Diisopropylethylamine → (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2'-methoxy-2-methyl-[1,1'-biphenyl]-4-yl)-methanone

HRID 2184444Notes

Reaction equation

HRID 2184444 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:24][C:23]=12

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 1554704810,11-Dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepineHCID 219477594-(2-Methoxyphenyl)-3-methylbenzoic acid

Product 1

HCID 21947842(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2'-methoxy-2-methyl-[1,1'-biphenyl]-4-yl)-methanoneYield 49.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 24386Thionyl ChlorideSolvent

Procedure

The 2-methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and the mixture heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane yielded a white foam which crystallized upon sonication with ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133-135° C.

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux for 30 minutes
  3. temperatureAfter cooling
  4. customthe thionyl chloride was removed in vacuo
  5. dissolutionThe residue was dissolved in toluene
  6. concentrationconcentrated in vacuo
  7. customto give the crude acid chloride as a brown oil
  8. customthe reaction was quenched with water
  9. washThe organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto give a yellow foam
  14. customPurification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane
  15. customyielded a white foam which
  16. customcrystallized upon sonication with ethanol/hexane

Sources & evidence

ORD record
ord-361f7620c64a464aa62a591d83cbb2dc
Source dataset
uspto-grants-2005_05
Patent number
US06900200B2

Reaction notes

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