1,2-Dichloroethane → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571194Notes

Reaction equation

HRID 571194 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:14][C:13](=[O:15])[CH2:12][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:11]=2)[CH:7]=[CH:8]1

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 670827152-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acidHCID 71092687HCID 71092687, compound

Product 1

HCID 86681613(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxideYield 48%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (130 mg, 0.308 mmol), EDC (83 mg, 0.432 mmol) and DMAP (75 mg, 0.617 mmol) in dry DCM (5 ml) was stirred at room temperature overnight. Aqueous 1N HCl was added to the reaction mixture and the organic phase was separated, washed with brine and dried over sodium sulfate. The solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel column (DCM/MeOH 96/4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (95 mg, 0.147 mmol, 48% yield). MS/ESI+ 645.03 [MH]+; [αD]=−2.157, c=0.510; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.67-7.85 (m, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.87 (dd, 1H), 7.03 (t, 1H), 6.61 (dd, 1H), 5.98 (dd, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 3.82 (d, 2H), 3.39 (dd, 1H), 3.19 (dd, 1H), 1.10-1.22 (m, 1H), 0.46-0.70 (m, 2H), 0.15-0.46 (m, 2H)

Workup

  1. customthe organic phase was separated
  2. washwashed with brine
  3. dry with materialdried over sodium sulfate
  4. customThe solvent was removed under vacuum
  5. customthe crude was purified by flash chromatography on silica gel column (DCM/MeOH 96/4)

Sources & evidence

ORD record
ord-8764e6e1786146f7aaa8aa42be780778
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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