Study On Synthesis Of Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which can be used in cure of type 2 diabetes with well curative effect and small side effect.In this paper, the preparation methods of Sitagliptin were summarized and Sitagliptin was finally synthesized from 2,4,5-Trifluorophenylacetic acid by eleven steps including C-acylation, alcoholysis reaction, hydride reduction, and so on.The mechanism of every reaction and the influence of the factors, such as raw material's ratio, reaction time, temperature, were also studied. The optimum reaction condition was obtained:C-acylation(step 1) accuring at 55℃in 3.5 h with 2,4,5-trifluorophenylacetic acid/ CDI/meldrum's acid on the ratio 1/1.3/1.1, in yield of 73.5%; Alcoholysis reaction(step 2) accuring under refluxing in 2.5 h in yield of 97.8%; Reduction(step 3) accuring in 1 MPa H2 at 80℃in 4 h with Methyl 4-(2,4,5-Trifluorophenyl)-3-oxobutanoate(5)/HBr/(S)-Binap/ RuCl3 on the ratio 1/0.1/0.002/0.002; Hydrolysis reaction(step 4) accuring with 1.1 eq. NaOH[based on (5)] in 4 h, in two-step yield of 84.5%; N-acylation(step 5) accuring at 20℃in 2 h with (S)-4-(2,4,5-Trifluorophenyl)-3-hydroxybutanoic acid(7)/BnONH2-HCl/LiOH/ EDC-HCl on the ratio 1/1.1/1/1.3; Mitsunobu reaction(step 6) accuring with 1.5 eq. PPh3 and 1.5 eq. DIAD[based on (7)] at 20℃in 18 h, in two-step yield of 70.6%; Hydrolysis reaction(step 7) accuring with (R)-N-Benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-oxoazetidine(9)/LiOH/CH3SO3H on the ratio 1/1.5/1.5; N-acylation(step 8) accuring with 1 eq. NMM,1.5 eq. EDC-HCl and 1.25 eq.3-trifluoromethyl-1,2,4-triazolo[4,3-a]piperazine hydrochloride[based on (9)]; Debenzyloxylation(step 9) accuring in 0.5 MPa H2 at 50℃in 12 h with 75 g 10%Pd/C per mole[based on (9)]; Salt-forming reaction(step 10) accuring with 0.86 eq.85 wt% phosphoric acid[based on (9)], in four-step yield of 86.0%; Neutralization(step 11) accuring with Sitagliptin phosphate/NaOH on the ratio 1/3, in yield of 88.9%. The total yield of the route was 32.8%.