1,2-Dichloroethane → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571327Notes

Reaction equation

HRID 571327 reaction equation
FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:25](=[O:34])[C:24]3=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1.[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)[O:32][C:31](=[O:33])[CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:29][CH:28]=2)[C:24](=[O:35])[C:25]1=[O:34]

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 866817412-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt

Product 1

HCID 71553993(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxideYield 34.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt (0.319 g, 0.607 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.170 g, 0.405 mmol), EDC (0.233 g, 1.214 mmol), and DMAP (0.099 g, 0.809 mmol) in DCM (25 ml) was stirred at room temperature for 3 days. The mixture was diluted with DCM and washed with aqueous 5% NaHCO3 and with sat. NH4Cl; the organic phase was dried over sodium sulfate, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 95:5). An additional purification by chromatography on silica gel column (DCM:MeOH=98:2 to 97:3) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.113 g, 0.139 mmol, 34.3% yield, MS/ESI+ 813.19 [MH]+, [αD]=−26.83, c=0.24, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.69 (d, 1H), 7.68 (dd, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.04 (dd, 1H), 4.69 (d, 1H), 4.58 (d, 1H), 3.93 (d, 2H), 3.74 (t, 2H), 3.46-3.55 (m, 4H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (s, 3H), 2.37 (t, 2H), 2.28-2.34 (m, 4H), 1.08-1.36 (m, 1H), 0.47-0.66 (m, 2H), 0.27-0.49 (m, 2H).

Workup

  1. washwashed with aqueous 5% NaHCO3 and with sat. NH4Cl
  2. dry with materialthe organic phase was dried over sodium sulfate
  3. customthe solvent was removed
  4. customThe crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 95:5)
  5. customAn additional purification by chromatography on silica gel column (DCM:MeOH=98:2 to 97:3)

Sources & evidence

ORD record
ord-21a85c3ec683450a99e195fdb1365fa8
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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