WO2015135096A1 - Method for synthesizing 3-ethoxy-4-ethoxycarbonyl phenylacetic acid - Google Patents

Method for synthesizing 3-ethoxy-4-ethoxycarbonyl phenylacetic acid Download PDF

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WO2015135096A1
WO2015135096A1 PCT/CN2014/000458 CN2014000458W WO2015135096A1 WO 2015135096 A1 WO2015135096 A1 WO 2015135096A1 CN 2014000458 W CN2014000458 W CN 2014000458W WO 2015135096 A1 WO2015135096 A1 WO 2015135096A1
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compound
reaction
ethoxy
synthesizing
acid
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张越
刘婷婷
于奕峰
尚振华
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河北科技大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the invention belongs to the field of pharmacy and relates to a method for synthesizing repaglinide intermediate, in particular to a 3-ethoxy-4-ethoxycarbonylbenzene A method of synthesizing acetic acid.
  • Reiglinide is jointly developed by Boehringer Ingelheim of Germany and Novo Nordisk of Denmark as non-sulfonylureas.
  • An insulin secretagogue that stimulates the pancreas in type II diabetic patients and mimics the secretion of physiological insulin with a high protein binding rate.
  • Fast absorption, easy elimination, good safety, can be used alone, or combined with other hypoglycemic agents to increase the efficacy, can adapt to not Patients with the same lifestyle improve the quality of life of patients.
  • Repaglinide mainly consists of two intermediates of (S)-3-methyl-1-(2-(1-piperidinyl)phenyl)butylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid
  • the synthesis methods of 3-ethoxy-4-ethoxycarbonylphenylacetic acid synthesized in the prior art are as follows:
  • the reaction uses 4-methylsalicylic acid as a raw material to form an ester compound with ethyl bromide under basic conditions, and anhydrous THF and DMPU at -75 °C.
  • the mixture is reacted with LDA, and then CO2 is involved in the oxo reaction to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid.
  • Reactive reagents such as LDA and DMPU, which are more toxic, involve ultra-low temperature reaction (-75 ° C), so they are not suitable for industrial production.
  • the method uses 4-methylsalicylic acid as a raw material to form an ester compound with ethyl bromide under basic conditions, and then undergoes bromination, cyanation, esterification and water. The reaction was carried out to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid.
  • This method uses highly toxic substances such as sodium cyanide and reagents such as NBS, AIBN and carbon tetrachloride. Danger of operation, serious environmental pollution, and not suitable for industrial production.
  • the technical problem to be solved by the present invention is to provide a method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, and synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid by three methods respectively.
  • the reaction reagents and reaction conditions involved are mild, and while reducing the risk of reaction, Reduced operational difficulty.
  • the technical solution adopted by the present invention is:
  • One of the compounds 3-ethoxy-4-ethoxycarbonylphenylacetic acid is compound 4:
  • Equation II The reaction equation is as in Equation II:
  • Equation III The reaction equation is as in Equation III:
  • the preparation method of the compound 5 in the route 2 is as shown in the following formula VI or formula VII:
  • the oxidation reaction process in the first, second or third route is:
  • Compound 1 Compound 5 or Compound 7 is used as a raw material, mixed with an oxidizing agent at a molar ratio of 1:2 to 10, and reacted at room temperature for 1 to 5 hours to acidify. Extraction, removal of solvent, compound 2, compound 6 or compound 8 are prepared according to formula I, II, III, respectively.
  • the oxidizing agent is silver oxide, silver nitrate, t-butyl hydroperoxide, hydrogen peroxide, chromium trioxide, Chromic acid, sodium dichromate, potassium dichromate, pyridine dichromate, pyridine chlorochromate, sodium hypohalite, potassium hypohalite, dimanganese trioxide, active dioxide One of manganese.
  • the process of the formylation reaction in the first, second or third route is:
  • the formylating agent is dimethylformamide, diethylformamide, diisopropylformamide, and Butylformamide, hexamethylenetetramine, N-methyl-N-phenylformamide, N-ethyl-N-phenylformamide, paraformaldehyde, chloroform, dichloromethyl One of methyl ether, dichloromethyl ether, and dichloromethyl butyl ether.
  • compound 2 Using compound 2, compound 7 or compound 11 as a raw material, mixing with ethyl bromide and an alkaline reagent at a molar ratio of 1:2 to 9:1 to 6 and refluxing 2 to 2 7h, adding water, extracting, removing the solvent, respectively, according to formula I, II to obtain compound 3, compound 5 or compound 10;
  • Compound 8 having a molar ratio of 1:3 to 9:3-6, mixed with ethyl bromide and an alkaline reagent, refluxed for 2 to 7 hours, added with water, extracted, and the solvent is removed.
  • Compound 3 is obtained according to formula III; wherein the alkaline reagent is potassium acetate, sodium acetate, sodium methoxide, sodium carbonate, potassium carbonate, sodium ethoxide, ethanol One of potassium.
  • the process of the esterification reaction in the first or second route is:
  • the process of the hydrolysis reaction in the first, second or third route is:
  • the molar ratio of the compound 3 to the alkaline agent is 1:1 to 3;
  • the alkaline reagent is sodium hydroxide or potassium hydroxide.
  • the invention adopts three ways to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetic acid, and the reaction reagents and reaction conditions involved are mild. While reducing the risk of reaction, it also reduces the difficulty of operation.
  • the molar ratio of the raw material to the oxidizing agent was determined to be 1:2 to 10. When the molar ratio is less than 1:2, the raw material reaction is incomplete; when the molar ratio is greater than 1:10, This leads to waste of oxidant and an increase in by-products.
  • reaction time of the raw material and the oxidizing agent is 1 to 5 hours.
  • the reaction time is less than 1 h, the reaction is incomplete; when the reaction time is more than 5 h, The by-products are significantly increased and the product yield is lowered.
  • the molar ratio of the starting material, ethyl bromide and alkaline reagent is determined to be from 1:2 to 9:1 to 6. When the molar ratio is less than 1:2:1, the reaction is incomplete and the product is miscellaneous. After the increase; when the molar ratio is greater than 1:9:6, the waste of the reaction reagent is caused. When the reaction temperature is lower than the reflux temperature, the reaction time is significantly increased. Should not be complete.
  • the molar ratio of the starting material to the formylating agent was determined to be from 1:1 to 8. When the molar ratio is less than 1:1, the raw material reaction is incomplete and the product yield is low; When the ratio is greater than 1:8, waste of the formylating agent is caused, by-products are increased, and product yield is lowered.
  • the temperature of the formylation reaction is 25 to 60 °C.
  • the reaction temperature is lower than 25 ° C, the raw material and the formylating agent hardly react; the reaction
  • the mixing degree is higher than 60 ° C, the by-products are obviously increased, and the product yield and purity are lowered.
  • the invention is applicable to the preparation of repaglinide intermediate, 3-ethoxy-4-ethoxycarbonylphenylacetic acid.
  • Figure 1 is a nuclear magnetic diagram of Compound 1 (i.e., 4-formyl-3-hydroxyphenylacetate) in Route 1 (a) of Example 1 of the present invention
  • Figure 3 is a nuclear magnetic diagram of Compound 4, i.e., 3-ethoxy-4-ethoxycarbonylphenylacetic acid, in Route 1 (a) of Example 1 of the present invention.
  • a method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, using m-hydroxyphenylacetic acid, compound 11, as raw material, and finally synthesizing 3-B Oxy-4-ethoxycarbonylphenylacetic acid is Compound 4.
  • the esterification reaction was first carried out to synthesize ethyl m-hydroxyphenylacetate, ie, compound 9, which was synthesized by formylation reaction. From ethyl acyl-3-hydroxyphenylacetate, compound 1, then oxidative reaction to synthesize 4-acetylethyl-2-hydroxybenzoic acid, compound 2, followed by esterification etherification to synthesize 3-ethoxy-4 Ethyl ethoxycarbonyl phenylacetate, Compound 3, was finally subjected to hydrolysis to give Compound 4.
  • ethyl 3-ethoxyphenylacetate, compound 10 was synthesized by esterification etherification reaction, and then subjected to formylation reaction.
  • Ethyl 4-formyl-3-ethoxyphenylacetate, compound 5, is synthesized by oxidation to synthesize 4-acetylethyl ester-2-ethoxybenzoic acid.
  • Compound 6, compound 3 is synthesized by esterification reaction, and finally compound 4 is obtained by hydrolysis reaction.
  • 4-formyl-3-hydroxyphenylacetic acid 7 was synthesized by formylation reaction, followed by esterification etherification reaction. 4-ethylformyl-3-ethoxyphenylacetate 5, followed by oxidation to synthesize 4-acetylethyl-2- benzobenzoic acid 6, and then esterified The reaction was carried out to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetate 3, and finally subjected to a hydrolysis reaction to finally obtain 3-ethoxy-4-ethoxycarbonylphenylacetic acid 4.
  • the specific preparation method is:
  • the nuclear magnetic data of Compound 3 is as follows:
  • the nuclear magnetic data of Compound 4 is as follows:
  • 4-formyl-3-hydroxyphenylacetic acid 7 is synthesized by formylation reaction, and then subjected to oxidation reaction.
  • 4-carboxymethyl-2-hydroxybenzoic acid 8 is synthesized, followed by esterification etherification to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetate 3, and finally passed through water. The reaction was finally carried out to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid 4.
  • the specific preparation method is:
  • the nuclear magnetic data of Compound 3 is as follows:
  • the nuclear magnetic data of Compound 4 is as follows:
  • Examples 2-26 are respectively a method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, which is similar to the synthesis method of Example 1, and is different. The only difference lies in the technical parameters involved. For details, see the table:
  • reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the corresponding yield is similar to the yield of the examples 2-6, which is:
  • the yield of the reaction I is 87.2 to 96.2%; the yield of the reaction II is 77 to 78.8%; the yield of the reaction III is 86.5 to 88%; The yield was 85 to 92%; the yield of the reaction V was 86 to 92%.
  • reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the corresponding yield is similar to the yield of the examples 7-11, which is:
  • the yield of the reaction I is 76 to 78.9%; the yield of the reaction II is 89 to 97%; the yield of the reaction III is 85 to 88.5%, and the reaction IV is received. The yield was 88 to 91%; the yield of the reaction V was 86 to 93%.
  • reaction charge of the reaction I to V is further increased to 0.5 to 1.0 kg, and the actual yield is similar to the yield of the examples 12-16, which is:
  • the yield of the reaction I is 87 to 91.5%; the yield of the reaction II is 77 to 80%; the yield of the reaction III is 84 to 88%; the yield of the reaction IV It is 87 to 97%; the yield of the reaction V is 85 to 91%.
  • reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the actual yield is similar to the yield of the examples 17-21, which is:
  • the yield of the reaction I is 75 to 79%; the yield of the reaction II is 86 to 92%: the yield of the reaction III is 80 to 88%; the yield of the reaction IV is 88 to 97%; the yield of the reaction V is 88 to 93%.
  • reaction amount of the reaction I to IV is also increased to 0.5 to 1 kg, and the corresponding yield is similar to the yield of the examples 22-26, which is:
  • the yield of the reaction I is 72 to 80%: the yield of the reaction II is 80 to 90%; the yield of the reaction III is 82 to 92%; and the yield of the reaction IV is 89 to 93%.

