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Synthetic method of 2, 4-dioxopiperidine

A synthesis method and a piperidinedione technology are applied in the field of synthesis of a pharmaceutical intermediate 2,4-piperidinedione, which can solve the problems of pollution, environment prone to by-products, strong corrosiveness of raw materials, etc., and achieves safe operation, The effect of few side reactions and high conversion rate

Active Publication Date: 2014-07-23
兰州精细化工有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a synthetic method of 2,4-piperidine diketone to solve the problem that the raw materials used in the existing process are highly corrosive, easily produce by-products and cause pollution to the environment

Method used

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  • Synthetic method of 2, 4-dioxopiperidine
  • Synthetic method of 2, 4-dioxopiperidine
  • Synthetic method of 2, 4-dioxopiperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: Compound I is 3-alanine methyl ester hydrochloride,

[0026] (1) Acylation: Add 150g of dichloromethane to the reaction bottle, add 20g of compound I under stirring, then lower the temperature in the reaction bottle to 10°C, add 35g of triethylamine, after the addition, control the temperature to 10 °C, 17.6g of raw material 1, 25g of DCC, and 1.5g of HATU were sequentially added, and the mixture was kept at 10°C and stirred for 20 hours, and the reaction was completed.

[0027] Post-treatment: first filter out the solid DCC in the reaction solution, wash the filtrate with dilute hydrochloric acid with a pH of 5, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain the compound II product as a light yellow liquid.

[0028] (2) Condensation: Dissolve the compound II prepared above in 60 g of toluene solution, add 6.8 g of sodium methoxide solid to the reaction liquid at a time at room temperature, heat the mixture under reflux for 1 hour, ...

Embodiment 2

[0030] Embodiment 2: Catalyst adopts HBTU, and compound I is 3-alanine methyl ester hydrochloride,

[0031] (1) Acylation: Add 120g of dichloromethane to the reaction bottle, add 25g of compound I under stirring, then lower the temperature in the reaction bottle to 8°C, add 30g of triethylamine, after the addition, control the temperature to 8 ℃, add 16g raw material 1, 20gDCC, 1.4gHBTU successively, keep the mixture at 8℃ and stir for 18h, and the reaction ends.

[0032] Post-processing: first filter out the solid DCC in the reaction solution, wash the filtrate with dilute hydrochloric acid with a pH of 5, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 30.6 g of compound II, which is a light yellow liquid.

[0033] (2) Condensation: Dissolve the compound II prepared above in 62.5 g of toluene solution, add 6.0 g of sodium methoxide solid to the reaction liquid at a time at room temperature, and heat the mixture under reflux for 1.5 h until the reaction...

Embodiment 3

[0035] Embodiment 3 catalyst adopts pyBOP, and compound I is 3-alanine methyl ester hydrochloride,

[0036] (1) Acylation: Add 100g of dichloromethane to the reaction bottle, add 20g of compound I under stirring, then lower the temperature in the reaction bottle to 5°C, add 37.5g of triethylamine, after the addition, control the temperature to At 5°C, 20g of raw material 1, 16g of DCC, and 1.25g of pyBOP were sequentially added, and the mixture was kept at 5°C and stirred for 18 hours, and the reaction was completed.

[0037] Post-treatment: first filter out the solid DCC in the reaction solution, wash the filtrate with dilute hydrochloric acid with a pH of 5, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 32.1 g of compound II, which is a light yellow liquid.

[0038] (2) Condensation: Dissolve the compound II prepared above in 75g of toluene solution, add 7.5g of sodium methoxide solid to the reaction solution at a time at room temperature, and heat t...

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Abstract

The invention discloses a synthetic method of 2, 4-dioxopiperidine. The method comprises the following steps: by taking monomethyl malonate, 3-amino methyl propionate hydrochloride or 3-amino ethyl propionate hydrochloride as an initial raw material, dichloromethane as a solvent, dicyclohexylcarbodiimide (DDC) as a dehydrator and triethylamine as an acid-binding agent, carrying out a reaction; acidylating a condensation product methyl-3-((3-methoxyl-3-carbonyl propyl) amino)-3-carbonyl propionate, wherein in the acidylating condensation reaction process, onium salt is used as a catalyst which is good in selectivity, few in side reaction and higher in yield; then, circularly condensing to obtain 3-(carbomethoxy(methoxycarbonyl))-4-carbonyl-1, 4, 5, 6-tetrapyridine-2-alcoholic sodium under the effect of sodium methylate; and then, decarboxylating in a hydrochloric acid system to obtain 2, 4-dioxopiperidine. In the whole reaction, as methoxyl is easy to remove, so that the synthetic method is available in the raw materials, mild in reaction condition, safe to operate and high in conversion rate.

Description

technical field [0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a method for synthesizing a pharmaceutical intermediate 2,4-piperidinedione. Background technique [0002] 2,4-piperidinedione is an important pharmaceutical intermediate, and its derivatives are widely used in antibacterial, anti-tumor and other fields, such as alosetron hydrochloride (Alosetron) prepared by 2,4-piperidinedione Hydrochloride, whose chemical name is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4, 3-b] indol-1-one hydrochloride), is an effective, highly selective 5-HT3 receptor antagonist, and is also the first drug approved by FDA in recent years for the treatment of irritable bowel syndrome ( new drug for IBS). 2,4-Piperidinedione is a colorless oil at room temperature, molecular formula: C 5 h 4 NO 2 , it is a relatively new pharmaceutical intermediate, the existing synthesis process is as follows: use mono...

Claims

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Application Information

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IPC IPC(8): C07D211/86
CPCC07D211/86
Inventor 霍利春李春新张鹏云刘生丽路彬王琴
Owner 兰州精细化工有限责任公司
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