Process for preparing optically active trimethyllactic acid...

Details Process for preparing optically active trimethyllactic acid... Process for preparing optically active trimethyllactic acid...

2001-05-24

2003-06-24

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C562S518000, C562S579000, C568S880000, C568S881000

Reexamination Certificate

active

06583312

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to a novel process for preparing optically active trimethyllactic acid and/or esters thereof by catalytic hydrogenation of trimethylpyruvic acid and/or esters thereof.
Optically active trimethyllactic acid or its esters are required, for example, as building blocks for HIV protease inhibitors (
Bioorg. Med. Chem. Lett.,
1995, 5, 1729-1734). Its synthesis is therefore of particular importance.
A number of synthesis routes are already known.
Biotechnol. Biotech.,
1986, 8-13, describes, for example, enzymatically reducing trimethylpyruvic acid in an enantioselective manner using an alcohol dehydrogenase. However, the process has the disadvantage that the reaction must be carried out in the presence of a cofactor whose regeneration is complex and expensive.
In addition, both chemical (
Bull. Chem,. Soc. Jpn.,
1968, 41, 2178-2179) and biological methods are described (
Appl. Environ. Microbio.,
1983, 45, 884-891) for the racemate resolution of trimethyllactic acid. The disadvantage of these methods is that the maximum yield for the target enantiomer, as is customary in racemate resolutions, is 50%, and the unwanted enantiomer must usually be discarded.
A further method is the diazotization of tert-leucine with subsequent hydrolysis of the diazonium compound with water (
Chem. Ber.,
1991, 124, 849-859). However, this process requires the very expensive enantiomerically pure tert-leucine and, due to unwanted rearrangement reactions, leads to by-products and is therefore uneconomic.
J. Org. Chem.,
1988, 53, 1231-1238 and
J. Org. Chem.,
1986, 51, 3396-3398 disclose the preparation of enantiomerically pure trimethyllactic esters by reducing trimethylpyruvic esters with chirally modified borane reagents. However, this process has the disadvantage that stoichiometric amounts of the borane reagent, which is expensive and complicated to synthesize, are required.
EP-A 901,997 discloses a process for preparing optically active alcohols by asymmetric hydrogenation of ketones. However, the process is restricted exclusively to aliphatic or aliphatic/aromatic ketones, hydrogenation being carried out in the presence of transition metal complex catalysts, a base, and a diamine. The transition metal complex catalysts contain bisphosphine ligands.
EP-A 643,065 discloses further specific bisphosphines which can be used for asymmetric hydrogenations in the form of their complexes with metals of Group VIII, in particular ruthenium. Suitable substrates mentioned are generally substituted or unsubstituted &agr;- or &bgr;-keto esters, &agr;- or &bgr;-keto amides, &agr;- or &bgr;-amino- or &agr;- or &bgr;-hydroxyketones and acetamidocinnamic acid derivatives. The focus of use is the asymmetric hydrogenation of 2-arylpropenoic acids.
In addition, EP-A 654,406 describes ferrocenyldiphosphines as ligands for homogeneous rhodium and iridium catalysts, which are used for the asymmetric hydrogenation of prochiral compounds containing carbon-carbon and carbon-heteroatom double bonds. Examples of such compounds are prochiral olefins, enamines, imines, and ketones.
For the sterically demanding methyl phenylpyruvate,
Tetrahedron: Asymmetry,
5, 675-690 describes an asymmetric hydrogenation in the presence of various phosphine ligands which, although they predominantly lead to very high yields, at the same time give only unsatisfactory enantiomeric excesses, some of which are in the range of only 27 or 30% ee.
The object of the present invention is thus to provide a novel process which makes possible the enantioselective preparation of optically active trimethyllactic acid and its esters with high yields and does not require the use of expensive reagents.
SUMMARY OF THE INVENTION
