sub.t = 2.45 min; m/z = 444 (M + H).sup.+.
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.79 (d, 3H),
1.19-1.28 (m, 1H), 1.38 (dt, 1H), 1.65-1.75 (m, 1H), 2.30- 2.40 (m,
1H), 4.12 (d, 1H), 6.88-6.97 (m, 1H), 7.13 (dd, 1H), 7.37-7.52 (m,
4H), 7.62 (dd. 1H), 10.06 (s, 1H), 12.30 (br. s, 1H).
Example 53 and Example 54
2-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-fluorophenyl)-trans-cyclopropanecarboxylic acid (diastereomers 1
and 2)
##STR00363##
[1189] 71 mg of the diastereomer mixture of
2-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butanoyl]amino-
}-4-fluorophenyl)-trans-cyclopropanecarboxylic acid (Example 52)
were dissolved in 2 ml of ethanol and 2 ml of isohexane and
separated further by preparative HPLC on a chiral phase [column:
Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.200 mm; injection
volume: 0.25 ml; temperature: 30.degree. C.; mobile phase: 15%
isopropanol/85% isohexane; flow rate: 15 ml/min; detection: 220
nm]. This gave 36 mg of diastereomer 1 (Example 53) and 37 mg of
diastereomer 2 (Example 54):
Example 53
Diastereomer 1
[1190] LC-MS (Method 6): R.sub.t=1.15 min; m/z=444 (M+H).sup.+.
[1191] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.24 (ddd, 1H), 1.38 (dt, 1H), 1.64-1.80 (m, 1H), 2.35 (ddd,
1H), 4.12 (d, 1H), 6.85-7.01 (m, 1H), 7.13 (dd, 1H), 7.37-7.56 (m,
4H), 7.62 (dd, 1H), 10.06 (s, 1H).
[1192] [.alpha.].sub.D.sup.20=+291.4.degree., c=0.48,
chloroform.
Example 54
Diastereomer 2
[1193] LC-MS (Method 6): R.sub.t=1.15 min; m/z=444 (M+H).sup.+.
[1194] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 1.24 (ddd, 1H), 1.38 (dt, 1H), 1.64-1.76 (m, 1H), 2.29-2.40
(m, 2H), 4.12 (d, 1H), 6.92 (ddd, 1H), 7.13 (dd, 1H), 7.39-7.52 (m,
4H), 7.62 (dd, 1H), 10.06 (s, 1H).
[1195] [.alpha.].sub.D.sup.20=+44.3.degree., c=0.40,
chloroform.
Example 55
3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}--
4-cyanophenyl)-propanoic acid
##STR00364##
[1197] 16.5 mg (33 .mu.mol) of tert-butyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
-4-cyanophenyl)propanoate were dissolved in 1.1 ml of
dichloromethane, and 275 .mu.l of trifluoroacetic acid were added.
The reaction mixture was stirred at RT for 1.5 h, then diluted with
20 ml of dichloromethane and concentrated under reduced pressure.
The residue was dried under high vacuum overnight. This gave 14.8
mg (97% of theory) of the title compound.
[1198] LC-MS (Method 6): R.sub.t=1.10 min; m/z=439
(M+NH.sub.4).sup.+.
[1199] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.81 (d,
3H), 2.80-2.94 (m, 2H), 4.01 (d, 1H), 7.22 (dd, 1H), 7.32 (s, 1H),
7.40-7.52 (m, 4H), 7.69 (d, 1H), 10.48 (s, 1H).
Example 56
(+/-)-3-(3-{[2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2--
fluorophenyl)propanoic acid (diastereomer 1)
##STR00365##
[1201] 270 mg (0.553 mmol) of
tert-butyl(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}-2-fluorophenyl]propanoic acid (diastereomer 1, Example
102A) were dissolved in 0.2 ml of dichloromethane, and 0.85 ml of
trifluoroacetic acid was added at RT. The reaction mixture was
stirred at RT for 4 h and then concentrated under reduced pressure.
The residue was purified by preparative RP-HPLC (acetonitrile/water
mixture). This gave 188 mg (78.7% of theory) of the target
compound.
[1202] LC-MS (Method 6): R.sub.t=1.16 min; m/z=432 (M+H).sup.+.
[1203] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 2.48-2.53 (m, 2H), 2.82 (t, 2H), 3.35-3.48 (m, 1H), 4.13 (d,
1H), 6.88-7.13 (m, 2H), 7.37-7.51 (m, 4H), 7.54-7.76 (m, 1H), 10.04
(s, 1H), 12.19 (br. s, 1H).
[1204] The compound below was prepared in an analogous manner
Example 57
(+/-)-3-(3-{[2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2--
fluorophenyl)propanoic acid (diastereomer 2)
##STR00366##
[1206] LC-MS (Method 6): R.sub.t=1.15 min; m/z=432 (M+H).sup.+.
[1207] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (d,
3H), 2.52-2.56 (m, 2H), 2.83 (t, 2H), 3.22 (dd, 1H), 4.15 (d, 1H),
6.98-7.10 (m, 2H), 7.36-7.43 (m, 2H), 7.45-7.53 (m, 2H), 7.62 (td,
1H), 10.13 (s, 1H), 12.19 (s, 1H).
[1208] The following examples were prepared in accordance with
General Procedure 2 (cleavage of tert-butyl esters to the
corresponding carboxylic acids using trifluoroacetic acid):
TABLE-US-00023 Example Name/Structure/Starting material Analytical
data 58 (+)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluoro- LC-MS
(Method 6): R.sub.t = 1.17
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}- min; m/z = 466 (M
+ H)+. phenyl)propanoic acid .sup.1H-NMR (400 MHz, DMSO-
##STR00367## d.sub.6): .delta. [ppm] = 0.83 (d, 3H), 2.49 (t, 2H),
2.76 (t, 2H), 3.34- 3.46 (m, 1H), 4.14 (d, 1H), 7.06 (dd, 1H),
7.28-7.41 (m, 3H), 7.49 (dd, 1H), 7.62 (t, 1H), 9.87 (s, 1H), 12.13
(s, 1H). [.alpha.].sub.D.sup.20 = +79.90.degree., c = 0.520,
chloroform. (from (+)-tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-
(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)propanoate) 59
(+)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methyl- LC-MS (Method 6):
R.sub.t = 1.20 phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
min; m/z = 462 (M + H).sup.+. phenyl)propanoic acid .sup.1H-NMR
(400 MHz, DMSO- ##STR00368## d6): .delta. [ppm] = 0.80 (d, 3H),
2.33 (s, 3H), 2.48 (t, 2H), 2.76 (t, 2H), 3.27-3.42 (m, 1H),
4.04-4.09 (m, 1H), 7.04 (dd, 1H), 7.29 (dd, 1H), 7.32-7.36 (m, 1H),
7.38-7.45 (m, 3H), 9.81 (s, 1H), 12.16 (br. s, 1H).
[.alpha.].sub.D.sup.20 = +86.0.degree., c = 0.250, chloroform.
(from tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chloro-3-methylphenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]-amino}phenyl)propanoate) 60
(+)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)- LC-MS (Method
6): R.sub.t = 1.23 4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-
min; m/z = 480/482 (M - H).sup.-. propanoic acid .sup.1H-NMR (400
MHz, DMSO- ##STR00369## d.sub.6): .delta. [ppm] = 0.83 (d, 3H),
2.47 (t, 2H), 2.72-2.81 (m, 2H), 3.35-3.47 (m, 1H), 4.09-4.17 (m,
1H), 7.06 (dd, 1H), 7.31- 7.41 (m, 2H), 7.45 (dd, 1H), 7.67 (d,
1H), 7.72 (d, 1H), 9.88 (s, 1H). [.alpha.].sub.D.sup.20 =
+98.8.degree., c = 0.325 methanol. (from tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(3,4- dichlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)propanoate) 61
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 6):
R.sub.t = 1.20 trifluoro-3-methylbutanoyl]amino}-2-methyl- min; m/z
= 476 (M + H).sup.+. phenyl)-2-methylpropanoic acid (diastereomer
.sup.1H-NMR (400 MHz, DMSO- mixture) d.sub.6): both diastereomers
##STR00370## .delta. [ppm] = 0.80 (d, 3H), 1.03 (br. s, 3H),
1.51/1.57 (2 br. s, together 2H), 2.15 (br. s, about 2H), 2.86 (br.
s, about 1H), 3.37-3.45 (m, about 1H), 3.90- 4.00 (m, 1H),
6.99-7.12 (m, 1H), 7.16 (br. s, 1H), 7.25 (br. s, 1H), 7.35-7.54
(m, 5H), 9.88 (br. s, 1H), 12.18 (br. s, 1H) [because of rotamers,
the signals are very broad]. (from tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}-2-methylphenyl)-2- methylpropanoate
(diastereomer mixture)) 62 (+)-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-
LC-MS (Method 6): R.sub.t = 1.26 chlorophenyl)-4,4,4-trifluoro-3-
min; m/z =476 (M + H).sup.+.
