* 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.
Step 3 4,6-Dichloro-pyridazine-3-carboxylic acid methyl ester A mixture of 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (10.5 g, 61.7 mmol) and POCl3 (70 mL) was heated to 95° C. for 5 h. The excess POCl3 was removed under reduced pressure, then the crude residue was added to ice-water (250 mL) and extracted with ethyl acetate (3*100 mL). The combined extracts were dried then concentrated to give a crude residue which was purified by chromatography (silica, 100-200 mesh, 30percent ethyl acetate in hexane) to give 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (9.2 g, 72percent) as an off white solid. LC-MS: 207.0 [M+H]+.
Reference：
[1] Patent: US2013/178478, 2013, A1, . Location in patent: Paragraph 0301;0302
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2683 - 2691
[3] Patent: US2004/77653, 2004, A1, . Location in patent: Page 18
2
[ 83878-89-1 ]
[ 372118-00-8 ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: With triphenylphosphine In diethyl ether at 20℃; for 24 h; Stage #2: With acetic acid In water for 10 h; Reflux
Step 2 4,6-Dihydroxy-pyridazine-3-carboxylic acid methyl ester A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl ester (50.0 g, 249.8 mmol) and triphenylphosphine (65.5 g, 249.8 mmol) in diethyl ether (500 mL) was stirred at room temperature for 24 h. The organic solvent was removed under vacuum and then acetic acid (500 mL) and water (50 mL) were added to the residue and the mixture was refluxed for 10 h. The reaction mixture was concentrated under reduced pressure to obtain a viscous residue. Trituration with ethyl acetate generated a yellow solid that was purified by chromatography (silica, 100-200 mesh, 1-5percent methanol in dichloromethane) to give 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (12.8 g, 30percent) as a yellow solid. LC-MS 169.2 [M+H]+.
Reference：
[1] Patent: US2013/178478, 2013, A1, . Location in patent: Paragraph 0299;0300
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2683 - 2691
[3] Patent: US2004/77653, 2004, A1, . Location in patent: Page 18
Step 2 4,6-Dihydroxy-pyridazine-3-carboxylic acid methyl ester A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl ester (50.0 g, 249.8 mmol) and triphenylphosphine (65.5 g, 249.8 mmol) in diethyl ether (500 mL) was stirred at room temperature for 24 h. The organic solvent was removed under vacuum and then acetic acid (500 mL) and water (50 mL) were added to the residue and the mixture was refluxed for 10 h. The reaction mixture was concentrated under reduced pressure to obtain a viscous residue. Trituration with ethyl acetate generated a yellow solid that was purified by chromatography (silica, 100-200 mesh, 1-5% methanol in dichloromethane) to give 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (12.8 g, 30%) as a yellow solid. LC-MS 169.2 [M+H]+.
A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl or diethyl ester (0.1 mol) and PPh3 (26.3 g, 0.1 mol) in ether (200 mL) is stirred at room temperature for 24 hours. Ether is removed in vacuo and HOAc (200 mL) and water (20 mL) are added to the residue. The mixture is then refluxed for 10 hours under nitrogen. The solvent is removed in vacuo and CHCl3 (150 mL), MeOH (150 mL) and silica gel (65 g) are added to the residue. The mixture is evaporated to dryness. The resultant yellow powder is then packed on the top of a column (480 g silica) and eluted with CHCl3:MeOH, 50:1 to 5:1. The desired 4,6 dihydroxy-pyridazine-3-carboxylic acid methyl or ethyl ester is obtained as a light yellow solid.
Step 3 4,6-Dichloro-pyridazine-3-carboxylic acid methyl ester A mixture of <strong>[372118-00-8]4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester</strong> (10.5 g, 61.7 mmol) and POCl3 (70 mL) was heated to 95 C. for 5 h. The excess POCl3 was removed under reduced pressure, then the crude residue was added to ice-water (250 mL) and extracted with ethyl acetate (3*100 mL). The combined extracts were dried then concentrated to give a crude residue which was purified by chromatography (silica, 100-200 mesh, 30% ethyl acetate in hexane) to give 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (9.2 g, 72%) as an off white solid. LC-MS: 207.0 [M+H]+.
