Preparation method of betahistine intermediate 2-vinylpyridine

Abstract

The invention discloses a preparation method of 2-vinylpyridine. The preparation method is characterized in that 2-hydroxyethyl pyridine is used as a raw material and is subjected to a reflux water diversion reaction with potassium hydroxide in toluene to prepare the 2-vinylpyridine. The method is wide in raw material source, short in reaction time, high in conversion rate of 99.77%, high in yield of 93.1%, simple and controllable in process, easy to reproduce and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing a betahistine intermediate. Background Art

[0002] 2-Vinylpyridine, English name 2-Vinylpyridine, is an important intermediate of the API betahistine hydrochloride and betahistine mesylate, and is also the impurity A of betahistine EP. Its structure is: . In the prior art, the patent document with application number CN201510661983.8 discloses a method for preparing betahistine hydrochloride, which includes preparing 2-vinylpyridine by dehydration reaction. The invention uses 2-hydroxyethylpyridine as a raw material, sodium hydroxide and anhydrous magnesium sulfate as a mixed dehydrating agent, and reacts at high temperature with a yield of 80%. The problems with the preparation method disclosed in the invention are: first, according to the description of the claims and the specification of the invention, the amount of NaOH used in the dehydration reaction is large (1.85 eq), and the amount of anhydrous magnesium sulfate used is also large (0.4 eq), resulting in a high raw material cost. Second, according to the description of the claims and the specification of the invention, the dehydration reaction is a solvent-free reaction, which will cause problems of difficult stirring and easy carbonization at high temperature and in the presence of a large amount of NaOH, resulting in a low yield.

[0003] The article titled Orthogonal Optimization of the Synthesis of Betahistine Hydrochloride was written by Jiang Min, Zhang Chuntao, Ye Luxing and Huang Laiying, and published by Sinopharm Guorui Pharmaceutical Co., Ltd., etc. It was published in Anhui Chemical Industry, Vol. 38, No. 6, 2012, and described a method for preparing 2-vinylpyridine. The feed ratio of 2-hydroxyethylpyridine to NaOH was 1:0.05, and after slowly adding NaOH, it was slowly heated to 95-100°C and stirred for 2h, and the yield was 25%. The problem with this preparation method is that the yield is too low and it is not suitable for industrial production.

[0004] The article titled Research on the Dehydration Reaction to Generate 2-Vinylpyridine was published in Shandong Chemical Industry, 2012, 41, 12-14. It reported a reaction using potassium hydroxide as a dehydrating agent. The dehydrating agent used in this method is 0.4 eq 2-hydroxyethylpyridine. The reaction is carried out at 100℃ for 2h, and the single-pass yield of the product is 81.2%, the product content reaches more than 98%, and the water content is less than 1%. The problems of this preparation method are: the dehydration reaction is a solvent-free reaction. When the temperature is high and the potassium hydroxide feed is large, it will cause the problem of difficult stirring and easy carbonization, resulting in a low yield.

[0005] In the prior art, the invention application with application number CN86 1 03091 discloses a normal pressure synthesis method for vinyl pyridine, wherein 2-hydroxyethyl pyridine is prepared by acid catalysis for 45-70 hours, and the method is repeated; sodium hydroxide aqueous solution and methylene blue are heated to a high temperature (140-190°C), and methylene blue and solid sodium hydroxide are added multiple times under 100 mm Hg to continuously dehydrate 2-hydroxyethyl pyridine to obtain vinyl pyridine, with a yield of 95%. The problems existing in the preparation method are as follows: First, according to the description in the claims and specification of the invention, the dehydration reaction requires multiple operations and feeding, and the operation is complicated and increases the production cost. Second, according to the description in the claims and specification of the invention, the dehydration reaction is carried out under high temperature and 100 mm Hg, which not only increases the risk of production, but also increases the cost of production. Third, according to the claims and description of the invention, methylene blue, which is mutagenic and toxic to aquatic animals, is added to the dehydration reaction. The 2-vinylpyridine obtained by this preparation method is not suitable for use as a pharmaceutical intermediate, which limits its scope of application and increases environmental pollution and processing costs.

