Borane;tetrahydrofuran → (10, 11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-((3R)-3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone

HRID 1794021Notes

Reaction equation

HRID 1794021 reaction equation
[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.B.O1CCCC1>O1CCCC1.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12

Participants

5

Reactant 2

HCID 2723981Borane;tetrahydrofuran3×HCID 102950443-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methyl-phenyl]-2-methyl-cyclohex-2-enone

Product 1

HCID 69313729(10, 11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-((3R)-3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanoneYield 92.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

(S)-(−)-CBS-oxazaborolidine (1.0 M in tetrahydrofuran, 1.06 mL, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (53.1 mL, distilled from sodium/benzophenone ketyl). To this solution was simultaneously added a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-3-oxo-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min.) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately 2/3 of borane-tetrahydrofuran. Upon completion of borane-tetrahydrofuran addition, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1N hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to afford the title compound (2.02 g) as a white solid. Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol in hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.

Workup

  1. extractionextracted with ethyl acetate
  2. washThe combined extracts were washed with 1 N sodium hydroxide, 1N hydrochloric acid, and brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-703314b250cf4c1a9b04813b34206691
Source dataset
uspto-grants-2006_04
Patent number
US07022699B2

Reaction notes

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