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

HRID 338152Notes

Reaction equation

HRID 338152 reaction equation
N1C=CC=CC=1.[F:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH:23]C(=O)C4C=CC=CC=4)[S:19][CH2:20]3)[CH2:15]2)=[N:12][CH:13]=1.Cl.CON>C(O)C>[F:7][C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH2:23])[S:19][CH2:20]3)[CH2:15]2)=[N:10][CH:9]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762233N-[(4aR,7aS)-6-(5-Fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 78318759(4aR,7aS)-6-(5-Fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-442b932d9fe34a7795e21b86142f4a82
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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