U.S. patent application number 11/436347 was filed with the patent office on 2006-11-23 for process for preparing 3-heteroaryl-3-hydroxypropanoic acid derivatives.
Invention is credited to Frank Berendes, Nils Brinkmann, Claus Dreisbach, Markus Eckert, Rainhard Koch, Ruth Meissner.
Application Number | 20060264641 11/436347 |
Document ID | / |
Family ID | 31984088 |
Filed Date | 2006-11-23 |
United States Patent
Application |
20060264641 |
Kind Code |
A1 |
Berendes; Frank ; et
al. |
November 23, 2006 |
Process for preparing 3-heteroaryl-3-hydroxypropanoic acid
derivatives
Abstract
The invention relates to a process for preparing
enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid
derivatives and 3-heteroaryl-1-aminopropan-3-ols, and to their
use.
Inventors: |
Berendes; Frank; (Munster,
DE) ; Eckert; Markus; (Shanghai, CN) ;
Brinkmann; Nils; (Leverkusen, DE) ; Dreisbach;
Claus; (Leichlingen, DE) ; Meissner; Ruth;
(Leverkusen, DE) ; Koch; Rainhard; (Koln,
DE) |
Correspondence
Address: |
Kurt G. Briscoe;Norris, McLaughlin & Marcus P.A.
18th Floor
875 Third Avenue
New York
NY
10022
US
|
Family ID: |
31984088 |
Appl. No.: |
11/436347 |
Filed: |
May 18, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10669424 |
Sep 24, 2003 |
|
|
|
11436347 |
May 18, 2006 |
|
|
|
Current U.S.
Class: |
546/341 ;
549/491; 549/492; 549/76 |
Current CPC
Class: |
C12P 17/12 20130101;
C12P 17/04 20130101; C07D 213/55 20130101; C12P 17/00 20130101;
C07D 307/54 20130101; C07D 333/24 20130101 |
Class at
Publication: |
546/341 ;
549/076; 549/491; 549/492 |
International
Class: |
C07D 333/22 20060101
C07D333/22; C07D 213/55 20060101 C07D213/55; C07D 307/02 20060101
C07D307/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 26, 2002 |
JP |
102 44 881.6 |
Claims
1. A method for preparing a 3-hydroxy-3-(2-thienyl)propionamide of
the formula: heteroaryl-CH(OH)--CH.sub.2--CO--NR.sup.2R.sup.3
wherein heteroaryl represents 2-thiophenyl, which is optionally
monosubstituted or polysubstituted by fluorine, chlorine, bromine,
nitro, hydroxyl, C.sub.1-8-alkyl, C.sub.1-4-fluoroalkyl and
C.sub.1-4-alkoxy; and R.sup.2 and R.sup.3 are each independently
hydrogen, C.sub.1-8-alkyl, C.sub.4-10-aryl or C.sub.5-11-arylalkyl;
which comprises: a) reducing the compound of the formula:
heteroaryl-CO--CH.sub.2--CO--OR.sup.1 wherein heteroaryl is as
defined above; and R.sup.1 represents hydrogen, C.sub.1-8-alkyl,
C.sub.4-10-aryl or C.sub.5-11-arylalkyl; in the presence of a
microorganism and/or cell preparation; to form the resulting
compound of the formula: heteroaryl-CH(OH)--CH.sub.2--CO--OR.sup.1
and then b) reacting said resulting compound with an amine of the
formula: HNR.sup.2R.sup.3 wherein R.sup.2 and R.sup.3 have the
meanings given above.
2. The method according to claim 1, wherein the microorganism is
one selected from the group consisting of microorganisms of the
genera Saccharomyces, Geotrichum, Candida, Pichia, Hansenula,
Yarrowia, Phizopus, Mortierella, Mucor, Sporotrichum, Rhodotorula,
Trichoderma, Aspergillus, Penicillium, Pullaria, Cunninghamella and
Curvularia.
3. The method according to claim 2, wherein the microorganism is
Saccharomyces cereviseae.
4. The method according to claim 2, wherein the microorganism is
Geotrichum candidum.
5. A method for preparing an optically active
3-hydroxy-3-(2-thienyl)propionic acid ester compound of the
formula: heteroaryl-CH(OH)--CH.sub.2--CO--OR.sup.1 wherein
heteroaryl represents 2-thiophenyl, which is optionally
monosubstituted or polysubstituted by fluorine, chlorine, bromine,
nitro, hydroxyl, C.sub.1-8-alkyl, C.sub.1-4-fluoroalkyl and
C.sub.1-4-alkoxy; and R.sup.1 represents hydrogen, C.sub.1-8-alkyl,
C.sub.4-10-aryl or C.sub.5-11-arylalkyl; which comprises reducing
the compound of the formula: heteroaryl-CO--CH.sub.2--CO--OR.sup.1
wherein heteroaryl and R.sup.1 are as defined above; in the
presence of a microorganism and/or cell preparation.
6. The method according to claim 5, wherein the microorganism is
one selected from the group consisting of microorganisms of the
genera Saccharomyces, Geotrichum, Candida, Pichia, Hansenula,
Yarrowia, Phizopus, Mortierella, Mucor, Sporotrichum, Rhodotorula,
Trichoderma, Aspergillus, Penicillium, Pullaria, Cunninghamella and
Curvularia.
7. The method according to claim 6, wherein the microorganism is
Saccharomyces cereviseae.
8. The method according to claim 6, wherein the microorganism is
Geotrichum candidum.
Description
[0001] This application is a divisional of U.S. Ser. No.
