Water → (4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

HRID 68427Notes

Reaction equation

HRID 68427 reaction equation
[CH3:1][NH:2][NH2:3].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([CH:22]([CH:28](OC)OC)[CH:23](OC)OC)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH:33]C(=O)C2C=CC=CC=2)=[N:13]3)[CH:11]=1.S(=O)(=O)(O)O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([C:22]4[CH:23]=[N:3][N:2]([CH3:1])[CH:28]=4)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH2:33])=[N:13]3)[CH:11]=1

Participants

6

Reactant 4

HCID 962WaterHCID 1118Sulfuric AcidHCID 6061MethylhydrazineHCID 86762663N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762664(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

Methylhydrazine (0.0834 mL, 1.60 mmol) followed by water (2.2 mL) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C44) (0.65 g, 1.06 mmol) in ethanol (5 mL). Sulfuric acid (0.110 mL, 2.07 mmol) was then added in a drop-wise manner to the reaction mixture. The resulting solution was heated to 60° C. for 16 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 the resulting aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated to give a mixture of product and benzoylated product (0.79 g), which was taken directly to the following step. LCMS m/z 427.1 [M+H+] (product) and m/z 527.1 [M+H+] (benzoylated product).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate (100 mL)
  2. customThe layers were separated
  3. extractionthe resulting aqueous layer was further extracted with ethyl acetate (3×100 mL)
  4. dry with materialThe combined organic layers were then dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give

Sources & evidence

ORD record
ord-9ce8ac73911c4316abe7214c29ed2c47
Source dataset
uspto-grants-2014_09
Patent number
US08822456B2

Reaction notes

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