U.S. patent application number 12/043401 was filed with the patent office on 2008-07-03 for protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use.
Invention is credited to Orlin Petrov, Johannes Platzek, Jurgen Westermann.
Application Number | 20080161580 12/043401 |
Document ID | / |
Family ID | 35449821 |
Filed Date | 2008-07-03 |
United States Patent
Application |
20080161580 |
Kind Code |
A1 |
Westermann; Jurgen ; et
al. |
July 3, 2008 |
PROTECTED 3,5-DIHYDROXY-2,2-DIMETHYL-VALEROAMIDES FOR THE SYNTHESIS
OF EPOTHILONES AND DERIVATIVES AND PROCESS FOR THE PRODUCTION AND
THE USE
Abstract
The invention relates to new protected
3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of
epothilones and derivatives and process for the production and the
use of the new compounds for the production of epothilones or
epothilone derivatives.
Inventors: |
Westermann; Jurgen; (Berlin,
DE) ; Platzek; Johannes; (Berlin, DE) ;
Petrov; Orlin; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
35449821 |
Appl. No.: |
12/043401 |
Filed: |
March 6, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11149331 |
Jun 10, 2005 |
7368568 |
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12043401 |
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10211242 |
Aug 5, 2002 |
6933385 |
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11149331 |
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60313015 |
Aug 20, 2001 |
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Current U.S.
Class: |
548/204 ; 560/1;
564/170; 564/192; 568/309 |
Current CPC
Class: |
C07C 235/16 20130101;
C07D 319/08 20130101; C07F 7/1804 20130101; C07C 235/06 20130101;
C07D 319/06 20130101; C07F 7/1892 20130101; C07D 493/04
20130101 |
Class at
Publication: |
548/204 ;
564/192; 564/170; 560/1; 568/309 |
International
Class: |
C07D 277/30 20060101
C07D277/30; C07C 233/04 20060101 C07C233/04; C07C 233/11 20060101
C07C233/11; C07C 69/00 20060101 C07C069/00; C07C 45/00 20060101
C07C045/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2001 |
DE |
10138348.7 |
Claims
1.-32. (canceled)
33. A method for producing a natural or synthetic epothilone
compound or derivative thereof, which comprises reacting a compound
of following formula (I) as a starting material in at least one
step in the method: ##STR00046## in which R.sub.1 and R.sub.2 are
the same or different and, independently of one another, stand for
an alcohol protective group or, R.sub.1 and R.sub.2 are bridged and
together stand for a ketal protective group, and Y stands for a
group --NA1A2, whereby A1 and A2, independently of one another,
stand for C.sub.1-C.sub.6 alkyl, aryl, aralkyl, --OH, --OMe, or
--O-benzyl, or Y stands for ##STR00047## where the dashed line
bonds indicate the point of attachment.
34. The method of claim 33, wherein the alcohol protective groups
are selected from: benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,
THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl and trityl
groups; and the ketal protective group is selected from groups of
the following formulae: ##STR00048## where the dashed line bonds
indicate the points of attachment.
35. The method of claim 33, wherein, for A1 and A2, aryl is phenyl
and aralkyl is benzyl.
36. A process for producing a compound of the following formula
(I): ##STR00049## in which R.sub.1 and R.sub.2 are the same or
different and, independently of one another, stand for an alcohol
protective group or, R.sub.1 and R.sub.2 are bridged and together
stand for a ketal protective group, and Y stands for a group
--NA1A2, whereby A1 and A2, independently of one another, stand for
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, --OH, --OMe, or --O-benzyl,
or Y stands for ##STR00050## where the dashed line bonds indicate
the point of attachment; which process comprises protecting a
corresponding compound having free alcohol groups in place of
OR.sub.1 and/or OR.sub.2 with an alcohol protective group R.sub.1
and/or R.sub.2 or a ketal protective group of R.sub.1 and R.sub.2
together.
37. A process of claim 36, wherein protective groups R.sub.1 and
R.sub.2 are both a TBDMS group or are, together, an acetone ketal
group.
38. A method for producing a natural or synthetic epothilone
compound or a derivative thereof, which comprises reacting a
compound of the following formula (II) as a starting material in at
least one step in the method of producing: ##STR00051## in which Y
stands for a group --NA1A2, where A1 and A2, independently of one
another, stand for C.sub.1-C.sub.6 alkyl, aryl, aralkyl, --OH,
--OMe, or --O-benzyl, or Y is ##STR00052## where the dashed line
bonds indicate the point of attachment.
39. The method of claim 38, wherein, for A1 and A2, aryl is phenyl
and aralkyl is benzyl.
40. A method for producing a natural or synthetic epothilone
compound or a derivative thereof, which comprises reacting a
compound of the following formula (III) as a starting material in
at least one step in the method of producing: ##STR00053## in which
R.sub.1 stands for an alcohol protective group, and Y stands for a
group --NA1A2, where A1 and A2, independently of one another,
stands for C.sub.1-C.sub.6 alkyl, aryl, aralkyl, --OH, --OMe, or
--O-benzyl, or Y is ##STR00054## where the dashed line bonds
indicate the point of attachment.
41. A method of claim 40, wherein the alcohol protective group is
selected from: benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP,
TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl and trityl groups.
42. A method of claim 40, wherein for A1 and A2, aryl is phenyl and
aralkyl is benzyl.
43. A process for producing an optically active compound of the
following formula (III) wherein the configuration at the C-atom of
the secondary alcohol is S: ##STR00055## in which R.sub.1 stands
for an alcohol protective group, and Y stands for a group --NA1A2,
where A1 and A2, independently of one another, stand for C1-C6
alkyl, aryl, aralkyl, --OH, --OMe, or --O-benzyl, or Y is
##STR00056## and, where the dashed line bonds indicate the point of
attachment, which process comprises: chirally reducing the keto
group of a compound of formula VII, ##STR00057## whereby radicals
R.sub.1 and Y have the above meaning.
44. The process of claim 43, wherein the chiral reduction of the
keto group is made by catalytic hydrogenation with a Noyori-type
catalyst.
45. The process of claim 43, wherein the chiral reduction of the
keto group is made by enzymatic reaction.
46. The compound
N,N-dimethyl-(5-benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentanoic
acid)amide of the formula: ##STR00058##
47. A compound of formula XII: ##STR00059## in which Y stands for a
group --NA1A2, where A1 and A2, independently of one another, stand
for C1-C6 alkyl, aryl, aralkyl, --OH, --OMe, or --O-benzyl, or Y is
##STR00060## where the dashed line bonds indicate the point of
attachment, and, R4 stands for a C.sub.1-C.sub.6 alkyl, phenyl or
benzyl group.
48. A compound of claim 47, wherein the configuration at the C-atom
of the secondary alcohol is R.
