阅读说明：本技术 一种阿立哌唑中间体的电还原制备方法 (Electro-reduction preparation method of aripiprazole intermediate ) 是由 胡斯登 谢雯雪 胡艾希 何湘宁 何嘉宸 梁梓鹏 于 2020-01-17 设计创作，主要内容包括：本发明公开了一种阿立哌唑中间体——3-[4-[4-(2,3-二氯苯基)哌嗪基]丁氧基]苯胺或其盐的电还原制备方法,包括在分隔式电解槽中,以1-(2,3-二氯苯基)-4-(4-(3-硝基苯氧基)丁基)哌嗪或其盐有机溶液和酸性溶液的混合液作为阴极电解液；阳极电解液选择酸性溶液；相对于参比电极,阴极工作电极电压为1.00V～2.50V；电解的电流密度在25.0mA/cm<Sup>2</Sup>～250.0mA/cm<Sup>2</Sup>之间,电解的温度在25℃～80℃之间；电解完全后得到3-[4-[4-(2,3-二氯苯基)哌嗪基]丁氧基]苯胺或其盐。本发明电还原反应中无需有毒或危险的还原剂,是发展“绿色制药工业”的重要组成部分；通过改变电极电位,可以控制转化率和选择性,从而获得高纯度和高收率中间体。(The invention discloses an aripiprazole intermediate 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl]Butoxy radical]The electroreduction preparation method of aniline or its salt includes using the mixed liquid of organic solution of 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or its salt and acid solution as cathode electrolyte in a separated electrolytic bath; selecting an acid solution as the anolyte; the voltage of the cathode working electrode is 1.00V-2.50V relative to the reference electrode; the current density of electrolysis is 25.0mA/cm 2 ～250.0mA/cm 2 The electrolysis temperature is between 25 and 80 ℃; after electrolysis, 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] is obtained]Butoxy radical]Aniline or a salt thereof. The invention does not need poisonous or dangerous reducing agent in the electro-reduction reaction, and is an important component for developing green pharmaceutical industry; by varying the electrode potential, the conversion and selectivity can be controlled, thereby obtaining high purity and high yield intermediates.)

1. A method for preparing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline shown as a structural formula I or a salt thereof by electro-reduction is characterized in that 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or a salt thereof, an organic solvent and an acidic solution are used as a cathode electrolyte in a divided electrolytic cell; selecting an acid solution as the anolyte; the 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or the salt thereof is obtained by electro-reduction reaction, and the preparation reaction is as follows:

wherein HY is selected from: HCl, HBr, H₂SO₄、H₃PO₄、4-CH₃C₆H₄SO₃H、CH₃SO₃H or CF₃SO₃H。

2. The process for the electroreductive preparation of 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or a salt thereof according to claim 1, wherein the reference electrode of the divided cell is a saturated potassium chloride calomel electrode; the cathode is a brass electrode, a red copper electrode, a titanium mesh electrode, a nickel electrode, a lead electrode, a tin electrode, a platinum electrode or a graphite electrode; the anode is a DSA electrode, a platinum net or a titanium-based platinum electrode; the diaphragm is a strong acid type cation exchange membrane.

3. 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl according to claim 1 or 2]Butoxy radical]The electroreduction preparation method of the aniline or the salt thereof is characterized in that the working voltage of the cathode of the divided electrolytic cell is 1.00V-2.50V relative to a reference electrode; the electrode current density of the cathode is 25.0mA/cm²～250.0mA/cm²To (c) to (d); the working temperature of the divided electrolytic cell is between 25 and 80 ℃.

4. The process for preparing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or its salt by electroreduction according to claim 1, wherein the organic solvent in the catholyte is one or more selected from ethyl acetate, tetrahydrofuran, dioxane, C1-C5 linear alcohols, C3-C5 branched alcohols, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether and ethylene glycol diethyl ether.

5. The process for the electroreductive preparation of 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or a salt thereof according to claim 1, wherein said acidic solution in said catholyte is: hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, hydrobromic acid solution, p-toluenesulfonic acid solution, methanesulfonic acid solution or trifluoromethanesulfonic acid solution.

6. The process for preparing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or a salt thereof by electroreduction according to claim 1, wherein the concentration of 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or a salt thereof in the catholyte is between 4.0g/L and 16.0g/L, and the concentration of the acid solution is between 0.05mol/L and 1.0 mol/L.

