* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 70℃; for 1 h;
Synthesis of Compound J.1. A flask was charged with 3,6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hour and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CH2Cl2 (2.x.250 mL). The combined organic extracts were filtered through a cotton plug, washed with aqueous 1 N NaOH (70 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (20percent EtOAc/hexanes) afforded the title compound (1.32 g, 64percent) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.5 (s, 1H), 1.5 (s, 9H); Rf=0.5 (80percent EtOAc/hexanes).
64%
With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 70℃; for 1 h;
A flask was charged with 3,6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hr and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CH2Cl2 (2.x.250 mL). The combined organic extracts were filtered through a cotton plug, washed with aqueous 1 N NaOH (70 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (20percent EtOAc/hexanes) afforded the title compound (1.32 g, 64percent) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.5 (s, 1 H), 1.5 (s, 9 H); Rf=0.5 (80percent EtOAc/hexanes).
Reference：
[1] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 39
[2] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 84
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7089 - 7092
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6030 - 6033
2
[ 141-30-0 ]
[ 22808-29-3 ]
Reference：
[1] Patent: US4628088, 1986, A,
3
[ 141-30-0 ]
[ 7664-93-9 ]
[ 75-98-9 ]
[ 22808-29-3 ]
Yield
Reaction Conditions
Operation in experiment
53%
With silver nitrate In hexane; water
a 3,6-Dichloro-4-(1,1-dimethylethyl)pyridazine Concentrated sulphuric acid (53.6 ml, 1.0 mol) was added carefully to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in water (1.25 l). This mixture was then heated to 70° C. (internal temperature) before the addition of trimethylacetic acid (47.5 ml, 0.41 mol). A solution of silver nitrate (11.4 g, 0.07 mol) in water (20 ml) was then added over approximately one minute. This caused the reaction mixture to become milky in appearance. A solution of ammonium persulphate (230 g, 1.0 mol) in water (0.63 l) was then added over 20-30 minutes. The internal temperature rose to approximately 85° C. During the addition the product formed as a sticky precipitate. Upon complete addition the reaction was stirred for an additional 10 minutes, then allowed to cool to room temperature. The mixture was then poured onto ice and basified with concentrated aqueous ammonia, with the addition of more ice as required to keep the temperature below 10° C. The aqueous was extracted with dichloromethane (3*300 ml). The combined extracts were dried (MgSO4), filtered and evaporated to give 55.8 g of crude product as an oil. This was purified by silica gel chromatography using 0-15percent ethyl acetate in hexane as eluent to give 37.31 g (53percent) of the desired compound. Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ1.50 (9H, s), 7.48 (1H, s); MS (ES+) m/e 205 [MH]+, 207 [MH]+.
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