WO2022110612A1 - Preparation method for s-configuration phenylethylamine hydrochloride compound - Google Patents

Preparation method for s-configuration phenylethylamine hydrochloride compound Download PDF

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WO2022110612A1
WO2022110612A1 PCT/CN2021/086613 CN2021086613W WO2022110612A1 WO 2022110612 A1 WO2022110612 A1 WO 2022110612A1 CN 2021086613 W CN2021086613 W CN 2021086613W WO 2022110612 A1 WO2022110612 A1 WO 2022110612A1
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preparation
organic solvent
configuration
compound
group
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PCT/CN2021/086613
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Chinese (zh)
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冯宇
黄宗玺
俞章丽
李守鑫
唐晨
朱涛
钱伟
许宏
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诚达药业股份有限公司
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Priority to AU2021388369A priority Critical patent/AU2021388369B2/en
Publication of WO2022110612A1 publication Critical patent/WO2022110612A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Definitions

  • the invention relates to the technical field of pharmaceutical synthesis and preparation, in particular to a preparation method of an S-configuration phenethylamine hydrochloride compound.
  • Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family of DNA (Hepadnaviridae). Its genome contains 4 overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode the three enveloped proteolipids), and the X gene. Before infection, the partially double-stranded DNA genome is converted in the host cell nucleus (open circular DNA, rcDNA) to covalently closed circular DNA (cccDNA) and the viral mRNA is transcribed.
  • dsDNA partially double-stranded DNA virus of the hepadnaviridae family of DNA
  • the pregenomic RNA (which also encodes the core protein and Pol) is used as a template for reverse transcription, which regenerates the portion of the dsDNA genome (rcDNA) in the nucleocapsid
  • HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected approximately 2 billion people worldwide, of which approximately 350 million developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of the development of cirrhosis and liver cancer.
  • HBV transmission is exposure to infectious blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titers of DNA in serum.
  • antiviral drugs tenofovir, lamivudine, adefovir, entecavir and telbivudine.
  • Patent CN110437132A discloses a class of HBV inhibitors with high potency and lower toxicity, wherein the compounds involved involve a key intermediate E1, a single chiral phenethylamine hydrochloride, as shown in the following figure shown:
  • a compound 2 is prepared by reacting compound 1 with formic acid and ammonia gas. Compound 2 is refluxed in a sodium hydroxide solution to obtain a racemate rac-2. The racemate rac-2 is attempted to be split by a chiral acid.
  • the specific synthetic route As follows:
  • the yield in the first two steps is only 21%, and the ee after three crystallizations is only 14% at the highest, which is difficult to meet the needs of drug quality.
  • the second method uses acetone as a cosolvent to synthesize compound E1 by using an enzyme-catalyzed method through racemic rac-2; the specific synthetic route is as follows:
  • Nitroethane solvent has a relatively large safety risk, and methylene chloride is much safer, but the overall cost still has a relatively large room for improvement.
  • the invention provides a preparation method of an S-configuration phenethylamine hydrochloride compound, which is low in cost, high in yield, simple in operation and suitable for industrial production.
  • the object of the present invention is to provide the preparation method of S-configuration phenethylamine hydrochloride compound in order to solve the problem existing in the above-mentioned prior art conditions.
  • the structure of the compound is:
  • R1 a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
  • R2 a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
  • intermediate A obtained in step (1) is reacted to obtain intermediate B under the conditions that hydroxylamine hydrochloride and triethylamine participate;
  • step (4) compound E is synthesized: the intermediate C of step (4) gained is reacted with sodium hydroxide and hydrogen chloride gas to generate compound E in an organic solvent;
  • step (1) the specific operations in step (1) are as follows: 1,3-disubstituted benzene and aluminum trichloride are dissolved in anhydrous organic solvent 1, and acetyl chloride is added at -20 to 30 °C, After reacting at -20 ⁇ 40°C for 1-5 hours, the reaction was quenched with water, and then concentrated to dryness to obtain intermediate A. Intermediate A does not need to be purified separately, and is used directly after preparing the next reaction solution;
  • step (2) The specific operation of step (2) is as follows: intermediate A is added with organic solvent 2, triethylamine, and hydroxylamine hydrochloride, the temperature is raised to 40 ⁇ 80° C. to continue the reaction for 3-8 h, then water is added, and the intermediate B is filtered and dried;
  • step (3) The specific operation of step (3) is as follows: adding intermediate B into organic solvent 3, adding reducing agent and catalyst, controlling the temperature of the system to 0-60 ° C, reacting at this temperature for 3-25 h, then cooling to room temperature, filtering, The filtrate is collected, and the filtrate is concentrated and dried to obtain intermediate C; the molar ratio of intermediate B, reducing agent and catalyst is 1:0.01-5:0.01-1.0;
  • step (4) adds the intermediate C into the organic solvent 3 to dissolve, adds a single chiral organic acid to the organic 4 to dissolve, and drops the organic acid solution into the intermediate C solution at room temperature, and the room temperature After stirring for 1 hour, a large amount of solid was precipitated, filtered, recrystallized and dried to obtain the organic salt of intermediate D, and the molar ratio of intermediate C and single chiral organic acid was 1:0.3-1.0;
  • step (5) The specific operation of step (5) is as follows: it adds the intermediate D organic acid into dichloromethane, adds 10% sodium hydroxide solution, stirs at room temperature for 30 minutes, after liquid separation, the dichloromethane phase is concentrated to dryness, and an organic solvent is added. 5. Dissolve, continue to feed dry hydrogen chloride gas in the solution for 30 minutes, there is a large amount of solid to separate out, filter, dry to obtain the target compound, both single chiral phenethylamine hydrochloride, described intermediate D organic acid, sodium hydroxide The molar ratio is 1:1.0-2.0.
  • the organic solvent 1 is any one of anhydrous dichloromethane and anhydrous 1,2-dichloroethane.
  • the molar ratio of 1,3-disubstituted benzene, aluminum trichloride, and acetyl chloride in step (1) is: 1.0:0.9-2:0.9-2.0.
  • the molar ratio of intermediate A, triethylamine, and hydroxylamine hydrochloride described in step (2) is: 1.0:0.9-2.0:0.9-2.0.
  • the organic solvent 2 described in step (2) is any one of methanol, ethanol, isopropanol, and tetrahydrofuran.
  • the organic solvent 3 described in the middle is any one of methanol, ethanol, isopropanol, tetrahydrofuran, and 1,4-dioxane;
  • the reducing agent is any one of hydrogen, sodium borohydride, sodium cyanoborocyanide, lithium aluminum tetrahydrogen, and sodium triacetoxyborohydride;
  • the catalyst is iodine, Raney nickel, palladium carbon, platinum carbon any of the .
  • the single chiral organic acid described in step (4) any one of D-mandelic acid, D-tartaric acid, L-aspartic acid, and L-malic acid;
  • the organic solvent 4 is: any one of isopropanol, ethanol, methanol, acetone, and ethyl acetate.
  • the organic solvent 5 in step (5) is any one of ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropanol, ethanol, and dichloromethane.
  • the advantages of the preparation method of the S-configuration phenethylamine hydrochloride compound provided by the present invention are that the target product compound is obtained through five-step reaction using 1,3-disubstituted benzene, a commercial basic chemical raw material with low price, as the starting material.
  • the synthetic cost of the target product compound E has the advantages of simple purification, low cost, high efficiency, high yield, and is suitable for large-scale industrial production, and provides a new synthetic route.
  • the preparation of a single chiral phenethylamine hydrochloride compound is characterized in that: the preparation of a single chiral phenethylamine hydrochloride compound is characterized in that: the structure of the compound is:
  • R1 one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy (the same below)
  • R2 one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy (the same below)
  • intermediate B the intermediate A obtained in step (1) is reacted under the conditions that hydroxylamine hydrochloride and triethylamine participate to obtain intermediate B; wherein, the structure of intermediate B is:
  • step (1) the specific operation described in step (1) is as follows: 1,3-disubstituted benzene and aluminum trichloride are dissolved in anhydrous organic solvent 1, acetyl chloride is added at -20 ⁇ 30°C, and acetyl chloride is added at -20 ⁇ 30°C. After reacting at 40°C for 1-5 hours, the reaction was quenched with water, and then concentrated to dryness to obtain intermediate A. Intermediate A does not need to be purified separately, and is used directly after preparing the next reaction solution.
  • the organic solvent 1 is one of anhydrous dichloromethane and anhydrous 1,2-dichloroethane, preferably dichloromethane.
  • the molar ratio of the 1,3-disubstituted benzene, aluminum trichloride, and acetyl chloride is: 1.0:0.9-2:0.9-2.0, preferably 1:1.0:1.0.