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Abstract

Disclosed is a method for synthesizing 3-ethoxy-4-ethoxycarbonyl phenylacetic acid. With m-hydroxyphenylacetic acid as a raw material, the 3-ethoxy-4-ethoxycarbonyl phenylacetic acid is separately synthesized in three ways. The involved reaction agents and reaction conditions are relatively mild, and the operation difficulty is lowered while the reaction risk is lowered. The present invention is applicable to the preparation of repaglinide intermediate-3-ethoxy-4-ethoxycarbonyl phenylacetic acid.

Description

3-乙氧基-4-乙氧羰基苯乙酸的合成方法 Method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid                  技术领域 Technical field                 
本发明属于制药领域，涉及一种瑞格列奈中间体的合成方法，具体涉及一种3-乙氧基-4-乙氧羰基苯 乙酸的合成方法。 The invention belongs to the field of pharmacy and relates to a method for synthesizing repaglinide intermediate, in particular to a 3-ethoxy-4-ethoxycarbonylbenzene           A method of synthesizing acetic acid.                 
背景技术 Background technique                 
瑞格列奈，化学名称为S(+)-2-乙氧基-4-{2-[(3-甲基-1-(2-(1-哌啶基)苯基)丁基)胺基]-2-氧代乙 基苯甲酸，属于氯茴苯酸类，其结构式如下： Regreline, chemical name is S(+)-2-ethoxy-4-{2-[(3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amine 2-oxo-B           Benzoic acid, belonging to the class of meglitinides, has the following structural formula:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f1
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f1
瑞格列奈是由德国的Boehringer Ingelheim公司和丹麦Novo Nordisk公司联合研发，为非磺酰脲类 促胰岛素分泌剂，可在II型糖尿病患者体内刺激胰腺而模拟生理性胰岛素的分泌，有较高的蛋白结合率， 吸收快，易消除，安全性良好，既可以单独使用，也可以和其它降糖药联合应用而增加疗效，可以适应不 同生活方式的患者，提高患者的生活质量。 Reiglinide is jointly developed by Boehringer Ingelheim of Germany and Novo Nordisk of Denmark as non-sulfonylureas.           An insulin secretagogue that stimulates the pancreas in type II diabetic patients and mimics the secretion of physiological insulin with a high protein binding rate.           Fast absorption, easy elimination, good safety, can be used alone, or combined with other hypoglycemic agents to increase the efficacy, can adapt to not           Patients with the same lifestyle improve the quality of life of patients.                 
瑞格列奈主要由(S)-3-甲基-1-(2-(1-哌啶基)苯基)丁胺和3-乙氧基-4-乙氧羰基苯乙酸两个中间体 合成而现有技术中3-乙氧基-4-乙氧羰基苯乙酸的合成方法有： Repaglinide mainly consists of two intermediates of (S)-3-methyl-1-(2-(1-piperidinyl)phenyl)butylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid           The synthesis methods of 3-ethoxy-4-ethoxycarbonylphenylacetic acid synthesized in the prior art are as follows:                 
M.Salman等在文献《Synthesis of3-Ethoxy-4-Ethoxycarbonyl Phenylacetic Acid，A Key Acid 
Figure PCTCN2014000458-appb-000002
of Repaglinide》中报道了3-乙氧基-4-乙氧羰基苯乙酸的合成路线： M. Salman et al. in the literature "Synthesis of 3-Ethoxy-4-Ethoxycarbonyl Phenylacetic Acid, A Key Acid
Figure PCTCN2014000458-appb-000002
The synthesis route of 3-ethoxy-4-ethoxycarbonylphenylacetic acid is reported in of Repaglinide:
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f2
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f2
该反应以4-甲基水杨酸为原料，碱性条件下与溴乙烷生成酯类化合物，-75℃下在无水THF和DMPU 的混合液中与LDA反应，然后用CO2参与羰基合成反应得到3-乙氧基-4-乙氧羰基苯乙酸。此方法采用了 毒性较大的LDA、DMPU等反应试剂，涉及到超低温反应(-75℃)，因此不适合工业化生产。 The reaction uses 4-methylsalicylic acid as a raw material to form an ester compound with ethyl bromide under basic conditions, and anhydrous THF and DMPU at -75 °C.           The mixture is reacted with LDA, and then CO2 is involved in the oxo reaction to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid. This method is adopted           Reactive reagents such as LDA and DMPU, which are more toxic, involve ultra-low temperature reaction (-75 ° C), so they are not suitable for industrial production.                 
M.S.Reddy等在文献《Process for the Preparation of3-Ethoxy-4-Alkoxy Carbonyl-Phenyl Acetic  Acid》报道了3-乙氧基-4-乙氧羰基苯乙酸的合成路线： M.S. Reddy et al. in the literature "Process for the Preparation of 3-Ethoxy-4-Alkoxy Carbonyl-Phenyl Acetic           Acid reports the synthesis route of 3-ethoxy-4-ethoxycarbonylphenylacetic acid:                                     
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f3
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f3
该方法以4-甲基水杨酸为原料，碱性条件下与溴乙烷生成酯类化合物，再经过溴代、氰化、酯化和水 解反应得到3-乙氧基-4-乙氧羰基苯乙酸。此法使用了剧毒物质氰化钠以及NBS、AIBN和四氯化碳等试剂， 操作危险，环境污染严重，也不适合工业化生产。 The method uses 4-methylsalicylic acid as a raw material to form an ester compound with ethyl bromide under basic conditions, and then undergoes bromination, cyanation, esterification and water.           The reaction was carried out to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid. This method uses highly toxic substances such as sodium cyanide and reagents such as NBS, AIBN and carbon tetrachloride.           Danger of operation, serious environmental pollution, and not suitable for industrial production.                 
因此，研究一种操作安全、反应条件温和、适合工业化生产的3-乙氧基-4-乙氧羰基苯乙酸的合成方 法，具有非常重要的意义。 Therefore, a synthetic formula of 3-ethoxy-4-ethoxycarbonylphenylacetic acid which is safe in operation, mild in reaction conditions and suitable for industrial production is studied.           Law, has a very important meaning.                 
发明内容 Summary of the invention                 
本发明要解决的技术问题，是提供一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法，分别采用三种途径 合成3-乙氧基-4-乙氧羰基苯乙酸，所涉及的反应试剂和反应条件均较温和，在降低了反应危险性的同时，
Figure PCTCN2014000458-appb-000005
降低了操作难度。 The technical problem to be solved by the present invention is to provide a method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, and synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid by three methods respectively. The reaction reagents and reaction conditions involved are mild, and while reducing the risk of reaction,
Figure PCTCN2014000458-appb-000005
Reduced operational difficulty.
为解决上述技术问题，本发明所采取的技术方案是： In order to solve the above technical problems, the technical solution adopted by the present invention is:                 
一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法，以间羟基苯乙酸即化合物11为原料，采用以下途径
Figure PCTCN2014000458-appb-000006
之一合成3-乙氧基-4-乙氧羰基苯乙酸即化合物4： A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, using m-hydroxyphenylacetic acid as compound 11 as the raw material, adopting the following route
Figure PCTCN2014000458-appb-000006
One of the compounds 3-ethoxy-4-ethoxycarbonylphenylacetic acid is compound 4:
①途径一 1 way one                 
以化合物11为原料，首先合成4-甲酰基-3-羟基苯乙酸乙酯即化合物1，后经过氧化反应合成4-乙酰 乙酯基-2-羟基苯甲酸即化合物2，再经过酯化醚化反应合成3-乙氧基-4-乙氧羰基苯乙酸乙酯即化合物3， 最后经过水解反应最终制得化合物4； Starting from compound 11 as the starting material, firstly, 4-formyl-3-hydroxyphenylethylacetate, compound 1, was synthesized, and then 4-acetyl was synthesized by oxidation reaction.           Ethyl 2-hydroxybenzoic acid, compound 2, is then subjected to esterification etherification to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetate, compound 3,           Finally, a hydrolysis reaction is finally carried out to obtain a compound 4;                 
反应方程式如式I： The reaction equation is as in Formula I:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f4
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f4
②途径二 2 route two                 
以化合物11为原料，首先合成4-甲酰基-3-乙氧基苯乙酸乙酯即化合物5，后经过氧化反应合成4- 乙酰乙酯基-2-乙氧基苯甲酸即化合物6，再经过酯化反应合成化合物3，最后经过水解反应制得化合物4； Starting from compound 11 as the starting material, firstly, 4-formyl-3-ethoxyphenylethylacetate, compound 5, is synthesized, and then synthesized by oxidation reaction 4-           Acetylethyl-2-ethoxybenzoic acid, compound 6, is esterified to synthesize compound 3, and finally hydrolyzed to obtain compound 4;                 
反应方程式如式II： The reaction equation is as in Equation II:                                     
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f5
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f5
③途径三 3 way three                 
以化合物11为原料，首先经过甲酰化反应合成4-甲酰基-3-羟基苯乙酸即化合物7，后经过氧化反应 合成4-羧甲基-2-羟基苯甲酸即化合物8，再经过酯化醚化反应合成化合物3，最后经过水解反应制得化合 物4； Using compound 11 as a raw material, firstly, 4-formyl-3-hydroxyphenylacetic acid, compound 7, is synthesized by formylation reaction, and then subjected to oxidation reaction.           Synthesis of 4-carboxymethyl-2-hydroxybenzoic acid, compound 8, followed by esterification and etherification to synthesize compound 3, and finally hydrolysis to obtain compound           Matter 4;                 
