Synthesis method for N-substituted-4-piperidone

A synthesis method and piperidone technology are applied in the field of synthesis of N-substituent-4-piperidone compounds, and can solve the problems of expensive 4-piperidone raw materials, high risk of metallic sodium, poor atom economy and the like, To achieve the effect of reducing production cost, good atomic economy and low price

Inactive Publication Date: 2012-10-17
WENZHOU IND SCI RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the synthesis methods reported at home and abroad mainly include: 1. Condensation and hydrolysis decarboxylation using diester as raw material; for example: benzylamine and acrylate as the basic Raw materials, N-benzyl-4-piperidone is synthesized through three steps of double bond and amino addition, ester group internal condensation, hydrochloric acid hydrolysis and decarboxylation; this process has been industrialized at present, and the synthesis steps are relatively mature. Accepted, but the process needs to remove the alcohol group and carboxyl group, the atom economy is poor, the cost is high, and the risk of using metal sodium is high; 2. The direct alkylation reaction of 4-piperidone and benzyl bromide; the method receives The yield is higher and the technique is simple, but the initial raw material is more expensive and economically unfeasible; 3. react and reduce with 4-piperidone and benzoyl chloride; Bromide is cheap, but the raw material of 4-piperidone is more expensive, and it adds a step reaction, which is also economically unfeasible

Method used

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  • Synthesis method for N-substituted-4-piperidone
  • Synthesis method for N-substituted-4-piperidone
  • Synthesis method for N-substituted-4-piperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1) Add 73 grams (1.01 mol) of acrylic acid and 7.2 grams (0.1 mol) of N,N-dimethylformamide into the reaction flask, heat up to 70°C, and add 145 grams (1.05 mol) of ) phosphorus trichloride, the dropwise addition is completed within 5 hours, and the reaction is continued for half an hour, and the reaction ends. Distilled under reduced pressure, collected fractions at 60°C / 6kPa to obtain 130 g of 3-chloropropionyl chloride (content 90.2%, yield 83.6%);

[0023] (2) Dissolve 277 g (2.08 mol) of aluminum trichloride in 250 mL of dichloroethane, cool down to 0°C, add 200 g (1.57 mol) of 3-chloropropionyl chloride dropwise for 30 minutes under constant temperature stirring, and keep When the temperature is below 5°C, ethylene gas is passed through, and after 3 hours of ventilation, stir for a while, and the reaction ends. Configure 10% hydrochloric acid aqueous solution, cool to 0°C, slowly pour the reaction solution under stirring, and keep the temperature below 10°C. S...

Embodiment 2

[0026] (1) Add 73 grams (1.01 mol) of acrylic acid and 7.2 grams (0.1 mol) of N,N-dimethylformamide into the reaction flask, heat up to 70°C, and add 125 grams (1.05 mol) of ) Thionyl chloride, the dropwise addition is completed within 5 hours, and the reaction is continued for half an hour, and the reaction ends. Distilled under reduced pressure, collected fractions at 60°C / 6kPa to obtain 130 g of 3-chloropropionyl chloride (content 90.2%, yield 83.6%);

[0027] (2) Dissolve 231 grams (1.73 mol) of aluminum trichloride in 250 mL of chloroform, cool down to 0°C, and add 200 grams (1.57 mol) of 3-chloropropionyl chloride dropwise for 30 minutes under constant temperature stirring, keeping the temperature Feed ethylene gas below 5°C for 3 hours and then stir for a while, the reaction is over. Configure 10% hydrochloric acid aqueous solution, cool to 0°C, slowly pour the reaction solution under stirring, and keep the temperature below 10°C. Static separation, the organic phase ...

Embodiment 3

[0030] (1) Add 73 grams (1.01 mol) of acrylic acid and 7.2 grams (0.1 mol) of N,N-dimethylformamide into the reaction flask, heat up to 70°C, and add 68 grams (0.53 mol) of ) Oxalyl chloride, the dropwise addition is completed within 5 hours, and the reaction is continued for half an hour, and the reaction ends. Distilled under reduced pressure, collected fractions at 60°C / 6kPa to obtain 130 g of 3-chloropropionyl chloride (content 90.2%, yield 83.6%).

[0031] (2) Dissolve 314 grams (2.36 mol) of aluminum trichloride in 250 mL of dichloromethane, cool down to 0°C, and add 200 grams (1.57 mol) of 3-chloropropionyl chloride dropwise for 30 minutes under constant temperature stirring, keeping the temperature Feed ethylene gas below 5°C for 3 hours and then stir for a while, the reaction is over. Configure 10% hydrochloric acid aqueous solution, cool to 0°C, slowly pour the reaction solution under stirring, and keep the temperature below 10°C. Static separation, the organic pha...

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Abstract

The present invention relates to an N-substituted-4-piperidone compound and a synthesis method thereof. In the general formula of the compound, R is alkyl with a carbon number of 1-8, phenyl or benzyl, and other groups. Characteristics of the method of the present invention are: selecting appropriate primary amine and 1,5-dichloro-3-pentanone, and carrying out a ring closing reaction to prepare N-substituted-4-piperidone, wherein the selected 1,5-dichloro-3-pentanone can directly be purchased or synthesized by a two-step synthesis method, and the two-step synthesis method comprises: (1) adding thionyl chloride to acrylic acid, and carrying out an addition reaction and acyl chlorination under catalysis of N,N-dimethyl formamide to obtain 3-chloropropionyl chloride; (2) introducing ethylene gas to a dichloromethane solution of 3-chloropropionyl chloride, and carrying out a Friedel-Crafts reaction to obtain the 1,5-dichloro-3-pentanone. The method of the present invention has characteristics of wide raw material source, mild reaction conditions, simple operation, low production costs, high yield, and good industrial production prospect.

Description

technical field [0001] The invention relates to a method for synthesizing N-substituent-4-piperidone compounds. These compounds are important intermediates for preparing medicines and belong to the technical field of pharmacy. Background technique [0002] As a drug intermediate, N-substituent-4-piperidone has important research value in the field of medicine. It is widely used in the synthesis of analgesic, anti-allergic, anti-hypertensive, anti-tumor and other drugs. The research on this type of compound has become a research hotspot in the field of drug synthesis. Therefore, it is very attractive work to look for a wide range of raw material sources, mild reaction conditions, low production cost and high yield of N-substituent-4-piperidone. [0003] The synthetic methods that have been reported both at home and abroad at present mainly contain: 1. Condensation and hydrolysis decarboxylation with diesters as raw materials; Synthesis of N-benzyl-4-piperidone in three step...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/74C07C49/16C07C45/00
Inventor 曾余瑶吴忠信蒋晓青
Owner WENZHOU IND SCI RES INST
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