methylbutanoyl]amino}-2-methylphenyl)-2- .sup.1H-NMR (400 MHz,
DMSO- methylpropanoic acid d.sub.6): .delta. [ppm] = 0.80 (d, 3H),
##STR00371## 1.03 (br. s, 3H), 2.42-2.62 (br. s, about 2H,
partially obscured), 3.30-3.44 (m, 1H), 3.94 (d, 1H), 7.05 (d, 1H),
7.23 (br. s, 1H), 7.45 (s, 4H), 12.15 (br. s, 1H) [because of
rotamers, the signals are very broad]. [.alpha.].sub.D.sup.20 =
+108.9.degree., c = 0.510 methanol (from (+)-tert-butyl
(2R)-3-(4-chloro-3-{[(2S,3R)-2- (4-chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}-2-methylphenyl)-2- methylpropanoate) 63
(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4- LC-MS (Method 6): R.sub.t =
1.26 chlorophenyl)-4,4,4-trifluoro-3- min; m/z =476 (M + H).sup.+.
methylbutanoyl]amino}-2-methylphenyl)-2- .sup.1H-NMR (400 MHz,
DMSO- methylpropanoic acid d.sub.6): .delta. [ppm] = 0.80 (d, 3H),
##STR00372## 1.03 (br. s, 3H), 3.17 (d, 1H), 3.34-3.43 (m, 1H),
3.94 (d, 1H), 7.05 (d, 1H), 7.45 (br. s, 4H), 9.86 (br. s, 1H),
12.15 (br. s, 1H) [because of rotamers, the signals are very
broad]. [.alpha.].sub.D.sup.20 = +143.7.degree., c = 0.505,
methanol (from (+)-tert-butyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-
(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}-2-methylphenyl)-2-methylpropanoate) 64
2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 6):
R.sub.t = 1.28 trifluoro-3-methylbutanoyl]amino}benzyl)- min; m/z =
490 (M + H).sup.+. 2-methylbutanoic acid (diastereomer mixture)
.sup.1H-NMR (400 MHz, DMSO- ##STR00373## d.sub.6): both
diastereomers .delta. [ppm] = 0.73-0.87 (m, 6H), 0.92 (d, 3H),
1.31-1.42 (m, 1H), 1.52-1.72 (m, 1H), 2.60 (d, 1H), 2.85/2.87 (2d,
together 1H), 3.32-3.36 (m, 1H), 3.94- 4.18 (m, 1H), 6.95 (dd, 1H),
7.27-7.37 (m, 2H), 7.39-7.53 (m, 4H), 9.84 (s, 1H). (from
tert-butyl 2-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}benzyl)-2-methylbutanoate (diastereomer mixture)) 65
(+)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)- LC-MS (Method 6):
R.sub.t = 1.26 4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)- min;
m/z = 490 (M + H).sup.+. 2-methylbutanoic acid (diastereomer B)
.sup.1H-NMR (400 MHz, DMSO- ##STR00374## d.sub.6): .delta. [ppm] =
0.73-0.85 (m, 6H), 0.92 (s, 3H), 1.32-1.41 (m, 1H), 1.57-1.66 (m,
1H), 2.60 (d, 1H), 2.85 (d, 1H), 3.35-3.43 (m, 1H), 4.11 (d, 1H),
6.94 (d, 1H), 7.34 (d, 2H), 7.41-7.53 (m, 4H), 9.82 (s, 1H), 12.27
(br. s, 1H). [.alpha.].sub.D.sup.20 = +80.6.degree., c = 0.350,
chloroform. (from tert-butyl 2-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}benzyl)-2-methylbutanoate (diastereomer B)) 66
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 6):
R.sub.t = 1.18 trifluoro-3-methylbutanoyl]amino}phenyl)-4,4,4- min;
m/z = 516 (M + H).sup.+. trifluorobutanoic acid (diastereomer
mixture) .sup.1H-NMR (400 MHz, DMSO- ##STR00375## d.sub.6): both
diastereomers .delta. [ppm] = 0.80 (d, 3H), 2.84 (dd, 1H), 2.95
(dd, 1H), 3.35- 3.44 (m, 1H), 4.01-4.09 (m, 1H), 4.14 (d, 1H), 7.26
(dd, 1H), 7.39-7.52 (m, 5H), 7.61 (dd, 1H), 9.95 (s, 1H), 12.55
(br. s, 1H). (from tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)-4,4,4- trifluorobutanoate
(diastereomer mixture)) 67
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 6):
R.sub.t = 1.29 trifluoro-3-methylbutanoyl]amino}phenyl)-2-cyclo-
min; m/z = 502 (M + H).sup.+. butylpropanoic acid (diastereomer
mixture) .sup.1H-NMR (400 MHz, DMSO- ##STR00376## d.sub.6): both
diastereomers .delta. [ppm] = 0.80 (d, 3H), 1.67- 1.83 (m, 4H),
1.86-1.99 (m, 2H), 2.30-2.42 (m, 1H), 2.43- 2.48 (m, 1H), 2.57-2.63
(m, 2H), 3.36-3.42 (m, 1H), 4.12 (d, 1H), 6.98 (d, 1H), 7.29-7.36
(m, 2H), 7.41-7.50 (m, 4H), 9.82 (s, 1H), 12.07 (s, 1H). (from
tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-cyclobutylpropanoate (diastereomer mixture)) 68
(+)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)- LC-MS (Method 6):
R.sub.t = 1.32 4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-2-
min; m/z = 502 (M + H).sup.+. cyclobutylpropanoic acid
(diastereomer A) .sup.1H-NMR (400 MHz, DMSO- ##STR00377## d.sub.6):
.delta. [ppm] = 0.80 (d, 3H), 1.65-1.83 (m, 4H), 1.88-1.98 (m, 2H),
2.29-2.43 (m, 1H), 2.43-2.48 (m, 1H), 2.56-2.63 (m, 2H), 3.37-3.41
(m, 1H), 4.12 (d, 1H), 6.98 (dd, 1H), 7.28-7.36 (m, 2H), 7.42-7.55
(m, 4H), 9.82 (s, 1H), 12.08 (br. s, 1H). [.alpha.].sub.D.sup.20 =
+50.3.degree., c = 0.520, chloroform. (from tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-cyclobutylpropanoate (diastereomer A)) 69
(+)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)- LC-MS (Method 6):
R.sub.t = 1.29 4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-2-
min; m/z =502 (M + H).sup.+. cyclobutylpropanoic acid (diastereomer
B) .sup.1H-NMR (400 MHz, DMSO- ##STR00378## d.sub.6): .delta. [ppm]
= 0.80 (d, 3H), 1.62-1.83 (m, 4H), 1.86-2.00 (m, 2H), 2.28-2.43 (m,
1H), 2.45-2.49 (m, 1H), 2.60 (d, 2H), 3.36-3.44 (m, 1H), 4.12 (d,
1H), 6.99 (dd, 1H), 7.24- 7.37 (m, 2H), 7.41-7.53 (m, 4H), 9.82 (s,
1H), 12.07 (s, 1H). [.alpha.].sub.D.sup.20 = +97.8.degree., c =
0.445, chloroform. (from tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3- methylbutanoyl]amino}phenyl)-2-
cyclobutylpropanoate (diastereomer B)) 70
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 4):
R.sub.t = 1.48 trifluoro-3-methylbutanoyl]amino}phenyl)-2-cyclo-
min; m/z = 488 (M + H).sup.+. propylpropanoic acid (diastereomer
mixture) .sup.1H-NMR (400 MHz, DMSO- ##STR00379## d.sub.6): both
diastereomers .delta. [ppm] = 0.05-0.13 (m, 1H), 0.20-0.25 (m, 1H),
0.42 (d, 2H), 0.79 (d, 3H), 0.82-0.92 (m, 1H), 1.78 (td, 1H), 2.74-
2.90 (m, 2H), 3.30-3.40 (m, 1H), 4.11 (d, 1H), 7.01 (d, 1H), 7.33
(d, 1H), 7.37 (d, 1H), 7.42-7.50 (m, 4H), 9.82 (s, 1H). (from
tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-cyclopropylpropanoate (diastereomer mixture))
Example 71
(+)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-
anoyl]amino}benzyl)-2-methylbutanoic acid (diastereomer A)
##STR00380##
[1210] 302 mg (0.553 mmol) of (+)-tert-butyl
2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}benzyl)-2-methylbutanoate (diastereomer A) were dissolved
in 2.3 ml of dichloromethane and 2 ml of TFA were added at RT.
After 30 min, the reaction mixture was concentrated under reduced
pressure and the residue was dried under high vacuum. The residue
was then purified by preparative RP-HPLC (mobile phase
acetonitrile/water). This gave 110.8 mg of the target product
(40.9% of theory).
[1211] LC-MS (Method 4): R.sub.t=1.50 min; m/z=490 (M+H).sup.+.
[1212] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.71-0.86
(m, 6H), 0.92 (s, 3H), 1.30-1.43 (m, 1H), 1.54-1.69 (m, 1H), 2.60
(d, 1H), 2.86 (d, 1H), 3.34-3.45 (m, 1H), 4.11 (d, 1H), 6.86-7.00
(m, 1H), 7.25-7.36 (m, 2H), 7.39-7.52 (m, 4H), 9.83 (s, 1H), 12.28
(s, 1H).
[1213] [.alpha.].sub.D.sup.20=+74.0.degree., c=0.280,
chloroform.
