Hydrochloric Acid → 4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid

HRID 1685779Notes

Reaction equation

HRID 1685779 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:14])[NH:12][OH:13])=[CH:7][CH:6]=1)[CH3:2].[CH2:16]([N:18]([CH2:21][C:22]1[S:26][C:25]([C:27]([OH:29])=O)=[CH:24][C:23]=1[CH3:30])[CH2:19][CH3:20])[CH3:17].Cl>[Li+].[OH-].CO>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:14]=[C:27]([C:25]3[S:26][C:22]([CH2:21][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[C:23]([CH3:30])[CH:24]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:19]([N:18]([CH2:21][C:22]1[S:26][C:25]([C:27]2[O:29][N:14]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:15])=[O:3])=[CH:6][CH:7]=3)[N:12]=2)=[CH:24][C:23]=1[CH3:30])[CH2:16][CH3:17])[CH3:20]

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 672654805-Diethylaminomethyl-4-methyl-thiophene-2-carboxylic acidHCID 178468924HCID 178468924, compound

Product 2

HCID 672653784-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acidHCID 672656264-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3939Lithium HydroxideSolvent

Procedure

4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester (1.42 g) is prepared starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester (1.01 g, 4.84 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.00 g, 4.40 mmol) according to Method A; LC-MS: tR=0.63 min; [M+1]+=400.12; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 1.45 (t, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 4.44 (q, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.16-8.20 (m, 2H), 8.22-8.25 (m, 2H). This material (1.42 g, 3.58 mmol) is dissolved in 2 M LiOH in methanol (50 mL) and the mixture is stirred at rt for 20 h before it is acidified by adding aq. HCl. The mixture is extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (710 mg) as a white solid; LC-MS: tR=0.52 min; [M+1]+=372.14. b) To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (400 mg, 1.08 mmol) in DMF (5 mL), HOBt (160 mg, 1.19 mmol) followed by EDC HCl (227 mg, 1.19 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (72 mg, 1.19 mmol) is added. The reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3. The washing is extracted back twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 4% of methanol to give the title compound (290 mg) as a white solid; LC-MS: tR=0.47 min; [M+1]+=415.14; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.67-3.72 (m, 2H), 3.73 (s, 2H), 3.90 (t, J=4.8 Hz, 2H), 6.69 (t br, J=5.3 Hz, 1H), 7.68 (s, 1H), 7.91-7.95 (m, 2H), 8.22-8.26 (m, 2H).

Workup

  1. extractionThe mixture is extracted twice with EA
  2. dry with materialThe combined organic extracts are dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product is purified by prep

Sources & evidence

ORD record
ord-b7e7be0ed2d942548b26f4cec3b7a7af
Source dataset
uspto-grants-2012_04
Patent number
US08148410B2

Reaction notes

Loading…