Dimethylformamide → N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1496739Notes

Reaction equation

HRID 1496739 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]1[O:28][CH2:27][C:13]2([C:29]3[CH:34]=[C:33](Br)[C:32]([F:36])=[CH:31][C:30]=3[F:37])[N:14]=[C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH2:17][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:28][CH2:27][C:13]2([C:29]3[CH:34]=[C:33]([C:38]#[N:39])[C:32]([F:36])=[CH:31][C:30]=3[F:37])[N:14]=[C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH2:17][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 86762635N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-bromo-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762636N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

C9 (300 mg, 0.511 mmol), zinc cyanide (72.0 mg, 0.613 mmol), tetrakis(triphenylphosphine)palladium(0) (342 mg, 0.296 mmol) and N,N-dimethylformamide (9 mL) were added to a 16 ml Emry microwave vial. The vial was sealed and purged with nitrogen for 10 minutes while stirring. The reaction was heated at 80° C. in a Biotage microwave for 120 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (1×200 mL), dried over sodium sulfate, filtered, and absorbed on silica gel. The obtained solid after removal of solvent was subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the desired product as a yellow solid. Yield: 269 mg, 0.503 mmol, 98%. LCMS m/z 534.3 [M+H+].

Workup

  1. customThe vial was sealed
  2. custompurged with nitrogen for 10 minutes
  3. customThe reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL)
  4. customThe organic was separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×50 mL)
  6. washThe combined organics were washed with brine (1×200 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. customabsorbed on silica gel
  10. customThe obtained solid after removal of solvent

Sources & evidence

ORD record
ord-db4ccdea2cd34762b7b1fe066097d7ac
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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