CN101967120A - Preparation method of 2-p-chlorobenzyl pyridine - Google Patents

Abstract

A kind of preparation method of 2-p-chlorobenzylpyridine, first adds chlorobenzene and aluminum trichloride reaction in 2-pyridine formyl chloride hydrochloride, obtains 1-(4-chlorophenyl)-1-(2- pyridyl) ketone; then add diethylene glycol, hydrazine hydrate and potassium hydroxide to the prepared 1-(4-chlorophenyl)-1-(2-pyridyl) ketone to react to obtain 2- 4-chlorobenzylpyridine. With the 2-p-chlorobenzylpyridine produced by the inventive method, as the intermediate for preparing chlorpheniramine, the product purity is high, the process is simple and convenient, the chlorpheniramine product prepared with it meets the Chinese Pharmacopoeia, and the cost is low, easy to industrialization, and has Significant economic and social benefits.

Description

The preparation method of 2-p-chlorobenzylpyridine

technical field

The invention belongs to the preparation method of the intermediate 2-p-chlorobenzylpyridine of the medicine chlorpheniramine. the

Background technique

Chlorpheniramine, alias: Chlorpheniramine. It is an antihistamine, mainly used for various allergic diseases, such as insect bites, urticaria, vasodilatory rhinitis, asthma, contact dermatitis, etc. It can also be combined with other Chinese and Western medicines to treat colds and so on. Chlorpheniramine has always occupied an important position in antiallergic drugs by virtue of its strong antiallergic activity and relatively small side effects. the

2-p-chlorobenzylpyridine is an important intermediate for preparing chlorpheniramine, and its related preparation technology has many reports. The traditional preparation method is to use 2-picoline after chlorination with aniline at pH=1 Condensation reaction is carried out at the time to obtain 2-p-aminobenzylpyridine, and then it is reacted with cuprous chloride through diazotization to obtain 2-p-chlorobenzylpyridine. This traditional preparation method not only has many steps, but also requires high reaction conditions. the

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for preparing 2-p-chlorobenzylpyridine with few steps, short process flow and low requirements on reaction conditions. the

The present invention solves the above technical problems with the following technical solutions:

The process steps of preparation are:

(1). Preparation of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone

Adding chlorobenzene with a molar ratio of 1:10 to 2-pyridineformyl chloride hydrochloride, using aluminum trichloride as a catalyst, the molar ratio of 2-pyridineformyl chloride hydrochloride to the catalyst is 1:2～5, and the reaction The temperature is 195-150°C, and the reaction time is 3-10 hours to obtain 1-(4-chlorophenyl)-1-(2-pyridyl)methanone;

(2). Preparation of 2-p-chlorobenzylpyridine

Using diethylene glycol as a solvent, add 1-(4-chlorophenyl)-1-(2-pyridyl)methanone, hydrazine hydrate and potassium hydroxide with a mass percentage of 85%, and the molar ratios added are respectively The ratio is 1:5:2, the reaction temperature is 190-220°C, and the reaction time is 3-10 hours. In 2-p-chlorobenzylpyridine. the

With the 2-p-chlorobenzylpyridine produced by the inventive method, as the intermediate for preparing chlorpheniramine, the product purity is high, the process is simple and convenient, the chlorpheniramine product prepared with it meets the Chinese Pharmacopoeia, and the cost is low, easy to industrialization, and has Significant economic and social benefits. the

the

Detailed ways

The intermediate of 2-p-chlorobenzylpyridine in the present invention is 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. The method for preparing 1-(4-chlorophenyl)-1-(2-pyridyl)methanone is: the initial raw material 2-pyridine carboxylic acid is reacted with thionyl chloride to generate 2-pyridine carboxylic acid chloride, and the reaction condition is based on chlorine Use thionyl chloride as solvent, the molar ratio of thionyl chloride to 2-pyridinecarboxylic acid is 1:5, the temperature is reflux, and the reaction time is 3 hours. The 2-pyridineformyl chloride of gained is solvent again with chlorobenzene, and aluminum trichloride is a catalyst, and the molar ratio is 2-pyridineformyl chloride: chlorobenzene: aluminum trichloride=1: 10: 2～3, and the temperature range is 95～150℃; the reaction time is 3～10 hours, and the reaction product is 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. the

The structural formulas of the above-mentioned reactants are respectively:

1-(4-chlorophenyl)-1-(2-pyridyl)methanone, its structural formula is I:

The structural formula of 2-pyridinecarbonyl chloride is Ia, and chlorobenzene is Ib:

The structural formula of 2-pyridinecarboxylic acid as starting material is Ic:

The product 1-(4-chlorophenyl)-1-(2-pyridyl) ketone that above-mentioned reaction obtains takes diethylene glycol as solvent again, mixes with 85% hydrazine hydrate, potassium hydroxide, at 200 The reaction is carried out at ℃ for 3-10 hours, and the molar ratio of each substance is 1:5:2. The reaction product is 2-p-chlorobenzylpyridine. the

