Potassium Carbonate → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,3-dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571185Notes

Reaction equation

HRID 571185 reaction equation
Br[CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:38][C:39]1([CH3:50])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41](=[O:49])(=[O:48])[NH:40]1>CN(C=O)C>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][N:40]1[C:39]([CH3:50])([CH3:38])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41]1(=[O:48])=[O:49]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 44473552,3-Dihydro-3,3-dimethyl-1,2-benzisothiazole 1,1-dioxideHCID 86679564(S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide

Product 1

HCID 86681608(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,3-dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)acetoxy)ethyl)pyridine 1-oxideYield 85%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine (mixture obtained as described in Example 5, Step 1, 100 mg, 0.18 mmol) is dissolved in DMF (2 ml), then K2CO3 (30 mg, 0.22 mmol) and 2,3-dihydro-3,3-dimethyl-1,2-benzisothiazole 1,1-dioxide (71 mg, 0.36 mmol) are added. The mixture is stirred at RT for 5 hours. The reaction is quenched with water (10 ml), and the product extracted with Ethyl Acetate. The organic layer is washed with H2O (3×15 ml), dried over Na2SO4 and evaporated under vacuum. The crude is purified by preparative HPLC (Method 2), to yield 100 mg of the title compound (85% yield). MS/ESI+ 657.51 [MH]+; 1H NMR (400 MHz, acetone) ppm 8.40 (s, 2H), 7.38 (m, 2H), 7.36 (m, 3H), 7.03 (m, 1H), 6.81 (m, 2H), 5.63 (m, 1H), 4.14 (s, 2H), 3.90 (d, 2H), 3.54-3.29 (2H), 3.25-3.00 (2m, 2H), 1.27 (s, 6H), 0.72 (m, 1H), 0.30-0.05 (2 m, 4H).

Workup

  1. customThe reaction is quenched with water (10 ml)
  2. extractionthe product extracted with Ethyl Acetate
  3. washThe organic layer is washed with H2O (3×15 ml)
  4. dry with materialdried over Na2SO4
  5. customevaporated under vacuum
  6. customThe crude is purified by preparative HPLC (Method 2)

Sources & evidence

ORD record
ord-74ee612bafb64c23b02cd9df64738648
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

Loading…