49. A method for producing a natural or synthetic epothilone or
derivative thereof, which comprises reacting a compound of formula
XII of claim 47 as a starting material in at least one step in the
method of producing.
50. A process for producing a ketone of formula A ##STR00061## in
which R.sub.1 and R.sub.2 are the same or different and,
independently of one another, stand for an alcohol protective group
or, R.sub.1 and R.sub.2 are bridged and together stand for a ketal
protective group, and V stands for a C.sub.1-C.sub.5 alkyl or
alkenyl radical, which comprises: reacting a compound of formula Ia
##STR00062## where R.sub.1 and R.sub.2 have the above meanings and
Y stands for a group --NA1A2, whereby A1 and A2, independently of
one another, stand for C.sub.1-C.sub.6 alkyl, aryl, aralkyl, --OH,
--OMe, or --O-benzyl, or Y is ##STR00063## where the dashed line
bonds indicate the point of attachment, with a compound of formula
B M-V (B) in which M is Li, MgCl, MgBr, or MgI, and then working up
the product under aqueous hydrolysis.
51. The process of claim 50, wherein the compound of formula B is
MeLi, EtLi, propyl-Li, BuLi, or
CH.sub.2.dbd.CH--CH.sub.2CH.sub.2--Li.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 60/313,015 filed Aug. 20,
2001.
[0002] The invention relates to the subject that is characterized
in the claims, i.e., new intermediate products and process for
their production and the use. The process for the production of new
intermediate products starts from economical starting materials,
yields the intermediate products in high enantiomer purities, in
high chemical purity, in good yields, and allows the
industrial-scale production.
[0003] The invention is used in the synthesis of component A from
natural and synthetically modified epothilones or derivatives.
Epothilones are 16-membered macrolide rings that were isolated from
the cultures of Myxobacterium Sorangium Cellosum and are
representatives of a class of promising anti-tumor agents that were
tested and found to be effective against a number of cancer lines.
A survey of the syntheses has been described by J. Mulzer et al. in
J. Org. Chem. 2000, 65, 7456-7467.
##STR00001##
[0004] In the literature, in addition to the natural epothilones, a
number of synthetic epothilone derivatives are described that vary
for the most part within radicals M and T. In most cases, M stands
for a heterocyclic radical here. Most syntheses of the natural
epothilones and the synthetic epothilone derivatives use the
A-component fragment, which represent carbon atoms C5-C10 in the
macrolide. Within this component A (see below), C1 is the C5 in the
macrolide and C6 is the C10 in the macrolide, etc.
##STR00002##
[0005] Within the component, T stands for a C1-C4 alkyl or alkenyl
radical, and Sg1 and Sg2 stand for the protective groups that are
familiar to one skilled in the art, such as, e.g., the TSDMS
group.
[0006] A possible production of the A-component is described in,
for example, WO00/58254 (University of Wisconsin). A synthesis of
.beta.-keto esters, which can be converted into multistage
sequences in component A, is disclosed therein. The chirality is
introduced by an asymmetric hydrogenation of a .beta.-keto ester
according to Noyori:
##STR00003##
[0007] In this connection, the conversion of the ester group into a
ketone can only be done by means of a multistage sequence. In this
case, after a protection of the 1- and 3-hydroxy group, the ester
group (C-5 atom) is reduced to form alcohol, the oxidation to
aldehyde is carried out, the Grignard addition of an alkyl radical
with an alkylmagnesium or alkyllithium compound yields a secondary
alcohol, which then is oxidized. To get from the ester to the
ketone, a total of 6 steps are necessary. The direct reaction of an
ester is not selective, since the intermediately produced product
is further reacted. The following diagram shows the entire
synthesis pathway:
##STR00004##
[0008] Another method for creating component A is described by B.
Paniker et al. in Tetrahedron 2000, 56, 78-59-7868. It is described
there that the aldol reaction with a chiral component yields a less
selective reaction. By the round-about way of an
N-methylthioacetyl-oxazolidinone, the synthesis of the chiral C3
atom in a multistage sequence with improved diastereoselectivity by
means of boron enolate is described. To achieve usable
diastereoselectivities, a methylthio substitution is necessary; the
thio ether is cleaved off after the aldol reaction.
[0009] Further, a sequence can be found in the prior art (R. E.
Taylor, Y. Chen, Org. Lett. (2001), 3(14), 2221-2224) in which a
phenyl ester is used. The yield that is achieved in this case is
indicated with 77%. In the example that is described by A. Furstner
in Chem. Comm. 2001, 1057-1059, a 67% yield is achieved. These
yields of the methods from the prior art are significantly less
than those of this invention.
[0010] In J. Org. Chem. 2000, 65, 7456-7467, an asymmetrical
synthesis of a .beta.-keto ester is further described, whereby a
variant in asymmetrical form is performed as an aldol reaction. In
this method, D-Ts-valine is used as a catalyst, which can be
produced from the expensive amino acid D-valine. This method yields
an ee-value of 90%. An asymmetrical aldol reaction, in which the
yield is 71%, is described by R. E. Taylor, Y. Chen, Org. Lett.
(2001), 3(14), 2221-2224 as another example in this regard.
[0011] Another method for the production of a double
TBDMS-protected A-component-ethyl ketone is finally described by
Nicolaou in Chem. Eur. J. 2000, 6, 2783-2800.
[0012] This invention includes the object of being able to produce
a universally usable starting intermediate compound of general
formula I as well as the optically pure antipodes of general
formulas Ia, Ib,
##STR00005##
in which R1, R2 can be the same or different and, independently of
one another, stand for an alcohol protective group that is familiar
to one skilled in the art, for example, benzyl, benzyl,
4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP,
TBDPS, MEM, MOM, allyl, trityl, or, in the case when R1 and R2 are
bridged, stand for a ketal protective group, such as, e.g.,
##STR00006##
[0013] Y stands for a group --NA1A2, whereby A1 and A2,
independently of one another, stand for the radicals C1-C6 alkyl,
such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl,
benzyl, OH, OMe, O-benzyl or for a radical
##STR00007##
to produce A-component fragments for epothilone total
syntheses.
[0014] To this end, compounds of general formula I are reacted as
described below:
##STR00008##
[0015] The reactions of the compounds of general formula I, as well
as their antipodes Ia, Ib to form ketones AK are carried out with
methyllithium or methyl-Grignard compounds according to the
standard process that is known to one skilled in the art; the
aqueous working-up then yields the ketone. The subsequent
alkylation with an alkyl or alkenyl-halide of formula T-Hal
(Hal=Cl, Br, I or tosylate, mesylate, triflate, etc.) with the
addition of a base yields the A-component fragments.
