CN107879969B - Synthesis method of N-benzyl-4-piperidinecarboxylic acid - Google Patents
Synthesis method of N-benzyl-4-piperidinecarboxylic acid Download PDFInfo
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- CN107879969B CN107879969B CN201711434637.1A CN201711434637A CN107879969B CN 107879969 B CN107879969 B CN 107879969B CN 201711434637 A CN201711434637 A CN 201711434637A CN 107879969 B CN107879969 B CN 107879969B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic method of N-benzyl-4-piperidinecarboxylic acid. The process comprises the following steps: 4-piperidine formic acid and benzyl chloride are used as raw materials, 1, 2-dichloroethane is used as a solvent for heating reaction, water is added for washing after cooling, an organic layer is dried, filtered and concentrated, and the N-benzyl-4-piperidine formic acid is obtained. The solvent 1, 2-dichloroethane used in the synthesis method is collected after concentration and can be recycled, so that the method is environment-friendly and greatly reduces the cost of raw materials.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic method of N-benzyl-4-piperidinecarboxylic acid.
Background
N-benzyl-4-piperidinecarboxylic acid is an important intermediate of medicines and chemical industry, and is widely concerned in the industries of medicines, chemical industry and the like. In the field of medicine, N-benzyl-4-piperidinecarboxylic acid is an important intermediate of donepezil hydrochloride which is a long-acting symptomatic treatment drug for Alzheimer's disease. Donepezil hydrochloride is a second-generation cholinesterase inhibitor, and the therapeutic effect of donepezil hydrochloride is to reversibly inhibit acetylcholinesterase-induced hydrolysis of acetylcholinesterase to increase the acetylcholine content at the receptor site. There are other mechanisms of donepezil, including its disposition to peptides, its direct action at neurotransmitter receptors or calcium ion channels; therefore, it is suitable for mild and moderate Alzheimer type dementia. Chemical formula of N-benzyl-4-piperidinecarboxylic acid C13H17NO2Molecular weight 219.28, CAS number 10315-07-8; the structural formula is
Patent WO2000059502 reports the reaction of benzaldehyde and 4-piperidinecarboxylic acid as raw materials, NaHB (OAC)3Three times of continuous feeding reaction for 52 hours are needed for reducing the reagent; after the reaction, the crude product of the N-benzyl-4-piperidinecarboxylic acid is obtained by treatment with ice water and concentrated hydrochloric acid. The method has several problems: the benzaldehyde is easy to oxidize in the reaction, and nitrogen is needed for protection in the reaction; also NaBH (OAc)3Expensive reagent, high production cost, long reaction time and the like. Document Bioorganic&Medicinal Chemistry, 24(18), 4324-4338, 2016 and GB2351733 report the substitution of benzyl bromide by reaction with acetonitrile and dichloromethane as solvents, hydrolysisThe yield of N-benzyl-4-piperidinecarboxylic acid was 99%. Although the problems of oxidation and long reaction time in the reaction are avoided, the benzyl bromide is expensive. In addition, the solvent acetonitrile after reaction is difficult to recycle due to mutual solubility with water; although dichloromethane can be used for this purpose, the solvent recovery is low because of the low boiling point.
In addition, GB2351733 reports that benzyl bromide is used as a raw material, N, N-diisopropylethylamine is used as an acid-binding agent to react to obtain N-benzyl-4-piperidine methyl formate, the yield of the obtained N-benzyl-4-piperidine methyl formate is 85%, and the obtained N-benzyl-4-piperidine methyl formate is hydrolyzed to obtain N-benzyl-4-piperidine formic acid; the overall yield will decrease. WO2008031227 also reports that methyl N-benzyl-4-piperidinecarboxylate is obtained first, and after the reaction ethyl acetate and petroleum ether are required to react in a ratio of 1: purifying by passing through a column according to the proportion of 3; hydrolyzing to obtain the N-benzyl-4-piperidinecarboxylic acid.
