Process for the production of sitagliptin
AssigneeChemo Iberica, S.A.
InventorsMarcello Rasparini, Roberto Rocco Tufaro, Cosima Minelli
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Abstract
A novel process is described for the synthesis of Sitagliptin, IUPAC name 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 2,4-triazolo[4,3-a]pyrazine, of formula (I).
Claims19
A process for producing 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine, Sitagliptin, of formula (I)
- comprising the following steps:
- a) alkylating an acyloxazolidinone of formula (II)
- containing an Evans' chiral auxiliary, with an alkylhaloacetate or a benzylhaloacetate of formula XCH2COOR4
- obtaining an intermediate compound (III):
- b) cleaving the Evans' chiral auxiliary from intermediate (III)
- obtaining the corresponding acid (IV):
- c) transforming acid (IV)
- into isocyanate (V),
- which treated with an alkylic or arylalkylic alcohol R5—OH leads to the formation of the corresponding carbamate (VI):
- d) selectively deprotecting the ester group of carbamate (VI)
- obtaining the corresponding acid (VII):
- e) condensing the thus obtained acid (VII)
- with the triazolpiperazine (VIII)
- to yield carbamate (IX):
- f) transforming carbamate (IX)
- into Sitagliptin (I):
- in which R1, R2 and R3 are, independently from each other, hydrogen, C1-C6 alkyl, or an aromatic or alkylaromatic group;
- R4 and R5 are alkyl or benzyl;
- and
- X is a halogen,
- with the provisos that:
- at most two of the substituents R1, R2 and R3 are simultaneously hydrogen;
- and when R4 is alkyl, then R5 is benzyl, and vice versa.
(R)-4-(tert-butoxy)-4-oxo-2-(2,4,5-trifluorobenzyl)butanoic acid, (IV).
Compound of general formula (II):
- wherein R1, R2 and R3 are, independently from each other, hydrogen, C1-C6 alkyl, or an aromatic or alkylaromatic group, with the proviso that at most two of the substituents R1, R2 and R3 are simultaneously hydrogen.
Compound of general formula (III):
- wherein R1, R2 and R3 are, independently from each other, hydrogen, C1-C6 alkyl, or an aromatic or alkylaromatic group, with the proviso that at most two of the substituents R1, R2 and R3 are simultaneously hydrogen;
- and R4 is alkyl or benzyl.
Compound of general formula (V):
- wherein R4 is alkyl or benzyl.
(R)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4-(2,4,5-trifluorophenyl) butanoate, compound of formula (VI′):
Dependencies are inferred from the claim text.