[0016] A can also be directly obtained, however, by the amides of
general formula I being reacted directly with organometallic
compounds, such as, e.g., the lithium compound Li--CH2-T and then
being worked up in aqueous form.
[0017] As a rule, the above-described reactions run smoothly and
produce the A-components in high yields.
[0018] There was therefore a need for an industrial-scale process
that allows it to prepare a universally usable intermediate
compound for the production of the A-component in the epothilone
total synthesis.
[0019] In addition to the high yields in the conversion into the
A-components, the relatively easy accessibility of the compounds of
general formula I from relatively inexpensive starting materials is
emphasized. Moreover, the compounds according to the invention are
stable in storage in contrast to the esters and ketones that are
known in the literature and are, for the most part, crystalline
solids and can be purified by crystallization. In this way, high
chemical and optical yields (e.e. >98%) can be achieved.
Variant I (General Access via Aldol Reactions)
[0020] a) In the case where R1 and R2 stand for a ketal protective
group, or R1=R2, compounds of general formula I can be produced
from compounds of general formula II
##STR00009##
whereby Y has the above-mentioned meaning, according to the methods
for protective group chemistry that are known to one skilled in the
art; thus, for example, their production and cleavage are described
by P. J. Kocienski in "Protecting Groups," Georg Thieme Verlag
Stuttgart, New York, 1994, as well as in Houben Weyl, 4th Edition,
Volume VI/1b, p. 737, Thieme Stuttgart 1984.
[0021] b) In the case that R1 and R2 do not represent any
ketal-protective group but nevertheless can be the same or
different, the production of the compounds of general formula I can
be carried out directly from the compounds of general formula III,
by protective group R2 being introduced according to methods that
are known in the literature (J. Mulzer et al., J. Org. Chem. 2000,
65, 7456-7467).
[0022] Compounds of general formula I can be produced from
compounds of general formula III
##STR00010##
in which Y stands for the above-indicated meaning, and R1 stands
for a protective group in the above-indicated meaning, by cleavage
of protective group R1 according to the process, known to one
skilled in the art, of the protective group cleavage of alcohols
(P. J. Kocienski in "Protecting Groups," Georg Thieme Verlag
Stuttgart, New York 1994/Houben Weyl, 4th Edition Volume VI/1b p.
737, Thieme Stuttgart 1984).
[0023] Compounds of general formula III can be produced from
compounds of general formula IV
##STR00011##
by reaction of the compounds of formula V
##STR00012##
in which Y and R1 are in the above-indicated meaning, and L stands
for a silyl protective group, such as, e.g., TBDMS, TMS, TES, TIP,
TBDPS, in a way that is known to one skilled in the art by the
techniques of aldol condensation. (C. H. Heathcock in Modern
Synthesis Methods, 1992 (Editors R. Scheffold, VECA Basel 1992, pp.
1-102).
[0024] The production of compounds of general formula IV are known
to one skilled in the art, however:
[0025] R1: THP in JOC, 1984, 49, 2301-2309
[0026] R1: benzyl in J. Chem, Soc. Perk. Trans 1, 2000,
2429-2454,
[0027] R1: TBDMS in JOC, 2000, 65, 7456-7467
[0028] The production of compounds of general formula V is novel
and is described in the examples.
Variant II (Production of Optically Active Intermediate Products of
General Formula Ia)
[0029] For the production of optically active compounds of general
formula Ia
##STR00013##
the procedure is analogous to that described under Variant I.
Starting from the optically active intermediate stage of general
formulas IIa and IIIa
##STR00014##
compounds of general formula Ia are produced.
[0030] Compounds of general formula IIa are produced analogously
from the optically active precursors of general formula IIIa
##STR00015##
[0031] Optically active compounds of general formula IIIa are
accessible as follows: [0032] 1. Separation of the racemic compound
of general formula III in the chiral phase (Lit.: G. Roussel, P.
Pirs, Chirabase, Pure and Applied Chemistry, 1993, 65, 235-244),
primarily by SMB technique: (A. Seidel-Morgenstern et al., Chromat.
A. 1998, 827/2, 175-191). [0033] 2. Starting from the racemic
alcohol of general formula III, by esters of general formula VI
[0033] ##STR00016## [0034] in which R3 stands for a C1-C6 alkyl
group or an allyl, phenyl or benzyl group, being produced according
to the process of esterification that is known to one skilled in
the art, and the latter being saponified enantioselectively by
enzymatic or microbiological methods. The alcohol that is produced
is clearly distinguished in its Rf value from the ester that is
used so that the two can easily be separated from another, e.g., by
column chromatography. [0035] 3. By aldol condensation that is
mediated with chiral catalysts, by compounds of general formulas IV
and V being reacted with use of a catalytic or stoichiometric
amount of a chiral aldol catalyst:
[0035] ##STR00017## [0036] Literature: See, e.g., J. Org, Chem.
2000, 65, 7456-7467. [0037] 4. By a chiral reduction of the ketone
of general formula VII
##STR00018##
[0037] being performed according to methods that are known to one
skilled in the art. Lit.: Noyori et al., J. Am. Chem. Soc. 1987,
109, 5850; Noyori et al., J. Am. Chem. Soc. 1988, 110, 629, R. C.
Larock in "Comprehensive Organic Transformations," VCH Publishers
New York 1989, ISBN 0-89573-710-8, pages 540-548.
[0038] Compounds of general formula VII, with R1 and Y in the
above-indicated meaning, can be obtained by reaction of the
compounds of general formula V with compounds of general formula
VIII
##STR00019##
in which Nu stands for a leaving group, such as Cl, Br, imidazole,
--OPh, --O--C6H4NO2, --O--C1-C4 alkyl, etc.
[0039] The reaction is carried out in a way that is known to one
skilled in the art. Lit.: Ann. 1962, 655, 90, R. C. Larock in
"Comprehensive Organic Transformations," VCH Publishers New York
1989, ISBN 0-89573-710-8, pages 685-702.
[0040] The production of compounds of general formula VIII is
described in the literature: J. Med. Chem. 1999, 706-721.
[0041] In some cases, it has proven advantageous when compounds of
general formula VII are produced by oxidation from the racemic
alcohols of general formula II according to the methods of
oxidation that are known to one skilled in the art (e.g., Swern
oxidation, PDC, PCC, etc.).
[0042] In some cases, it has proven advantageous when compounds of
general formula V are reacted with propiolactone to form compounds
of general formula IX:
##STR00020##
[0043] Compounds of general formula IX can be converted very easily
into compounds of general formula VII by introducing protective
groups according to the methods that are known to one skilled in
the art (see. P. J. Kocienski described in "Protecting Groups,"
Georg Thieme Verlag Stuttgart, New York 1994, as well as in Houben
Weyl, 4th Edition, Volume VI/1b, p. 737, Thieme Stuttgart
1984).
