Sodium hydride → (RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

HRID 1367035Notes

Reaction equation

HRID 1367035 reaction equation
[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH3:40].C(N(CC)C(C)C)(C)C>CN(C=O)C.[I-].[K+]>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH2:37][CH2:38][O:39][CH3:40])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 809722-Bromoethyl methyl etherHCID 81531DiisopropylethylamineHCID 17973672(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

Product 1

HCID 66967856(RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzoimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneYield 65%

Reagents, catalysts & solvents 2

HCID 4875Potassium IodideCatalystHCID 6228DimethylformamideSolvent

Procedure

(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (300 mg, 0.64 mmol) was added slowly to an ice-cooled slurry of sodium hydride (51 mg, 1.3 mmol, 60% dispersion in mineral oil) in DMF (10 ml). After stirring for 0.5 h 1-bromo-2-methoxy-ethane (139 mg, 10 mmol), N,N-diisopropylethylamine (0.3 ml) and potassium iodide (5 mg) was added. The mixture was stirred at room temperature for 0.5 h then 100° C. for 16 h. The volatiles were removed in vacuo from the cooled reaction mixture. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with ethyl acetate to afford the title compound as a solid (306 mg, 65%). Mass spectrum (Electrospray LC/MS) Found 529 (MH+). C27H27F3N4O2S requires 528. The product was dissolved in methanol and treated with 1M HCl in diethyl ether (excess). The volatiles were removed in vacuo and the residue triturated with methanol-ethyl acetate to afford the hydrochloride salt of the title compound as a white solid (66 mg).

Workup

  1. additionwas added
  2. wait100° C. for 16 h
  3. customThe volatiles were removed in vacuo from the cooled reaction mixture
  4. customThe residue was partitioned between ethyl acetate and water
  5. extractionThe aqueous phase was extracted with ethyl acetate (2×)
  6. dry with materialThe combined organics were dried (Na2SO4)
  7. customthe solvent removed in vacuo
  8. customThe residue was triturated with ethyl acetate

Sources & evidence

ORD record
ord-33b3279b60f24ee2bcc9a663200814af
Source dataset
uspto-grants-2011_02
Patent number
US07893090B2

Reaction notes

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