[0006] The article entitled "One-Flask Pyridylethylation of Amines by 2-(2-Pyridyl)-ethanol" published in Archiv der Pharmazie, 1989, 322 (3), 181-182 discloses a method of using 2-hydroxyethylpyridine as a raw material to reflux in glacial acetic acid solution for 12 hours and then post-treating to obtain 2-vinylpyridine with a yield of 69%. The problems of this preparation method are: long reaction time, low yield, and increased production cost.

[0007] Patent document No. US 6727365 B1 discloses a method for preparing 2-vinylpyridine by catalyzing 2-ethylpyridine to remove one molecule of hydrogen at high temperature and high pressure using a Cr-Ni catalyst. The problem with this preparation method is that according to the claims and description of the invention, the reaction needs to be carried out at high temperature and high pressure, and a Cr-Ni catalyst is used, which has strict requirements on experimental conditions and a low reaction yield, which increases the difficulty and danger of production, and also increases the raw material and production costs. Summary of the invention

[0008] It can be seen that although there are many preparation methods of betahistine intermediate 2-vinylpyridine reported in the prior art, there are still shortcomings such as harsh reaction conditions, inconvenient operation or insufficient yield conversion rate. The technical problem to be solved by the present invention is to overcome the shortcomings and defects of the prior art and provide a method for producing a betahistine intermediate 2-vinylpyridine with a simple production operation process and a high conversion rate and high yield at a relatively low cost.

[0009] Specifically, a method for preparing 2-vinylpyridine, an intermediate of betahistine, uses 2-hydroxyethylpyridine as a raw material and performs a reflux reaction under the conditions of potassium hydroxide and toluene, specifically comprising the following steps: (1) 2-Hydroxyethylpyridine, potassium hydroxide and toluene are mixed in a reaction vessel, heated under reflux for reaction, and water separation is performed during the reaction. When TLC detects that the raw material 2-hydroxyethylpyridine is completely consumed, heating is stopped; (2) Cooling the mixture naturally to room temperature, filtering to remove potassium hydroxide, collecting the filtrate and distilling under reduced pressure to remove toluene to obtain 2-vinylpyridine.

[0010] Furthermore, the molar ratio of potassium hydroxide to 2-hydroxyethylpyridine is 0.05:1-0.1:1, preferably 0.05:1; the potassium hydroxide can be ground before feeding to make it more evenly dispersed in the solution; Further, the ratio of the volume of toluene in milliliters to the mass of 2-hydroxyethylpyridine in grams is 5:1; Furthermore, the heating temperature for the reflux reaction is suitably in the range of 111°C-140°C, preferably 111-120°C; the toluene used in the reaction is preferably dry toluene, and the drying method is molecular sieve dehydration treatment.

[0011] Further, the time required for the reflux reaction in this scheme is 2-3 hours, preferably 2.5 hours. Under most conditions, the raw materials can be substantially completely converted within 3 hours.

[0012] The 2-vinylpyridine obtained through the above post-treatment process is a crude product, and the product content is confirmed to be more than 90% by chromatography. Subsequently, a high-purity fine product can be obtained through a simple refining process.

[0013] Beneficial effects: In the prior art, there are those that require high-temperature reactions, and the cost of raw materials is high. Some solutions propose to use solvent-free reactions, but the reaction is high-temperature and requires a large amount of alkali to be added, which makes stirring difficult and the yield is low, or some solutions use substances that are highly polluting to the environment and are not suitable as pharmaceutical intermediates. Compared with the prior art, this solution has the advantages of cheap and easy-to-obtain raw materials, only 2-hydroxyethylpyridine, potassium hydroxide and toluene are used in the raw materials, the reaction conditions are relatively simple and mild, no special instruments and equipment are required, the reaction time is short, the reaction yield reaches more than 97%, no complicated post-processing process is required, the product purity is high, and the operation process is simple. Implementation Example 1