[0044] Starting from compounds of general formula IX, however,
compounds of general formula IIa
##STR00021##
can also be obtained by the keto group being reduced chirally with
chemical or microbiological methods (e.g., according to: J. Org.
Chem. 1985, 50, 127/J. Chem. Soc., Chem. Commun. 1987, 1368).
Variant III
[0045] Compounds of general formula Ia
##STR00022##
can also be produced by introducing protective groups according to
methods that are known in the literature for introducing alcohol
protective groups from the compounds of general formula X
##STR00023##
(see literature cited above for introducing protective groups).
[0046] Compounds of general formula X can be produced from
compounds of general formula XI
##STR00024##
in which R4 stands for a methyl, ethyl or benzyl group, by ester
reduction according to methods that are known to one skilled in the
art. Lit.: R. C. Larock in "Comprehensive Organic Transformations,"
VCH Publishers New York 1989, ISBN 0-89573-710-8, pages
549-551).
[0047] Compounds of general formula XI can be produced from
compounds of general formula XII
##STR00025##
in which R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl,
phenyl or benzyl group, by introducing protective group R2
according to methods that are known to one skilled in the art (see
above).
[0048] Compounds of general formula XII can be obtained from
.beta.-keto esters of general formula XIII
##STR00026##
by methods of chiral reduction (chemical or enzymatic). Lit.:
Chemie in unserer Zeit [Chemistry in Our Time], 1996, 30, 201-213,
R. C. Larock in "Comprehensive Organic Transformations," VCH
Publishers New York 1989, ISBN 0-89573-710-8, pages 540-547).
[0049] Compounds of general formula XIII are obtained by reaction
of compounds of general formula XIV with compounds of general
formula V
##STR00027##
[0050] Compounds of general formula XIV are known in the
literature: Compounds of general formula V are novel, for
production see above and the examples, or can also be obtained from
the reaction of compounds of general formulas XIIIa and XIIIB.
##STR00028##
[0051] Here, Nu is in the meaning of the leaving group that is
already mentioned above, and Q stands for a hydrogen atom or a COOH
group. If Q is a hydrogen atom, XIIIa is deprotonated with an
organic base, such as, e.g., LDA and then is reacted with the
activated acid derivative according to the methods that are
familiar to one skilled in the art.
[0052] In the case of Q being equal to COOH, the procedure is
performed with the methods of the malonic acid-semi-ester
condensation, as described in, e.g., J. Am. Chem. Soc. 1999, 121,
7050-7062, Synth. Commun. 1997, 27, 3227-3234.
[0053] Compounds of general formula XIIIa are commercially
available (e.g., Aldrich).
[0054] Compounds of general formula XIIIb are produced as described
in R. C. Larock in "Comprehensive Organic Transformations," VCH
Publishers New York 1989, ISBN 0-89573-710-8, pages 963-964).
[0055] In some cases, it has proven advantageous to run the diols
of general formula IIa
##STR00029##
directly through the compounds of general formula XII
##STR00030##
by reduction of the ester group according to the above-mentioned
process.
[0056] The production of the racemic diol of general formula II can
also use as starting compounds .beta.-keto esters of general
formula XIII
##STR00031##
according to the commonly used methods for reduction of esters and
ketones.
Variant IV
[0057] For the production of optically active diols of general
formula IIa, it has proven advantageous to undertake a
chromatographic separation or crystallization of the diastereomeric
ketals of general formulas XIVa and XIVb
##STR00032##
in which A is taken for the radical of an optically active ketone,
such as, e.g., (-) menthone, (-) camphor, etc., and then the ketal
group is cleaved off according to the methods of protective group
chemistry that are known to one skilled in the art.
[0058] The production of diastereomeric 1,3 diol-ketals of general
formulas XIVa and XIVb is carried out from the racemic diol of
general formula II by reaction with chiral ketones according to
processes that are known in the literature. Lit.: T. Harada et al.,
J. Org. Chem. 1992, 57, 1412-1421.
[0059] Of course, the corresponding enantiomer compounds of general
formula Ib
##STR00033##
can also be produced with use of mirror-image catalysts or other
enzyme systems.
[0060] There is also the possibility of obtaining the corresponding
enantiomers in intermediate stages of general formula IIIb
##STR00034##
by inversion of the hydroxyl group (e.g.) according to Mitsunobu
(Lit.: O. Mitsunobu, Synthesis 1981, 1-28).
[0061] Of protective groups R1 and R2 that are used in the
synthesis, in particular the benzyl group and the TBDMS group are
preferred. In the case that R1, R2 stands for a ketal protective
group, especially --(C(CH3)2)- is preferred.
[0062] Group Y cat preferably stand for the radicals:
##STR00035##
but the dimethylamino group is especially preferred.
[0063] Of the different production variants here, the following
partial sequences are especially preferred for the creation of
achiral precursors: [0064] 1. Production of the compounds of
general formula VII from the intermediate stages of general
formulas V and VIII [0065] L in the meaning of TMS, R1=benzyl,
Nu=Cl, Y=dimethylamino
[0065] ##STR00036## [0066] 2. Production of the compounds of
general formula XIII from compounds of general formulas V and XIV.
[0067] L in the meaning of TMS, R4=ethyl, Nu=Cl,
Y=dimethylamino
[0067] ##STR00037## [0068] 3. Production of the compounds of
general formula VII by aldol condensation and subsequent oxidation
[0069] L in the meaning of TMS, R1=benzyl, Nu=Cl,
Y=dimethylamino
[0069] ##STR00038## [0070] 4. Production of the compounds of
general formula IX (with Y dimethylamino)
##STR00039##
[0071] For the production of chiral precursors, especially the
partial steps that are indicated below are preferred:
[0072] 1. Chiral aldol condensation with a chiral catalyst
##STR00040##
[0073] 2. Enantioselective saponification of an acetate with the
aid of an enzyme
##STR00041##
[0074] 3. Chiral reduction of a .beta.-keto amide (Noyori type)
##STR00042##
[0075] 4. Chiral reduction of the .beta.-keto ester with subsequent
reduction
##STR00043##
[0076] The production of the compounds according to the invention
is carried out preferably in the sequences that are described
below:
[0077] 1. Production of acetone ketals
##STR00044##
[0078] 2. Production of the Di-TBDMS-protected compound
##STR00045##
[0079] The production of the compounds and process according to the
invention is to be explained in more detail in the embodiments
below.
[0080] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
In the foregoing and in the following examples, all temperatures
are set forth uncorrected in degrees Celsius and, all parts and
percentages are by weight, unless otherwise indicated.