[1214] The examples below were prepared according to General
Procedure 3 (cleavage of methyl or ethyl esters to the
corresponding carboxylic acids in mixtures of hydrochloric acid or
sulphuric acid with acetic acid):
TABLE-US-00024 Example Name/Structure/Starting material Analytical
data 72 (+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2- LC-MS
(Method 6): R.sub.t = 1.22
fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]- min; m/z = 480 (M
+ H).sup.+. amino}phenyl)-2-methylpropanoic acid .sup.1H-NMR (400
MHz, DMSO- ##STR00381## d.sub.6): .delta. [ppm] = 0.86 (d, 3H),
1.03 (d, 3H), 2.55-2.63 (m, 2H), 2.79-2.90 (m, 1H), 3.36- 3.44 (m,
1H), 4.36 (d, 1H), 7.04 (dd, 1H), 7.26-7.39 (m, 3H), 7.52 (dd, 1H),
7.62 (t, 1H), 10.02 (s, 1H), 12.18 (br. s, 1H).
[.alpha.].sub.D.sup.20 = +92.1.degree., c = 0.365, chloroform.
(from (+)-ethyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-
(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-2-methylpropanoate) 73
(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2- LC-MS (Method 6):
R.sub.t = 1.26 methylphenyl)-4,4,4-trifluoro-3- min; m/z = 476 (M +
H).sup.+. methylbutanoyl]amino}phenyl)-2-methylpropanoic
.sup.1H-NMR (400 MHz, DMSO- acid d.sub.6): .delta. [ppm] = 0.77 (d,
3H), ##STR00382## 1.02 (d, 3H), 2.54-2.63 (m, 2H), 2.79-2.91 (m,
1H), 3.38 (br. s, 1H), 4.15 (d, 1H), 7.03 (dd, 1H), 7.22-7.38 (m,
4H), 7.52 (d, 1H), 9.89 (s, 1H), 12.18 (br. s, 1H).
[.alpha.].sub.D.sup.20 = +124.3.degree., c = 0.390, chloroform.
(from (+)-ethyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-
(4-chloro-2-methylphenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-2-methylpropanoate) 74
(+)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3- LC-MS (Method 6):
R.sub.t = 1.20 fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
min; m/z = 480 (M + H).sup.+. amino}phenyl)-2-methylpropanoic acid
.sup.1H-NMR (400 MHz, DMSO- ##STR00383## d.sub.6): .delta. [ppm] =
0.83 (d, 3H), 1.02 (d, 3H), 2.55-2.62 (m, 2H), 2.77-2.88 (m, 1H),
3.36- 3.48 (m, 1H), 4.05-4.21 (m, 1H), 7.02 (dd, 1H), 7.25-7.41 (m,
3H), 7.49 (dd, 1H), 7.62 (t, 1H), 9.87 (s, 1H), 12.16 (br. s, 1H).
[.alpha.].sub.D.sup.20 = +95.7.degree., c = 0.470, chloroform.
(from (+)-ethyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-
(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-2-methylpropanoate) 75
(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3- LC-MS (Method 4):
R.sub.t = 1.44 methylphenyl)-4,4,4-trifluoro-3- min; m/z = 476 (M +
H).sup.+. methylbutanoyl]amino}phenyl)-2-methylpropanoic
.sup.1H-NMR (400 MHz, DMSO- acid d.sub.6): .delta. [ppm] =
0.78-0.85 (m, ##STR00384## 3H), 1.02 (d, 3H), 2.33 (s, 3H),
2.55-2.61 (m, 2H), 2.77-2.89 (m, 1H), 3.34-3.41 (m, about 1H,
obscured), 4.04-4.10 (m, 1H), 7.00 (dd, 1H), 7.26-7.45 (m, 5H),
9.81 (s, 1H), 12.17 (br. s, 1H). [.alpha.].sub.D.sup.20 =
+397.5.degree., c = 0.340, chloroform. (from ethyl
(2S)-3-(4-chloro-3-{[(2S,3R)-2-
(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-2-methylpropanoate) 76
(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4- LC-MS (Method 6): R.sub.t
= 1.24 dichlorophenyl)-4,4,4-trifluoro-3- min; m/z = 496/498 (M +
H).sup.+. methylbutanoyl]amino}phenyl)-2-methylpropanoic
.sup.1H-NMR (400 MHz, DMSO- acid d.sub.6): .delta. [ppm] = 0.83 (d,
3H), ##STR00385## 1.02 (d, 3H), 2.54-2.62 (m, 2H), 2.77-2.91 (m,
1H), 3.35- 3.48 (m, 1H), 4.08-4.17 (m, 1H), 7.02 (dd, 1H),
7.31-7.39 (m, 2H), 7.45 (dd, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 9.87
(s, 1H), 12.16 (br. s, 1H). [.alpha.].sub.D.sup.20 =
+109.5.degree., c = 0.305, methanol. (from
ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-
dichlorophenyl)-4,4,4-trifluoro-3- methylbutanoyl]amino}phenyl)-2-
methylpropanoate) 77
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method 6):
R.sub.t = 1.12 trifluoro-3-methylbutanoyl]amino}-2-methyl- min; m/z
= 462 (M + H).sup.+. phenyl)propanoic acid .sup.1H-NMR (400 MHz,
DMSO- ##STR00386## d.sub.6): .delta. [ppm] = 0.80 (d, 3H),
1.91/2.14 (2 br. s, together 3H), 2.42 (br. s, 2H), 2.73 (d, 2H),
3.34-3.43 (m, 1H), 3.96 (d, 1H), 7.04-7.14 (m, 1H), 7.14- 7.35 (m,
1H), 7.45 (s, 4H), 9.91 (br. s, 1H), 12.13 (br. s, 1H) [because of
rotamers, the signals are very broad]. (from methyl
3-(4-chloro-3-{[(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}- 2-methylphenyl)propanoate) 78
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3- LC-MS (Method
6): R.sub.t = 1.14 methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-
min; m/z = 500 (M + H).sup.+. trifluorobutanoic acid (diastereomer
mixture) .sup.1H-NMR (400 MHz, DMSO- ##STR00387## d.sub.6): both
diastereomers .delta. [ppm] = 0.79 (d, 3H), 2.83 (dd, 1H), 2.95
(dd, 1H), 3.25- 3.46 (m, 2H), 3.96-4.07 (m, 1H), 4.13 (d, 1H),
7.19-7.29 (m, 2H), 7.41-7.50 (m, 4H), 7.88 (d, 1H), 10.17 (s, 1H).
(from ethyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-
4,4,4-trifluorobutanoate)
Example 79 and Example 80
(+)-3-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]ami-
no}-4-fluorophenyl)-4,4,4-trifluorobutanoic acid (diastereomers 1
and 2)
##STR00388##
[1216] The mixture obtained above of the diastereomeric
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-
-4-fluorophenyl)-4,4,4-trifluorobutanoic acids (Example 78) was
separated further by preparative HPLC on a chiral phase [column:
Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 15
ml/min; detection: 230 nm; injection volume: 0.80 ml; temperature:
45.degree. C.; mobile phase: 92% isohexane/8% isopropanol]. 1.95 g
of diastereomer mixture gave 556 mg of diastereomer 1 (Example 79)
and 730 mg of diastereomer 2 (Example 80):
Example 79
Diastereomer 1
[1217] Diastereomer 1 was once more repurified by preparative
RP-HPLC (mobile phase methanol/water). This gave 418 mg.
[1218] LC-MS (Method 4): R.sub.t=1.49 min; m/z=500 (M+H).sup.+.
[1219] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 2.82 (dd, 1H), 2.94 (dd, 1H), 3.37-3.44 (m, 1H), 4.02 (td,
1H), 4.13 (d, 1H), 7.17-7.30 (m, 2H), 7.40-7.50 (m, 4H), 7.87 (d,
1H), 10.18 (s, 1H), 12.53 (br. s, 1H).
[1220] [.alpha.].sub.D.sup.20=+130.degree., c=0.29, chloroform.
Example 80
Diastereomer 2
[1221] Diastereomer 2 was once more repurified by preparative
RP-HPLC (mobile phase methanol/water). This gave 352 mg.
[1222] LC-MS (Method 6): R.sub.t=1.18 min; m/z=500 (M+H).sup.+.
[1223] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.79 (d,
3H), 2.82 (dd, 1H), 2.94 (dd, 1H), 3.94-4.08 (m, 1H), 4.13 (d, 1H),
7.17-7.33 (m, 2H), 7.40-7.52 (m, 4H), 7.88 (d, 1H), 10.18 (s,
1H).
[1224] [.alpha.].sub.D.sup.20=+104.degree., c=0.260,
chloroform.
Example 81
3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}phenyl)-hexanoic acid (Diastereomer Mixture)
##STR00389##
[1226] 1.50 g (2.97 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butan-
oyl]amino}phenyl)hexanoate (Diastereomer Mixture) were dissolved in
5 ml of acetic acid, 5 ml of 30% strength sulphuric acid were added
and the mixture was heated at reflux (bath temperature about
140.degree. C.). After 1.5 h, a further 2.5 ml of acetic acid were
added, and the reaction mixture was stirred under reflux for
another 2.5 h. After cooling, the mixture was allowed to stand at
RT overnight, then added to water and extracted three times with
ethyl acetate. The combined organic phases were washed with 5%
strength sodium bicarbonate solution and sat. sodium chloride
solution, dried over magnesium sulphate and concentrated under
reduced pressure, and the residue was dried under high vacuum. This
gave 1.44 g of the target product (98.8% of theory).
