Process for preparing chiral dipeptidyl peptidase-IV inhibitors
View Patent ↗A process for the preparation of pyrazolopyrolidines of structural formula I: and W is or P, wherein in P is an amine protecting group. These compounds are useful in the synthesis of dipeptidyl peptidase-IV inhibitors for the treatment of Type 2 diabetes. Also provided are useful intermediates obtained from the process.
1. The process of preparing a compound of structural formula IIa:
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
R 2 is selected from the group consisting of:
C 1-6 alkyl; and
C 3-6 cycloalkyl;
comprising the steps of:
forming a salt of formula I
wherein W is H; and
forming a compound of formula II
wherein P is an amine protecting group;
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
R 2 is selected from the group consisting of:
C 1-6 alkyl; and
C 3-6 cycloalkyl,
through reductive amination of the salt of formula I and a ketone of formula IV
wherein P is an amine protecting group;
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
R 2 is selected from the group consisting of:
C 1-6 alkyl; and
C 3-6 cycloalkyl.
2. The process of claim 1 , further comprising the step of removing the protecting group (P) of formula II.
3. The process of claim 2 , further comprising the step of re-crystallizing the de-protected formula II.
4. The process of claim 1 , wherein Ar is 2,5-difluorophenyl and R 2 is methyl and wherein the salt of the compound of formula I is the BSA salt.