  • step (2) The specific operation described in the step (2) is: adding organic solvent 2, triethylamine and hydroxylamine hydrochloride to intermediate A, heating to 40 ⁇ 80 °C and continuing to react for 3-8 h, then adding water, filtering and drying to obtain intermediate B;
  • the molar ratio of the intermediate A, triethylamine and hydroxylamine hydrochloride is: 1.0:0.9-2.0:0.9-2.0, preferably 1.0:1.5:1.5.
  • the organic solvent 2 is one of methanol, ethanol, isopropanol and tetrahydrofuran, preferably ethanol.
  • step (3) The specific operation of step (3) is: adding intermediate B into organic solvent 2, adding reducing agent and catalyst, controlling the temperature of the system to 0-60°C, reacting at this temperature for 3-25h, then cooling to room temperature, filtering, The filtrate is collected, and the filtrate is concentrated and dried to obtain intermediate C; the molar ratio of intermediate B, reducing agent and catalyst is 1:0.01-5:0.01-1.0, preferably 1.0:5:0.03.
  • the organic solvent 2 described in the above is one of methanol, ethanol and tetrahydrofuran, preferably methanol.
  • the reducing agent described in the middle is one of hydrogen, sodium borohydride, sodium cyanoborocyanide, lithium aluminum tetrahydrogen, and sodium triacetoxyborohydride, preferably hydrogen.
  • the catalyst is one of iodine, Raney nickel, palladium carbon and platinum carbon, preferably Raney nickel.
  • step (4) adds the intermediate C into the organic solvent 3 to dissolve, adds a single chiral organic acid to the organic 4 to dissolve, and drops the organic acid solution into the intermediate C solution at room temperature, and the room temperature After stirring for 1 hour, a large amount of solid was precipitated, filtered, recrystallized and dried to obtain the organic salt of intermediate D.
  • the molar ratio of intermediate C and single chiral organic acid was 1:0.3-1.0, preferably 1:0.5
  • the organic solvent 3 described in the middle is: one of ethyl acetate, acetone, and tetrahydrofuran, preferably ethyl acetate.
  • the single chiral organic acid described in the above is one of D-mandelic acid, D-tartaric acid, L-aspartic acid and L-malic acid, preferably D-mandelic acid.
  • the organic solvent 4 is one of isopropanol, ethanol, methanol, acetone and ethyl acetate, preferably isopropanol.
  • step (5) The specific operation of step (5) is as follows: it adds the intermediate D organic acid into dichloromethane, adds 10% sodium hydroxide solution, stirs at room temperature for 30 minutes, after liquid separation, the dichloromethane phase is concentrated to dryness, and an organic solvent is added. 5. Dissolve, continue to feed dry hydrogen chloride gas in the solution for 30 minutes, there is a large amount of solid to separate out, filter, dry to obtain the target compound, both single chiral phenethylamine hydrochloride, described intermediate D organic acid, sodium hydroxide The molar ratio is 1:1.0-2.0, preferably 1:1.5
  • the organic solvent 5 described in the above is one of ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropanol, ethanol, and dichloromethane, preferably isopropyl acetate.
  • intermediate C 40g
  • ethyl acetate 140g
  • R-mandelic acid 16.8g
  • isopropanol 48g
  • the mandelic acid solution was added dropwise to the intermediate C solution, after the dropwise addition, the temperature was naturally cooled to room temperature and stirred for 1 hour, filtered, and then recrystallized from ethyl acetate and ethanol, filtered and dried to obtain intermediate D mandelic acid salt, white Solid 18.4g, yield 25%, ee%: 99.1%;

Abstract

The present invention relates to the technical field of the synthetic preparation for medicines, and relates to a preparation method for an S-configuration phenylethylamine hydrochloride compound. The preparation method comprises the following steps: step (1), performing a Friedel-Crafts reaction on m-dimethoxybenzene and acetyl chloride under a Lewis acid condition to generate an intermediate A; (2) reacting the intermediate A with hydroxylamine hydrochloride, without isolating the intermediate A, to generate an intermediate B; step (3), reducing the intermediate B under a reducing agent condition to obtain a compound C; step (4) resolving the compound C by means of an organic acid to obtain an organic salt of an S-configuration compound D; and step (5) dissociating the organic salt and then performing saltification to obtain a target product compound E. The preparation method of the present invention has the characteristics of simple purification, low cost, high efficiency, high yield and suitability for industrial mass production.

Description

一种S构型苯乙胺盐酸盐化合物的制备方法A kind of preparation method of S configuration phenethylamine hydrochloride compound 技术领域technical field
本发明涉及医药合成制备技术领域，具体涉及一种S构型苯乙胺盐酸盐化合物的制备方法。The invention relates to the technical field of pharmaceutical synthesis and preparation, in particular to a preparation method of an S-configuration phenethylamine hydrochloride compound.
背景技术Background technique
乙型肝炎病毒(HBV)是一种有包膜的、部分双链DNA(dsDNA)的、嗜肝病毒DNA家族(肝病毒科(Hepadnaviridae))的病毒。它的基因组包含4个重叠阅读框：前核/核基因，聚合酶基因，UM和S基因(它们编码三个包膜蛋臼质)，以及X基因。在感染前时，该部分双链DNA基因组在宿主细胞核中(开环DNA,rcDNA)转变为共价闭合环状DNA(cccDNA)并且该病毒mRNA进行转录。一旦被壳体化，该前基因组RNA(pgRNA)(其还为核心蛋臼和Pol编码)作为模板用千逆转录，这种逆转录在核衣壳中再生该部分dsDNA基因组(rcDNA)Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family of DNA (Hepadnaviridae). Its genome contains 4 overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode the three enveloped proteolipids), and the X gene. Before infection, the partially double-stranded DNA genome is converted in the host cell nucleus (open circular DNA, rcDNA) to covalently closed circular DNA (cccDNA) and the viral mRNA is transcribed. Once encapsidated, the pregenomic RNA (pgRNA) (which also encodes the core protein and Pol) is used as a template for reverse transcription, which regenerates the portion of the dsDNA genome (rcDNA) in the nucleocapsid
HBV在亚洲和非洲的部分地区造成了流行病，并且它在中国是地方性的。HBV已经在全球感染了大约20亿人，其中大约3.5亿人发展成了慢性传染病。该病毒造成了乙型肝炎疾病并且慢性传染病与肝硬化和肝癌的发展的高增加风险相关联。HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected approximately 2 billion people worldwide, of which approximately 350 million developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of the development of cirrhosis and liver cancer.
乙型肝炎病毒的传播来源千暴露千传染性的血液或体液，同时在血清中具有高效价DNA的慢性携带者的唾液、泪液以及尿液中检测到了病毒DNA。虽然目前存在一种有效的并且具有良好耐受性的疫苗，但是直接治疗的选择目前还限千干扰素以及以下的抗病毒药；替诺福韦、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。The source of HBV transmission is exposure to infectious blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titers of DNA in serum. Although an effective and well-tolerated vaccine currently exists, the options for direct treatment are currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
然而，在这些直接的HBV抗病毒药中存在毒性、至突变性、缺乏选择性、疗效差、生物利用度差以及合成困难等问题。However, toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis exist among these direct HBV antiviral drugs.
专利CN110437132A中公开了一种一类效价高、毒性更低的HBV抑制剂，其中所涉及到的化合物中涉及到一个关键中间体E1，一种单一手性苯乙胺盐酸盐，如下图所示：Patent CN110437132A discloses a class of HBV inhibitors with high potency and lower toxicity, wherein the compounds involved involve a key intermediate E1, a single chiral phenethylamine hydrochloride, as shown in the following figure shown:
Figure PCTCN2021086613-appb-000001
Figure PCTCN2021086613-appb-000001
其公布的合成方法可见Tetrahedron Asymmetry,2014,vol.25,#5,p.435-442，该文献中报告了2种从化合物1合成化合物E1的方法。Its published synthesis method can be found in Tetrahedron Asymmetry, 2014, vol.25, #5, p.435-442, in which two methods for synthesizing compound E1 from compound 1 are reported.
一种通过化合物1与甲酸、氨气反应制备化合物2，化合物2在氢氧化钠溶液中回流得到消旋体rac-2，消旋体rac-2尝试通过手性酸拆分，具体的合成路线如下所示：A compound 2 is prepared by reacting compound 1 with formic acid and ammonia gas. Compound 2 is refluxed in a sodium hydroxide solution to obtain a racemate rac-2. The racemate rac-2 is attempted to be split by a chiral acid. The specific synthetic route As follows:
Figure PCTCN2021086613-appb-000002
Figure PCTCN2021086613-appb-000002
上述方法中，前两步收率仅有21％，通过三次结晶后ee最高仅有14％，很难满足药物质量需要。In the above method, the yield in the first two steps is only 21%, and the ee after three crystallizations is only 14% at the highest, which is difficult to meet the needs of drug quality.
