Oxalyl chloride → 10-[(2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5h-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid bis-(3-dimethylamino-propyl)-amide

HRID 2215114Notes

Reaction equation

HRID 2215114 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(Cl)(=O)C(Cl)=O.[CH3:43][N:44]([CH3:55])[CH2:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:54][N:52]([CH3:53])[CH2:51][CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][N:44]([CH3:43])[CH3:55])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:36])[F:34])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81207N'-(3-(Dimethylamino)propyl)-N,N-dimethyl-1,3-propanediamineHCID 81531DiisopropylethylamineHCID 1027808210-(2-methyl-2'-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

Product 1

HCID 1012243010-[(2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5h-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid bis-(3-dimethylamino-propyl)-amideYield 35.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A suspension of 10-[(2-methyl-2′-trifluoromethyl-[1,1 l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) in dichloromethane (5 mL) containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (0.12 mL, 1.38 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes. The cooled solution was evaporated to dryness to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of bis-(3-dimethylamino-propyl)-amine (0.90 mL, 4.04 mmol) and N,N-diisopropylethyl amine (1.1 mL, 6.31 mmol) in dichloromethane (5 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially 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 brown oil. Purification was achieved by preparative HPLC on a Primesphere S C18 column (0.21×15 cm) using a solvent gradient from 60:40:0.1 to 80:20:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was basified with 2.5 N sodium hydroxide then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.24 g) as a white foam, m.p. 55–64 ° C.

Workup

  1. temperaturethe reaction mixture was refluxed for an additional 15 minutes
  2. customThe cooled solution was evaporated to dryness
  3. customto give the crude acid chloride as a brown solid
  4. customthe reaction was quenched with water
  5. washThe organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a brown oil
  10. customPurification
  11. customAfter removal of the acetonitrile in vacuo
  12. extractionthen extracted with dichloromethane
  13. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4a08fe3874f94bd283155732ecd596a2
Source dataset
uspto-grants-2006_09
Patent number
US07109193B2

Reaction notes

Loading…