Preparation method of trazodone intermediate

Abstract

The invention relates to a preparation method of a trazodone intermediate pyridine triazolone (a compound as shown in a formula 1). The method comprises the following steps: reacting 2-hydroxypyridine with hydrazine hydrate to generate 2-hydrazinopyridine, and reacting the 2-hydrazinopyridine with diphosgene or triphosgene to generate the trazodone intermediate pyridine triazolone. The method is mild in synthesis condition, high in yield and purity, continuous in two-step reaction and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, more specifically relates to a preparation method of pyridine triazolone, an intermediate of trazodone. BACKGROUND

[0002] Pyridine triazolone (full name: 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one) is an important intermediate for preparing trazodone hydrochloride. There are two main existing technologies: one is to condense 2-hydrazine pyridine with urea at high temperature (> 130℃) to obtain pyridine triazolone, which has high energy consumption and low reaction yield, with the highest reported yield of 75.6% (see documents WO2017 / 46318 and CN112062762).

[0003] .

[0004] The second is to condense 2-chloropyridine or 2-bromopyridine with carbamoyl hydrazine at high temperature to obtain pyridine triazolone, which also has high energy consumption and low reaction yield, with the highest reported yield of 59% (see documents US2009 / 209550 and US4254124).

[0005] .

[0006] 2-hydrazine pyridine is usually prepared by nucleophilic substitution reaction of 2-chloropyridine or 2-bromopyridine with hydrazine hydrate, which requires long time reaction at high temperature (WO2025 / 3414) or special equipment for precise control (CN111440144), and the post-treatment process is complex.

[0007] In summary, the existing preparation methods of pyridine triazolone have the problems of high reaction temperature, long reaction time, low yield and difficult post-treatment, which are difficult to be industrialized. SUMMARY

[0008] In view of the deficiencies of the prior art, the present application provides a new preparation method of pyridine triazolone, an intermediate of trazodone. The method is realized by the following scheme: 2-hydroxypyridine and hydrazine hydrate are dissolved in water, and 2-hydrazine pyridine is generated by reacting at 20~50℃ for 3~6h; after the reaction is completed, an organic solvent is added and stirred to separate the layers, then bis(trichloromethyl) carbonate or triphosgene is added to the organic layer, and the reaction is carried out at 0~30℃ for 2~5h; after the reaction is completed, distillation is carried out to dryness to obtain pyridine triazolone.

[0009] The chemical equation of the present application is: .

[0010] According to the above scheme, the molar ratio of 2-hydroxypyridine to hydrazine hydrate used is 1:1~3.

[0011] According to the above scheme, the molar ratio of 2-hydroxypyridine to diphosgene or triphosgene is 1:0.35~1.

[0012] According to the above scheme, the organic solvent is dichloromethane, chloroform, dichloroethane, 2-methyltetrahydrofuran or toluene.

[0013] The present application has the following advantages: 1. The cheap and readily available 2-hydroxypyridine is used as a starting material, and the pyridine triazolone is prepared by a two-step method. The synthesis route is novel and has not been reported in the literature.

[0014] 2. The reaction conditions are mild, each step of the reaction is carried out at a lower temperature, the reaction time is short, and no special reaction equipment is required.

[0015] 3. The process is simple and easy to operate. After the 2-hydrazine pyridine reaction is completed, it is directly subjected to the next step reaction by extraction and layer separation, which is convenient for industrial continuous operation. The product has high yield (more than 95% in total for two-step reaction) and good purity (HPLC purity is more than 99%), and no further solvent refining is required. DETAILED DESCRIPTION

[0016] The present application will be further explained below in conjunction with examples, and the examples of the present application are only used to illustrate the technical solutions of the present application, and are not intended to limit the scope of the present application.

[0017] Example 1: In a 1000ml three-necked flask, 2-hydroxypyridine 100g and water 100ml were added, the temperature was controlled at 20~30℃, 50% hydrazine hydrate 158g was added under stirring, and the reaction was carried out for 4h after completion of addition; then dichloromethane 200ml was added, and after stirring, the reaction was allowed to stand and separate into layers, the dichloromethane layer was separated, and then a solution of triphosgene 132.5g in dichloromethane 200ml was slowly added, the temperature of the reaction liquid was controlled at 5~15℃, and the reaction was carried out for 3h under stirring. The reaction liquid was distilled to dryness, then water 300ml was added, and after stirring, the mixture was filtered under suction, the filter cake was dried at 60℃ under reduced pressure for 8h, and pyridine triazolone solid 136.4g was obtained, with a yield of 96.0% and a purity of 99.3%.

[0018] Example 2: In a 1000ml three-necked flask, 2-hydroxypyridine 100g and water 100ml were added, the temperature was controlled at 25~35℃, 50% hydrazine hydrate 174g was added under stirring, and the reaction was carried out for 3h after completion of addition; then toluene 200ml was added, and after stirring, the reaction was allowed to stand and separate into layers, the toluene layer was separated, and then a solution of diphosgene 124.8g in toluene 200ml was slowly added, the temperature of the reaction liquid was controlled at 0~10℃, and the reaction was carried out for 2h under stirring. The reaction liquid was distilled to dryness, then water 300ml was added, and after stirring, the mixture was filtered under suction, the filter cake was dried at 60℃ under reduced pressure for 8h, and pyridine triazolone solid 138.1g was obtained, with a yield of 97.2% and a purity of 99.5%.

Claims

1. A method for preparing pyridinetriazolone, an intermediate of trazodone, characterized in that: 2-Hydroxypyridine and hydrazine hydrate are dissolved in water and reacted at 20-50℃ for 3-6 hours to generate 2-hydrazinepyridine. After the reaction is complete, an organic solvent is added and stirred to separate the layers. Diphosgene or triphosgene is then added to the organic layer and reacted at 0-30℃ for 2-5 hours. After the reaction is complete, the mixture is distilled to dryness to obtain pyridinetriazolone.

2. The method according to claim 1, characterized in that: The molar ratio of 2-hydroxypyridine to hydrazine hydrate used is 1:1~3.

3. The method according to claim 1, characterized in that: The molar ratio of 2-hydroxypyridine to diphosgene or triphosgene used is 1:0.35~1.

4. The method according to claim 1, characterized in that: The organic solvent is dichloromethane, chloroform, dichloroethane, 2-methyltetrahydrofuran, or toluene.