Trifluoroacetic acid → N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-2-cyclohexyl-ethyl}-3-methoxy-benzamide

HRID 132142

Reaction equation

HRID 132142 reaction equation
C(O[C:6](=[O:40])[NH:7][C@H:8]([C:16](=[O:39])[NH:17][C@@H:18]([CH2:30][O:31][CH2:32]C1C=CC=CC=1)[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.F[C:42](F)(F)[C:43](O)=O.C(O)(=O)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=1.CN(C(ON1N=N[C:69]2[CH:70]=[CH:71]C=N[C:68]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.ClCCl.O>[CH2:32]([O:31][CH2:30][C@H:18]([NH:17][C:16]([C@@H:8]([NH:7][C:6](=[O:40])[C:53]1[CH:54]=[CH:49][CH:50]=[C:51]([O:55][CH3:56])[CH:52]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:39])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[C:43]1[CH:42]=[CH:71][CH:70]=[CH:69][CH:68]=1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 114613-Methoxybenzoic AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 69196165{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester

Product 1

HCID 69195896N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-2-cyclohexyl-ethyl}-3-methoxy-benzamideYield 87%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A sample of {1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester (210 mg, 0.34 mmol) was treated with a mixture of trifluoroacetic acid, dichloromethane and water (45:45:10) and allowed to age for 2 hours. The solvent was then removed by rotary evaporation. The resulting oil was treated with m-anisic acid (75 mg, 0.49 mmol), HATU (187 mg, 0.49 mmol) and dichloromethane (2 mL). The reaction was then treated with diisopropylethylamine (245 mg, 1.9 mmol) and stirred for 2 hours. The reaction was diluted with ethyl acetate, extracted with saturated aqueous NaHCO3 twice, dried over MgSO4 and the solvent was removed. The resulting oil was purified over silica gel using a gradient of 0 to 100% ethyl acetate in hexane to afford 195 mg (87%) of the title material; 1H NMR (CDCl3, 400 MHz) δ 0.84-1.03 (m, 2H), 1.06-1.22 (m, 3H), 1.32-1.45 (m, 1H), 1.58-1.87 (m, 7H), 2.92 (dd, 1H, J1=J2=8.2), 3.13-3.25 (m, 2H), 3.31-3.46 (m, 2H), 3.54 (dd, 1H, J1=54.2, J2=9.4), 3.68 (dd, 1H, J1=2.4, J2=9.3), 3.84 (s, 3H), 4.26-4.36 (m, 1H), 4.53 (dd, 2H, J1=11.8, J2=26.0), 4.65-4.74 (m, 1H), 6.46 (dd, 1H, J1=4.1, J2=8.4), 6.46 (d, 1H, J=8.3), 6.69-6.83 (m, 2H), 7.02-7.09 (m, 1H), 7.27-7.39 (m, 7H); HPLC-MS calcd. for C35H42FN3O4 (M+H+) 587.3, found 587.5.

Workup

  1. customThe solvent was then removed by rotary evaporation
  2. extractionextracted with saturated aqueous NaHCO3 twice
  3. dry with materialdried over MgSO4
  4. customthe solvent was removed
  5. customThe resulting oil was purified over silica gel using a gradient of 0 to 100% ethyl acetate in hexane

Sources & evidence

ORD record
ord-42ea1a4a92ae48aa9889d3a1d874903b
Source dataset
uspto-grants-2008_06
Patent number
US07384970B2

Linked notes

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