1,2-Dichloroethane → ((2R,5R)-5-{5-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

HRID 2196291Notes

Reaction equation

HRID 2196291 reaction equation
[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 666658465-Cyano-3-methylpyridine-2-carboxylic acidHCID 66666212[(2R,5R)-5-(5-Amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 66665686((2R,5R)-5-{5-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (2.2 g, 5.43 mmol) in DMF (20 ml) was added at 0-5° C. 5-cyano-3-methyl-pyridine-2-carboxylic acid (0.968 g, 5.97 mmol), EDC (1.095 g, 7.05 mmol), HOAt (1.182 g, 8.68 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was added to cold saturated NaHCO3 solution and the product was extracted with TBME. Combined TBME layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain after crystallization from diisopropylether the title compound as colorless crystals: UPLC RtH5=1.472 min); ESIMS: 550; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 10.11 (s, 1H), 8.79 (br s, 1H), 8.01 (s, 1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.21 (dd, 1H), 4.49 (d, 1H), 4.16 (d, 1H), 1.76 (s, 3H), 1.64 (s, 3H), 1.62 (s, 9H).

Workup

  1. extractionthe product was extracted with TBME
  2. washCombined TBME layers were washed with H2O and brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto obtain
  7. customafter crystallization from diisopropylether the title compound as colorless crystals
  8. customUPLC RtH5=1.472 min

Sources & evidence

ORD record
ord-21ea29526cb2417f9c6f912b4a54b4a4
Source dataset
uspto-grants-2012_12
Patent number
US08338413B1

Reaction notes

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