WO2024088279A1 - Preparation method for topramezone intermediate - Google Patents

Preparation method for topramezone intermediate Download PDF

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WO2024088279A1
WO2024088279A1 PCT/CN2023/126314 CN2023126314W WO2024088279A1 WO 2024088279 A1 WO2024088279 A1 WO 2024088279A1 CN 2023126314 W CN2023126314 W CN 2023126314W WO 2024088279 A1 WO2024088279 A1 WO 2024088279A1
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compound
formula
sodium
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preparing
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刘彬龙
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帕潘纳(北京)科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • 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
    • 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
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention relates to the field of pesticide synthesis, and in particular to a method for preparing a 4-methylthio-3-aldehyde-2-methylbenzoate compound which is an intermediate of a fenpyroxene compound.
  • Topramezone is a benzoyl pyrazolone herbicide first developed by BASF. It belongs to the class of hydroxyphenylpyruvate dioxidase (HPPD) inhibitors. Its English common name is topramezone, its Chinese name is topramezone or benpyrazoline, and its trade name is CampusR or "Baowei”. It can effectively control annual grass weeds and broadleaf weeds in corn fields and is safe for corn. However, its scope of use has gradually expanded to crops such as rice and sugarcane, and it can be safely used in combination with other pesticides.
  • HPPD hydroxyphenylpyruvate dioxidase
  • topramezone In 2018, the global topramezone market size was approximately US$109 million, and the total amount of technical application was approximately 269.35 tons, of which the market share for corn was as high as 65.55%, and other crops accounted for approximately 34.45%. Topramezone has broad market prospects due to its excellent efficacy, but its extremely difficult synthesis process makes it expensive and thus limits its widespread promotion and use.
  • the bromination step in this route has low selectivity, which makes separation and purification after the reaction difficult;
  • n-butyl lithium is used to react under ultra-low temperature conditions of -100 to -60°C, which makes industrial production difficult;
  • Hydroxylamine has a dual-reactive functional group, which inevitably produces a large amount of impurities.
  • the compound is used as an intermediate compound to prepare benzathone, which can overcome the defects in the process for synthesizing benzathone in the prior art.
  • the new process conditions for synthesizing benzathone are mild and environmentally friendly, so that the synthesized benzathone has a higher yield, which reduces the synthesis cost of benzathone and will be beneficial to the promotion and use of benzathone.
  • the invention provides a method for preparing a 4-methylthio-3-aldehyde-2-methylbenzoate compound which is a fenpyroxil intermediate.
  • the present invention provides a formula V: A method for synthesizing a compound, wherein R is an ester group, a carboxylic acid group, an amide group or a cyano group.
  • the present invention adopts the following technical scheme, a method for preparing a compound of formula V, comprising the following reaction steps:
  • Step (1) reacting the compound of formula I with Vilsmeier reagent to obtain a compound of formula II;
  • Step (2) hydrolyzing the compound of formula II prepared in step (1) to obtain a compound of formula III;
  • Step (3) subjecting the compound of formula III prepared in step (2) to a substitution reaction with sodium methyl mercaptan in the presence of a base to obtain a compound of formula IV;
  • Step (4) oxidizing the compound of formula IV prepared in step (3) to obtain a compound of formula V, wherein the structures of formula I, formula II, formula III, formula IV and formula V are as follows: Wherein R is an ester group, a carboxylic acid, an amide or a cyano group, R1 and R2 are independently selected from optionally substituted alkyl groups, preferably optionally substituted C1 - C4 alkyl groups, and X is a halogen, preferably fluorine, chlorine, bromine and iodine.
  • reaction conditions for preparing the compound of formula V in the present invention are mild, the process is green and environmentally friendly, and the use of the compound of formula V to synthesize benzathine can reduce the synthesis cost of benzathine technical.
  • the raw materials used in the synthesis of the compound of formula V of the present invention are easily available, the reaction yield is high, and industrialization is easy.
  • ester group in the present invention refers to -COOR 0 ; wherein R 0 refers to an optionally substituted alkyl group, an optionally substituted aryl group or a heteroaryl group;
  • amide group in the present invention refers to -CONR a R b ; wherein R a and R b are the same or different hydrogen, optionally substituted alkyl, optionally substituted aryl or heteroaryl;
  • the alkyl or alkane in the present invention refers to a straight chain or branched chain alkyl, preferably a C1 - C10 alkyl, specifically, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, more preferably a C1 - C4 alkyl, for example, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl.
  • the aryl group in the present invention is preferably a phenyl group or a naphthyl group.
  • Heteroaryl refers to a five-membered or six-membered ring containing one or more heteroatoms of N, O, or S.
  • pyrrolyl furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinone, indolyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, quinoxalinyl, etc.
  • Cyano refers to -CN.
  • Carboxylic acid refers to -COOH.
  • the substituent is alkyl, halogen, -OH, NO2, -CN, amino.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention provides a method for preparing a compound of formula V, comprising the following reaction steps:
  • Step (1) reacting the compound of formula I with Vilsmeier reagent to obtain a compound of formula II;
  • Step (2) hydrolyzing the compound of formula II prepared in step (1) to obtain a compound of formula III;
  • Step (3) subjecting the compound of formula III prepared in step (2) to a substitution reaction with sodium thiomethoxide under alkaline conditions to obtain a compound of formula IV;
  • Step (4) oxidizing the compound of formula IV prepared in step (3) to obtain a compound of formula V, wherein the structures of formula I, formula II, formula III, formula IV and formula V are as follows:
  • R is an ester group, a carboxylic acid, an amide or a cyano group
  • R1 and R2 are independently selected from an optionally substituted alkyl group, preferably an optionally substituted C1 - C4 alkyl group
  • X is a halogen, preferably fluorine, chlorine, bromine and iodine.
  • reaction formula of step (1) is as follows:
  • the Vilsmeier reagent in the reaction of step (1) is prepared by reacting one of DMF, N,N-diethylformamide, N-methyl-N-ethylformamide with one of phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, and oxalyl chloride.
  • the reaction temperature is 0-100°C, preferably 10-60°C.
  • reaction formula of the above reaction step (2) is as follows:
  • step (2) the compound represented by formula II is hydrolyzed to obtain a compound represented by formula III, and the hydrolysis is preferably carried out in the presence of an acid, wherein the acid is an inorganic acid, preferably sulfuric acid, hydrochloric acid, phosphoric acid, and most preferably hydrochloric acid.
  • the hydrolysis reaction is carried out in a solvent, wherein the solvent is one or more of an organic solvent and water, and the organic solvent is a halogenated alkane, preferably one of dichloromethane and dichloroethane.
  • reaction formula of step (3) is as follows: The compound of formula III undergoes a substitution reaction with sodium thiomethoxide in the presence of a base to obtain the compound of formula IV.
  • the base described in the above reaction is an organic base or an inorganic base;
  • the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate;
  • the organic base is preferably one or more of sodium methoxide, sodium ethoxide, sodium acetate, ammonium acetate; more preferably one or more of sodium bicarbonate, sodium acetate, and ammonium acetate.
  • the above reaction is carried out in a non-protonic polar solvent
  • the non-polar solvent is preferably any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dioxane, and most preferably any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, and acetonitrile.
  • the molar ratio of the compound of formula III, the base, and sodium methyl mercaptan is 1:0.1-2:1-4, preferably Choose 1:0.1-0.5:1-3.
  • the reaction formula of step (4) is as follows:
  • the compound of formula IV is oxidized by an oxidant to obtain a compound of formula V.
  • the oxidant used in the reaction is one of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride and sulfur trioxide, preferably one of hydrogen peroxide, thionyl chloride and sulfur powder; wherein the molar ratio of the compound of formula IV to the oxidant is 1:0.1-5, preferably 1:1-2; and the reaction temperature of the above reaction is 10-50°C.
  • Conversion rate (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input ⁇ 100%
  • Selectivity actual molar amount of target product / theoretical molar amount of target product ⁇ 100%
  • the method for preparing 4-methylthio-3-aldehyde-2-methylbenzoate compounds according to the present invention can achieve higher reaction conversion rate and selectivity, and the cost is greatly reduced.