EXAMPLE 1A
1-Dimethylamino-2-methyl-1-trimethylsilyl-propene
[0081] 294 ml (0.45 ml) of butyllithium is added in drops at
-35.degree. C. under inert gas to 0.43 mol of diisopropylamine in
300 ml of THF. Then, 50 g (0.434 mol) of
N,N-dimethyl-2-methylpropinoic acid amide is added in drops at
0.degree. C. and stirred for 30 minutes at this temperature. Then,
60.3 ml (0.47 mol) of trimethylsilyl chloride is added at
-35.degree. C. and stirred for two more hours. The solvent is
distilled off in a rotary evaporator. The residue is distilled in a
vacuum at 65-69.degree. C./30 mbar.
[0082] .sup.1H-NMR (300 LHz, CDCl.sub.3, 25.degree. C., TMS),
.delta.=0.2 (s, 9H), 1.53 (s, 3H), 1.63 (s, 3H), 2.5 (s, 6H)
TABLE-US-00001 Elementary analysis: C H Cld. 57.70 11.30 Fnd. 58.00
11.40
EXAMPLE 1B
rac.
N,N-Dimethyl-(5-benzyloxy-2,2-dimethyl-3(R,S)-hydroxy-pentanoic
acid)amide
[0083] 68.8 g (0.367 mol) of
1-dimethylamino-2-methyl-1-trimethylsilyl-propene of the title
compound of Example 1a, 67 g of benzyloxy-propanol (0.4 mol) and
5.56 g>>ZnCl.sub.2 are stirred in 500 ml of THF for 1 hour.
13.88 g of NH.sub.4F and 300 ml of MeOH are added and stirred for
18 hours at room temperature. It is distilled off, the residue is
extracted with 200 ml of ethyl acetate, and the organic phase is
washed with 10% citric acid solution. After chromatography on
silica gel with ethyl acetate/hexane as an eluant, 60.8 g of
product is obtained (60% of theory).
TABLE-US-00002 Elementary analysis: C H Cld. 68.79 9.02 Fnd. 68.80
9.00
EXAMPLE 1C
N,N-Dimethyl-(5-benzyloxy-2,2,-dimethyl-3-oxy-pentanoic
acid)amide
[0084] 2.47 g of oxalyl chloride is cooled in 25 ml of methylene
chloride to -60.degree. C., 4.4 ml of DMSO in 10 ml of methylene
chloride is added, and it is stirred for 15 more minutes; 7.26 g of
N,N-dimethyl-(5-benzyloxy-2,2-dimethyl-3-hydroxy-pentanoic acid
amide) of the title compound of Example 1b is added in 20 ml of
methylene chloride, and it is stirred for 30 more minutes. 8.7 ml
of triethylamine is added in drops, and it is stirred for 30 more
minutes while being heated to -20.degree. C. It is hydrolyzed with
25 ml of water, and the phase is separated. After the solvent is
evaporated, 7.18 g of product is obtained. After chromatography,
3.6 g of product (50% of theory) is obtained, in addition to 1.36 g
of educt.
TABLE-US-00003 Elementary analysis: C H Cld. 69.29 8.36 Fnd. 69.40
8.50
EXAMPLE 1D
N,N-Dimethyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide
[0085] 500 mg of
N,N-dimethyl-(5-benzyloxy-2,2,-dimethyl-3-oxy-pentanoic acid)amide
of the title compound of Example 1c is hydrogenated with a catalyst
(produced from 23.3 mg of RuCl.sub.2 (Ph).sub.2 and 62.6 mg of
S.-BiNAP according to R. Selke, Angew. Chem. [Applied Chemistry]
1998, 110, 1927-1930) (2 days at 40.degree. C./100 bar).
[0086] Yield: quantitative
TABLE-US-00004 Elementary analysis: C H Cld. 68.79 9.02 Fnd. 69.00
9.00
EXAMPLE 1E
N,N-Dimethyl-3(S)-(3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide
[0087] 13.13 g (47.70 mmol) of
N,N-dimethyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide of the title compound of Example 1d, dissolved in 110 ml
of tetrahydrofuran, is added to 16 g of Pearlman's catalyst
(Pd(OH).sub.2 on carbon, 20%). It is now hydrogenated for 7.5 hours
at 10 bar and at room temperature. Catalyst is filtered out, and
the filtrate is evaporated to the dry state in a vacuum.
[0088] Yield: 8.63 g (97% of theory) of a colorless, viscous
oil.
TABLE-US-00005 Elementary analysis: C H N Cld. 57.12 10.12 7.40
Fnd. 57.10 10.00 7.39
EXAMPLE 1F
N,N-Dimethyl-(3(S)-(3,5)-Acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide
[0089] 8.89 g (47 mmol) of
N,N-dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic acid)
amide of the title compound of Example 1e is dissolved in 27 ml of
acetone dimethylketal, and 546 mg of camphor-10-sulfonic acid is
added. It is heated for 15 hours to 50.degree. C. It is evaporated
to the dry state in a vacuum, the residue is taken up in 200 ml of
methylene chloride and washed with saturated sodium bicarbonate
solution, then with saturated sodium chloride solution. The organic
phase is dried on sodium sulfate and evaporated to the dry state in
a vacuum. The oil that is obtained is crystallized while
standing.
[0090] Yield: 8.30 g, (77% of theory) of a colorless, crystalline
solid.
TABLE-US-00006 Elementary analysis: C H N Cld. 62.85 10.11 6.11
Fnd. 62.90 10.00 6.00
EXAMPLE 1G
N,N-Dimethyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide
[0091] 29.8 g (0.11 mol) of N-toluenesulfonyl-D-valine (Lit.: 3.
Am. Chem. Soc. 1937, 59, 116-118) is dissolved at 0.degree. C. in
100 ml of dichloromethane. At 0.degree. C., 100 ml of BH.sub.3-THF
solution (1 mol) is added in drops over 30 minutes and stirred for
30 more minutes. The solution is cooled to -78.degree. C. At
-78.degree. C., 16.42 g of benzyloxy-propanal (0.1 mol) in 100 ml
of dichloromethane and 22.4 g (0.12 mol) of
1-dimethylamino-2-methyl-1-trimethylsilyl-propene of the compound
of Example 1a are stirred for 2 hours at -78.degree. C. and for
another 2 hours while being heated to 0.degree. C.
[0092] 5 g of NH.sub.4F and 100 ml of MeOH are added and stirred
for 18 hours at room temperature. For hydrolysis, 150 ml of water
is added. It is extracted with 200 ml of ethyl acetate, and the
organic phase is washed with 10% citric acid solution. After
chromatography on silica gel with ethyl acetate/hexane as an
eluant, 24 g of product is obtained (85% of theory).
[0093] The enantiomer purity was determined by means of HPLC, stat.
