U.S. patent application number 14/212422 was filed with the patent office on 2014-07-17 for process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof.
This patent application is currently assigned to Intendis GmbH. The applicant listed for this patent is Intendis GmbH. Invention is credited to Steffen SCHWEIZER.
Application Number | 20140200354 14/212422 |
Document ID | / |
Family ID | 39744996 |
Filed Date | 2014-07-17 |
United States Patent
Application |
20140200354 |
Kind Code |
A1 |
SCHWEIZER; Steffen |
July 17, 2014 |
Process for the Manufacture of Non-Steroidal Anti-Inflammatory
Agents and Intermediates Thereof
Abstract
The current invention describes novel chiral synthetic routes
and intermediates for the manufacture of chiral anti-inflammatory
agents of general formula VIII ##STR00001## in which at least one
of the groups X.sup.1, X.sup.2, X.sup.3 is selected from fluoro,
chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl, amino
whereas the other groups X.sup.1, X.sup.2, X.sup.3 have the meaning
of a hydrogen atom, in which at least one of the groups Z.sup.1,
Z.sup.2, Z.sup.3 is selected from --O--, --S--, --N(--CH.sub.3)--,
whereas the other groups Z.sup.1, Z.sup.2, Z.sup.3 have the meaning
of a --CH.sub.2-- group, and in which Ar is an aromatic group.
Inventors: |
SCHWEIZER; Steffen; (Berlin,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intendis GmbH |
Berlin |
|
DE |
|
|
Assignee: |
Intendis GmbH
Berlin
DE
|
Family ID: |
39744996 |
Appl. No.: |
14/212422 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13273472 |
Oct 14, 2011 |
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14212422 |
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12104772 |
Apr 17, 2008 |
8071796 |
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13273472 |
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Current U.S.
Class: |
548/482 ;
548/490; 549/437; 549/469; 549/58 |
Current CPC
Class: |
C07D 307/79 20130101;
C07D 209/44 20130101; C07D 405/12 20130101; C07D 333/54 20130101;
A61P 29/00 20180101; C07D 209/08 20130101; C07D 317/06 20130101;
C07D 307/87 20130101; C07D 307/78 20130101; C07D 333/72
20130101 |
Class at
Publication: |
548/482 ;
549/469; 548/490; 549/58; 549/437 |
International
Class: |
C07D 333/72 20060101
C07D333/72; C07D 209/08 20060101 C07D209/08; C07D 317/06 20060101
C07D317/06; C07D 209/44 20060101 C07D209/44; C07D 307/87 20060101
C07D307/87; C07D 307/78 20060101 C07D307/78; C07D 307/79 20060101
C07D307/79; C07D 333/54 20060101 C07D333/54 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 18, 2007 |
EP |
07090075.8 |
May 9, 2007 |
EP |
07008931.3 |
Claims
1.-18. (canceled)
19. A process for producing a compound according to formula VIII
##STR00011## in which at least one of the groups X.sup.1, X.sup.2,
X.sup.3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy,
trifluoromethyl or amino and the other groups X.sup.1, X.sup.2,
X.sup.3 are hydrogen, and in which at least one of the groups
Z.sup.1, Z.sup.2, Z.sup.3 is --O--, --S--, --NH--, or
--N(--CH.sub.3)--, and the other groups Z.sup.1, Z.sup.2, Z.sup.3
are --CH.sub.2-- groups and in which Ar stands for an aromatic
group comprising reducing an enantiomerically pure imine of formula
VII ##STR00012## in which at least one of the groups X.sup.1,
X.sup.2, X.sup.3 is fluoro, chloro, bromo, hydroxy, methoxy,
ethoxy, trifluoromethyl or amino and the other groups X.sup.1,
X.sup.2, X.sup.3 are hydrogen, and in which at least one of the
groups Z.sup.1, Z.sup.2, Z.sup.3 is --O--, --S--, --NH-- or
--N(--CH.sub.3)--, and the other groups Z.sup.1, Z.sup.2, Z.sup.3
are --CH.sub.2-- groups and in which Ar stands for an aromatic
group.
20. The process of claim 19, wherein said compound of formula VII
is obtained by reacting a compound according VI H.sub.2N--Ar (VI)
in which Ar is an aromatic group with an enantiomerically pure
aldehyde of formula V ##STR00013## in which X.sup.1, X.sup.2,
X.sup.3, Z.sup.1, Z.sup.2, Z.sup.3 have the above described
meaning.
