CN101967120A - Preparation method of 2-p-chlorobenzyl pyridine - Google Patents
Preparation method of 2-p-chlorobenzyl pyridine Download PDFInfo
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- CN101967120A CN101967120A CN2010100456228A CN201010045622A CN101967120A CN 101967120 A CN101967120 A CN 101967120A CN 2010100456228 A CN2010100456228 A CN 2010100456228A CN 201010045622 A CN201010045622 A CN 201010045622A CN 101967120 A CN101967120 A CN 101967120A
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- pyridine
- chlorobenzyl
- pyridyl
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- KHXSJSBQIWAIEG-UHFFFAOYSA-N O=C(c(cc1)ccc1Cl)c1ncccc1 Chemical compound O=C(c(cc1)ccc1Cl)c1ncccc1 KHXSJSBQIWAIEG-UHFFFAOYSA-N 0.000 description 1
- PSAYJRPASWETSH-UHFFFAOYSA-N O=C(c1ncccc1)Cl Chemical compound O=C(c1ncccc1)Cl PSAYJRPASWETSH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of 2-p-chlorobenzyl pyridine, comprising the following steps of: firstly adding chlorobenzene and alchlor to 2-pyridine formyl chloride hydrochloride for reaction so as to obtain 1-(4-chlorphenyl)-1-(2-pyridyl) ketone; and then adding diglycol, hydrazine hydrate and potassium hydroxide to the prepared 1-(4-chlorphenyl)-1-(2-pyridyl) ketone for reaction so as to obtain the 2-p-chlorobenzyl pyridine. The 2-p-chlorobenzyl pyridine produced by the method is used as an intermediate for preparing chlorpheniramine and has high product purity and simple and convenient process, and the chlorpheniramine prepared by using the 2-p-chlorobenzyl pyridine accords with Chinese pharmacopoeia; in addition, the invention has low cost, easy industrialization and outstanding economic benefit and social benefit.
Description
Technical field
The invention belongs to the preparation method of the intermediate 2-p-chlorobenzyl pyridine of preparation medicine Toldrin.
Background technology
Toldrin Chlorpheniramine, another name: chlorphenamine.Be antihistaminic, be mainly used in various anaphylactic diseases, as insect bite, urticaria, vasorelaxation rhinitis, asthma, contact dermatitis etc.Can also with other in, western modern medicine combines, treatment flu etc.The Toldrin medicine relies on its strong antiallergic activity and less side effect to occupy critical role in Claritin always.
2-p-chlorobenzyl pyridine is the important intermediate of preparation Toldrin medicine, its relevant technology of preparing also has many reports, traditional preparation method carries out condensation reaction with aniline when the PH=1 with the 2-picoline after by chlorination to get 2-PAB pyridine again, and then with its by diazotization and cuprous chloride react 2-p-chlorobenzyl pyridine.Not only step is many for this traditional preparation method, and reaction conditions requires high.
Summary of the invention
The technical problem to be solved in the present invention provides that a kind of step is few, technical process is short, the low method for preparing 2-p-chlorobenzyl pyridine of reaction conditions requirement.
The present invention solves the problems of the technologies described above with following technical scheme:
The processing step of preparation 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.
2-p-chlorobenzyl pyridine with the inventive method production, intermediate as the preparation Toldrin, product purity height, technology be easy, meet Chinese Pharmacopoeia with the Toldrin product of its preparation, and cost low, be easy to industrialization, remarkable economic efficiency and social benefit are arranged.
Embodiment
2-p-chlorobenzyl pyridine among the present invention, its intermediate are 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketones.The method for preparing 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone is: initial feed 2-pyridine carboxylic acid and sulfur oxychloride reaction are generated 2-pyridine formyl chloride, reaction conditions is to be solvent with the sulfur oxychloride, the mol ratio of sulfur oxychloride and 2-pyridine carboxylic acid is 1: 5, temperature is for refluxing, and the reaction times is 3 hours.The 2-pyridine formyl chloride of gained is solvent again with the chlorobenzene, and aluminum chloride is a catalyzer, and mol ratio is a 2-pyridine formyl chloride: chlorobenzene: aluminum chloride=1: 10: 2～3, range of temperature are 95～150 ℃; Reaction times is 3～10 hours, and reaction product is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone.
