Method for producing esters of triazolopyrimidine...

Details Method for producing esters of triazolopyrimidine... Method for producing esters of triazolopyrimidine...

1999-06-14

2001-05-22

Saucier, Sandra E. (Department: 1651)

Electrical connectors

Uninterrupted support rail or uninterrupted contact

With mating part having mating connector portion and another...

C435S280000

Reexamination Certificate

active

06234811

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to a process for preparing enantiomerically pure alcohols.
Kinetic resolutions of racemic esters with lipases and esterases are described in a large number of publications and patents. Only a few studies on the resolution of racemic esters or alcohols which have a heteroaromatic radical have been published.
Thus, for example, Akita et al. (Tetrahedron Lett. 27 (1986), No. 43, 5241-5244) describe the enantioselective hydrolysis of methyl 3-acetoxy-3-(2-furyl)-2-methylpropanoates or methyl 3-acetoxy-3-(2-thienyl)-2-methylpropanoates with an Aspergillus niger lipase.
De Amici et al. describe, in J. Org. Chem. 54 (1989) 2646-2650, an enzymatically catalyzed transesterification with porcine liver esterase, Candida cylindracea lipase, chymotrypsin, subtilisin, porcine pancreatic lipase and lipase P.
Tsukamoto et al. (Tetrahedron Asym. 2 (1991), No. 8,759-762) describe the synthesis of (R)- and (S)-N,N-diethyl-2,2-difluoro-3-(2-furyl)-3-hydroxypropionamide from the corresponding esters with Candida cylindracea lipase MY and P in water.
DE/OS 3743824 and Schneider et al. (Tetrahedron Asym. 3 (1992), No. 7, 827-830) describe the preparation of 1-pyridylethanol.
The disadvantages of these methods are the low selectivity of the enzymes, the low enantiomeric purities of the products obtained, the low chemical yields, and the large amounts of enzyme required for the reaction.
An optimal racemate resolution should advantageously comply with a number of conditions, such as:
1. high enantiomeric purity of the antipodes
2. high chemical yield
3. high enzyme selectivity
4. small amounts of catalyst (amounts of enzyme)
5. good solubility of precursor and product under the reaction conditions
6. good space-time yield
7. easy purification of the products
8. low-cost synthesis.
WO 95/10521 claims 1,2,4-triazolo[1,5-a]pyrimidines, their chemical synthesis and their use in pharmaceutical compositions.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to develop a stereoselective synthesis of intermediates for 1,2,4-triazolo-[1,5-a]pyrimidines which provides these compounds advantageously with high optical purities and good chemical yields and which permits easy workup of the products.
DETAILED DESCRIPTION OF THE INVENTION
We have found that this object is achieved by a process for preparing enantiomerically pure esters of the formula I (Ia or Ib)
 where the substituents have the following meanings:
 R
1
 hydrogen or substituted or unsubstituted C
1
-C
6
-alkyl, C
3
-C
6
-alkoxy or C
1
-C
6
-alkanoyl,
 R
2
and R
3
 independently of one another hydrogen or substituted or unsubstituted C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-alkanoyl, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl or C
1
-C
6
-alkylsulfonyl,
 R
4
and R
5
 R
4
≠R
5
and independently of one another hydrogen or substituted or unsubstituted C
1
-C
6
-alkyl or R
4
and R
5
form together with the carbon atoms to which they are bonded a substituted or unsubstituted C
3
-C
6
-cycloalkylidene,
 R
6
 substituted or unsubstituted aryl, C
1
-C
20
-alkyl, C
3
-C
20
-alkenyl, C
3
-C
20
-alkynyl, C
1
-C
20
-alkoxy-C
1
-C
20
-alkyl
 which comprises converting racemic compounds of the formula II,
 where the substituents R
1
to R
5
have the abovementioned meanings, with a lipase or esterase in the presence of vinyl esters of the formula III,
 where R
6
has the abovementioned meaning, and R
7
is hydrogen or methyl, into compounds of the formula I.
R
1
in the formulae I and II is hydrogen or substituted or unsubstituted C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy or C
1
-C6-alkanoyl.
Examples of meanings for the radicals mentioned for R
1
are the following:
 alkyl branched or unbranched Cl-C
6
-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl,
 alkoxy branched or unbranched C
1
-C
6
-alkoxy chains as mentioned above, eg. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-l-methylpropoxy or 1-ethyl-2-methylpropoxy,
 alkanoyl branched or unbranched C
1
-C
6
-alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1,1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 1,1-dimethylpropanoyl, 1,2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoyl, 1,2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1,1-dimethylbutanoyl, 1,2-dimethylbutanoyl, 1,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 3,3-dimethylbutanoyl, 1-ethylbutanoyl, 2-ethylbutanoyl, 1,1,2-trimethylpropanoyl, 1,2,2-trimethylpropanoyl, 1-ethyl-1-methylpropanoyl and 1-ethyl-2-methylpropanoyl.
Suitable substituents for the alkyl, alkoxy or alkanoyl radicals mentioned for R
1
are one or more substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, mercapto, alkyl, alkoxy or aryl.
R
2
and R
3
in the formulae I and II are, independently of one another, hydrogen or substituted or unsubstituted C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-alkanoyl, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl or C
1
-C
6
-alkylsulfonyl.
Examples of meanings of the radicals mentioned for R
2
and R
3
are the following:
 alkyl branched or unbranched C
1
-C
6
-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl or 1-ethyl-2-methylpropyl,
 alkoxy branched or unbranched C
1
-C
6
-alkoxy chains as mentioned above, eg. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-l-methylpropoxy or 1-ethyl-2-methylpropoxy,
 alkanoyl branched or unbranched C
1
-C
6
-alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1,1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 1,1-dimethylpropanoyl, 1,2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoyl, 1,2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1,1-dimethylbutanoyl, 1,2-dimethylbutanoyl, 1,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 3,3-dimethyl

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