1,2-Dichloroethane → diethyl ether (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(6-morpholino-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571264Notes

Reaction equation

HRID 571264 reaction equation
[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:46]=[C:45]3[C:41]([C:42](=[O:52])[C:43](=[O:51])[N:44]3[CH2:47][C:48](O)=[O:49])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:48](=[O:49])[CH2:47][N:44]1[C:45]2[C:41](=[CH:40][CH:39]=[C:38]([N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH:46]=2)[C:42](=[O:52])[C:43]1=[O:51].[CH2:13]([O:21][CH2:22][CH3:23])[CH3:12]

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 71092687(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxideHCID 866816782-(6-Morpholino-2,3-dioxoindolin-1-yl)acetic acid

Product 1

HCID 86681679diethyl ether (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(6-morpholino-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxideYield 44%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol) in DCM (15 ml), DMAP (0.070 g, 0.571 mmol), EDC (0.274 g, 1.428 mmol) and 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetic acid (0.166 g, 0.571 mmol) were added in one portion at room temperature, and the resulting solution was stirred overnight. The solvent was removed under vacuum and the crude was purified by silica gel flash chromatography (DCM:MeOH=98:2) to afford a red solid. After trituration with diethyl ether (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(6-morpholino-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide was obtained (0.145 mg, 0.209 mmol, 44% yield). MS/ESI+ 692.31 [MH]+; [αD]=+227.4, c=0.25, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.33 (s, 2H), 7.44 (d, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 6.94 (dd, 1H), 7.08 (t, 1H), 6.59 (dd, 1H), 6.48 (d, 1H), 6.01 (dd, 1H), 4.56 (s, 2H), 3.90 (d, 2H), 3.63-3.80 (m, 4H), 3.43-3.55 (m, 4H), 3.37 (dd, 1H), 3.18 (dd, 1H), 1.13-1.35 (m, 1H), 0.50-0.66 (m, 2H), 0.23-0.48 (m, 2H)

Workup

  1. customThe solvent was removed under vacuum
  2. customthe crude was purified by silica gel flash chromatography (DCM:MeOH=98:2)
  3. customto afford a red solid

Sources & evidence

ORD record
ord-76db208b5f074759b7a71fe3fdeadbc0
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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