第二种方法通过消旋体rac-2用丙酮作为助溶剂，使用酶催化的方法合成化合物E1；具体合成路线如下所示：The second method uses acetone as a cosolvent to synthesize compound E1 by using an enzyme-catalyzed method through racemic rac-2; the specific synthetic route is as follows:
Figure PCTCN2021086613-appb-000003
Figure PCTCN2021086613-appb-000003
文献中报道尝试四种已有报道的酶进行尝试，唯一有效的酶为Novozym435，其收率能达到49％，ee％达到99％以上，但该酶的成本昂贵，对底物的适应性单一，同时在反应过程中对pH以及温度的要求范围很窄，大批量工业化生 产对设备的要求非常高。It is reported in the literature that four reported enzymes have been tried. The only effective enzyme is Novozym435, whose yield can reach 49% and ee% can reach more than 99%, but the cost of this enzyme is expensive and the adaptability to the substrate is single At the same time, the range of pH and temperature requirements in the reaction process is very narrow, and the requirements for large-scale industrial production are very high.
化合物1的合成方法在文献N.Al-Maharik,N.P.Botting/Tetrahedron 60 (2004)1637–1642以及文献Synthetic Communications1,44:540–546,2014有报道。The synthesis method of compound 1 is reported in the literature N.Al-Maharik, N.P.Botting/Tetrahedron 60 (2004) 1637–1642 and the literature Synthetic Communications 1, 44:540–546, 2014.
文中使用1,3-二甲氧基苯，在乙酰氯、三氯化铝参与下，以硝基乙烷或二氯甲烷作为溶剂，进行反应，具体路线如下：In this paper, 1,3-dimethoxybenzene is used, and under the participation of acetyl chloride and aluminum trichloride, nitroethane or dichloromethane is used as a solvent to carry out the reaction, and the specific route is as follows:
Figure PCTCN2021086613-appb-000004
Figure PCTCN2021086613-appb-000004
硝基乙烷溶剂有比较大的安全风险，二氯甲烷安全性高很多，但是整体成本还有比较大的提升空间。Nitroethane solvent has a relatively large safety risk, and methylene chloride is much safer, but the overall cost still has a relatively large room for improvement.
上述的合成方法中，都存在难以产业化生产的问题，为了解决上述问题，我们提供了一种简单、高效、成本低、产率高且适合工业化大生产的单一手性苯乙胺盐酸盐合成方法。In the above-mentioned synthetic method, there is the problem of being difficult to industrialized production. In order to solve the above-mentioned problem, we provide a single chiral phenylethylamine hydrochloride that is simple, efficient, low in cost, high in yield and suitable for industrialized large-scale production. resolve resolution.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种S构型苯乙胺盐酸盐化合物的制备方法，该制备方法成本低、产率高、操作简单、适合工业化生产。The invention provides a preparation method of an S-configuration phenethylamine hydrochloride compound, which is low in cost, high in yield, simple in operation and suitable for industrial production.
本发明的目的就是为了解决上述现有技术条件存在的问题，提供S构型苯乙胺盐酸盐化合物的制备方法。The object of the present invention is to provide the preparation method of S-configuration phenethylamine hydrochloride compound in order to solve the problem existing in the above-mentioned prior art conditions.
为了达到上述目的，本发明采用了以下技术方案：In order to achieve the above object, the present invention adopts the following technical solutions:
一种S构型苯乙胺盐酸盐化合物的制备方法，A kind of preparation method of S configuration phenethylamine hydrochloride compound,
化合物的结构为：The structure of the compound is:
Figure PCTCN2021086613-appb-000005
Figure PCTCN2021086613-appb-000005
R1:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种；R1: a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
R2:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种；R2: a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
包括以下制备步骤：Include the following preparation steps:
(1)中间体A的合成：1,3-二取代基苯在乙酰氯以在三氯化铝得到中间体A， 中间体A不单独分离；(1) Synthesis of intermediate A: 1,3-disubstituted benzene is in acetyl chloride to obtain intermediate A in aluminum trichloride, and intermediate A is not separated separately;
(2)中间体B的合成：将步骤(1)所得到的中间体A在盐酸羟胺与三乙胺参与的条件下反应得中间体B；(2) synthesis of intermediate B: intermediate A obtained in step (1) is reacted to obtain intermediate B under the conditions that hydroxylamine hydrochloride and triethylamine participate;
(3)中间体C合成：将步骤(2)所得的中间体B在还原剂作用下得到化合物C；(3) Synthesis of Intermediate C: Compound C is obtained from the intermediate B obtained in step (2) under the action of a reducing agent;
(4)单一手性拆分：将步骤(3)所得的中间体C与单一手性酸在有机溶剂中拆分成盐得到S构型化合物D的有机盐；(4) single chirality resolution: the intermediate C obtained in step (3) and a single chiral acid are separated into salts in an organic solvent to obtain the organic salt of S-configuration compound D;
(5)化合物E合成：将步骤(4)所得的中间体C与氢氧化钠以及氯化氢气体在有机溶剂反应生成化合物E；(5) compound E is synthesized: the intermediate C of step (4) gained is reacted with sodium hydroxide and hydrogen chloride gas to generate compound E in an organic solvent;
上述步骤的总反应式为：The overall reaction formula of the above steps is:
Figure PCTCN2021086613-appb-000006
Figure PCTCN2021086613-appb-000006
作为本方案的进一步改进，步骤(1)中的具体操作为：1,3-二取代基苯、三氯化铝溶于无水有机溶剂1中，在-20～30℃下加入乙酰氯，在-20～40℃下反应1-5h后，用水淬灭反应，后浓缩至干，得到中间体A，中间体A不需要单独纯化，配制下一步反应溶液后直接使用；As a further improvement of this scheme, the specific operations in step (1) are as follows: 1,3-disubstituted benzene and aluminum trichloride are dissolved in anhydrous organic solvent 1, and acetyl chloride is added at -20 to 30 °C, After reacting at -20～40°C for 1-5 hours, the reaction was quenched with water, and then concentrated to dryness to obtain intermediate A. Intermediate A does not need to be purified separately, and is used directly after preparing the next reaction solution;
步骤(2)的具体操作为：中间体A加入有机溶剂2与三乙胺、盐酸羟胺，升温至40～80℃继续反应3-8h，之后加水，过滤干燥得中间体B；The specific operation of step (2) is as follows: intermediate A is added with organic solvent 2, triethylamine, and hydroxylamine hydrochloride, the temperature is raised to 40～80° C. to continue the reaction for 3-8 h, then water is added, and the intermediate B is filtered and dried;
步骤(3)的具体操作为：将中间体B加入到有机溶剂3中，加入还原剂、催化剂，体系温度控制0-60℃，在该温度下反应3-25h，之后冷却到室温，过滤，收集滤液，滤液浓缩干燥得到中间体C；所述中间体B、还原剂、催化剂的摩尔比例为1:0.01-5:0.01-1.0；The specific operation of step (3) is as follows: adding intermediate B into organic solvent 3, adding reducing agent and catalyst, controlling the temperature of the system to 0-60 ° C, reacting at this temperature for 3-25 h, then cooling to room temperature, filtering, The filtrate is collected, and the filtrate is concentrated and dried to obtain intermediate C; the molar ratio of intermediate B, reducing agent and catalyst is 1:0.01-5:0.01-1.0;
步骤(4)的具体操作为：其将中间体C加入到有机溶剂3中溶解，将有单一手性机酸加入有机4中溶解，将有机酸溶液室温滴加至中间体C溶液中，室温搅拌1小时，有大量固体析出，过滤、重结晶、干燥得到中间体D的有机盐， 所述中间体C、单一手性有机酸的摩尔比例为1:0.3-1.0；The specific operation of step (4) is as follows: it adds the intermediate C into the organic solvent 3 to dissolve, adds a single chiral organic acid to the organic 4 to dissolve, and drops the organic acid solution into the intermediate C solution at room temperature, and the room temperature After stirring for 1 hour, a large amount of solid was precipitated, filtered, recrystallized and dried to obtain the organic salt of intermediate D, and the molar ratio of intermediate C and single chiral organic acid was 1:0.3-1.0;
步骤(5)的具体操作为：其将中间体D有机酸加入到二氯甲烷中，加入10％氢氧化钠溶液，室温搅拌30分钟，分液后二氯甲烷相浓缩至干，加入有机溶剂5溶解，向溶液中持续通入干燥的氯化氢气体30分钟，有大量固体析出，过滤、干燥得到目标化合物，既单一手性苯乙胺盐酸盐，所述中间体D有机酸、氢氧化钠的摩尔比例为1:1.0-2.0。The specific operation of step (5) is as follows: it adds the intermediate D organic acid into dichloromethane, adds 10% sodium hydroxide solution, stirs at room temperature for 30 minutes, after liquid separation, the dichloromethane phase is concentrated to dryness, and an organic solvent is added. 5. Dissolve, continue to feed dry hydrogen chloride gas in the solution for 30 minutes, there is a large amount of solid to separate out, filter, dry to obtain the target compound, both single chiral phenethylamine hydrochloride, described intermediate D organic acid, sodium hydroxide The molar ratio is 1:1.0-2.0.
