Trifluoroacetic acid → NB-360

HRID 39242Notes

Reaction equation

HRID 39242 reaction equation
C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 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

Product 1

HCID 66665322NB-360

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of ((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 in CH2Cl2 (0.3 ml) was added TFA (0.6 ml) and the reaction mixture was kept at 25° C. for 2 h. The reaction was added to cold 10% aqueous K2CO3 solution and the product extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated, then purified by CombiFlash (120 g silica gel, hexane —(CH2Cl2/MeOH 10:1) gradient 10:1 to 0:10) to provide 5-cyano-3-methyl-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide as a colorless foam. The amorphous 5-cyano-3-methyl-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide (2.6 g, 5.6 mmol) was dissolved in EtOH (15 mL) and after warming to 40° C. the solution was saturated with H2O (ca. 6-7 mL). The crystallization was kept for 16 h at 25° C. before the crystals were collected, washed with cold EtOH—H2O and dried under high vacuum for 16 h at 25° C. to provide the title compound as white needles: mp 101-102° C. UPLC RtH5=0.957 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): δ 10.73 (br s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 7.80 (dd, 1H), 7.73 (m, 1H), 7.16 (dd, 1H), 6.08 (s, 2H), 3.92 (d, 1H), 3.80 (d, 1H), 2.54 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H).

Workup

  1. extractionthe product extracted with EtOAc
  2. washCombined organic layers were washed with brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by CombiFlash (120 g silica gel, hexane —(CH2Cl2/MeOH 10:1) gradient 10:1 to 0:10)

Sources & evidence

ORD record
ord-85776a4003c14361b7f43609cec8e1aa
Source dataset
uspto-grants-2013_09
Patent number
US08524897B2

Reaction notes

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