GB1569486A - Racemisationof 6-oxo-2-piperidine-carboxylic acid entantiomers - Google Patents

Description

(54) RACEMIZATION OF 6-OXO-2-PIPERIDINE-CARBOXYLIC ACID ENANTIOMERS (71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United States of America, of Rahway, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement: The present invention is concerned with racemization of an enantiomer of 6-oxo-2piperidine carboxylic acid.

Racemic-d, 1-6-oxo-2-piperidine carboxylic acid may be separated into its individual isomers (entantiomers) by direct resolution using quinine as the resolving agent. This process is described and claimed in the specification of our copending Application No.

52292/77 (Serial No. 1569485). Whether the 1- or d-isomer is the desired product, the other isomer is necessarily a yield-lowering (50%) by-product. It is advantageous if the undesired by-product enantiomer can be racemized for recycling in the resolution process.

A straightforward process for racemizing the enantiomers of 6-oxo-2-piperidine carboxylic acid has now been discovered and the present invention provides a method of racemizing an enantiomer of 6-oxo-2-piperidine carboxylic acid by heating it to a temperature substantially above its melting point in an inert atmosphere.

6-Oxo-2-piperidine carboxylic acid has the formula:

It is also referred to as homopyrrolidonecarboxylic acid (HPCA).

The preferred racemization temperature for the d-isomer is not less than 205"C, particularly in the range 205C - 250"C. The time required to effect complete racemization is ;dependent on the temperature at which the enantiomer is heated; a longer time being required at a lower temperature and vice versa.

The inert atmosphere can be, for example, nitrogen or helium.

The individual isomers as well as the racemate are useful for preparing tripeptides described in U.S. 3,959,248.

Following are examples illustrating the resolution of d, 1-6-oxo-2-piperidine carboxylic -acid (HPCA), the racemization of the d-enantiomer for recycling to the resolution and the racemization of l-enantiomer. All temperatures are in "C unless otherwise indicated.

Example I A. Preparation of d-HPCA quinine salt Dissolve 2.27 g of anhydrous quinine in 208 ml of acetonitrile with warming and add a suspension of 1 g of dl-HPCA in 180 ml of warm acetonitrile. Seed with the quinine salt of d-HPCA and allow to crystallize at room temperature. When crystallization is complete, filter and wash with two 5-ml portions of acetonitrile and air dry the precipitate. The yield is 1.71 g, mp 213.5-215.5 dec.

B. Preparation of l-HPCA quinine salt Concentrate the combined mother liquors and wash from the previous step to 25 ml, add 0.25 ml of water and seed with the quinine salt of l-HPCA. Allow to crystallize at room temperature. Filter and wash with two 3-ml portions of acetonitrile and air dry the precipitate. The yield is 1.19 g of solvated product, mp 180-183 .

To purify, disperse 1 g in 67 ml of acetonitrile containing 1% water warmed to 39 and filter the solution from a trace of insoluble material. Concentrate the filtrate to 11.5 ml, seed with l-HPCA quinine salt and allow to crystallize at room temperature. Filter and wash with three 2-ml portions of acetonitrile and air dry the precipitate. The yield is 0.8759g. Mp 159-160"C, resolidifying and remelting at 182-184". The material may be desolvated by heating in vacuo at 1000. The rotation (dry basis) [a]2l = -140.2", C = 2 in 6N HC1.

C. Preparation of l-HPCA Dissolve 0.6495 g of 1-HPCA quinine salt in 19.5 ml of water and make the solution alkaline with 1 ml of 2.5N NaOH. Filter the precipitated quinine after it becomes granular.

Acidify the filtrate with 0.85 ml of 2.5N HC1 and evaporate to a residue. Extract the residue with anhydrous ethanol and concentrate the extract to a residue. Dissolve the residue in a small amount of water and allow the l-HPCA to crystallize. Filter and wash with water, and vacuum dry at room temperature. The yield is 0.1306 g of partially solvated material. [a] = +35.3 , C = 2 in 6N HC1 or +39.0 corrected for solvation.

Example 2 A. Preparation of d-HPCA Dissolve 22.21 g. of crude d-HPCA quinine salt in 30 parts of water and make the solution alkaline with 60 ml of 2.5N NaOH. Filter off the precipitated quinine after it becomes granular. Acidify the filtrate with 15 ml of conc. HC1 and concentrate the solution to a residue. Extract the residue, portionwise, with a total of 125 ml of boiling absolute ethanol and concentrate the extracts to a residue. Dissolve the residue in 9 ml of water and allow to crystallize. Filter off the precipitated hydrate of d-HPCA, wash with 2 ml of water and air dry. The yield is 1.87 g. Crop I. Obtain a further crop by concentration of the mother liquors, and additional material by known chromatographic procedures for a total of 4.09 g.

