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

HRID 571230Notes

Reaction equation

HRID 571230 reaction equation
[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]

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 866816502-(5-(Methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid

Product 1

HCID 86681651(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxideYield 4.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalyst2×HCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid (141 mg, 0.473 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (166 mg, 0.394 mmol), EDC (227 mg, 1.182 mmol) and DMAP (24.06 mg, 0.197 mmol) in DCM (25 ml) was stirred at room temperature overnight. The solvent was evaporated, DMF (10 ml) was added, and the resulting solution was stirred at 80° C. for 6 hours. DMAP (48.1 mg, 0.394 mmol) was added, and stirring at 80° C. was continued for 2 days. The solvent was evaporated, DCM was added, and the mixture was washed with NaHCO3 5% and 1N HCl; the organic layer was dried over Na2SO4, filtered and evaporated affording a crude that was purified by flash chromatography on silica gel (DCM:Ethyl acetate from 50:50 to 30:70; then 100% DCM and then DCM:MeOH from 99:1 to 97:3). The product was further purified by Preparative HPLC (Method 3) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.012 g, 0.017 mmol, 4% yield). MS/ESI+ 700.16 [MH]+; [αD]=+63.50, c=0.12 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.75 (br. s., 1H), 8.43 (s, 2H), 7.45 (dd, 1H), 7.41 (d, 1H), 7.18 (d, 1H), 7.07 (d, 1H), 7.05 (d, 1H), 6.95 (dd, 1H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.64 (d, 1H), 4.56 (d, 1H), 3.91 (d, 2H), 3.40 (dd, 1H), 3.22 (dd, 1H), 3.02 (s, 3H), 1.12-1.31 (m, 1H), 0.54-0.63 (m, 2H), 0.31-0.44 (m, 2H).

Workup

  1. customThe solvent was evaporated
  2. additionDMF (10 ml) was added
  3. stirringthe resulting solution was stirred at 80° C. for 6 hours
  4. stirringstirring at 80° C.
  5. waitwas continued for 2 days
  6. customThe solvent was evaporated
  7. additionDCM was added
  8. washthe mixture was washed with NaHCO3 5% and 1N HCl
  9. dry with materialthe organic layer was dried over Na2SO4
  10. filtrationfiltered
  11. customevaporated
  12. customaffording a crude that
  13. customwas purified by flash chromatography on silica gel (DCM
  14. customThe product was further purified by Preparative HPLC (Method 3)

Sources & evidence

ORD record
ord-eb681eac00b549568f937e65e027c79a
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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