The structural formula of above-mentioned reactant is respectively:
1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone, its structural formula is I:
The structural formula of 2-pyridine formyl chloride is Ia, and chlorobenzene is Ib:
Structural formula as the 2-pyridine carboxylic acid of initial feed is Ic:
The product 1-that above-mentioned reaction obtains (4-chloro-phenyl-)-1-(2-pyridyl) ketone is solvent again with the glycol ether, mixes with 85% hydrazine hydrate, potassium hydroxide, and 200 ℃ of reactions 3-10 hour down, the mol ratio of each material is 1: 5: 2.Reaction product is a 2-p-chlorobenzyl pyridine.
The structural formula of 2-p-chlorobenzyl pyridine is II:
When with 2-p-chlorobenzyl pyridine during as intermediate preparation medicine Toldrin, to prepare the Toldrin alkali in the usual way earlier: be about to 2-p-chlorobenzyl pyridine and N, N dimethylamine base monochloroethane and sodium amide reaction get Toldrin alkali 1-(4-chloro-phenyl-)-1-(2-pyridyl)-3-dimethylin propane;
The structural formula of Toldrin alkali 1-(4-chloro-phenyl-)-1-(2-pyridyl)-3-dimethylin propane is III:
N, the structural formula of N dimethylamine base monochloroethane is II a
With Toldrin alkali and maleic acid salify get final product the Toldrin finished product.
The structural formula of Toldrin 1-(4-chloro-phenyl-)-1-(2-pyridyl)-3-dimethylin propane maleic acid salt is IV:
The structural formula of maleic acid is IIIa:
Embodiment 1 preparation 2-p-chlorobenzyl pyridine
Add 2.46g 2-pyridine carboxylic acid in the 100ml reaction flask, then the 10ml sulfur oxychloride is slowly added wherein in constant pressure funnel, slowly be warming up to backflow, reacted 3 hours.Stop heating, the remaining sulfur oxychloride of reclaim under reduced pressure, getting dark red solid is 2-pyridine formyl chloride hydrochloride.Add the 20ml chlorobenzene under the condition of ice bath, stir down and slowly add the 5.34g aluminum chloride, finish, continue to stir, after half an hour reaction flask changed over to and slowly be heated in the oil bath pan about 100 ℃, reacted stopped reaction 3 hours.Reclaim under reduced pressure residue chlorobenzene slowly adds ice cube (be added with in the 20ml water 2ml concentrated hydrochloric acid freeze make) then under condition of ice bath, react very violent, care should be used to adding ice cube.Slowly add concentrated NaOH solution again, adding to PH is about 12, filters to such an extent that red solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone and impurity.Added 60ml normal hexane and 3g activated carbon reflux 1 hour.Filtration of active charcoal gets hexane solution.At last the hexane solution crystallisation by cooling being got white solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone, filter, and washing, after draining, 50 ℃ of dry white powder solid 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 0.61g that get in vacuum drying oven.Residue behind the recovery normal hexane is through column chromatography (silica gel 200～300 orders, eluent: V
Ethyl acetate: V
Sherwood oil=1: 3) separation obtains product 0.11g, gets product 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 0.72g altogether, and yield is 16.7%, fusing point: 60-61 ℃.GC-MS：98％。
Get the obtained 1-of aforesaid method (4-chloro-phenyl-)-1-(2-pyridyl) ketone 2.18g, add glycol ether 6ml, 85% hydrazine hydrate 12ml, potassium hydroxide 1.3g refluxed 1 hour, and an edge height temperature of reaction steams the water in the reaction flask on one side then.Temperature is risen to 190 ℃, reacted 3 hours.Cool off the back and add 100ml water, with 10ml * 3 toluene extraction, underpressure distillation gets colourless oil liquid 2-p-chlorobenzyl pyridine 1.52g, yield 75% behind the recovery toluene; GC-MS:99%.
