反应详情

To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH2Cl2 (100 mL), was added TFA (41.8 mL) and the mixture stirred at rt for 1 h. Concentrated in vacuo and partitioned between 2M NaOH(aq) (300 mL) and CH2Cl2 (200 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (2×200 mL). The organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown foam. The foam was dissolved in CH2Cl2 (50 mL) and was added simultaneously portionwise with sat.NaHCO3(aq) (50 mL) to a vigourously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH2Cl2 (50 mL) at rt. The resulting biphasic mixture was stirred at rt for 1 h. Further propionyl chloride (0.566 g, 6.12 mmol) was added and continued stirring vigorously for 20 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give a brown gum. The gum was stirred in EtOAc (100 mL) and the resulting solid filtered (9.4 g). The mother liquors were concentrated in vacuo and purified by column chromatography through a Biotage® amino silica gel eluting with EtOAc/MeOH, 100/0 to 90/10 to give a yellow foam which was then stirred in EtOAc (20 mL) and the resulting solid filtered (870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1 h. Filtered to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (9.42 g, 76% yield). 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.05 (m, 3H) 1.87-2.32 (m, 4H) 2.77-2.86 (m, 2H) 3.25-3.88 (m, 6H) 3.93 (s, 3H) 3.98 (s, 2H) 4.55-4.80 (m, 1H) 6.70-6.80 (m, 1H, N—H) 7.86-7.92 (m, 1H) 8.27-8.33 (m, 1H) 8.33-8.37 (m, 1H) LCMS: [M+H]+=451.0, Rt(6)=1.49 min.

1. concentrationConcentrated in vacuo
2. custompartitioned between 2M NaOH(aq) (300 mL) and CH2Cl2 (200 mL)
3. customThe organic phase was separated
4. extractionthe aqueous phase extracted with CH2Cl2 (2×200 mL)
5. dry with materialdried (MgSO4)
6. customevaporated in vacuo
7. customto give a brown foam
8. additionwas added simultaneously portionwise
9. customat rt
10. stirringThe resulting biphasic mixture was stirred at rt for 1 h
11. stirringcontinued stirring vigorously for 20 min
12. customThe organic layer was separated
13. extractionthe aqueous layer extracted with CH2Cl2 (100 mL)
14. dry with materialdried (MgSO4)
15. concentrationconcentrated in vacuo
16. customto give a brown gum
17. filtrationthe resulting solid filtered (9.4 g)
18. concentrationThe mother liquors were concentrated in vacuo
19. custompurified by column chromatography through a Biotage® amino silica gel eluting with EtOAc/MeOH, 100/0 to 90/10
20. customto give a yellow foam which
21. filtrationthe resulting solid filtered (870 mg)
22. stirringstirred
23. temperaturein refluxing EtOAc (50 mL) for 1 h
24. filtrationFiltered