Benzoyl isothiocyanate → N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

HRID 930286Notes

Reaction equation

HRID 930286 reaction equation
Cl.[NH2:2][C@@:3]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH3:11])[CH2:4][C@H:5]([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(C(C)C)CC)(C)C.[C:29]([N:37]=[C:38]=S)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCC[N+](C)(C)C.[I-]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C@:3]2([CH3:11])[CH2:4][C@@H:5]([C:6]([F:7])([F:8])[F:9])[O:10][C:38]([NH:37][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:2]2)[CH:17]=1

Participants

7

Reactant 4

HCID 68284Benzoyl isothiocyanateHCID 81531DiisopropylethylamineHCID 1222421-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide methiodideHCID 86732117(2S,4S)-4-amino-4-(5-bromo-2-fluorophenyl)-1,1,1-trifluoropentan-2-ol hydrochloride

Product 1

HCID 86732116N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamideYield 90.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
50 °C

Procedure

A solution of (2S,4S)-4-amino-4-(5-bromo-2-fluorophenyl)-1,1,1-trifluoropentan-2-ol hydrochloride (4f, 693 mg, 1.890 mmol) in THF (10 mL) was treated with diisopropylethylamine (Aldrich; 823 μL, 4.73 mmol) and stirred for 5 min. Benzoyl isothiocyanate (Aldrich; 280 μL, 2.083 mmol) was added dropwise and the reaction mixture was stirred for 3 h. The reaction mixture was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (Aldrich; 674 mg, 2.270 mmol) and heated to 70° C. for 2 h and subsequently to 50° C. for 16 h. The reaction mixture was concentrated and extracted into EtOAc from saturated brine. The combined organic extracts were dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→25% EtOAc/hexane to give N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (789 mg, 1.718 mmol) as a white solid. MS m/z=460.9 [M+H]+. Calculated for C19H15BrF4N2O2: 459.2

Workup

  1. stirringthe reaction mixture was stirred for 3 h
  2. concentrationThe reaction mixture was concentrated
  3. extractionextracted into EtOAc from saturated brine
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. concentrationconcentrated
  6. custompurified by flash chromatography on silica gel (Gradient

Sources & evidence

ORD record
ord-0d4b42e25a614545997b2232249e71f8
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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