Ammonia → (RS)-5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

HRID 1929505Notes

Reaction equation

HRID 1929505 reaction equation
[NH3:1].[CH:2]1([C:5]2([C:12]3[CH:13]=[C:14]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=4)=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])[CH2:10][O:9][CH2:8][C:7](=S)[NH:6]2)[CH2:4][CH2:3]1.C(OO)CCC>CO>[NH2:1][C:7]1[CH2:8][O:9][CH2:10][C:5]([C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[F:18])([CH:2]2[CH2:4][CH2:3]2)[N:6]=1

Participants

5

Reactant 3

HCID 222AmmoniaHCID 123219n-ButylhydroperoxideHCID 86651226(RS)-5-chloro-pyridine-2-carboxylic acid [3-(3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide

Product 1

HCID 50992036(RS)-5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

A solution of ammonia in methanol (7 M) (5.1 ml, 35 mmol) was added to a suspension of (RS)-5-chloro-pyridine-2-carboxylic acid [3-(3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide (=5-chloro-pyridine-2-carboxylic acid [3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide) (0.240 g, 0.59 mmol) in methanol (18 ml). Thereafter, tent-butyl hydroperoxide (70% in water) (0.81 ml, 5.9 mmol) was added at room temperature and the mixture stirred for 16 hours. For the workup, the clear solution was evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a 80:10:1-mixture of ethyl acetate, methanol, and ammoniumhydroxide as the eluent. The pure fractions were combined and evaporated, then the residue was treated with a mixture of dichloromethane and water. After evaporation of the organic layer, the 5-chloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide (22) was obtained as a white solid (99 mg, 43% of theory). Mass (calculated) C19H18ClFN4O2S [388.828]; (found) [M+H]+=389.

Workup

  1. customFor the workup, the clear solution was evaporated at reduced pressure
  2. customThe residue was purified by chromatography on silica gel using a 80:10
  3. customevaporated
  4. additionthe residue was treated with a mixture of dichloromethane and water
  5. customAfter evaporation of the organic layer

Sources & evidence

ORD record
ord-a054351e9761491984246872f4d0997a
Source dataset
uspto-grants-2012_05
Patent number
US08188079B2

Reaction notes

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