[1227] LC-MS (Method 6): R.sub.t=1.29 min; m/z=490 (M+H).sup.+.
[1228] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.74-0.83 (m, 6H), 0.99-1.14 (m, 2H), 1.37-1.60 (m,
2H), 2.39 (dd, 1H), 2.85-2.99 (m, 1H), 3.36-3.44 (m, 1H), 4.13 (d,
1H), 6.97-7.10 (m, 1H), 7.32-7.40 (m, 2H), 7.42-7.53 (m, 4H), 9.83
(s, 1H), 12.02 (br. s, 1H).
Example 82 and Example 83
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-
anoyl]amino}phenyl)-hexanoic acid (diastereomers 1 and 2)
##STR00390##
[1230] The mixture obtained above of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)hexanoic acids (Example 81) was separated further
by preparative HPLC on a chiral phase [column: Daicel Chiralpak
AD-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 20 ml/min; detection:
230 nm; injection volume: 0.60 ml; temperature: 25.degree. C.;
mobile phase: 95% isohexane/5% isopropanol]. 59.2 mg of
diastereomer mixture gave 19 mg of diastereomer 1 (Example 82) and
17 mg of diastereomer 2 (Example 83):
Example 82
Diastereomer 1
(+)-(3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)hexanoic acid
##STR00391##
[1232] LC-MS (Method 6): R.sub.t=1.27 min; m/z=490 (M+H).sup.+.
[1233] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.72-0.86
(m, 6H), 0.98-1.19 (m, 2H), 1.37-1.61 (m, 2H), 2.34-2.44 (m, 1H),
2.88-2.97 (m, 1H), 3.34-3.43 (m, 1H), 4.13 (d, 1H), 7.05 (dd, 1H),
7.26-7.40 (m, 2H), 7.41-7.63 (m, 4H), 9.82 (s, 1H), 12.02 (s,
1H).
[1234] [.alpha.].sub.D.sup.20=+52.degree., c=0.30, chloroform.
[1235] A larger amount (1.40 g) of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)hexanoic acids (Example 81) was likewise separated
by the same preparative HPLC method. In this case, the diastereomer
1 obtained was once more repurified by RP-HPLC [column: Sunfire 250
mm.times.20 mm; mobile phase: 80% acetonitrile/5% aq. TFA (1%
strength)/15% water]. This gave 337 mg of pure diastereomer 1.
[1236] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.74-0.86
(m, 6H), 0.97-1.16 (m, 2H), 1.40-1.60 (m, 2H), 2.35-2.44 (m, 1H),
2.89-2.97 (m, 1H), 3.35-3.43 (m, 1H), 4.13 (d, 1H), 7.05 (dd, 1H),
7.30-7.40 (m, 2H), 7.41-7.54 (m, 4H), 9.83 (s, 1H), 12.02 (br. s,
1H).
[1237] [.alpha.].sub.D.sup.20=+86.degree., c=0.480, chloroform.
Example 83
Diastereomer 2
(+)-(3R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)hexanoic acid
##STR00392##
[1239] LC-MS (Method 6): R.sub.t=1.27 min; m/z=490 (M+H).sup.+.
[1240] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.77-0.83
(m, 6H), 1.00-1.12 (m, 2H), 1.41-1.60 (m, 2H), 2.35-2.44 (m, 1H),
2.88-2.98 (m, 1H), 3.35-3.45 (m, 1H), 4.13 (d, 1H), 7.05 (dd, 1H),
7.32-7.40 (m, 2H), 7.43-7.64 (m, 4H), 9.82 (s, 1H), 12.04 (br. s,
1H).
[1241] [.alpha.].sub.D.sup.20=+22.1.degree., c=0.40,
chloroform.
Example 84 and Example 85
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-
anoyl]amino}phenyl)-4,4,4-trifluorobutanoic acid (diastereomers 1
and 2)
##STR00393##
[1243] The mixture obtained above of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)-4,4,4-trifluorobutanoic acids (Example 66) was
separated further by preparative HPLC on a chiral phase [column:
Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 15
ml/min; detection: 220 nm; injection volume: 0.25 ml; temperature:
30.degree. C.; mobile phase: 93% isohexane/7% isopropanol]. 150 mg
of diastereomer mixture gave 70 mg of diastereomer 1 (Example 84)
and 79 mg of diastereomer 2 (Example 85):
Example 84
Diastereomer 1
(+)-(3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)-4,4,4-trifluorobutanoic acid
##STR00394##
[1245] LC-MS (Method 6): R.sub.t=1.18 min; m/z=516 (M+H).sup.+.
[1246] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 2.84 (dd, 1H), 2.95 (dd, 1H), 3.36-3.43 (m, 1H), 4.06 (td,
1H), 4.14 (d, 1H), 7.26 (dd, 1H), 7.40-7.52 (m, 5H), 7.60 (d, 1H),
9.95 (s, 1H), 12.54 (br. s, 1H).
[1247] [.alpha.].sub.D.sup.20=+78.degree., c=0.52, chloroform.
[1248] Alternatively,
(+)-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-met-
hylbuta-noyl]amino}phenyl)-4,4,4-trifluorobutanoic acid could also
be prepared by the following route:
[1249] 1.76 g (3.08 mmol) of
(+)-tert-butyl(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifl-
uoro-3-methylbutanoyl]amino}phenyl)-4,4,4-trifluorobutanoate
(Example 203A) were dissolved in 4.9 ml of dichloromethane, and 4.7
ml of TFA were added at RT. The reaction mixture was stirred at RT
for 2 h and then concentrated under reduced pressure. The residue
was taken up in ethyl acetate and washed with sat. sodium
bicarbonate solution and sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product was purified by preparative RP-HPLC (mobile phase
methanol/water). This gave 1.30 g of the target product (81.9% of
theory).
[1250] LC-MS (Method 4): R.sub.t=1.46 min; m/z=515 (M).sup.+.
[1251] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 2.83 (dd, 1H), 2.95 (dd, 1H), 3.37-3.45 (m, 1H), 4.06 (td,
1H), 4.14 (d, 1H), 7.26 (dd, 1H), 7.43-7.52 (m, 5H), 7.60 (d, 1H),
9.95 (s, 1H), 12.56 (br. s, 1H).
[1252] [.alpha.].sub.D.sup.20=+79.9.degree., c=0.475,
chloroform.
Example 85
Diastereomer 2
(+)-(3R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)-4,4,4-trifluorobutanoic acid
##STR00395##
[1254] LC-MS (Method 6): R.sub.t=1.19 min; m/z=516 (M+H).sup.+.
[1255] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 2.84 (dd, 1H), 2.95 (dd, 1H), 3.28-3.44 (m, 1H), 3.95-4.11 (m,
1H), 4.15 (d, 1H), 7.22-7.30 (m, 1H), 7.41-7.53 (m, 5H), 7.57-7.70
(m, 1H), 9.95 (s, 1H), 12.55 (br. s, 1H).
[1256] [.alpha.].sub.D.sup.20=+40.2.degree., c=0.52,
chloroform.
[1257] Alternatively,
(+)-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-met-
hylbuta-noyl]amino}phenyl)-4,4,4-trifluorobutanoic acid could also
be prepared by the following route:
[1258] 1.17 g (2.04 mmol) of
(+)-tert-butyl(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifl-
uoro-3-methylbutanoyl]amino}phenyl)-4,4,4-trifluorobutanoate
(Example 204A) were dissolved in 4.9 ml of dichloromethane, and 3.2
ml of TFA were added at RT. The reaction mixture was stirred at RT
for 2 h and then concentrated under reduced pressure. The residue
was taken up in ethyl acetate and washed with sat. sodium
bicarbonate solution and sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. The
crude product was purified by preparative RP-HPLC (mobile phase
methanol/water). This gave 0.76 g of the target product (72% of
theory).
[1259] LC-MS (Method 6): R.sub.t=1.19 min; m/z=516 (M+H).sup.+.
[1260] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.80 (d,
3H), 2.83 (dd, 1H), 2.94 (dd, 1H), 3.37-3.47 (m, 1H), 3.93-4.10 (m,
1H), 4.15 (d, 1H), 7.26 (dd, 1H), 7.43-7.52 (m, 5H), 7.58-7.66 (m,
1H), 9.95 (s, 1H), 12.57 (br. s, 1H).
[1261] [.alpha.].sub.D.sup.20=+44.8.degree., c=0.47,
chloroform.
Example 86
3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoy-
l]amino}phenyl)-pentanoic Acid (Diastereomer Mixture)
##STR00396##
[1263] 650 mg (1.33 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)pentanoate (Diastereomer Mixture) were dissolved in
2 ml of acetic acid, 1 ml of 30% strength sulphuric acid was added
and the mixture was heated at reflux (bath temperature about
140.degree. C.). After 1.5 h, the reaction mixture was cooled and
added to water. The mixture was extracted three times with ethyl
acetate. The combined organic phases were washed with sat. sodium
bicarbonate solution and sat. sodium chloride solution, dried over
magnesium sulphate and concentrated under reduced pressure. After
drying under high vacuum, the residue was purified by
chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 50:1). This gave 600 mg of the target product (95% of
theory).
[1264] LC-MS (Method 6): R.sub.t=1.24 min; m/z=476 (M+H).sup.+.
