Dichloromethane → HCID 15952181, compound

HRID 2244248Notes

Reaction equation

HRID 2244248 reaction equation
[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.ClCCl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][C:36]([C:38]2[N:47]3[C:41]([CH2:42][NH:43][C:44]4[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=4[CH2:46]3)=[CH:40][CH:39]=2)=[O:37])[CH:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:43]2[C:44]3[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=3[CH2:46][N:47]3[C:38]([C:36]([NH:35][CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[O:37])=[CH:39][CH:40]=[C:41]3[CH2:42]2)=[O:18])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]

Participants

8

Reactant 5

HCID 6344DichloromethaneHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 200999564-(2-Acetylphenyl)benzoic acidHCID 22053658N-(3-Pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Product 1

HCID 15952181HCID 15952181, compoundYield 88.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2′-acetyl-biphenyl-4-carboxylic acid of Step A (0.340 g, 1.41 mmol) in dry tetrahydrofuran (30 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (1 drop) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (1.17 mL, 2.34 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (30 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a cream solid. The acid chloride was dissolved in tetrahydrofuran (30 mL); N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 11 (0.300 g, 0.942 mmol) was added, followed by N,N-diisopropylethylamine (0.49 mL, 2.83 mmol) and the reaction mixture stirred at room temperature under nitrogen for 19 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (20 mL), the mixture stirred vigorously for 5 minutes and then partitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL). The organic phase was separated, washed with 2 M sodium hydroxide (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 3.5% methanol in dichloromethane gave a cream foam that was crystallized from ethyl acetate/hexane to afford the title compound (0.45 g, 88%) as a white solid, m.p. 149-150° C.

Workup

  1. concentrationthen concentrated in vacuo
  2. dissolutionthe residue redissolved in dry dichloromethane (30 mL)
  3. concentrationThe solution was concentrated in vacuo
  4. customto afford the crude acid chloride as a cream solid
  5. stirringthe reaction mixture stirred at room temperature under nitrogen for 19 hours
  6. customThe reaction was quenched by the addition of 2 M sodium hydroxide (20 mL)
  7. stirringthe mixture stirred vigorously for 5 minutes
  8. custompartitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL)
  9. customThe organic phase was separated
  10. washwashed with 2 M sodium hydroxide (100 mL), water (100 mL) and brine (100 mL)
  11. dry with materialdried over anhydrous magnesium sulfate
  12. concentrationconcentrated in vacuo
  13. customto give a yellow foam
  14. customPurification by flash chromatography
  15. customgave a cream foam that
  16. customwas crystallized from ethyl acetate/hexane

Sources & evidence

ORD record
ord-77ff8e971bc34948be523a1cbad12dd1
Source dataset
uspto-grants-2010_03
Patent number
US07678787B2

Reaction notes

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