Phase Chiracel AD 4.6.times.250 nm, UV 208 nm, eluant
hexane/isopropanol 99:1, flow 1 ml/min, t.sub.R (S)=75 minutes
(97%), t.sub.R (R)=79 minutes (3%).
TABLE-US-00007 Elementary analysis: C H Cld. 68.79 9.02 Fnd. 68.65
9.08
[0094] After a reaction to form
2-(2,2-dimethyl-[1,3]dioxan-4-yl)2-methyl-butanon-3-one analogously
to Examples 1e, 1f and 10, the enantiomer purity of compound 10 can
be increased after crystallization to 99% ee.
EXAMPLE 2
N,N-Dimethyl-(3(S)-3,5-Di-tert-butyldimethylsilyloxy-2,2,-dimethyl-pentano-
ic acid)amide
[0095] 7.13 g (104.75=mmol) of imidazole and 7.9 g (52.37 mmol) of
tert-butyldimethylsilyl chloride are added to a solution that
consists of 3.96 g (20.95 mmol) of
N,N-dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic acid)amide
of the title compound of Example 1e, in 20 ml of dimethylformamide,
and it is stirred for 16 hours at room temperature. The solution is
poured onto 200 ml of water and extracted twice with 50 ml each of
cyclohexane. The organic phases are combined and evaporated to the
dry state in a vacuum. The residue is purified by flash
chromatography on silica gel (hexane/MTB-ether).
[0096] Yield: 8.31 g, (95% of theory) of a colorless, viscous
oil.
TABLE-US-00008 Elementary analysis; C H N Cld. 60.37 11.34 3.35
Fnd. 60.40 11.36 3.29
EXAMPLE 3
N,N-Dimethyl-(3(S)-3,5-Cyclohexanone-dimethylketal-2,2,-dimethyl-pentanoic
acid)amide
[0097] 10 mg of p-toluenesulfonic acid is added to a solution that
consists of 3.96 g (20.95 mmol) of
N,N-dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic acid)amide
of the title compound of Example 1e in 30.21 g (0.2095 mol) of
cyclohexanone-dimethylketal, and it is stirred for 6 hours at
100.degree. C. The solution is poured onto 200 ml of water and
extracted twice with 50 ml each of ethyl acetate. The organic
phases are combined and evaporated to the dry state in a vacuum.
The residue is purified by flash chromatography on silica gel
(hexane/MTB-ether).
[0098] Yield: 5.08 g (90% of theory) of a colorless, viscous
oil.
TABLE-US-00009 Elementary analysis: C H N Cld. 68.88 10.10 5.20
Fnd. 66.90 10.20 5.21
EXAMPLE 4
N,N-Dimethyl-(3(S)-3,5-benzaldehyde-dimethylacetal-2,2,-dimethyl-pentanoic
acid)amide
[0099] 31.9 g (0.2095 mol) of benzaldehyde-dimethylacetal and 50 mg
of p-toluenesulfonic acid are added to a solution that consists of
3.96 g (20.95 mmol) of
N,N-dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic acid)amide
of the title compound of Example 1e, in 20 ml of dimethylformamide,
and it is stirred for 16 hours at 100.degree. C. The solution is
poured onto 200 ml of water and extracted twice with 50 ml each of
ethyl acetate. The organic phases are combined and evaporated to
the dry state in a vacuum. The residue is purified by flash
chromatography on silica gel (hexane/MTB-ether).
[0100] Yield: 5.11 g (88% of theory) of a colorless, viscous
oil.
TABLE-US-00010 Elementary analysis: C H N Cld. 69.29 8.36 5.05 Fnd.
69.30 8.39 5.00
EXAMPLE 5A
N,N-Dimethyl-(5-benzyloxy-2,2,-dimethyl-3R,S)-acetoxy-pentanoic
acid)amide
[0101] 14.56 g (142.64 mmol) of acetic acid anhydride is added at
0.degree. C. to a solution that consists of 30.65 g (109.7 mmol) of
N,N-dimethyl-(5-benzyloxy-2,2,-dimethyl-3(R,S)-hydroxy-pentanoic
acid)amide of the title compound of Example 1b, 14.43 g (142.64
mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine
(DMAP), dissolved in 128 ml of MTB-ether, and it is stirred for 5
hours at room temperature. It is poured onto 2 l of ice water and
extracted twice with 300 ml each of MTB-ether. The combined MTB
phases are washed once with 300 ml of 5% hydrochloric acid and then
with water. It is evaporated to the dry state in a vacuum.
[0102] Yield: 33.50 g (95% of theory), colorless oil.
TABLE-US-00011 Elementary analysis: C H N Cld. 67.26 8.47 4.36 Fnd.
67.30 8.50 4.40
EXAMPLE 5B
N,N-Dimethyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide
[0103] 11.67 g (36.31 mmol) of
N,N-dimethyl-(5-benzyloxy-2,2,-dimethyl-3(R,S)-acetoxy-pentanoic
acid)amide of the title compound of Example 5a is added to a buffer
solution, produced from 0.88 g of potassium dihydrogen phosphate
and 1.82 g of disodium hydrogen phosphate in 250 ml of water. Then,
5 g of the enzyme lipase AYS "Amano" (related to Amano) is added,
and it is stirred for 42.5 hours at room temperature. The pH is
brought to 7 by adding 2.062 g of disodium hydrogen phosphate, and
then it is stirred for another 44.5 hours. Working-up: It is
extracted 5 times with 400 ml of ethyl acetate. The organic phases
are combined and evaporated to the dry state in a vacuum. The
purification is carried out by chromatography on silica gel
(hexane/ethyl acetate gradient).
[0104] Yield: 4.60 g (40% of theory of a colorless oil.
TABLE-US-00012 Elementary analysis: C H N Cld. 68.79 9.02 5.01 Fnd.
68.80 9.00 5.01
EXAMPLE 5C
N,N-Dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide
[0105] 16 g of Pearlman's catalyst (Pd(OH).sub.2 on carbon, 20%) is
added to 13.13 g (47.70 mmol) of
N,N-dimethyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid) amide of the title compound of Example 5b, dissolved in 110
ml of tetrahydrofuran. It is now hydrogenated for 7.5 hours at 10
bar and at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[0106] Yield: 8.72 g (98% of theory) of a colorless, viscous
oil.
TABLE-US-00013 Elementary analysis: C H N Cld. 57.12 10.12 7.40
Fnd. 57.10 10.10 7.39
EXAMPLE 5D
N,N-Dimethyl-(3(S)-3,5-acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide
[0107] 6.62 g (35.00 mmol) of
N,N-dimethyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic acid)amide
of the title compound of Example 5c is dissolved in 27 ml of
acetonedimethylketal, and 546 mg of camphor-10-sulfonic acid is
added. It is heated for 15 hours to 50.degree. C. It is evaporated
to the dry state in a vacuum, the residue is taken up in 200 ml of
methylene chloride and washed with saturated sodium bicarbonate
solution, then with saturated sodium chloride solution. The organic
phase is dried on sodium sulfate and evaporated to the dry state in
a vacuum. The oil that is obtained crystallizes while standing.