10/669,424, which is pending and claims foreign priority benefit
under 35 U.S.C. .sctn.119 of the German Patent Application No. 102
44 811.6 filed Sep. 26, 2002.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to a process for preparing
enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid
derivatives and 3-heteroaryl-1-aminopropan-3-ols, and to their
use.
[0004] 2. Description of Related Art
[0005] 3-Heteroaryl-3-hydroxypropanoic acid derivatives and
3-heteroaryl-1-aminopropan-3-ols have gained industrial
significance, in particular, as intermediates for producing
medicaments. Thus, some 3-heteroaryl-3-hydroxypropanoic acid
derivatives and 3-heteroaryl-1-aminopropan-3-ols are used, for
example, as precursor substances for preparing inhibitors of the
uptake of serotonin or noradrenaline. In the case of some of these
inhibitors, it has been shown that certain enantiomers are not only
inactive, or less active, but are even able to exhibit undesirable
side-effects (U.S. Pat. No. 5,104,899).
[0006] A process for preparing enantiomer-enriched
(1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol proceeding from
1-(2-thiophenyl)-3-chloropropan-1-one is described in Chirality
2000, 12, 26-29. Following reduction to the racemic
3-chloro-1-(2-thienyl)-1-propanol, the racemate is resolved
enzymically and the (S) enantiomer is subjected to further reaction
with NaI and methylamine to give
(S)-3-(methylamino)-1-(2-thiophenyl)propan-1-ol. This method
suffers from the disadvantage that, in principle, only 50% of the
desired enantiomer can be obtained when racemates are resolved
enzymically and the total yield is therefore economically
unacceptable.
[0007] It is already known that microorganisms, such as yeasts or
fungi, can be used to reduce 3-oxocarboxylic acid derivatives
enantioselectively to give the corresponding enantiomer-enriched
3-hydroxycarboxylic acid derivatives (see also Sybesma et al.,
Biocatalysis and Biotransformation, 1998, Vol. 16, 95-134; Dahl et
al., Tetrahedron: Asymmetry 10, 1999, 551-559, Dehli et al.,
Tetrahedron: Asymmetry 11, 2000, 3693-3700, Hayakawa et al,
Tetrahedron Letters, 1998, Vol. 39, 67-70, Cabon et al.,
Tetrahedron: Asymmetry 6, 1995, 2199-2210 and Smallridge et al.,
Tetrahedron Letters, 1998, Vol. 39, 5121-5124).
[0008] In addition, EP-A 447 938 describes the enantioselective
synthesis of 2-halo-3-hydroxy-3-phenylpropanoic esters by using
various organisms to reduce the 2-halo-3-oxo-3-phenylpropanoic
esters.
[0009] Furthermore, Chenevert et al., Tetrahedron 1992, Vol. 48,
6769-6776 disclose the asymmetric synthesis of both enantiomers of
the antidepressant fluoxetine
(N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine
hydrochloride). An important step in the multi-stage synthesis is
that of using microorganisms to effect the enantioselective
reduction of the ethyl 3-oxo-3-phenylpropanoate.
[0010] An analogous synthesis, for preparing (R)-tomoxetine, which
acts as an antidepressant, is described in Kumar A. et al.,
Tetrahedron Letters, 1991, Vol. 32, 1901-1904. The enantioselective
reduction of the ethyl 3-oxo-3-phenylpropanoate to give ethyl
3-hydroxy-3-phenylpropanoate is an important step in this synthesis
as well.
[0011] However, the enantioselective reduction of heteroaryl
ketones has not previously been described.
[0012] There was still the need, therefore, to provide a process
which makes it possible to prepare enantiomer-enriched
3-heteroaryl-3-hydroxypropanoic acid derivatives.
SUMMARY OF THE INVENTION
[0013] A process for preparing stereoisomer-enriched
3-heteroaryl-3-hydroxypropanoic acid derivatives has now been
found, which process is characterized in that [0014] compounds of
the formula (I) heteroaryl-CO--CH.sub.2W (I) [0015] in which [0016]
heteroaryl is a monocyclic or bicyclic aromatic radical having a
total of from 5 to 10 ring atoms, where none, one or two ring
atoms, selected from the group oxygen, sulphur and nitrogen, can be
present per cycle and one or two can be present in the entire
aromatic radical, and where the monocyclic or bicyclic aromatic
radical is optionally substituted, once, twice or three times, by
radicals which are selected, in each case independently of each
other, from the group hydroxyl, C.sub.1-C.sub.8-alkyl, cyano, COOH,
COOM, where M is an alkali metal ion or a half equivalent of an
alkaline earth metal ion, COO--(C.sub.1-C.sub.4-alkyl),
O--(C.sub.1-C.sub.4-alkyl), N(C.sub.1-C.sub.4-alkyl).sub.2,
NH--(C.sub.1-C.sub.4-alkyl), fluorine, NO.sub.2, chlorine, bromine,
C.sub.1-C.sub.4-fluoroalkyl, CONH.sub.2 or
CONH--(C.sub.1-C.sub.4-alkyl), and [0017] W is C(O)YR.sup.1.sub.n,
where Y is=oxygen and n is=1 or Y is nitrogen and n is=2, or [0018]
W is CN, and [0019] R.sup.1 are, in each case independently of each
other, hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.4-C.sub.10-aryl or
C.sub.5-C.sub.11-arylalkyl or, when Y is nitrogen, the two radicals
R.sup.1 are together C.sub.3-C.sub.5 alkylene, [0020] are reacted
in the presence of microorganisms and/or cell preparations thereof,
and [0021] in the presence of water having a pH range of from 3 to
11, based on 25.degree. C., and, in this way, enantiomer-enriched
compounds of the formula (II), heteroaryl-CH(OH)--CH.sub.2W (II) in
which heteroaryl and W have the abovementioned meaning, are
obtained.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Within the context of the invention, all the radical
definitions, parameters and specifications which are general or
which are mentioned in preference ranges, and which are given above
or cited in that which follows, can be combined amongst themselves,
that is between the respective ranges and preference ranges as
well, in any arbitrary manner.
