1-Methylpiperazine → [4-((3R)-3-Hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-[3-(4-methyl-piperazine-1-carbonyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-10-yl]-methanone

HRID 2053745Notes

Reaction equation

HRID 2053745 reaction equation
[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34].[CH3:35][N:36]1CCNC[CH2:37]1.ON1C2C=CC=CC=2N=N1.Cl.[CH2:53]([N:55]=[C:56]=N)[CH3:54].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28]([N:55]5[CH2:53][CH2:54][N:36]([CH3:37])[CH2:35][CH2:56]5)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34]

Participants

7

Reactant 5

HCID 531671-MethylpiperazineHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 1029800410-[4-((3R)-3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acidHCID 21883477Ethylcarbodiimide hydrochloride

Product 1

HCID 10119605[4-((3R)-3-Hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-[3-(4-methyl-piperazine-1-carbonyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-10-yl]-methanoneYield 84.8%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

10-[4-((3R)-3-Hydroxy-2-methyl-cyclohex-1-enyl)-3-methyl-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step B (0.200 g, 0.438 mmol), N-methyl piperazine (0.058 mL, 0.526 mmol), 1-hydroxy benzotriazole (0.065 g, 0.482 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.482 mmol) were combined in amine-free N,N-dimethylformamide (1.8 mL), followed by addition of N,N-diisopropylethyl amine (0.114 mL, 0.657 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 8% of methanol in chloroform followed by precipitation from diethyl ether with petroleum ether, to provide 0.200 g of the title compound as a white solid, m.p.102-153° C., [β]589=+18.89 (c=1, chloroform).

Workup

  1. washwashed with water, saturated aqueous sodium bicarbonate, and brine
  2. extractionextracted with ethyl acetate
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 8% of methanol in chloroform
  7. customfollowed by precipitation from diethyl ether with petroleum ether

Sources & evidence

ORD record
ord-8b9adf3e1a294f6e9d379afb6bd67e02
Source dataset
uspto-grants-2008_02
Patent number
US07326700B2

Reaction notes

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