[1265] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers
.delta. [ppm]=0.69 (td, 3H), 0.80 (d, 3H), 1.40-1.52 (m, 1H),
1.55-1.68 (m, 1H), 2.40 (dd, 1H), 2.55-2.59 (m, 1H), 2.78-2.89 (m,
1H), 3.36-3.43 (m, 1H), 4.13 (d, 1H), 7.04 (dd, 1H), 7.31-7.41 (m,
2H), 7.42-7.57 (m, 4H), 9.84 (s, 1H), 12.04 (br. s, 1H).
Example 87 and Example 88
(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-
anoyl]amino}phenyl)-pentanoic Acid (Diastereomers 1 and 2)
##STR00397##
[1267] The mixture obtained above of the diastereomeric
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yflamino}phenyl]pentanoic acids (Example 86) was separated further
by preparative HPLC on a chiral phase [column: Daicel Chiralpak
AD-H, 5 .mu.m, 250 mm.times.20 mm; flow rate: 18 ml/min; detection:
230 nm; injection volume: 0.25 ml; temperature: 25.degree. C.;
mobile phase: 95% isohexane/5% isopropanol]. 545 mg of diastereomer
mixture gave 140 mg of diastereomer 1 (Example 87) and 156 mg of
diastereomer 2 (Example 88):
Example 87
Diastereomer 1
(+)-(3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)pentanoic Acid
##STR00398##
[1269] LC-MS (Method 4): R.sub.t=1.47 min; m/z=476 (M+H).sup.+.
[1270] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.69 (t,
3H), 0.80 (d, 3H), 1.37-1.51 (m, 1H), 1.54-1.68 (m, 1H), 2.35-2.44
(m, 1H), 2.55-2.59 (m, 1H), 2.80-2.87 (m, 1H), 3.36-3.40 (m, 1H),
4.13 (d, 1H), 7.04 (dd, 1H), 7.32-7.40 (m, 2H), 7.42-7.50 (m, 4H),
9.83 (s, 1H), 12.03 (br. s, 1H).
[1271] [.alpha.].sub.D.sup.20=+87.0, c=0.47, chloroform.
Example 88
Diastereomer 2
(+)-(3R)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-meth-
ylbutanoyl]amino}-phenyl)pentanoic Acid
##STR00399##
[1273] LC-MS (Method 4): R.sub.t=1.47 min; m/z=476 (M+H).sup.+.
[1274] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.69 (t,
3H), 0.80 (d, 3H), 1.39-1.50 (m, 1H), 1.56-1.65 (m, 1H), 2.35-2.45
(m, 1H), 2.52-2.58 (m, 1H), 2.80-2.87 (m, 1H), 3.35-3.41 (m, 1H),
4.13 (d, 1H), 7.04 (dd, 1H), 7.31-7.41 (m, 2H), 7.42-7.52 (m, 4H),
9.83 (s, 1H), 12.04 (br. s, 1H).
[1275] [.alpha.].sub.D.sup.20=+71.4, c=0.48, chloroform.
[1276] The examples below were prepared in accordance with General
Procedure 2 (cleavage of tert-butyl esters to the corresponding
carboxylic acids using trifluoroacetic acid):
TABLE-US-00025 Example Name/Structure/Starting material Analytical
data 89 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS
(Method 6): trifluoro-3-methylbutanoyl]amino}phenyl)- R.sub.t =
1.24 min; m/z = 476/478 2,2-dimethylpropanoic acid (M + H).sup.+.
##STR00400## .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.80 (d, 3H), 1.046 (s, 3H), 1.051 (s, 3H), 2.74 (s, 2H), 3.29-3.45
(m, 1H, partially obscured by H.sub.2O signal), 4.11 (d, 1H), 6.95
(dd, 1H), 7.31-7.37 (m, 2H), 7.42- 7.50 (m, 4H), 9.84 (s, 1H),
12.17-12.44 (br. s, 1H). (from tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)-2,2- dimethylpropanoate) 90
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- MS: m/z = 488 (M
+ H).sup.+. trifluoro-3-methylbutanoyl]amino}phenyl)- .sup.1H-NMR
(400 MHz, DMSO- cyclobutyl]acetic acid d.sub.6): .delta. [ppm] =
0.80 (d, 3H), ##STR00401## 1.67-1.81 (m, 1H), 1.96-2.08 (m, 1H),
2.17-2.35 (m, 4H), 2.69 (s, 2H), 3.27-3.42 (m, 1H, partially
obscured by H.sub.2O signal), 4.14 (d, 1H), 6.99 (dd, 1H), 7.35 (d,
1H), 7.41 (d, 1H), 7.43-7.50 (m, 4H), 9.81 (s, 1H), 11.88 (s, 1H).
[.alpha.].sub.D.sup.20 = +88.degree., c = 0.290, methanol. (from
tert-butyl [1-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-
methylbutanoyl]amino}phenyl)cyclobutyl]acetate) 91
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3- LC-MS (Method
4): methylbutanoyl]amino}-2-methylphenyl)propanoic R.sub.t = 1.27
min; m/z = 428 acid (M + H).sup.+. ##STR00402## .sup.1H-NMR (400
MHz, DMSO- d.sub.6): .delta. [ppm] = 0.80 (d, 3H), 1.92 (s, 3H),
2.43 (t, 2H), 2.79 (t, 2H), 3.28-3.44 (m, 1H, partially obscured by
H.sub.2O signal), 3.94 (d, 1H), 6.93-7.09 (m, 3H), 7.39-7.52 (m,
4H), 9.69 (s, 1H), 12.14 (s, 1H). (from tert-butyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-2-methyl-
phenyl)propanoate) 92 3-[4-chloro-3-({(2S,3R)-2-[4-(3,3- LC-MS
(Method 6): difluorocyclobutyl)phenyl]-4,4,4-trifluoro-3- R.sub.t =
1.20 min; m/z = 502/504 methylbutanoyl}amino)phenyl]propanoic acid
(M - H).sup.-. ##STR00403## .sup.1H-NMR (400 MHz, DMSO- d.sub.6):
.delta. [ppm] = 0.79 (d, 3H), 2.48 (t, 2H, partially obscured by
DMSO signal), 2.60-2.73 (m, 2H), 2.76 (t, 2H), 2.92- 3.06 (m, 2H),
3.29-3.46 (m, 2H, partially obscured by H.sub.2O signal), 4.10 (d,
1H), 7.03 (dd, 1H), 7.32 (t, 3H), 7.41 (d, 3H), 9.76 (s, 1H),
12.02-12.26 (br. s, 1H). (from tert-butyl
3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-
difluorocyclobutyl)phenyl]-4,4,4-trifluoro-3-methyl-
butanoyl}amino)phenyl]propanoate) 93
3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxy- LC-MS (Method 6):
phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}- Rt = 1.10 min; m/z
= 476/478 phenyl)propanoic acid (M - H).sup.-. ##STR00404##
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.83 (d, 3H),
2.48 (t, 2H, partially obscured by DMSO signal), 2.77 (t, 2H),
3.33-3.48 (m, 1H), 3.87 (s, 3H), 4.09 (d, 1H), 7.00-7.08 (m, 2H),
7.23 (d, 1H), 7.35 (d, 1H), 7.40 (d, 1H), 7.42 (d, 1H), 9.81 (s,
1H), 11.50-12.57 (br. s, 1H). (from tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
3-methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)propanoate) 94
3-(3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4- LC-MS (Method
6): trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)- R.sub.t =
1.06 min; m/z = 460/462 propanoic acid (M - H).sup.-. ##STR00405##
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.81 (d, 3H),
2.48 (t, 2H, partially obscured by DMSO signal), 2.75 (t, 2H),
3.32-3.47 (m, 1H, partially obscured by H.sub.2O signal), 3.87 (s,
3H), 4.07 (d, 1H), 6.94-7.06 (m, 2H), 7.13 (t, 1H), 7.20 (s, 1H),
7.42 (d, 1H), 7.64 (d, 1H), 10.01 (s, 1H), 11.77- 12.45 (br. s,
1H). (from tert-butyl 3-(3-{[(2S,3R)-2-(4-chloro-3-
methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}-4-fluorophenyl)propanoate) 95
3-[4-chloro-3-({(2S,3R)-2-[4-(2,2- LC-MS (Method 7):
difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3- R.sub.t = 2.52 min;
m/z = 488/490 methylbutanoyl}amino)phenyl]propanoic acid (M -
H).sup.-. ##STR00406## .sup.1H-NMR (400 MHz, DMSO- d.sub.6):
.delta. [ppm] = 0.77 (d, 3H), 1.87-2.04 (m, 2H), 2.48 (t, 2H,
partially obscured by DMSO signal), 2.76 (t, 2H), 2.92-3.05 (m,
1H), 3.27-3.41 (m, 1H), 4.09 (d, 1H), 7.04 (dd, 1H), 7.28 (d, 2H),
7.34 (d, 1H), 7.38-7.44 (m, 3H), 9.78 (s, 1H), 11.60-12.59 (br. s,
1H). (from tert-butyl 3-[4-chloro-3-({(2S,3R)-2-[4-(2,2-
difluorocyclopropyl)phenyl]-4,4,4-trifluoro-
3-methylbutanoyl}amino)phenyl]propanoate) 96
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method
6): trifluoro-3-methylbutanoyl]amino}phenyl)- R.sub.t = 1.21 min;
m/z = 474/476 cyclopropyl]acetic acid (M + H).sup.+. ##STR00407##
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.75-0.82 (m,
5H), 0.85-0.91 (m, 2H), 2.52 (s, 2H, partially obscured by DMSO
signal), 3.29-3.43 (m, 1H, partially obscured by H.sub.2O signal),
4.13 (d, 1H), 7.07 (dd, 1H), 7.32 (d, 1H), 7.42-7.50 (m, 5H), 9.82