The invention relates to a process for preparing optically active trimethyllactic acid and/or esters thereof of formula (I)
wherein R
1
represents hydrogen, alkyl, aryl, aralkyl, or heterocyclyl, comprising enatiomerically hydrogenating trimethylpyruvic acid and/or its esters of formula (II)
wherein R
1
has the meanings specified for formula (I), in the presence of a catalyst comprising one or more noble metal complexes containing optically active bisphosphines as ligands.
DETAILED DESCRIPTION OF THE INVENTION
The inventive process makes possible the enantiomerically pure preparation of trimethyllactic acid and/or its esters of the general formula (I), where the radical R
1
represents H, alkyl, aryl, aralkyl, or heterocyclyl. The alkyl radicals in the above-mentioned substituents can in each case be unbranched or branched.
Preferably, the radical R
1
represents H, C
1
-C
20
-alkyl, C
6
-C
14
-aryl, C
7
-C
15
-aralkyl, or C
2
-C
12
-heterocyclyl. Suitable C
2
-C
12
-heterocyclyl groups can have one or more three- to- seven-membered rings having at least one ring nitrogen, oxygen, and/or sulfur heteroatom in addition to the specified number of ring carbon atoms and are preferably C
2
-C
12
-heteroaryl groups in which at least one of the rings is aromatic. Particularly preferably, R
1
represents H, C
1
-C
10
-alkyl, C
6
-C
10
-aryl, C
7
-C
11
-aralkyl or C
2
-C
9
-heteroaryl and, in particular hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, neopentyl, isopentyl, phenyl, benzyl, naphthyl, 2-furyl, 3-furyl, 2-pyrrolyl, and 3-pyrrolyl.
The alkyl, aryl, aralkyl, and heteroaryl radicals can, in addition, also be further substituted by Cl, Br, F, I, C
1
-C
4
-alkoxy, or C
1
-C
4
-alkyl.
In the inventive process, catalysts having the following enantiomerically pure bisphosphines of the general formula (B1) to (B15) can be used, for example:
(1) a bisphosphine of the general formula (B1)
where
R
2
denotes phenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, cyclohexyl, or cyclopentyl, or
(2) a bisphosphine of the general formula (B2)
where
R
3
denotes phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, or cyclohexyl, or
(3) a bisphosphine of the general formula (B3)
where
R
3
denotes phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, or cyclohexyl,
R
4
denotes H, methyl, or methoxy,
R
5
denotes H, methyl, methoxy, or chlorine, and
R
6
denotes methyl, methoxy, or trifluoromethyl, or
(4) a bisphosphine of the general formula (B4)
where
R
7
represents methyl, ethyl, propyl, or isopropyl, or
(5) 2,3-bis(diphenylphosphino)butane of the formula (B5)
(6) 1,2-bis(diphenylphosphino)propane of the formula (B6)
(7) 5,6-bis(diphenylphosphino)-2-norbornane of the formula (B7)
(8) 1-substituted 3,4-bis(diphenylphosphino)pyrrolidine of the formula (B8)
(9) 2,4-bis(diphenylphosphino)pentane of the formula (B9)
(10) 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butane of the formula (B10)
(11) 1,2-bis-[(o-methoxyphenyl)phenylphosphino]ethane of the formula (B11)
(12) 1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethanol of the formula (B12)
(13) 1-tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-methyl-pyrrolidine of the formula (B13)
(14) a bisphosphine of the general formula (B14)
where
R
8
denotes phenyl, cyclohexyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 4-tert-butyl, or 3,5-di-tert-butyl, or
(15) a ferrocenyldiphosphine of the general formula (B15)
where
R
8
has the meaning specified for formula (B14) and
R
9
denotes C
1
-C
8
-alkyl, phenyl, or phenyl monosubstituted to trisubstituted by C
1
-C
4
-alkoxy.
Suitable bisphosphines of the above-mentioned formula (B1) are.
2,2&mgr;-bis(diphenylphosphino)-1,1&mgr;-binaphthyl,
2,2&mgr;-bis(di-4-tolylphosphino)-1,1&mgr;-binaphthyl
described in
J. Org. Chem.,
1986, 51, 629.
Suitable bisphosphines of the above-mentioned formula (B3) are
(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bisdiphenylphosphine
described in EP-A 749,973
(4,4′,6,6′-tetramethyl-5,5′-dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine)
(4,4′,6,6′-tetram

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