Lithiumtriethylborohydride → N-[(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 2168281Notes

Reaction equation

HRID 2168281 reaction equation
C([BH-](CC)CC)C.[Li+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH2:34]F)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:25]2>O1CCCC1.ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH3:34])[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[N:25]2

Participants

5

Reactant 2

HCID 23664628LithiumtriethylborohydrideHCID 86762647N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762649N-[(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamideYield 106.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Lithium triethylborohydride (1.13 mL, 1.13 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (60 mg, 0.11 mmol) in tetrahydrofuran (4 mL). The reaction mixture was allowed to stir at room temperature for 16 hours and then partitioned between ethyl acetate (25 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted further with ethyl acetate (3×25 mL). The combined organics were then washed sequentially with water (100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a white solid. The organic crude was re-dissolved in dichloromethane (20 mL) and the resulting solution was washed with 1 N sodium hydroxide (3×25 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the product as an orange solid (60 mg), which was taken directly to the following step. LCMS m/z 514 [M+H+].

Workup

  1. custompartitioned between ethyl acetate (25 mL)
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted further with ethyl acetate (3×25 mL)
  4. washThe combined organics were then washed sequentially with water (100 mL) and with brine (100 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customto yield a white solid
  9. washthe resulting solution was washed with 1 N sodium hydroxide (3×25 mL), water (100 mL), and brine (100 mL)
  10. dry with materialThe organic layer was dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-167f043943fe405ab21ce145524394e8
Source dataset
uspto-grants-2015_06
Patent number
US09045498B2

Reaction notes

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