Therefore, a process with stability and short reaction time, and a method for synthesizing the N-benzyl-4-piperidinecarboxylic acid, which is environmentally friendly, by treating and then mechanically applying a solvent used in the process, are needed to be researched.
Disclosure of Invention
In order to solve the technical problem, the invention provides a synthesis method of N-benzyl-4-piperidinecarboxylic acid. Directly taking 4-piperidinecarboxylic acid and cheap chlorobenzyl as raw materials, taking 1, 2-dichloroethane as a solvent, washing to remove salt after the reaction is finished, and drying and concentrating the obtained organic layer to obtain the N-benzyl-4-piperidinecarboxylic acid; the distilled and recovered organic solvent 1, 2-dichloroethane can be recycled. The N-benzyl-4-piperidinecarboxylic acid obtained by the process synthesis method has high yield, is environment-friendly and greatly reduces the cost of raw materials; the selected reaction conditions obviously shorten the reaction time; the production period is shortened, and the production cost is reduced.
The invention is realized by the following technical scheme:
a synthetic method of N-benzyl-4-piperidinecarboxylic acid comprises the following steps:
4-piperidine formic acid and benzyl chloride react in a reaction solvent for 8-25h at 60-85 ℃ under the condition of an acid-binding agent, and after the reaction of the raw materials is finished, the raw materials are post-treated to obtain the N-benzyl-4-piperidine formic acid.
The synthesis reaction formula of the N-benzyl-4-piperidinecarboxylic acid is as follows:
in the above synthesis method of N-benzyl-4-piperidinecarboxylic acid, the reaction solvent is one or more of petroleum ether, toluene, dichloromethane, chloroform and 1, 2-dichloroethane.
Preferably, in the above method for synthesizing N-benzyl-4-piperidinecarboxylic acid, the reaction solvent is 1, 2-dichloroethane.
In the synthesis method of the N-benzyl-4-piperidinecarboxylic acid, the acid-binding agent is one or two of triethylamine, diethylamine, diisopropylethylamine, sodium carbonate, potassium hydroxide and sodium hydroxide.
Preferably, in the above method for synthesizing N-benzyl-4-piperidinecarboxylic acid, the acid-binding agent is triethylamine.
In the above method for synthesizing N-benzyl-4-piperidinecarboxylic acid, the weight ratio of the 4-piperidinecarboxylic acid to the reaction solvent is 1: 4-15; the molar ratio of the 4-piperidinecarboxylic acid to the benzyl chloride is 1: 1-5; the molar ratio of the 4-piperidinecarboxylic acid to the acid-binding agent is 1: 1-5.
Preferably, in the above method for synthesizing N-benzyl-4-piperidinecarboxylic acid, the weight ratio of the 4-piperidinecarboxylic acid to the organic solvent is 1: 6; the molar ratio of the 4-piperidinecarboxylic acid to the benzyl chloride is 1: 1.5; the molar ratio of the 4-piperidinecarboxylic acid to the acid-binding agent is 1: 1.3.
in the above synthesis method of N-benzyl-4-piperidinecarboxylic acid, the reaction temperature is 83.5 ℃, and the reaction time is 10 hours.
In the above method for synthesizing N-benzyl-4-piperidinecarboxylic acid, the post-treatment step is: after the reaction is finished, cooling the reaction solution to room temperature, adding water for washing, and separating liquid; washing the organic layer with saturated brine, and separating; drying the organic layer, filtering and concentrating to obtain the N-benzyl-4-piperidinecarboxylic acid.
The synthesis method of the N-benzyl-4-piperidinecarboxylic acid comprises the following steps:
4-piperidinecarboxylic acid and benzyl chloride react in 1, 2-dichloroethane at 60-85 ℃ for 8-25h under the condition that triethylamine is used as an acid-binding agent, the reaction solution is cooled to room temperature after the reaction is finished, and water washing and liquid separation are added; washing the organic layer with saturated brine, and separating; drying the organic layer, filtering and concentrating to obtain the N-benzyl-4-piperidinecarboxylic acid.