反应方程式如式III： The reaction equation is as in Equation III:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f6
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f6
作为本发明的一种限定，途径一中化合物1的制备方法为以下式IV或式V所示： As a limitation of the present invention, the preparation method of Compound 1 in Route 1 is as shown in the following Formula IV or Formula V:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f7
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f7
作为本发明的另一种限定，途径二中化合物5的制备方法为以下式VI或式VII所示： As another limitation of the present invention, the preparation method of the compound 5 in the route 2 is as shown in the following formula VI or formula VII:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f8
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f8
作为本发明的第三种限定，所述途径一、二或三中的氧化反应的过程为： As a third limitation of the present invention, the oxidation reaction process in the first, second or third route is:                 
以化合物1、化合物5或化合物7为原料，以摩尔比1∶2～10与氧化剂混合，室温反应1～5h，酸化， 萃取，除去溶剂，分别按照式I、II、III制得化合物2、化合物6或化合物8。 Compound 1, Compound 5 or Compound 7 is used as a raw material, mixed with an oxidizing agent at a molar ratio of 1:2 to 10, and reacted at room temperature for 1 to 5 hours to acidify.           Extraction, removal of solvent, compound 2, compound 6 or compound 8 are prepared according to formula I, II, III, respectively.                 
作为上述限定的进一步限定，所述氧化剂为氧化银、硝酸银、叔丁基过氧化氢、过氧化氢、三氧化铬、 铬酸、重铬酸钠、重铬酸钾、重铬酸吡啶、氯铬酸吡啶、次卤酸钠、次卤酸钾、三氧化二锰、活性二氧化 锰中的一种。 As further defined by the above definition, the oxidizing agent is silver oxide, silver nitrate, t-butyl hydroperoxide, hydrogen peroxide, chromium trioxide,           Chromic acid, sodium dichromate, potassium dichromate, pyridine dichromate, pyridine chlorochromate, sodium hypohalite, potassium hypohalite, dimanganese trioxide, active dioxide           One of manganese.                 
作为本发明的第四种限定，所述途径一、二或三中的甲酰化反应的过程为： As a fourth limitation of the present invention, the process of the formylation reaction in the first, second or third route is:                 
以化合物9、化合物10或化合物11为原料，以摩尔比1∶1～8与甲酰化试剂混合，25～60℃反应1～ 6h、加水，萃取，除去溶剂，分别按照式I、式II、式III制得化合物1、化合物5或化合物7。 Using compound 9, compound 10 or compound 11 as a raw material, mixing with a formylating reagent at a molar ratio of 1:1 to 8, and reacting at 25 to 60 ° C for 1 to           6h, adding water, extracting, removing the solvent, respectively, according to formula I, formula II, formula III, compound 1, compound 5 or compound 7.                 
作为上述限定的进一步限定，所述甲酰化试剂为二甲基甲酰胺、二乙基甲酰胺、二异丙基甲酰胺、二 丁基甲酰胺、六亚甲基四胺、N-甲基-N-苯基甲酰胺、N-乙基-N-苯基甲酰胺、多聚甲醛、氯仿、二氯甲基 甲醚、二氯甲基乙醚、二氯甲基丁醚中的一种。 As a further definition of the above definition, the formylating agent is dimethylformamide, diethylformamide, diisopropylformamide, and           Butylformamide, hexamethylenetetramine, N-methyl-N-phenylformamide, N-ethyl-N-phenylformamide, paraformaldehyde, chloroform, dichloromethyl           One of methyl ether, dichloromethyl ether, and dichloromethyl butyl ether.                 
作为本发明的第五种限定， As a fifth limitation of the present invention,                 
①所述途径一或途径二中的酯化醚化反应的过程为： 1 The process of the esterification etherification reaction in Route 1 or Route 2 is:                 
以化合物2、化合物7或化合物11为原料，以摩尔比1∶2～9∶1～6与溴乙烷、碱性试剂混合，回流2～ 7h、加水，萃取，除去溶剂，分别按照式I、II制得化合物3、化合物5或化合物10； Using compound 2, compound 7 or compound 11 as a raw material, mixing with ethyl bromide and an alkaline reagent at a molar ratio of 1:2 to 9:1 to 6 and refluxing 2 to 2           7h, adding water, extracting, removing the solvent, respectively, according to formula I, II to obtain compound 3, compound 5 or compound 10;                 
②途径三中的酯化醚化反应的过程为： The process of the esterification etherification reaction in Route 3 is:                 
摩尔比为1∶3～9∶3～6的化合物8、溴乙烷、碱性试剂混合，回流2～7h，加水，萃取，除去溶剂， 按照式III制得化合物3；其中，碱性试剂为醋酸钾、醋酸钠、甲醇钠、碳酸钠、碳酸钾、乙醇钠、乙醇 钾中的一种。 Compound 8 having a molar ratio of 1:3 to 9:3-6, mixed with ethyl bromide and an alkaline reagent, refluxed for 2 to 7 hours, added with water, extracted, and the solvent is removed.           Compound 3 is obtained according to formula III; wherein the alkaline reagent is potassium acetate, sodium acetate, sodium methoxide, sodium carbonate, potassium carbonate, sodium ethoxide, ethanol           One of potassium.                 
作为本发明的第六种限定，所述的途径一或二中的酯化反应的过程为： As a sixth limitation of the present invention, the process of the esterification reaction in the first or second route is:                 
以化合物6、化合物7或化合物11为原料，与无水乙醇、浓硫酸混合，回流1～4h后除去乙醇，萃取， 除去溶剂，分别按照式1、II制得化合物1、化合物3或化合物9；其中原料和浓硫酸的摩尔比为1∶0.05～
Figure PCTCN2014000458-appb-000012
Compound 6, compound 7 or compound 11 is used as a raw material, mixed with absolute ethanol and concentrated sulfuric acid, refluxed for 1 to 4 hours, then ethanol is removed, extracted, solvent is removed, and compound 1, compound 3 or compound 9 is obtained according to formula 1, II, respectively. Wherein the molar ratio of the raw material to concentrated sulfuric acid is 1:0.05~
Figure PCTCN2014000458-appb-000012
本发明还有一种限定，所述途径一、二或三中的水解反应的过程为： There is still another limitation of the present invention, the process of the hydrolysis reaction in the first, second or third route is:                 
无水乙醇、化合物3、碱性试剂混合，室温反应0.5～3h后加水，萃取，除去溶剂，按照式I、II、 III制得3-乙氧基-4-乙氧羰基苯乙酸(4)；其中， Anhydrous ethanol, compound 3, alkaline reagent are mixed, reacted at room temperature for 0.5 to 3 hours, then added with water, extracted, and the solvent is removed, according to formula I, II,           III, 3-ethoxy-4-ethoxycarbonylphenylacetic acid (4); wherein                 
化合物3与碱性试剂的摩尔比为1∶1～3； The molar ratio of the compound 3 to the alkaline agent is 1:1 to 3;                 
碱性试剂为氢氧化钠或氢氧化钾。 The alkaline reagent is sodium hydroxide or potassium hydroxide.                 
由于采用了上述的技术方案，本发明与现有技术相比，所取得的技术进步在于： Due to the adoption of the above technical solution, the technical progress achieved by the present invention compared to the prior art is:                 
本发明分别采用三种途径合成3-乙氧基-4-乙氧羰基苯乙酸，所涉及的反应试剂和反应条件均较温和， 在降低了反应危险性的同时，还降低了操作难度。 The invention adopts three ways to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetic acid, and the reaction reagents and reaction conditions involved are mild.           While reducing the risk of reaction, it also reduces the difficulty of operation.                 
本发明中，合成3-乙氧基-4-乙氧羰基苯乙酸过程中影响收率的关键性因素主要有： In the present invention, the key factors affecting the yield in the process of synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid are as follows:                 
(1)氧化反应 (1) Oxidation reaction                 
确定原料与氧化剂的摩尔比为1∶2～10。摩尔比小于1∶2时，原料反应不完全；摩尔比大于1∶10时， 导致氧化剂的浪费，副产物增加。 The molar ratio of the raw material to the oxidizing agent was determined to be 1:2 to 10. When the molar ratio is less than 1:2, the raw material reaction is incomplete; when the molar ratio is greater than 1:10,           This leads to waste of oxidant and an increase in by-products.                                     
另外，原料与氧化剂的反应时间为1～5h。反应时间少于1h时，反应不完全；反应时间多于5h时， 副产物明显增加，产品收率降低。 Further, the reaction time of the raw material and the oxidizing agent is 1 to 5 hours. When the reaction time is less than 1 h, the reaction is incomplete; when the reaction time is more than 5 h,           The by-products are significantly increased and the product yield is lowered.                 
(2)酯化醚化反应 (2) Esterification etherification reaction                 
确定原料、溴乙烷、碱性试剂的摩尔比为1∶2～9∶1～6。摩尔比小于1∶2∶1时，反应不完全，产品杂 后增多；摩尔比大于1∶9∶6时，导致反应试剂的浪费。反应温度低于回流温度时，反应时间明显增加，反 应不完全。 The molar ratio of the starting material, ethyl bromide and alkaline reagent is determined to be from 1:2 to 9:1 to 6. When the molar ratio is less than 1:2:1, the reaction is incomplete and the product is miscellaneous.           After the increase; when the molar ratio is greater than 1:9:6, the waste of the reaction reagent is caused. When the reaction temperature is lower than the reflux temperature, the reaction time is significantly increased.           Should not be complete.                 
