Sodium Carbonate → (1R,2R)-2-methyl-cyclopropane carboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide

HRID 2079745Notes

Reaction equation

HRID 2079745 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:12]([Br:13])=[C:11]([NH:14][C:15]([C@@H:17]2[CH2:19][C@H:18]2[CH3:20])=[O:16])[S:10][N:9]=1.[CH3:21][N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28]2)=[N:23]1>COCCOC>[Br:13][C:12]1[C:8]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][N:22]([CH3:21])[N:23]=3)[CH:28]=2)=[N:9][S:10][C:11]=1[NH:14][C:15]([C@@H:17]1[CH2:19][C@H:18]1[CH3:20])=[O:16]

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 441182532-Methyl-2H-indazole-5-boronic acid, pinacol esterHCID 67103560(R,R)-N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropanecarboxamide

Product 1

HCID 67103132(1R,2R)-2-methyl-cyclopropane carboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amideYield 51%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
83 °C

Procedure

Add a 2; M aqueous solution of sodium carbonate (606.3; mL, 1.21; mol) to a stirring mixture of (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (148.1; g, 0.404; mol) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (123.40; g, 0.444; mol) in HPLC grade 1,2-dimethoxyethane (1.21; L) and degas using vacuum and nitrogen. Add bis(triphenylphosphine) palladium(II) dichloride (56.77; g, 80.84; mmol) in one portion, heat at 83° C. for 10; h, cool to room temperature and filter through a pad of Celite® using ethyl acetate to give a biphasic solution. Separate the layers and extract the aqueous layer three times with dichloromethane (200; mL). Combine all the organic layers, wash with brine (200; mL) and concentrate to approximately a volume of 400; mL. Separate into two portions and purify each by silica gel chromatography by gradient 50:50; to 10:90; eluting with n-hexane:ethyl acetate to give the title compound as a light brown solid (107.32; g, 51%). MS (m/z): 391,393; (M+1).

Workup

  1. additionAdd a 2
  2. customdegas
  3. temperatureh, cool to room temperature
  4. filtrationfilter through a pad of Celite®
  5. customto give a biphasic solution
  6. customSeparate the layers
  7. extractionextract the aqueous layer three times with dichloromethane (200; mL)
  8. washCombine all the organic layers, wash with brine (200; mL)
  9. concentrationconcentrate to approximately a volume of 400
  10. customSeparate into two portions
  11. custompurify each by silica gel chromatography by gradient 50:50
  12. washeluting with n-hexane

Sources & evidence

ORD record
ord-64398a2c7d964a259887197b780fbb17
Source dataset
uspto-grants-2011_04
Patent number
US07932274B2

Reaction notes

Loading…