Acetonitrile → HCID 71008637, compound

HRID 1626094Notes

Reaction equation

HRID 1626094 reaction equation
[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br.C(#N)C>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]

Participants

5

Reactant 3

HCID 6342Acetonitrile3×HCID 10476Cyanogen Bromide3×HCID 71008696HCID 71008696, compound

Product 1

HCID 71008637HCID 71008637, compoundYield 67%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (542 mg, 2.28 mmol) and cyanogen bromide in acetonitrile (5M; 685 μl, 3.43 mmol) in ethanol (14 ml) was heated at 75° C. for 7 hours. In order to complete the reaction another volume of cyanogen bromide in acetonitrile (5M; 228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 6 hours, and again cyanogen bromide in acetonitrile (228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 24 hours. For the workup, the solution was evaporated, the residual oil was washed once with a solution of sodium carbonate (2M) and twice with ethyl acetate, then dried over sodium sulphate, filtered and concentrated at reduced pressure. The light yellow oil (731 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (404 mg, 67% yield) was obtained as a colorless oil. MS (ISP): m/z=263.2 [M+H]+.

Workup

  1. additionwas added
  2. temperatureheating
  3. temperatureheating
  4. waitcontinued at 75° C. for 24 hours
  5. customFor the workup, the solution was evaporated
  6. washthe residual oil was washed once with a solution of sodium carbonate (2M) and twice with ethyl acetate
  7. dry with materialdried over sodium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated at reduced pressure
  10. customThe light yellow oil (731 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent

Sources & evidence

ORD record
ord-314afffe334149df98d135bc72a23f55
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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