1,2-Dichloroethane → ((S)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamic acid tert-butyl ester

HRID 221759Notes

Reaction equation

HRID 221759 reaction equation
[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH:24][C:35]([C:32]3[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=3)=[O:36])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 124007345-Cyanopyridine-2-carboxylic acidHCID 66666063[(S)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 66666436((S)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamic acid tert-butyl esterYield 98.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of [(S)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (51.2 mg, 0.137 mmol), 5-cyano-2-pyridinecarboxylic acid (30.5 mg, 0.206 mmol) and HOAT (33.6 mg, 0.247 mmol) in 0.6 mL DMF was cooled to 0-5° C. EDC (39.4 mg, 0.206 mmol) and DIPEA (35.4 mg, 0.274 mmol) were added. The resulting solution was allowed to warm up to rt over night. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1->1.5/1 to give 67.7 mg of the title compound as a colorless resin.

Workup

  1. customThe reaction mixture was then partitioned between saturated aqueous NaHCO3 solution and EtOAc
  2. customThe layers were separated
  3. washwashed with saturated aqueous NaHCO3 solution, brine and EtOAc
  4. dry with materialThe combined organic layers were dried over MgSO4.H2O
  5. customevaporated
  6. customThe crude product was purified on a silica gel column
  7. washby eluting with hexane/EtOAc 3/1->1.5/1

Sources & evidence

ORD record
ord-364b80bd10db4f5992da7282e5f2901c
Source dataset
uspto-grants-2012_06
Patent number
US08207164B2

Reaction notes

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