[0023] Within the meaning of the invention, the term
enantiomer-enriched encompasses, in particular, enantiomerically
pure compounds or arbitrary mixtures of enantiomers in which one
enantiomer is present in a larger proportion than the other
enantiomer, preferably in a relative proportion of from 60% to 100
mol %, particularly preferably from 80 to 100 mol % and, very
particularly preferably, from 90 to 100 mol %.
[0024] Within the context of the invention, alkyl is, in each case
independently, a straight-chain or cyclic, independently thereof
branched or unbranched, alkyl radical which can be further
substituted by C.sub.1-C.sub.4-alkoxy radicals. The same applies to
the nonaromatic moiety of an arylalkyl radical.
[0025] For example, within the context of the invention,
C.sub.1-C.sub.4-alkyl is methyl, ethyl, 2-ethoxyethyl, n-propyl,
isopropyl, n-butyl and tert-butyl, while C.sub.1-C.sub.8-alkyl is,
in addition to this, for example, n-pentyl, cyclohexyl, n-hexyl,
n-heptyl, n-octyl or iso-octyl.
[0026] Fluoroalkyl is, in each case independently, a
straight-chain, cyclic, branched or unbranched alkyl radical which
is substituted, once, more than once or completely, by fluorine
atoms.
[0027] For example, C.sub.1-C.sub.4-fluoroalkyl is trifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, nonafluorobutyl and
heptafluoroisopropyl.
[0028] Within the context of the invention, aryl is, for example
and preferably, carbocyclic aromatic radicals or heteroaromatic
radicals which contain no, one or two, but at least one in the
entire heteroaromatic radical, heteroatom(s) which is/are selected
from the group nitrogen, sulphur and oxygen.
[0029] In addition, the carbocyclic aromatic radicals or
heteroaromatic radicals can be substituted by one or two
substituents per cycle, which substituents are selected, in each
case independently of each other, for example and preferably, from
the group hydroxyl, C.sub.1-C.sub.4-alkyl, cyano, COOH, COOM, where
M is an alkali metal ion or a half equivalent of an alkaline earth
metal ion, COO--(C.sub.1-C.sub.4-alkyl),
O--(C.sub.1-C.sub.4-alkyl), N(C.sub.1-C.sub.4-alkyl).sub.2,
NH--(C.sub.1-C.sub.4-alkyl), fluorine, chlorine, bromine,
C.sub.1-C.sub.4-fluoroalkyl, CONH.sub.2 or
CONH--(C.sub.1-C.sub.4-alkyl). The same applies to the aryl moiety
of an arylalkyl radical.
[0030] In the formulae (I) and (II), heteroaryl is preferably a
monocyclic aromatic radical having a total of 5 or 6 ring atoms in
which one or two ring atoms are selected from the group oxygen,
sulphur and nitrogen and where the monocyclic aromatic radical
contains no, one or two radical(s) which is/are selected, in each
case independently of each other, from the group methyl, ethyl,
n-propyl, isopropyl, cyano, COOH, COONa, COOK, COO-methyl,
COO-ethyl, COO-tert-butyl, COO-phenyl, methoxy, ethoxy,
dimethylamino, diethylamino, methylamino, ethylamino, fluorine,
chlorine, NO.sub.2, trifluoromethyl, pentafluoroethyl,
heptafluoroisopropyl, CONH.sub.2 and CONH-methyl.
[0031] Heteroaryl is, particularly preferably, 2- or 3-thiophenyl,
2- or 3-furanyl, 2- or 3-pyrrolyl, 3- or 4-pyrazolyl, 1-, 2- or
4-thiazolyl, 1-, 2- or 4-oxazolyl, 2-, 4- or 5-imidazolyl, 2-, 3-
or 4-pyridyl, 2- or 3-pyrazinyl, 2-, 4- or 5-pyrimidyl, 3-, 4-, 5-
or 6-pyridazinyl, 2- or 3-indolyl, 3-indazolyl, indazolyl, 2- or
3-benzofuranyl, 2- or 3-benzothiophenyl, 2-, 3- or 4-quinolinyl or
isoquinolinyl, where each of the radicals mentioned carries no, one
or two, and preferably no, substituents which are in each case
selected, independently of each other, from the group methyl,
ethyl, n-propyl, isopropyl, cyano, methoxy, ethoxy, fluorine,
chlorine, trifluoromethyl, pentafluoroethyl and
heptafluoroisopropyl.
[0032] Heteroaryl is very particularly preferably 2-thiophenyl.
[0033] R.sup.1 is preferably CN or COOR.sup.1, where R.sup.1 is
hydrogen or methyl or ethyl.
[0034] Preferred compounds of the formula (I) are methyl
3-oxo-3-(2-thiophenyl)propanoate, ethyl
3-oxo-3-(2-thiophenyl)propanoate, methyl
3-oxo-3-(3-thiophenyl)propanoate, ethyl
3-oxo-3-(3-thiophenyl)propanoate, methyl
3-oxo-3-(2-furanyl)propanoate, ethyl 3-oxo-3-(2-furanyl)propanoate,
methyl 3-oxo-3-(3-furanyl)propanoate, ethyl
3-oxo-3-(3-furanyl)propanoate, methyl
3-oxo-3-(2-pyridinyl)propanoate, ethyl
3-oxo-3-(2-pyridinyl)propanoate, methyl
3-oxo-3-(3-pyridinyl)propanoate, ethyl
3-oxo-3-(3-pyridinyl)propanoate, methyl
3-oxo-3-(4-pyridinyl)propanoate, ethyl
3-oxo-3-(4-pyridinyl)propanoate,
3-oxo-3-(2-thiophenyl)propanonitrile,
3-oxo-3-(3-thiophenyl)propanonitrile,
3-oxo-3-(2-furanyl)propanonitrile,
3-oxo-3-(3-furanyl)propanonitrile,
3-oxo-3-(2-pyridinyl)propanonitrile,
3-oxo-3-(3-pyridinyl)propanonitrile,
3-oxo-3-(4-pyridinyl)propanonitrile and
N-(methyl)-3-oxo-3-(2-thiophenyl)propanamide.
