PROCESS FOR PRODUCING LOWER ALKYL ESTERS OF R-(+)-3-OXOCYCLOALKANE CARBOXYLIC ACIDS

PROCEDE D'OBTENTION D'ESTERS D'ALKYLES A CHAINE COURTE D'ACIDES R-(+)-3-OXOCYCLOALCANECARBOXYLIQUES

English Abstract

Abstract
In a process for obtaining lower alkyl esters of R-(+)3-oxocycloalkane carboxylic
acids, the corresponding racemate undergoes hydrolysis at a pH between 7 and 8 in
order to hydrolyse the unwanted enantiomer. The ester of interest can then be
isolated from the reaction medium.

Claims

- 3 -
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of R-(+)3-oxocyclopenlane - or
-hexanecarboxylic acid from racemic methyl 3-oxocyclopenlane- or
-hexanecarboxylate, characterized in that the racemate is treated in an
aqueous medium with porcine liver esterase (PLE), the acid formed by the
hydrolysis of the unwanted enantiomer or the salt of the acid is
separated off and the methyl R-(+)-3-oxocycloalkanecarboxylate is
isolated.
2. Process according to claim 1, characterized in that it is carried out at
a pH between about 7 and 8.
3. Process according to claim 1 or 2, characterized in that the reaction medium
used is water in admixture with cosolvents, preferably methanol,
dimethylformamide or dimethylsulphoxide.
4. Process according to claim 1, 2 or 3, characterized in that the reaction
temperature is 0 to 40°C.
5. Methyl R-(+)-3-oxocyclopentanecarboxylate.

Description

2~6~2~
Process for the preparation of lower alkylestars of
R~ 3-oxocycloalkanecarboxylic acid
The invention relates to a process for preparing lower alkytesters of R-(+)-
3-oxocycloalkanecarboxylic acid (where '7cycloalkane" represents cyclopentane and
cyclohexane and "lower alkyl" represents C1-4-alkyl) by enzymatic resolution of the
corresponding racemates.
The enantiomeres which may be prepared according to the invention ar~ important
starting product~ for the preparation of certain known hetrazepines which oan beused as pharmaceutical substances. When synthasisin~3 enantio-
merically pure cornpounds of this category ~ substance it is advant~geous to use 3-
oxocycloalkanecarboxylic acid esters which have the same connguration at the
optica~ly active centre as the active substance itself.
It is known to separate 3-~xocyclopentanecarboxylic acid using the optically active
base brucine (Bull. Chem. Soc. Jap. 31, 333-335 (1958)). In or~sr to prepare theestsr required for the he~razepine synthesis, the R-(+)-3-oxocyclo-
pentanecarbo~ylic acid released c~n then be converted into the ester by
conventional methods.
However, this process is not really suitable for application on an industrial scale
because brucine is highly toxic and difficult to obtain.
Aocording to the invention, the R-(+~-3-oxocycloalkanecarboxylic acid esters
can now be obtained in good yields and of suitable purity even on an industrial
scale by treating racemic 3-oxocycloalkanecarboxylic acid esters with hydrolaseswhish cleave the unwanted ester, so that the resulting acid oan readily been
separated from the desired ester and the latter can then be isolated. The new
process is appropriately carried out in a mixture o~ water and water-miscible
cosolvents such as methanol, dimethylformamide or dimethylsulfoxide at
temperatures between about 0 and ~0, prefer~bly between 5 and 30C, the pll being
malntained at betYveen about 7 and 8 by means of conventional phosphate buffer
and the addition of alkali.
Particularly suitab~e hydrolases ar~ carboxyl ester hydrolases such as porcine
pancreas lipase (PPL) or lipase from Candida cylinderaos (CCL). Porcine liver
esterase (PLE) is particularly suitable. The enzymes may ~Iso be used after being
immobilised in a manner known per se, e. 9. bound to the comrnercial product
Eupergit C (made by Rohrn Phanna of Darmstadt).
Th0 quarrffly of enzyme required is about 20 to 200 ~Jg of substrate. The substra~e
may be, in particular, the lower alkyl ester$, particularly the methyl or ethyl ester of 3-

2 ~ 4 8
oxocyclopentanecarboxylic acid and 3-oxocyclohexanacarboxylic acid.
An example of the canying out of the process, which rnay be medified if desired, will
now be given.
Preparation of methyl R-(~)-3-oxocyclopentanecarboxylate
20,000 uni~s of porcine liver esterase are added at 20C to a stirred suspension of
142.2 ~ (1 mol) of racemic methyl 3-oxocyclopentanecarboxylate in 1,~00 ml
of 0.1 rnolar phosphate buffer, pH 7.5 ~potassium dihydrogen phosphate, disodiumhydrogen phosphate). The proton concentration ~pH 7.5) is kept const~nt by adding
m~tered amounts o~ 1 N sodium hydroxide solution using an au~o~itrator. After 700 ml
of 1 N sodiurn hydroxide sohution have bean consumed the hydrolysis is stopped by
extraction*. The unreacted ester is ex~ract~d by st~rring three times wi~h 500 ml of
m~thylene chloride. The methylene chloride phase is dried o~er sodium sulphate and
filtered and the solvent is distilled off in vacuo. The residue is further processed
without distillation.
Yield: 40 ~ (56.3% of theo~ a l~ ~ + 27.44, c ~ 1.618 (methanol).
The product is sufliciently isomerically pure for hJrther processing.
~ If immobilised enzyme is used the process can be ended by flltenng off.