21. The process according to claim 20, wherein said compound of
formula V is obtained by oxidizing an enantiomerically pure
compound according to formula I ##STR00014## in which at least one
of the groups X.sup.1, X.sup.2, X.sup.3 is fluoro, chloro, bromo,
hydroxy, methoxy, ethoxy, trifluoromethyl or amino and the other
groups X.sup.1, X.sup.2, X.sup.3 are hydrogen, and in which at
least one of the groups Z.sup.1, Z.sup.2, Z.sup.3 is --O--, --S--,
--NH--, or --N(--CH.sub.3)--, and the other groups Z.sup.1,
Z.sup.2, Z.sup.3 are --CH.sub.2--.
22. A process according to claim 21, wherein the compound of
formula I is reacted with SO.sub.3/pyridine complex to form the
aldehyde of formula V.
23. A process according to claim 20, wherein, in producing the
compound of formula VII the compound of formula V is dissolved in
acetic acid, the amine of formula VI is added at room temperature,
toluene is added and the mixture is refluxed for 5-50 h to yield
the imine of formula VII.
24. A process according to claim 20, wherein the amine of formula
VI is: 1-amino-2-methyl-benzene 1-amino-4-methyl-benzene
2-amino-4-methylpyridine 2-amino-pyridine 2-amino-pyrimidine
3-amino-quinoline 4-amino-pyridine 4-amino-pyrimidine
5-amino-isoquinoline 5-amino-1-methyl-isoquinoline
5-amino-2,6-di-methylquinoline 5-amino-2-methyl-indole
5-amino-2-methyl-isoquinol-1(2H)-one 5-amino-2-methylquinoline
5-amino-6-chloro-2-methylquinoline
5-amino-6-fluoro-2-methylquinoline 5-amino-isoquinol-2(1H)-one
5-amino-quinoline amino-benzene or N-(4-aminophenyl)-piperidine
25. A process according to claim 24, wherein the amine of formula
VI is 5-amino-2-methylquinoline.
26. A process according to claim 19, wherein the imine of formula
VII is reacted with sodium borohydride in alcoholic solution to
yield the compound according to formula VIII.
27. A process according to claim 19, wherein the compound of
formula VIII is: 1,1,1
trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[-
(2-methyl-5-quinoline-5-ylimino]methyl}pentane-2-ol).
28. A process according to claim 19, wherein the compound of
formula VIII is: 1,1,1
trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[-
(2-methyl-5-quinolinyl]methyl}pentane-2-ol).
29. A process according to claim 21, wherein the enantiomerically
pure compound of formula I is: TABLE-US-00004 Z.sup.1 Z.sup.2
Z.sup.3 X.sup.1 X.sup.2 X.sup.3 enantiomer a) O F R b) O F R c) O F
R d) NH F R e) O F R f) S F R g) NH Cl R h) NH Cl R i) S Cl R j) S
CF.sub.3 R k) S CF.sub.3 R l) O CF.sub.3 R m) O O--CH.sub.3 R n) O
O--CH.sub.3 R o) O O O--CH.sub.3 R p) O F R q) NH F R r) NH
NH.sub.2 R s) NH NH.sub.2 R t) O Br R u) O F S v) O F S w) O F S x)
NH F S y) O F S z) S F S aa) NH Cl S bb) NH Cl S cc) S Cl S dd) S
CF.sub.3 S ee) S CF.sub.3 S ff) O CF.sub.3 S gg) O O--CH.sub.3 S
hh) O O--CH.sub.3 S ii) O O O--CH.sub.3 S jj) O F S kk) NH F S ll)
NH NH.sub.2 S mm) NH NH.sub.2 S nn) O Br S.
30. A process according to claim 19, wherein one of the groups
X.sup.1, X.sup.2, X.sup.3 is fluoro and the other groups X.sup.1,
X.sup.2, X.sup.3 are hydrogen.
31. A process according to claim 19, wherein one of the groups
Z.sup.1, Z.sup.2, Z.sup.3 is --O-- and the others are --CH.sub.2--
groups.
32. A process according to claim 19, wherein Ar is 5-amino
2-methylquinoline.