[0108] Yield; 5.93 g, (74% of theory) of a colorless, crystalline
solid.
TABLE-US-00014 Elementary analysis: C H N Cld. 62.85 10.11 6.11
Fnd. 62.90 10.10 6.10
N-Methyl-N-phenyl-amide Synthesis
EXAMPLE 6A
1-Methyl-1-phenylamino-2-methyl-1-trimethylsilyl-propene
[0109] 294 ml (0.45 ml) of butyllithium is added in drops at
-35.degree. C. under inert gas to 0.43 mot of diisopropylamine in
300 ml of THF. Then, 76.92 g (0.434 mol) of
N-methyl-N-phenyl-2-methylopropionic acid amide is added in drops
at 0.degree. C. and stirred for 30 minutes at this temperature.
Then, 60.3 ml (0.47 mol) of trimethylsilyl chloride is added at
-35.degree. C. and stirred for two more hours. The solvent is
distilled off in a rotary evaporator. The residue is distilled in a
vacuum at 65-69.degree. C./30 mbar.
[0110] Yield: 70.36 g (65% of theory) of an oil
TABLE-US-00015 Elementary analysis: C H Cld. 67.42 9.29 Fnd. 67.50
9.30
EXAMPLE 6B
N-Methyl-N-phenyl-(5-benzyloxy-2,2,-dimethyl-3-oxo-pentanoic
acid)amide
[0111] 68.8 g (0.367 mol) of
1-methyl-1-phenylamino-2-methyl-1-trimethylsilyl-propene, 81.06 g
(0.401 mmol) of 3-benzyloxy-propanoic acid chloride (0.4 mol) and
5.56 g>>ZnCl.sub.2 are stirred in 500 ml of THF for 1 hour.
13.88 g of NH.sub.4F and 300 ml of MeOH are added and stirred for
18 hours at room temperature. It is distilled off, the residue is
extracted with 200 ml of ethyl acetate, and the organic phase is
washed with 10% citric acid solution. After chromatography on
silica gel with ethyl acetate/hexane as an eluant, 74.74 g of
product is obtained (60% of theory).
TABLE-US-00016 Elementary analysis: C H Cld. 74.31 7.42 Fnd. 74.29
7.40
EXAMPLE 6C
N-Methyl-N-phenyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide
[0112] 500 mg of
N-methyl-N-phenyl-(5-benzyloxy-2,2,-dimethyl-3-oxo-pentanoic
acid)amide of the title compound of Example 6b is hydrogenated with
a catalyst (produced from 23.3 mg of RuCl.sub.2 (Ph).sub.2 and 62.6
mg of S-BiNAP according to R. Selke, Angew. Chem. 1998, 110,
1927-1930) (2 days at 40.degree. C./100 bar).
[0113] Yield: quantitative
TABLE-US-00017 Elementary analysis: C H Cld. 73.87 7.97 Fnd. 74.00
8.00
EXAMPLE 6D
N-Methyl-N-phenyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide
[0114] 16 g of Pearlman's catalyst (Pd(OH).sub.2 on carbon, 20%) is
added [to] 16.29 g (47.70 mmol) of
N-methyl-N-phenyl-(5-benzyloxy-2,2,-dimethyl-3(S)-hydroxy-pentanoic
acid)amide of the title compound of Example 6c, dissolved in 110 ml
of tetrahydrofuran. It is now hydrogenated for 7.5 hours at 10 bar
and at room temperature. Catalyst is filtered out, and the filtrate
is evaporated to the dry state in a vacuum.
[0115] Yield: 11.98 g (98% of theory) of a colorless, viscous
oil.
TABLE-US-00018 Elementary analysis: C H N Cld. 66.91 8.42 5.57 Fnd.
66.90 8.40 5.60
EXAMPLE 6E
N-Methyl-N-phenyl-(3(S)-(3,5)-acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide
[0116] 11.81 g (47 mmol) of
N-methyl-N-phenyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide of the title compound of Example 6d is dissolved in 27
ml of acetonedimethylketal, and 546 mg of camphor-10-sulfonic acid
is added. It is heated for 15 hours to 50.degree. C. It is
evaporated to the dry state in a vacuum, the residue is taken up in
200 ml of methylene chloride and washed with saturated sodium
bicarbonate solution, then with saturated sodium chloride solution.
The organic phase is dried on sodium sulfate and evaporated to the
dry state in a vacuum. The oil that is obtained crystallizes while
standing.
[0117] Yield: 10.54 g, (77% of theory) of a colorless, crystalline
solid.
TABLE-US-00019 Elementary analysis: C H N Cld. 70.07 8.65 4.81 Fnd.
70.00 8.50 4.90
EXAMPLE 7
N-Methyl-N-phenyl-(3(S)-3,5-cyclopentanonedimethylketal-2,2,-dimethyl-pent-
anoic acid)amide
[0118] 10 mg of p-toluenesulfonic acid is added to a solution that
consists of 5.26 g (20.95 mmol) of
N-methyl-N-phenyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide of the title compound of Example 6d) in 30.21 g (0.2095
mol) of cyclopentanone-dimethylketal, and it is stirred for 6 hours
at 100.degree. C. The solution is poured onto 200 ml of water and
extracted twice with 50 ml each of ethyl acetate. The organic
phases are combined and evaporated to the dry state in a vacuum.
The residue is purified by flash chromatography on silica gel
(hexane/MTB-ether).
[0119] Yield: 5.98 g (90% of theory) of a colorless, viscous
oil.
TABLE-US-00020 Elementary analysis: C H N Cld. 71.89 8.57 4.41 Fnd.
71.90 8.60 4.50
EXAMPLE 8
N-Methyl-N-phenyl-(3(S)-3,5-dichlorodiphenylsilane-2,2,-dimethyl-pentanoic
acid)amide
[0120] 3.14 g (46.09 mmol) of imidazole and 5.83 g (23.05 mmol) of
dichlorodiphenylsilane are added to a solution that consists of
5.26 g (20.95 mmol) of
N-methyl-N-phenyl-(3(S)-3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide of the title compound of Example 6d, in 20 ml of
dimethylformamide, and it is stirred for 16 hours at room
temperature. The solution is poured onto 200 ml of water and
extracted twice with 50 ml each of methylene chloride. The organic
phases are combined and evaporated to the dry state in a vacuum.
The residue is purified by flash chromatography on silica gel
(hexane/MTB-ether).
