Isobenzofuranone derivatives, their preparation method and their application in medicine
A technology for medicines and compounds, applied in the field of isobenzofuranone derivatives, their preparation methods and pharmaceutical compositions containing the derivatives, can solve the problems of increasing the morbidity and mortality of cardiovascular diseases and the like
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Embodiment 1
[0145] (R)-5-(2-(4-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)piperazin-1-yl)-1-hydroxyethyl)-4- Methylisobenzofuran-1(3H)-one
[0146]
[0147] first step
[0148] 3-Chloro-6-(1H-tetrazol-1-yl)pyridazine
[0149] 6-chloropyridazin-3-amine 1a (200mg, 1.54mmol, prepared by the method disclosed in the patent application "WO2012048258"), sodium azide (100mg, 1.54mmol), and triethyl orthoformate (912mg , 6.16mmol) was dissolved in 5mL of acetic acid, stirred and reacted at 80°C for 3 hours. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 3-chloro-6 -(1H-tetrazol-1-yl)pyridazine 1b (200 mg, white solid), the product was directly carried on to the next reaction without purification.
[0150]MS m...
Embodiment 2
[0165] (R)-5-(2-(4-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)piperazin-1-yl)-1-hydroxyethyl)-4- Methylisobenzofuran-1(3H)-one
[0166]
[0167] first step
[0168] 2-Bromo-5-(1H-tetrazol-1-yl)pyrazine
[0169] Dissolve 5-bromopyrazin-2-amine 2a (500mg, 2.87mmol), sodium azide (187mg, 2.87mmol), and triethyl orthoformate (1.7g, 11.48mmol) in 10mL of acetic acid, 80°C The reaction was stirred for 2 hours. Cooled to room temperature, a solid precipitated, suction filtered, washed with water, and dried in vacuo to obtain the crude title product 2-bromo-5-(1H-tetrazol-1-yl)pyrazine 2b (700mg, yellow solid), the product was directly proceed to the next reaction.
[0170] MS m / z(ESI):229.0[M+1]
[0171] second step
[0172] tert-butyl 4-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)piperazine-1-carboxylate
[0173] 2-Bromo-5-(1H-tetrazol-1-yl)pyrazine 2b (363mg, 1.68mmol), piperazine-1-carboxylic acid tert-butyl ester (300mg, 1.68mmol), N,N-diiso Propylethylamine (1.5 mL, 8.52 mmol) was disso...
Embodiment 3
[0185] (R)-5-(2-(4-(5-(1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)-1-hydroxyethyl)-4-methyl Isobenzofuran-1(3H)-one
[0186]
[0187] first step
[0188] tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate
[0189] Dissolve 2-chloro-5-nitropyrimidine 3a (500mg, 3.13mmol), piperazine-1-carboxylate tert-butyl ester (584mg, 3.13mmol), potassium carbonate (540mg, 4mmol) In methylacetamide, heated to 80°C and continued to stir for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V:V=10:1), filtered, the filtrate was concentrated under reduced pressure, the residue was slurried with ethanol, filtered, and dried to obtain the title Product tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate 3b (856 mg, yellow solid), yield: 88%. MS m / z(ESI):310.2[M+1]
[0190] second step
[0191] tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate
...
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