Citric Acid → Methyl 4-{2-[4-({[2-({3-[cyclopropyl(5-methoxy-5-oxopentyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate

HRID 926058Notes

Reaction equation

HRID 926058 reaction equation
[CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:1]1([N:4]([CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 11430Potassium Carbonate2×HCID 79557Methyl 5-bromovalerate2×HCID 71238739Methyl 4-[2-(4-{[(2-{[3-(cyclopropylsulfamoyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate

Product 1

HCID 68207813Methyl 4-{2-[4-({[2-({3-[cyclopropyl(5-methoxy-5-oxopentyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoateYield 72.6%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(cyclopropylsulfamoyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 111 mg of methyl 5-bromopentanoate, 105 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 80° C. overnight. Further, 42 mg of tetrabutyl ammonium iodide was added thereto, followed by stirring at 100° C. for 3 hours. In addition, 370 mg of methyl 5-bromopentanoate, 140 mg of tetrabutyl ammonium iodide, and 262 mg of potassium carbonate were added thereto, followed by stirring at 100° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 213 mg of methyl 4-{2-[4-({[2-({3-[cyclopropyl(5-methoxy-5-oxopentyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a yellow solid.

Workup

  1. stirringby stirring at 100° C. for 3 hours
  2. stirringby stirring at 100° C. overnight
  3. extractionfollowed by extraction with ethyl acetate
  4. washThe organic layer was washed with water and saturated brine in this order
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (hexane-chloroform)

Sources & evidence

ORD record
ord-e9bd0e8c5ccc44aebd2310588e2695a5
Source dataset
uspto-grants-2016_03
Patent number
US09284295B2

Reaction notes

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