作为本方案的进一步改进，所述有机溶剂1为无水二氯甲烷、无水1,2-二氯乙烷中的任意一种。As a further improvement of this scheme, the organic solvent 1 is any one of anhydrous dichloromethane and anhydrous 1,2-dichloroethane.
作为本方案的进一步改进，步骤(1)中1,3-二取代基苯、三氯化铝、乙酰氯、的摩尔比例为：1.0:0.9-2:0.9-2.0。As a further improvement of this scheme, the molar ratio of 1,3-disubstituted benzene, aluminum trichloride, and acetyl chloride in step (1) is: 1.0:0.9-2:0.9-2.0.
作为本方案的进一步改进，步骤(2)中所述中间体A、三乙胺、盐酸羟胺的摩尔比例为：1.0:0.9-2.0:0.9-2.0。As a further improvement of this scheme, the molar ratio of intermediate A, triethylamine, and hydroxylamine hydrochloride described in step (2) is: 1.0:0.9-2.0:0.9-2.0.
作为本方案的进一步改进，步骤(2)中所述有机溶剂2为甲醇、乙醇、异丙醇、四氢呋喃中的任意一种。As a further improvement of this scheme, the organic solvent 2 described in step (2) is any one of methanol, ethanol, isopropanol, and tetrahydrofuran.
作为本方案的进一步改进，步骤(3)中，所述中所述有机溶剂3为甲醇、乙醇、异丙醇、四氢呋喃、1,4-二氧六环中的任意一种；所述中所述还原剂为氢气、硼氢化钠、氰基硼***、四氢铝锂、三乙酰氧基硼氢化钠中的任意一种；所述催化剂为碘、雷尼镍、钯炭、铂炭中的任意一种。As a further improvement of this scheme, in step (3), the organic solvent 3 described in the middle is any one of methanol, ethanol, isopropanol, tetrahydrofuran, and 1,4-dioxane; The reducing agent is any one of hydrogen, sodium borohydride, sodium cyanoborocyanide, lithium aluminum tetrahydrogen, and sodium triacetoxyborohydride; the catalyst is iodine, Raney nickel, palladium carbon, platinum carbon any of the .
作为本方案的进一步改进，步骤(4)中所述单一手性有机酸：D-扁桃酸、D-酒石酸、L-天冬氨酸、L-苹果酸中的任意一种；所述有机溶剂4为：异丙醇、乙醇、甲醇、丙酮、乙酸乙酯中的任意一种。As a further improvement of this scheme, the single chiral organic acid described in step (4): any one of D-mandelic acid, D-tartaric acid, L-aspartic acid, and L-malic acid; the organic solvent 4 is: any one of isopropanol, ethanol, methanol, acetone, and ethyl acetate.
作为本方案的进一步改进，步骤(5)中有机溶剂5为：乙酸乙酯、乙酸异丙脂、1,4-二氧六环、异丙醇、乙醇、二氯甲烷中的任意一种。As a further improvement of this scheme, the organic solvent 5 in step (5) is any one of ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropanol, ethanol, and dichloromethane.
本发明提供的S构型苯乙胺盐酸盐化合物的制备方法优点在于：以价格低廉的商业化基础化工原料1,3-二取代基苯作为起始原料，经过五步反应得到目标产物化合物E,具体为：不分离中间态，经过傅克、成肟、还原、拆分、成盐得到单一手性苯乙胺盐酸盐，避免使用成本高且不易得的起始原料，大大降低了目标产物化合物E合成成本，具有纯化简单、成本低、效率高、得率高、适合工业化大生产的优点，提供了一种新的合成路线。The advantages of the preparation method of the S-configuration phenethylamine hydrochloride compound provided by the present invention are that the target product compound is obtained through five-step reaction using 1,3-disubstituted benzene, a commercial basic chemical raw material with low price, as the starting material. E, specifically: do not separate the intermediate state, obtain single chiral phenylethylamine hydrochloride through Friedel-Crafts, oxime formation, reduction, splitting, and salt formation, avoiding the use of high-cost and difficult-to-obtain starting materials, greatly reducing the The synthetic cost of the target product compound E has the advantages of simple purification, low cost, high efficiency, high yield, and is suitable for large-scale industrial production, and provides a new synthetic route.
具体实施方式Detailed ways
为了使本发明的目的、技术方案和优点更加清楚，以下结合实施例对本发 明作进一步说明：In order to make the purpose of the present invention, technical scheme and advantage clearer, the present invention is further described below in conjunction with embodiment:
下面结合实施例对本发明内容进行详细说明：Below in conjunction with embodiment, the content of the present invention is described in detail:
一种单一手性苯乙胺盐酸盐化合物的制备，其特征在于：一种单一手性苯乙胺盐酸盐化合物的制备，其特征在于：化合物的结构为：The preparation of a single chiral phenethylamine hydrochloride compound is characterized in that: the preparation of a single chiral phenethylamine hydrochloride compound is characterized in that: the structure of the compound is:
Figure PCTCN2021086613-appb-000007
Figure PCTCN2021086613-appb-000007
R1:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种(下同)R1: one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy (the same below)
R2:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种(下同)R2: one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy (the same below)
包括以下合成步骤：它包括以下步骤：The following synthetic steps are included: It includes the following steps:
(1)中间体A的合成：1,3-二取代基苯在乙酰氯以在三氯化铝得到中间体A，中间体A不单独分离，其中中间体A的结构为：(1) Synthesis of intermediate A: 1,3-disubstituted benzene obtains intermediate A in acetyl chloride with aluminum trichloride, intermediate A is not separated separately, and the structure of intermediate A is:
Figure PCTCN2021086613-appb-000008
Figure PCTCN2021086613-appb-000008
(2)中间体B的合成：将步骤(1)所得到的中间体A在盐酸羟胺与三乙胺参与的条件下反应得中间体B；其中，中间体B的结构为：(2) the synthesis of intermediate B: the intermediate A obtained in step (1) is reacted under the conditions that hydroxylamine hydrochloride and triethylamine participate to obtain intermediate B; wherein, the structure of intermediate B is:
Figure PCTCN2021086613-appb-000009
Figure PCTCN2021086613-appb-000009
(3)中间体C合成：将步骤(2)所得的中间体B在还原剂参与的条件下还原得到化合物C的有机盐；其中，化合物C的结构为：(3) Synthesis of intermediate C: the intermediate B obtained in step (2) is reduced to obtain the organic salt of compound C under the condition that a reducing agent participates; wherein, the structure of compound C is:
Figure PCTCN2021086613-appb-000010
Figure PCTCN2021086613-appb-000010
(4)单一手性拆分：将步骤(2)所得的中间体C与单一手性酸在有机溶剂中拆分成盐得到S构型化合物D的有机盐；其中，化合物C的有机盐结构为：(4) single chirality resolution: the intermediate C obtained in step (2) and a single chiral acid are separated into salts in an organic solvent to obtain an organic salt of S-configuration compound D; wherein, the organic salt structure of compound C is for:
Figure PCTCN2021086613-appb-000011
Figure PCTCN2021086613-appb-000011
(5)化合物E合成：将步骤(3)所得的中间体C与氢氧化钠以及氯化氢气体在有机溶剂反应生成化合物E；其中，化合物E的结构为：(5) Compound E is synthesized: the intermediate C obtained in step (3) is reacted with sodium hydroxide and hydrogen chloride gas to generate compound E in an organic solvent; wherein, the structure of compound E is:
Figure PCTCN2021086613-appb-000012
Figure PCTCN2021086613-appb-000012
其中，步骤(1)中所述具体操作为：1,3-二取代基苯、三氯化铝溶于无水有机溶剂1中，在-20～30℃下加入乙酰氯，在-20～40℃下反应1-5h后，用水淬灭反应，后浓缩至干，得到中间体A，中间体A不需要单独纯化，配制下一步反应溶液后直接使用。Wherein, the specific operation described in step (1) is as follows: 1,3-disubstituted benzene and aluminum trichloride are dissolved in anhydrous organic solvent 1, acetyl chloride is added at -20～30°C, and acetyl chloride is added at -20～30°C. After reacting at 40°C for 1-5 hours, the reaction was quenched with water, and then concentrated to dryness to obtain intermediate A. Intermediate A does not need to be purified separately, and is used directly after preparing the next reaction solution.
