Pyridine → tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 1486120Notes

Reaction equation

HRID 1486120 reaction equation
[C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[CH:31][C:30]=3[CH:39]3[CH2:41][CH2:40]3)[C:8](=[O:27])[C@@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:50](Cl)(=[O:52])[CH3:51]>C(Cl)Cl.O>[C:50]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH3:16])[C:8](=[O:27])[N:7]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[CH:39]2[CH2:40][CH2:41]2)[C:6]2[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:52])[CH3:51]

Participants

6

Reactant 3

HCID 1049PyridineHCID 6367Acetyl chlorideHCID 118292692tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

Product 1

HCID 118292668tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 36%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (70 mg, 120 μmol) in CH2Cl2 (801 μl) was added pyridine (29.4 μl, 360 μmol), followed by acetyl chloride (12.8 μl, 180 μmol), dropwise. The reaction was stirred at rt for 22 h, then diluted with H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase preparative HPLC then flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (26.8 mg, 36%) as a white solid. MS m/z 625 (MH)+.

Workup

  1. extractionextracted with CH2Cl2
  2. washThe combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-3102dd3d405a4f5e9f60e456e02cc1c7
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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