Process for the preparation of proline derivatives

摘要

The present invention relates in part to a process for the preparation of a proline derivative of formula I;
wherein,
R1 is C1-7-alkyl or;wherein R4 is selected from the group consisting of C1-7-alkyl, halogen-C1-7-alkyl and phenyl optionally substituted by halogen;R2 is halogen or halogen-C1-7-alkyl; and

R3 is selected from the group consisting of hydrogen, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, halogen-C1-7-alkoxy and a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, said ring being optionally substituted by C1-7-alkyl or halogen.
;The proline derivatives of the formula I are preferential inhibitors of the cysteine protease Cathepsin S and are therefore useful to treat metabolic diseases like diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease and diabetic nephropathy.

主权项

1. Process for the preparation of proline derivatives of formula Iwherein,
R1 is selected from C1-7-alkyl or from wherein R4 is selected from C1-7-alkyl, halogen-C1-7-alkyl or from phenyl which is optionally substituted by halogen; R2 is selected from halogen or halogen-C1-7-alkyl; and R3 is selected from hydrogen, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, halogen-C1-7-alkoxy or from a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, the ring which is optionally substituted by C1-7-alkyl or halogen; comprising the steps a) transforming an alcohol of formula II wherein R1 has the meaning as above with a sulfonating agent in the presence of an organic solvent at a temperature of −10° C. to 40° C. into the sulfonate of the formula III wherein R1 has the meaning as above and R5 is C1-7-alkyl, halogen-C1-7-alkyl or phenyl which is optionally substituted by C1-7-alkyl, nitro or bromo b) reacting the sulfonate of formula III with a thio compound of formula IV wherein R2 and R3 are as outlined above and R6 is hydrogen or a protecting group in the presence of lithium-, sodium- or potassium tert-butylate in an organic solvent at temperatures between 10° C. and 90° C. to form the thioether of the formula V wherein R1, R2 and R3 are as outlined above and c) oxidizing the thioether of formula V with an oxidating agent selected from peroxymonosulfate or magnesium monoperoxyphthalate hexahydrate in the presence of an organic solvent at temperature between 0° C. and 60° C. to form the proline derivative of formula I wherein R1, R2 and R3 are as outlined above and wherein the process is further characterized in that the alcohol of formula II is prepared by a1) reacting a hydroxy proline ester of formula VI wherein R7 is C1-7-alkyl with a carbonyl compound of formula VII
R1COY  VII wherein R1 is as above and Y is halogen or OH to form a carbonyl proline ester of formula IX wherein R1 and R7 are as above; b1) subsequent forming of a sulfonate of formula X wherein R1 and R7 are as above and R8 is C1-7-alkyl optionally substituted by halogen or phenyl which is optionally substituted by C1-7-alkyl, nitro or bromo and c1) converting the sulfonate of formula X in the presence of an amino cyclopropane carbonitrile of formula XI into the alcohol of formula II.