7. The process for the electroreductive preparation of 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or a salt thereof according to claim 1, 4, 5 or 6, wherein said catholyte is prepared by: dissolving 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or salt thereof in an organic solvent to obtain an organic solution, and mixing the organic solution and the acidic solution according to a volume ratio of 1: 0.5-2 to obtain a cathode electrolyte.

8. The process for producing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or a salt thereof according to claim 1, wherein the anolyte is a phosphoric acid solution or a sulfuric acid solution.

Technical Field

The invention relates to an organic electrosynthesis reaction, in particular to a method for preparing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or salt thereof by carrying out an electroreduction reaction on 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine which is an intermediate of aripiprazole or lauroyl aripiprazole.

Background

Aripiprazole was developed by tsukamur medicine (Otsuka) [ pharmaceutical Proc., 2016, 51(12):1809-]Approval by the Food and Drug Administration (FDA) was obtained on day 11 and 15 in 2002, and approval by the European drug administration (EMA) and the pharmaceutical and medical device Integrated agency (PMDA) in Japan was obtained on day 6 and 4 in 2004 and on day 1 and 23 in 2006, respectively, with the trade name Bosiqing,

aripiprazole has the effect of modulating the dopaminergic and 5-hydroxytryptamine energy systems, and is a third generation antipsychotic.

Prodrugs of aripiprazole, lauroyl aripiprazole also known as aripiprazole dodecanoate [ china journal of pharmaceutical chemistry, 2016, 26, 267; results in Pharma Sciences,2014,4: 19-25. Lauroyl aripiprazole compounds patent: WO 2010151689a1, 24/6/2010. Currently, it is authorized in the united states and japan, etc., for a protective period of 2024. Lauroyl aripiprazole is marketed in the united states at 10 months and 5 days 2015 under the trade name aritada; 10 months 2015, the us FDA approved a lauroyl aripiprazole (aripiprazole lauroxil) sustained release injection by oxumes (Alkerme) for the treatment of adult patients with schizophrenia.

The lauroyl aripiprazole is converted into N-hydroxymethyl aripiprazole by intramuscular injection and then into aripiprazole by means of enzymatic hydrolysis [ J. chem. Chinese medicinal J.Chem., 2016, 26:267 ]:

the routes for the synthesis of lauroyl aripiprazole are all based on the synthesis of aripiprazole [ Results in pharma Sciences,2014,4:19-25 ]:

the synthesis of aripiprazole via the 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine intermediate is as follows:

reacting 3- (4-bromobutoxy) nitrobenzene with 1- (2, 3-dichlorophenyl) piperazine hydrochloride to prepare 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine; the latter is reduced by zinc powder in acetic acid to obtain 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline; acylation reaction is carried out on the reduction product and 3-chloropropionyl chloride, and finally Friedel-crafts reaction is carried out to obtain aripiprazole [ a preparation method of aripiprazole, CN1569845, 2005 ]; the yield of the reduction reaction was 78.5%, and the total yield was 12%.

1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine (A) or salt thereof is subjected to reduction reaction to prepare 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline (I). The conventional reduction method comprises the following steps: metal reduction, sulfide reduction, catalytic hydrogenation, double hydride (lithium aluminum hydride, sodium borohydride) reduction method [ a preparation method of aripiprazole, CN1569845, 2005 ].

The chemical synthesis or catalytic hydrogenation preparation method of the aripiprazole intermediate I, 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline, has the following problems:

the method adopting the stannous chloride reducing agent comprises the following steps: the stannous chloride is expensive, and the residual trace stannous chloride is easy to form a complex which is difficult to separate with the intermediate I, namely 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline.

An iron powder reduction method is adopted: because a large amount of iron powder is used as a reducing agent, a large amount of iron mud is generated, and the environmental pollution is serious: the iron mud adsorbs aniline compound I, namely 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline, and is strong in environmental destruction.

Adopting a hydrazine hydrate reduction method: hydrazine hydrate is highly toxic (carcinogenic toxicity); the residual hydrazine hydrate has strong destructiveness to the environment and is difficult to separate, and the hydrazine hydrate has genotoxicity; minute amounts of hydrazine hydrate seriously affect the quality of the intermediate I, 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline and aripiprazole products.

A catalytic hydrogenation method is adopted: the nickel and palladium catalysts and the intermediate I, namely 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline form a complex which is difficult to separate, so that the purity of the intermediate and the overproof heavy metals in the aripiprazole product are influenced.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides the method for preparing the aripiprazole intermediate by adopting an electroreduction method, which is environment-friendly, mild in operation condition, controllable in process and improved in yield and purity of the intermediate.