所述有机溶剂1为无水二氯甲烷、无水1,2-二氯乙烷中的一种，优选二氯甲烷。The organic solvent 1 is one of anhydrous dichloromethane and anhydrous 1,2-dichloroethane, preferably dichloromethane.
其中所述1,3-二取代基苯、三氯化铝、乙酰氯、的摩尔比例为：1.0:0.9-2:0.9-2.0，优选1:1.0:1.0。The molar ratio of the 1,3-disubstituted benzene, aluminum trichloride, and acetyl chloride is: 1.0:0.9-2:0.9-2.0, preferably 1:1.0:1.0.
步骤(2)中所述具体操作为：中间体A加入有机溶剂2与三乙胺、盐酸羟胺，升温至40～80℃继续反应3-8h，之后加水，过滤干燥得中间体B；The specific operation described in the step (2) is: adding organic solvent 2, triethylamine and hydroxylamine hydrochloride to intermediate A, heating to 40～80 ℃ and continuing to react for 3-8 h, then adding water, filtering and drying to obtain intermediate B;
其中所述中间体A、三乙胺、盐酸羟胺的摩尔比例为：1.0:0.9-2.0:0.9-2.0，优选1.0:1.5:1.5。The molar ratio of the intermediate A, triethylamine and hydroxylamine hydrochloride is: 1.0:0.9-2.0:0.9-2.0, preferably 1.0:1.5:1.5.
所述有机溶剂2为甲醇、乙醇、异丙醇、四氢呋喃中的一种，优选乙醇。The organic solvent 2 is one of methanol, ethanol, isopropanol and tetrahydrofuran, preferably ethanol.
步骤(3)的具体操作为：将中间体B加入到有机溶剂2中，加入还原剂、催化剂，体系温度控制0-60℃，在该温度下反应3-25h，之后冷却到室温，过滤，收集滤液，滤液浓缩干燥得到中间体C；所述中间体B、还原剂、催化剂的摩尔比例为1:0.01-5:0.01-1.0，优选1.0:5:0.03。The specific operation of step (3) is: adding intermediate B into organic solvent 2, adding reducing agent and catalyst, controlling the temperature of the system to 0-60°C, reacting at this temperature for 3-25h, then cooling to room temperature, filtering, The filtrate is collected, and the filtrate is concentrated and dried to obtain intermediate C; the molar ratio of intermediate B, reducing agent and catalyst is 1:0.01-5:0.01-1.0, preferably 1.0:5:0.03.
所述中所述有机溶剂2为：甲醇、乙醇、四氢呋喃中的一种，优选甲醇。The organic solvent 2 described in the above is one of methanol, ethanol and tetrahydrofuran, preferably methanol.
所述中所述还原剂为：氢气、硼氢化钠、氰基硼***、四氢铝锂、三乙酰氧基硼氢化钠中的一种，优选氢气。The reducing agent described in the middle is one of hydrogen, sodium borohydride, sodium cyanoborocyanide, lithium aluminum tetrahydrogen, and sodium triacetoxyborohydride, preferably hydrogen.
所述催化剂为：碘、雷尼镍、钯碳、铂炭中的一种，优选雷尼镍。The catalyst is one of iodine, Raney nickel, palladium carbon and platinum carbon, preferably Raney nickel.
步骤(4)的具体操作为：其将中间体C加入到有机溶剂3中溶解，将有单 一手性机酸加入有机4中溶解，将有机酸溶液室温滴加至中间体C溶液中，室温搅拌1小时，有大量固体析出，过滤、重结晶、干燥得到中间体D的有机盐，所述中间体C、单一手性有机酸的摩尔比例为1:0.3-1.0，优选1:0.5The specific operation of step (4) is as follows: it adds the intermediate C into the organic solvent 3 to dissolve, adds a single chiral organic acid to the organic 4 to dissolve, and drops the organic acid solution into the intermediate C solution at room temperature, and the room temperature After stirring for 1 hour, a large amount of solid was precipitated, filtered, recrystallized and dried to obtain the organic salt of intermediate D. The molar ratio of intermediate C and single chiral organic acid was 1:0.3-1.0, preferably 1:0.5
所述中所述有机溶剂3为：乙酸乙酯、丙酮、四氢呋喃中的一种,优选乙酸乙酯。The organic solvent 3 described in the middle is: one of ethyl acetate, acetone, and tetrahydrofuran, preferably ethyl acetate.
所述中所述单一手性有机酸：D-扁桃酸、D-酒石酸、L-天冬氨酸、L-苹果酸中的一种，优选D-扁桃酸。The single chiral organic acid described in the above is one of D-mandelic acid, D-tartaric acid, L-aspartic acid and L-malic acid, preferably D-mandelic acid.
所述有机溶剂4为：异丙醇、乙醇、甲醇、丙酮、乙酸乙酯中的一种，优选异丙醇。The organic solvent 4 is one of isopropanol, ethanol, methanol, acetone and ethyl acetate, preferably isopropanol.
步骤(5)的具体操作为：其将中间体D有机酸加入到二氯甲烷中，加入10％氢氧化钠溶液，室温搅拌30分钟，分液后二氯甲烷相浓缩至干，加入有机溶剂5溶解，向溶液中持续通入干燥的氯化氢气体30分钟，有大量固体析出，过滤、干燥得到目标化合物，既单一手性苯乙胺盐酸盐，所述中间体D有机酸、氢氧化钠的摩尔比例为1:1.0-2.0，优选1:1.5The specific operation of step (5) is as follows: it adds the intermediate D organic acid into dichloromethane, adds 10% sodium hydroxide solution, stirs at room temperature for 30 minutes, after liquid separation, the dichloromethane phase is concentrated to dryness, and an organic solvent is added. 5. Dissolve, continue to feed dry hydrogen chloride gas in the solution for 30 minutes, there is a large amount of solid to separate out, filter, dry to obtain the target compound, both single chiral phenethylamine hydrochloride, described intermediate D organic acid, sodium hydroxide The molar ratio is 1:1.0-2.0, preferably 1:1.5
所述中所述有机溶剂5为：乙酸乙酯、乙酸异丙脂、1,4-二氧六环、异丙醇、乙醇、二氯甲烷中的一种，优选乙酸异丙脂。The organic solvent 5 described in the above is one of ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropanol, ethanol, and dichloromethane, preferably isopropyl acetate.
实施例1Example 1
1L反应瓶中，加入间苯二甲醚(100g)、二氯甲烷(665g)、三氯化铝(96.5g)中，在5℃下滴加加入乙酰氯(56.8g)，滴加后在25℃保温1小时，反应结束后，加入水(500g)淬灭反应，分液后有机相浓缩至干，加入乙醇(300g)、三乙胺(110g)、盐酸羟胺(76.0g)，在45℃下保温3小时后滴加入水(783g)，有大量固体析出，降温至室温过滤，干燥，得中间体B109g，收率为78％；In a 1L reaction flask, add iso-xylylene ether (100g), dichloromethane (665g), and aluminum trichloride (96.5g), and add acetyl chloride (56.8g) dropwise at 5°C. Incubate at 25°C for 1 hour. After the reaction, water (500g) was added to quench the reaction. After separation, the organic phase was concentrated to dryness. Ethanol (300g), triethylamine (110g), and hydroxylamine hydrochloride (76.0g) were added. Water (783g) was added dropwise after being incubated at ℃ for 3 hours, a large amount of solid was precipitated, cooled to room temperature, filtered, and dried to obtain Intermediate B109g, with a yield of 78%;
中间体A：1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.7Hz,1H),6.50(dd,J＝8.7,2.3Hz,1H),6.44(d,J＝2.3Hz,1H),3.87(s,3H),3.83(d,J＝0.9Hz,3H),2.56(d,J＝0.9Hz,3H)。Intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81 (d, J=8.7Hz, 1H), 6.50 (dd, J=8.7, 2.3Hz, 1H), 6.44 (d, J=2.3Hz, 1H), 3.87 (s, 3H), 3.83 (d, J=0.9Hz, 3H), 2.56 (d, J=0.9Hz, 3H).