The structural formula of 2-p-chlorobenzylpyridine is II:

When 2-p-chlorobenzylpyridine is used as an intermediate to prepare the drug chlorpheniramine, the chlorpheniramine base will be prepared in a conventional manner: 2-p-chlorobenzylpyridine and N,N-dimethylaminoethyl chloride Alkanes and sodium amide reaction, get chlorpheniramine base 1-(4-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane;

The structural formula of chlorpheniramine base 1-(4-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane is III:

The structural formula of N, N-dimethylaminoethyl chloride is II a

The finished product of chlorpheniramine can be obtained by forming a salt of chlorpheniramine base and maleic acid. the

The structural formula of chlorpheniramine 1-(4-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane maleate is IV:

The structural formula of maleic acid is IIIa:

Example 1 Preparation of 2-p-chlorobenzylpyridine

Add 2.46g of 2-pyridinecarboxylic acid into a 100ml reaction flask, then slowly add 10ml of thionyl chloride into the constant pressure dropping funnel, slowly raise the temperature to reflux, and react for 3 hours. Heating was stopped, and the remaining thionyl chloride was recovered under reduced pressure to obtain a dark red solid of 2-pyridinecarbonyl chloride hydrochloride. Add 20ml of chlorobenzene under the condition of ice bath, slowly add 5.34g of aluminum trichloride under stirring, continue to stir after adding, after half an hour, transfer the reaction bottle into an oil bath and slowly heat to about 100°C, and react for 3 hours , stop responding. Recover the remaining chlorobenzene under reduced pressure, and then slowly add ice cubes (made by adding 2ml of concentrated hydrochloric acid to 20ml of water) under ice bath conditions. The reaction is very violent, and ice cubes should be added carefully. Then slowly add concentrated NaOH solution until the pH is about 12, and the red solid is 1-(4-chlorophenyl)-1-(2-pyridyl)methanone and impurities by filtration. Add 60ml of n-hexane and 3g of activated carbon and heat to reflux for 1 hour. Filter activated carbon to obtain n-hexane solution. Finally, the n-hexane solution was cooled and crystallized to obtain a white solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone, which was filtered, washed with water, and dried in a vacuum oven at 50°C to obtain a white solid. 0.61 g of powder solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. The residue after recovery of n-hexane was separated by column chromatography (silica gel 200-300 mesh, eluent: V _{ethyl acetate} : V _{petroleum ether} = 1:3) to obtain 0.11 g of the product, and a total of the product 1-(4-chloro Phenyl)-1-(2-pyridyl)methanone 0.72g, yield 16.7%, melting point: 60-61°C. GC-MS: 98%.

Take 2.18g of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone obtained by the above method, add 6ml of diethylene glycol, 12ml of 85% hydrazine hydrate, and 1.3g of potassium hydroxide, After reflux for 1 hour, the water in the reaction flask was distilled off while raising the reaction temperature. The temperature was raised to 190° C. and reacted for 3 hours. After cooling, add 100ml of water, extract with 10ml×3 toluene, recover toluene and distill under reduced pressure to obtain 1.52g of colorless oily liquid 2-p-chlorobenzylpyridine, yield 75%; GC-MS: 99%. the

Example 2 Preparation of 2-p-chlorobenzylpyridine

Add 2.46g of 2-pyridinecarboxylic acid into a 100ml reaction flask, then slowly add 10ml of thionyl chloride into the constant pressure dropping funnel, slowly raise the temperature to reflux, and react for 3 hours. Heating was stopped, and the remaining thionyl chloride was recovered under reduced pressure to obtain a dark red solid of 2-pyridinecarbonyl chloride hydrochloride. Add 20ml of chlorobenzene under the condition of ice bath, slowly add 7.24g of aluminum trichloride under stirring, continue to stir after the addition, after half an hour, transfer the reaction bottle to an oil bath and slowly heat to about 108°C, and react for 6 hours , stop responding. Recover the remaining chlorobenzene under reduced pressure, and then slowly add ice cubes (made by adding 2ml of concentrated hydrochloric acid to 20ml of water) under ice bath conditions. The reaction is very violent, and ice cubes should be added carefully. Then slowly add concentrated NaOH solution until the pH is about 12, and the red solid is 1-(4-chlorophenyl)-1-(2-pyridyl)methanone and impurities by filtration. Add 60ml of n-hexane and 3g of activated carbon and heat to reflux for 1 hour. Filter activated carbon to obtain n-hexane solution. Finally, the n-hexane solution was cooled and crystallized to obtain a white solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone, which was filtered, washed with water, and dried in a vacuum oven at 50°C to obtain a white solid. 1.17 g of powder solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. The residue after recovering n-hexane was separated by column chromatography (silica gel 200-300 mesh, eluent: V _{ethyl acetate} : V _{petroleum ether} = 1:3) to obtain 0.17 g of the product, and the product 1-(4-chloro 1.27 g of phenyl)-1-(2-pyridyl)methanone, the yield was 31.2%. Melting point: 60-61°C; GC-MS: 98%.