(3)甲酰化反应 (3) Formylation reaction                 
确定原料与甲酰化试剂的摩尔比为1∶1～8。摩尔比小于1∶1时，原料反应不完全，产品收率较低；摩 尔比大于1∶8时，导致甲酰化试剂的浪费，副产物增加，产品收率降低。 The molar ratio of the starting material to the formylating agent was determined to be from 1:1 to 8. When the molar ratio is less than 1:1, the raw material reaction is incomplete and the product yield is low;           When the ratio is greater than 1:8, waste of the formylating agent is caused, by-products are increased, and product yield is lowered.                 
另外，甲酰化反应的温度为25～60℃。反应温度低于25℃时，原料与甲酰化试剂几乎不反应；反应 混度高于60℃时，副产物明显增加，产品收率及纯度降低。 Further, the temperature of the formylation reaction is 25 to 60 °C. When the reaction temperature is lower than 25 ° C, the raw material and the formylating agent hardly react; the reaction           When the mixing degree is higher than 60 ° C, the by-products are obviously increased, and the product yield and purity are lowered.                 
本发明适用于瑞格列奈中间体——3-乙氧基-4-乙氧羰基苯乙酸的制备。 The invention is applicable to the preparation of repaglinide intermediate, 3-ethoxy-4-ethoxycarbonylphenylacetic acid.                 
本发明下面将结合附图说明和具体实施例作进一步详细说明。 The invention will be further described in detail below with reference to the drawings and specific embodiments.                 
附图说明 DRAWINGS                 
图1为本发明实施例1中途径一(a)中化合物1即4-甲酰基-3-羟基苯乙酸乙酯的核磁图； Figure 1 is a nuclear magnetic diagram of Compound 1 (i.e., 4-formyl-3-hydroxyphenylacetate) in Route 1 (a) of Example 1 of the present invention;                 
图2为本发明实施例1中途径一(a)中化合物3即3-乙氧基-4-乙氧羰基苯乙酸乙酯的核磁图； 2 is a nuclear magnetic diagram of Compound 3, ie, 3-ethoxy-4-ethoxycarbonylphenylacetate, in Route 1 (a) of Example 1 of the present invention;                 
图3为本发明实施例1中途径一(a)中化合物4即3-乙氧基-4-乙氧羰基苯乙酸的核磁图。 Figure 3 is a nuclear magnetic diagram of Compound 4, i.e., 3-ethoxy-4-ethoxycarbonylphenylacetic acid, in Route 1 (a) of Example 1 of the present invention.                 
具体实施方式 detailed description                 
实施例13-乙氧基-4-乙氧羰基苯乙酸的合成方法 Example 13 - Synthesis of ethoxy-4-ethoxycarbonylphenylacetic acid                 
一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法，以间羟基苯乙酸即化合物11为原料，最终合成3-乙 氧基-4-乙氧羰基苯乙酸即化合物4。 A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, using m-hydroxyphenylacetic acid, compound 11, as raw material, and finally synthesizing 3-B           Oxy-4-ethoxycarbonylphenylacetic acid is Compound 4.                 
途径一(a)： Pathway one (a):                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f9
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f9
以化合物11为原料，首先经过酯化反应合成间羟基苯乙酸乙酯即化合物9，后经过甲酰化反应合成
Figure PCTCN2014000458-appb-000014
由酰基-3-羟基苯乙酸乙酯即化合物1，后经过氧化反应合成4-乙酰乙酯基-2-羟基苯甲酸即化合物2， 再经过酯化醚化反应合成3-乙氧基-4-乙氧羰基苯乙酸乙酯即化合物3，最后经过水解反应制得化合物4。 Starting from compound 11 as the starting material, the esterification reaction was first carried out to synthesize ethyl m-hydroxyphenylacetate, ie, compound 9, which was synthesized by formylation reaction.
Figure PCTCN2014000458-appb-000014
From ethyl acyl-3-hydroxyphenylacetate, compound 1, then oxidative reaction to synthesize 4-acetylethyl-2-hydroxybenzoic acid, compound 2, followed by esterification etherification to synthesize 3-ethoxy-4 Ethyl ethoxycarbonyl phenylacetate, Compound 3, was finally subjected to hydrolysis to give Compound 4.
具体制备过程为： The specific preparation process is:                 
(I)酯化反应 (I) esterification reaction                 
将149.4ml的无水乙醇、150g的化合物11和9.67g的浓硫酸混合，回流反应2h，旋蒸除去乙醇， 二氯甲烷萃取，合并萃取液浓缩后制得17.0g化合物9。收率为95.7％。其中，化合物11和浓硫酸的反应 摩尔比为1∶1。 149.4 ml of absolute ethanol, 150 g of compound 11 and 9.67 g of concentrated sulfuric acid were mixed, refluxed for 2 h, and evaporated to remove ethanol.           Extraction with dichloromethane and concentration of the combined extracts gave 17.0 g of Compound 9. The yield was 95.7%. Among them, the reaction of compound 11 and concentrated sulfuric acid           The molar ratio is 1:1.                 
(II)甲酰化反应 (II) formylation reaction                                     
将5.0g的化合物9与4.06g的二甲基甲酰胺混合，30℃反应2h，反应结束后加水，乙酸乙酯萃取， 合并萃取液浓缩后制得4.51g化合物1。收率为78.0％。其中，化合物9和二甲基甲酰胺的反应摩尔比为1∶2。 5.0 g of the compound 9 was mixed with 4.06 g of dimethylformamide, and reacted at 30 ° C for 2 h. After the reaction was completed, water was added, and ethyl acetate was extracted.           The combined extracts were concentrated to give 4.51 g of Compound 1. The yield was 78.0%. Among them, the reaction molar ratio of the compound 9 to the dimethylformamide was 1:2.                 
化合物1，即4-甲酰基-3-羟基苯乙酸乙酯的核磁数据如下： The nuclear magnetic data of Compound 1, 4-methylformyl-3-hydroxyphenylacetate, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，11.040(s，1H)，9.869(s，1H)，7.525(s，1H)，6.960(s.
Figure PCTCN2014000458-appb-000015
6.948(s，1H)，4.177(q，2H)，3.631(s，2H)，1.264(t，3H)。核磁图如图1所示。 1H NMR (CDCl3, 500 Hz, δ: ppm), 11.040 (s, 1H), 9.869 (s, 1H), 7.525 (s, 1H), 6.960 (s.
Figure PCTCN2014000458-appb-000015
6.948 (s, 1H), 4.177 (q, 2H), 3.631 (s, 2H), 1.264 (t, 3H). The nuclear magnetic map is shown in Figure 1.
(III)氧化反应 (III) Oxidation reaction                 
将2.5g的化合物1与13.93g的氧化银混合，室温反应3h，反应结束后用盐酸酸化，乙酸乙酯萃取， 合并萃取液浓缩后制得2.35g化合物2。收率为87.3％。其中化合物1和氧化银的反应摩尔比为1∶5。 2.5 g of compound 1 was mixed with 13.93 g of silver oxide, and reacted at room temperature for 3 hours. After the reaction was completed, it was acidified with hydrochloric acid and extracted with ethyl acetate.           The combined extracts were concentrated to give 2.35 g of Compound 2. The yield was 87.3%. Wherein the reaction molar ratio of the compound 1 to the silver oxide is 1:5.                 
(IV)酯化醚化反应 (IV) esterification etherification reaction                 
将1.3g的化合物2、2.53g的溴乙烷和1.18g的乙醇钠混合，回流4h，反应结束后加水，乙醚萃取， 合并萃取液浓缩后制得1.46g化合物3。收率为90％。其中化合物2、溴乙烷和乙醇钠的反应摩尔比为1∶4∶3。 1.3 g of the compound 2, 2.53 g of ethyl bromide and 1.18 g of sodium ethoxide were mixed and refluxed for 4 h. After the reaction was completed, water was added and the mixture was extracted with diethyl ether.           The combined extracts were concentrated to give 1.46 g of Compound 3. The yield was 90%. The reaction molar ratio of the compound 2, ethyl bromide and sodium ethoxide is 1:4:3.                 
化合物3，即3-乙氧基-4-乙氧羰基苯乙酸乙酯的核磁数据如下： The nuclear magnetic data of Compound 3, ethyl 3-ethoxy-4-ethoxycarbonylphenylacetate, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.742(s，1H)，6.898(s，1H)，6.883(s，1H)，4.350(q，2H)， 4.455(q，2H)，4.119(q，2H)，3.604(s，2H)，1.452(t，3H)，1.368(t，3H)，1.243(t，3H)。核 磁图如图2所示。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.742 (s, 1H), 6.988 (s, 1H), 6.883 (s, 1H), 4.350 (q, 2H),           4.455 (q, 2H), 4.119 (q, 2H), 3.604 (s, 2H), 1.452 (t, 3H), 1.368 (t, 3H), 1.243 (t, 3H). nuclear           The magnetic map is shown in Figure 2.                 
(V)水解反应 (V) hydrolysis reaction                 
将31.2ml的无水乙醇、3.0g的化合物3与0.86g的氢氧化钠混合，室温反应1h，反应结束后加水， 二氯甲烷萃取，合并萃取液浓缩后制得2.40g化合物4。收率为89.0％。其中，化合物(3)与氢氧化钠的 反应摩尔比为1∶2。 31.2 ml of absolute ethanol, 3.0 g of compound 3 and 0.86 g of sodium hydroxide were mixed, and reacted at room temperature for 1 hour, and water was added after the reaction was completed.           Extraction with dichloromethane and concentration of the combined extracts gave 2.40 g of Compound 4. The yield was 89.0%. Among them, the compound (3) and sodium hydroxide           The reaction molar ratio was 1:2.                 
化合物4，即3-乙氧基-4-乙氧羰基苯乙酸的核磁数据如下： The nuclear magnetic data of Compound 4, 3-ethoxy-4-ethoxycarbonylphenylacetic acid, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.751(s，1H)，6.890(s，1H)，6.879(s，1H)，4.352(q，2H)， 4.112(q，2H)，3.650(s，2H)，1.449(t，3H)，1.367(t，3H)。核磁图如图3所示。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.751 (s, 1H), 6.890 (s, 1H), 6.879 (s, 1H), 4.352 (q, 2H),           4.112 (q, 2H), 3.650 (s, 2H), 1.449 (t, 3H), 1.367 (t, 3H). The nuclear magnetic map is shown in Figure 3.                 
途径一(b)： Path 1 (b):                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f10
