反应详情

温度

-52 °C

To a dry, nitrogen purged 1 liter, 4 neck, round bottom flask, equipped with a mechanical stirrer, a nitrogen capped condenser, a thermocouple, and an addition funnel was added 3a-benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one (L)-tartrate (prepared according to Preparation One, Step D, 66.09 g, 0.168 moles, 1.12 equivalents) and ethyl acetate (660 mL, 10 volumes). A slurry formed. The slurry was agitated and cooled to an internal temperature of −68° C. to −66° C. To the cooled, agitated slurry was added triethyl amine (TEA, 58 mL, 42.5 g, 0.42 moles, 2.8 equivalents) via the addition funnel. The internal temperature was maintained at −68° C. to −66° C. during addition. The reaction mixture was agitated for about 1.5 hours while the internal temperature was warmed to about −52° C. To the reaction mixture (which was a slurry of the tartrate salt of triethylamine and the free base of 3a-benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one (L)-tartrate) was added triethylamine (96.5 ml, 70 g, 0.69 moles, 4.6 equivalents) over 5 minutes. An internal temperature of −53° C. to −50° C. was maintained during addition. To the reaction mixture was added 3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionic acid (prepared according to Preparation Three, Step B, 57.07 g, 0.150 moles, 1.0 equivalents), all in one portion. An internal temperature −55° C. to −50° C. was maintained during addition. To the reaction mixture was added propane phosphonic acid anhydride (PPAA, 180 ml, 190 g, 2.0 equivalents) as a 50% solution of propane phosphonic acid anhydride in ethyl acetate. The PPAA was added over 15 minutes and the internal temperature rose to about −30° C. during the addition. The reaction mixture was agitated at about −30° C. for about 0.5 hours. The reaction mixture was poured into a vigorously agitated mixture of diisopropyl ether (IPE, 660 mL, 10 volumes) and water (660 mL, 10 volumes). The resulting biphasic mixture was agitated for 1 hour and then the reaction mixture was allowed to settle. The aqueous portion was decanted and the organic portion was then washed sequentially with aqueous HCl (1N, 165 mL, 2.5 volumes, 1.3 equivalents), 10% aqueous Na2CO3 (330 mL, 5 volumes, 2.1 equivalents), and 15% aqueous NaCl (165 mL). The washed organic portion was concentrated in vacuo to the lowest stirrable volume and to the concentrate was added IPE (300 mL, about 5 volumes). The solution was again concentrated in vacuo to the lowest stirrable volume. To the concentrate was added IPE (330 mL, about 5 volumes) and the solution was heated atmospherically to an internal temperature of about 67° C. Precipitates were observed and the slurry was cooled to an internal temperature of about 1° C. over 1 hour with agitation. The solids were filtered and dried in vacuo at about 50° C. to afford 54.85 g of the title compound (60.4% yield).

1. customTo a dry, nitrogen purged 1 liter, 4 neck, round bottom flask
2. customequipped with a mechanical stirrer, a nitrogen capped condenser
3. customA slurry formed
4. temperaturecooled to an internal temperature of −68° C. to −66° C
5. stirringTo the cooled, agitated slurry
6. temperatureThe internal temperature was maintained at −68° C. to −66° C. during addition
7. stirringThe reaction mixture was agitated for about 1.5 hours while the internal temperature
8. temperatureAn internal temperature of −53° C. to −50° C. was maintained during addition
9. temperatureAn internal temperature −55° C. to −50° C. was maintained during addition
10. additionthe internal temperature rose to about −30° C. during the addition
11. stirringThe reaction mixture was agitated at about −30° C. for about 0.5 hours
12. stirringThe resulting biphasic mixture was agitated for 1 hour
13. customThe aqueous portion was decanted
14. concentrationThe washed organic portion was concentrated in vacuo to the lowest stirrable volume and to the concentrate
15. additionwas added IPE (300 mL, about 5 volumes)
16. concentrationThe solution was again concentrated in vacuo to the lowest stirrable volume
17. additionTo the concentrate was added IPE (330 mL, about 5 volumes)
18. temperaturethe solution was heated atmospherically to an internal temperature of about 67° C
19. customPrecipitates
20. temperaturethe slurry was cooled to an internal temperature of about 1° C. over 1 hour with agitation
21. filtrationThe solids were filtered
22. customdried in vacuo at about 50° C.