868071-16-3

Upstream product

• 769195-26-8 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 209995-38-0 (2,4,5-trifluorophenyl)acetic acid 

Downstream Products

• 868071-17-4 3(S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoic acid 
• 1256815-04-9 N-benzyloxy-4-(2,4,5-trifluorophenyl)-3(S)-hydroxybutanamide 
• 654671-78-0 sitagliptin phosphate 
• 767352-29-4 (R)-3-((benzyloxy)amino)-4-(2,4,5-trifluorophenyl)butanoic acid 

Relevant academic research and scientific papers

Preparation method of sitagliptin phosphate

The invention discloses a preparation method of sitagliptin phosphate. The preparation method comprises the following steps: taking 4-(2, 4, 5-trifluorophenyl)-3-methyl oxobutyrate I as a raw material; the reaction is mainly divided into five steps: carrying out asymmetric reduction on the raw material I through an N-heterocyclic carbene palladium catalyst to obtain chiral alcohol ester s-4-(2, 4,5-trifluorophenyl)-3-methyl hydroxybutyrate II; carrying out intramolecular condensation cyclization on the II to obtain chiral lactam quaternary ring (R)-N-benzyloxy-4-[1-methyl-(2, 4, 5-trifluorophenyl)]-2-azetidinone III; carrying out ring opening on the III under an alkaline condition to obtain IV; performing condensation reaction to form amide to obtain V; carrying out catalytic reduction onthe V through recycled N-heterocyclic carbene palladium to remove benzyloxy and form phosphate to obtain sitagliptin phosphate VI, wherein the N-heterocyclic carbene palladium catalyst is Pd (IPr-NHC) (acac) Cl or Pd (IPr-NHC) (acac) Oac or Pd (IPr-NHC) (dba) Cl or Pd (IPr-NHC) (dba) OAc; the catalyst is cheap and easily available, can be recycled, and is beneficial to batch production.

PROCESSES FOR THE PREPARATION OF R-SITAGLIPTIN AND INTERMEDIATES THEREOF

The present invention relates to the synthesis of R-sitagliptin. The present invention also relates to a compound of formula (IV) or its salt, that are useful as key intermediate in the synthesis of R-sitagliptin or pharmaceutically acceptable salts thereof.

Highly efficient asymmetric transfer hydrogenation of ketones in emulsions

Ru-TsDPEN (TsDPEN = N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine) catalyzed asymmetric transfer hydrogenation of ketones in emulsions is reported for the first time. The new protocol provides markedly enhanced activity and enantioselectivities (up to 99% ee) as compared with results when performed either in an aqueous medium or in common organic solvents.

First generation process for the preparation of the DPP-IV inhibitor sitagliptin

A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.