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f10
以化合物11为原料，首先经过甲酰化反应合成4-甲酰基-3-羟基苯乙酸即化合物7，后经过酯化反应 合成化合物1，后经过氧化反应合成化合物2，再经过酯化醚化反应合成化合物3，最后经过水解反应制得 化合物4。 Using compound 11 as a raw material, firstly, 4-formyl-3-hydroxyphenylacetic acid, compound 7, is synthesized by formylation reaction, followed by esterification reaction.           Compound 1 is synthesized, and then compound 2 is synthesized by oxidation reaction, and then compound 3 is synthesized by esterification etherification reaction, and finally obtained by hydrolysis reaction.           Compound 4.                 
具体制备过程为： The specific preparation process is:                 
(I)甲酰化反应 (I) formylation reaction                 
将2.8g的化合物11与9.32g的二乙基甲酰胺混合，40℃反应3h，反应结束后加水，乙酸乙酯萃取， 合并萃取液浓缩后制得2.58g化合物7。收率为77.8％。其中，化合物11和二乙基甲酰胺的反应摩尔比为 1∶5。 2.8 g of compound 11 was mixed with 9.32 g of diethylformamide, and reacted at 40 ° C for 3 h. After the reaction was completed, water was added, and ethyl acetate was extracted.           The combined extracts were concentrated to give 2.58 g of Compound 7. The yield was 77.8%. Wherein the reaction molar ratio of the compound 11 and the diethylformamide is           1:5.                 
(II)酯化反应 (II) Esterification reaction                                     
将6.5ml的无水乙醇、2.5g的化合物7和0.07g的浓硫酸混合，回流反应1h，旋蒸陈去乙醇，二氯 甲烷萃取，合并萃取液浓缩后制得2.75g化合物1。收率为95.3％。其中，化合物7和浓硫酸的反应摩尔 比为1∶0.05。 Mix 6.5 ml of absolute ethanol, 2.5 g of compound 7 and 0.07 g of concentrated sulfuric acid, reflux for 1 h, spin-off to remove ethanol, dichloro           Methane extraction and concentration of the combined extracts gave 2.75 g of Compound 1. The yield was 95.3%. Among them, the reaction mole of compound 7 and concentrated sulfuric acid           The ratio is 1:0.05.                 
化合物1，即4-甲酰基-3-羟基苯乙酸乙酯的核磁数据如下： The nuclear magnetic data of Compound 1, 4-methylformyl-3-hydroxyphenylacetate, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，11.042(s，1H)，9.870(s，1H)，7.527(s，1H)，6.963(s，
Figure PCTCN2014000458-appb-000017
6.945(s，1H)，4.179(q，2H)，3.630(s，2H)，1.266(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 11.04 (s, 1H), 9.870 (s, 1H), 7.527 (s, 1H), 6.963 (s,
Figure PCTCN2014000458-appb-000017
6.945 (s, 1H), 4.179 (q, 2H), 3.630 (s, 2H), 1.266 (t, 3H).
(III)氧化反应 (III) Oxidation reaction                 
将3.2g的化合物1与1.57g的过氧化氢混合，室温反应3h，反应结束后用稀硫酸酸化，乙醚萃取， 合并萃取液浓缩后制得3.0g化合物2。收率为87％。其中化合物1和过氧化氢的反应摩尔比为1：3。 3.2 g of compound 1 was mixed with 1.57 g of hydrogen peroxide, and reacted at room temperature for 3 h. After the reaction was completed, it was acidified with dilute sulfuric acid and extracted with diethyl ether.           The combined extracts were concentrated to give 3.0 g of Compound 2. The yield was 87%. Wherein the reaction molar ratio of the compound 1 to hydrogen peroxide is 1:3.                 
(IV)酯化醚化反应 (IV) esterification etherification reaction                 
将2.5g的化合物2、2.43g的溴乙烷和0.76g的乙醇钠混合，回流2h，反应结束后加水，乙醚萃取， 合并萃取液浓缩后制得2.8g化合物3。收率为89.6％。其中化合物2、溴乙烷和乙醇钠的反应摩尔比为1∶2∶1。 2.5 g of the compound 2, 2.43 g of ethyl bromide and 0.76 g of sodium ethoxide were mixed and refluxed for 2 h. After the reaction was completed, water was added and the mixture was extracted with diethyl ether.           The combined extracts were concentrated to give 2.8 g of Compound 3. The yield was 89.6%. The reaction molar ratio of the compound 2, ethyl bromide and sodium ethoxide is 1:2:1.                 
化合物3，即3-乙氧基-4-乙氧羰基苯乙酸乙酯的核磁数据如下： The nuclear magnetic data of Compound 3, ethyl 3-ethoxy-4-ethoxycarbonylphenylacetate, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.744(s，1H)，6.895(s，1H)，6.882(s，1H)，4.336(q，2H)， 4.152(q，2H)，4.123(q，2H)，3.601(s，2H)，1.453(t，3H)，1.365(t，3H)，1.246(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.744 (s, 1H), 6.895 (s, 1H), 6.482 (s, 1H), 4.336 (q, 2H),           4.152 (q, 2H), 4.123 (q, 2H), 3.601 (s, 2H), 1.453 (t, 3H), 1.365 (t, 3H), 1.246 (t, 3H).                 
(V)水解反应 (V) hydrolysis reaction                 
将3.7ml的无水乙醇、1.8g的化合物3与0.36g的氢氧化钾混合，室温反应2h，反应结束后加水， 二氯甲烷萃取，合并萃取液浓缩后制得1.45g3-乙氧基-4-乙氧羰基苯乙酸4。收率为89.2％。其中，化合 物3与氢氧化钾的反应摩尔比为1∶1。 3.7 ml of absolute ethanol, 1.8 g of compound 3 and 0.36 g of potassium hydroxide were mixed and reacted at room temperature for 2 h, and water was added after the reaction was completed.           Dichloromethane extraction and concentration of the combined extracts gave 1.45 g of 3-ethoxy-4-ethoxycarbonylphenylacetic acid. The yield was 89.2%. Among them, the combination           The reaction molar ratio of the product 3 to potassium hydroxide was 1:1.                 
化合物4，即3-乙氧基-4-乙氧羰基苯乙酸的核磁数据如下： The nuclear magnetic data of Compound 4, 3-ethoxy-4-ethoxycarbonylphenylacetic acid, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.749(s，1H)，6.891(s，1H)，6.877(s，1H)，4.350(q，2H)，
Figure PCTCN2014000458-appb-000018
(q，2H)，3.651(s，2H)，1.448(t，3H)，1.366(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.749 (s, 1H), 6.891 (s, 1H), 6.877 (s, 1H), 4.350 (q, 2H),
Figure PCTCN2014000458-appb-000018
(q, 2H), 3.651 (s, 2H), 1.448 (t, 3H), 1.366 (t, 3H).
途径二(a)： Route 2 (a):                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f11
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f11
以化合物11为原料，经过酯化醚化反应合成3-乙氧基苯乙酸乙酯即化合物10，后经过甲酰化反应合 成4-甲酰基-3-乙氧基苯乙酸乙酯即化合物5，后经过氧化反应合成4-乙酰乙酯基-2-乙氧基苯甲酸即化合 物6，再经过酯化反应合成化合物3，最后经过水解反应制得化合物4。 Using compound 11 as a raw material, ethyl 3-ethoxyphenylacetate, compound 10, was synthesized by esterification etherification reaction, and then subjected to formylation reaction.           Ethyl 4-formyl-3-ethoxyphenylacetate, compound 5, is synthesized by oxidation to synthesize 4-acetylethyl ester-2-ethoxybenzoic acid.           Compound 6, compound 3 is synthesized by esterification reaction, and finally compound 4 is obtained by hydrolysis reaction.                 
具体制备过程为： The specific preparation process is:                 
(1)酯化醚化反应 (1) Esterification etherification reaction                 
将3.2g的化合物11、6.88g的溴乙烷和10.33g的醋酸钾混合，回流6h，反应结束后加水，二氯甲烷 萃取，合并萃取液浓缩后制得3.97g化合物10。收率为90.6％。其中化合物11、溴乙烷和酯酸钾的反应摩 尔比为1∶3∶5。 3.2 g of compound 11, 6.88 g of ethyl bromide and 10.33 g of potassium acetate were mixed, refluxed for 6 h, and water was added after completion of the reaction.           After extraction, the combined extracts were concentrated to give 3.97 g of Compound 10. The yield was 90.6%. Among them, the reaction of compound 11, bromoethane and potassium carboxylate           The ratio is 1:3:5.                 
(II)甲酰化反应 (II) formylation reaction                                     
将4.0g的化合物10与11.46g的N-乙基-N-苯基甲酰胺混合，25℃反应6h，反应结束后加水，乙酸 乙酯萃取，合并萃取液浓缩后制得3.55g化合物5。收率为78.3％。其中，化合物10和N-乙基-N-苯基甲 酰胺的反应摩尔比为1∶4。 Mix 4.0g of compound 10 with 11.46g of N-ethyl-N-phenylformamide, react at 25 ° C for 6h, add water after the reaction, acetic acid           The ethyl ester was extracted, and the combined extracts were concentrated to give 3.55 g of Compound 5. The yield was 78.3%. Among them, compound 10 and N-ethyl-N-phenyl group           The reaction molar ratio of the amide was 1:4.                 
(III)氧化反应 (III) Oxidation reaction                 
将4.2g的化合物5与14.24g的三氧化铬混合，室温反应4h，反应结束后用稀盐酸酸化，二氯甲烷萃 取、合并萃取液浓缩后制得3.90g化合物6。收率为86.9％。其中化合物5和三氧化铬的反应摩尔比为1∶8。 4.2g of compound 5 was mixed with 14.24g of chromium trioxide, reacted at room temperature for 4h, and then acidified with dilute hydrochloric acid after completion of the reaction.           The extract was combined and concentrated to give 3.90 g of Compound 6. The yield was 86.9%. Wherein the reaction molar ratio of the compound 5 to the chromium trioxide is 1:8.                 
(IV)酯化反应 (IV) Esterification reaction                 
将8.1ml的无水乙醇、3.5g的化合物6和0.109g的浓硫酸混合，回流反应4h，旋蒸除去乙醇，乙酸 乙酯萃取，合并萃取液浓缩后制得3.73g化合物3。收率为96.0％。其中，化合物6和浓硫酸的反应摩尔 比为1∶0.08。 8.1 ml of absolute ethanol, 3.5 g of compound 6 and 0.109 g of concentrated sulfuric acid were mixed, refluxed for 4 h, and evaporated to remove ethanol, acetic acid.           The ethyl ester was extracted, and the combined extracts were concentrated to give 3.73 g of Compound 3. The yield was 96.0%. Among them, the reaction mole of compound 6 and concentrated sulfuric acid           The ratio is 1:0.08.                 
