阅读说明：本技术 一种盐酸左旋米那普仑杂质的制备方法 (Preparation method of levomilnacipran hydrochloride impurity ) 是由 陈鹏 李恩民 赵国磊 于 2019-02-27 设计创作，主要内容包括：本发明涉及一种药物中杂质的合成,提供了一种合成盐酸左旋米那普仑杂质的制备方法。本发明以苯乙腈和R-环氧氯丙烷为起始原料,经取代、氯代、盖博瑞尔合成伯胺、氰基水解、关环。得到盐酸左旋米那普仑杂质。有利于研究盐酸左旋米那普仑的有关物质。(The invention relates to synthesis of impurities in a medicament, and provides a preparation method for synthesizing levomilnacipran hydrochloride impurities. The invention takes benzyl cyanide and R-epichlorohydrin as initial raw materials, and synthesizes primary amine, cyano-group hydrolysis and ring closure through substitution, chlorination and Gaborrelil. To obtain the levomilnacipran hydrochloride impurity. Is beneficial to researching the related substances of the levomilnacipran hydrochloride.)

1. A synthesis method of levomilnacipran hydrochloride impurity is characterized by comprising the following steps:

taking phenylacetonitrile and R-epichlorohydrin as starting materials, selecting sodium amide as alkali, and taking methylbenzene as a reaction solvent to obtain (1S,2R) -2- (hydroxymethyl) -1-phenylcyclopropane-1-nitrile, namely a compound (1); and carrying out chlorination reaction on the compound (1) and thionyl chloride to obtain a compound (2). The compound (2) and phthalimide sylvite are subjected to substitution reaction to obtain a compound (3)

Reacting the compound (3) with hydrazine hydrate to obtain a compound (4); the compound (4) is obtained by hydrolyzing a cyano group under an alkaline condition and then closing a ring under an acidic condition.

2. The process for the synthesis of (1) according to claim 1, characterized in that the molar ratio of the reaction base sodium amide to phenylacetonitrile is 1: 1.05 to 1.3.

3. The method according to claim 1, wherein the reaction reagent is hydrazine hydrate or ethanolamine.

4. The synthesis process as claimed in claim 1 (5), wherein the reaction base is potassium hydroxide; the concentration of the alkali is 10-30% (m/v).

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a levomilnacipran hydrochloride impurity.

Background

The levo-milnacipran hydrochloride is an oral selective 5-hydroxytryptamine and norepinephrine reuptake inhibitor researched, developed and popularized by Pierre Fabre company of France, is widely used for treating major depression, has obvious curative effect and no anticholinergic effect, and is safer and more reliable. It was approved for marketing by the FDA in the united states in 2009.

The pharmaceutical value of l-milnacipran hydrochloride is not paid attention to many chemists, and a plurality of synthesis reports of l-milnacipran hydrochloride or milnacipran intermediates are reported at present. But relatively few reports on the study of impurities are reported. This patent has mainly studied the preparation method of levomilnacipran hydrochloride impurity, and its impurity structural formula is:

the current literature reports the preparation method of levomilnacipran hydrochloride, and the main synthetic route is as follows:

route one:

and a second route:

the two routes are the main flow routes for preparing the levomilnacipran hydrochloride, but the two routes inevitably use alkali when amino is prepared, and the process can cause the hydrolysis of amido bond, so that the cyclization generates lactam structure, namely levomilnacipran hydrochloride impurity 1.

Disclosure of Invention

The invention aims to provide a preparation method of levomilnacipran hydrochloride impurity, and in order to realize the aim, the invention adopts the following technical scheme:

a synthesis method of levomilnacipran hydrochloride impurity is characterized by comprising the following steps:

(1) taking benzyl cyanide and R-epichlorohydrin as starting materials, selecting sodium amide as alkali, and taking methylbenzene as a reaction solvent to obtain (1S,2R) -2- (hydroxymethyl) -1-phenylcyclopropane-1-nitrile:

(2) and carrying out chlorination reaction on (1S,2R) -2- (hydroxymethyl) -1-phenylcyclopropane-1-nitrile and thionyl chloride to obtain (1S,2R) -2- (chloromethyl) -1-phenylcyclopropane-1-nitrile.

(3) (1S,2R) -2- (chloromethyl) -1-phenylcyclopropane-1-nitrile and phthalimide potassium salt are subjected to substitution reaction to obtain (1S,2R) -2- (phthalimide methyl) -1-phenylcyclopropane-1-nitrile:

(4) (1S,2R) -2- (phthalimidomethyl) -1-phenylcyclopropane-1-nitrile reacts with hydrazine hydrate to obtain (1S,2R) -2- (aminomethyl) -1-phenylcyclopropane-1-nitrile

(5) (1S,2R) -2- (aminomethyl) -1-phenylcyclopropane-1-carbonitrile the cyano group was hydrolyzed under basic conditions, and then subjected to ring closure under acidic conditions to give the objective compound (5)

The synthesis method as shown in (1), which is characterized in that the molar ratio of the reaction alkali sodium amide to the phenylacetonitrile is 1: 1.05 to 1.3.

A synthesis method according to (4), characterized in that the reaction reagent is hydrazine hydrate or ethanolamine

The synthesis process according to (5), characterized in that the reaction base is potassium hydroxide; the concentration of the alkali is 10 to 30% (m/v)

Detailed Description