B. Racemization of d-HPCA Heat 100 mg of the d-HPCA obtained as above under a slow stream of nitrogen in an oil bath (250 ) four minutes and cool to a glass. Triturate the residue under ethanol until the glass changes to a flocculent precipitate. Remove the ethanol in vacuo to obtain a residue of dl-HPCA, [cr]D = 0.00, m.p. 160-172", IR matching that of anhydrous d-HPCA.

C. Racemization of l-HPCA l-HPCA is racemized using substantially the same procedure as used for racemizing d-HPCA.

WHAT WE CLAIM IS: 1. A method of racemizing an enantiomer of 6-oxo-2-piperidine carboxylic acid that comprises heating the enantiomer to a temperature substantially above its melting point in an inert atmosphere.

2. A method as claimed in Claim 1, in which the enantiomer is the d-isomer and the temperature is above 205"C.

3. A method as claimed in Claim 2, in which the temperature is 205 C to 250 C.

4. A method as claimed in Claim 1, in which the enantiomer is the l-isomer.

5. A method as claimed in Claim 1, substantially as hereinbefore described in Example 2.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (5)

**WARNING** start of CLMS field may overlap end of DESC **. suspension of 1 g of dl-HPCA in 180 ml of warm acetonitrile. Seed with the quinine salt of d-HPCA and allow to crystallize at room temperature. When crystallization is complete, filter and wash with two 5-ml portions of acetonitrile and air dry the precipitate. The yield is 1.71 g, mp 213.5-215.5 dec. B. Preparation of l-HPCA quinine salt Concentrate the combined mother liquors and wash from the previous step to 25 ml, add 0.25 ml of water and seed with the quinine salt of l-HPCA. Allow to crystallize at room temperature. Filter and wash with two 3-ml portions of acetonitrile and air dry the precipitate. The yield is 1.19 g of solvated product, mp 180-183 . To purify, disperse 1 g in 67 ml of acetonitrile containing 1% water warmed to 39 and filter the solution from a trace of insoluble material. Concentrate the filtrate to 11.5 ml, seed with l-HPCA quinine salt and allow to crystallize at room temperature. Filter and wash with three 2-ml portions of acetonitrile and air dry the precipitate. The yield is 0.8759g. Mp 159-160"C, resolidifying and remelting at 182-184". The material may be desolvated by heating in vacuo at 1000. The rotation (dry basis) [a]2l = -140.2", C = 2 in 6N HC1. C. Preparation of l-HPCA Dissolve 0.6495 g of 1-HPCA quinine salt in 19.5 ml of water and make the solution alkaline with 1 ml of 2.5N NaOH. Filter the precipitated quinine after it becomes granular. Acidify the filtrate with 0.85 ml of 2.5N HC1 and evaporate to a residue. Extract the residue with anhydrous ethanol and concentrate the extract to a residue. Dissolve the residue in a small amount of water and allow the l-HPCA to crystallize. Filter and wash with water, and vacuum dry at room temperature. The yield is 0.1306 g of partially solvated material. [a] = +35.3 , C = 2 in 6N HC1 or +39.0 corrected for solvation. Example 2 A. Preparation of d-HPCA Dissolve 22.21 g. of crude d-HPCA quinine salt in 30 parts of water and make the solution alkaline with 60 ml of 2.5N NaOH. Filter off the precipitated quinine after it becomes granular. Acidify the filtrate with 15 ml of conc. HC1 and concentrate the solution to a residue. Extract the residue, portionwise, with a total of 125 ml of boiling absolute ethanol and concentrate the extracts to a residue. Dissolve the residue in 9 ml of water and allow to crystallize. Filter off the precipitated hydrate of d-HPCA, wash with 2 ml of water and air dry. The yield is 1.87 g. Crop I. Obtain a further crop by concentration of the mother liquors, and additional material by known chromatographic procedures for a total of 4.09 g. B. Racemization of d-HPCA Heat 100 mg of the d-HPCA obtained as above under a slow stream of nitrogen in an oil bath (250 ) four minutes and cool to a glass. Triturate the residue under ethanol until the glass changes to a flocculent precipitate. Remove the ethanol in vacuo to obtain a residue of dl-HPCA, [cr]D = 0.00, m.p. 160-172", IR matching that of anhydrous d-HPCA. C. Racemization of l-HPCA l-HPCA is racemized using substantially the same procedure as used for racemizing d-HPCA. WHAT WE CLAIM IS:

1. A method of racemizing an enantiomer of 6-oxo-2-piperidine carboxylic acid that comprises heating the enantiomer to a temperature substantially above its melting point in an inert atmosphere.

2. A method as claimed in Claim 1, in which the enantiomer is the d-isomer and the temperature is above 205"C.

3. A method as claimed in Claim 2, in which the temperature is 205 C to 250 C.

4. A method as claimed in Claim 1, in which the enantiomer is the l-isomer.

5. A method as claimed in Claim 1, substantially as hereinbefore described in Example 2.