WO2017166050A1 - Method for preparing trazodone hydrochloride - Google Patents

Abstract

The present invention is applied to the field of chemistry and chemical engineering, and provides a method for preparing trazodone hydrochloride, comprising the following steps: mixing N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in a solvent, adding alkali to the mixture, and reflowing while heating; performing hot filtration in a reaction system, adding alkali liquid, and reflowing while heating again in sequence; obtaining trazodone by crystallization; and reacting the obtained trazodone with hydrochloric acid to obtain trazodone hydrochloride. The method for preparing trazodone hydrochloride provided by the present invention improves the total product yield and significantly reduces the content of the impurity, N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, and thus can directly meet the requirements speculated in the industry. The method simplifies process steps, reduces production costs, has good process stability, and is applicable to industrial production.

Description

 Preparation method of trazodone hydrochloride Technical field

The invention belongs to the field of chemistry and chemical industry, and in particular relates to a preparation method of trazodone hydrochloride.

Background technique

Trazodone hydrochloride Hydrochloride is a derivative of triazopyridine, which is mainly used for the treatment of depression and anxiety disorders accompanied by depressive symptoms and mood disorders after drug withdrawal. The product has low side effects and strong tolerance. Its mechanism of action is: inhibiting the uptake of 5-HT by synaptic neurons, thereby increasing the concentration of 5-HT in the synaptic cleft to transmit information and achieve antidepressant purposes. Clinically, it has also been demonstrated that the antidepressant and anxiolytic properties of trazodone hydrochloride can be used to treat withdrawal symptoms from cocaine, benzodiazepines and alcohol. In addition, trazodone hydrochloride has a significant effect on improving sleep disorders.

At present, the preparation of trazodone hydrochloride is accompanied by a variety of impurities, wherein the impurity alkyl compound N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is identified as a suspected gene. Toxic impurities, which are listed as key impurities in USP 38, are considered to be no more than 2.5 ppm, considering that the maximum daily dose of trazodone hydrochloride is 600 mg. Since 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 the residue becomes a difficult point and a key process for preparing trazodone hydrochloride, how to koji Controlling the yield of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine during the synthesis of oxazolone, providing a method for preparing a rarer to produce less trazodone hydrochloride. It has become a technical problem to be solved in the field.

technical problem

In order to solve the above technical problems, the present invention provides a preparation method of trazodone hydrochloride, which aims to reduce the impurity N-(3-chloro-phenyl)-N'-(3-chlorochloride) in the preparation product of trazodone hydrochloride. The content of propyl)-piperazine.

Technical solution

The present invention is achieved by a method for preparing trazodone hydrochloride comprising the following steps:

N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is mixed with pyridine triazolone in a solvent, a base is added, and the mixture is heated to reflux;

The reaction system is sequentially subjected to hot filtration, lye is added, and the temperature is raised again by reflux;

Crystallization to obtain trazodone;

The resulting trazodone is reacted with hydrochloric acid.

Further, the ratio of the amount of the pyridine triazolone to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is from 1 to 1.5: 1.

Further, the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine; the base and the N-(3- The ratio of the amount of the substance of chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is from 2 to 3:1.

Further, the solvent is n-butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or N, One of N-dimethylacetamide; the volume-to-mass ratio of the solvent to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 10 to 30 mL: 1 g.

Further, the product of the temperature rise and reflux includes N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, and the end point of the temperature rise reflux is the N-( The content of 3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is less than 0.05%.

Further, the temperature of the hot filtration is 50 to 75 °C.

Further, the concentration of the alkali liquid is 5% to 20% by weight; the solute of the alkali liquid is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, One of pyridine.

Further, the volume ratio of the lye to the solvent is from 1% to 15%:1.

Further, the temperature of the temperature rise and reflux is 80 to 85 °C.

Further, the temperature for re-heating and refluxing is 82 to 87 ° C, and the time is 6 to 8 hours.

Further, the temperature of the crystallization is -5 to 15 ° C, and the time is 1 to 4 hours.

