Details for Patent: 4,959,472
✉ Email this page to a colleague
Title: | Process for preparing substantially pure diastereoisomers of tetrahydrofolic derivatives |
Abstract: | The present invention related to the preparation of substantially pure diastereoisomers of derivatives of tetrahydrofolate and the use of such diastereoisomers. More particularly the present invention provides a process for the preparation of a desired substantially pure (6R or 6S) diastereoisomer of a derivative of tetrahydrofolic acid or salt or ester. The process comprises the steps of: attaching a chiral auxiliary group at either N-5 or N-10 of a mixture of 6R and 6S diastereoisomers of tetrahydrofolic acid, separating the new diastereoisomers, recovering the desired new diastereoisomer (6R or 6S) corresponding to the desired (6R or 6S) diastereoisomer, and converting the substantially pure new diastereoisomer recovered into the corresponding diastereoisomer. |
Inventor(s): | Wood; Hamish C. S. (Glasgow, GB6), Suckling; Colin J. (Glasgow, GB6), Rees; Lilias G. (Glasgow, GB6) |
Assignee: | University of Strathclyde (Glasgow, GB6) |
Filing Date: | Sep 01, 1989 |
Application Number: | 07/403,917 |
Claims: | 1. A process for the preparation of a desired substantially pure (6R or 6S) disastereoisomer of a derivative of tetrahydrofolic acid selected from leucovorin (5- formyltetrahydrofolic acid) or a salt or ester thereof, and 5- methyl-or 5,10-methylene or 5,10 methanol-tetrahydrofolic acid or a salt or ester thereof which process compresses the steps of: (a) attaching a chiral auxiliary group at either N-5 or N-10 of a mixture of 6R and 6S disastereoisomers tetrahydrofolic acid or of a substituted tetrahydrofolic acid or said or ester thereof, so as to form a pair of new diastereoismers, said chiral auxiliary group is one alcohol selected from the group consisting of (-) menthol, (-) boneol, (-) isoborneol; (b) separating the pair of new diastereoisomers and recovering the new diastereoisomer (6R or 6S) diastereoisomer; and corresponding to said desired (6R or 6S) diastereoisomer; and (c) converting the substantially pure new diastereoisomer so isolated into the corresponding desired substantially pure (6R or 6R) diastereoisomer of a derivative of tetrahydrofolic acid or salt or ester thereof. 2. A process according to claim 1 which includes the step or removal of the chiral auxiliary group. 3. A process according to claim 6 in which process is obtained a substantially pure (6S) diastereoisomer of 5,10-methenyltetrahydrofolic acid or a salt or ester thereof, which process includes the step of further converting the substantially pure (6S) diastereoisomer of 5,10-methenyltetrahydrofolate into a substantially pure (6S) diastereoisomer of 5-formyl-or 5-methyl tetrahydrofolic acid or salt or ester thereof. 4. A process according to claim 1 wherein said new diastereoisomer is isolated by means of solvent extraction or fractional crystallisation or chromatography. 5. A process according to claim 8 wherein said solvent extraction or fractional crystallisation is effected with a polar solvent. 6. A process according to claim 9 wherein said solvent extraction or fractional crystallisation is repeated until the recovered new diastereoisomer has a purity of greater than 90%. 7. A process according to claim 1 wherein the derivative of tetrahydrofolic acid or salt or ester thereof obtained is a substantially pure (6R) diastereoisomer of leucovorin (5-formyltetrahydrofolic acid) or said or ester thereof. 8. A process for the preparation of a desired substantially pure (6R or 6S) diastereoisomer of a derivative of tetrahydrofolic acid selected from leucovorin (5-formyltetrahydrofolic acid) or a salt or ester thereof, and 5-methyl-or 5,10-methylene or 5,10 methanol-tetrahydrofolic acid or a salt or ester thereof which process comprises the steps of: (a) attaching a chiral auxiliary group selected from (-) menthol, (-) borneol, or (-) isoborneol, at either N-5 or N-10 of a mixture of 6R and 6S disastereoisomers of tetrahydrofolic acid or of a substituted tetrahydrofolic acid or salt or ester thereof by reaction with (-) menthyl chloroformate, (-) borneol chloroformate, or (-) isoborneol chloroformate respectively, so as to form a pair of new diastereoisomers; (b) separating the pair of new diastereoisomers and recovering the new diastereoisomer (6R or 6S) diastereoisomer; and corresponding to said desired (6R or 6S) diastereoisomer; and (c) converting the substantially pure new diasteroisomer so isolated into the corresponding desired substantially pure (6R or 6S) diastereoisomer of a derivative of tetrahydrofolic acid or salt or ester thereof. |