Process for preparing chiral dipeptidyl peptidase-IV inhibitors

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.

Process for preparing chiral dipeptidyl peptidase-IV inhibitors

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:

PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:

PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

A process for the preparation of pyrazolopyrolidines of structural formula I: 111-. (canceled)13. The process of claim 12 , further comprising the step of removing the protecting group (P) of formula II.14. The process of claim 13 , further comprising the step of re-crystallizing the de-protected formula II.15. The process of claim 12 , wherein Ar is 2 claim 12 ,5-difluorophenyl and Ris methyl and wherein the salt of the compound of formula I is the BSA salt. The present invention is directed to a novel process for the preparation of pyrazolopyrolidines which are useful intermediates in making dipeptidyl peptidase-IV (DPP-4) inhibitors for the treatment of Type 2 diabetes.The present invention is directed to novel synthetic methods in the manufacture of pharmaceutically active pyrazolopyrolidines, and pyrazolopyrolidine intermediates in the manufacture of pharmaceutically active compounds. The present invention is further directed to intermediates useful in the disclosed process.The synthesis of pyrazolopyrolidines has previously been described in PCT international patent application WO 2010/056708. The syntheses taught in Intermediate 6 of WO 2010/056708 yielded a 1:1 mixture of products of formulas Ia and Ib:WO 2010/056708 taught an additional step of resolution of the desired product Ib by column chromatography.The pyrazolopyrolidines of structural formula Ib described in WO 2010/056708 are used in processes to synthesize effective DPP-IV inhibitors, such as formula IIb:A regioisomer-selective process, yielding a greater percentage of the desired pyrazolopyrolidine regioisomer product, was desired. The inventors have now discovered efficient regioisomer-selective processes, comprising sulfonylation of the pyrazolopyrolidines and isomerization of the sulfonylated pyrazolopyrolidines.This invention is concerned with a process for preparing regioisomer-selective pyrazolopyrolidines of structural formula I:wherein Ris selected from the group consisting of:Calkyl and ...

PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

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. 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 I and I′ III comprises combining the compound of formula III claim 2 , a sulfonylating agent and a suitable base in a suitable solvent.4. The process of wherein the sulfonylating agent is MsCl claim 3 , 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 claim 5 , a sulfonylating agent claim 5 , a first base in a suitable first solvent.7. The process of claim 6 , wherein the sulfonylating agent is MsCl claim 6 , the first base is TEA and the first solvent is MeTHF.8. The process of claim 5 , 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 claim 5 , 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 results in greater than 70% conversion to formula I.13. The process of claim 12 , further comprising the step of removing the protecting group of formula II.14. The process of claim 13 , further comprising the step of re-crystallizing the de-protected formula II.15. The process of wherein Ar is 2 claim 12 ,5-difluorophenyl and Ris methyl and wherein the salt of ...

Processes for the preparation of (s)-tert-butyl 4,5-diamino-5-oxopentanoate

Provided are processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof. Also provided are solid forms of various intermediates and products obtained from the processes.

Process for preparing chiral dipeptidyl peptidase-iv inhibitors

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of:  and reductive amination of:

Processes for preparing 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Provided herein are processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.

PROCESSES FOR THE PREPARATION OF (S)-TERT-BUTYL 4,5-DIAMINO-5-OXOPENTANOATE

Provided are processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof. Also provided are solid forms of various intermediates and products obtained from the processes. 6. The process of claim 5 , wherein the formaldehyde source is paraformaldehyde or 1 claim 5 ,3 claim 5 ,5-trioxane.7. The process of or claim 5 , wherein step (x) occurs in the presence of an acid.8. The process of claim 7 , wherein the acid is p-TsOH claim 7 , MsOH claim 7 , benzenesulfonic acid claim 7 , trifluoromethanesulfonic acid claim 7 , trifluoroacetic acid claim 7 , sulfuric acid claim 7 , or trichloroacetic acid.9. The process of any one of - claim 7 , wherein Ris hydrogen.10. The process of claim 9 , wherein the NH—R(i.e. claim 9 , NH) in step (a) is provided in the form of an ammonia solution in water or MeOH or in the form of gaseous ammonia.11. The process of any one of - claim 9 , wherein Ris a suitable amino protecting group.12. The process of claim 11 , wherein the deprotection of the —NH—Rgroup and the deprotection of the —NH—Rgroup in step (c) are conducted separately.13. The process of claim 11 , wherein the deprotection of the —NH—Rgroup and the deprotection of the —NH—Rgroup in step (c) are conducted simultaneously.14. The process of any one of - claim 11 , wherein Ris benzyl claim 11 , 4-methoxybenzyl claim 11 , or 3 claim 11 ,4-dimethoxybenzyl.15. The process of any one of - claim 11 , wherein Ris (S)-1-phenylethyl.16. The process of any one of - claim 11 , wherein Ris benzyl claim 11 , 4-methoxybenzyl claim 11 , 3 claim 11 ,4-dimethoxybenzyl claim 11 , benzyloxycarbonyl claim 11 , or p-methoxybenzyloxycarbonyl.17. The process of claim 16 , wherein Ris benzyloxycarbonyl.18. The process of any one of - claim 16 , wherein step (b) occurs in the presence of t-butyl 2 claim 16 ,2 claim 16 ,2-trichloroacetimidate.19. The process of any one of - claim 16 , wherein step (b) ...

Processes for preparing 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Provided herein are processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.

Processes for the preparation of (s)-tert-butyl 4,5-diamino-5-oxopentanoate

Provided are processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof. Also provided are solid forms of various intermediates and products obtained from the processes.

Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate

Provided are processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof. Also provided are solid forms of various intermediates and products obtained from the processes.

Procesos para preparar 2-(4-clorofenil)-n-((2-(2,6-dioxopiperidin- 3-il)-1-oxoisoindolin-5-il)metil)-2,2-difluoroacetamida.

La presente invención se refiere a procesos para preparar 2-(4-clorofenil)-N-((2-(2,6-dioxopiperidin-3-il)-1-oxoisoindolin- 5-il)metil)-2,2-difluoroacetamida.

Processes for preparing 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Processes for the preparation of (s)-tert-butyl 4,5-diamino-5-oxopentanoate

Provided are processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof. Also provided are solid forms of various intermediates and products obtained from the processes.