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Synthetic method of 3-chlorine-5-aminopyridazines serving as medicine and pesticide intermediates

A technology of aminopyridazine and synthesis method, which is applied in the field of synthesis of pharmaceutical and pesticide intermediates, can solve the problems of large waste acid waste gas emission, unsuitable for industrial production, cannot be used, etc., achieves improvement of total yield, avoids high carcinogenic chromium Metal, the effect of increasing productivity

Active Publication Date: 2014-12-17
JINAN TRIO PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] This method has many steps, complex operation, low total yield (29.2%), and is not suitable for industrial production. The large amount of waste acid and waste gas caused by the extensive use of phosphorus oxychloride and thionyl chloride is large, and what is more serious is the use of metal Chromium and hydrazine are recognized as strong carcinogens and cannot be used in pharmaceuticals

Method used

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  • Synthetic method of 3-chlorine-5-aminopyridazines serving as medicine and pesticide intermediates
  • Synthetic method of 3-chlorine-5-aminopyridazines serving as medicine and pesticide intermediates
  • Synthetic method of 3-chlorine-5-aminopyridazines serving as medicine and pesticide intermediates

Examples

Experimental program
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Effect test

Embodiment 1

[0088] Heat a mixture of 147.5 grams (1.00 moles) of chloral, 200 milliliters of toluene and 4.9 grams (0.064 moles) of ammonium acetate to reflux (the internal temperature is 87 ° C), and start to drop a 40% mass fraction of chloroacetaldehyde aqueous solution , and use a water separator to separate the water. The amount of addition is 127 grams (0.65 moles) of 100% chloroacetaldehyde. After the addition is complete, reflux and stir for 3 hours, add 9.8 grams of p-toluenesulfonic acid (0.057 moles), and continue to reflux for 4 hours , stop responding. The reaction solution was cooled to room temperature, evaporated to dryness, added 5000 ml of dichloromethane to dilute and filtered, the filtrate was concentrated under reduced pressure, the residue was distilled under reduced pressure, and the fraction at 90-100°C was collected under 12 mm Hg to obtain product 2. 4,4,4-Tetrachlorocrotonaldehyde is 78 grams of yellow oily liquid. The yield is 75%.

example 2

[0090] Dissolve 207.5 grams (1.00 moles) of 2,4,4,4-tetrachlorocrotonaldehyde in 1100 milliliters of tetrahydrofuran, cool to 15°C, add dropwise 118 grams (1.06 moles) of semicarbazide hydrochloride, 440 milliliters of water, and 150 milliliters of tetrahydrofuran The mixture was added dropwise under temperature control at 15°C. Stirring was maintained at this temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, THF was removed, 3000 ml of water was added, the temperature was lowered to 5°C, a solid precipitated, filtered, and the filter cake was recrystallized with dichloromethane petroleum ether to obtain pure 3,5-dichloropyridazine as a white solid 90 gram. The yield is 60%. 1 HNMR (600MHz, CDCl 3 ) δ ppm 7.61 (s, 1H), 9.14 (s, 1H).

example 3

[0092] Dissolve 149 grams (1.00 moles) of 3,5-dichloropyridazine in 750 milliliters of 1,4-dioxane, add 680 milliliters of 25% concentrated ammonia (10 moles), and place in a stainless steel reactor , after sealing, the temperature was raised to 60°C, and the reaction was carried out for 8 hours. The reaction solution was cooled to room temperature and suction filtered, the filtrate was extracted with ethyl acetate (1000 ml × 3), the organic phase was dried and concentrated to obtain a gray solid crude product, which was recrystallized from ethanol to obtain an off-white solid 3-chloro-5-aminopyridazine 104.5 gram. The yield is 81%. 1 HNMR (600MHz, d 6 -DMSO) δ ppm 6.65 (d, 1H, J =2.4), 6.83 (s, 2H), 8.48 (d, 1H, J =2.4).

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Abstract

The invention relates to a synthetic method of 3-chlorine-5-aminopyridazines serving as medicine and pesticide intermediates. A process route comprises chloroacetaldehyde and trichloracetic aldehyde serving as initial raw materials, three steps of reactions including condensation, cyclization and amination are carried out to prepare the 3-chlorine-5-aminopyridazines. In order to further improve technical effects of the synthetic method, an inventor of the synthetic method conducts an optimization evaluation on process conditions such as using quantity proportion of the raw material, used solvent types and reaction temperature and time in each step. Total recovery of 3-chlorine-5-aminopyridazines products prepared by using optimized process conditions is improved from 29.2% to 36.5%.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a synthesis method of medicine and pesticide intermediates. Background technique [0002] 3-Chloro-5-aminopyridazine (or 4-amino-6-chloropyridazine, CAS No.: 29049-45-4) is a commonly used intermediate in chemical synthesis, and has been widely used in the preparation of medicines and pesticides in recent years. Research and development, such as anticancer drugs (US2004 / 54186) and plant growth regulators (US1988 / 4728355). [0003] The synthesis of 3-chloro-5-aminopyridazine is mainly obtained by hydrolyzing 3-chloro-5-amino-6-hydrazine with sodium hydroxide at present, such as US1988 / 4728355, US1976 / 3978057 and J. Chem. Soc., Perkin Trans. 1, 1974, 696-698., and 3-chloro-5-amino-6-hydrazine pyridazine needs a very complicated multi-step reaction to prepare. Its chemical reaction formula is as follows: [0004] [0005] This method has many steps, complex operation, low t...

Claims

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Application Information

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IPC IPC(8): C07D237/20
Inventor 路国梁刘凤军孙学英齐放高砚芳
Owner JINAN TRIO PHARMATECH
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