(1R,2R)-2-methyl-cyclopropane carboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide → (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-(6-methoxy-pyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide

HRID 2079758Notes

Reaction equation

HRID 2079758 reaction equation
[Br-].[CH3:2][O:3][C:4]1[N:9]=[C:8]([Zn+])[CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:13]([C:24]2[CH:32]=[CH:31][C:30]3[C:26](=[CH:27][N:28]([CH3:33])[N:29]=3)[CH:25]=2)=[N:14][S:15][C:16]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]>O1CCCC1.COCCOC>[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:12]2[C:13]([C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH3:33])[N:29]=4)[CH:25]=3)=[N:14][S:15][C:16]=2[NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])[CH:7]=[CH:6][CH:5]=1

Participants

5

Reactant 2

HCID 67103132(1R,2R)-2-methyl-cyclopropane carboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amideHCID 178491785HCID 178491785, compound

Product 1

HCID 57908399(1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-(6-methoxy-pyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

Add a 0.5M solution of 6-methoxy-2-pyridylzinc bromide in tetrahydrofuran (6.13 mL, 3.07; mmol) to a solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide (0.24; g, 0.61; mmol) in anhydrous 1,2-dimethoxyethane (3.1; mL) and degas by bubbling with nitrogen for 20 min. Add bis(tri-t-butylphosphine)palladium (0) (0.01; g, 12.27; μmol), stir at room temperature under nitrogen overnight and then heat at 55° C. for 48; h. Dilute with brine and extract with ethyl acetate. Dry the ethyl acetate layers over magnesium sulfate, filter and concentrate. Purify by silica gel chromatography, gradient eluting from 0:100; to 30:70; eluting using ethyl acetate:chloroform and then further purify by reverse phase HPLC (water w/ammonium bicarbonate (pH=9)/acetonitrile) to give the title compound (29.6; mg). 1H NMR (CD3OD) δ 0.85; (m, 1H), 1.18; (d, 3H), 1.35; (m, 1H), 1.44 (m, 1H), 1.62; (m, 1H), 4.11; (s, 3H), 4.24; (s, 3H) 6.57; (d, 1H), 6.62; (d, 1H), 7.27; (m, 1H), 7.34; (t, 1H), 7.65; (d, 1H), 7.91; (d, 2H), 12.17; (bs, 1H).

Workup

  1. customdegas
  2. customby bubbling with nitrogen for 20 min
  3. temperatureheat at 55° C. for 48
  4. additionDilute with brine
  5. extractionextract with ethyl acetate
  6. dry with materialDry the ethyl acetate layers over magnesium sulfate
  7. filtrationfilter
  8. concentrationconcentrate
  9. customPurify by silica gel chromatography
  10. washgradient eluting from 0:100
  11. washeluting
  12. customchloroform and then further purify by reverse phase HPLC (water w/ammonium bicarbonate (pH=9)/acetonitrile)

Sources & evidence

ORD record
ord-e0daf9cf50bd4add85ba29a6b4a6c3db
Source dataset
uspto-grants-2011_04
Patent number
US07932274B2

Reaction notes

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