(s, 1H), 11.89- 12.10 (br. s, 1H). (from tert-butyl
[1-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)cyclopropyl]acetate) 97
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro- LC-MS (Method
6): 3-methylbutanoyl]amino}-4-cyanophenyl)- R.sub.t = 1.07 min; m/z
= 453/455 2-methylpropanoic acid (M + H).sup.+. ##STR00408##
.sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] = 0.81 (d, 3H),
1.03 (d, 3H), 2.57-2.73 (m, 2H), 2.85-2.95 (m, 1H), 3.27- 3.44 (m,
1H, partially obscured by H.sub.2O signal), 4.02 (d, 1H), 7.18 (d,
1H), 7.30 (s, 1H), 7.40-7.52 (m, 4H), 7.70 (d, 1H), 10.50 (s, 1H),
12.23 (br. s, 1H). (from tert-butyl
3-(3-{[(2S,3R)-2-(4-chlorophenyl)-
4,4,4-trifluoro-3-methylbutanoyl]amino}-4-cyano-
phenyl)-2-methylpropanoate)
[1277] The examples below were prepared according to General
Procedure 3 (cleavage of methyl or ethyl esters to the
corresponding carboxylic acids in mixtures of hydrochloric acid or
sulphuric acid with acetic acid):
TABLE-US-00026 Example Name/Structure/Starting material Analytical
data 98 (2S)-3-[4-chloro-3-({(2S,3R)-4,4,4-trifluoro-3- LC-MS
(Method 4): methyl-2-[4-(1,1,1-trifluoro-2-methylpropan-2- R.sub.t
= 1.49 min; m/z = 536/538 yl)phenyl]butanoyl}amino)phenyl]-2- (M -
H).sup.-. methylpropanoic acid .sup.1H-NMR (400 MHz, DMSO-
##STR00409## d.sub.6): .delta. [ppm] = 0.69 (d, 3H), 1.02 (d, 3H),
1.54 (s, 6H), 2.51-2.62 (m, 2H, partially obscured by DMSO signal),
2.78-2.89 (m, 1H), 3.29-3.45 (m, 1H, partially obscured by H.sub.2O
signal), 4.14 (d, 1H), 7.00 (dd, 1H), 7.35 (d, 1H), 7.45 (d, 1H),
7.48 (d, 2H), 7.54 (d, 2H), 9.80 (s, 1H), 12.14 (s, 1H). (from
ethyl (2S)-3-[4-chloro-3-({(2S,3R)-4,4,4-
trifluoro-3-methyl-2-[4-(1,1,1-trifluoro-2-
methylpropan-2-yl)phenyl]butanoyl}amino)phenyl]-
2-methylpropanoate) 99
(2S)-3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4- LC-MS (Method
4): (2,2,2-trifluoroethyl)phenyl]butanoyl}amino)- R.sub.t = 1.39
min; m/z = 508/510 phenyl]-2-methylpropanoic acid (M - H).sup.-.
##STR00410## .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.70 (d, 3H), 1.01 (d, 3H), 2.50-2.61 (m, 2H, partially obscured by
DMSO signal), 2.78-2.90 (m, 1H), 3.29-3.45 (m, 1H, partially
obscured by H.sub.2O signal), 3.63 (q, 2H), 4.11 (d, 1H), 7.00 (dd,
1H), 7.35 (d, 2H), 7.39 (d, 2H), 7.46 (d, 2H), 9.80 (s, 1H), 12.15
(s, 1H). (from ethyl (2S)-3-[4-chloro-3-({4,4,4-trifluoro-3-
methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}-
amino)phenyl]-2-methylpropanoate) 100
(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-difluoro- LC-MS (Method 6):
cyclobutyl)phenyl]-4,4,4-trifluoro-3-methyl- R.sub.t = 1.24 min;
m/z = 516/518 butanoyl}amino)phenyl]-2-methylpropanoic acid (M -
H).sup.-. ##STR00411## .sup.1H-NMR (400 MHz, DMSO- d.sub.6):
.delta. [ppm] = 0.79 (d, 3H), 1.01 (d, 3H), 2.46-2.60 (m, 2H,
partially obscured by DMSO signal), 2.60-2.76 (m, 2H), 2.77-2.87
(m, 1H), 2.91-3.06 (m, 2H), 3.26-3.46 (m, 2H, partially obscured by
H.sub.2O signal), 4.10 (d, 1H), 6.99 (dd, 1H), 7.33 (t, 3H), 7.42
(d, 3H), 9.76 (s, 1H), 11.86-12.37 (br. s, 1H). (from ethyl
(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-
difluorocyclobutyl)phenyl]-4,4,4-trifluoro-3-methyl-
butanoyl}amino)phenyl]-2-methylpropanoate) 101
(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxy- LC-MS (Method
6): phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}- R.sup.t = 1.15
min; m/z = 492/494 phenyl)-2-methylpropanoic acid (M + H).sup.+.
##STR00412## .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.83 (d, 3H), 1.02 (d, 3H), 2.46-2.61 (m, 2H, partially obscured by
DMSO signal), 2.77-2.88 (m, 1H), 3.36-3.47 (m, 1H), 3.87 (s, 3H),
4.09 (d, 1H), 6.98-7.06 (m, 2H), 7.23 (d, 1H), 7.36 (d, 1H), 7.38
(d, 1H), 7.43 (d, 1H), 9.81 (s, 1H), 12.04-12.26 (br. s, 1H). (from
ethyl (2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-
3-methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-2-methylpropanoate) 102
[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS (Method
6): trifluoro-3-methylbutanoyl]amino}phenyl)- R.sub.t = 1.22 min;
m/z = 524/526 3,3-difluorocyclobutyl]acetic acid (M + H).sup.+.
##STR00413## .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.80 (d, 3H), 2.76 (s, 2H), 2.81-2.94 (m, 2H), 2.95-3.09 (m, 2H),
3.29- 3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.15 (d,
1H), 7.12 (dd, 1H), 7.41 (d, 1H), 7.42-7.49 (m, 4H), 7.50 (d, 1H),
9.88 (s, 1H), 12.09-12.24 (br. s, 1H). (from ethyl
[1-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-
amino}phenyl)-3,3-difluorocyclobutyl]acetate)
Example 103 and Example 104
(2S)-3-[4-Chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyflp-
henyl]butanoyl}amino)-phenyl]-2-methylpropanoic acid (diastereomers
1 and 2)
##STR00414##
[1279] 74 mg (0.15 mmol) of the isomer mixture of
(2S)-3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyfl-
phenyl]butanoyl}amino)phenyl]-2-methylpropanoic acid (Example 99)
were separated further by preparative HPLC on a chiral phase
[column: Daicel Chiralpak AY-H, 5 .mu.m, 250 mm.times.20 mm; mobile
phase: isohexane/ethanol 1:1 (v/v); flow rate: 15 ml/min; UV
detection: 220 nm; temperature: 45.degree. C.]:
Example 103
Diastereomer 1
[1280] Yield: 39 mg
[1281] R.sub.t=3.72 min; chemical purity >98%; >99% de
[1282] [column: Daicel Chiralpak AY-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/(isopropanol+0.2% TFA+1% water) 70:30
(v/v); flow rate: 1 ml/min; temperature: 45.degree. C.; UV
detection: 220 nm].
[1283] LC-MS (Method 6): R.sub.t=1.16 min; m/z=508/510
(M-H).sup.-.
Example 104
Diastereomer 2
[1284] Yield: 39 mg
[1285] R.sub.t=6.09 min; chemical purity >98%; >99% de
[1286] [column: Daicel Chiralpak AY-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/(isopropanol+0.2% TFA+1% water) 70:30
(v/v); flow rate: 1 ml/min; temperature: 45.degree. C.; UV
detection: 220 nm].
[1287] LC-MS (Method 6): R.sub.t=1.16 min; m/z=508/510
(M-H).sup.-.
Examples 105-108
(2S)-3-(4-Chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amino-
}phenyl)-2-methyl-propanoic acid (isomers 1-4)
##STR00415##
[1289] 205 mg (0.44 mmol) of the diastereomer mixture of
(2S)-3-(4-chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amin-
o}phenyl)-2-methylpropanoic acid (Example 20) were separated
further by preparative HPLC on a chiral phase [column: Daicel
Chiralcel OJ-H, 5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol 70:30 (v/v); flow rate: 25 ml/min; UV detection:
230 nm; temperature: 25.degree. C.]. This gave two different
fractions each consisting of a mixture of two isomers. These two
fractions were separated into the individual isomers by another
preparative HPLC on a chiral phase [Fraction 1: column: Daicel
Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/isopropanol 80:20 (v/v); flow rate: 20 ml/min; UV
detection: 230 nm; temperature: 25.degree. C. Fraction 2: column:
Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol 90:10 (v/v); flow rate: 20 ml/min; UV detection:
230 nm; temperature: 25.degree. C.]:
Example 105
Isomer 1
[1290] Yield: 30 mg
[1291] R.sub.t=15.70 min; chemical purity >89.8%
[1292] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/isopropanol 70:30 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1293] LC-MS (Method 6): R.sub.t=1.22 min; m/z=470/472
(M+H).sup.+.
