Phosgene → (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-propyl ester

HRID 585153Notes

Reaction equation

HRID 585153 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.C(Cl)(Cl)=[O:26].ClC1C=C[C:33]([O:54][CH3:55])=[C:34]([C@@:36]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C(Cl)=O)C2=O)C=1.ClC(O)=O.OCCC[O:64][P:65](=[O:76])([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>ClCCl.N1C=CC=CC=1>[C:72]([O:71][P:65]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([O:76][CH:34]([CH3:36])[CH2:33][O:54][C:55]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C@@:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:23][CH3:24])([F:22])[C:9]1=[O:21])=[O:26])=[O:64])([CH3:75])([CH3:74])[CH3:73]

Participants

7

Reactant 4

HCID 6371PhosgeneHCID 214350Bms 204352HCID 85869323Phosphoric acid di-tert-butyl ester 3-hydroxy-propyl esterHCID 86589942chloroformate (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carbonyl chloride

Product 1

HCID 69330300(S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-propyl esterYield 63%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II) (720 mg, 2 mmol) in dichloromethane was dropped in phosgene (2.2 mL, 20% solution in toluene, 4 mmol) and pyridine (0.6 mL). The resulting chloroformate (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carbonyl chloride ((S)-VI) was stirred at room temperature under N2 atmosphere over night. To this reaction mixture was dropped in another 0.6 mL of pyridine, followed by the addition of phosphoric acid di-tert-butyl ester 3-hydroxy-propyl ester (1.55 g, ˜5.78 mmol), the preparation of which is given below. The resulting mixture was stirred at room temperature for another hour, was diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and condensed by evaporator. The residue was chromatographed on a silica gel flash column packed with ethyl acetate:hexane (v/v, 4:1) and eluted with ethyl acetate:hexane (v/v, 4:1˜2:1) to afford the title compound (818 mg, 63%). 1H NMR (CDCl3, 500 MHz) δ 10.06 (s, 1H), 8.31 (s, 1H), 7.78 (t, 1H), 7.43 (d, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 6.76 (dd, 1H), 4.59 (m, 2H), 4.16 (m, 2H), 3.52 (s, 3H), 2.18 (m, 2H), 1.48 (s, 18H); LC-MS, 654.1 (MH+).

Workup

  1. customthe preparation of which
  2. washwashed with water
  3. dry with materialThe organic layer was dried over Na2SO4 and condensed by evaporator
  4. customThe residue was chromatographed on a silica gel flash column
  5. washhexane (v/v, 4:1) and eluted with ethyl acetate

Sources & evidence

ORD record
ord-1c7ca2c8d2d9438e994836882a4e1758
Source dataset
uspto-grants-2005_08
Patent number
US06930100B2

Reaction notes

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