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Preparation method of hydrochloric acid cyclobenzaprine

A technology of cyclobenzaprine hydrochloride and alcohol hydrochloride, applied in the field of medicine and chemical industry, can solve the problems of cumbersome process, large amount of high-salt wastewater, time and energy consumption of concentrated solvents, etc.

Active Publication Date: 2015-05-20
佛山市隆信医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition to using a large amount of expensive THF, the process has a low yield, and the concentrated solvent consumes a lot of time and energy, and also produces a large amount of high-salt wastewater
This shows that by the above-mentioned process of synthesizing cyclobenzaprine hydrochloride is loaded down with trivial details, and produces a large amount of high-salt waste water

Method used

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  • Preparation method of hydrochloric acid cyclobenzaprine
  • Preparation method of hydrochloric acid cyclobenzaprine
  • Preparation method of hydrochloric acid cyclobenzaprine

Examples

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preparation example Construction

[0024] The embodiment of the present invention discloses a preparation method of cyclobenzaprine hydrochloride, comprising the following steps:

[0025] a) Reaction of dibenzocyclohepten-5-one of formula (IV) with N,N-dimethyl-3-propylamine magnesium chloride of formula (III) in a solution of tetrahydrofuran and toluene , to obtain 5-(3-(dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol as shown in (V);

[0026] b) reacting one of hydrogen chloride gas or hydrogen chloride alcohol solution with the 5-(3-(dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol to obtain 5-(3-(Dimethylamino)propyl)5H-dibenzo[a,d]cyclohepten-5-ol hydrochloride as (VII);

[0027] c) dehydrating the 5-(3-(dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol hydrochloride to obtain cyclobenzaprine hydrochloride.

[0028] According to the present invention, the reaction formula of preparing described cyclobenzaprine hydrochloride is shown in the following formula:

[0029]

[0030] The prepa...

Embodiment 1

[0044] A 1000mL dried glass-jacketed reaction kettle was added under nitrogen protection with 11.77g (484mmol) of metal magnesium chips, 80mL of anhydrous tetrahydrofuran (THF) and 12mL of a toluene solution of N,N-dimethyl-3-chloropropylamine, in which N , the content of N-dimethyl-3-chloropropylamine is 25wt%, and 0.2g of iodine particles are added, after initiating the reaction, a total of 49.7g (404mmol) of N,N-dimethyl-3-chloropropylamine ( II) in toluene solution, and then stirred at 80-100°C for 1 hour to obtain N,N-dimethyl-3-propylamine magnesium chloride toluene / THF solution.

[0045] 75g (364mmol) of dibenzocyclohepten-5-one and 340ml of toluene were added dropwise to the toluene / THF solution of N,N-dimethyl-3-propylamine magnesium chloride at a temperature below 35°C, and stirred for 1 ~4 hours, detected by HPLC; 80 g of saturated ammonium chloride solution was added dropwise to obtain a solid-containing mixed solution, which was then filtered, and 20 g (544 mmol) ...

Embodiment 2

[0048] The preparation of N,N-dimethyl-3-propylamine magnesium chloride toluene / THF solution is the same as in Example 1. 75g (364mmol) of dibenzocyclohepten-5-one and 340ml of toluene were added dropwise to the toluene / THF solution of N,N-dimethyl-3-propylamine magnesium chloride at a temperature below 35°C, and stirred for 1 ~4 hours, HPLC detection; slowly add 120g of saturated ammonium chloride solution dropwise to obtain a mixed solution containing solids, filter, and pass the filtrate into 100g of isopropanol solution containing 20g (544mmol) of hydrogen chloride, after passing through, stir for 1 hours, filtered to obtain 106 g of 5-(3-(dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol hydrochloride, which was directly used in the next step without drying.

[0049] 5-(3-(Dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol hydrochloride was heated to 80 °C with 700 mL of isopropanol and stirred for 1 h, monitored by HPLC Reaction, when 5-(3-(dimethylamino)propyl)-...

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Abstract

The invention relates to the technical field of pharmaceutical chemical industry and provides a preparation method of hydrochloric acid cyclobenzaprine. The preparation method comprises the following steps of reacting N,N-dimethyl-3-propylamine magnesium chloride with dibenzo cycloheptatriene-5-ketone in a mixed solution of tetrahydrofuran and toluene so as to obtain 5-(3-(dimethylamino) propyl)-5H-dibenzo [a,b] cycloheptene-5-alcohol, then adding hydrogen chloride gas or hydrogen chloride alcoholic solution, separating so as to obtain 5-(3-(dimethylamino) propyl group)-5H-dibenzo [a,b] cycloheptene-5-alcoholic hydrochloride, and finally dewatering the 5-(3-(dimethylamino) propyl)-5H-dibenzo [a,b] cycloheptene-5-alcoholic hydrochloride so as to obtain cyclobenzaprine hydrochloride. According to the processes, the preparation method of the cyclobenzaprine hydrochloride is simple and does not generate waste water.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of cyclobenzaprine hydrochloride. Background technique [0002] Cyclobenzaprine hydrochloride has the structural formula of (I), the chemical name is 5-(3-dimethylaminopropylidene-dibenzo[a,d]cycloheptene hydrochloride, cyclobenzaprine hydrochloride is produced by Merck Company It was developed and marketed in 1977. It is clinically used to relieve muscle spasm and the accompanying intense pain in skeletal muscles. It also has great effects on discomfort and pain caused by other connective tissues. [0003] Patent WO2012098563A reported a method for synthesizing cyclobenzaprine hydrochloride, firstly preparing N,N-dimethyl-3-propylamine magnesium chloride, then reacting with dibenzocyclohepten-5-one in THF to obtain 5-( 3-(Dimethylamino)propyl)-5H-dibenzo[a,d]cyclohepten-5-ol, water was added after the reaction and dehydration with hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/32C07C209/68
Inventor 陈奕文黄绍智许雅文
Owner 佛山市隆信医药科技有限公司
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