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Synthesis process of amlodipine besylate

A kind of technology of amlodipine besylate and synthesis technology, applied in the field of synthesis technology of amlodipine besylate, can solve problems such as unfavorable product quality control, difficult to completely eliminate, increase reaction steps and the like, and achieve product quality controllability The effect of strengthening, reducing synthesis cost and reducing product cost

Inactive Publication Date: 2018-08-28
上海峰林生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Amlodipine needs to be salified earlier during its preparation, and then reacted with besylate, which increases the reaction steps and increases the cost for industrial production
This method is owing to utilize metathesis reaction to prepare amlodipine besylate in addition, so raw material amlodipine salt is difficult to completely eliminate in the obtained amlodipine besylate, and purity is low, unfavorable to the quality control of product

Method used

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  • Synthesis process of amlodipine besylate
  • Synthesis process of amlodipine besylate
  • Synthesis process of amlodipine besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: a kind of synthetic technique of amlodipine besylate, comprises the following steps:

[0036] Step 1, the preparation of N-(2-hydroxyethyl)-phthalimide:

[0037]In the reaction tank, put 133kg of toluene, add 40kg of phthalic anhydride under stirring condition, raise the temperature to 60°C, add 16.4kg of ethanolamine dropwise, after adding, raise the temperature to 110°C, reflux and dehydrate for more than 12 hours, cool down to 15°C, and centrifugally filter. Wash the filter residue with toluene, spin dry, dry, dry at 65°C and a vacuum of -0.1MPa, cool down to normal temperature, and discharge to obtain 51kg of N-(2-hydroxyethyl)-phthaloyl Imine, yield 99%, purity 98.5%;

[0038] Step 2, the preparation of 4-[(2-phthalimide) ethoxy] ethyl acetoacetate:

[0039] Put 350kg of toluene into the reaction tank, stir and heat up, and distill the toluene. After the liquid in the water separator is full, keep reflux and water separation for 60 minutes, and take...

Embodiment 2

[0054] Embodiment 2: A kind of synthesis technique of amlodipine besylate, the difference with embodiment 1 is that step 2 specifically includes: in the reaction tank, drop into 350kg toluene, stir and heat up, distill toluene, wait for water separator After the medium liquid is full, keep reflux for 60 minutes to divide the water, and take samples to measure the water division. When the water content of the reflux liquid is ≤0.2%, change the reflux to distillation, distill out toluene, stir and lower the temperature, and when the temperature in the tank drops to 45°C, give Fill the reaction tank with nitrogen, continue to cool down to 5°C, add 40kg of N-(2-hydroxyethyl)-phthalimide under stirring, then add 20kg of sodium hydride, after the addition is complete, cover the tank tightly, Stir under the condition of ℃, pump 38.4kg of ethyl 4-chloroacetoacetate and 45kg of toluene into the metering tank and mix evenly, add the toluene solution of ethyl 4-chloroacetoacetate dropwise...

Embodiment 3

[0055] Embodiment 3: a kind of synthesis technique of amlodipine besylate, the difference with embodiment 1 is that step 4 specifically includes: in the reaction tank, drop into 2-(2-chloro-benyl)-4-[ The toluene solution of (2-phthalimide)ethoxy]ethyl acetoacetate was distilled under reduced pressure below 65°C, the toluene was recovered, 56kg of n-hexane was added, stirred for 25 minutes, cooled to 25°C, and allowed to stand After 15 minutes, take out the n-hexane lotion, then add 56kg of n-hexane, stir at 25°C, let stand, then draw out the n-hexane lotion, distill the remaining n-hexane under reduced pressure at 25°C, add 240kg of glacial acetic acid , stir to dissolve the material, add 64kg methyl 3-aminocrotonate, maintain the internal temperature at 25°C, stir and react for more than 65 hours, centrifugally filter, wash the filter residue with 50kg glacial acetic acid, spin dry, and dry at 60°C until it loses weight on drying ≤5%, cooled to normal temperature, and discha...

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Abstract

The invention discloses a synthesis process of amlodipine besylate, relates to the technical field of medicine synthesis and solves the problems of low product purity and poor product quality controllability of products prepared by the existing synthesis process. According to the synthesis process, phthalic anhydride is used as raw materials; the parameters of the synthesis process are controlled;the technical flow process is shortened; the synthesis cost is reduced; the product yield is as high as 91 percent; the purity of the prepared amlodipine besylate is as high as 99.5 percent. The self-made amlodipine besylate are used as raw materials for further preparing the amlodipine besylate tablets; the product cost is reduced; the product quality controllability is high.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, more specifically, it relates to a synthesis process of amlodipine besylate. Background technique [0002] Amlodipine besylate is a dihydropyridine calcium antagonist (calcium antagonist or slow channel blocker). The contraction of cardiac and smooth muscles depends on the entry of extracellular calcium ions into the cells through specific ion channels. This product selectively inhibits the transmembrane entry of calcium ions into smooth muscle cells and cardiomyocytes, and its effect on smooth muscle is greater than that on cardiac muscle. [0003] In the Chinese invention patent whose publication number is CN1263525A, a kind of preparation method of amlodipine besylate is disclosed. Amlodipine is first formed into a salt with organic or inorganic acid, and then mixed with alkali metal besylate in water- Prepared by reaction in alcohol mixed solvent, the yield is 81-90%. [0004] S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 郑玉林陈玉双刘丽娟高欢欢于曜荧
Owner 上海峰林生物科技有限公司
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