Embodiment 2 preparation 2-p-chlorobenzyl pyridines
Add 2.46g 2-pyridine carboxylic acid in the 100ml reaction flask, then the 10ml sulfur oxychloride is slowly added wherein in constant pressure funnel, slowly be warming up to backflow, reacted 3 hours.Stop heating, the remaining sulfur oxychloride of reclaim under reduced pressure, getting dark red solid is 2-pyridine formyl chloride hydrochloride.Add the 20ml chlorobenzene under the condition of ice bath, stir down and slowly add the 7.24g aluminum chloride, finish, continue to stir, after half an hour reaction flask changed over to and slowly be heated in the oil bath pan about 108 ℃, reacted stopped reaction 6 hours.Reclaim under reduced pressure residue chlorobenzene slowly adds ice cube (be added with in the 20ml water 2ml concentrated hydrochloric acid freeze make) then under condition of ice bath, react very violent, care should be used to adding ice cube.Slowly add concentrated NaOH solution again, adding to PH is about 12, filters to such an extent that red solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone and impurity.Added 60ml normal hexane and 3g activated carbon reflux 1 hour.Filtration of active charcoal gets hexane solution.At last the hexane solution crystallisation by cooling being got white solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone, filter, and washing, after draining, 50 ℃ of dry white powder solid 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 1.17g that get in vacuum drying oven.Residue behind the recovery normal hexane is through column chromatography (silica gel 200～300 orders, eluent: V
Ethyl acetate: V
Sherwood oil=1: 3) separation obtains product 0.17g, gets product 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 1.27g altogether, and yield is 31.2%.Fusing point: 60-61 ℃; GC-MS:98%.
Get above-mentioned obtained 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 2.18g, add glycol ether 6ml, 85% hydrazine hydrate 12ml, potassium hydroxide 1.3g refluxed 1 hour, and an edge height temperature of reaction steams the water in the reaction flask on one side then.Temperature is risen to 200 ℃, reacted 8 hours.Cool off the back and add 100ml water, with 10ml * 3 toluene extraction, underpressure distillation gets colourless oil liquid 2-p-chlorobenzyl pyridine 1.73g, yield 85% behind the recovery toluene; GC-MS:99%.
Embodiment 3 preparation 2-p-chlorobenzyl pyridines
Add 2.46g 2-pyridine carboxylic acid in the 100ml reaction flask, then the 10ml sulfur oxychloride is slowly added wherein in constant pressure funnel, slowly be warming up to backflow, reacted 3 hours.Stop heating, the remaining sulfur oxychloride of reclaim under reduced pressure, getting dark red solid is 2-pyridine formyl chloride hydrochloride.Add the 20ml chlorobenzene under the condition of ice bath, stir down and slowly add the 6.7g aluminum chloride, finish, continue to stir, after half an hour reaction flask changed over to and slowly be heated in the oil bath pan about 145 ℃, reacted stopped reaction 10 hours.Reclaim under reduced pressure residue chlorobenzene slowly adds ice cube (be added with in the 20ml water 2ml concentrated hydrochloric acid freeze make) then under condition of ice bath, react very violent, care should be used to adding ice cube.Slowly add concentrated NaOH solution again, adding to PH is about 12, filters to such an extent that red solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone and impurity.Added 60ml normal hexane and 3g activated carbon reflux 1 hour.Filtration of active charcoal gets hexane solution.At last the hexane solution crystallisation by cooling being got white solid is 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone, filter, and washing, after draining, 50 ℃ of dry white powder solid 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 0.31g that get in vacuum drying oven.Residue behind the recovery normal hexane is through column chromatography (silica gel 200～300 orders, eluent: V
Ethyl acetate: V
Sherwood oil=1: 3) separation obtains product 0.09g, gets product 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 0.4g altogether, and yield is 10.1%; Fusing point: 60-61 ℃; GC-MS:98%.