Further, the preparation method further comprises: filtering and drying after crystallization.

Further, the concentration of the hydrochloric acid is 12 mol/L, and the condition that the trazodone is reacted with hydrochloric acid is to adjust the reaction system to a pH of 1 to 5.

The invention also provides a method for reducing the content of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in the preparation of trazodone hydrochloride, which adopts the preparation method described above Carry out the reaction.

Beneficial effect

Compared with the prior art, the invention has the beneficial effects that: the invention improves the preparation process of the trazodone hydrochloride, adjusts the reaction parameters in the reaction process, and further increases the reaction after adding the alkali aqueous solution after the completion of the synthesis reaction, and performs the temperature rising reflux. And cooling and crystallization, etc., to make the impurity N-(3-chloro-benzene Base The residual amount of -N'-(3-chloropropyl)-piperazine is within 2.5 ppm, reaching industry-standard standards. The preparation method of the trazodone hydrochloride of the invention improves the total yield of the product; the process streamlining step reduces the production cost; and the process is stable and can be industrially produced.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a chemical structural formula of trazodone hydrochloride prepared by the present invention.

2 is a chemical reaction formula for preparing trazodone hydrochloride according to an embodiment of the present invention.

FIG. 3 is a detection device according to an embodiment of the present invention.

FIG. 4 is an MS/MS method parameter provided by an embodiment of the present invention.

FIG. 5 is a detection result provided by an embodiment of the present invention.

Embodiments of the invention

The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The preparation of trazodone hydrochloride according to the technical scheme of the present invention is as follows:

Step 1: Mixing N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride with pyridine triazolone, adding a base, and heating to reflux;

Step 2: sequentially heat-filtering the reaction system, adding an alkali solution, and heating the reflux again;

Step three: crystallization, filtration, and drying to obtain trazodone;

Step 4: The obtained trazodone is reacted with hydrochloric acid to obtain trazodone hydrochloride.

The specific process is: sequentially adding N-(3-chloro-phenyl group) to the reaction flask at room temperature. )-N'-(3-chloropropyl)-piperazine hydrochloride, pyridine triazolone, reaction solvent, mechanical stirring, addition of alkali, nitrogen protection, heating to reflux, after the reaction reaches the end point, control temperature is hot Filtration, the filtrate was added with an aqueous alkali solution, and the temperature was refluxed to continue the reaction. The filtrate was cooled and crystallized, kept warm, filtered, and dried under vacuum at 50 ° C to give a pale yellow solid.

Specifically, in the first step, the ratio of the amount of the pyridine triazolone to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 1 to 1.5:1, preferably 1.1 to 1.3:1. The base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine; wherein the base and the N-(3-chloro-phenyl) The ratio of the amount of the substance of -N'-(3-chloropropyl)-piperazine hydrochloride is from 2.0 to 3.0:1, preferably from 2.1 to 2.4:1. The solvent is n-butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethyl One of acetamide; the volume-to-mass ratio of the solvent to N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 10 to 30 mL: 1 g, preferably 15 ~20mL: 1g.

During the temperature rise and reflux, the reaction product includes N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, and the temperature at reflux is 80-85 ° C. The content of N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is detected by HPLC to be less than 0.05%, preferably less than 0.02%, and the time is generally 24 to 28 hours, preferably 26 hours.

Specifically, in the second step, the temperature of the hot filtration is 50 to 75 ° C, preferably 60 to 70 ° C. The concentration of the added alkali solution is 5%~20%wt, preferably 10%~15%wt; the solute of the alkali solution is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, three One of ethylamine and pyridine is preferably sodium hydroxide or potassium hydroxide. Wherein, the volume ratio of the lye to the solvent is from 1% to 15%:1, preferably from 5% to 10%:1. The temperature at which the temperature is again refluxed is 82 to 87 ° C, and the time is 6 to 8 hours, preferably 8 hours.