The invention provides an electroreduction preparation method of aripiprazole intermediate 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or salt thereof, which is shown as a structural formula I, and comprises the following preparation reactions:

HY is selected from: HCl, H₂SO₄、H₃PO₄、HBr、4-CH₃C₆H₄SO₃H、CH₃SO₃H or CF₃SO₃H。

In order to achieve the above objects, the process for preparing 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or its salt as an intermediate of aripiprazole by electroreduction comprises:

in a divided electrolytic cell, 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or salt thereof, an organic solvent and an acidic solution are used as a catholyte; selecting an acid solution as the anolyte; the 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline or the salt thereof is obtained through an electro-reduction reaction.

The voltage of the cathode working electrode is 1.00V-2.50V relative to the reference electrode; the current density of the cathode working electrode is 25.0mA/cm²～250.0mA/cm²To (c) to (d); the electrolysis temperature is between 25 ℃ and 80 ℃.

Preferably, the reference electrode of the divided electrolytic cell is a saturated potassium chloride calomel electrode.

The cathode of the separated electrolytic cell is as follows: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, tin, platinum or graphite electrodes.

The anode of the separated electrolytic cell is a DSA electrode, a platinum mesh or a titanium-based platinum electrode; the DSA electrode and the metal oxide anode are mainly oxides of titanium, manganese, cobalt, noble metals such as ruthenium and iridium, and the matrix is titanium.

The diaphragm of the divided electrolytic cell is an HF-101 strong acid type cation exchange membrane.

The organic solvent in the catholyte is any one or more of ethyl acetate, tetrahydrofuran, dioxane, C1-C5 straight-chain alcohol, C3-C5 branched-chain alcohol, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether or ethylene glycol diethyl ether;

the acid solution in the catholyte is: hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, hydrobromic acid solution, p-toluenesulfonic acid solution, methanesulfonic acid solution or trifluoromethanesulfonic acid solution.

Preferably, the concentration of the 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or the salt thereof in the catholyte is between 4.0g/L and 16.0g/L, and the concentration of the acid solution is between 0.05mol/L and 1.0 mol/L.

The acidic solution serves as an electrolyte for the electro-reduction reaction, and the catholyte has suitable conductivity in this concentration range.

Further preferably, the preparation method of the catholyte comprises the following steps: dissolving 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or salt thereof in an organic solvent to obtain an organic solution, and mixing the organic solution and the acidic solution according to a volume ratio of 1: 0.5-2 to obtain a mixed solution.

Preferably, the anolyte is a phosphoric acid solution or a sulfuric acid solution, and the acidic solution is favorable for proton movement.

Preferably, the liquid levels of the catholyte and the anolyte are at the same level.

The electric reduction reaction end point is judged by adopting a Thin Layer Chromatography (TLC); after thin layer chromatography, stopping electrolysis when the raw material point basically disappears; the developing agent is V_{Petroleum ether}∶V_{Ethyl acetate}4:1, ultraviolet lamp color development.

After the electrolysis is completed, the intermediate I of the aripiprazole, 3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline, is obtained.

The principle of the electro-reduction reaction of 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine is that the reaction formula of a cathode under an acidic condition is as follows:

the stepwise reaction and side reactions are as follows:

in the reaction formula, the structural formula (A) is taken as a raw material, and the structural formulas (B-G) are taken as byproducts; the structural formula I is a main product aripiprazole intermediate-3- [4- [4- (2, 3-dichlorophenyl) piperazinyl ] butoxy ] aniline.

The reaction formula of the anode under the acidic condition is as follows:

6H₂O→12H⁺+3O₂+12e

the overall reaction formula is:

the invention has the beneficial effects that:

(1) the electro-reduction reaction of the 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or the salt thereof does not need toxic or dangerous reducing agents, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.

(2) During the electro-reduction process of the 1- (2, 3-dichlorophenyl) -4- (4- (3-nitrophenoxy) butyl) piperazine or the salt thereof, the conversion rate and the selectivity can be controlled by changing the electrode potential; thereby obtaining the intermediate with high purity and high yield.

(3) In industrial production, the process flow is simplified, the operation condition is mild, the organic solvent can be recycled, the production cost is reduced, and the method is safe, environment-friendly and suitable for large-scale popularization and application.

Drawings

FIG. 1 is a schematic view of a divided electrolytic cell.

Detailed Description

The invention is further illustrated by the following specific examples, which are intended only for a better understanding of the content of the invention and do not limit the scope of the invention.