Phosgene → HCID 475397, compound

HRID 2298534Notes

Reaction equation

HRID 2298534 reaction equation
[NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:3]=1[C:4]([OH:14])([C:9]#[C:10][CH:11]1[CH2:13][CH2:12]1)[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]([F:19])[C:2]2[NH:1][C:28](=[O:29])[O:14][C:4]([C:9]#[C:10][CH:11]3[CH2:13][CH2:12]3)([C:5]([F:6])([F:7])[F:8])[C:3]=2[CH:15]=1

Participants

5

Reactant 3

HCID 6371PhosgeneHCID 8471TriethylamineHCID 54068872HCID 54068872, compound

Product 1

HCID 475397HCID 475397, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
-25 °C

Procedure

To a stirred, cooled (−25° C.) solution of 144 mg (0.47 mmol) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperatue and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F NMR (282 MHz, CDCl3) δ−132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.

Workup

  1. temperaturewas warmed to ambient temperatue
  2. customquenched with 0.5 N aq. citric acid
  3. extractionThe mixture was extracted once with ether and once with ethyl acetate
  4. washthe combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine
  5. dry with materialThe solution was dried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customto afford a tan solid
  8. customThe crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether)
  9. customto afford
  10. concentrationafter concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid

Sources & evidence

ORD record
ord-6d4a00a28aa144faad24ce205256eedf
Source dataset
uspto-grants-2002_12
Patent number
US06492515B2

Reaction notes

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