1-Hydroxybenzotriazole → (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone

HRID 598584Notes

Reaction equation

HRID 598584 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[F:18][C:19]1[C:27]2[N:26]=[C:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)[NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[F:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C.CO.ClCCl>[F:18][C:19]1[C:27]2[N:26]=[C:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])[NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[F:35]

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 17973676(RS)-4,5-Difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazoleHCID 234501385-(4-Fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid

Product 1

HCID 66968516(RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanoneYield 33%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A stirring solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (320 mg, 1.0 mmol, 80% pure) and (RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 (250 mg, 1.0 mmol) in DMF (10 ml) was treated with EDC.HCl (194 mg, 1.0 mmol) and 1-hydroxybenzotriazole (50 mg, 0.4 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h. The resulting solution was diluted with diethyl ether then washed with saturated aqueous NaHCO3, water (3×) and brine. Drying (MgSO4) and removal of the solvent in vacuo afforded an orange gum. Chromatography (silica gel, 0-2% methanol-dichloromethane) afforded the title compound as an orange powder (160 mg, 33%). Mass spectrum (Electrospray LC/MS) Found 487 (MH+). C24H21F3N4O2S requires 486.

Workup

  1. washthen washed with saturated aqueous NaHCO3, water (3×) and brine
  2. customDrying
  3. custom(MgSO4) and removal of the solvent in vacuo
  4. customafforded an orange gum

Sources & evidence

ORD record
ord-cbe11634ff8e458e85fde3ad0032b459
Source dataset
uspto-grants-2011_03
Patent number
US07897618B2

Reaction notes

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