The synthesis method of the N-benzyl-4-piperidinecarboxylic acid comprises the following detailed steps:
775g of 1, 2-dichloroethane was put into a 2000ml reaction flask, 129.16g of 4-piperidinecarboxylic acid and 131.55g of triethylamine were added with stirring, and 189.87g of chlorobenzyl were added under a temperature of 20 ℃. After dripping, slowly heating to 83.5 ℃ for reflux reaction for 10 hours, cooling the reaction liquid to room temperature, adding 300g of water, stirring uniformly, and separating liquid; adding 150g of saturated saline solution into the organic layer, washing, and separating and drying the organic layer; the filtrate was concentrated by filtration to give 201.96g of N-benzyl-4-piperidinecarboxylic acid as an oily substance.
The invention has the beneficial effects that:
(1) piperidine formic acid and benzyl chloride are used as raw materials, 1, 2-dichloroethane is used as a solvent, and triethylamine is used as an acid-binding agent; compared with the literature report, the reaction time is obviously shortened, and the time cost is reduced.
(2) In the synthesis method of the N-benzyl-4-piperidinecarboxylic acid, benzyl chloride is used as a raw material, so that benzyl bromide with higher use price in the prior art is avoided; the raw materials of the solvent 1, 2-dichloroethane and the acid-binding agent triethylamine are relatively low in price, the 1, 2-dichloroethane as the solvent can be recycled and reused, the post-reaction treatment is simplified, the production cost is further reduced, and the environmental protection pressure is relieved.
(3) The synthesis method of the N-benzyl-4-piperidinecarboxylic acid reduces the cost of raw materials, is simple to operate, and is suitable for pilot plant test and large-scale industrial production of the N-benzyl-4-piperidinecarboxylic acid.
(4) The molar yield of the N-benzyl-4-piperidinecarboxylic acid prepared by the method is more than 90%, and the liquid phase purity is more than 96.5%.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1
1500g of methylene chloride is added into a 3000ml reaction bottle, 129.16g of 4-piperidinecarboxylic acid and 121.43g of triethylamine are added under stirring, and 139.24g of benzyl chloride is added under temperature control of 20 ℃. Slowly heating to reflux reaction for 24h after dripping, cooling the reaction liquid to room temperature, adding 600g of water, stirring uniformly, and separating liquid; adding 300g of saturated saline solution into the organic layer, washing, and separating and drying the organic layer; filtering the obtained filtrate, and concentrating the filtrate to obtain 197.79g of oily N-benzyl-4-piperidinecarboxylic acid; the molar yield is 90.2%, and the liquid phase purity is 96.53%.
Example 2
775g of 1, 2-dichloroethane was put into a 2000ml reaction flask, 129.16g of 4-piperidinecarboxylic acid and 155.1g of diisopropylethylamine were added with stirring, and 139.24g of chlorobenzyl chloride was added thereto under temperature control of 20 ℃. After the dripping is finished, slowly heating to 83.5 ℃, refluxing and reacting for 8.5h, cooling the reaction liquid to room temperature, adding 300g of water, stirring uniformly, and separating liquid; adding 150g of saturated saline solution into the organic layer, washing, and separating and drying the organic layer; filtering the obtained filtrate, and concentrating the filtrate to obtain 201.52g of oily N-benzyl-4-piperidinecarboxylic acid; the molar yield is 91.9 percent, and the purity of the liquid phase is 96.81 percent.
Example 3
775g of 1, 2-dichloroethane was put into a 2000ml reaction flask, 129.16g of 4-piperidinecarboxylic acid and 131.55g of triethylamine were added with stirring, and 189.87g of chlorobenzyl were added under a temperature of 20 ℃. After dripping, slowly heating to 83.5 ℃ for reflux reaction for 10 hours, cooling the reaction liquid to room temperature, adding 300g of water, stirring uniformly, and separating liquid; adding 150g of saturated saline solution into the organic layer, washing, and separating and drying the organic layer; filtering the obtained filtrate, and concentrating the filtrate to obtain 201.96g of oily N-benzyl-4-piperidinecarboxylic acid; the molar yield is 92.1%, and the liquid phase purity is 97.21%.
