Oxalyl chloride → (10,11-Dihydro-5H-pyrrolo[2,1-c](1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-biphenyl-4-yl)-methanone

HRID 2246845Notes

Reaction equation

HRID 2246845 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[CH3:17].C(Cl)(=O)C(Cl)=O.[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30][CH2:29][C:28]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]([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[CH3:17])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:29][C:28]=12

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 1554704810,11-Dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepineHCID 219373032,2'-Dimethyl-[1,1'-biphenyl]-4-carboxylic acid

Product 1

HCID 68680291(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-biphenyl-4-yl)-methanoneYield 31.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a suspension of 2,2′-dimethyl-biphenyl-4-carboxylic acid of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1 M aqueous hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g) as a white solid, m.p. 145-148° C.

Workup

  1. concentrationthen concentrated in vacuo
  2. dissolutionthe residue redissolved in dry dichloromethane (200 mL)
  3. concentrationThe solution was concentrated in vacuo
  4. customto afford the crude acid chloride as a brown oil
  5. stirringthe reaction mixture stirred at room temperature under nitrogen for 16 hours
  6. washThe reaction mixture was then washed with 1 M aqueous hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL)
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give a dark foam
  11. customPurification by flash chromatography
  12. customgave a tan solid
  13. customthat was recrystallized from ethyl acetate/hexane

Sources & evidence

ORD record
ord-90eea5c3395e443a9a903849d8eb9d01
Source dataset
uspto-grants-2010_03
Patent number
US07687623B2

Reaction notes

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