[0014] 30.0 g 2-hydroxyethylpyridine, 1.38 g potassium hydroxide and 150 mL toluene were added to a three-necked flask, and the mixture was refluxed at 116 °C to separate water for 2.5 h. The reaction of 2-hydroxyethylpyridine was completed by thin layer chromatography, and the conversion rate was 99.76%. The mixture was cooled to room temperature, potassium hydroxide was removed by filtration, and the filtrate was collected and distilled under reduced pressure to remove toluene to obtain 2-vinylpyridine with a yield of 92.0%. Example 2

[0015] 5.0 g of 2-hydroxyethylpyridine, 0.11 g of potassium hydroxide and 25 mL of toluene were added to a three-necked flask, and the mixture was refluxed at 117 °C for 2 h to separate water. The reaction of 2-hydroxyethylpyridine was completed by thin layer chromatography, and the conversion rate was 99.77%. The mixture was cooled to room temperature, the potassium hydroxide was removed by filtration, and the filtrate was distilled under reduced pressure to remove toluene to obtain 2-vinylpyridine with a yield of 93.1%. Example 3

[0016] 5.0 g of 2-hydroxyethylpyridine, 0.11 g of potassium hydroxide and 20 mL of toluene were added to a three-necked flask, and the mixture was refluxed at 115 °C for 2 h to separate water. The reaction of 2-hydroxyethylpyridine was completed by thin layer chromatography, and the conversion rate was 99.73%. The mixture was cooled to room temperature, potassium hydroxide was removed by filtration, and toluene was removed by distillation under reduced pressure from the filtrate to obtain 2-vinylpyridine with a yield of 91.7%. Example 4

[0017] 4 g of 2-hydroxyethylpyridine, 0.1 g of potassium hydroxide and 20 mL of toluene were added to a three-necked flask, and the mixture was refluxed at 117 °C for 2 h to separate water. The reaction of 2-hydroxyethylpyridine was completed by thin layer chromatography, and the conversion rate was 99.01%. The mixture was cooled to room temperature, the potassium hydroxide was removed by filtration, and the filtrate was distilled under reduced pressure to remove toluene to obtain 2-vinylpyridine with a yield of 92.1%. Example 5

[0018] 1 g of 2-hydroxyethylpyridine, 40 mg of potassium hydroxide and 5 mL of toluene were added to a three-necked flask, and the mixture was refluxed at 130 °C to separate water for 2.5 h. The reaction of 2-hydroxyethylpyridine was completed by thin layer chromatography, and the conversion rate was 99.53%. The mixture was cooled to room temperature, potassium hydroxide was removed by filtration, and the filtrate was collected and distilled under reduced pressure to remove toluene to obtain 2-vinylpyridine with a yield of 90.1%.

Claims

1. A method for preparing 2-vinylpyridine, an intermediate of betahistine, characterized in that: Using 2-hydroxyethylpyridine as a raw material, a reflux reaction is carried out under the conditions of potassium hydroxide and toluene, which specifically comprises the following steps: (1) 2-hydroxyethylpyridine, potassium hydroxide and toluene are mixed in a reaction container, heated to reflux for reaction, and water separation is performed during the reaction. When it is detected that the raw material 2-hydroxyethylpyridine is completely consumed, heating is stopped; (2) Cooling the mixture to room temperature, filtering to remove potassium hydroxide, collecting the filtrate and distilling under reduced pressure to remove toluene to obtain 2-vinylpyridine.

2. The method according to claim 1, characterized in that: The molar ratio of potassium hydroxide to 2-hydroxyethylpyridine is 0.05:1-0.1:1, preferably 0.05:

1.

3. The method according to claim 1, characterized in that: The ratio of the volume of toluene in milliliters to the mass of 2-hydroxyethylpyridine in grams is 5:

1.

4. The method according to claim 1, characterized in that: The heating temperature for the reflux reaction is suitably in the range of 111°C-140°C, preferably 111-120°C; the toluene used in the reaction is preferably dry toluene, and the drying method is molecular sieve dehydration treatment.

5. The method according to claim 1, characterized in that: The time required for the reflux reaction in this scheme is 2-3 hours, preferably 2.5 hours.