Hydrochloric Acid → 10-[4-(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

HRID 2053742Notes

Reaction equation

HRID 2053742 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][CH:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.ClC(Cl)(Cl)[C:43](Cl)=[O:44].[OH-:48].[Na+].Cl>ClCCl.C(OCC)(=O)C.CC(C)=O>[OH:29][CH:25]1[CH2:26][CH2:27][CH2:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[C:3]([C:43]([OH:44])=[O:48])=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:16])=[CH:18][C:19]=2[CH3:31])=[C:24]1[CH3:30]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6420Trichloroacetyl chlorideHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 10273123Racemic (10,11-Dihydro-5H-pyrrolo[2,1-c](1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone

Product 1

HCID 1027608810-[4-(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 acidYield 49%

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 9 (0.590 g, 1.43 mmol), and N,N-diisopropylethyl amine (1.25 mL, 7.15 mmol) were dissolved in anhydrous dichloromethane (7.2 mL) followed by dropwise addition of trichloroacetyl chloride (0.638 mL, 5.72 mmol). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue filtered through a plug of silica gel eluting with 30% ethyl acetate in hexane. The filtrate was concentrated and the residue dried in vacuo to afford the crude bis-trichloroacetate as an orange oil which was redissolved in acetone (9.5 mL) and treated with 2.5 N aqueous sodium hydroxide (2.86 mL, 7.15 mmol). The reaction mixture was stirred at room temperature for 18 hours, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic phase was extracted with 1 N sodium hydroxide and the combined basic extracts acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform, to afford 0.320 g of the title compound as a brown solid which was used as such in the next step.

Workup

  1. washwashed with water, saturated aqueous sodium bicarbonate and brine
  2. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. filtrationthe residue filtered through a plug of silica gel eluting with 30% ethyl acetate in hexane
  6. concentrationThe filtrate was concentrated
  7. customthe residue dried in vacuo
  8. customto afford the crude bis-trichloroacetate as an orange oil which
  9. stirringThe reaction mixture was stirred at room temperature for 18 hours
  10. extractionextracted with ethyl acetate
  11. extractionThe organic phase was extracted with 1 N sodium hydroxide
  12. extractionextracted with ethyl acetate
  13. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform

Sources & evidence

ORD record
ord-4fe1d697511f4a9dabd7659fc3da564a
Source dataset
uspto-grants-2008_02
Patent number
US07326700B2

Reaction notes

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