Example 4
1290g of chloroform is added into a 2000ml reaction flask, 129.16g of 4-piperidinecarboxylic acid and 151.79g of triethylamine are added with stirring, and 164.55g of benzyl chloride is added under the temperature of 20 ℃. Slowly heating to reflux reaction for 16h after dripping, cooling the reaction liquid to room temperature, adding 300g of water, stirring uniformly, and separating liquid; adding 150g of saturated saline solution into the organic layer, washing, and separating and drying the organic layer; filtering the obtained filtrate, and concentrating the filtrate to obtain 200.64g of oily N-benzyl-4-piperidinecarboxylic acid; the molar yield is 91.5%, and the liquid phase purity is 97.08%.
Claims (4)
1. A synthetic method of N-benzyl-4-piperidinecarboxylic acid is characterized by comprising the following steps:
4-piperidinecarboxylic acid and benzyl chloride react in 1, 2-dichloroethane at 60-85 ℃ for 8-25h under the condition that triethylamine is used as an acid-binding agent, the reaction solution is cooled to room temperature after the reaction is finished, and water washing and liquid separation are added; washing the organic layer with saturated brine, and separating; drying the organic layer, filtering and concentrating to obtain the N-benzyl-4-piperidinecarboxylic acid.
2. The method for synthesizing N-benzyl-4-piperidinecarboxylic acid as claimed in claim 1, wherein the weight ratio of 4-piperidinecarboxylic acid to 1, 2-dichloroethane is 1: 4-15; the molar ratio of the 4-piperidinecarboxylic acid to the benzyl chloride is 1: 1-5; the molar ratio of the 4-piperidinecarboxylic acid to the acid-binding agent is 1: 1-5.
3. The method for synthesizing N-benzyl-4-piperidinecarboxylic acid as claimed in claim 2, wherein the weight ratio of 4-piperidinecarboxylic acid to 1, 2-dichloroethane is 1: 6; the molar ratio of the 4-piperidinecarboxylic acid to the benzyl chloride is 1: 1.5; the molar ratio of the 4-piperidinecarboxylic acid to the acid-binding agent is 1: 1.3.
4. the method for synthesizing N-benzyl-4-piperidinecarboxylic acid according to claim 1, wherein the reaction temperature is 83.5 ℃ and the reaction time is 10 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017086832A1 (en) * | 2015-11-19 | 2017-05-26 | Акционерное Общество "Р-Фарм" (Ао "Р-Фарм") | Substituted n2-(4-amino-2-methoxyphenyl)-n4-[2-(dimethylphosphinoyl)-phenyl]-5-chloro-pyrimidine-2,4-diamines as alk and egfr modulators intended for treating cancer |
| WO2017175066A1 (en) * | 2016-04-08 | 2017-10-12 | Mankind Pharma Ltd. | Heterocyclic gpr119 agonist compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017086832A1 (en) * | 2015-11-19 | 2017-05-26 | Акционерное Общество "Р-Фарм" (Ао "Р-Фарм") | Substituted n2-(4-amino-2-methoxyphenyl)-n4-[2-(dimethylphosphinoyl)-phenyl]-5-chloro-pyrimidine-2,4-diamines as alk and egfr modulators intended for treating cancer |
| WO2017175066A1 (en) * | 2016-04-08 | 2017-10-12 | Mankind Pharma Ltd. | Heterocyclic gpr119 agonist compounds |
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Denomination of invention: A synthetic method of n-benzyl-4-pipecolic acid Effective date of registration: 20220616 Granted publication date: 20210219 Pledgee: Shandong Pingyuan Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG CHENGHUI SHUANGDA PHARMACEUTICAL CO.,LTD. Registration number: Y2022980007784 |
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