反应详情

温度

50 °C

To a solution of crude [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (assumed 39.73 g, 69.74 mmol) in MeOH (350 mL) was added 10% Pd/C (50% water, 7.9 g). The suspension was hydrogenated under balloon pressure for 3 h, and was then filtered through two glass fiber filters with MeOH washings. The resulting solution was concentrated in vacuo to a volume of approximately 70 mL, and was then diluted with EtOAc (500 mL). The solution was concentrated in vacuo to remove approximately 100 mL of solvent. The resulting solid was collected by vacuum filtration, and washed well with EtOAc followed by hexanes. The mother liquor was concentrated in vacuo, and then diluted with EtOAc (200 mL). The mixture was concentrated in vacuo to approximately 50% volume, and the resulting solid was collected by vacuum filtration and washed well with EtOAc followed by hexanes. The two batches of solid were combined and placed under high vacuum overnight. To this material was then added approximately 466 mg of material prepared through a similar sequence, and the combined batch was heated at 50° C. under high vacuum overnight to afford [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (28.27 g, 83% yield for 2 steps). LC/MS: (M+H)+: 480.3. The resulting solid was analytically characterized and found to be polymorphic form, Form 1.

1. filtrationwas then filtered through two glass fiber filters with MeOH washings
2. concentrationThe resulting solution was concentrated in vacuo to a volume of approximately 70 mL
3. additionwas then diluted with EtOAc (500 mL)
4. concentrationThe solution was concentrated in vacuo
5. customto remove approximately 100 mL of solvent
6. filtrationThe resulting solid was collected by vacuum filtration
7. washwashed well with EtOAc
8. concentrationThe mother liquor was concentrated in vacuo
9. additiondiluted with EtOAc (200 mL)
10. concentrationThe mixture was concentrated in vacuo to approximately 50% volume
11. filtrationthe resulting solid was collected by vacuum filtration
12. washwashed well with EtOAc
13. customplaced under high vacuum overnight
14. additionTo this material was then added approximately 466 mg of material
15. customprepared through a similar sequence