Water → 3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-(4,5-dihydro-1H-imidazol-1-ylmethyl)thiophene-2-carboxamide

HRID 2300949Notes

Reaction equation

HRID 2300949 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[CH2:31]([NH2:34])[CH2:32][NH2:33].O.[CH:36](OCC)(OCC)OCC>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:33]3[CH2:32][CH2:31][N:34]=[CH:36]3)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 3301EthylenediamineHCID 31214Ethyl orthoformateHCID 16731661N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide

Product 1

HCID 167330063-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-(4,5-dihydro-1H-imidazol-1-ylmethyl)thiophene-2-carboxamideYield 53.8%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Procedure

To N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (1.5 g, 3.0 mmol) in DMF (15 mL), was added ethylene diamine (0.09 g, 15 mmol) at ambient temperature. After 2 hours, the reaction was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried (NaSO4) and concentrated in vacuo to afford the crude amine adduct. To the adduct was added triethyl orthoformate (1.33 g, 9 mmol) in acetic acid (20 mL). After stirring at ambient temperature for 1 hour, the reaction was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried (NaSO4), concentrated in vacuo, and purified by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford 0.87 g of N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (870 mg), trifludroacetic acid salt; NMR (DMSO-d6/TFA) 10.9 (s, 1), 10.3 (s., 1), 9.4 (s, 1), 8.6 (d, 2), 8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.3 (d, 1), 7.2 (d, 1), 4.6 (s, 2), 3.7˜3.9 (m, 7) ppm.

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe ethyl acetate solution was dried (NaSO4)
  3. concentrationconcentrated in vacuo
  4. customto afford the crude amine adduct
  5. extractionextracted with ethyl acetate
  6. dry with materialThe ethyl acetate layer was dried (NaSO4)
  7. concentrationconcentrated in vacuo
  8. custompurified by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1% trifluoroacetic acid

Sources & evidence

ORD record
ord-271025219f384c73b94bb5279d0025f2
Source dataset
uspto-grants-2002_12
Patent number
US06498185B1

Reaction notes

Loading…