Sitagliptin synthesis
View Patent ↗The present invention relates to novel processes for the preparation of enantiomerically enriched β-amino acid derivatives such as β-amino esters useful for the synthesis of enantiomerically enriched biologically active molecules such as sitagliptin. The key step involves the resolution of the racemate with mandelic acid.
1. A process for the preparation of enantiomerically enriched sitagliptin, or a pharmaceutically acceptable salt thereof, comprising the steps:
(i) resolving a racemic β-amino acid, or a derivative thereof, with an acid resolving agent to form an enantiomerically enriched β-amino acid or a derivative thereof;
(ii) reacting the enantiomerically enriched β-amino acid or derivative thereof with 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine or a salt thereof; and
(iii) isolating enantiomerically enriched sitagliptin;
wherein the derivative is an alkyl, alkenyl, alkynyl, aryl or arylalkyl ester.
2. A process according to claim 1 , wherein the β-amino acid derivative is
a C1 to C6 alkyl ester or a benzyl ester or substituted benzyl ester.
3. A process according to claim 1 , wherein the β-amino acid is
3-amino-4-(2,4,5-trifluorophenyl)butanoic acid or a derivative thereof,
wherein the derivative is an alkyl, alkenyl, alkynyl, aryl or arylalkyl ester.
4. A process according to claim 1 , wherein the acid resolving agent is
an enantiomer of mandelic acid, tartaric acid, camphor-10-sulphonic acid, camphor-3-sulphonic acid, 3-bromo-camphor-9-sulphonic acid, 2-keto-gulonic acid, α-methoxyphenylacetic acid, 2-nitrotartranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N-(α-methylbenzyl)succinamic acid, N-(α-methylbenzyl)phthalamic acid, quinic acid, di-O-isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulphonic acid, O,O′-di-p-toluoyl-(L)-tartaric acid, O,O′-dibenzoyl-(L)-tartaric acid, (R)-3-chloro-mandelic acid, or (R)-3-bromo-mandelic acid.
5. A process according to claim 1 , comprising the steps of:
(a) treating a racemic β-amino acid, or a derivative thereof, with an acid resolving agent, to obtain an enantiomerically enriched salt;
(b) optionally crystallising the enantiomerically enriched salt; and
(c) dissolving or suspending the enantiomerically enriched salt obtained in step (a) or (b) in an organic solvent or water or a mixture thereof, and adjusting the pH of the solution or suspension with a base to obtain an enantiomerically enriched β-amino acid or a derivative thereof,
wherein the derivative is an alkyl, alkenyl, alkynyl, aryl or arylalkyl ester.
6. A process according to claim 5 , wherein:
(i) the base used in step (c) is selected from an organic base, an inorganic base or a mixture thereof; and
(ii) step (a) is carried out in an organic solvent, optionally in the presence of water.
7. A process according to claim 1 , wherein the salt of sitagliptin is the dihydrogen phosphate salt.
8. A process according to claim 4 , wherein the enantiomer of mandelic acid is (R)-(−)-mandelic acid or (S)-(+)-mandelic acid.
9. A process according to claim 5 , wherein the acid resolving agent is (R)-(−)-mandelic acid.
10. A process according to claim 1 , wherein the β-amino acid derivative is a C1 to C6 alkyl ester.
11. A process according to claim 1 , wherein the β-amino acid derivative is a methyl or ethyl ester.
12. A process according to claim 1 , wherein the β-amino acid is methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate.
13. A process according to claim 6 , wherein the base used in step (c) is an organic base, wherein the organic base is an amine selected from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine, cyclohexylamine, or a mixture thereof.
14. A process according to claim 6 , wherein the base used in step (c) is an inorganic base, wherein the inorganic base is ammonia, a metal hydroxide, a metal carbonate, or a mixture thereof, wherein the metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide, and/or wherein the metal carbonate is sodium carbonate, lithium carbonate or calcium carbonate.
15. A process according to claim 6 , wherein step (a) is carried out in an organic solvent, optionally in the presence of water, wherein the organic solvent is an alcohol, a ketone, an ether, an alkane, a cycloalkane, a formamide, an acetate, a halogenated solvent or a mixture thereof.
16. A process according to claim 6 , wherein step (a) is carried out in an organic solvent, optionally in the presence of water, wherein the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, i-butanol, t-butanol, 2-pentanol, 3-pentanol, 4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-1-ol, glycerol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 3-octanol or a mixture thereof.