Specifically, in the third step, the temperature of the crystallization is -5 to 15 ° C, preferably 0 to 5 ° C; and the time is 1 to 4 hours, preferably 2 to 3 hours. The filtration was carried out at room temperature, and the drying was naturally air-dried.

Specifically, in the fourth step, the concentration of hydrochloric acid used is 12 mol/L, and the reaction between the trazodone and hydrochloric acid is such that the reaction system is adjusted to have a pH of 1 to 5, preferably 2.5 to 3.5.

In the preparation process of the existing trazodone hydrochloride, there is no step of adding an aqueous alkali solution to continue the reaction, and the key impurity of the obtained trazodone hydrochloride is N-(3-chloro-phenyl)-N'-(3-chloro The propyl)-piperazine residue is 100 ppm or more, and if the impurity is not separately purified, the trazodone hydrochloride is directly obtained, and even if it is purified a plurality of times, it is difficult to achieve the requirement of 2.5 ppm or less. Patent CN 101772490 The method of B requires an increase in the step of separately purifying the impurity by trazodone or trazodone hydrochloride. Although the patent reports a yield higher than 85%, the method is cumbersome, uses a high boiling point and is not commonly used as a solvent; Large; when using a solvent that is miscible with water, it is difficult to recover trazodone, and it is used in azeotropic distillation to consume energy during production. The preparation method of the invention has low solvent and small water ratio; on the basis of the conventional preparation method of trazodone, the hot filtration, the addition of alkaline water and the reheating and refluxing operation are carried out, and the improved operation is compared with the original process. Combine, reduce energy consumption and save time. The preparation method of the present invention solves the problems existing in the prior art, and the effect is remarkable.

The technical solution of the invention will be further described below in conjunction with the comparative examples and specific examples.

Comparative Example 1 Preparation of trazodone by existing process

100 g (0.323 mol) of N-(3-chloro-phenyl group) was sequentially added to a 2 L three-necked flask at room temperature. -N'-(3-chloropropyl)-piperazine hydrochloride, 52.4 g (0.388 mol) of pyridine triazolone (Compound II), 1500 mL of isopropanol, mechanical stirring, adding 29.7 g (0.743 Mol) sodium hydroxide, nitrogen protection, warming to reflux, reaction for 26 hours, HPLC detection of N-(3-chloro-phenyl The content of -N'-(3-chloropropyl)-piperazine was 0.02%. The temperature is controlled to 60~70 °C for hot filtration, the filtrate is cooled to 5 ° C for crystallization, the mixture is stirred for 2 hours, filtered, and vacuum dried at 50 ° C to obtain 107 g (0.288). Mol) trazodone, yield 89%.

Example 1 Preparation of trazodone by supplementing sodium hydroxide solution of the present invention

Add 100 g (0.323) to a 2 L three-necked flask at room temperature. Mol) N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride, 52.4 g (0.388 mol) pyridine triazolone, 1500 mL isopropyl alcohol, mechanical stirring, 29.7 g (0.743 mol) sodium hydroxide, nitrogen protection, heating to reflux, reaction for 26 hours, HPLC detection of N-(3-chloro-phenyl The content of -N'-(3-chloropropyl)-piperazine was 0.02%. Control the temperature to 60~70 °C for hot filtration, transfer the filtrate to the reaction flask, add 120 mL 10% aqueous sodium hydroxide solution was stirred and refluxed for 8 hours, cooled to 5 ° C for crystallization, stirred for 2 hours with heat, filtered, and vacuum dried at 50 ° C to obtain 110 g (0.296 mol) of trazodone in a yield of 92%.

