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. A process for preparing a compound of structural formula I:
wherein R 2 is selected from the group consisting of:
C 1-6 alkyl and C 3-6 cycloalkyl; and
W is hydrogen; P, wherein P is an amine protecting group; or
wherein R 3 is hydrogen or P, wherein P is an amine protecting group;
comprising sulfonylation of a compound of formula III:
and
isomerization of a mixture of compounds of formula I′ and formula I:
wherein the sulfonylation of a compound of formula III and isomerization of the sulfonylated formula III comprises mixing a compound of formula III with a sulfonylating agent and at least one base in at least one suitable organic solvent.
2. The process of claim 1 , wherein in the process is done as a single-step process.
3. The process of claim 2 , wherein the sulfonylation of the compound of formula III and isomerization of the intermediate mixture of sulfonylated compounds of formula I and I′ comprises combining the compound of formula III, a sulfonylating agent and a suitable base in a suitable solvent.
4. The process of claim 3 wherein the sulfonylating agent is MsCl, the base is NaHMDS and the solvent comprises a mixture of THF and DMF.
5. The process of claim 1 , wherein the process is done as a two-step process.
6. The process of claim 5 , wherein the first step is sulfonylation of the compound of formula III comprising mixing the compound of formula III, a sulfonylating agent, and a first base in a suitable first solvent.
7. The process of claim 6 , wherein the sulfonylating agent is MsCl, the first base is TEA and the first solvent is MeTHF.
8. The process of claim 7 , wherein the second step is isomerization of the mixture of compounds of formula I and formula I′ comprising mixing the mesylated compound of formula III, and a second base in a suitable second solvent.
9. The process of claim 8 , wherein the second base is KOtBu or NaHMDS and the second solvent is MeTHF or DMAc.
10. The process of claim 1 wherein greater than 70% conversion to formula I is achieved.