Claims
- 1. A process for the separation of the (6R) and (6S) diastereoisomers of folinic acid or the calcium salt thereof of the desired high optical purity, which comprises the steps of:
- a) reacting racemic folinic acid in a liquid medium consisting of 1) water; 2) a mixture of water and a protic organic solvent which is a member selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, formamide and N-methyl-formamide; 3) water, said protic organic solvent as in 2) and a dipolar aprotic organic solvent which is dimethylformamide, dimethylacetamide, dimethylsulphoxide, N-methyl-pyrrolidone or hexamethylphosphoramide; 4) dimethyl acetamide or 5) a mixture of water and dimethyl acetamide with a basic diamine, said diamine having formula I, II or III ##STR2## wherein: R.sub.1 to R.sub.8 are the same or different, and are H or straight or branched C.sub.1-6 alkyl groups, unsubstituted or substituted by 1-4 OH groups, 1-4 alkoxy groups or hydroxyalkoxy groups,
- R.sub.9 and R.sub.10 are the same or different, and are the same as R.sub.1 or OH,
- n is 0-6, and
- m is 2-8;
- at a temperature of 5.degree.-35.degree. C. followed by cooling at 25.degree.-5.degree. C. whereby the racemic salt of folinic acid and said diamine is obtained;
- b) dissolving said racemic salt from step a) in a solvent as the solvent defined in step a) hereinabove at a temperature of 25.degree.-70.degree. C., followed by cooling to about 0.degree. C. whereby the first solid which separates upon cooling contains a major portion of a first one of the said (6R) or (6S) diastereoisomers, the major portion of the other second isomer remaining in the crystallization mother-liquors;
- c) purifying by recrystallization at least once the isomer-enriched solid from step b), from the same solvent used in said step b) until the first diastereoisomeric salt with said diamine is obtained in a desired optical purity, and then converting said salt with said diamine into the calcium salt and when free folinic acid as the first diastereoisomer is desired reacting said calcium salt with hydrochloric acid in water and cooling to precipitate said free folinic acid from said first diastereoisomer;
- d) isolating the second diastereoisomeric salt from the mother-liquors from step b).
- 2. The process according to claim 1 wherein said diamine in step a) is a member selected from the group consisting of ethylenediamine, 1,2-diaminopropane, 1,3-diamino-propane, 1,3-diamino-2-hydroxy-propane, (cis)-1,2-diamino-cyclohexane, (trans)-1,2-diamino-cyclohexane, piperazine, 2-methyl-piperazine, 1,4-dimethyl-piperazine and 2,5-dimethyl-piperazine.
- 3. The process according to claim 2 wherein said diamine in step a) is ethylene diamine and said first diastereoisomer in step b) is the (6R) diastereoisomer.
- 4. The process according to claim 2 wherein said diamine in step a) is piperazine and said first diastereoisomer in step b) is the (6S) diastereoisomer.
- 5. The process according to claim 1 wherein in step d) said second diastereoisomer is isolated from the mother liquor from step b) by concentrating said mother liquor under vacuo at 25.degree.-50.degree. C. adding calcium chloride, whereby a solid calcium folinate enriched in said second diastereoisomer is obtained and recrystallizing said solid with 10-100 volumes of water at a temperature of 0.degree.-25.degree. C. until the desired optical purity is obtained.
- 6. The process according to claim 1 wherein in step d) a dipolar aprotic solvent or a protic organic solvent as defined in step a) is added, in an amount of 0.05-5 volumes based on the volume of said mother liquor, then cooling at 0.degree.-20.degree. C. to precipitate the second diastereoisomer of said salt of the diamino folinate with a degree of purity higher than 70%, and recrystallizing said salt at least once from a mixture of water and a dipolar aprotic solvent as defined hereinabove to achieve a degree of purity higher than 99%.
- 7. The process according to claim 1 wherein in said step a) the reaction is carried out with said basic diamine in a stoichiometric amount or in molar excess not higher than 20%.
- 8. The process according to claim 1 wherein said steps b) and c) are performed in a solvent mixture consisting of the components water and one of said water-soluble dipolar aprotic organic solvents, wherein said components range, in a volumetric ratio, from 1:0.5 (v/v) to 1:20 (v/v), or said steps are performed in a solvent containing said water/water-soluble dipolar aprotic organic solvent mixture together with one of said protic organic solvents in amounts up to 70% in volume.
- 9. The process according to claim 1 wherein the weight/volume ratio between said racemic diamine folinate salts and said solvent in step b), ranges from 1:2 (w/v) to 1:60 (w/v).
- 10. The process according to claim 1 wherein the optically pure salts of folinic acid, obtained in steps c) or d), are dissolved in water and the resulting aqueous solutions are acidified by adding a mineral acid to a pH value of 1-3 at a temperature ranging from 0.degree. to 25.degree. C., wherein said (6R) or (6S) diastereoisomers of folinic acid precipitate with an O.P. higher than 99%.
- 11. A diamino-folinate which is a member selected from the group consisting of:
- Ethylenediamino (6S)-folinate;
- Piperazino (6S)-folinate;
- 1,4-dimethyl-piperazino (6S)-folinate;
- 1,3-diamino-2-hydroxy-propyl (6S)-folinate.
Priority Claims (1)
Number |
Date |
Country |
Kind |
MI92A0367 |
Feb 1992 |
ITX |
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Parent Case Info
This is a continuation of application Ser. No. 08/290,812, filed Aug. 17, 1994, now abandoned.
US Referenced Citations (9)
Foreign Referenced Citations (2)
Number |
Date |
Country |
93-15076 |
Aug 1993 |
WOX |
93-17022 |
Sep 1993 |
WOX |
Continuations (1)
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Number |
Date |
Country |
Parent |
290812 |
Aug 1994 |
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