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Synthesis method of mivacurium chloride intermediate

A synthesis method, the technology of mivacurium chloride, applied in the field of synthesis of mivacurium chloride intermediates, can solve the problems that are not conducive to safe production and environmental protection, high requirements for explosion and fire protection, and high reaction temperature, so as to avoid the threat of production safety , few steps, high reaction yield

Active Publication Date: 2022-02-18
GUANGDONG JIABO PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Preparation of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl) as described in the above-mentioned patents, papers and published articles Although the method of -3,4-dihydroisoquinoline has certain advantages, the defect is also obvious. 3,4-dimethoxyphenethylamine is an unstable compound, and it is combined with 3,4,5- Trimethoxyphenylacetic acid is refluxed and dehydrated in xylene to prepare amide. The high temperature of 140°C is very easy to degrade and destroy it to produce impurities, and then use phosphorus oxychloride to reflux and dehydrate in toluene to prepare 6,7-dimethoxy- 1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline, high reaction temperature, prone to side reactions to produce by-products, high energy consumption for two-step reactions, and trichloroxy Phosphorus will release hydrogen chloride gas during the reaction, which will corrode equipment and pollute the environment. Toluene and xylene used are toxic and harmful flammable and explosive chemical raw materials, and toluene is a restricted precursor solvent. The two are refluxed at high temperature Response, high level of explosion-proof and fire-proof requirements, extremely unfavorable for safe production and environmental protection

Method used

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  • Synthesis method of mivacurium chloride intermediate
  • Synthesis method of mivacurium chloride intermediate
  • Synthesis method of mivacurium chloride intermediate

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Effect test

Embodiment 1

[0037] A method of synthesis of a riceus chloride intermediate 6,7-dimethoxy-1- (3,4,5-trimethoxy) -3,4-dihydroisoquinoline The first step is carbonate as a solvent, 3,4,5-trimethoxyethylethylene acetic acid, 3,4-dimethoxyethylethylamine and 1- (3-dimethylaminopropyl) -3- (Ethyl carbon diimide hydrochloride) has a molar ratio of 1: 1.05: 1.2; second step reaction with dichloromethane as a solvent, N- (3,4-dimethoxybenylethylthyl) -2 (3,4,5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine molar ratio of 1: 1.1: 1.1; the total reactivity rate is 91.20%; the specific synthesis method is as follows:

[0038] (1) N- (3,4-dimethoxyphenyl) -2- (3,4,5-trimethoxyphenyl) acetamide synthesis:

[0039] 3,4,5-trimethoxycene (2.26 g, 10.00 mmol) and 3,4-dimethoxytine (1.90 g, 10.49 mmol) were weighed in a 100 ml round bottom flask equipped with stirre. Add 50 mL of dichloromethane, stirred under ice water bath and stirred and dissolved 1- (3-dimethylaminoprop...

Embodiment 2

[0045] A method of synthesis of a riceus chloride intermediate 6,7-dimethoxy-1- (3,4,5-trimethoxy) -3,4-dihydroisoquinoline The first step is to N, N-dimethylformamide is solvent, 3,4,5-trimethoxyethyleneethylene acetic acid, 3,4-dimethoxytinthylamine and 1- (3-dimethyl amino) The molar ratio of propyl) -3- (ethyl carbon diimide hydrochloride) is 1: 1.05: 1.2; the second step reaction is solvent with dichloromethane, N- (3,4-dimethoxybenzene) Basethyl) -2- (3,4,5-trimethoxyenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine molar ratio of 1: 1.1: 1.1; the total yield of reaction is 88.35% The specific synthesis method is as follows:

[0046] (1) N- (3,4-dimethoxyphenyl) -2- (3,4,5-trimethoxyphenyl) acetamide synthesis:

[0047] Those 3,4,5-trimethoxyethylethylacetate (226 g, 1 mol) and 3,4-dimethoxy) and 3,4-dimethoxy) and 3,4-dimethoxycene (190 g, 1.05 mol) were added. 500 ml n, N-dimethylformamide, stirred under ice water bath and dissolved 1- (3-dimethylami...

Embodiment 3

[0051] A method of synthesis of a riceus chloride intermediate 6,7-dimethoxy-1- (3,4,5-trimethoxy) -3,4-dihydroisoquinoline The first step is carbonate as a solvent, 3,4,5-trimethoxyethylethylene acetic acid, 3,4-dimethoxyethylethylamine and 1- (3-dimethylaminopropyl) -3- (Ethyl carbon diimide hydrochloride) has a molar ratio of 1: 1.0: 1.1; second step reaction with dichloromethane as a solvent, N- (3,4-dimethoxyphenylthyl) -2 - (3,4,5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine molar ratio were 1: 1.2: 1.2; the total rate of reaction was 84.63%; the specific synthesis method is as follows:

[0052] (1) N- (3,4-dimethoxyphenyl) -2- (3,4,5-trimethoxyphenyl) acetamide synthesis:

[0053]3,4,5-trimethoxyethylene (2.26 g, 10.00 mmol) and 3,4-dimethoxytine (1.81 g, 10.00 mmol) were weighed in 100 ml round bottom flasks equipped with stirre. Add 50 mL of dichloromethane, stirred under ice water bath and stirred and dissolved 1- (3-dimethylaminop...

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Abstract

The invention discloses a synthesis method of a mivacurium chloride intermediate 6, 7-dimethoxy-1-(3, 4, 5-trimethoxybenzyl)-3, 4-dihydroisoquinoline, and belongs to the technical field of organic synthesis. According to the technical scheme, EDCI is used as a dehydrating agent, 3, 4, 5-trimethoxy phenylacetic acid and 3, 4-dimethoxy phenylethylamine are subjected to efficient dehydration at the temperature of 0-30 DEG C, then prepared amide is subjected to efficient cyclization at the temperature of 0-30 DEG C through trifluoromethanesulfonic anhydride and 2-fluoropyridine, and a product is obtained; according to the technical scheme provided by the invention, the reaction is carried out at the temperature of 0-30 DEG C, so that the damage of the high-temperature reflux reaction to the unstable raw material 3, 4-dimethoxyphenylethylamine can be avoided, and the high energy consumption of the high-temperature reflux and the threat to the production safety can also be avoided; meanwhile, the synthesis method has few steps, is easy to operate, does not need to use complex equipment, and has high reaction yield, the yield of each step is more than 90%, the total yield of two steps can reach 91.2%, and the prepared product has high purity which can reach 99.88%; therefore, the synthesis method can be applied to actual industrial production.

Description

Technical field [0001] The present invention belongs to the art of organic synthesis, and more particularly to a method of synthesizing a melamine chloride intermediate, the mikin chloride intermediate is 6,7-dimethoxy-1- (3, 4, 5-three) Oxybenzyl) -3,4-dihydroisoquinoline. Background technique [0002] The benzoquinoline compound is a non-polarized muscle relaxant approved by the US FDA in 1992. Because of its shortness of action, no accumulation, fast, clinical use to cardiovascular system, cranial There is no effect in internal pressure and intraocular pressure, and the characteristics of histamine release effect are small, so it is used for tracheal intubation and maintaining muscle pine, and can be used in intravenous administration of neurosuscies. Surnse control, It is very suitable for children to conduct anesthesia surgery, which has received more and more applications and concerns, and their molecular formulas are as follows: [0003] [0004] The key intermediate 5'-...

Claims

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Application Information

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IPC IPC(8): C07D217/20
CPCC07D217/20Y02P20/55
Inventor 王小刚袁民政
Owner GUANGDONG JIABO PHARM CO LTD