[1294] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.02 (d,
3H), 1.21-1.35 (m, 1H), 1.45-1.58 (m, 1H), 1.84-2.20 (m, 3H),
2.28-2.43 (m, 1H), 2.53-2.62 (m, 2H, partially obscured by DMSO
signal), 2.76-2.90 (m, 2H), 3.75 (d, 1H), 7.03 (dd, 1H), 7.32-7.49
(m, 6H), 9.74 (s, 1H), 12.04-12.35 (br. s, 1H).
Example 106
Isomer 2
[1295] Yield: 35 mg
[1296] R.sub.t=20.07 min; chemical purity >98.9%
[1297] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/isopropanol 70:30 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1298] LC-MS (Method 5): R.sub.t=2.58 min; m/z=470/472
(M+H).sup.+.
[1299] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.02 (d,
3H), 1.52-1.69 (m, 2H), 1.81-1.96 (m, 1H), 1.98-2.29 (m, 3H),
2.52-2.62 (m, 2H, partially obscured by DMSO signal), 2.78-2.92 (m,
2H), 3.78 (d, 1H), 7.03 (dd, 1H), 7.33-7.48 (m, 6H), 9.78 (s, 1H),
12.04-12.26 (br. s, 1H).
Example 107
Isomer 3
[1300] Yield: 37 mg
[1301] R.sub.t=14.17 min; chemical purity >95.7%
[1302] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min;
UV detection: 230 nm; temperature: 25.degree. C.].
[1303] LC-MS (Method 5): R.sub.t=2.57 min; m/z=470/472
(M+H).sup.+.
[1304] .sup.1H-NMR: see Example 106 (isomer 2).
Example 108
Isomer 4
[1305] Yield: 29 mg
[1306] R.sub.t=17.77 min; chemical purity >99.5%
[1307] [Column: Daicel Chiralpak AD-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min;
UV detection: 230 nm; temperature: 25.degree. C.].
[1308] LC-MS (Method 5): R.sub.t=2.58 min; m/z=470/472
(M+H).+-..
[1309] .sup.1H-NMR: see Example 105 (isomer 1).
Examples 109-112
(2R)-3-(4-Chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyflacetyl]amino-
}phenyl)-2-methyl-propanoic Acid (Isomers 1-4)
##STR00416##
[1311] 160 mg (0.32 mmol) of the diastereomer mixture of
(2R)-3-(4-chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amin-
o}phenyl)-2-methylpropanoic acid (Example 21) were separated into
the four isomers by preparative HPLC [column: Daicel Chiralcel
OJ-H, 5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol/methanol 90:5:5 (v/v); flow rate: 20 ml/min; UV
detection: 230 nm; temperature: 25.degree. C.]:
Example 109
Isomer 1
[1312] Yield: 16.7 mg
[1313] R.sub.t=10.49 min; chemical purity >92.8%
[1314] [Column: Daicel Chiralpak OJ-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol/methanol 90:5:5 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1315] LC-MS (Method 4): R.sub.t=1.39 min; m/z=470/472
(M+H).sup.+.
Example 110
Isomer 2
[1316] Yield: 24.4 mg
[1317] R.sub.t=12.26 min; chemical purity >94.7%
[1318] [Column: Daicel Chiralpak OJ-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol/methanol 90:5:5 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1319] LC-MS (Method 4): R.sub.t=1.39 min; m/z=470/472
(M+H).sup.+.
Example 111
Isomer 3
[1320] Yield: 22 mg
[1321] R.sub.t=18.89 min; chemical purity >97.8%
[1322] [Column: Daicel Chiralpak OJ-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol/methanol 90:5:5 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1323] LC-MS (Method 4): R.sub.t=1.39 min; m/z=470/472
(M+H).sup.+.
Example 112
Isomer 4
[1324] Yield: 25 mg
[1325] R.sub.t=28.37 min; chemical purity >97.8%
[1326] [Column: Daicel Chiralpak OJ-H, 5 .mu.m, 250 mm.times.4 mm;
mobile phase: isohexane/ethanol/methanol 90:5:5 (v/v); flow rate: 1
ml/min; UV detection: 230 nm; temperature: 25.degree. C.].
[1327] LC-MS (Method 4): R.sub.t=1.39 min; m/z=470/472
(M+H).sup.+.
[1328] The example below was prepared according to General
Procedure 3:
TABLE-US-00027 Example Name/Structure/Starting Material Analytical
Data 113 3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4- LC-MS
(Method 6): trifluoro-3-methylbutanoyl]amino}phenyl)- R.sub.t =
1.23 min; m/z = 476/478 3-methylbutanoic acid (M + H).sup.+.
##STR00417## .sup.1H-NMR (400 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.80 (d, 3H), 1.31 (s, 6H), 2.53 (s, 2H, partially obscured by DMSO
signal), 3.30-3.44 (m, 1H, partially obscured by H.sub.2O signal),
4.14 (d, 1H), 7.20 (dd, 1H), 7.35 (d, 1H), 7.42-7.50 (m, 4H), 7.56
(d, 1H), 9.83 (s, 1H), 11.85-11.97 (br. s, 1H). (from ethyl
3-(4-chloro-3-{[(2S,3R)-2-(4-
chlorophenyl)-4,4,4-trifluoro-3-methyl-
butanoyl]amino}phenyl)-3-methylbutanoate)
B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY
[1329] The pharmacological effect of the compounds according to the
invention can be shown in the following assays:
B-1. Stimulation of Recombinant Soluble Guanylate Cyclase (sGC) In
Vitro:
[1330] Investigations on the stimulation of recombinant soluble
guanylate cyclase (sGC) by the compounds according to the invention
with and without sodium nitroprusside, and with and without the
haem-dependent sGC inhibitor
1H-1,2,4-oxadiazolo-(4,3a)-quinoxalin-1-one (ODQ) are carried out
by the method described in detail in the following reference: M.
Hoenicka, E.M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R.
Gerzer and J.-P. Stasch, "Purified soluble guanylyl cyclase
expressed in a baculovirus/Sf9 system: Stimulation by YC-1, nitric
oxide, and carbon oxide", J. Mol. Med. 77 (1999), 14-23. The
haem-free guanylate cyclase is obtained by adding Tween 20 to the
sample buffer (0.5% in the final concentration).
[1331] The activation of sGC by a test substance is reported as
x-fold stimulation of the basal activity. The result for Example 15
is shown in Table 1A and that for Example 17 in Table 1B:
TABLE-US-00028 TABLE 1A Stimulation (x-fold) of recombinant soluble
guanylate cyclase (sGC) in vitro by Example 15 Concentra-
Haem-containing sGC Haem-free sGC tion Example Basal +0.01 .mu.M
+10 .mu.M Basal 15 [.mu.M] (n = 8) DEA/NO ODQ (n = 8) 0 1.0 .+-.
0.0 6.5 .+-. 0.8 4.4 .+-. 0.8 1.0 .+-. 0.0 0.01 1.1 .+-. 0.1 5.9
.+-. 0.7 4.6 .+-. 0.8 1.7 .+-. 0.3 0.1 1.0 .+-. 0.1 7.4 .+-. 0.8
4.5 .+-. 0.6 1.8 .+-. 0.2 1.0 0.9 .+-. 0.1 8.5 .+-. 0.7 4.8 .+-.
0.8 3.0 .+-. 0.5 10 3.1 .+-. 0.3 11.5 .+-. 0.9 16.3 .+-. 1.3 17.9
.+-. 3.1 100 31.6 .+-. 2.6 45.9 .+-. 3.1 97.3 .+-. 7.7 40.3 .+-.
6.6
TABLE-US-00029 TABLE 1B Stimulation (x-fold) of recombinant soluble
guanylate cyclase (sGC) in vitro by Example 17 Concentra-
Haem-containing sGC Haem-free sGC tion Example Basal +0.01 .mu.M
+10 .mu.M Basal 17 [.mu.M] (n = 6) DEA/NO ODQ (n = 6) 0 1.0 .+-.
0.0 7.9 .+-. 0.7 2.8 .+-. 0.6 1.0 .+-. 0.0 0.01 0.7 .+-. 0.2 9.6
.+-. 0.8 4.9 .+-. 1.2 1.7 .+-. 0.2 0.1 0.6 .+-. 0.1 8.8 .+-. 1.2
5.3 .+-. 1.3 2.0 .+-. 0.3 1.0 0.6 .+-. 0.1 9.8 .+-. 1.2 4.5 .+-.
1.1 4.1 .+-. 0.3 10 1.8 .+-. 0.3 10.7 .+-. 1.0 8.3 .+-. 1.4 22.9
.+-. 1.8 100 4.9 .+-. 0.7 11.4 .+-. 1.2 15.0 .+-. 2.0 33.5 .+-. 3.3
[DEA/NO = 2-(N,N-diethylamino)diazenolate 2-oxide; ODQ =
1H,2,4-oxadiazolo[4,3-a]quin-oxalin-1-one].
[1332] It is evident from Tables 1A and 1B that stimulation both of
the haem-containing and of the haem-free enzyme is achieved.
