1-Hydroxybenzotriazole → 10-[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 acid methyl-pyridin-3-yl methyl-amide

HRID 1070484Notes

Reaction equation

HRID 1070484 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].CNC[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O[N:45]1[C:49]2C=CC=C[C:48]=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:48][CH2:49][N:45]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[C:28]([C:25]1[N:17]2[C:16]([CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:31]=[CH:32][C:8]([C:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([OH:1])[C:3]=4[CH3:34])=[C:9]([CH3:33])[CH:10]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18]2)=[CH:27][CH:26]=1)=[O:29]

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 883933-(Methylaminomethyl)pyridineHCID 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 acid

Product 1

HCID 8658744610-[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 acid methyl-pyridin-3-yl methyl-amideYield 87.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

10-[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 acid of Step C (0.250 g, 0.548 mmol), 3-(methylaminomethyl)pyridine (0.080 mL, 0.658 mmol), 1-hydroxy benzotriazole (0.081 g, 0.603 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.116 g, 0.603 mmol) were combined in amine-free N,N-dimethylformamide (2.2 mL), followed by addition of N,N-diisopropylethyl amine (0.143 mL, 0.822 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, to afford 0.270 g of the title compound as an oil which was dissolved in diethyl ether and precipitated with petroleum ether to afford a white solid, m.p.100-144° C., [α]589=+18.49 (c=1.0, 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

Sources & evidence

ORD record
ord-5a3621fc3607432f92c302c25120c39e
Source dataset
uspto-grants-2005_06
Patent number
US06903087B2

Reaction notes

Loading…