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 1793974Notes

Reaction equation

HRID 1793974 reaction equation
[CH2:1]1[C:5]2=[CH:6][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])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]2[CH:3]=[CH:2]1.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;tetrahydrofuranHCID 222197193-[4-(5H,1H-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)-(−)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaboro-borane [(S)-2-methyl-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 3-[4-(5H,1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methyl-phenyl]-2-methyl-cyclohex-2-enone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min) and borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately ⅔ of the borane-tetrahydrofuran complex. Upon completion of the borane-tetrahydrofuran complex addition, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1 N hydrochloric acid and brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane followed by reprecipitation from diethyl ether upon addition of petroleum ether, to afford 2.02 g of the title compound as a white solid, [α]589=+34.30 (c=1, chloroform). Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol/hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.

Workup

  1. additionwas complete upon addition of approximately ⅔ of the borane-tetrahydrofuran complex
  2. additionUpon completion of the borane-tetrahydrofuran complex addition
  3. extractionextracted with ethyl acetate
  4. washThe combined extracts were washed with 1 N sodium hydroxide, 1 N hydrochloric acid and brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane
  9. customfollowed by reprecipitation from diethyl ether upon addition of petroleum ether

Sources & evidence

ORD record
ord-30dd851a4e2b4aeabc5591d4db364bfd
Source dataset
uspto-grants-2006_04
Patent number
US07022699B2

Reaction notes

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