中间体B：1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.13(d,J＝8.3Hz,1H),6.59(d,J＝2.3Hz,1H),6.50(dd,J＝8.4,2.4Hz,1H),3.78(s,3H),3.78(s,3H),2.02(s,3H)。Intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85 (s, 1H), 7.13 (d, J=8.3Hz, 1H), 6.59 (d, J=2.3Hz, 1H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 2.02 (s, 3H).
2L高压反应釜中，加入中间体B(100g)、甲醇(792g)、雷尼镍(3.3g)，在60℃下氢气加压0.8Mpa反应5h，之后冷却到室温，过滤，收集滤液，滤液浓缩，加入二氯甲烷，经过盐酸溶液洗涤，氢氧化钠溶液洗涤，浓缩得淡黄色 油状物56g，收率为61％；In a 2L autoclave, add intermediate B (100g), methanol (792g), Raney nickel (3.3g), pressurize hydrogen at 60°C for 0.8Mpa and react for 5h, then cool to room temperature, filter, collect filtrate, filtrate Concentrated, added dichloromethane, washed with hydrochloric acid solution, washed with sodium hydroxide solution, and concentrated to obtain 56 g of light yellow oil with a yield of 61%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H)。1H NMR (400MHz, Chloroform-d)δ7.24-7.18(m,1H),6.45(dd,J=6.5,2.4Hz,2H),4.28(q,J=6.7Hz,1H),3.80(s, 3H), 3.78 (s, 3H), 1.37 (d, J=6.7 Hz, 3H).
500mL反应瓶中，加入中间体C(40g)、乙酸乙酯(140g)升温至50℃搅拌溶解，将R-扁桃酸(16.8g)加入异丙醇(48g)升温至40℃溶解，将R-扁桃酸溶液滴加至中间体C溶液中，滴加结束后自然降温至室温搅拌1小时，过滤，后经乙酸乙酯、乙醇重结晶，过滤，干燥，得中间体D扁桃酸盐，白色固体18.4g，收率为25％，ee％：99.1％；In a 500mL reaction flask, intermediate C (40g) and ethyl acetate (140g) were added and the temperature was raised to 50°C and stirred to dissolve. R-mandelic acid (16.8g) was added to isopropanol (48g) and the temperature was raised to 40°C to dissolve. - The mandelic acid solution was added dropwise to the intermediate C solution, after the dropwise addition, the temperature was naturally cooled to room temperature and stirred for 1 hour, filtered, and then recrystallized from ethyl acetate and ethanol, filtered and dried to obtain intermediate D mandelic acid salt, white Solid 18.4g, yield 25%, ee%: 99.1%;
100mL反应瓶中，加入中间体D(18g)、二氯甲烷(36g)、10％氢氧化钠溶液(36g),室温搅拌20分钟，分液，二氯甲烷浓缩后，加入乙酸异丙脂(25.9g)，再向溶液中通入干燥的氯化氢气体15分钟，有大量固体析出，过滤，干燥，得淡黄色固体10.98g，收率93％，HPLC纯度：99.9％，ee％：99.1％。In a 100 mL reaction flask, add Intermediate D (18 g), dichloromethane (36 g), and 10% sodium hydroxide solution (36 g), stir at room temperature for 20 minutes, separate the liquids, concentrate the dichloromethane, add isopropyl acetate ( 25.9g), then passed dry hydrogen chloride gas into the solution for 15 minutes, a large amount of solid was precipitated, filtered and dried to obtain 10.98g of pale yellow solid, yield 93%, HPLC purity: 99.9%, ee%: 99.1%.
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64–6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz,3H)。1H NMR (400MHz, DMSO-d6)δ8.38(s,3H),7.39(d,J=8.4Hz,1H),6.64-6.55(m,2H),4.48(p,J=6.2Hz,1H) , 3.82(s, 3H), 3.77(s, 3H), 1.46(d, J=6.8Hz, 3H).
HPLC(RPLC)图谱：HPLC (RPLC) spectrum:
Figure PCTCN2021086613-appb-000013
Figure PCTCN2021086613-appb-000013
HPLC(NPLC)图谱：HPLC (NPLC) spectrum:
Figure PCTCN2021086613-appb-000014
Figure PCTCN2021086613-appb-000014
保留时间keep time 构型structure
RT15.27minRT15.27min S构型S configuration
RT18.38minRT18.38min R构型R configuration
实施例2Example 2
1L反应瓶中，加入间苯二甲醚(100g)、1,2-二氯乙烷(435g)、三氯化铝(96.5g)中，在5℃下滴加加入乙酰氯(56.8g)，滴加后在25℃保温1小时，反应结束后，加入水(500g)淬灭反应，分液后有机相浓缩至干，加入甲醇(200g)、三乙胺(110g)、盐酸羟胺(76.0g)，在45℃下保温3小时后滴加入水(783g)，有大量固体析出，降温至室温过滤，干燥，得中间体B91.83g，收率为65％；In a 1L reaction flask, add iso-xylylene ether (100g), 1,2-dichloroethane (435g), and aluminum trichloride (96.5g), and add acetyl chloride (56.8g) dropwise at 5°C , and kept at 25°C for 1 hour after the dropwise addition. After the reaction was completed, water (500g) was added to quench the reaction. After the liquid separation, the organic phase was concentrated to dryness. Methanol (200g), triethylamine (110g), hydroxylamine hydrochloride (76.0 g), water (783g) was added dropwise after being incubated at 45 ° C for 3 hours, a large amount of solid was precipitated, cooled to room temperature, filtered, and dried to obtain intermediate B91.83g, the yield was 65%;
中间体A：1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.7Hz,1H),6.50(dd,J＝8.7,2.3Hz,1H),6.44(d,J＝2.3Hz,1H),3.87(s,3H),3.83(d,J＝0.9Hz,3H),2.56(d,J＝0.9Hz,3H).Intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81 (d, J=8.7Hz, 1H), 6.50 (dd, J=8.7, 2.3Hz, 1H), 6.44 (d, J=2.3Hz, 1H), 3.87(s, 3H), 3.83(d, J=0.9Hz, 3H), 2.56(d, J=0.9Hz, 3H).
中间体B：1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.13(d,J＝8.3Hz,1H),6.59(d,J＝2.3Hz,1H),6.50(dd,J＝8.4,2.4Hz,1H),3.78(s,3H),3.78(s,3H),2.02(s,3H)。Intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85 (s, 1H), 7.13 (d, J=8.3Hz, 1H), 6.59 (d, J=2.3Hz, 1H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 2.02 (s, 3H).
5L反应瓶中，加入中间体B(90g)、四氢呋喃(783g)溶解后，加入硼氢化钠(52.3g)，降温至0℃，将碘(58.5g)与四氢呋喃(292.5g)混合后在0℃滴加入中间体B溶液中，滴加完成后60℃反应8小时，之后冷却到室温，过滤，收集滤液，滤液浓缩，加入二氯甲烷，经过盐酸溶液洗涤，氢氧化钠溶液洗涤，浓 缩得淡黄色油状物43.2g，收率为51％；In a 5L reaction flask, add intermediate B (90g) and tetrahydrofuran (783g) to dissolve, add sodium borohydride (52.3g), cool down to 0°C, mix iodine (58.5g) and tetrahydrofuran (292.5g) at 0 ℃ was added dropwise to the intermediate B solution, after the dropwise addition was completed, the reaction was performed at 60 ℃ for 8 hours, then cooled to room temperature, filtered, the filtrate was collected, the filtrate was concentrated, dichloromethane was added, washed with hydrochloric acid solution, washed with sodium hydroxide solution, and concentrated to obtain Light yellow oil 43.2g, yield 51%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H).1H NMR (400MHz, Chloroform-d)δ7.24-7.18(m,1H),6.45(dd,J=6.5,2.4Hz,2H),4.28(q,J=6.7Hz,1H),3.80(s, 3H), 3.78(s, 3H), 1.37(d, J=6.7Hz, 3H).