33. A process according to claim 19, wherein X.sup.1 is H, X.sup.2
is fluoro, X.sup.3 is H, Z.sup.1 is CH.sub.2, Z.sup.2 is CH.sub.2,
and Z.sup.3 is O.
34. A process according to claim 19, wherein said compound
according to formula VIII is: ##STR00015##
35. A process according to claim 29, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>80%.
36. A process according to claim 35, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>90%.
37. A process according to claim 36, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>95%.
38. A process according to claim 37, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>97%.
39. An enantiomerically pure compound of formula I ##STR00016##
wherein: TABLE-US-00005 Z.sup.1 Z.sup.2 Z.sup.3 X.sup.1 X.sup.2
X.sup.3 enantiomer a) O F R b) O F R c) O F R d) NH F R e) S F R f)
NH Cl R g) NH Cl R h) S Cl R i) S CF.sub.3 R j) S CF.sub.3 R k) O
CF.sub.3 R l) O O--CH.sub.3 R m) O O--CH.sub.3 R n) O O O--CH.sub.3
R o) O F R p) NH F R q) NH NH.sub.2 R r) NH NH.sub.2 R s) O Br R t)
O F S u) O F S v) O F S w) NH F S x) S F S y) NH Cl S z) NH Cl S
aa) S Cl S bb) S CF.sub.3 S cc) S CF.sub.3 S dd) O CF.sub.3 S ee) O
O--CH.sub.3 S ff) O O--CH.sub.3 S gg) O O O--CH.sub.3 S hh) O F S
ii) NH F S jj) NH NH.sub.2 S kk) NH NH.sub.2 S ll) O Br S.
40. A compound according to claim 39, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>80%.
41. A compound according to claim 39, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>90%.
42. A compound according to claim 39, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>95%.
43. A compound according to claim 39, wherein said enantiomerically
pure compound of formula I has an enantiomeric excess
(ee)>97%.
44. A process according to claim 29, wherein one of the groups
X.sup.1, X.sup.2, X.sup.3 is F, Cl, CF.sub.3, OCH.sub.3, NH.sub.2
or Br and the other groups X.sup.1, X.sup.2, X.sup.3 are each H;
and one of the groups Z.sup.1, Z.sup.2, Z.sup.3 is O, S or NH and
the other groups Z.sup.1, Z.sup.2, Z.sup.3 are each --CH.sub.2--.
Description
[0001] This application claims the priorities of earlier filed
European patent applications EP 07090075.8 (filed 18 Apr. 2007) and
EP 07008931.3 (filed 9 May 2007) as well as all benefits of U.S.
application 60/912,596 (filed 18 Apr. 2007).
BACKGROUND OF THE INVENTION
[0002] Compounds of general formula VIII
##STR00002##
in which at least one of the groups X.sup.1, X.sup.2, X.sup.3 is
selected from fluoro, chloro, bromo, hydroxy, methoxy, ethoxy,
trifluoromethyl, amino whereas the other groups X.sup.1, X.sup.2,
X.sup.3 have the meaning of a hydrogen atom, in which at least one
of the groups Z.sup.1, Z.sup.2, Z.sup.3 is selected from --O--,
--S--, --NH--, --N(--CH.sub.3)--, whereas the other groups Z.sup.1,
Z.sup.2, Z.sup.3 have the meaning of a --CH.sub.2-- group, and in
which Ar is an aromatic group are described as powerful
anti-inflammatory agents (e.g. WO 98/54159, WO 00/32584, WO
02/10143, WO 03/082827, WO 03/082280, WO 2004/063163 and WO
2006/050998).
[0003] However, the processes for the manufacturing of the
compounds of general formula VIII have quite a number of steps,
resulting in low yields of the whole chain of reactions and are not
suitable for large scale productions.
OBJECT OF THE INVENTION
[0004] It is therefore the object of the invention to make
available a novel process characterized a higher total yield
achieved by the same or lower number of steps which is suitable for
pharmaceutical production. The object of the invention is achieved
by the processes described herein.
GENERAL DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0005] An essential element of the synthetic route described herein
is the compound of general formula I
##STR00003##
in which at least one of the groups X.sup.1, X.sup.2, X.sup.3 is
selected from fluoro, chloro, bromo, hydroxy, methoxy, ethoxy,
trifluoromethyl, amino whereas the other groups X.sup.1, X.sup.2,
X.sup.3 have the meaning of a hydrogen atom, and in which at least
one of the groups Z.sup.1, Z.sup.2, Z.sup.3 is selected from --O--,
--S--, --NH--, --N(--CH.sub.3)--, whereas the other groups Z.sup.1,
Z.sup.2, Z.sup.3 have the meaning of a --CH.sub.2-- group.
[0006] Another aspect of the invention is a manufacturing method
according to which the compounds of general formula VIII can be
produced in an enantiomerically pure form (enantiomeric excess
ee>>80%). It is clear to the expert in the art that the
compounds of the prior art are--when used as
pharmaceuticals--usually in an enantiomerically pure form. It is
therefore important to develop a manufacturing route that is able
to produce the compounds of general formula VIII in
enantiomerically pure form. This object is also achieved by the
present invention. The starting materials of the process described
herein (2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid) may
be used in the described processes in enantiomerically pure form,
subsequently yielding the final compound in enantiomerically pure
form.
[0007] The compound 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic
acid may be generated according to the method described by Miami
(Tetrahedron: Asymmetry 15 (2004) 3885-3889). It is also possible
to use racemic alkyl
2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoate or the free acid
thereof and separate the enantiomers by enzymatic hydrolysis.
[0008] It is therefore an object of the present invention to
provide a process in which the desired enantiomerically pure
2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid is separated
from the undesired enantiomer by way of enzymatic hydrolysis.
[0009] Using enantiomerically pure or enriched (ee>>80%)
2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid as the starting
materials results in an enantiomerically pure compound of general
formula VIII. The advantage of the described reaction starting with
enantiomerically pure or enriched
2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid is that it
avoids the synthesis of an undesired enantiomer and it avoids
carrying the same through following steps, therefore avoiding the
separation of the enantiomers at a later stage (or even in the
final product) and therefore being much more efficient.
[0010] The general method for the production of the compounds of
general formula VIII via the compound of general formula I is
described below in detail. The expert in the art is fully aware of
the fact that a number of variants of the reaction route are
possible without deviating from the general teaching of the present
invention. It is for example possible to not isolate all
intermediates of the synthetic route.
[0011] The process for the manufacturing starts with a compound of
general formula IV
##STR00004##
in which X.sup.1, X.sup.2, X.sup.3, Z.sup.1, Z.sup.2, Z.sup.3 have
meaning described above.
[0012] The compound of general formula IV is reacted with
2-hydroxy-4-methyl-2-(trifluoro-methyl)pentenoic acid
##STR00005##
to yield a compound of general formula II
##STR00006##
in which X.sup.1, X.sup.2, X.sup.3, Z.sup.1, Z.sup.2, Z.sup.3 have
the above described meaning.
[0013] The reaction described above is carried out in a organic
solvent in the presence of a lewis acid. Suitable solvents are e.g.
polar solvents or halogenated solvents, the preferred solvents
include dichloromethane and dichloroethane. The lewis acid may be
aluminium chloride, BF.sub.3, HF, or phosphoric acid.
[0014] In a preferred embodiment of the invention the compound
according to formula IV is solved in a halogenated solvent (e.g.
CH.sub.2Cl.sub.2) AlCl.sub.3 is added and finally the
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added to
the stirred solution. In an even more preferred embodiment the
addition of AlCl.sub.3 and the
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is carried out
at 0-5.degree. C., the mixture is allowed to come to room
temperature and the mixture is continued to stir for 4-120 hours at
room temperature.
[0015] It is furthermore preferred that 1.5 equivalents of the
compound according to formula IV are used, 2 equivalents AlCl.sub.3
and 1.0 equivalent of
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
[0016] The reaction described above can be carried out with
enantiomerically pure
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid. The
enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic
acid may be synthesized under asymmetric catalysis as described by
Mikami (see above) or the racemic form may be enzymatically
hydrolized.
[0017] The asymmetric hydrolysis may be carried out in water. If
necessary polar organic solvents (e.g. DMSO, lower alcohols) may be
added to enhance solubility of the substrate. The reaction mixture
may be buffered (phosphate or similar suitable buffers) to keep the
pH of the reaction mixture at constant level as required by the
individual enzyme.
[0018] Quite a number of enzymes are possible for the enzymatic
hydrolysis. These include the hydrolases (EC3.hydrolases) of the
subclasses EC3.1. (carboxylic esterhydrolasis in particular).
[0019] Such hydrolases are commercially available from various
sources, e.g.
I. Alphamerics Limited, UK
[0020] Lipase C1, Lipase C2, Lipase A, Lipase AS1, Lipase AN,
Lipase PC, Lipase PF, Lipase B (CALB)
2. Amano Enzyme Inc., Japan
[0020] [0021] Lipase AH, Lipase AK, Lipase AYS, Lipase PS, Protease
K, Protease N, Protease P
3. Biocatalytics Incorporated, USA
[0021] [0022] ICR-101, ICR-102, ICR-103, ICR-104, ICR-105, ICR-106,
ICR-107, ICR-108, ICR-109, ICR-110, ICR-111, ICR-112, ICR-113,
ICR-114, ICR-115, ICR-116, ICR-117, ICR-118, ICR-119, ICR-120,
IMW-102, IMW-105
4. Julich Chiral Solutions, Germany
[0022] [0023] Esterase BS1, Esterase BS2, Esterase BS3, Esterase
PF2, Esterase PL
5. NovoNordisk/Novozyme (Denmark)
[0023] [0024] Duramyl, Novozyme 868, Novozyme 525L, Novozyme 388,
Neutrase 0, Liopoase
6. Sigma, Germany
[0024] [0025] Lipase from porcine pancreas Type II, Esterase
porcine liver, Lipase candida rugosa.
[0026] The expert in the art is aware of further enzymes that may
achieve the same result.
[0027] The enzymatic hydrolysis is carried out as follows: Racemic
alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as
starting material. The alkyl group may be a C.sub.1-C.sub.5 alkyl
group which may be a straight chain or branched. Preferably the
alkyl group is an ethyl group. It is emulsified in water, the pH is
adjusted, the enzyme is added at temperature from about 10.degree.
C. to about 60.degree. C. Temperature, pH and reaction time may
vary depending on the individual enzyme. The reaction time may be
up to 300 hours. The reaction conditions have to be tested under
control (e.g. GC control) to find the optimum.
[0028] It is an advantageous feature of the process according to
the invention that no saponification step is needed. A
saponification is needed in a process in which alkyl
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate bis reacted with a
compound of formula IV yielding an alkyl ester of compound II.
[0029] It is surprising for the expert skilled in the art that the
reaction of the compound of formula IV with
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid in the
presence of a lewis acid yields the compound of general formula
II.
[0030] It is even more surprising that the reaction of the compound
of formula IV with 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic
acid in the presence of a lewis acid (i.e. under Friedel-Craft
conditions) is carried out up to 10 times faster and with higher
yields than with alkyl esters.
[0031] The compound of general formula II may be reduced to the key
compound of general formula I
##STR00007##
by e.g. lithium aluminium hydride or lithium borohydride.
[0032] Enantiomerically pure compounds of general formula I are key
compounds of the process, and are therefore a further object of the
invention. Preferred embodiments of the compounds of formula I are
those which have one of the following substitution patterns:
TABLE-US-00001 Z.sup.1 Z.sup.2 Z.sup.3 X.sup.1 X.sup.2 X.sup.3
enantiomer a) O F R b) O F R c) O F R d) NH F R e) O F R f) S F R
g) NH Cl R h) NH Cl R i) S Cl R j) S CF.sub.3 R k) S CF.sub.3 R l)
O CF.sub.3 R m) O O--CH.sub.3 R n) O O--CH.sub.3 R o) O O
O--CH.sub.3 R p) O F R q) NH F R r) NH NH.sub.2 R s) NH NH.sub.2 R
t) O Br R u) O F S v) O F S w) O F S x) NH F S y) O F S z) S F S
aa) NH Cl S bb) NH Cl S cc) S Cl S dd) S CF.sub.3 S ee) S CF.sub.3
S ff) O CF.sub.3 S gg) O O--CH.sub.3 S hh) O O--CH.sub.3 S ii) O O
O--CH.sub.3 S jj) O F S kk) NH F S ll) NH NH.sub.2 S mm) NH
NH.sub.2 S nn) O Br S
[0033] Enantiomerically pure in the context of this invention means
an enantiomeric excess (ee)>80%. It has to be understood that
according to the present invention it is possible to synthesize
compounds of ee>90%, ee>95%, ee>97% and even
ee>99%.
[0034] The compound of general formula I is then oxydized to form
the aldehyde of general formula V
##STR00008##
in which X.sup.1, X.sup.2, X.sup.3, Z.sup.1, Z.sup.2, Z.sup.3 have
the meaning described above.
[0035] The oxidation may be carried out by SO.sub.3/pyridin complex
or with oxalylchloride/DMSO (Swern oxidation). The expert in the
art is aware of other possibilities to oxydize the alcohol of
formula I to the aldehyd of formula V.
[0036] The aldehyde of general formula V is then reacted with an
aromatic amine of general formula VI
H.sub.2N--Ar (VI)
in which Ar is an aromatic group.
[0037] The compound according to general formula VI may be any
aromatic amine. Preferred embodiments of the compounds of general
formula VI are selected from the following list: [0038]
1-amino-2-methyl-benzene [0039] 1-amino-4-methyl-benzene [0040]
2-amino-4-methylpyridine [0041] 2-amino-pyridine [0042]
2-amino-pyrimidine [0043] 3-amino-quinoline [0044] 4-amino-pyridine
[0045] 4-amino-pyrimidine [0046] 5-amino-isoquinoline [0047]
5-amino-1-methyl-isoquinoline [0048] 5-amino-2,6-di-methylquinoline
[0049] 5-amino-2-methyl-indole [0050]
5-amino-2-methyl-isoquinol-1(2H)-one [0051]
5-amino-2-methylquinoline [0052] 5-amino-6-chloro-2-methylquinoline
[0053] 5-amino-6-fluoro-2-methylquinoline [0054]
5-amino-isoquinol-2(1H)-one [0055] 5-amino-quinoline [0056]
amino-benzene [0057] N-(4-aminophenyl)-piperidine.
[0058] The generated imine of formula VII
##STR00009##
in which X.sup.1, X.sup.2, X.sup.3, Z.sup.1, Z.sup.2, Z.sup.3 and
Ar have the meaning described above is subsequently reduced in
order to yield the compound according to general formula VIII. The
reaction may be carried out by sodium borohydride in alcoholic
solution (or in THF), it may also be carried out by H.sub.2/Ni.
[0059] A key advantage of the present invention compared to state
of the art synthesis that it avoids the purification of an alkyl
ester of compound II. Such alkyl ester (which is the product of the
reaction of alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate
with a compound of formula IV) needs to be separated from the
starting compound IV by crystallization. According to the present
invention the necessary separation of compound IV can be made at
the stage of compound II (i.e. by using free acid
2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoic acid as the
starting material). At the stage of compound II the separation from
compound IV can be made using acid-base-extraction (which is more
efficient compared to crystallization of the alkyl ester of
compound II).
[0060] As described above the expert in the art knows a number of
variations and deviations from the process steps described herein.
It is therefore clear that the invention described in the claims
encompasses further variants and deviations which are obvious to
the expert in the art or can easily be identified by the expert in
the art without any need to be inventive.
[0061] The process steps described above are furthermore described
in the following examples which are not meant to limit the
invention in any way.
EXAMPLES
1) Synthesis of
ethyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate
[0062] A suspension of 0.27 mol Mn and 0.01 mol ZnCl.sub.2 in 105
ml THF is heated to reflux. 0.01 mol 3-bromo-2-methyl-1-propene is
added to the boiling mixture and after 30 minutes a solution of
0.11 mmol ethyl-trifluoropyruvate and 0.18 mol
2-bromo-2-methyl-1-propene in 90 ml THF is dropped to the reaction
mixture within 2.5 hours. After 3 hours under reflux the mixture is
stirred for 19 hours at room temperature. The reaction mixture is
poured on 90 ml of a saturated NH.sub.4Cl and ice mixture. After
vigorous stirring for 30 minutes the mixture is extracted four
times with 110 ml of MTBE each. The combined organic extracts are
washed with 30 ml of brine, dried over magnesiumsulfate and
concentrated in vacuo. The residue is destilled under reduced
pressure. ethyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is
obtained in 73% yield.
2) Synthesis of 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic
acid
[0063] Ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is
used as starting material. 27.1 g (120 mmole) ethyl
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is emulsified in
60 mL water, the pH is adjusted to 8.0 with sodium hydroxide
solution, the solution is stirred at room temperature. 6 g of the
enzyme (Novozyme 388) is added at room temperature. The mixture is
stirred for 10 hours under GC control.
[0064] The aqueous solution is extracted two times with 100 mL of
MTBE. The aqueous phase is acidified to pH 1 with HCl solution,
treated with diatomaceous earth and MTBE and filtered. The aqueous
is was separated and extracted three times with MTBE. The organic
phase is evaporated to dryness to obtain a light brownish solid.
The crude 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is
crystallized from n-heptane. The yield of
(R)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is
25%.
[0065] The reaction conditions have to adapted to the individual
enzyme by changing solvent, buffer, pH, temperature, reaction time
in order to achieve optimum results for the desired (R)- or
(S)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
3) Synthesis of
4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluorom-
ethyl)pentanoic acid
[0066] A solution of 0.07 mol 5-fluoro-2,3-dihydro-benzofurane in
21 ml of dichloromethan is cooled to 3.degree. C. To this solution
0.1 mol of AlCl.sub.3 is added over a period of 30 minutes. After
this addition 0.05 mol of
2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added
dropwise over 30 minutes. The mixture is stirred for at least 6 h
under reflux conditions. After complete reaction the solution is
poured on a mixture of ice (50 ml) and 1M HCl (10 ml) and stirred
for at least 1 hour. The aqueous phase is extracted three times
with 51 ml of ethylacetate. The combined organic phases are washed
with water, saturated sodium chloride solution (brine) and dried
over magnesiumsulfate. The solvent is evaporated under vacuum. The
product may be recrystallized from n-heptane. As the title compound
is yielded in highly pure form the recrystallization is not
necessary. The title compound may be used directly to start the
next step.
[0067] The same reaction described above may be carried out with
other compounds according to formula IV
##STR00010##
wherein X.sup.1, X.sup.2, Z.sup.1, Z.sup.2, Z.sup.3 have the
meaning according to the following table:
TABLE-US-00002 Z.sup.1 Z.sup.2 Z.sup.3 X.sup.1 X.sup.2 X.sup.3 A O
F B O F C O F D NH F E O F F S F G NH Cl H NH Cl I S Cl J S
CF.sub.3 K S CF.sub.3 L O CF.sub.3 M O O--CH.sub.3 N O O--CH.sub.3
O O O O--CH.sub.3 P O F Q NH F R NH NH.sub.2 S NH NH.sub.2 T O
Br
4) Synthesis of
[4-(5-fluoro-2,3-dihydrobenzo-furan-7-yl)-4-methyl-2-(trifluoromethyl)pen-
tane-1,2-diol]
[0068] A solution of 6.6 mol
4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluorom-
ethyl)pentanoic acid in 77 ml of THF is cooled to 4.degree. C. 12
mmol of lithium aluminiumhydride is added portionwise to the
solution. The mixture is stirred at 4.degree. C. for 60 minutes,
and stirred for 8-9 hours under reflux conditions. After complete
reaction (TLC control) the mixture is cooled to 4.degree. C. and
treated with 1 ml of saturated NaHCO.sub.3 solution. The mixture is
stirred for at least 2 hours whereupon the colour of the mixture
turns from grey to white. The precipitated aluminium salts are
filtered off and washed with 10 ml of hot THF. The solvent is
evaporated under vacuum. The residue is purified by
recrystallization from dichloromethane and n-heptane. (yield
73.7%).
[0069] Using the compounds according to the table in example 3
further derivatives may be produced in comparable yields.
