反应详情

温度

27.5 °C

To a solution of 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) (1.0 eq, 28.0 gm), diisopropylethylamine (2.0 eq, 31.0 gm), 1-hydroxybenzotriazole (1.2 eq, 22.0 gm), and EDC-HCl (1.2 eq, 28.0 gm) in N,N-dimethylformamide (4.0 vol, 160.0 ml), a solution of (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) (40.0 gm, 0.12 mol) in N,N-dimethylformamide (4.0 vol, 160.0 ml) was charged at 0-5° C. within 1 hour. The clear pale yellow solution was further stirred for 12 hours at 25-30° C. After stirring for 12 hours, the N,N-dimethylformamide was distilled out completely at 55-65° C. under reduced pressure to give a brown coloured residue. The brown coloured residue was further basified with 10% Na2CO3 solution (1.0 vol, 40.0 ml) and the product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml). The combined ethyl acetate layers were washed with water, charcoalized and filtered, and the ethyl acetate was distilled out completely to give a white coloured product. The product was triturated with hexane (10.0 vol, 400.0 ml) and filtered at 25-30° C. The crude Boc-protected sitagliptin free base (12) was further purified by crystallising it from a mixture of isopropanol (20.0 vol) and water (2.0 vol).

1. stirringAfter stirring for 12 hours
2. distillationthe N,N-dimethylformamide was distilled out completely at 55-65° C. under reduced pressure
3. customto give a brown coloured residue
4. extractionthe product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml)
5. washThe combined ethyl acetate layers were washed with water
6. filtrationfiltered
7. distillationthe ethyl acetate was distilled out completely
8. customto give a white coloured product
9. customThe product was triturated with hexane (10.0 vol, 400.0 ml)
10. filtrationfiltered at 25-30° C
11. customThe crude Boc-protected sitagliptin free base (12) was further purified
12. customby crystallising it
13. additionfrom a mixture of isopropanol (20.0 vol) and water (2.0 vol)