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Preparation method of trazodone hydrochloride

A technology of trazodone hydrochloride and hydrochloride, applied in the field of preparation of trazodone hydrochloride, can solve problems such as inability to completely convert trazodone, and achieve the effects of reducing production cost, improving total yield and stabilizing process

Inactive Publication Date: 2016-07-20
SHENZHEN FONCOO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the impurity is one of the reactants for the synthesis of trazodone, according to the principle of chemical reaction equilibrium, it cannot be completely converted into trazodone, so controlling its residue has become a difficult and key process for preparing trazodone hydrochloride. How to prepare trazodone hydrochloride Control the output of impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine during the synthesis process of oxazolone, and provide a method for preparing trazodone hydrochloride with less impurity generation, Has become a technical problem to be solved urgently in this field

Method used

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  • Preparation method of trazodone hydrochloride
  • Preparation method of trazodone hydrochloride
  • Preparation method of trazodone hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1 The present invention adds sodium hydroxide solution to prepare trazodone

[0043] Into a 2L three-necked flask at room temperature, add 100g (0.323mol) N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride, 52.4g (0.388mol) pyridine Triadimefon, 1500mL isopropanol, start mechanical stirring, add 29.7g (0.743mol) sodium hydroxide, nitrogen protection, heat up to reflux, react for 26 hours, HPLC detects N-(3-chloro-phenyl)-N' The -(3-chloropropyl)-piperazine content was 0.02%. Control the temperature to 60-70°C for hot filtration, transfer the filtrate into a reaction flask, add 120mL of 10% sodium hydroxide aqueous solution, stir and heat up to reflux for 8 hours, cool down to 5°C for crystallization, keep stirring for 2 hours, filter, and vacuum dry at 50°C 110 g (0.296 mol) of trazodone was obtained, with a yield of 92%.

Embodiment 2

[0044] Embodiment 2 The present invention adds potassium hydroxide solution to prepare trazodone

[0045] Into a 2L three-necked flask at room temperature, add 100g (0.323mol) N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride, 52.4g (0.388mol) pyridine Triadimefon, 1500mL isopropanol, start mechanical stirring, add 29.7g (0.743mol) sodium hydroxide, nitrogen protection, heat up to reflux, react for 26 hours, N-(3-chloro-phenyl)-N The '-(3-chloropropyl)-piperazine content was 0.02%. Control the temperature to 60-70°C for hot filtration, transfer the filtrate to a reaction flask, add 120mL of 10% potassium hydroxide aqueous solution, stir and heat up to reflux for 8 hours, cool down to 5°C for crystallization, keep stirring for 2 hours, filter, and vacuum dry at 50°C 108 g (0.290 mol) of trazodone was obtained, with a yield of 90%.

Embodiment 3

[0046] Embodiment 3 uses the trazodone prepared by the present invention to synthesize trazodone hydrochloride

[0047] Into a 500mL three-necked flask at room temperature, add 50g (0.134mol) trazodone and 300mL ethanol in sequence, start mechanical stirring, heat up to 60°C, after the solid dissolves, add 12mol / L HCl aqueous solution dropwise, adjust the pH of the system to 3, and then slowly The temperature was lowered to 0°C, a large amount of white solid was precipitated, kept stirring for 2 hours, filtered, and vacuum-dried at 50°C to obtain 51 g (0.125 mol) of trazodone hydrochloride with a yield of 93%.

[0048] The residual amount of impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in Comparative Example 1 and Examples 1-3 was detected respectively. The detection method and process used are:

[0049] 1.1 Instruments and equipment, as shown in Table 1 below.

[0050] Table 1

[0051]

[0052] 1.2 Solution preparation

[0053] Standard solution (0.025μg...

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Abstract

The invention is applicable to the field of chemistry and chemical engineering and provides a preparation method of trazodone hydrochloride. The preparation method comprises the following steps: mixing N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride and 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in a solvent; adding an alkali, and heating and reflowing; carrying out heat filtering into a reaction system, adding alkali liquid and heating and reflowing again in sequence; crystallizing to obtain trazodone; taking the trazodone to react with hydrochloric acid to obtain the trazodone hydrochloride. According to the preparation method of the trazodone hydrochloride, provided by the invention, the total yield of the product is improved, and the content of an impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is remarkably reduced, so that the industry limitation requirements can be directly met. The preparation method has simple flow steps so that the production cost is reduced; the process is stable and industrial production can be carried out.

Description

technical field [0001] The invention belongs to the field of chemistry and chemical engineering, and in particular relates to a preparation method of trazodone hydrochloride. Background technique [0002] Trazodone hydrochloride (trazodonehydrochloride) is a derivative of triazopyridine, which is mainly used clinically for the treatment of depression and anxiety accompanied by depressive symptoms, as well as mood disorders after drug dependence withdrawal. This product has low side effects and strong tolerance. Its mechanism of action is to inhibit the uptake of 5-HT by synaptic neurons, thereby increasing the concentration of 5-HT in the synaptic gap to transmit information and achieve the purpose of antidepressant. The antidepressant and anxiolytic properties of trazodone hydrochloride have also been clinically proven useful in the treatment of withdrawal symptoms from cocaine, benzodiazepines and alcohol. In addition, trazodone hydrochloride has obvious curative effect o...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 彭锦安王秋成闫鹏朱杭杭
Owner SHENZHEN FONCOO PHARMACEUTICAL CO LTD
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