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

HRID 571275Notes

Reaction equation

HRID 571275 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[N:7]([CH2:15][C:16]([OH:18])=[O:17])[C:6]2=[O:19].C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:17][C:16](=[O:18])[CH2:15][N:7]1[C:6](=[O:19])[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14]

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 858316312-(5,6-Dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid

Product 1

HCID 71554084(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxideYield 41%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a suspension of 2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid (151 mg, 0.571 mmol) in DCM (25 ml), DMAP (69.8 mg, 0.571 mmol), EDC (274 mg, 1.428 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol) were added in one portion at room temperature, and the resulting mixture was stirred for 4 hours. The solution was diluted with DCM (40 ml) and washed with a saturated solution of NaHCO3 (40 ml), with 1N HCl (30 ml) and finally with brine (30 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by crystallization from ethyl acetate (40 ml) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (130 mg, 0.195 mmol, 40.9% yield). MS/ESI+ 667.16 [MH]+; [αD]=−42.80, c=0.25, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.43 (s, 2H), 7.19 (d, 1H), 7.02-7.13 (m, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.37 (s, 2H), 3.96 (s, 6H), 3.92 (d, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 1.12-1.34 (m, 1H), 0.52-0.67 (m, 2H), 0.29-0.46 (m, 2H).

Workup

  1. additionwere added in one portion at room temperature
  2. washwashed with a saturated solution of NaHCO3 (40 ml), with 1N HCl (30 ml) and finally with brine (30 ml)
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. customevaporated to dryness
  6. customThe crude was purified by crystallization from ethyl acetate (40 ml)

Sources & evidence

ORD record
ord-08c5b08369884276bfa2359cb43e615f
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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