[0121] Yield: 7.68 g (85% of theory) of a colorless, viscous
oil.
TABLE-US-00021 Elementary analysis: C H N Cld. 72.35 6.77 3.25 Fnd.
72.37 6.80 3.30
EXAMPLE 9A
rac. N,N-Dimethyl-(3-hydroxy-3-oxo-pentanoic acid)amide
[0122] 13 ml (26 mmol) of a 2 mol LDA-THF solution is added at
-50.degree. C. to 2.99 g (26 mmol) of
N,N-dimethyl-2-methylpropinonic acid amide and stirred for 30
minutes at this temperature. Then, 1.44 g (20 mmol) of
propiolactone is added, and it is stirred for 20 more hours while
being heated to room temperature. It is hydrolyzed with saturated
ammonium chloride solution and extracted with ethyl acetate. After
drying at 1 mbar, 2.8 g of Example 9a (77% of theory) is
obtained.
TABLE-US-00022 Elementary analysis: C H N Cld. 57.72 9.15 7.47 Fnd.
58.05 8.95 7.75
EXAMPLE 9B
N,N-Dimethyl-3(S)-(3,5-dihydroxy-2,2,-dimethyl-pentanoic
acid)amide
[0123] 1.87 g (10 mmol) of rac.
N,N-dimethyl-(3-hydroxy-3-oxo-pentanoic acid)amide of the title
compound of Example 1c is hydrogenated with a catalyst (produced
from 75 mg of RuCl.sub.2 (Ph).sub.2 and 190 mg of S-BiNAP according
to R. Selke, Angew, Chem. 1998, 110, 1927-1930) (2 days at
40.degree. C./100 bar).
[0124] Yield: quantitative
TABLE-US-00023 Elementary analysis: C H N Cld. 57.11 10.1 7.4 Fnd.
57.60 10.3 7.7
EXAMPLE 10
(S)-3-(2,2-Dimethyl-[1,3]dioxan-4-yl)-3-methyl-butan-2-one
[0125] 35.6 ml of methyllithium-lithium bromide complex (1.5 M in
diethyl ether) is added in drops at -20.degree. C. to 4.08 g (17.79
mmol) of the title compound of Example 1f,
N,N-dimethyl-(3(S)-3,5-acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide, dissolved in 5 ml of diethyl ether. Then, it is stirred
for 30 minutes at -20.degree. C. and then heated to room
temperature. It is stirred overnight at room temperature. 10 ml of
saturated ammonium chloride solution is added, and it is stirred
for 6 hours at room temperature. The organic phase is separated and
washed twice with water. The organic phase is evaporated to the dry
state in a vacuum. The purification is carried out by
chromatography on silica gel (hexane/ethyl acetate gradient).
[0126] Yield: 2.77 g (78% of theory) of an oil.
TABLE-US-00024 Elementary analysis: C H Cld. 65.97 10.07 Fnd. 65.84
10.19
EXAMPLE 11
(S)-2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-heptan-3-one
[0127] 34 ml of n-butyllithium 15% (1.6 M in hexane) is added in
drops at -65.degree. C. to 4.08 g (17.79 mmol) of the title
compound of Example 1f,
N,N-dimethyl-(3(S)-3,5-acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide, dissolved in 5 ml of THF. Then, it is stirred for 5
hours at -65.degree. C. and then heated to room temperature. It is
stirred overnight at room temperature. 10 ml of saturated ammonium
chloride solution is added, and it is stirred for 6 hours at room
temperature. The organic phase is separated and washed twice with
water. The organic phase is evaporated to the dry state in a
vacuum. The purification is carried out by chromatography on silica
gel (hexane/ethyl acetate gradient).
[0128] Yield: 4.13 g (96% of theory) of an oil.
TABLE-US-00025 Elementary analysis: C H Cld. 69.38 10.81 Fnd. 69.27
10.96
EXAMPLE 12
(4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-[1,3]
dioxane
[0129] 50 ml of 3-butenyllithium solution (produced from
4-bromo-1-butene and lithium wire or tert-butyllithium, according
to J. Org. Chem. Vol. 56, No. 21, pp. 6094-6103 (1991) or J. Chem.
Soc. Perkin Trans. I pp. 2937, (1988)) is added in drops at
-90.degree. C. to 4.08 g (17.79 mmol) of the title compound of
Example 1f,
N,N-dimethyl-(3(S)-3,5-acetonedimethylketal-2,2,-dimethyl-pentanoic
acid)amide, dissolved in 5 ml of diethyl ether. Then, it is stirred
for 17 hours at -90.degree. C. and then heated to room temperature.
It is stirred overnight at room temperature for 17 hours. 10 ml of
saturated ammonium chloride solution is added, and it is stirred
for 6 hours at room temperature. The organic phase is separated and
washed twice with water. The organic phase is evaporated to the dry
state in a vacuum. The purification is carried out by
chromatography on silica gel (hexane/ethyl acetate gradient).
[0130] Yield 2.74 g (70% of theory) of a colorless oil
TABLE-US-00026 Elementary analysis: C H Cld. 69.96 10.06 Fnd. 69.90
10.05
EXAMPLE 13
N,N-Dimethyl-2,2-dimethyl-pentane-1,5-dicarboxylic
acid-1-amide-5-ethyl ester
[0131] 0.81 g (5.35 mmol) of malonic acid monoethyl ester chloride
is added at 0.degree. C. to 1 g of
1-dimethylamino-2-methyl-1-trimethylsilyl-propene (5.35 mmol); 72
mg of anhydrous ZnCl2 is subsequently added as catalyst, and it is
stirred for 2 hours at 0.degree. C. It is added to 10 ml of water,
chromatographed twice with 10 ml each of ethyl acetate and
chromatographed on silica gel.
[0132] Yield: 0.958 g (77% of theory).
[0133] MS-CI/NH.sub.3 (70 eV), M/Z 230 [M-H].sup.+
[0134] .sup.1H-NMR (300 MHz, CDCl.sub.3, 25.degree. C., TMS)
.delta.=01.4 (s, 6H), 2.9 (m, 6H), 3.48 (s, 2H), 4.25 (m, 4H)
Abbreviations of the Ether Protective Groups that are Used:
TES=Triethylsilyl
TMS=Trimethylsilyl
TIP=Triisopropyl
[0135] TBDPS=tert-Butyl-dimethylsilyl
MEM=Methylethoxymethyl
MOM=Methyloxymethyl
THP=Tetrahydropyranyl-(ether)
[0136] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding German application
No. 101 38 348.7, filed Aug. 3, 2001, and U.S. Provisional
Application Ser. No. 60/313,015, filed Aug. 20, 2001, are
incorporated by reference herein.
[0137] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0138] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *