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

HRID 338166Notes

Reaction equation

HRID 338166 reaction equation
[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[ClH:31].CON.N1C=CC=CC=1>C(O)C>[ClH:31].[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762240N-[(4aR,7aR)-6-(5-Fluoropyrimidin-2-yl)-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 78318765(4aR,7aR)-6-(5-Fluoropyrimidin-2-yl)-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine hydrochloride

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of N-[(4aR,7aR)-6-(5-fluoropyrimidin-2-yl)-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (645 mg, 1.47 mmol), O-methylhydroxylamine hydrochloride (613 mg, 7.34 mmol), and pyridine (1.16 g, 14.7 mmol) in ethanol (10 mL) is stirred at 55° C. for 4 hours. The mixture is quenched with a solution of saturated sodium bicarbonate in water and extracted with ethyl acetate. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:1) to hexane/ethyl acetate (0:1). The residue is further purified by portioning between ethyl acetate and 1 N hydrochloric acid. The acidic aqueous phase is collected and the pH is adjusted to >8 with 5 N sodium hydroxide. The basic aqueous phase is extracted with dichloromethane, dried and concentrated to give the title compound as the free base. The free base is dissolved in dichloromethane. To the solution is added a saturated solution of hydrogen chloride in dichloromethane, followed by diethyl ether (10 mL). The resulting white solid is collected by filtration to give the title compound (0.40 g, 74%). ES/MS (m/e): 336 (M+H).

Workup

  1. customThe mixture is quenched with a solution of saturated sodium bicarbonate in water
  2. extractionextracted with ethyl acetate
  3. customdried
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto give a residue
  7. customThe residue is purified by silica gel flash chromatography
  8. washeluting with hexane/ethyl acetate (1:1) to hexane/ethyl acetate (0:1)
  9. customThe residue is further purified
  10. customThe acidic aqueous phase is collected
  11. extractionThe basic aqueous phase is extracted with dichloromethane
  12. customdried
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-6e2e621022174f0c8815a50c0759f2d6
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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