阅读说明：本技术 N-苄基-3-氧代哌啶-4-羧酸乙酯盐酸盐的制备方法 (Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride ) 是由 胡峻 计炜 刘苏林 张兆伟 于 2019-11-11 设计创作，主要内容包括：本发明提供一种N-苄基-3-氧代哌啶-4-羧酸乙酯盐酸盐的制备方法,包含如下步骤：(1)制备中间体2：将N-苄基甘氨酸乙酯溶解于有机溶剂中,加入4-卤代丁酸乙酯、碱,反应得到N-苄基甘氨酸乙酯；(2)将所述中间体2溶解于有机溶剂中,与碱反应,反应完毕后调节pH＝7～8,加入水洗涤,有机层调节pH＝1～2,析出晶体得到粗品；(3)将所述粗品溶解于水中,加入碱调节pH＝7～8,加入有机溶剂提取、洗涤,有机层调节pH＝1～2,结晶得到产品。本发明工艺操作简单,产品收率高、纯度高,易于工业化生产。(The invention provides a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochlorides, which comprises the following steps of (1) preparing an intermediate 2, dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, reacting to obtain N-benzyl glycine ethyl ester, (2) dissolving the intermediate 2 in the organic solvent, reacting with the alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, precipitating crystals to obtain a crude product, and (3) dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding the organic solvent for extraction and washing, adjusting the pH to 1-2 in the organic layer, and crystallizing to obtain a product.)

The preparation method of kinds of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride is characterized in that the reaction equation is as follows:

x: br or Cl, and (b) in the presence of a catalyst,

the method comprises the following specific steps:

(1) preparation of intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain 4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate;

(2) dissolving the intermediate 2 in an organic solvent, reacting with alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, and separating out crystals to obtain a crude product;

(3) and dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding an organic solvent to extract and wash, adjusting the pH to 1-2 in an organic layer, and crystallizing to obtain the product.

2. The method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (1), the molar ratio of ethyl N-benzylglycine to ethyl 4-halobutyrate to base is 1:1 to 1.5.

3. The method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (2), the molar ratio of intermediate 2 to base is 1:1 to 1.5.

4. The method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (1) the organic solvent is selected from methanol, ethanol, toluene and benzene, the ethyl 4-halobutyrate is selected from ethyl 4-chlorobutyrate and ethyl 4-bromobutyrate, and the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

5. The process for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (2) the organic solvent is selected from ethyl acetate, tetrahydrofuran, toluene and benzene, and the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide.

6. The process for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (3) the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and the organic solvent is selected from the group consisting of toluene, benzene, ethyl acetate and dichloromethane.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochlorides.

Background

The invention discloses a method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride, which is an important intermediate of a new -substituted fluoroquinolone antibacterial drug balofloxacin, and the conventional synthetic method (CN105622444B) is a method for preparing kinds of ethyl N-benzyl glycinate, and comprises the following steps of dissolving benzylamine in an organic solvent, adding 2-halogenated ethyl acetate, alkali and quaternary ammonium salt, and reacting to obtain the ethyl N-benzyl glycinate, and also discloses a method for preparing kinds of 1-benzyl-3-piperidone hydrochloride, wherein the specific steps comprise (1) preparing the intermediate 1 (ethyl N-benzyl glycinate), (2) dissolving the intermediate 1 in the organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain the intermediate 2, (3) reacting the intermediate 2 with the alkali, adjusting the pH value to 6-8 reversely, concentrating under reduced pressure, extracting with ethyl acetate, washing, drying and concentrating under reduced pressure to obtain the intermediate 3, (4) reacting the intermediate 3 with acid, concentrating by evaporation, adding a crystallization solvent, crystallizing to obtain the product, wherein the intermediate 105622444B in the invention is a product, and the intermediate is a low-purity product, and the intermediate 3 is obtained by adopting a low-purity mode of the free intermediate.

Disclosure of Invention

The invention aims to provide a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochlorides.

The technical scheme is as follows:

A process for preparing N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, the reaction equation is:

the method comprises the following specific steps:

(1) preparation of intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain 4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate;

(2) dissolving the intermediate 2 in an organic solvent, reacting with alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, and separating out crystals to obtain a crude product;

(3) and dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding an organic solvent to extract and wash, adjusting the pH to 1-2 in an organic layer, and crystallizing to obtain the product.

The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (1), wherein the molar ratio of the N-benzyl glycine ethyl ester to the 4-halogenated ethyl butyrate to the alkali is 1: 1-1.5.

The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (2), wherein the molar ratio of the intermediate 2 to the alkali is 1: 1-1.5.

The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the following steps of (1) selecting organic solvents from methanol, ethanol, toluene or benzene, selecting 4-halogenated ethyl butyrate from 4-chloroethyl butyrate or 4-bromoethyl butyrate, and selecting alkali from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (2) of selecting organic solvents from ethyl acetate, tetrahydrofuran, toluene or benzene and selecting bases from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.

The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (3) of selecting the alkali from of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and the organic solvent from of toluene, benzene, ethyl acetate or dichloromethane.

The invention has the beneficial effects that: the method for preparing the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride by condensing the N-benzyl glycine ethyl ester serving as the starting raw material with the 4-halogenated ethyl acetate and then cyclizing the condensation product has the advantages of short synthetic route step, simple process operation, low cost of the used raw materials, high product yield and high purity, and is easy for industrial production.

Detailed Description

The present invention is described in further detail in with reference to the following examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above contents of the present invention are within the scope of the present invention.