Example 2 Preparation of trazodone by supplementing potassium hydroxide solution of the present invention

100 g (0.323 mol) of N-(3-chloro-phenyl group) was sequentially added to a 2 L three-necked flask at room temperature. -N'-(3-chloropropyl)-piperazine hydrochloride, 52.4 g (0.388 mol) of pyridine triazolone, 1500 mL of isopropanol, mechanical stirring, 29.7 g (0.743) Mol) sodium hydroxide, nitrogen protection, warming to reflux, reaction for 26 hours, HPLC detection of N-(3-chloro-phenyl The content of -N'-(3-chloropropyl)-piperazine was 0.02%. Control the temperature to 60~70 °C for hot filtration, transfer the filtrate to the reaction flask, add 120 mL The aqueous solution of 10% potassium hydroxide was stirred and refluxed for 8 hours, cooled to 5 ° C for crystallization, stirred for 2 hours with heat, filtered, and vacuum dried at 50 ° C to obtain 108 g (0.290 mol) of trazodone in a yield of 90%.

Example 3 Synthesis of trazodone hydrochloride using trazodone prepared by the present invention

50 g (0.134 mol) of trazodone, 300 mg, in a 500 mL three-necked flask at room temperature mL ethanol, start mechanical stirring, warm to 60 ° C, dissolve the solid, add 12mol / L HCl aqueous solution, adjust the system pH to 3, then slowly reduce the temperature to 0 ° C, precipitate a large amount of white solid, stir for 2 hours, filter, vacuum drying at 50 ° C to obtain 51g (0.125 Mol) trazodone hydrochloride, yield 93%.

The residual N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine residue in Comparative Example 1 and Example 1-3 was separately detected. The testing methods and processes used are:

1.1 Instruments and equipment, as shown in Figure 3.

1.2 Solution preparation

Standard solution (0.025μg/mL)

Thinner: acetonitrile, water and formic acid (100:900:1, v/v/v)

Sample solution

Sample solution (10 mg/mL).

Diluent (acetonitrile, water and formic acid (100:900:1, v/v/v)).

1.2.1 MS/MS method parameters, as shown in Figure 4 below.

The test results are shown in Figure 5 below.

It can be seen from the above test results that the preparation method of trazodone hydrochloride provided by the invention can achieve the key impurity N-(3-chloro-phenyl)-N'-(3-chloropropene) which is produced during the preparation process. The residual amount of the base)-piperazine is controlled within 2.5 ppm, which is significantly lower than the content of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in the prior preparation process. Therefore, it can directly meet the limit requirement of the impurity in the industry.

The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope.

Claims (10)

A method for preparing trazodone hydrochloride, which comprises the following steps: N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is mixed with pyridine triazolone in a solvent, a base is added, and the mixture is heated to reflux; The reaction system is sequentially subjected to hot filtration, lye is added, and the temperature is raised again by reflux; Crystallization to obtain trazodone; The resulting trazodone is reacted with hydrochloric acid. The process according to claim 1, wherein said pyridine triazolone and said N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride The ratio of the amount of the substance is from 1 to 1.5:1. The preparation method according to claim 1, wherein the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, and pyridine; The ratio of the amount of the base to the substance of the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is from 2 to 3:1. The preparation method according to claim 1, wherein the solvent is n-butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, tetrahydrofuran, 1,4-dioxane, N One of N-dimethylformamide or N,N-dimethylacetamide; the solvent and the N-(3-chloro-phenyl)-N'-(3-chloropropyl) The volume-to-mass ratio of piperazine hydrochloride is 10 to 30 mL: 1 g. The method according to claim 1, wherein the temperature of the hot filtration is 50 to 75 °C. The preparation method according to claim 1, wherein the concentration of the alkali liquid is 5% to 20% by weight; the solute of the alkali liquid is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and carbonic acid. One of sodium hydrogen, potassium hydrogencarbonate, triethylamine, and pyridine. The method according to claim 1, wherein the volume ratio of the alkali solution to the solvent is from 1% to 15%:1. The method according to claim 1, wherein said temperature-increasing reflux product comprises N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, said temperature rising reflux The end point of the assay was that the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine content was less than 0.05% by HPLC. The preparation method according to claim 1, wherein the crystallization temperature is -5 to 15 ° C for a period of 1 to 4 hours. A method for reducing the content of an impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in the preparation of trazodone hydrochloride, characterized in that the method according to claims 1-9 is used The preparation method is carried out.