Take 2.18g of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone obtained above, add 6ml of diethylene glycol, 12ml of 85% hydrazine hydrate, 1.3g of potassium hydroxide, and reflux After 1 hour, the water in the reaction bottle was distilled off while raising the reaction temperature. The temperature was raised to 200°C and reacted for 8 hours. After cooling, add 100ml of water, extract with 10ml×3 toluene, recover the toluene and distill under reduced pressure to obtain 1.73g of 2-p-chlorobenzylpyridine as a colorless oily liquid, with a yield of 85%; GC-MS: 99%. the

Example 3 Preparation of 2-p-chlorobenzylpyridine

Add 2.46g of 2-pyridinecarboxylic acid into a 100ml reaction flask, then slowly add 10ml of thionyl chloride into the constant pressure dropping funnel, slowly raise the temperature to reflux, and react for 3 hours. Heating was stopped, and the remaining thionyl chloride was recovered under reduced pressure to obtain a dark red solid of 2-pyridinecarbonyl chloride hydrochloride. Add 20ml of chlorobenzene under the condition of ice bath, slowly add 6.7g of aluminum trichloride under stirring, continue to stir after adding, transfer the reaction bottle into an oil bath pot and slowly heat to about 145°C after half an hour, and react for 10 hours , stop responding. Recover the remaining chlorobenzene under reduced pressure, and then slowly add ice cubes (made by adding 2ml of concentrated hydrochloric acid to 20ml of water) under ice bath conditions. The reaction is very violent, and ice cubes should be added carefully. Then slowly add concentrated NaOH solution until the pH is about 12, and the red solid is 1-(4-chlorophenyl)-1-(2-pyridyl)methanone and impurities by filtration. Add 60ml of n-hexane and 3g of active carbon and heat under reflux for 1 hour. Filter activated carbon to obtain n-hexane solution. Finally, the n-hexane solution was cooled and crystallized to obtain a white solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone, which was filtered, washed with water, and dried in a vacuum oven at 50°C to obtain a white solid. 0.31 g of powder solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. The residue after recovering n-hexane was separated by column chromatography (silica gel 200-300 mesh, eluent: V _{ethyl acetate} : V _{petroleum ether} = 1:3) to obtain 0.09 g of the product, and a total of the product 1-(4-chloro Phenyl)-1-(2-pyridyl)methanone 0.4g, yield 10.1%; melting point: 60-61°C; GC-MS: 98%.

Take 2.18g of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone obtained above, add 6ml of diethylene glycol, 12ml of 85% hydrazine hydrate, 1.3g of potassium hydroxide, and reflux After 1 hour, the water in the reaction bottle was distilled off while raising the reaction temperature. The temperature was raised to 220° C. and reacted for 10 hours. After cooling, add 100ml of water, extract with 10ml×3 toluene, recover toluene and distill under reduced pressure to obtain 1.75g of colorless oily liquid 2-p-chlorobenzylpyridine, yield 86%; GC-MS: 99%. the

Embodiment 4: prepare chlorpheniramine

1. Take the 2-p-chlorobenzylpyridine prepared by any method described in Examples 1-3;

2. Preparation of chlorpheniramine base 1-(4-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane:

Weigh 0.6g of sodium amide and crush it in toluene solution, add it into a three-necked flask containing 4ml of toluene, then add 0.06g of cetyltrimethylammonium bromide, heat to reflux, and then slowly add 2- A solution of 2g and 2.13g of p-chlorobenzylpyridine dissolved in 5ml of toluene. Reflux reaction for 6 hours, filter after cooling to obtain a toluene solution containing chlorpheniramine base. After recovering toluene, distilled under reduced pressure to obtain 1.8 g of dark red oily liquid chlorpheniramine base. Yield 67%. the

3. Preparation of chlorpheniramine 1-(4-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane maleate: combine chlorpheniramine base with maleic di Acid into salt to get chlorpheniramine finished product. the

Claims (1)

1. the preparation method of a 2-p-chlorobenzyl pyridine is characterized by processing step and is:

(1). preparation 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone

The adding mol ratio is 1: 10 a chlorobenzene in 2-pyridine formyl chloride hydrochloride, with the aluminum chloride is catalyzer, the mol ratio of 2-pyridine formyl chloride hydrochloride and catalyzer is 1: 2～5,195～150 ℃ of temperature of reaction, in 3～10 hours reaction times, get 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone;

(2). preparation 2-p-chlorobenzyl pyridine

With the glycol ether is solvent, and adding 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone, mass percent are 85% hydrazine hydrate and potassium hydroxide, and the mol ratio of adding was respectively 1: 5: 2, and temperature of reaction is 190-220 ℃, reaction times 3-10 hour.Get 2-p-chlorobenzyl pyridine.