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

HRID 2168289Notes

Reaction equation

HRID 2168289 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][N:35](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>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 86762654N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762656N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-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

N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C36) (0.100 g, 0.189 mmol), zinc cyanide (0.027 g, 0.227 mmol), tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.110 mmol) and N,N-dimethylformamide (6 mL) were added to an Emrys microwave reaction vial. The vial was sealed and purged with nitrogen gas for 10 minutes with stirring. After that time, the vial was placed on a Biotage microwave processor and heated to 80° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and aqueous layer was extracted further with ethyl acetate (3×50 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 51 mg, 57%. LCMS m/z 477.3 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.09 (br s, 2H), 7.83-7.87 (m, 2H), 7.40-7.59 (m, 4H), 4.97 (d, J=9.2 Hz, 1H), 4.30 (dd, J=11.7, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=12.9, 3.9 Hz, 1H), 2.82 (dd, J=13.2, 3.0 Hz, 1H).

Workup

  1. customThe vial was sealed
  2. custompurged with nitrogen gas for 10 minutes
  3. customThe reaction mixture was partitioned between ethyl acetate (100 mL)
  4. customThe layers were separated
  5. extractionaqueous layer was extracted further with ethyl acetate (3×50 mL)
  6. washThe combined organics were washed with brine (200 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-a45bfb147bed44119780ffb5feb8c5d5
Source dataset
uspto-grants-2015_06
Patent number
US09045498B2

Reaction notes

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