Furthermore, combination of Example 15 or Example 17 and
2-(N,N-diethylamino)diazenolate 2-oxide (DEA/NO), an NO donor,
shows no synergistic effect, i.e. the effect of DEA/NO is not
potentiated as would be expected with an sGC activator acting via a
haem-dependent mechanism In addition, the effect of the sGC
activator according to the invention is not blocked by the
haem-dependent inhibitor of soluble guanylate cyclase
1H-1,2,4-oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), but is in fact
increased by it. The results in Tables 1A and 1B thus confirm the
mechanism of action of the compounds according to the invention as
activators of soluble guanylate cyclase.
B-2. Action at Recombinant Guanylate Cyclase Reporter Cell Line
[1333] The cellular action of the compounds according to the
invention is determined at a recombinant guanylate cyclase reporter
cell line, as described in F. Wunder et al., Anal. Biochem. 339,
104-112 (2005).
[1334] Representative results for the compounds according to the
invention are listed in Table 2:
TABLE-US-00030 TABLE 2 sGC-activating activity in the CHO reporter
cell in vitro Example No. MEC [nM] 2 0.3 5 3.0 7 0.2 10 5.2 15 10
17 4.8 18 10 28 1.0 30 0.3 37 10 50 30 53 300 71 10 81 0.3 82 0.23
84 1 87 1 89 3 90 1 96 1 99 10 100 3 102 1 105 30 (MEC = minimal
effective concentration).
[1335] B-3. Stimulation of sGC enzyme activity
[1336] Soluble guanylate cyclase (sGC) converts on stimulation GTP
into cGMP and pyrophosphate (PPi). PPi is detected with the aid of
the assay described below. The signal produced in the assay
increases as the reaction progresses and serves as a measure of the
sGC enzyme activity under the given stimulation.
[1337] To carry out the assay, 29 .mu.l of enzyme solution [0-10 nM
soluble guanylate cyclase (prepared according to flonicka et al.,
J. Mol. Med. 77, 14-23 (1999)) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1%
BSA (fraction V), 0.005% Brij.RTM., pH 7.5] are initially
introduced into a microplate, and 1 .mu.l of the substance to be
tested (as a serially diluted solution in DMSO) is added. The
mixture is incubated at room temperature for 10 min Then 20 .mu.l
of detection mix [1.2 nM Firefly Luciferase (Photinus pyralis
luciferase, Promega), 29 .mu.M dehydroluciferin (prepared according
to Hitler & McElroy, Arch. Biochem. Biophys. 72, 358 (1957)),
122 .mu.M luciferin (Promega), 153 .mu.M ATP (Sigma) and 0.4 mM DTT
(Sigma) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1% BSA (fraction V),
0.005% Brij.RTM., pH 7.5] are added. The enzyme reaction is started
by adding 20 .mu.l of substrate solution [1.25 mM guanosine
5'-triphosphate (Sigma) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1% BSA
(fraction V), 0.005% Brij.RTM., pH 7.5] and measured continuously
in a luminometer. The extent of the stimulation by the substance to
be tested can be determined relative to the signal of the
unstimulated reaction.
[1338] The activation of haem-free guanylate cyclase is examined by
addition of 25 .mu.M of 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ) to the enzyme solution and subsequent incubation for 30
minutes, and compared to the stimulation of the native enzyme.
[1339] Representative results for the compounds according to the
invention are listed in Table 3:
TABLE-US-00031 TABLE 3 Activating action at the sGC enzyme in vitro
Example No. MEC [nM] EC.sub.50 [nM] 15 10 290 17 7 130 (MEC =
minimal effective concentration; EC.sub.50 = concentration at 50%
of maximum efficacy).
B-4. Radiotelemetric Measurement of Blood Pressure and Heart Rate
on Conscious SH Rats
[1340] A commercially available telemetry system from Data Sciences
International DSI, USA, is employed for the measurements on
conscious SH rats described below.
[1341] The system consists of 3 main components: (1) implantable
transmitters, (2) receivers, which are linked via a multiplexer to
a (3) data acquisition computer. The telemetry system makes it
possible to continuously record the blood pressure and heart rate
of conscious animals in their usual habitat.
[1342] The investigations are carried out on adult female
spontaneously hypertensive rats (SH rats) with a body weight of
>200 g. After transmitter implantation, the experimental animals
are housed singly in type 3 Makrolon cages. They have free access
to standard feed and water. The day/night rhythm in the
experimental laboratory is changed by the room lighting at 6.00 am
and at 7.00 .mu.m.
[1343] The telemetry transmitters (TAM PA-C40, DSI) as employed are
surgically implanted under aseptic conditions in the experimental
animals at least 14 days before the first experimental use. The
animals instrumented in this way can be employed repeatedly after
the wound has healed and the implant has settled.
[1344] For the implantation, the fasted animals are anesthetized
with pentobarbital (Nembutal, Sanofi, 50 mg/kg i.p.) and shaved and
disinfected over a large area of their abdomens. After the
abdominal cavity has been opened along the linea alba, the
liquid-filled measuring catheter of the system is inserted into the
descending aorta in the cranial direction above the bifurcation and
fixed with tissue glue (VetBonD.TM., 3M). The transmitter housing
is fixed intraperitoneally to the abdominal wall muscle, and
layered closure of the wound is performed. An antibiotic
(Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administered
postoperatively for prophylaxis of infection.
Outline of Experiment:
[1345] The substances to be investigated are administered orally by
gavage in each case to a group of animals (n=6). The test
substances are dissolved in suitable solvent mixtures, or suspended
in 0.5% strength Tylose, appropriate for an administration volume
of 5 ml/kg of body weight. A solvent-treated group of animals is
employed as control.
[1346] The telemetry measuring unit is configured for 24 animals.
Each experiment is recorded under an experiment number.
[1347] Each of the instrumented rats living in the system is
assigned a separate receiving antenna (1010 Receiver, DSI). The
implanted transmitters can be activated externally by means of an
incorporated magnetic switch and are switched to transmission in
the run-up to the experiment. The emitted signals can be detected
online by a data acquisition system (Dataquest.TM. A.R.T. for
Windows, DSI) and be appropriately processed. The data are stored
in each case in a file created for this purpose and bearing the
experiment number.
[1348] In the standard procedure, the following are measured for
10-second periods in each case: (1) systolic blood pressure (SBP),
(2) diastolic blood pressure (DBP), (3) mean arterial pressure
(MAP) and (4) heart rate (HR).
[1349] The acquisition of measured values is repeated under
computer control at 5-minute intervals. The source data obtained as
absolute value are corrected in the diagram with the currently
measured barometric pressure and stored as individual data. Further
technical details are given in the documentation from the
manufacturing company (DSI).
[1350] The test substances are administered at 9.00 am on the day
of the experiment. Following the administration, the parameters
described above are measured over 24 hours. After the end of the
experiment, the acquired individual data are sorted using the
analysis software (Dataquest.TM. A.R.T. Analysis). The void value
is assumed to be the time 2 hours before administration of the
substance, so that the selected data set includes the period from
7.00 am on the day of the experiment to 9.00 am on the following
day.
[1351] The data are smoothed over a presettable time by
determination of the average (15-minute average, 30-minute average)
and transferred as a text file to a storage medium. The measured
values presorted and compressed in this way are transferred into
Excel templates and tabulated.
C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS
[1352] The compounds according to the invention can be converted
into pharmaceutical preparations in the following ways:
Tablet:
Composition:
[1353] 100 mg of the compound according to the invention, 50 mg of
lactose (monohydrate), 50 mg of maize starch (native), 10 mg of
polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany)
and 2 mg of magnesium stearate.
[1354] Tablet weight 212 mg, diameter 8 mm, radius of curvature 12
mm
Production:
[1355] The mixture of compound according to the invention, lactose
and starch is granulated with a 5% strength solution (m/m) of the
PVP in water. The granules are dried and then mixed with the
magnesium stearate for 5 minutes. This mixture is compressed in a
conventional tablet press (see above for format of the tablet). A
guideline compressive force for the compression is 15 kN.
Suspension which can be Administered Orally:
Composition:
[1356] 1000 mg of the compound according to the invention, 1000 mg
of ethanol (96%), 400 mg of Rhodigel.RTM. (xanthan gum from FMC,
Pennsylvania, USA) and 99 g of water.
[1357] 10 ml of oral suspension correspond to a single dose of 100
mg of the compound according to the invention.
Production:
[1358] The Rhodigel is suspended in ethanol, and the compound
according to the invention is added to the suspension. The water is
added while stirring. The mixture is stirred for about 6 h until
the swelling of the Rhodigel is complete.
Solution which can be Administered Orally:
Composition:
[1359] 500 mg of the compound according to the invention, 2.5 g of
polysorbate and 97 g of polyethylene glycol 400.20 g of oral
solution correspond to a single dose of 100 mg of the compound
according to the invention.
Production:
[1360] The compound according to the invention is suspended in the
mixture of polyethylene glycol and polysorbate with stirring. The
stirring process is continued until the compound according to the
invention has completely dissolved.
[1361] i.v. Solution:
[1362] The compound according to the invention is dissolved in a
concentration below the saturation solubility in a physiologically
tolerated solvent (e.g. isotonic saline, 5% glucose solution and/or
30% PEG 400 solution). The solution is sterilized by filtration and
used to fill sterile and pyrogen-free injection containers.
* * * * *