化合物3，即3-乙氧基-4-乙氧羰基苯乙酸乙酯的核磁数据如下： The nuclear magnetic data of Compound 3, ethyl 3-ethoxy-4-ethoxycarbonylphenylacetate, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.740(s，1H)，6.897(s，1H)，6.884(s，1H)，4.337(q，2H)， 4.154(q，2H)，4.125(q，2H)，3.602(s，2H)，1.450(t，3H)，1.367(t，3H)，1.244(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.740 (s, 1H), 6.879 (s, 1H), 6.084 (s, 1H), 4.337 (q, 2H),           4.154 (q, 2H), 4.125 (q, 2H), 3.602 (s, 2H), 1.450 (t, 3H), 1.367 (t, 3H), 1.244 (t, 3H).                 
(V)水解反应 (V) hydrolysis reaction                 
将15ml的无水乙醇、3.6g的化合物3与1.54g的氢氧化钠混合，室温反应3h，反应结束后加水，二 氯甲烷萃取，合并萃取液浓缩后制得2.87g化合物4 3-乙氧基-4-乙氧羰基苯乙酸。收率为88.5％。其中， 化合物3与氢氧化钠的反应摩尔比为1∶3。 Mix 15ml of absolute ethanol, 3.6g of compound 3 with 1.54g of sodium hydroxide, react at room temperature for 3h, add water after the reaction, two           The methyl chloride extraction and concentration of the combined extracts gave 2.87 g of compound 4 3-ethoxy-4-ethoxycarbonylphenylacetic acid. The yield was 88.5%. among them,           The reaction molar ratio of the compound 3 to sodium hydroxide was 1:3.                 
合物4，即3-乙氧基-4-乙氧羰基苯乙酸的核磁数据如下： The nuclear magnetic data of Compound 4, 3-ethoxy-4-ethoxycarbonylphenylacetic acid, is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.750(s，1H)，6.891(s，1H)，6.877(s，1H)，4.351(q，2H)， 4.110(q，2H)，3.651(s，2H)，1.447(t，3H)，1.366(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.750 (s, 1H), 6.891 (s, 1H), 6.877 (s, 1H), 4.351 (q, 2H),           4.110 (q, 2H), 3.651 (s, 2H), 1.447 (t, 3H), 1.366 (t, 3H).                 
途径二(b)： Path 2 (b):                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f12
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f12
以间羟基苯乙酸11为原料，经过甲酰化反应合成4-甲酰基-3-羟基苯乙酸7，后经过酯化醚化反应合 成4-甲酰基-3-乙氧基苯乙酸乙酯5，后经过氧化反应合成4-乙酰乙酯基-2-乙氧基苯甲酸6，再经过酯化 反应合成3-乙氧基-4-乙氧羰基苯乙酸乙酯3，最后经过水解反应最终制得3-乙氧基-4-乙氧羰基苯乙酸4。 Using m-hydroxyphenylacetic acid 11 as raw material, 4-formyl-3-hydroxyphenylacetic acid 7 was synthesized by formylation reaction, followed by esterification etherification reaction.           4-ethylformyl-3-ethoxyphenylacetate 5, followed by oxidation to synthesize 4-acetylethyl-2- benzobenzoic acid 6, and then esterified           The reaction was carried out to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetate 3, and finally subjected to a hydrolysis reaction to finally obtain 3-ethoxy-4-ethoxycarbonylphenylacetic acid 4.                 
具体制备方法为： The specific preparation method is:                 
(1)甲酰化反应 (1) Formylation reaction                 
将2.9g的化合物11与1.72g的多聚甲醛混合，60℃反应1h，反应结束后加水，乙醚萃取，合并萃取 液浓缩后制得2.7g化合物7。收率为78.5％。其中，化合物11和多聚甲醛的反应摩尔比为1∶3。 2.9 g of compound 11 was mixed with 1.72 g of paraformaldehyde, and reacted at 60 ° C for 1 h. After the reaction was completed, water was added, and the mixture was extracted with diethyl ether.           After the liquid was concentrated, 2.7 g of Compound 7 was obtained. The yield was 78.5%. Among them, the reaction molar ratio of the compound 11 to the paraformaldehyde was 1:3.                 
(II)酯化醚化反应 (II) Esterification etherification reaction                 
将5.0g的化合物7、27.24g的溴乙烷和23.04g的碳酸钾混合，回流6h，反应结束后加水，二氯甲烷 萃取合并萃取液浓缩后制得5.95g化合物5。收率为90.8％。其中化合物7、溴乙烷和碳酸钾的反应摩尔 比为4∶9∶6。 5.0 g of compound 7, 27.24 g of ethyl bromide and 23.04 g of potassium carbonate were mixed and refluxed for 6 h. After completion of the reaction, water was added, dichloromethane.           The extract was combined and concentrated to give 5.95 g of Compound 5. The yield was 90.8%. Among them, the reaction moles of compound 7, ethyl bromide and potassium carbonate           The ratio is 4:9:6.                                     
(III)氧化反应 (III) Oxidation reaction                 
将2.6g的化合物5与6.96g的三氧化二锰混合，室温反应5h，反应结束后用稀硫酸酸化，乙酸乙酯 萃取，合并萃取液浓缩后制得2.4g化合物6。收率为86.9％。其中化合物5和三氧化二锰的反应摩尔比为 1∶1。 2.6 g of compound 5 was mixed with 6.96 g of dimanganese trioxide, reacted at room temperature for 5 h, and acidified with dilute sulfuric acid after completion of the reaction, ethyl acetate           After extraction, the combined extracts were concentrated to give 2.4 g of Compound 6. The yield was 86.9%. Wherein the reaction molar ratio of compound 5 and dimanganese trioxide is           1:1.                 
(IV)酯化反应 (IV) Esterification reaction                 
将14.3ml的无水乙醇、5.6g的化合物6和0.131g的浓硫酸混合，回流反应4h，旋蒸除去乙醇，乙 酸乙酯萃取，合并萃取液浓缩后制得5.97g化合物3。收率为96.0％。其中，化合物6和浓硫酸的反应摩 尔比为1∶0.06。 14.3 ml of absolute ethanol, 5.6 g of compound 6 and 0.131 g of concentrated sulfuric acid were mixed, refluxed for 4 h, and evaporated to remove ethanol.           The acid ethyl ester was extracted, and the combined extracts were concentrated to give 5.97 g of Compound 3. The yield was 96.0%. Among them, the reaction of compound 6 and concentrated sulfuric acid           The ratio is 1:0.06.                 
化合物3的核磁数据如下： The nuclear magnetic data of Compound 3 is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.741(s，1H)，6.899(s，1H)，6.8831(s，1H)，4.333(q， 2H)，4.153(q，2H)，4.125(q，2H)，3.603(s，2H)，1.451(t，3H)，1.366(t，3H)，1.242(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.741 (s, 1H), 6.899 (s, 1H), 6.8831 (s, 1H), 4.33 (q,           2H), 4.153 (q, 2H), 4.125 (q, 2H), 3.603 (s, 2H), 1.451 (t, 3H), 1.366 (t, 3H), 1.242 (t, 3H).                 
(V)水解反应 (V) hydrolysis reaction                 
将12ml的无水乙醇、4.8g的化合物3与1.03g的氢氧化钠混合，室温反应2.5h，反应结束后加水， 二氯甲烷萃取，合并萃取液浓缩后制得3.85g3-乙氧基-4-乙氧羰基苯乙酸4。收率为89.2％。其中，化合 物3与氢氧化钠的反应摩尔比为1∶1.5。 12 ml of absolute ethanol, 4.8 g of compound 3 and 1.03 g of sodium hydroxide were mixed, and reacted at room temperature for 2.5 h. After the reaction, water was added.           Extraction with dichloromethane and concentration of the combined extracts gave 3.85 g of 3-ethoxy-4-ethoxycarbonylphenylacetic acid. The yield was 89.2%. Among them, the combination           The reaction molar ratio of the product 3 to sodium hydroxide was 1:1.5.                 
化合物4的核磁数据如下： The nuclear magnetic data of Compound 4 is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.749(s，1H)，6.892(s，1H)，6.878(s，1H)，4.351(q，2H)， 4.510(q，2H)，3.651(s，2H)，1.446(t，3H)，1.366(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.749 (s, 1H), 6.892 (s, 1H), 6.78 (s, 1H), 4.351 (q, 2H),           4.510 (q, 2H), 3.651 (s, 2H), 1.446 (t, 3H), 1.366 (t, 3H).                 
途径三： Path three:                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-f13
[Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-f13
以间羟基苯乙酸11为原料，首先经过甲酰化反应合成4-甲酰基-3-羟基苯乙酸7，后经过氧化反应合 成4-羧甲基-2-羟基苯甲酸8，再经过酯化醚化反应合成3-乙氧基-4-乙氧羰基苯乙酸乙酯3，最后经过水 解反应最终制得3-乙氧基-4-乙氧羰基苯乙酸4。 Using m-hydroxyphenylacetic acid 11 as a raw material, firstly, 4-formyl-3-hydroxyphenylacetic acid 7 is synthesized by formylation reaction, and then subjected to oxidation reaction.           4-carboxymethyl-2-hydroxybenzoic acid 8 is synthesized, followed by esterification etherification to synthesize 3-ethoxy-4-ethoxycarbonylphenylacetate 3, and finally passed through water.           The reaction was finally carried out to give 3-ethoxy-4-ethoxycarbonylphenylacetic acid 4.                 
具体制备方法为： The specific preparation method is:                 
(I)甲酰化反应 (I) formylation reaction                 
将4.6g的化合物11与12.73g的六亚甲基四胺混合，30℃反应3h，反应结束后加水，乙醚萃取，合 并萃取液浓缩后制得4.25g化合物7。收率为78.1％。其中，化合物11和六亚甲基四按的反应摩尔比为1∶3。 4.6 g of compound 11 was mixed with 12.73 g of hexamethylenetetramine, and reacted at 30 ° C for 3 h. After the reaction was completed, water was added and the mixture was extracted with diethyl ether.           After the extract was concentrated, 4.25 g of Compound 7 was obtained. The yield was 78.1%. Among them, the reaction molar ratio of the compound 11 and the hexamethylenetetrazole was 1:3.                 
(II)氧化反应 (II) Oxidation reaction                 