[0035] The microorganisms which are preferably employed are
bacteria, yeasts or fungi, with both wild types and transformed
strains being included.
[0036] Microorganisms which are particularly preferred are yeasts
and fungi, very particularly preferably those of the genera
Saccharomyces, Geotrichum, Candida, Pichia, Hansenula, Yarrowia,
Rhizopus, Mortierella, Mucor, Sporotrichum, Rhodotorula,
Trichoderma, Aspergillus, Penicillium, Pullaria, Cunninghamella and
Curvularia.
[0037] Microorganisms which are even more preferred are
Saccharomyces cereviseae and Geotrichum candidum.
[0038] Cell preparations are to be understood as meaning: purified
or unpurified lysed cells which can be used either in the moist
state or in the dried state, for example as lyophilisates.
[0039] Preference is given to using microorganisms.
[0040] In a preferred embodiment, the microorganisms are grown,
prior to the compounds of the formula (I) being reacted, on complex
or mineral nutrient media, using culturing methods which are
customary per se for growing the given microorganisms, such as
culturing in shaken flasks, batch fermentations, fed-batch
fermentations or continuous fermentations, up to an optical density
of from 1 to 800, preferably of from 5 to 300, measured at a
wavelength of 600 nm (OD.sub.600), and concentrated, where
appropriate, after having been grown.
[0041] The microorganisms can be grown, for example, at
temperatures of between 10 and 60.degree. C., preferably of between
20 and 40.degree. C.
[0042] In addition, the pH when growing the microorganisms can, for
example, be between pH 3 and pH 9, preferably between pH 4 and pH
8, particularly preferably between pH 5 and pH 7.5. In this
connection, pH values are in each case based on 25.degree. C.,
within the entire scope of the invention.
[0043] The microorganisms can be grown under aerobic or anaerobic
conditions; they are preferably grown aerobically.
[0044] For the reaction, the compound of the formula (I) is, in a
preferred embodiment, added to the microorganisms which are either
present in the growth medium or resuspended, where appropriate
after prior sedimentation, in an isotonic solution.
[0045] In this connection, the isotonic solution can be a mineral
salt solution or also a nutrient medium for microorganisms.
[0046] The mixture can, for example and preferably, be shaken or
stirred and, where appropriate, aerated.
[0047] The process according to the invention can be carried out in
a pH range of from pH 3 to pH 11, preferably of from pH 4 to pH 10,
and particularly preferably of from pH 6 to pH 8.
[0048] The process according to the invention is, furthermore,
customarily carried out at a temperature of from 10 to 60.degree.
C., preferably of from 18 to 45.degree. C.
[0049] The duration of the reaction can be from 10 min to 96 hours,
preferably from 60 min to 72 hours and particularly preferably from
2 to 48 hours.
[0050] The process according to the invention can be carried out
such that the compounds of the formula (I) are added once, several
times or continuously.
[0051] The sum of the concentrations of the compounds of the
formulae (I) and (II) in the cell suspension can be between 1 and
900 mM, preferably between 2 and 500 mM, particularly preferably
between 3 and 250 mM.
[0052] In order to increase the solubility of the starting compound
in the reaction medium, it is possible, in a preferred embodiment,
to add auxiliary substances such as polar, water-miscible solvents,
such as glycerol, dimethylformamide or dimethyl sulphoxide, or
other auxiliary substances, such as cyclodextrins.
[0053] In addition, the process according to the invention can be
carried out in the presence of an organic solvent, for example in a
multiphase system such as, in particular, a two-phase system.
[0054] Organic solvents which are suitable for this purpose are,
for example, organic solvents which are not miscible with water or
which are miscible with at most 10% by volume, such as aliphatic or
aromatic, where appropriate chlorinated, solvents, such as
petroleum ether, hexane, octane, heptane, toluene, the isomeric
xylenes, chlorobenzene, dichloromethane and silicone oils.
Frequently, the starting compound can also itself be used as the
organic phase.
[0055] The compounds of the formula (II) can be isolated in a
manner known per se, for example by extracting with an organic
solvent, or isolated, if a multiphase system was used, by means of
separating off the organic phase and, where appropriate, further
extraction and subsequent removal of the organic solvent.
[0056] Preference is given to using, for this purpose, solvents
such as toluene, ethyl acetate, dichloromethane, isobutyl ketone,
cyclohexane and methylcyclohexane, preferably ethyl acetate. The
extraction can in this case be effected by either continuously or
discontinuously supplying the extracting agent. In the simplest
case, the purification is effected by extracting, while shaking,
with the previously mentioned extracting agents.
[0057] If desired, a further purification can be effected by means
of distillation or, in the case of compounds of the formula (I)
which are solid at room temperature, by means of
recrystallization.
[0058] If the process according to the invention is carried out in
a multiphase system, the product can also be isolated directly by
subjecting the organic phase to fractional distillation.
[0059] In a manner according to the invention, the
enantiomer-enriched compounds of the formula (II) are obtained,
with the stereogenic carbon atom which carries the heteroaryl group
and the hydroxyl group usually exhibiting the (S)
configuration.
[0060] The process according to the invention is particularly
suitable for preparing
methyl(S)-3-hydroxy-3-(2-thiophenyl)propanoate,
ethyl(S)-3-hydroxy-3-(2-thiophenyl)propanoate,
methyl(S)-3-hydroxy-3-(3-thiophenyl)propanoate,
ethyl(S)-3-hydroxy-3-(3-thiophenyl)propanoate,
methyl(S)-3-hydroxy-3-(2-furanyl)propanoate,
ethyl(S)-3-hydroxy-3-(2-furanyl)propanoate,
methyl(S)-3-hydroxy-3-(3-furanyl)propanoate,
ethyl(S)-3-hydroxy-3-(3-furanyl)propanoate,
methyl(S)-3-hydroxy-3-(2-pyridinyl)propanoate,
ethyl(S)-3-hydroxy-3-(2-pyridinyl)propanoate,
methyl(S)-3-hydroxy-3-(3-pyridinyl)propanoate,
ethyl(S)-3-hydroxy-3-(3-pyridinyl)propanoate,
methyl(S)-3-hydroxy-3-(4-pyridinyl)propanoate,
ethyl(S)-3-hydroxy-3-(4-pyridinyl)propanoate,
(S)-3-hydroxy-3-(2-thiophenyl)propanonitrile,
(S)-3-hydroxy-3-(3-thiophenyl)propanonitrile,
(S)-3-hydroxy-3-(2-furanyl)propanonitrile,
(S)-3-hydroxy-3-(3-furanyl)propanonitrile,
(S)-3-hydroxy-3-(2-pyridinyl)propanonitrile,
(S)-3-hydroxy-3-(3-pyridinyl)propanonitrile,
(S)-3-hydroxy-3-(4-pyridinyl)propanonitrile and
N-(methyl)-(S)-3-hydroxy-3-(2-thiophenyl)propanamide.
[0061] The process according to the invention is furthermore
suitable, in particular, as step a) in a process for preparing
enantiomer-enriched compounds of the formula (VI),
heteroaryl-CH(OH)--CH.sub.2--CH.sub.2--NR.sup.2R.sup.3 (VI) [0062]
in which [0063] heteroaryl has the same meaning as that given under
formula (I), and [0064] R.sup.2 and R.sup.3 are, in each case
independently of each other, hydrogen, C.sub.1-C.sub.8-alkyl,
C.sub.4-C.sub.14-aryl or C.sub.5-C.sub.15-arylalkyl, or the two
radicals R.sup.2 and R.sup.3 are together
C.sub.3-C.sub.12-alkylene, which is characterized in that [0065] in
a step a), [0066] compounds of the formula (I) are converted, as
previously described, into enantiomer-enriched compounds of formula
(II) heteroaryl-CH(OH)--CH.sub.2--CO--CH.sub.2W (II) [0067] where,
in each case, [0068] heteroaryl and W have the meanings mentioned
under formula (I), and [0069] in a step b) [0070] i) when W is
COOR.sup.1 and R.sup.1 is hydrogen, C.sub.1-C.sub.8-alkyl,
C.sub.4-C.sub.10-aryl or C.sub.5-C.sub.11-arylalkyl, [0071] the
enantiomer-enriched compounds of formula (II) are reacted with
amines of the formula (III) HNR.sup.2R.sup.3 (III) [0072] in which
R.sup.2 and R.sup.3 have the meaning mentioned under formula (VI),
to give enantiomer-enriched compounds of the formula (IV)
heteroaryl-CH(OH)--CH.sub.2--CO--NR.sup.2R.sup.3 (IV) [0073] in
which heteroaryl, R.sup.2 and R.sup.3 have the previously mentioned
meanings, or [0074] ii) when W is CON(R.sup.1).sub.2 and the
R.sup.1 radicals are in each case, independently of each other,
hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.4-C.sub.10-aryl or
C.sub.5-C.sub.11-arylalkyl, or the two R.sup.1 radicals are
together C.sub.3-C.sub.5-alkylene, [0075] the enantiomer-enriched
compounds of the formula (II) are converted, where appropriate by
reacting with amines of the formula (III), into enantiomer-enriched
compounds of the formula (IV), and [0076] iii) when W is CN, the
compounds of the formula (II) are converted directly, by means of
aminolysis/hydrolysis, into compounds of the formula (IV), or are
initially converted, by means of hydrolysis, partial hydrolysis or
mixed alcoholysis/hydrolysis, into compounds of the formula (V)
heteroaryl-CH(OH)--CH.sub.2--CO--R.sup.4 (V) [0077] in which
heteroaryl has the meaning given under formula (I) [0078] and
R.sup.4 is OR.sup.1 or NH.sub.2, where R.sup.1 has the
abovementioned meaning, and [0079] are then converted, by amidation
in analogy with i) or, where appropriate, in analogy with ii), into
enantiomer-enriched compounds of the formula (IV) [0080] in a step
c), [0081] the enantiomer-enriched compounds of the formula (IV)
are converted, by means of reduction, into enantiomer-enriched
compounds of the formula (VI) having the abovementioned
meaning.
[0082] In the formulae (III), (IV) and (VI), R.sup.2 and R.sup.3
are particularly preferably, in each case independently, hydrogen,
methyl, ethyl, isopropyl, phenyl or benzyl.
[0083] In the formulae (III), (IV) and (VI), NR.sup.1R.sup.2 is, in
its entirety, particularly preferably methylamino, ethylamino and
isopropylamino.
[0084] In the formulae (III), (IV) and (VI), NR.sup.1R.sup.2 is, in
its entirety, very particularly preferably methylamino.
[0085] The compounds of the formula (I) which can be used for the
process according to the invention comprising steps a), b) and c)
are either known from the literature or can be prepared in analogy
with the literature.
[0086] Compounds of the formula (I) in which W is not CN are
preferably obtained by reacting compounds of formula (VII)
heteroaryl-CO--CH.sub.3 (VII) in which heteroaryl has the meaning
and preference ranges mentioned under formula (I), with compounds
of the formula (VIII), R.sup.1--O--W (VIII) [0087] in which [0088]
R.sup.1 and W have the same meanings as those which were given
under the formula (I), with W not being CN, in the presence of a
base.
[0089] The reaction of 2-acetylthiophene with dimethyl carbonate,
diethyl carbonate, diphenyl carbonate or dibenzyl carbonate, methyl
N-methyl carbamate, ethyl N-methyl carbamate, methyl N,N-dimethyl
carbamate or ethyl N,N-dimethyl carbamate may be mentioned by way
of example.
[0090] Such a reaction is described, for example, in Tetrahedron
Lett. 1998, 39, 4995 and can be applied in an analogous manner, for
example, for the reaction of 2-acetylthiophene with methyl N-methyl
carbamate or ethyl N-methyl carbamate to give
N-(methyl)-3-oxo-3-(2-thiophenyl)propanamide.
[0091] It is furthermore also possible to obtain compounds of the
formula (Ia) heteroaryl-CH(OH)--CH.sub.2--CO--NHR.sup.2 (Ia) by
reacting compounds of the formula (VII) with compounds of the
formula (IX) R.sup.2--NCO (IX) in the presence of a base.
[0092] In step b) of the process according to the invention, the
enantiomer-enriched compounds of the formula (II) are converted in
a manner known per se, in accordance with i), ii) or iii), into
enantiomer-enriched compounds of the formula (IV).
[0093] Houben Weyl "Methoden der Organischen Chemie [Methods of
organic chemistry]", 4th edition, volume E 5, 941-1010 provides a
review of the preparation of carboxamides from carboxylic acids,
carboxylic esters or other carboxamides.
[0094] If liquid or gaseous amines of the formula (III) are
employed at room temperature, preference is then given to using
solutions of the amines. For example, in the case of methylamine,
it is possible to advantageously use solutions consisting of
methylamine in water, methanol or ethanol for reacting compounds of
the formula (II) in which W is COOR.sup.1. Reactions of amines of
the formula (III) in the presence of coupling reagents such as
2-halopyridinium or 2-halo-1,3-thiazolium salts, or in the presence
of acid cation exchangers, are suitable, for example, for
converting free carboxylic acids of the formula (II) into the
amides of the formula (IV).
[0095] According to step b), enantiomer-enriched compounds of the
formula (IV) are then obtained from enantiomer-enriched compounds
of the formula (II).
[0096] The compounds of the formula (IV) can then be reduced to
give the compounds of the formula (VI). The reduction of
carboxamides to give the corresponding amines is known in principle
and is presented in summary in Houben Weyl "Methoden der
Organischen Chemie", 4th edition, volume E 16 d, 987-1003.
[0097] Preference is given to reacting compounds of the formula
(VI) with complex boron hydrides or aluminium hydrides, such as
lithium aluminium hydride, Red-Al.RTM. (sodium
bis(2-methoxyethoxy)dihydroaluminate) or sodium borohydride.
[0098] Particular preference is given to reacting compounds of the
formula (VI) with lithium aluminium hydride.
[0099] The reductions are preferably carried out at temperatures in
the range from room temperature to 150.degree. C., particularly
preferably in the range from 50 to 110.degree. C. While the
reductions are usually carried out in ethers as solvents,
preferably in cyclic ethers such as tetrahydrofuran or dioxane,
reactions using Red-Al.RTM. can also be carried out in toluene as
the solvent.
[0100] The enantiomer-enriched compounds of the formula (VI) are
obtained in a manner according to the invention.
[0101] The following may be mentioned as being preferred compounds
of the formula (VI):
[0102] (1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol,
(1R)-3-(methylamino)-1-(2-thio-phenyl)-1-propanol,
(1S)-3-(dimethylamino)-1-(2-thiophenyl)-1-propanol and
(1R)-3-(dimethylamino)-1-(2-thiophenyl)-1-propanol, with
(1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol being even more
preferred.
[0103] The enantiomer-enriched compounds of the formula (VI) which
can be prepared in accordance with the invention are particularly
suitable for preparing enantiomer-enriched compounds of the formula
(X) heteroaryl-CH(OR.sup.6)--CH.sub.2--CH.sub.2NR.sup.2R.sup.3 (X)
[0104] in which [0105] heteroaryl, R.sup.2 and R.sup.3 have the
meanings and preference regions given under formula (I), and [0106]
R.sup.6 is phenyl or naphthyl which can be substituted, not at all,
once or more than once, by substituents which are selected, in each
case independently of each other, from the group cyano,
CO--(C.sub.1-C.sub.12-alkyl), O--(C.sub.1-C.sub.12-alkyl),
(C.sub.1-C.sub.12-alkyl), fluorine, chlorine, bromine or
C.sub.1-C.sub.12-fluoroalkyl. [0107] R.sup.6 is preferably
naphthyl.
[0108] Preferred compounds of the formula (X) are
[0109] (S)--N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine
and (R)--N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine
and their ammonium salts.
[0110] The invention therefore also encompasses a process which
[0111] as step d), [0112] encompasses the reaction of
enantiomer-enriched compounds of the formula (VI) with compounds of
the formula (XI) to give enantiomer-enriched compounds of the
formula (X) in the presence of a base.
[0113] In formula (XI), R.sup.6-Hal (XI) [0114] R.sup.6 has the
meaning mentioned under the formula (X), and [0115] Hal is
fluorine, chlorine, bromine or iodine, preferably fluorine.
[0116] 1-Fluoronaphthalene and 4-chlorobenzotrifluoride are
preferably used as compounds of the formula (XI).
[0117] The bases which can be used are those which are able to at
least partially deprotonate the compounds of the formula (VI) at
the alcohol function.
[0118] These bases include, for example, alkaline earth metal or
alkali metal hydrides, hydroxides, amides, alcoholates or
carbonates, such as sodium hydride, sodium amide, lithium
diethylamide, sodium methoxide, sodium ethoxide, potassium
tert-butoxide, sodium hydroxide and potassium hydroxide.
[0119] The compounds which can be prepared in accordance with the
invention are particularly suitable for use as active compounds in
medicaments such as, in particular, inhibitors of serotonin or
noradrenaline uptake, or as intermediates thereof.
[0120] The process according to the invention enjoys the advantage
that it is possible to use readily available starting compounds to
synthesize enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid
derivatives and 3-heteroaryl-1-aminopropan-3-ols, and their
secondary products, on an industrial scale in high overall yields,
high enantiomer excesses and high purities.
EXAMPLES
Examples 1 and 2
Reduction of methyl 3-oxo-(2-thiophenyl)propanoate Using Different
Strains of the Baker's Yeast Saccharomyces cereviseae
[0121] The yeast strains (Saccharomyces cereviseae NG 247, Uniferm
GmbH & Co KG, Monheim; Saccharomyces cereviseae Y278, Deutsche
Hefe Werke [German Yeast Works] GmbH & Co oHG, Hamburg) were
grown overnight, at 28.degree. C. and with shaking (200 rpm), in
100 ml Erlenmeyer flasks containing 25 ml of YM medium (yeast
extract, 3.0 g/l; malt extract, 3.0 g/l; peptone, 5.0 g/l; glucose,
10.0 g/l).
[0122] Each of the two yeast strains was incubated, at 28.degree.
C. and while shaking (200 rpm), in three 1-litre Erlenmeyer flasks
which contained 200 ml of YM medium which had previously been
inoculated with 12 ml of preliminary culture. Growth was monitored
by measuring the optical density at 600 nm (OD.sub.600). After 6-7
h, the cultures reached an OD.sub.600 of 3 and were harvested by
centrifugation (15 min, 8 000.times.g) and stored overnight at
4.degree. C. in a refrigerator. For the reaction, 250 .mu.l of 1 M
potassium phosphate buffer (pH 7) and 250 .mu.l of 1M methyl
3-oxo-(2-thiophenyl)propanoate were added to 5 ml of the cell
pellet and the whole was shaken in screw cap 13 ml glass tubes. 300
.mu.l of the reaction mixture were removed at regular intervals and
extracted with 300 .mu.l of ethyl acetate or toluene. After the
subsequent centrifugation (5 min, 5000.times.g) for separating the
phases, the organic phase was analysed by chiral gas
chromatography. The results are recorded in Tab. 1. TABLE-US-00001
TABLE 1 Reduction of methyl 3-oxo-(2-thiophenyl)propanoate using
different yeast strains. [c] of starting Reaction Example Yeast
strain compound time [h] Product Yield ee (S) 1 NG 247 50 mM 24
##STR1## 75% >97% 2 Y278 50 mM 24 ##STR2## 77% >97%
Example 3
Reduction of 3-(2-thiophenyl)-3-oxopropano-1-nitrile Using
Saccharomyces cereviseae Y278
[0123] The yeast cells were grown, and the reaction was carried
out, as described in Examples 1 and 2. The result is recorded in
Table 2. TABLE-US-00002 TABLE 2 Starting Reaction Yield of Example
Yeast strain compound conc. time [h] Product product ee (S) 3 Y278
20 mM 9 ##STR3## 22% 85%
Examples 4 and 5
Reduction of methyl 3-(2-thiophenyl)-3-oxopropanoate Using
Geotrichum candidum
[0124] 200 ml of YM medium were inoculated, in a 1-litre Erlenmeyer
flask and as the 1st preliminary culture, with the strain
Geotrichum candidum ATCC34614 and the flasks were incubated at
28.degree. C. for 18 h while being shaken. As the 2nd preliminary
culture, two 1-litre Erlenmeyer flasks, in each case containing 200
ml of GC medium (KH.sub.2PO.sub.4, 11.18 g/l; K.sub.2HPO.sub.4,
3.12 g/l; glycerol, 30.0 g/l; yeast extract, 10.0 g/l; polypeptone,
5.0 g/l), were in each case inoculated with 10 ml of the 1st
preliminary culture and likewise shaken at 28.degree. C. for 18
h.
[0125] As the main culture, a 10 litre fermenter was loaded with
4.6 litres of GC medium and inoculated with 400 ml of the 2nd
preliminary culture. The culture was grown at 28.degree. C. using
an aeration rate of 10 l/min and a stirring rate of 800 rpm. After
10 h, the fermenter was harvested. The cells were sedimented by
being centrifuged for 15 min at 6000.times.g and were then taken up
in 100 mM potassium phosphate buffer (PP buffer), pH 6.4, and
stored at 4.degree. C. in a refrigerator.
[0126] 1.8 g of glucose, 9 ml of 1M PP buffer (pH 7.3) and 71 .mu.l
(final concentration 20 mM) or 143 .mu.l (final concentration 40
mM) of methyl 3-(2-thiophenyl)-3-oxopropanoate were added to 16 g
of moist biomass and the whole was stirred at 28.degree. C. in a 25
ml Schott bottle using a magnetic stirrer. 300 .mu.l of the
reaction mixture were removed at regular intervals and extracted
with 300 .mu.l of ethyl acetate or toluene and the organic phase
was analysed by gas chromatography. The results were recorded in
Table 3. TABLE-US-00003 TABLE 3 Reduction of methyl
3-(2-thiophenyl)-3-oxo-propanoate with the strain Geotrichum
candidum ATCC34614. Starting Reaction Yield of Example compound
conc. time [h] Product product ee (S) 4 20 mM 10 ##STR4## 71%
>98% 5 20 mM 10 ##STR5## 72% >98%
Examples 6 to 12
Reduction of Various .beta.-Ketoesters Using Saccharomyces
cereviseae
[0127] A preliminary culture of the strain Saccharomyces cereviseae
NG247 was grown overnight, at 28.degree. C. and while shaking, in
100 ml of YM medium in a 1-litre Erlenmeyer flask. As the main
culture, three 1-litre Erlenmeyer flasks, which had each been
loaded with 200 ml of YM medium, were in each case inoculated with
10 ml of the preliminary culture and shaken at 28.degree. C. After
6 h, the cultures had reached an optical density of between 7 and 8
as measured at 600 nm (OD.sub.600). The cells were harvested by
centrifugation (15 min, 6000.times.g) and resuspended in 100 mM PP
buffer (pH 7)+3% (w/v) glucose as a 10-fold concentrated cell
suspension. 1 M ethanolic solutions of the test substances were
prepared. In the reaction mixtures, the cell suspension was in each
case made to 20 mM with respect to the test substance and incubated
at 30.degree. C. while being shaken. 300 .mu.l of the reaction
mixture were withdrawn at regular intervals and extracted with 300
.mu.l of ethyl acetate or toluene and the organic phase was
analysed by gas chromatography. The results are recorded in Tab. 4.
TABLE-US-00004 TABLE 4 Enantioselective reduction of heterocyclic
.beta.-ketoesters. Starting Reaction Example Starting compound
compound conc. time [h] Product Conversion ee 6 ##STR6## 20 mM 24 h
##STR7## 92% 98% 7 ##STR8## 20 mM 24 h ##STR9## 50% 87% 8 ##STR10##
20 mM 24 h ##STR11## 59% 93% 9 ##STR12## 20 mM 24 h ##STR13## 92%
81% 10 ##STR14## 20 mM 24 h ##STR15## 69% 96% 11 ##STR16## 20 mM 24
h ##STR17## 76% 96% 12 ##STR18## 20 mM 24 h ##STR19## 99% 99%
Example 13
Preparation of methyl 3-oxo-(2-thiophenyl)propanoate
[0128] 510 ml of dimethyl carbonate and 1500 ml of toluene were
heated to 100.degree. C. in a 2 L flask and a solution of 257 g of
2-acetylthiophene in 510 ml of dimethyl carbonate was then added
dropwise within the space of 4 hours. The methanol which was formed
in the reaction was distilled off as an azeotrope. 120 ml of conc.
sulphuric acid were introduced, in 900 g of ice, into a 4 L flask
and the cooled reaction mixture was added such that 40.degree. C.
was not exceeded. The mixture was then stirred and the pH was
adjusted to pH 1. The phases were separated and the organic phase
was extracted three times by shaking with an aqueous solution of
sodium sulphate and then concentrated in vacuo. Vacuum distillation
of the crude product yielded 278 g of methyl
3-oxo-(2-thiophenyl)propanoate as a transparent, slightly yellowish
liquid (98% pure according to GC, 74% of theory).
Example 14
Preparation of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide
[0129] 23 g of methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate from
experiments described in the Examples 1 and [lacuna] were initially
introduced, and 130 ml of a 2-molar methanolic solution of
methylamine were added. This mixture is stirred at 60.degree. C.
for 4 h, cooled and then concentrated in vacuo. 24 g (purity 87%;
90% of theory) are obtained in this way. The crude product can be
used as such for the next step or else recrystallized from
methylene chloride and hexane. This yielded 18 g of
N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (75% of theory) in
the form of white crystals.
Example 15
Preparation of (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
[0130] 350 ml of dry tetrahydrofuran are initially introduced
together with 10 g of lithium aluminium hydride and heated to
reflux. At the same time, a start is made in adding 17 g of
N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide from Example 14,
dissolved in 150 g of tetrahydrofuran, dropwise. After this
dropwise addition is complete, the mixture is subsequently stirred
overnight under reflux. The mixture is then cooled down to room
temperature and 200 ml of water are carefully added dropwise. 135
ml of a 10% solution of sodium hydroxide were then added dropwise
and the solution was filtered. The solvent was removed in vacuo.
370 ml of 1 N sodium hydroxide solution were added to the crude
solution and the whole was extracted 3 times with in each case 370
ml of toluene. The organic phases are combined and the volatile
constituents are removed in vacuo, thereby providing 76 g (84%
purity, 70% of theory).
Example 16
Purification of (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
[0131] 15 g from Example 15 were dissolved in 150 ml of water at
boiling heat, after which 5 g of active charcoal were added and the
mixture was subsequently stirred under reflux for a further hour.
The suspension was filtered in the hot. The filtrate was extracted
three times with in each case 100 ml of dichloromethane. The
combined organic phases were evaporated and the residue was
dissolved, at boiling heat, in 50 ml of cyclohexane; it was then
crystallized, during cooling, using 600 ml of petroleum ether. The
crystals were filtered, washed with a little petroleum ether and
dried. This resulted in 12 g of
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol (98% purity, 93%
yield).
* * * * *