64.3%
With trichlorophosphate; for 3h;Reflux;
A slurry of <strong>[372118-00-8]methyl 4,6-dihydroxypyridazine-3-carboxylate</strong> (11.7 g, 68.8 mmol) in POCl3 (110 mL, 1180 mmol) was heated to reflux for 3h during which time the mixture became a nearly homogeneous dark brown solution. The reaction mixture was cooled to rt, allowed to stand overnight and concentrated in vacuo. The resulting dark brown residue was dissolved in DCM (?300 mL) and was slowly poured onto ?500 mL of crushed ice with swirling of the flask. After the addition was complete, water was slowly added (?200 mL) until the mixture became stirrable and the mixture was stirred while warming to rt over ?3 h. The resulting phases were separated and the aqueous portion was extracted with additional DCM (3*100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, decanted and concentrated under vacuum to afford a white solid as the pure product, methyl 4,6-dichloropyridazine-3-carboxylate (9.16 g, 44.2 mmol, 64.3% yield). Material was used as is without any further purification. MS (M+1) m/z: 206.9 (MH+). LC retention time 0.80 min [A].
With trichlorophosphate; at 95℃; for 4h;
Step 3.Preparation of 4,6-dichloro-pyridazine-3-carboxylic acid methyl or ethyl ester 5 A mixture of 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl or ethyl ester (50 mmol) and POCl3 (90 ML) is heated at 95 C. for 4 hours.The excess POCl3 is evaporated in vacuo and to the residue cooled to 0 C. was added ice (150 g) followed by EtOAc (200 ML).The layers are separated and the aqueous layer is extracted with EtOAc (2*100 ML).The combined extracts are washed with brine (200 ML), dried (Na2SO4) and evaporated in vacuo.This residue is purified by flash column chromatography (225 g silica gel, eluted with 4:1 hexane, EtOAc).The desired 4,6 dichloro-pyridazine-3-carboxylic acid methyl ester is obtained as a white solid, while the 4,6 dichloro-pyridazine-3-carboxylic acid ethyl ester is a colorless liquid.
To a mixture of the crude product dimethyl 2-diazo-3-oxopentanedioate (20.92 g, 104 mmol) in diethyl ether (250 mL) at rt was added Ph3P (27.3 g, 104 mmol) and the resulting mixture was stirred at rt for 1 day. The heterogeneous reaction mixture was concentrated to remove the ether and the resulting solids were taken up in AcOH (240 mL) and water (24 mL) and refluxed for 4 h. The reaction was cooled and concentrated in vacuo to give a pale yellow semi solid which was co-evaporated with 2 portions of toluene (2*50 mL) to remove the residual AcOH. The resulting solids were then slurried in 75 mL of sat. aq sodium carbonate and 75 mL of water and the mixture was extracted with DCM (4*200 mL) to remove the impurities. The aqueous layers were filtered to give a clear yellow solution which was cooled in an ice bath and carefully made acidic by a dropwise addition of 6N aq HCl. Once the desired pH was reached (?1-2), a heavy cream colored precipitate formed. The mixture was stirred at 0 C. for ?5 min, then the solid was collected by vacuum filtration and rinsed sparingly with ice cold water. The solid was allowed to partially air dry in the funnel then the still moist solid was transferred into an rb flask and allowed to dry under vacuum over the weekend to give methyl 4,6-dihydroxypyridazine-3-carboxylate (11.76 g, 69.1 mmol, 66.5% yield).
Multi-step reaction with 3 steps
1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 16 h / 20 °C
2: trichlorophosphate / 4 h / 100 °C
3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; dichloromethane / 0.5 h / 0 - 20 °C
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