将3.5g的化合物7与7.04g的次氯酸钾混合，室温反应5h，反应结束后用稀盐酸酸化，二氯甲烷萃 取，合并萃取液浓缩后制得3.3g化合物8。收率为86.6％。其中化合物7和次氯酸钾的反应摩尔比为4∶4。 3.5 g of compound 7 was mixed with 7.04 g of potassium hypochlorite, and reacted at room temperature for 5 h. After the reaction was completed, it was acidified with dilute hydrochloric acid, and dichloromethane was extracted.           The combined extracts were concentrated to give 3.3 g of Compound 8. The yield was 86.6%. Wherein the reaction molar ratio of the compound 7 to potassium hypochlorite is 4:4.                 
(III)酯化醚化反应 (III) Esterification etherification reaction                                     
将4.2g的化合物8、9.34g的溴乙烷和4.63g的甲醇钠混合，回流3h，反应结束后加水，乙酸乙酯萃 取，合并萃取液浓缩后制得5.46g化合物3。收率为91％。其中化合物8、溴乙烷和甲醇钠的反应摩尔比为 1∶4∶4。 4.2g of compound 8, 9.34g of ethyl bromide and 4.63g of sodium methoxide were mixed and refluxed for 3 hours. After the reaction was completed, water was added, and ethyl acetate was added.           The combined extracts were concentrated to give 5.46 g of Compound 3. The yield was 91%. The reaction molar ratio of compound 8, ethyl bromide and sodium methoxide is           1:4:4.                 
化合物3的核磁数据如下： The nuclear magnetic data of Compound 3 is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.742(s，1H)，6.898(s，1H)，6.883(s，1H)，4.335(q，2H)， 4.155(q，2H)，4.126(q，2H)，3.604(s，2H)，1.452(t，3H)，1.368(t，3H)，1.243(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.742 (s, 1H), 6.988 (s, 1H), 6.883 (s, 1H), 4.335 (q, 2H),           4.155 (q, 2H), 4.126 (q, 2H), 3.604 (s, 2H), 1.452 (t, 3H), 1.368 (t, 3H), 1.243 (t, 3H).                 
(IV)水解反应 (IV) hydrolysis reaction                 
将13.8ml的无水乙醇、5.1g的化合物3与1.09g的氢氧化钠混合，室温反应2.5h，反应结束后加水， 二氯甲烷萃取，合并萃取液浓缩后制得4.22g化合物4。收率为92％。其中，化合物3与氢氧化钠的反应 摩尔比为1∶1.5。 13.8 ml of absolute ethanol, 5.1 g of compound 3 and 1.09 g of sodium hydroxide were mixed, and reacted at room temperature for 2.5 h. After the reaction was completed, water was added.           Dichloromethane extraction and concentration of the combined extracts gave 4.22 g of Compound 4. The yield was 92%. Among them, the reaction of compound 3 with sodium hydroxide           The molar ratio is 1:1.5.                 
化合物4的核磁数据如下： The nuclear magnetic data of Compound 4 is as follows:                 
1H NMR(CDCl3，500Hz，δ：ppm)，7.753(s，1H)，6.889(s，1H)，6.878(s，1H)，4.352(q，2H)， 4.110(q，2H)，3.651(s，2H)，1.447(t，3H)，1.366(t，3H)。 1H NMR (CDCl3, 500 Hz, δ: ppm), 7.753 (s, 1H), 6.889 (s, 1H), 6.78 (s, 1H), 4.352 (q, 2H),           4.110 (q, 2H), 3.651 (s, 2H), 1.447 (t, 3H), 1.366 (t, 3H).                 
实施例2-263-乙氧基-4-乙氧羰基苯乙酸的合成方法 Example 2-63-Ethoxy-4-ethoxycarbonylphenylacetic acid synthesis method                 
实施例2-26分别为一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法，与实施例1的合成方法相似，不同 之处仅在于所涉及的技术参数的不同，具体参见表： Examples 2-26 are respectively a method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, which is similar to the synthesis method of Example 1, and is different.           The only difference lies in the technical parameters involved. For details, see the table:                 
途径一(a)中所涉及的技术参数 Technical parameters involved in Route 1 (a)                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t1
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t1
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t2
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t2
本实施例还增加反应I～V的反应投料量至0.5～1.0kg，相应的收率与实施例2-6的收率相近似，为： In this embodiment, the reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the corresponding yield is similar to the yield of the examples 2-6, which is:                 
反应I的收率为87.2～96.2％；反应II的收率为77～78.8％；反应III的收率为86.5～88％；反应IV 的收率为85～92％；反应V的收率为86～92％。 The yield of the reaction I is 87.2 to 96.2%; the yield of the reaction II is 77 to 78.8%; the yield of the reaction III is 86.5 to 88%;           The yield was 85 to 92%; the yield of the reaction V was 86 to 92%.                 
途径一(b)中所涉及的技术参数 Technical parameters involved in pathway one (b)                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t3
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t3
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t4
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t4
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t5
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t5
本实施例还增加反应I～V的反应投料量至0.5～1.0kg，相应的收率与实施例7-11的收率相近似，为： In this embodiment, the reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the corresponding yield is similar to the yield of the examples 7-11, which is:                 
反应I的收率为76～78.9％；反应II的收率为89～97％；反应III的收率为85～88.5％，反应IV的收 率为88～91％；反应V的收率为86～93％。 The yield of the reaction I is 76 to 78.9%; the yield of the reaction II is 89 to 97%; the yield of the reaction III is 85 to 88.5%, and the reaction IV is received.           The yield was 88 to 91%; the yield of the reaction V was 86 to 93%.                 
途径二(a)中所涉及的技术参数 Technical parameters involved in approach 2 (a)                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t6
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t6
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t7
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t7
本实施例还增加反应I～V的反应投料最至0.5～1.0kg，实际收率与实施例12-16的收率相近似，为： In this embodiment, the reaction charge of the reaction I to V is further increased to 0.5 to 1.0 kg, and the actual yield is similar to the yield of the examples 12-16, which is:                 
反应I的收率为87～91.5％；反应II的收率为77～80％；反应III的收率为84～88％；反应IV的收率 为87～97％；反应V的收率为85～91％。 The yield of the reaction I is 87 to 91.5%; the yield of the reaction II is 77 to 80%; the yield of the reaction III is 84 to 88%; the yield of the reaction IV           It is 87 to 97%; the yield of the reaction V is 85 to 91%.                 
途径二(b)中所涉及的技术参数 Technical parameters involved in route 2 (b)                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t8
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t8
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t9
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t9
本实施例还增加反应I～V的反应投料量至0.5～1.0kg，实际收率与实施例17-21的收率相近似，为： In this embodiment, the reaction amount of the reaction I to V is also increased to 0.5 to 1.0 kg, and the actual yield is similar to the yield of the examples 17-21, which is:                                     
反应I的收率为75～79％；反应II的收率为86～92％：反应III的收率为80～88％；反应IV的收率为 88～97％；反应V的收率为88～93％。 The yield of the reaction I is 75 to 79%; the yield of the reaction II is 86 to 92%: the yield of the reaction III is 80 to 88%; the yield of the reaction IV is           88 to 97%; the yield of the reaction V is 88 to 93%.                 
途径三中所涉及的技术参数 Technical parameters involved in Route 3                 
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t10
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t10
[根据细则26改正09.06.2014]　
Figure WO-DOC-FIGURE-t11
 [Correct according to Rule 26 09.06.2014]
Figure WO-DOC-FIGURE-t11
本实施例还增加反应I～IV的反应投料量至0.5～1kg，相应收率与实施例22-26的收率相近似，为： In this embodiment, the reaction amount of the reaction I to IV is also increased to 0.5 to 1 kg, and the corresponding yield is similar to the yield of the examples 22-26, which is:                 
反应I的收率为72～80％：反应II的收率为80～90％；反应III的收率为82～92％；反应IV的收率为89～93％。 The yield of the reaction I is 72 to 80%: the yield of the reaction II is 80 to 90%; the yield of the reaction III is 82 to 92%; and the yield of the reaction IV is 89 to 93%.                 
以上所述，仅是本发明的较佳实施例而已，并非是对本发明所作的其它形式的限定。任何熟悉本专业 的技术人员可能利用上述技术内容作为启示，加以变更或改型为等同变化的等效实施例。但是凡是未脱离 本发明技术方案内容，依据本发明的技术实质对以上实施例所作出的简单修改，等同变化与改型，仍属于 本发明权利要求的保护范围。 The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Anyone familiar with this major           A person skilled in the art may use the above technical content as a revelation, and change or modify it to an equivalent embodiment of equivalent changes. But nothing is left           The content of the technical solution of the present invention, the simple modification, the equivalent change and the modification made by the above embodiments according to the technical essence of the present invention still belong to           The scope of protection of the claims of the present invention.                                     

