Sodium Iodide → N-((4aS,7aS)-7a-(5-Amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

HRID 2060755Notes

Reaction equation

HRID 2060755 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.FC(F)(F)C([NH2:31])=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.O.CO>[NH2:31][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1

Participants

9

Reactant 5

HCID 5238Sodium IodideHCID 11430Potassium CarbonateHCID 438061,2-Diaminocyclohexane, trans-HCID 67717TrifluoroacetamideHCID 57504885HCID 57504885, compound

Product 1

HCID 57504887N-((4aS,7aS)-7a-(5-Amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamideYield 49.9%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
22 °C

Procedure

To a 2 L round bottom flask is added N-((4aS,7aS)-7a-(5-bromo-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (35.0 g, 80.4 mmol), trifluoroacetamide (16.2 g, 143 mmol), copper(I) iodide (2.66 g, 13.7 mmol), sodium iodide (21.3 g, 141 mmol) and potassium carbonate (21.5 g, 153 mmol). The flask is capped with a septum, vacuum and back filled with nitrogen. 1,4-dioxane (731 mL) (previously degassed with vacuum-nitrogen) is added via cannula, and N,N′-dimethyl-, trans (+/−) 1,2-cyclohexanediamine (10.1 g, 70.8 mmol) is added. The mixture is placed in a preheated oil bath at 100° C. and stirred at this temperature for 19 h. The septum is replaced by a reflux condenser and a mixture of methanol (154 mL) and water (154 mL) is added through the condenser. The mixture is stirred at 100° C. for 3.5 h, cooled to 22° C., and concentrated partially under reduced pressure (to 0.6 L volume). Aqueous ammonium hydroxide (25%, 154 mL) is added and the mixture is stirred for 10 min. The mixture is extracted three times with ethyl acetate (3×500 mL) and the solvent is removed under reduced pressure. A residue is obtained that is purified by flash chromatography with a linear gradient of 50% to 75% ethyl acetate in hexane to give the title compound (14.9 g, 47%). ES/MS m/e: 372 (M+1).

Workup

  1. customThe flask is capped with a septum, vacuum
  2. additionback filled with nitrogen
  3. custom1,4-dioxane (731 mL) (previously degassed with vacuum-nitrogen)
  4. additionis added
  5. customThe mixture is placed in a preheated oil bath at 100° C.
  6. customThe septum is replaced by a reflux condenser
  7. additionis added through the condenser
  8. stirringThe mixture is stirred at 100° C. for 3.5 h
  9. concentrationconcentrated partially under reduced pressure (to 0.6 L volume)
  10. additionAqueous ammonium hydroxide (25%, 154 mL) is added
  11. stirringthe mixture is stirred for 10 min
  12. extractionThe mixture is extracted three times with ethyl acetate (3×500 mL)
  13. customthe solvent is removed under reduced pressure
  14. customA residue is obtained
  15. customthat is purified by flash chromatography with a linear gradient of 50% to 75% ethyl acetate in hexane

Sources & evidence

ORD record
ord-cadae58793e44ec5a256aafea856697c
Source dataset
uspto-grants-2012_10
Patent number
US08278441B2

Reaction notes

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