(R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid → N-Boc-sitagliptin

Beteiligte Stoffe

Reaktionsschritte

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) was coupled with 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) to obtain Boc-protected sitagliptin free base, 7-[(3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (12). The coupling was preferably carried out by using coupling agents such as EDC-HCl, 1-hydroxybenzotriazole and a suitable base such as N,N-diisopropylethylamine. The coupling was preferably carried out in an aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide at 0-30° C. for 1-12 hours, preferably at 25-30° C. for 8-10 hours. The Boc-protected sitagliptin free base (12) was preferably isolated by an aqueous work up procedure, preferably involving removal of N,N-dimethylformamide at 50-55° C. under reduced pressure followed by basification preferably using sodium carbonate, and extraction of the product into an organic solvent such as ethyl acetate. The Boc-protected sitagliptin free base (12) was preferably isolated by removal of the organic solvent under reduced pressure to obtain a white solid, which was preferably triturated with a non-polar solvent such as hexane.

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