500mL反应瓶中，加入中间体C(40g)、丙酮(120g)升温至50℃搅拌溶解，将L-天冬氨酸(14.6g)加入甲醇(43.8g)中升温至50℃溶解，将天冬氨酸溶液滴加入中间体C溶液中，自然降温至室温搅拌1小时，过滤，干燥，得中间体D天冬氨酸盐，白色固体14.56g，收率为21.0％，ee％：93.2％；In a 500mL reaction flask, add Intermediate C (40g) and acetone (120g) and heat up to 50°C and stir to dissolve, add L-aspartic acid (14.6g) to methanol (43.8g) and heat up to 50°C to dissolve, and the mixture is heated to 50°C to dissolve. The aspartic acid solution was added dropwise to the intermediate C solution, naturally cooled to room temperature and stirred for 1 hour, filtered and dried to obtain intermediate D aspartate, 14.56 g of white solid, the yield was 21.0%, ee%: 93.2% ;
1000mL反应瓶中，加入中间体D(14g)、二氯甲烷(28g)、10％氢氧化钠溶液(28g),室温搅拌20分钟，分液，二氯甲烷浓缩后，加入乙酸乙酯(14g)，再向溶液中通入干燥的氯化氢气体15分钟，有大量固体析出，过滤，干燥，得淡黄色固体8.66g，收率89.4％，ee％：93.2％In a 1000mL reaction flask, add Intermediate D (14g), dichloromethane (28g), and 10% sodium hydroxide solution (28g), stir at room temperature for 20 minutes, separate the liquids, concentrate the dichloromethane, add ethyl acetate (14g) ), then passed dry hydrogen chloride gas into the solution for 15 minutes, a large amount of solid was precipitated, filtered and dried to obtain 8.66g of pale yellow solid, yield 89.4%, ee%: 93.2%
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64–6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz,3H).1H NMR (400MHz, DMSO-d6)δ8.38(s,3H),7.39(d,J=8.4Hz,1H),6.64-6.55(m,2H),4.48(p,J=6.2Hz,1H) ,3.82(s,3H),3.77(s,3H),1.46(d,J=6.8Hz,3H).
HPLC(RPLC)图谱：HPLC (RPLC) spectrum:
Figure PCTCN2021086613-appb-000015
Figure PCTCN2021086613-appb-000015
HPLC(NPLC)图谱：HPLC (NPLC) spectrum:
Figure PCTCN2021086613-appb-000016
Figure PCTCN2021086613-appb-000016
保留时间keep time 构型structure
RT15.21minRT15.21min S构型S configuration
RT18.38minRT18.38min R构型R configuration
实施例3Example 3
1L反应瓶中，加入间苯二甲醚(100g)、二氯甲烷(665g)、三氯化铝(96.5g)中，在5℃下滴加加入乙酰氯(56.8g)，滴加后在25℃保温1小时，反应结束后，加入水(500g)淬灭反应，分液后有机相浓缩至干，加入四氢呋喃(261g)、三乙胺(110g)、盐酸羟胺(76.0g)，在45℃下保温3小时后滴加入水(783g)，有大量固体析出，降温至室温过滤，干燥，得中间体B100.3g，收率为75.0％；In a 1L reaction flask, add iso-xylylene ether (100g), dichloromethane (665g), and aluminum trichloride (96.5g), and add acetyl chloride (56.8g) dropwise at 5°C. Incubate at 25°C for 1 hour. After the reaction, water (500g) was added to quench the reaction. After separation, the organic phase was concentrated to dryness. Tetrahydrofuran (261g), triethylamine (110g), and hydroxylamine hydrochloride (76.0g) were added. Water (783g) was added dropwise after being incubated at ℃ for 3 hours, a large amount of solid was precipitated, cooled to room temperature, filtered, and dried to obtain Intermediate B100.3g, with a yield of 75.0%;
中间体A：1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.7Hz,1H),6.50(dd,J＝8.7,2.3Hz,1H),6.44(d,J＝2.3Hz,1H),3.87(s,3H),3.83(d,J＝0.9Hz,3H),2.56(d,J＝0.9Hz,3H).Intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81 (d, J=8.7Hz, 1H), 6.50 (dd, J=8.7, 2.3Hz, 1H), 6.44 (d, J=2.3Hz, 1H), 3.87(s, 3H), 3.83(d, J=0.9Hz, 3H), 2.56(d, J=0.9Hz, 3H).
中间体B：1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.13(d,J＝8.3Hz,1H),6.59(d,J＝2.3Hz,1H),6.50(dd,J＝8.4,2.4Hz,1H),3.78(s,3H),3.78(s,3H),2.02(s,3H).Intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85 (s, 1H), 7.13 (d, J=8.3Hz, 1H), 6.59 (d, J=2.3Hz, 1H), 6.50 (dd, J=8.4, 2.4Hz, 1H), 3.78(s, 3H), 3.78(s, 3H), 2.02(s, 3H).
2L高压反应釜中，加入中间体B(100g)、乙醇(790g)、10％钯碳(15g)，在60℃下氢气加压1.0Mpa反应12h，之后冷却到室温，过滤，收集滤液，滤液浓缩，加入二氯甲烷，经过盐酸溶液洗涤，氢氧化钠溶液洗涤，浓缩得淡黄色 油状物52.4g，收率为56.4％；In a 2L autoclave, add Intermediate B (100g), ethanol (790g), 10% palladium-carbon (15g), pressurize hydrogen at 60°C for 1.0Mpa and react for 12h, then cool to room temperature, filter, collect filtrate, filtrate Concentrated, added dichloromethane, washed with hydrochloric acid solution, washed with sodium hydroxide solution, and concentrated to obtain 52.4 g of light yellow oil with a yield of 56.4%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H).1H NMR (400MHz, Chloroform-d)δ7.24-7.18(m,1H),6.45(dd,J=6.5,2.4Hz,2H),4.28(q,J=6.7Hz,1H),3.80(s, 3H), 3.78(s, 3H), 1.37(d, J=6.7Hz, 3H).
500mL反应瓶中，加入中间体C(40g)、四氢呋喃(107g)室温搅拌溶解，将D-酒石酸(16.5g)加入乙醇(33g)升温至40℃溶解，将D-酒石酸溶液滴加至中间体C溶液中，滴加结束后自然降温至室温搅拌1小时，过滤干燥，得中间体D的酒石酸盐，白色固体17.1g，收率为23.4％，ee％：95.5％；In a 500mL reaction flask, add intermediate C (40g) and tetrahydrofuran (107g), stir and dissolve at room temperature, add D-tartaric acid (16.5g) to ethanol (33g) and heat up to 40°C to dissolve, add D-tartaric acid solution dropwise to the intermediate In solution C, after the dropwise addition was completed, it was naturally cooled to room temperature and stirred for 1 hour, filtered and dried to obtain the tartrate of Intermediate D, 17.1 g of white solid, the yield was 23.4%, ee%: 95.5%;
1000mL反应瓶中，加入中间体D(17g)、二氯甲烷(34g)、10％氢氧化钠溶液(34g),室温搅拌20分钟，分液，二氯甲烷浓缩后，加入乙1,4-二氧六环(20.7g)，再向溶液中通入干燥的氯化氢气体15分钟，有大量固体析出，过滤，干燥，得淡黄色固体10.5g，收率93.3％，ee％：95.5％。In a 1000mL reaction flask, add Intermediate D (17g), dichloromethane (34g), and 10% sodium hydroxide solution (34g), stir at room temperature for 20 minutes, separate the liquid, and concentrate the dichloromethane, add ethyl 1,4- Dioxane (20.7g) was passed into the solution with dry hydrogen chloride gas for 15 minutes, a large amount of solid was precipitated, filtered and dried to obtain 10.5g of pale yellow solid, yield 93.3%, ee%: 95.5%.
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64–6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz,3H)。1H NMR (400MHz, DMSO-d6)δ8.38(s,3H),7.39(d,J=8.4Hz,1H),6.64-6.55(m,2H),4.48(p,J=6.2Hz,1H) , 3.82(s, 3H), 3.77(s, 3H), 1.46(d, J=6.8Hz, 3H).
HPLC(RPLC)图谱：HPLC (RPLC) spectrum:
Figure PCTCN2021086613-appb-000017
Figure PCTCN2021086613-appb-000017
HPLC(NPLC)图谱：HPLC (NPLC) spectrum:
Figure PCTCN2021086613-appb-000018
Figure PCTCN2021086613-appb-000018
保留时间keep time 构型structure
RT15.27minRT15.27min S构型S configuration
RT18.38minRT18.38min R构型R configuration
以上所述仅为本发明的优选实施方式，并非因此限制本发明的专利范围，凡是利用本发明所作的等效变换，均在本发明的专利保护范围内。The above descriptions are only the preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent transformations made by using the present invention are within the scope of the patent protection of the present invention.

