Chloroacetyl chloride → (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 1475485Notes

Reaction equation

HRID 1475485 reaction equation
Cl[CH2:2][C:3](Cl)=[O:4].Cl.[F:7][C:8]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=1[CH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:13]=2[CH:12]=1.C(N(CC)CC)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][OH:48])[NH:44][CH2:43][C@H:42]1[CH3:49])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][OH:48])[N:44]([CH2:2][C:3]([N:19]2[C:13]3[CH:12]=[C:11]([CH2:10][C:9]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:8]=4[F:7])[N:16]=[CH:15][C:14]=3[C:17]([CH3:21])([CH3:20])[CH2:18]2)=[O:4])[CH2:43][C@H:42]1[CH3:49])=[O:40])([CH3:37])([CH3:36])[CH3:35]

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 8471Triethylamine2×HCID 709806496-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochlorideHCID 71003242(2R,5R)-tert-Butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate2×

Product 1

HCID 86724032(2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl esterYield 80.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Chloroacetyl chloride (0.995 mL, 12.0 mmol) was added dropwise to a stirred solution of 6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (3.10 g, 10.0 mmol) and triethylamine (4.6 mL, 33.0 mmol) in anhydrous DCM (50 mL) and the mixture was stirred at room temperature for 16 hours. (2R,5R)-5-Hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.76 g, 12.0 mmol) was added and the mixture was stirred at room temperature for a further 16 hours. Further triethylamine (1 mL) and (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (700 mg) were added and the mixture stirred for a further 16 hours. The mixture was diluted with DCM, washed with water, the organic layer separated and the solvent removed in vacuo. Chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether) afforded (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 80%) as a pale tan foam. MS: [M+H]+ 545. Methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise to a stirred solution of (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed successively with saturated aqueous sodium hydrogen carbonate and then water. The organic layer was separated and the solvent removed in vacuo to afford the title compound (4.0 g, 71%) as a pale yellow foam. MS: [M+H]+=563, 565.

Workup

  1. stirringthe mixture was stirred at room temperature for a further 16 hours
  2. stirringthe mixture stirred for a further 16 hours
  3. washwashed with water
  4. customthe organic layer separated
  5. customthe solvent removed in vacuo
  6. washChromatography (silica, elution with 30-100% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-84602318568149b98e30987dc2c17130
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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