Get above-mentioned obtained 1-(4-chloro-phenyl-)-1-(2-pyridyl) ketone 2.18g, add glycol ether 6ml, 85% hydrazine hydrate 12ml, potassium hydroxide 1.3g refluxed 1 hour, and an edge height temperature of reaction steams the water in the reaction flask on one side then.Temperature is risen to 220 ℃, reacted 10 hours.Cool off the back and add 100ml water, with 10ml * 3 toluene extraction, underpressure distillation gets colourless oil liquid 2-p-chlorobenzyl pyridine 1.75g, yield 86% behind the recovery toluene; GC-MS:99%.
Embodiment 4: the preparation Toldrin
1. take the 2-p-chlorobenzyl pyridine of the described either party's method preparation of embodiment 1-3;
2. prepare Toldrin alkali 1-(4-chloro-phenyl-)-1-(2-pyridyl)-3-dimethylin propane:
Take by weighing sodium amide 0.6g and pulverize in toluene solution, its adding is contained in the there-necked flask of 4ml toluene, add the cetyl trimethylammonium bromide of 0.06g again, reflux slowly drips the solution that 2-p-chlorobenzyl pyridine 2g and 2.13g are dissolved in 5ml toluene then.Back flow reaction 6 hours, cooled and filtered must contain the toluene solution of Toldrin alkali.Underpressure distillation gets garnet oily liquids Toldrin alkali 1.8g after reclaiming toluene.Yield 67%.
3. prepare Toldrin 1-(4-chloro-phenyl-)-1-(2-pyridyl)-3-dimethylin propane maleic acid salt: Toldrin alkali and maleic acid salify are got the Toldrin finished product.
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.
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| CN2010100456228A CN101967120A (en) | 2010-01-08 | 2010-01-08 | Preparation method of 2-p-chlorobenzyl pyridine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787958A (en) * | 2014-03-10 | 2014-05-14 | 悦康药业集团有限公司 | Chlorpheniramine maleate compound and pharmaceutical composition thereof |
| CN105175318A (en) * | 2015-07-29 | 2015-12-23 | 张燕梅 | Synthesis method of pheniramine maleate |
| CN105237469A (en) * | 2015-10-27 | 2016-01-13 | 杭州澳医保灵药业有限公司 | Preparation method of 4-chlorophenyl-2-pyridyl methanol |
| CN106883167A (en) * | 2015-12-16 | 2017-06-23 | 张燕梅 | A kind of new chlorphenamine maleate synthetic method |
| CN110372578A (en) * | 2019-05-31 | 2019-10-25 | 嘉实（湖南）医药科技有限公司 | A kind of new chlorphenamine maleate synthetic method |
-
2010
- 2010-01-08 CN CN2010100456228A patent/CN101967120A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787958A (en) * | 2014-03-10 | 2014-05-14 | 悦康药业集团有限公司 | Chlorpheniramine maleate compound and pharmaceutical composition thereof |
| CN103787958B (en) * | 2014-03-10 | 2016-01-27 | 悦康药业集团有限公司 | Chlorpheniramine maleate compound and pharmaceutical composition thereof |
| CN105175318A (en) * | 2015-07-29 | 2015-12-23 | 张燕梅 | Synthesis method of pheniramine maleate |
| CN105237469A (en) * | 2015-10-27 | 2016-01-13 | 杭州澳医保灵药业有限公司 | Preparation method of 4-chlorophenyl-2-pyridyl methanol |
| CN106883167A (en) * | 2015-12-16 | 2017-06-23 | 张燕梅 | A kind of new chlorphenamine maleate synthetic method |
| CN110372578A (en) * | 2019-05-31 | 2019-10-25 | 嘉实（湖南）医药科技有限公司 | A kind of new chlorphenamine maleate synthetic method |
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Open date: 20110209 |