Pyridine → (4aR,7aS)-6-(5-Fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine

Temperature

60 °C

Pyridine (20 mL, 197 mmol) is added to a mixture of N-[(4aR,7aS)-6-(5-fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (9.5 g, 22 mmol), O-methylhydroxylamine hydrochloride (15 g, 175 mmol) in ethanol (85 mL) and the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water (100 mL) and ethyl acetate (100 mL) and the pH to 2 using 1 M hydrochloric acid. The aqueous layer is separated and the pH is adjusted to 10 using 2 M sodium hydroxide. The resulting aqueous solution is extracted with ethyl acetate (2×100 mL). The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a 5% solution of dichloromethane/2 M ammonia in methanol. Chiral Analysis of the product; column: Chiralpak AD 0.46×15 cm, 5 μm; eluent: 100% (methanol with 0.2% dimethylethylamine); flow: 0.75 ml/min at UV 254 nm; Rt=6.9 minutes. (4.6 g, 64%, >98% ee). ES/MS (m/e): 330 (M+H).

1. temperatureThe mixture is cooled to ambient temperature
2. concentrationconcentrated
3. additionThe mixture is diluted with water (100 mL) and ethyl acetate (100 mL)
4. customThe aqueous layer is separated
5. extractionThe resulting aqueous solution is extracted with ethyl acetate (2×100 mL)
6. dry with materialdried over magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. customThe crude product is purified over silica gel using a 5% solution of dichloromethane/2 M ammonia in methanol

ORD record

ord-b96efea5742744269a176c9d100652f3

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08629270B2