[0070] Starting the reaction sequence with R- or
S-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid in
combination with the compounds of general formula IV as described
above the following compounds according to formula I may be
produced in enantiomerically pure form:
TABLE-US-00003 Z.sup.1 Z.sup.2 Z.sup.3 X.sup.1 X.sup.2 X.sup.3
enantiomer a) O F R b) O F R c) O F R d) NH F R e) O F R f) S F R
g) NH Cl R h) NH Cl R i) S Cl R j) S CF.sub.3 R k) S CF.sub.3 R l)
O CF.sub.3 R m) O O--CH.sub.3 R n) O O--CH.sub.3 R o) O O
O--CH.sub.3 R p) O F R q) NH F R r) NH NH.sub.2 R s) NH NH.sub.2 R
t) O Br R u) O F S v) O F S w) O F S x) NH F S y) O F S z) S F S
aa) NH Cl S bb) NH Cl S cc) S Cl S dd) S CF.sub.3 S ee) S CF.sub.3
S ff) O CF.sub.3 S gg) O O--CH.sub.3 S hh) O O--CH.sub.3 S ii) O O
O--CH.sub.3 S jj) O F S kk) NH F S ll) NH NH.sub.2 S mm) NH
NH.sub.2 S nn) O Br S
5) Synthesis of 1,1,1
trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl--
5-quinoline-5-ylimino]methyl}pentane-2-ol)
[0071] To a solution of 3.84 g
4-(fluoro-2,3-dihydrobenzo-furan-7-yl)-4-methyl-2-(trifluoromethyl)pentan-
al] in 7 ml of acetic acid is added 2.28 g of
5-amino-2-methylquinoline at 25.degree. C. 50 ml of toluene is
added to the solution and refluxed under Dean-Stark trap for at
least 12 hours. After complete reaction (TLC control) the solvent
is evaporated under vacuum. Acetic acid is removed by aceotropic
destillation with toluene. The evaporation residue (Yield 88.7%) is
dissolved in alcohol and further processed.
[0072] The reaction may be carried out under similar conditions
with the amines listed below with comparable results: [0073]
1-amino-2-methyl-benzene [0074] 1-amino-4-methyl-benzene [0075]
2-amino-4-methylpyridine [0076] 2-amino-pyridine [0077]
2-amino-pyrimidine [0078] 3-amino-quinoline [0079] 4-amino-pyridine
[0080] 4-amino-pyrimidine [0081] 5-amino-isoquinoline [0082]
5-amino-1-methyl-isoquinoline [0083] 5-amino-2,6-di-methylquinoline
[0084] 5-amino-2-methyl-indole [0085]
5-amino-2-methyl-isoquinol-1(2H)-one [0086]
5-amino-2-methylquinoline [0087] 5-amino-6-chloro-2-methylquinoline
[0088] 5-amino-6-fluoro-2-methylquinoline [0089]
5-amino-isoquinol-2(1H)-one [0090] 5-amino-quinoline [0091]
amino-benzene [0092] N-(4-aminophenyl)-piperidine
6) Synthesis of 1,1,1
trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl--
5-quinolinyl]methyl}pentane-2-ol)
[0093] 10 mmol 1,1,1
trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl--
5-quinoline-5-ylimino]methyl}pentane-2-ol) are dissolved in 255 ml
of ethanol. To this solution 5 mmol of sodium bicarbonate is added.
The mixture is stirred at 25.degree. C. for 20 minutes. 34 mmol of
sodium boronhydride are added to this solution during 10 minutes
maintaining the temperature at 0-10.degree. C. The mixture is
stirred for 6 hours and another 34 mmol portion of sodium
borohydride is added to the solution over 10 minutes maintaining
the temperature at 25.degree. C. Then the mixture is stirred at
room temperature for 6 hours (TLC control). After completion
saturated sodium bicarbonate solution is added over 10 minutes
keeping the temperature at 25.degree. C. The mixture is stirred for
60 minutes, and finally the solvent is evaporated under vacuum. The
residue is diluted with water and extracted two times with 150 ml
of ethyl acetate each. The solvent is evaporated and the residue
obtained is purified by recrystallization from ethanol (yield
71.2%).
[0094] Using other amines in the reaction of example 5 (e.g. those
listen in example 5) and using the other compounds of formula I
(e.g. those listed in the table in example 3) quite a number of
compounds of general formula VIII may be generated using the
methods described herein.
[0095] According to the examples described above, it is possible to
synthesize the compound according to general formula VIII in 6
steps, whereas the prior art methods needed 13 steps. The overall
yield of the present 6 steps synthesis of compounds of general
formula VIII is 14.3% whereas it is 8.7% using the prior art
methods.
[0096] Moreover, the whole synthetic route can be carried out in
enantiomerically pure form, i.e. generating only the desired
enantiomer of general formula VIII. This is possible in using
chiral 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
[0097] It is important to understand that the total yield using
chiral 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid remains
approximately 14% whereas it drops to less than 5% according to
prior art methods due to the necessary separation of the
enantiomers of compound VIII.
[0098] The reaction conditions according to the described steps are
moreover suitable for production at industrial scale. Excess
compounds (e.g. compound IV) can be re-isolated and recycled.
* * * * *