Acetic Acid → N-(2-aminophenyl)-5-[(benzylamino)methyl]-1-benzothiophene-2-carboxamide

HRID 1172872Notes

Reaction equation

HRID 1172872 reaction equation
[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([O:13]CC)=O)=[CH:8][C:7]=2[CH:16]=1)=O.C(O)(=O)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Li+].[OH-].[CH:31]1[CH:32]=[CH:33][C:34]2[N:39](O)N=[N:37][C:35]=2[CH:36]=1.C1(N)C=CC=CC=1N>ClCCCl>[NH2:37][C:35]1[CH:36]=[CH:31][CH:32]=[CH:33][C:34]=1[NH:39][C:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:7]=2[CH:8]=1)=[O:13]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 3939Lithium HydroxideHCID 7243O-PhenylenediamineHCID 7504BenzylamineHCID 757711-HydroxybenzotriazoleHCID 574439705-Formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester

Product 1

HCID 57624561N-(2-aminophenyl)-5-[(benzylamino)methyl]-1-benzothiophene-2-carboxamide

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

A mixture of ethyl 5-formyl-1-benzothiophene-2-carboxylate (100 mg, 0.427 mmol), acetic acid (0.100 mL, 1.78 mmol), NaHB(OAc)3 (270 mg, 1.27 mmol) and benzyl amine (0.150 mL, 1.23 mmol) in 2 mL of 1,2-dichloroethane was stirred overnight. The reaction mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer was dried (Na2SO4), and concentrated. The residue was then dissolved in 2:1 THF/water (3 mL), treated with LiOH (120 mg, 1.2 mmol) and stirred for 5 hours and concentrated. The residue was dried azeotropically with MeCN, dissolved in DMF (2 mL) and treated with EDC (160 mg, 0.84 mmol), HOBt (100 mg, 0.74 mmol) and 1,2-phenylenediamine (140 mg, 1.30 mmol). After stirring for 12 h, the reaction mixture was then concentrated and purified by reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA). The fractions were poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4) and concentrated giving the desired product: 1H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.25-7.35 (m, 3H), 7.21 (d, J=7.6 Hz, 2H), 7.13 (d, J=6.7 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.57 (t, J=7.3 Hz, 1H), 4.96 (br s, 2H), 3.79 (bs s, 2H), 3.67 (br s, 2H); MS: cal'd 388 (MH+), exp 388 (MH+).

Workup

  1. customThe reaction mixture was partitioned between EtOAc
  2. dry with materialthe organic layer was dried (Na2SO4)
  3. concentrationconcentrated
  4. dissolutionThe residue was then dissolved in 2:1 THF/water (3 mL)
  5. stirringstirred for 5 hours
  6. concentrationconcentrated
  7. dry with materialThe residue was dried azeotropically with MeCN
  8. dissolutiondissolved in DMF (2 mL)
  9. stirringAfter stirring for 12 h
  10. concentrationthe reaction mixture was then concentrated
  11. custompurified by reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA)
  12. additionThe fractions were poured into EtOAc
  13. washwashed with sat'd NaHCO3
  14. dry with materialdried (Na2SO4)
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-7666d17652ac45b1853fd82ad3ff168f
Source dataset
uspto-grants-2010_11
Patent number
US07834034B2

Reaction notes

Loading…