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A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 3 (2.5 g, 14.8 mmol), phosphorus oxychloride (45 mL, 481 mmol), and pyridine (4.57 mL, 55 mmol) and refluxed for 2.5 h. The reaction was cooled to rt and poured over ice. The mixture was separated and the aqueous layer was extracted with chloroform (4 x 75 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a dark yellow solid. Desired 4,7- dichlorothieno[2,3-d]pyridazine (Intermediate B; 1.5 g, 7.3 mmol; 49percent yield); mp = 260-263 0C; 1H NMR (DMSO-d6) 8.55 (d, J = 5.7, 1), 7.80 (d, J = 5.7, 1); ES MS (M+H)+= 206; TLC (hexane- EtOAc, 70:30); Rf = 0.56. See also Robba, M.; Bull. Soc. Chim. Fr.; 1967, 4220-4235.
49%
for 2.5 h; Heating / reflux
A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 3 (2.5 g, 14.8 mmol), phosphorus oxychloride (45 mL, 481 mmol), and pyridine (4.57 mL, 55 mmol) and refluxed for 2.5 h. The reaction was cooled to rt and poured over ice. The mixture was separated and the aqueous layer was extracted with chloroform (4.x.75 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a dark yellow solid. Desired 4,7-dichlorothieno[2,3-d]pyridazine (Intermediate B; 1.5 g, 7.3 mmol; 49percent yield); mp=260-263° C.; 1H NMR (DMSO-d6) 8.55 (d, J=5.7, 1), 7.80 (d, J=5.7, 1); ES MS (M+H)+=206; TLC (hexane-EtOAc, 70:30); Rf=0.56. See also Robba, M.; Bull. Soc. Chim. Fr.; 1967, 4220-4235.
Reference:
[1] Patent: WO2007/118602, 2007, A1, . Location in patent: Page/Page column 57
[2] Patent: US6689883, 2004, B1, . Location in patent: Page column 50
[3] Bulletin de la Societe Chimique de France, 1967, p. 4220 - 4235
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1964, vol. 259, p. 4726 - 4728
With pyridine; trichlorophosphate; for 2.5h;Heating / reflux;
A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 3 (2.5 g, 14.8 mmol), phosphorus oxychloride (45 mL, 481 mmol), and pyridine (4.57 mL, 55 mmol) and refluxed for 2.5 h. The reaction was cooled to rt and poured over ice. The mixture was separated and the aqueous layer was extracted with chloroform (4 x 75 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a dark yellow solid. Desired 4,7- dichlorothieno[2,3-d]pyridazine (Intermediate B; 1.5 g, 7.3 mmol; 49% yield); mp = 260-263 0C; 1H NMR (DMSO-d6) 8.55 (d, J = 5.7, 1), 7.80 (d, J = 5.7, 1); ES MS (M+H)+= 206; TLC (hexane- EtOAc, 70:30); Rf = 0.56. See also Robba, M.; Bull. Soc. Chim. Fr.; 1967, 4220-4235.
49%
With pyridine; trichlorophosphate; for 2.5h;Heating / reflux;
A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 3 (2.5 g, 14.8 mmol), phosphorus oxychloride (45 mL, 481 mmol), and pyridine (4.57 mL, 55 mmol) and refluxed for 2.5 h. The reaction was cooled to rt and poured over ice. The mixture was separated and the aqueous layer was extracted with chloroform (4×75 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a dark yellow solid. Desired 4,7-dichlorothieno[2,3-d]pyridazine (Intermediate B; 1.5 g, 7.3 mmol; 49% yield); mp=260-263 C.; 1H NMR (DMSO-d6) 8.55 (d, J=5.7, 1), 7.80 (d, J=5.7, 1); ES MS (M+H)+=206; TLC (hexane-EtOAc, 70:30); Rf=0.56. See also Robba, M.; Bull. Soc. Chim. Fr.; 1967, 4220-4235.