Claims (9)

  1. 一种S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，A preparation method of S-configuration phenethylamine hydrochloride compound, is characterized in that,
    化合物的结构为：The structure of the compound is:
    Figure PCTCN2021086613-appb-100001
    Figure PCTCN2021086613-appb-100001
    R1:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种；R1: a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
    R2:甲基、乙基、异丙基、环丙基、甲氧基、乙氧基、环丙基氧基中的一种；R2: a kind of in methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, ethoxy group, cyclopropyloxy group;
    包括以下制备步骤：Include the following preparation steps:
    (1)中间体A的合成：1,3-二取代基苯在乙酰氯以在三氯化铝得到中间体A，中间体A不单独分离；(1) Synthesis of intermediate A: 1,3-disubstituted benzene is in acetyl chloride to obtain intermediate A in aluminum trichloride, and intermediate A is not separated separately;
    (2)中间体B的合成：将步骤(1)所得到的中间体A在盐酸羟胺与三乙胺参与的条件下反应得中间体B；(2) the synthesis of intermediate B: the intermediate A obtained in step (1) is reacted to obtain intermediate B under the conditions that hydroxylamine hydrochloride and triethylamine participate;
    (3)中间体C合成：将步骤(2)所得的中间体B在还原剂作用下得到化合物C；(3) Synthesis of Intermediate C: Compound C is obtained from the intermediate B obtained in step (2) under the action of a reducing agent;
    (4)单一手性拆分：将步骤(3)所得的中间体C与单一手性酸在有机溶剂中拆分成盐得到S构型化合物D的有机盐；(4) single chirality resolution: the intermediate C obtained in step (3) and a single chiral acid are separated into salts in an organic solvent to obtain the organic salt of S-configuration compound D;
    (5)化合物E合成：将步骤(4)所得的中间体C与氢氧化钠以及氯化氢气体在有机溶剂反应生成化合物E；(5) compound E is synthesized: the intermediate C of step (4) gained is reacted with sodium hydroxide and hydrogen chloride gas to generate compound E in an organic solvent;
    上述步骤的总反应式为：The overall reaction formula of the above steps is:
    Figure PCTCN2021086613-appb-100002
    Figure PCTCN2021086613-appb-100002
  2. 根据权利要求1所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(1)中的具体操作为：1,3-二取代基苯、三氯化铝溶于无水有机溶剂1中，在-20～30℃下加入乙酰氯，在-20～40℃下反应1-5h后，用水淬灭反应， 后浓缩至干，得到中间体A，中间体A不需要单独纯化，配制下一步反应溶液后直接使用；The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 1, is characterized in that, the concrete operation in step (1) is: 1,3-disubstituted benzene, aluminum trichloride are dissolved in In anhydrous organic solvent 1, add acetyl chloride at -20 to 30 °C, react at -20 to 40 °C for 1-5 h, quench the reaction with water, and then concentrate to dryness to obtain intermediate A. It needs to be purified separately and used directly after preparing the next reaction solution;
    步骤(2)的具体操作为：中间体A加入有机溶剂2与三乙胺、盐酸羟胺，升温至40～80℃继续反应3-8h，之后加水，过滤干燥得中间体B；The specific operation of step (2) is as follows: intermediate A is added with organic solvent 2, triethylamine and hydroxylamine hydrochloride, the temperature is raised to 40～80° C. to continue the reaction for 3-8 h, then water is added, and the intermediate B is filtered and dried;
    步骤(3)的具体操作为：将中间体B加入到有机溶剂3中，加入还原剂、催化剂，体系温度控制0-60℃，在该温度下反应3-25h，之后冷却到室温，过滤，收集滤液，滤液浓缩干燥得到中间体C；所述中间体B、还原剂、催化剂的摩尔比例为1:0.01-5:0.01-1.0；The specific operation of step (3) is: adding intermediate B into organic solvent 3, adding reducing agent and catalyst, controlling the temperature of the system to 0-60°C, reacting at this temperature for 3-25h, then cooling to room temperature, filtering, The filtrate is collected, and the filtrate is concentrated and dried to obtain intermediate C; the molar ratio of intermediate B, reducing agent and catalyst is 1:0.01-5:0.01-1.0;
    步骤(4)的具体操作为：其将中间体C加入到有机溶剂3中溶解，将有单一手性机酸加入有机4中溶解，将有机酸溶液室温滴加至中间体C溶液中，室温搅拌1小时，有大量固体析出，过滤、重结晶、干燥得到中间体D的有机盐，所述中间体C、单一手性有机酸的摩尔比例为1:0.3-1.0；The specific operation of step (4) is as follows: it adds the intermediate C into the organic solvent 3 to dissolve, adds a single chiral organic acid to the organic 4 to dissolve, and drops the organic acid solution into the intermediate C solution at room temperature. After stirring for 1 hour, a large amount of solid was precipitated, filtered, recrystallized and dried to obtain the organic salt of intermediate D, and the molar ratio of intermediate C and single chiral organic acid was 1:0.3-1.0;
    步骤(5)的具体操作为：其将中间体D有机酸加入到二氯甲烷中，加入10％氢氧化钠溶液，室温搅拌30分钟，分液后二氯甲烷相浓缩至干，加入有机溶剂5溶解，向溶液中持续通入干燥的氯化氢气体30分钟，有大量固体析出，过滤、干燥得到目标化合物，既单一手性苯乙胺盐酸盐，所述中间体D有机酸、氢氧化钠的摩尔比例为1:1.0-2.0。The specific operation of step (5) is as follows: it adds the intermediate D organic acid into dichloromethane, adds 10% sodium hydroxide solution, stirs at room temperature for 30 minutes, after liquid separation, the dichloromethane phase is concentrated to dryness, and an organic solvent is added. 5. Dissolve, continue to feed dry hydrogen chloride gas in the solution for 30 minutes, there is a large amount of solid to separate out, filter, dry to obtain the target compound, both single chiral phenethylamine hydrochloride, described intermediate D organic acid, sodium hydroxide The molar ratio is 1:1.0-2.0.
  3. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，所述有机溶剂1为无水二氯甲烷、无水1,2-二氯乙烷中的任意一种。The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, described organic solvent 1 is any in anhydrous dichloromethane, anhydrous 1,2-dichloroethane A sort of.
  4. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(1)中1,3-二取代基苯、三氯化铝、乙酰氯、的摩尔比例为：1.0:0.9-2:0.9-2.0。The preparation method of S configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, in step (1), the molar ratio of 1,3-disubstituted benzene, aluminum trichloride, acetyl chloride, is: 1.0:0.9-2:0.9-2.0.
  5. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(2)中所述中间体A、三乙胺、盐酸羟胺的摩尔比例为：1.0:0.9-2.0:0.9-2.0。The preparation method of S configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, the molar ratio of intermediate A, triethylamine, hydroxylamine hydrochloride described in step (2) is: 1.0:0.9 -2.0:0.9-2.0.
  6. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(2)中所述有机溶剂2为甲醇、乙醇、异丙醇、四氢呋喃中的任意一种。The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, organic solvent 2 described in step (2) is any one in methanol, ethanol, isopropanol, tetrahydrofuran .
  7. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(3)中，所述中所述有机溶剂3为甲醇、乙醇、异丙醇、四氢呋喃、1,4-二氧六环中的任意一种；所述中所述还原剂为氢气、硼氢化钠、氰基硼***、四氢铝锂、三乙酰氧基硼氢化钠中的任意一种；所述催化剂为碘、雷尼 镍、钯炭、铂炭中的任意一种。The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, in step (3), described in the organic solvent 3 is methanol, ethanol, isopropanol, tetrahydrofuran, Any one in 1,4-dioxane; the reducing agent described in the middle is any of hydrogen, sodium borohydride, sodium cyanoborocyanide, lithium aluminum tetrahydrogen, and sodium triacetoxyborohydride One; the catalyst is any one of iodine, Raney nickel, palladium carbon and platinum carbon.
  8. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(4)中所述单一手性有机酸：D-扁桃酸、D-酒石酸、L-天冬氨酸、L-苹果酸中的任意一种；所述有机溶剂4为：异丙醇、乙醇、甲醇、丙酮、乙酸乙酯中的任意一种。The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, single chiral organic acid described in step (4): D-mandelic acid, D-tartaric acid, L-day any one of aspartic acid and L-malic acid; the organic solvent 4 is: any one of isopropanol, ethanol, methanol, acetone, and ethyl acetate.
  9. 根据权利要求2所述的S构型苯乙胺盐酸盐化合物的制备方法，其特征在于，步骤(5)中有机溶剂5为：乙酸乙酯、乙酸异丙脂、1,4-二氧六环、异丙醇、乙醇、二氯甲烷中的任意一种。The preparation method of S-configuration phenethylamine hydrochloride compound according to claim 2, is characterized in that, in step (5), organic solvent 5 is: ethyl acetate, isopropyl acetate, 1,4-dioxygen Any one of hexacyclic, isopropanol, ethanol, and dichloromethane.
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