Process for preparing chiral dipeptidyl peptidase-IV inhibitor intermediates

1. A process for preparing a compound of structural formula (I):

wherein Ar is phenyl optionally substituted with one to five R 1 substituents;

each R 1 is independently selected from the group consisting of:

fluorine,

chlorine,

C 1-6 alkyl, optionally substituted with one to five fluorines, and

C 1-6 alkoxy, optionally substituted with one to five fluorines;

and P represents a primary amine protecting group;

comprising the step of treating a compound of structural formula (VII) with an oxidizing agent in a suitable solvent:

2. The process of claim 1 additionally comprising the step of producing a compound of structural formula (VII):

by hydroboration of a compound of structural formula (VI) with a borane reagent followed by oxidative work-up:

3. The process of claim 2 additionally comprising the step of producing a compound of structural formula (VI):

by subjecting a compound of structural formula (V):

to rhodium- or ruthenium-catalyzed cycloisomerization conditions in a suitable organic solvent.

4. The process of claim 3 additionally comprising the step of producing a compound of structural formula (V):

by treating a compound of structural formula (III):

in a suitable organic solvent with a source of hydrogen, a base, and a Ru(η 6 -arene)-N-sulfonyl-1,2-diamine catalyst.

5. The process of claim 4 additionally comprising the step of producing a compound of structural formula (III):

by treating a compound of structural formula (II):

with a Grignard reagent of structural formula (IV):

ArMgBr or ArMgI   (IV)

in a suitable organic solvent.

6. The process of claim 5 additionally comprising the step of producing a compound of structural formula (II):

by (i) alkylating a C 1-6 alkyl N-(diphenylmethylene)glycinate with a propargyl sulfonate or propargyl halide in the presence of base followed by treatment with acid to liberate the free primary amine; (ii) reacting said liberated primary amine with a primary amine protecting reagent in the presence of base; and (iii) treating the resulting N-protected amino acid with N,O-dimethylhydroxylamine in the presence of an activating reagent in a suitable organic solvent.

7. The process of claim 6 additionally comprising the step of isolating the compound of structural formula (I).

8. The process of claim 1 wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.

9. The process of claim 1 wherein P is t-butyloxycarbonyl.

10. The process of claim 9 wherein Ar is 2,5-difluorophenyl.

11. A process for preparing a compound of structural formula (VIII):

wherein V is selected from the group consisting of:

and R 2 and R 3 are each independent selected from the group consisting of hydrogen, C 1-3 alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl;

comprising the steps of:

(a) producing a compound of structural formula (II):

by (i) alkylating a C 1-6 alkyl N-(diphenylmethylene)glycinate with a propargyl sulfonate or propargyl halide in the presence of base followed by treatment with acid to liberate the free primary amine; (ii) reacting said liberated primary amine with a primary amine protecting reagent in the presence of base; and (iii) treating the resulting N-protected amino acid with N,O-dimethylhydroxylamine in the presence of an activating reagent in a suitable organic solvent;

(b) producing a compound of structural formula (III):

by treating a compound of structural formula (II) with a Grignard reagent of structural formula (IV):

ArMgBr or ArMgI  (IV)

in a suitable organic solvent;

(c) producing a compound of structural formula (V):

by treating a compound of structural formula (III) in a suitable organic solvent with a source of hydrogen, a base, and a Ru(η 6 -arene)-N-sulfonyl-1,2-diamine catalyst;

(d) producing a compound of structural formula (VI):

by subjecting a compound of structural formula (V) to rhodium- or ruthenium-catalyzed cycloisomerization conditions in a suitable organic solvent;

(e) producing a compound of structural formula (VII):

by hydroboration of a compound of structural formula (VI) with a suitable borane reagent followed by oxidative work-up;

(f) treating a compound of structural formula (VII) with a suitable oxidizing agent in a suitable solvent to afford a compound of structural formula (I):

wherein Ar is phenyl optionally substituted with one to five R 1 substituents;

each R 1 is independently selected from the group consisting of:

fluorine,

chlorine,

C 1-6 alkyl, optionally substituted with one to five fluorines, and

C 1-6 alkoxy, optionally substituted with one to five fluorines;

and P represents a primary amine protecting group; and

(g) converting the compound of structural (I) into a compound of structural formula (VIII).

12. The process of claim 11 wherein Ar is 2,5-difluorophenyl.