Process for preparing chiral dipeptidyl peptidase-iv inhibitors

Patent metadata

Field	Value
Publication number	US-2017158701-A1
Application number	US-201515325100-A
Country	US
Kind code	A1
Filing date	Jul 16, 2015
Priority date	Jul 21, 2014
Publication date	Jun 8, 2017
Grant date	—

Abstract

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

First claim

What is claimed is:

1 . A process for preparing a compound of structural Formula Ia:

comprising reacting a compound of Formula 1 with TFA:

to produce a TFA salt of a compound of Formula 1a:

 and
reacting the TFA salt of a compound of Formula 1a with a compound of Formula 7 under reductive amination conditions:

to produce the compound of Formula Ia.

2 . The process of claim 1 , wherein the process is done as a through process.

3 . The process of claim 1 , further comprising the step of crystallizing Formula Ia.

4 . The process of claim 1 , wherein the amount of TFA is 1-5 volumes.

5 . The process of claim 1 , wherein the amount of TFA is 3 volumes.

6 . A process of preparing a compound of structural Formula I:

comprising reacting a compound of Formula 1 with TFA:

to produce a TFA salt of a compound of Formula 1a:

reacting the TFA salt of a compound of Formula 1a with a compound of Formula 7 under reductive amination conditions:

to produce a compound of Formula Ia;

 and
removing the Boc group of Formula Ia to produce the compound of Formula I.

7 . The process of claim 6 , wherein the compound of Formula Ia is crystallized prior to removing the Boc protecting group.

8 . A process of preparing a compound of Formula 7

comprising reacting 2,4-difluorobenzaldehyde and nitromethane in the present of a copper salt, ligand, base and solvent to produce a compound of Formula 17:

9 . The process of claim 8 further comprising the step of reacting the compound of Formula 17 with acrolein in the presence of a base and solvent to produce a compound of Formula 18:

10 . The process of claim 9 further comprising the step of reacting the compound of Formula 18 with a chlorinating agent in the presence of a base and a solvent to produce a compound of Formula 19:

11 . The process of claim 10 further comprising the step of crystallizing the compound of Formula 19 under basic conditions to produce a compound of Formula 19t:

12 . The process of claim 11 further comprising the steps of reacting the compound of Formula 19t with a hydroborating agent and an oxidant to product a compound of Formula 20:

and
reacting the compound of Formula 20 with a reducing agent and a protecting group to produce a compound of Formula 21:

13 . A process of making the compound of Formula 12:

comprising reacting the compound of Formula 13 and (R) 2 NH, wherein R is C 1 -C 6 alkyl in the presence of Raney Ni, Pd or Pt catalyst in methanol or aqueous methanol:

to produce a compound of Formula 14:

reacting the compound of Formula 14 with hydrazine to produce a compound of Formula 15:

 and
treating the compound of Formula 15 with pTsOH or MsOH to produce the compound of Formula 12:

14 . A process of making a compound of Formula 15

comprising hydrogenation of a compound of Formula 13

using hydrazine.

15 . The process of making a compound of Formula 1 comprising reacting a compound of Formula 10 with a copper salt in the presence of a metal catalyst, a ligand, a base and an oxidant in solvent:

to produce the compound of Formula 1:

Assignees

• Merck Sharp & Dohme

Inventors

• Chung John Y L
• Peng Feng
• Chen Yonggang
• Kassim Amude Mahmoud
• Chen Cheng-Yi
• Maust Mathew
• Mclaughlin Mark
• Zacuto Michael J
• Chen Qinghao
• Tan Lushi
• Song Zhiguo Jake
• Cao Yang
• Xu Feng

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D309/30

  Oxygen atoms, e.g. delta-lactones · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title