Synthesis process of N-sustituent-4-piperidyl alcohol

A synthesis method and a substituent technology are applied in the field of preparation of N-substituent-4-piperidinol, can solve the problems of high equipment requirements, increased production cost, many reaction steps, etc., and can reduce production costs and save production costs. , the effect of mild reaction conditions

Inactive Publication Date: 2009-05-20
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material piperidone is mainly produced through reactions such as diester condensation, salt formation, hydrolysis, and neutralization. There are many reaction steps, complicated intermediate product processing, high product loss, and low yield.
In terms of reduction methods, catalytic hydrogenation reduction generally has a higher yield, but it requires catalytic hydrogenation under high temperature and high pressure conditions, which requires high equipment and certain risks in the process; using LiAlH 4 As a reducing agent, although the reaction speed is fast and the yield is high, the price is high, and it needs to be operated in an anhydrous environment, so it cannot be industrialized; the use of NaBH 4 As a reducing agent, the price is relative to LiAlH 4 Reduced a lot, the reaction conditions are milder, and the industrial operation is convenient, but the yield is low, and NaBH 4 The demand is large, which increases the production cost
[0004] Another document, Helv Chem Acta, 1966, 49 (1) 690-695, reported that pyrrolo [1,2-α] pyridone was used as raw material to obtain 4-piperidinol through reduction and then substitution reaction with iodide to obtain the corresponding For the target compound, the raw material preparation of this method is more complicated, the reduction yield is lower, and the price of the iodide used to replace it is also more expensive, so it is not suitable for industrialization

Method used

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  • Synthesis process of N-sustituent-4-piperidyl alcohol
  • Synthesis process of N-sustituent-4-piperidyl alcohol
  • Synthesis process of N-sustituent-4-piperidyl alcohol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1) Add 200g of ethyl acrylate (containing a polymerization inhibitor) and 100ml of triethylamine into the reaction flask, heat up to 70°C, feed dry methylamine gas under constant temperature stirring, ventilate for 3 hours, stir for a while, and end reaction. Recover low boilers by distillation under reduced pressure, steam to an internal temperature of 120°C / 3mmHg, there is no distillate, cool to room temperature, take a sample for GC analysis, the diester content is 92.3%, and orange liquid N,N-bis(β-acrylic acid Ethyl ester) methylamine 212.4g, yield 84.6%.

[0027] (2) Add 5ml of ethanol and 3.5g of sodium into the reaction flask, add 70ml of toluene after 10 minutes of reaction, heat to reflux, and slowly drop the mixture of 25g of diester and 30ml of toluene prepared above into the reaction system under stirring During the reaction process, the mixture of toluene and ethanol is continuously separated by a water separator, and the reaction is terminated when the ...

Embodiment 2

[0030] (1) Add 200g of ethyl acrylate (containing polymerization inhibitor) and 100ml of 1,4-dioxane into the reaction flask, heat up to 70°C, slowly add 36g of ethylamine dropwise under stirring, and the dropwise addition is completed Then keep stirring for 1 h to end the reaction. Low boilers were recovered by distillation under reduced pressure, and steamed to an internal temperature of 120°C / 3mmHg. There was no distillate, cooled to room temperature, sampled for GC analysis, the diester content was 90.6%, and 173.4 g of orange liquid N,N-bis(β-ethyl acrylate)ethylamine was obtained, with a yield of 80.3%.

[0031] (2) Add 5ml of methanol and 3.5g of sodium into the reaction flask, add 70ml of toluene after 10 minutes of reaction, heat to reflux, and slowly drop the mixture of 27g of diester and 30ml of toluene prepared above into the reaction system under stirring In the process, after the dropwise addition of the mixed solution is completed, keep warm and reflux. During ...

Embodiment 3

[0034] (1) Add 200g of ethyl acrylate (containing a polymerization inhibitor) and 100ml of tetrahydrofuran into the reaction bottle and heat up to 60°C. Slowly add 85.6g of benzylamine dropwise while stirring. After the dropwise addition, keep stirring for 1 hour to end the reaction . Recover low boilers by distillation under reduced pressure, and steam to an internal temperature of 130°C / 3mmHg. There was no distillate, cooled to room temperature, sampled for GC analysis, the diester content was 90.8%, and 238.0 g of orange liquid N,N-bis(β-ethyl acrylate) benzylamine was obtained, with a yield of 88.2%.

[0035] (2) Add 5ml of ethanol and 3.5g of sodium into the reaction flask, add 70ml of benzene after reacting for 10min, heat to reflux, slowly add the mixed solution of 34g of diester and 30ml of benzene into the reaction system dropwise under stirring, when After the dropwise addition of the mixed solution is completed, heat-preserve and reflux. During the reaction process...

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Abstract

The synthesis process of preparing N-substituent-4-piperidyl alcohol includes the following steps: 1. adding primary amine into ethyl acrylate to react to obtain the secondary addition product; 2. adding cyclizing agent into the secondary addition product and adding concentrated hydrochloric acid after finishing cyclization to obtain N-substituent-4-piperidone hydrochloride; 3. reducing N-substituent-4-piperidone hydrochloride with NaBH4-Amberlyst-15(H+) system and regulating pH value to extract N-substituent-4-piperidyl alcohol; and 4. recovering and treating resin for reuse. The present invention has wide raw material resource, mild reaction condition, simple operation, low production cost, high yields in different steps, and excellent industrial application foreground.

Description

technical field [0001] The invention relates to a preparation method of N-substituent-4-piperidinol. These compounds are used as active ingredients for preparing medicines and belong to the technical field of pharmacy. Background technique [0002] N-substituent-4-piperidinol is an important drug intermediate, which is widely used in the synthesis of various drugs, such as loratadine, azatadine, dibenzidine, which are used more in clinical treatment for anti-skin allergies Lin, cyproheptadine, Kaisiting; anti-asthma drug ketotifen; methemoglobinemia drug propiverine hydrochloride tablets. [0003] Most of the current reports are to synthesize such compounds by reducing the corresponding piperidones. The raw material, piperidone, is mainly produced through reactions such as diester condensation, salt formation, hydrolysis, and neutralization. There are many reaction steps, complicated handling of intermediate products, high product loss, and low yield. In terms of reduction...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/46
Inventor 肖国民陈绘如陶中东
Owner SOUTHEAST UNIV
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