Lithium Chloride → 7-chloro-3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one

HRID 1186086Notes

Reaction equation

HRID 1186086 reaction equation
Cl[C:2]1[C:3]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:4]=2[N:5]([CH2:18][CH2:19]Cl)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[CH3:26][N:27]1[C:31]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:30]=2[NH:29][C:28]1=[O:45].[Cl-].[Li+].[OH2:48].[OH-].[Cs+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:25][C:23]1[CH:22]=[CH:21][C:4]2[N:5]([CH2:18][CH2:19][OH:48])[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]4[NH:29][C:28](=[O:45])[N:27]([CH3:26])[C:31]=4[CH:32]=3)[C:3]=2[CH:24]=1

Participants

8

Reactant 4

HCID 433294Lithium ChlorideHCID 23679066Caesium hydroxide--water (1/1/1)HCID 579505771-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-oneHCID 670608705,7-Dichloro-3-(2-chlorobenzyl)-1-(2-chloroethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one

Product 1

HCID 670608617-chloro-3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

5,7-Dichloro-3-(2-chlorobenzyl)-1-(2-chloroethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.31 g, 0.75 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.2 g, 0.75 mmol) were dissolved in anhydrous 1,4-dioxane (12 mL) while bubbling nitrogen into the solution. Lithium chloride (95 mg, 2.2 mmol) and [Tetrakis(triphenylphosphine)]palladium(0) (0.09 g, 0.074 mmol) were added followed by cesium hydroxide monohydrate (0.38 g, 2.2 mmol) and water (1 mL). The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 20 hours. The mixture was cooled, diluted with ethyl acetate, washed with water, then brine, dried with sodium sulfate, decanted and concentrated in vacuo. The product was purified by column chromatography eluting with a gradient of 80-100% ethyl acetate in hexanes, followed by 0-10% methanol in ethyl acetate. It was further purified by column chromatography eluting with a gradient of 0-12% methanol in dichloromethane to yield 7-chloro-3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 1HNMR (DMSO-d6, 400 MHz) δ 11.09 (s, 1H), 7.81 (d, 1H), 7.68 (dd, 1H), 7.49 (d, 1H), 7.38 (d, 1H), 7.31-7.19 (m, 4H), 6.98 (m, 2H), 4.72 (t, 1H), 4.08 (m, 1H), 3.8 (m, 2H), 3.6-3.3 (m, 4H), 3.26 (s, 3M. HRMS [M+H]+ predicted: 509.1147. found: 509.1133.

Workup

  1. customwhile bubbling nitrogen into the solution
  2. temperatureThe mixture was cooled
  3. washwashed with water
  4. dry with materialbrine, dried with sodium sulfate
  5. customdecanted
  6. concentrationconcentrated in vacuo
  7. customThe product was purified by column chromatography
  8. washeluting with a gradient of 80-100% ethyl acetate in hexanes
  9. customIt was further purified by column chromatography
  10. washeluting with a gradient of 0-12% methanol in dichloromethane

Sources & evidence

ORD record
ord-35e7c9207c254524b74ce2140bee9aac
Source dataset
uspto-grants-2014_03
Patent number
US08673897B2

Reaction notes

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