Triphenylphosphine → Ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate

HRID 2274029Notes

Reaction equation

HRID 2274029 reaction equation
[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[C:25]#[N:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([CH:29]=[C:28]([O:30][C:31]([F:32])([F:34])[F:33])[CH:27]=1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:26]

Participants

7

Reactant 4

HCID 11776Triphenylphosphine2×HCID 5363146Diisopropyl azodicarboxylate2×HCID 53345675Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetateHCID 668475343-(Hydroxymethyl)-5-(trifluoromethoxy)benzonitrile

Product 1

HCID 67220818Ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetateYield 28.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (100 mg, 0.386 mmol) and 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (84 mg, 0.386 mmol) were dissolved in THF (3.0 mL) and cooled to 0° C. Triphenylphosphine (202 mg, 0.771 mmol) and diisopropylazodicarboxylate (DIAD) (0.15 mL, 0.771 mmol) were added. The mixture was warmed to room temperature and stirred for 1 h. Additional DIAD (0.15 mL, 0.771 mmol) and triphenylphosphine (202 mg, 0.771 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 50.8 mg of impure ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The material was dissolved in dioxane (1.3 mL) and 1.0 M aqueous LiOH (0.33 mL, 0.33 mmol) was added. The reaction was monitored by HPLC until judged complete and then acidified to pH 2 with 1.0 M HCL. The aqueous mixture was extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by HPLC to give the title compound (1.1 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 2.11-2.20 (m, 1H), 2.50 (dd, J=15.8, 8.0 Hz, 1H), 2.66-2.84 (m, 4H), 3.51-3.60 (m, 1H), 5.18 (s, 2H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.64 (s, 1H), 7.73 (s, 1H), 7.84 (s, 1H).

Workup

  1. temperatureThe mixture was warmed to room temperature
  2. stirringthe reaction mixture was stirred for 1 h
  3. extractionextracted three times with ethyl acetate
  4. dry with materialThe combined organics were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-bdb5625226fc427ea6e43595af2e82be
Source dataset
uspto-grants-2015_09
Patent number
US09126932B2

Reaction notes

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