Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1993-04-16
1996-01-30
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560126, 562504, 562508, C07C 6974
Patent
active
054881366
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a new process by which nonracemic 3-oxocyclopentane- or 3-oxocyclohexanecarboxylic acids or their esters with lower alcohols can be racemized to the corresponding racemic acids or esters.
Pure enantionmers of 3-oxocycloalkanecarboxylic acids are required e.g. for the production of hetrazepines which can be used as drugs. As during the synthesis of those acids racemates are formed a resolution of the racemates is necessary. In order that also the unsuitable enantiomer can be utilized it has to be racemized and then be subjected to resolution of racemate.
The invention solves the problem to convert enantiomers or nonracemic mixtures of enantiomers of 3-oxocycloalkanecarboxylic acids or of their esters with lower alcohols into the racemates.
In this manner particularly the unsuitable enantiomers or nonracemic mixtures of enantiomers remaining after the resolution of the racemates mentioned above can be processed into a useful product.
Racemization of nonracemic 3-oxocycloalkanecarboxylic acids or their esters is not possible by usual methods e.g. by treatment with bases because condensation products are formed.
It has now be found a process by means of which enantiomeres or nonracemic mixtures of enantiomers of 3-oxocyclopentane- or 3-oxocyclohexanecarboxylic acids or of their C.sub.1 -C.sub.6 -alkyl esters can surprisingly be transformed into the corresponding racemates.
The process is characterized in that the enantiomer or the nonracemic mixture of enantiomers is first esterified in an alcohol with an orthoformic acid lower alkyl ester in the presence of a catalytical amount of a strong acid (if the starting material is not yet an ester) and then ketalized, the resulting product is racemized by means of an alcoholate and subsequently hydrolized to form the racemic acid or the racemic ester followed by isolating of the racemic compounds according to usual methods.
The steps of the process are advantageously performed without isolation of intermediates.
The alcohol to be used is an aliphatic alcohol with 1-6 C-atoms, preferably methanol, ethanol, propanol. It is prefered to use orthoformic acids and alcoholates derived from the same alcohol which is used as reaction medium.
As catalysts there are used the acids usual for these purposes (strong mineral acids such as sulfuric acid, hydrochloric acid, toluene sulfonic acid, methane sulfonic acid).
The manufacture of the ketals is carried out preferably at the boiling temperature of the reaction mixture. The hydrolysis of the ketal group (to form the ester) is carried out at room temperature or with cooling. If the ester group shall be hydrolized too this is carried out under reflux temperature.
An example for carrying out each of the process variants which the expert, if desired, can easily modify will now be given.
EXAMPLE 1
318.36 g (3 mol) of trimethylorthoformate are added gradually to a solution of 128.2 g (1 mol) of nonracemic 3-oxocyclopentanecarboxylic acid and 11.4 g (0.06 mol) of p-toluene sulfonic acid hydrate in 380 ml of methanol within 5-10 minutes while stirring, The mixture is heated and during 25 minutes a mixture of formic acid methyl ester and methanol is distilled off (about 185 g of distillate), Thereafter 29 g of 30% sodium methylate solution (0.16 mol) are added and the reaction mixture is kept boiling under reflux for 2 hours; methanol is distilled off, the residue cooled to 10.degree. C. and dissolved by adding 230 ml of methylene chloride and 200 ml of water. By adding 5% sulfuric acid the mixture is adjusted to pH 1.4 and stirred at 10.degree. C. for 30 minutes. The methylene chloride phase is separated and the aqueous phase extracted again with 100 ml of methylene chloride. The combined organic phases are stirred with 50 ml of water, separated and the solvent is distilled off in vacuo. The residue is fractionated in vacuo.
Main fraction: 13.4 g; bp.sub.23 mbar: 110.degree. C.; 92% of theory. In a polarimeter a sample showed an angle of rotation of 0.degree..
EXAMPLE 2
As described in Example 1 7.11 g (0
REFERENCES:
Abstract to JP, A, 6446, 01 Jan 1989, Azumai, T.
Boehringer Ingelheim KG
Dees Jos,e G.
Devlin M-E. M.
Jones Dwayne C.
Raymond R. P.
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