Claims (10)

  1. [根据细则26改正09.06.2014]　
    一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于它以间羟基苯乙酸即化合物11 为原料，采用以下途径一～三之一合成3-乙氧基-4-乙氧羰基苯乙酸即化合物4：
    ①途径一
    以化合物11为原料，首先合成4-甲酰基-3-羟基苯乙酸乙酯即化合物1，后经过氧化反应合成 4-乙酰乙酯基-2-羟基苯甲酸即化合物2，再经过酯化醚化反应合成3-乙氧基-4-乙氧羰基苯乙酸乙 酯即化合物3，最后经过水解反应最终制得化合物4；
    反应方程式如式I：
    Figure WO-DOC-FIGURE-i

    ②途径二
    以化合物11为原料，首先合成4-甲酰基-3-乙氧基苯乙酸乙酯即化合物5，后经过氧化反应合 成4-乙酰乙酯基-2-乙氧基苯甲酸即化合物6，再经过酯化反应合成化合物3，最后经过水解反应制 得化合物4；
    反应方程式如式II：
    Figure WO-DOC-FIGURE-ii

    ③途径三
    以化合物11为原料，首先经过甲酰化反应合成4-甲酰基-3-羟基苯乙酸即化合物7，后经过氧 化反应合成4-羧甲基-2-羟基苯甲酸即化合物8，再经过酯化醚化反应合成化合物3，最后经过水解 反应制得化合物4；
    反应方程式如式III：
    Figure WO-DOC-FIGURE-iii

    Figure PCTCN2014000458-appb-100004
    [Correct according to Rule 26 09.06.2014]
    A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, which comprises synthesizing 3-ethoxy-4 using m-hydroxyphenylacetic acid as compound 11 and using one of the following routes 1-3. - ethoxycarbonyl phenylacetic acid, compound 4:
    1 Route 1 using compound 11 as a raw material, first synthesizing ethyl 4-formyl-3-hydroxyphenylacetate, compound 1, and then synthesizing 4-acetylethyl-2-hydroxybenzoic acid, compound 2, by oxidation reaction, and then passing through Esterification etherification reaction to synthesize 3-ethoxy-4-ethoxycarbonyl phenyl ethyl acetate, compound 3, and finally hydrolyzed to finally obtain compound 4;
    The reaction equation is as in Formula I:
    Figure WO-DOC-FIGURE-i

    2, route 2, using compound 11 as a raw material, first synthesizing ethyl 4-formyl-3-ethoxyphenylacetate, compound 5, and then synthesizing 4-acetylethyl ester-2-ethoxybenzoic acid as a compound by oxidation reaction 6, after esterification reaction to synthesize compound 3, and finally by hydrolysis reaction to obtain compound 4;
    The reaction equation is as in Equation II:
    Figure WO-DOC-FIGURE-ii

    3, route 3, using compound 11 as a raw material, first synthesizing 4-formyl-3-hydroxyphenylacetic acid, compound 7, by formylation reaction, and then synthesizing 4-carboxymethyl-2-hydroxybenzoic acid, compound 8, by oxidation reaction. Further, compound 3 is synthesized by esterification etherification reaction, and finally, compound 4 is obtained by hydrolysis reaction;
    The reaction equation is as in Equation III:
    Figure WO-DOC-FIGURE-iii

    Figure PCTCN2014000458-appb-100004
  2. [根据细则26改正09.06.2014]　
    根据权利要求1所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于途径一中化合 物1的制备方法为以下式IV或式V所示：
    Figure WO-DOC-FIGURE-iv
    [Correct according to Rule 26 09.06.2014]
    The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 1, wherein the preparation method of the compound 1 in the route 1 is as shown in the following formula IV or formula V:
    Figure WO-DOC-FIGURE-iv
  3. [根据细则26改正09.06.2014]　
    根据权利要求1所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于途径二中化合 物5的制备方法为以下式VI或式VII所示：
    Figure WO-DOC-FIGURE-v
    [Correct according to Rule 26 09.06.2014]
    The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 1, wherein the preparation method of the compound 5 in the route 2 is as shown in the following formula VI or formula VII:
    Figure WO-DOC-FIGURE-v
  4. 根据权利要求1-3中任一项所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所 述途径一、二或三中的氧化反应的过程为： A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to any one of claims 1 to 3, characterized in that              The process of the oxidation reaction in the first, second or third route is:                       
    以化合物1、化合物5或化合物7为原料，以摩尔比1∶2～10与氧化剂混合，室温反应1～5h， 酸化，萃取，除去溶剂，分别按照式I、II、III制得化合物2、化合物6或化合物8。 Compound 1, Compound 5 or Compound 7 is used as a raw material, mixed with an oxidizing agent at a molar ratio of 1:2 to 10, and reacted at room temperature for 1 to 5 hours.              Acidification, extraction, removal of solvent, compound 2, compound 6 or compound 8 are prepared according to formula I, II, III, respectively.                       
  5. 根据权利要求4所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所述氧化剂为 氧化银、硝酸银、叔丁基过氧化氢、过氧化氢、三氧化铬、铬酸、重铬酸钠、重铬酸钾、重铬酸吡 啶、氯铬酸吡啶、次卤酸钠、次卤酸钾、三氧化二锰、活性二氧化锰中的一种。 The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 4, wherein the oxidizing agent is              Silver oxide, silver nitrate, t-butyl hydroperoxide, hydrogen peroxide, chromium trioxide, chromic acid, sodium dichromate, potassium dichromate, pyridinium dichromate              One of pyridine, chlorochromate pyridine, sodium hypohalite, potassium hypohalite, dimanganese trioxide, and active manganese dioxide.                       
  6. 根据权利要求1-3中任一项所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所 述途径一、二或三中的甲酰化反应的过程为： A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to any one of claims 1 to 3, characterized in that              The process of the formylation reaction in the first, second or third route is:                       
    以化合物9、化合物10或化合物11为原料，以摩尔比1∶1～8与甲酰化试剂混合，25～60℃反 应1～6h，加水，萃取，除去溶剂，分别按照式1、式II、式lII制得化合物1、化合物5或化合物 7。 Compound 9, Compound 10 or Compound 11 is used as a raw material, mixed with a formylating reagent at a molar ratio of 1:1 to 8, and reacted at 25 to 60 ° C.              After 1 to 6 hours, add water, extract, remove the solvent, and obtain compound 1, compound 5 or compound according to formula 1, formula II, and formula III, respectively.              7.                       
  7. 根据权利要求6所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所述甲酰化试 剂为二甲基甲酰胺、二乙基甲酰胺、二异丙基甲酰胺、二丁基甲酰胺、六业甲基四胺、N-甲基-N-苯 基甲酰胺、N-乙基-N-苯基甲酰胺、多聚甲醛、氯仿、二氯甲基甲醚、二氯甲基乙醚、二氯甲基丁醚 中的一种。 The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 6, characterized in that the formylation test              The agent is dimethylformamide, diethylformamide, diisopropylformamide, dibutylformamide, hexamethyltetramine, N-methyl-N-benzene                                        Carboxamide, N-ethyl-N-phenylformamide, paraformaldehyde, chloroform, dichloromethyl methyl ether, dichloromethyl ether, dichloromethylbutyl ether              One of them.                       
  8. 根据权利要求1-3中任一项所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于 A method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to any one of claims 1 to 3, characterized in that                       
    ①所述途径一或途径二中的酯化醚化反应的过程为： 1 The process of the esterification etherification reaction in Route 1 or Route 2 is:                       
    以化合物2、化合物7或化合物11为原料，以摩尔比1∶2～9∶1～6与溴乙烷、碱性试剂混合， 回流2～7h，加水，萃取，除去溶剂，分别按照式I、II制得化合物3、化合物5或化合物10； Compound 2, compound 7 or compound 11 is used as a raw material, and is mixed with ethyl bromide and an alkaline reagent at a molar ratio of 1:2 to 9:1 to 6.              After refluxing for 2-7 h, adding water, extracting, removing the solvent, respectively preparing compound 3, compound 5 or compound 10 according to formula I, II;                       
    ②途径三中的酯化醚化反应的过程为： The process of the esterification etherification reaction in Route 3 is:                       
    摩尔比为1∶3～9∶3～6的化合物8、溴乙烷、碱性试剂混合，回流2～7h，加水，萃取，除去溶 剂，按照式III制得化合物3；其中，碱性试剂为醋酸钾、醋酸钠、甲醇钠、碳酸钠、碳酸钾、乙醇 钠、乙醇钾中的一种。 Compound 8 with a molar ratio of 1:3 to 9:3-6, mixed with ethyl bromide and an alkaline reagent, refluxed for 2 to 7 hours, added with water, extracted, and dissolved.              Compound 3 is prepared according to formula III; wherein the alkaline reagent is potassium acetate, sodium acetate, sodium methoxide, sodium carbonate, potassium carbonate, ethanol              One of sodium and potassium ethoxide.                       
  9. 根据权利要求1所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所述的途径一 或二中的酯化反应的过程为： The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 1, characterized in that the route one is              The process of the esterification reaction in or two is:                       
    以化合物6、化合物7或化合物11为原料，与无水乙醇、浓硫酸混合，回流1～4h后除去乙醇， 萃取，除去溶剂，分别按照式I、II制得化合物1、化合物3或化合物9；其中原料和浓硫酸的摩尔 比为1∶0.05～1。 Compound 6, compound 7 or compound 11 is used as a raw material, mixed with anhydrous ethanol and concentrated sulfuric acid, and refluxed for 1 to 4 hours to remove ethanol.              Extracting, removing the solvent, respectively preparing the compound 1, the compound 3 or the compound 9 according to the formula I, II; wherein the starting material and the molar of concentrated sulfuric acid              The ratio is 1:0.05 to 1.                       
  10. 根据权利要求1所述的3-乙氧基-4-乙氧羰基苯乙酸的合成方法，其特征在于所述途径一、 二或三中的水解反应的过程为： The method for synthesizing 3-ethoxy-4-ethoxycarbonylphenylacetic acid according to claim 1, characterized in that the route is              The process of hydrolysis in two or three is:                       
    无水乙醇、化合物3、碱性试剂混合，室温反应0.5～3h后加水，萃取，除去溶剂，按照式I、 II、III制得3-乙氧基-4-乙氧羰基苯乙酸(4)；其中， Anhydrous ethanol, compound 3, alkaline reagent are mixed, reacted at room temperature for 0.5 to 3 hours, then added with water, extracted, and the solvent is removed, according to formula I,              2-Ethyl-4-ethoxycarbonylphenylacetic acid (4);                       
    化合物3与碱性试剂的摩尔比为1∶1～3； The molar ratio of the compound 3 to the alkaline agent is 1:1 to 3;                       
    碱性试剂为氢氧化钠或氢氧化钾。 The alkaline reagent is sodium hydroxide or potassium hydroxide.                                                 
PCT/CN2014/000458 2014-03-13 2014-05-04 Method for synthesizing 3-ethoxy-4-ethoxycarbonyl phenylacetic acid WO2015135096A1 (en)

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