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Abstract

Disclosed in the present invention is a synthesis method for a 4-methylthio-3-aldehyde-2-methylbenzoate topramezone intermediate represented by general formula V. The reaction synthesis route thereof is as follows: R is an ester, carboxylic acid, amide or cyano group, R1 and R2 are independently selected from alkyls, preferably C1-C4 alkyls, and X is a halogen, preferably fluorine, chlorine, bromine and iodine. The preparation method provided in the present invention has good reaction selectivity in each step and high yield, and effectively solves technical problems in the synthesis of some other topramezone intermediates. The entire process route can easily achieve industrialization.

Description

一种苯唑草酮中间体的制备方法A preparation method of fenpyrazone intermediate 技术领域Technical Field
本发明涉及农药合成领域，特别是涉及一种用于制备苯唑草酮化合物中间体4-甲硫基-3-醛基-2-甲基苯甲酸酯类化合物的制备方法。The invention relates to the field of pesticide synthesis, and in particular to a method for preparing a 4-methylthio-3-aldehyde-2-methylbenzoate compound which is an intermediate of a fenpyroxene compound.
背景技术Background technique
苯唑草酮是巴斯夫首创研制的苯甲酯吡唑酮类除草剂，属于对羟基苯基丙酮酸酯双氧化酶(HPPD)类抑制剂，其英文通用名称为topramezone，中文名称为苯唑草酮或苯吡唑草酮，商品名为CampusR或“苞卫”。能有效防除玉米地一年生禾本科杂草和阔叶杂草，对玉米安全，但其使用范围也已逐渐扩大至水稻及甘蔗等作物，且与其他农药可安全进行复配使用。2018年全球苯唑草酮市场规模约为1.09亿美元，原药应用总量约为269.35吨，其中用于玉米的市场占比高达65.55％左右，其他作物约占34.45％。苯唑草酮因其优异的药效，具有广阔的市场前景，但是其难度极高的合成工艺使其售价高昂并因此限制了它的广泛推广和使用。Topramezone is a benzoyl pyrazolone herbicide first developed by BASF. It belongs to the class of hydroxyphenylpyruvate dioxidase (HPPD) inhibitors. Its English common name is topramezone, its Chinese name is topramezone or benpyrazoline, and its trade name is CampusR or "Baowei". It can effectively control annual grass weeds and broadleaf weeds in corn fields and is safe for corn. However, its scope of use has gradually expanded to crops such as rice and sugarcane, and it can be safely used in combination with other pesticides. In 2018, the global topramezone market size was approximately US$109 million, and the total amount of technical application was approximately 269.35 tons, of which the market share for corn was as high as 65.55%, and other crops accounted for approximately 34.45%. Topramezone has broad market prospects due to its excellent efficacy, but its extremely difficult synthesis process makes it expensive and thus limits its widespread promotion and use.
目前报道的苯唑草酮的制备工艺主要是以下两条：The two main preparation processes of fenpyroxetine reported so far are as follows:
路线1：
Route 1:
路线2：
Route 2:
其中路线1中化合物(8)的制备(参见专利：US20026469176)需要经过超低温反应构建异噁唑环，同时该路线还用到剧毒的一氧化碳和昂贵的金属钯催化剂，导致成本居高不下。路线2中化合物(7)报道有以下的制备方法：The preparation of compound (8) in route 1 (see patent: US20026469176) requires ultra-low temperature reaction to construct the isoxazole ring. In addition, the route also uses highly toxic carbon monoxide and expensive metal palladium catalyst, resulting in high costs. The following preparation method is reported for compound (7) in route 2:
1)参见专利：US6100421
1) See patent: US6100421
本路线中溴代反应步骤选择性低，导致反应后分离和纯化困难；The bromination step in this route has low selectivity, which makes separation and purification after the reaction difficult;
2)参见专利：CN201410083163
2) See patent: CN201410083163
本路线中起始原料的来源困难，也是参照US20026469176中的方法制备，同时在转变为羧基的过程中用到正丁基锂在-100～-60℃的超低温条件下反应，工业化生产困难；The source of the starting material in this route is difficult, and it is also prepared by referring to the method in US20026469176. At the same time, in the process of converting to carboxyl, n-butyl lithium is used to react under ultra-low temperature conditions of -100 to -60°C, which makes industrial production difficult;
3)参见专利：CN201910517379
3) See patent: CN201910517379
本路线中的起始原料同样来源困难，在羟胺和腈基的反应过程中由于 羟胺有双反应官能团，不可避免的产生大量杂质。The starting materials in this route are also difficult to obtain. Hydroxylamine has a dual-reactive functional group, which inevitably produces a large amount of impurities.
上述工艺路线长，反应条件较为苛刻，反应收率不高，存在大量三废，并且处理难度大。The above process route is long, the reaction conditions are relatively harsh, the reaction yield is not high, there are a lot of three wastes, and it is difficult to handle.
综上，现有方法在制备苯唑草酮中间体化合物时，存在三废量大、成本高、生产环境恶劣等缺点。In summary, the existing methods for preparing fenpyroxetine intermediate compounds have the disadvantages of large amount of three wastes, high cost, and poor production environment.
申请人在CN202210390195.X中披露了化合物：该化合物作为中间体化合物用于制备苯唑草酮可以克服现有技术中合成苯唑草酮工艺中存在的缺陷，新的合成苯唑草酮的工艺条件反应条件温和，绿色环保，使得合成苯唑草酮具有较高的收率，对降低苯唑草酮合成成本，将有利于苯唑草酮的推广和使用。The applicant disclosed the compound in CN202210390195.X: The compound is used as an intermediate compound to prepare benzathone, which can overcome the defects in the process for synthesizing benzathone in the prior art. The new process conditions for synthesizing benzathone are mild and environmentally friendly, so that the synthesized benzathone has a higher yield, which reduces the synthesis cost of benzathone and will be beneficial to the promotion and use of benzathone.
发明内容Summary of the invention
本发明提供一种苯唑草酮中间体4-甲硫基-3-醛基-2-甲基苯甲酸酯类化合物的制备方法。The invention provides a method for preparing a 4-methylthio-3-aldehyde-2-methylbenzoate compound which is a fenpyroxil intermediate.
具体的，本发提供一种式V：化合物的合成方法，其中，R为酯基，羧酸，酰胺或氰基。Specifically, the present invention provides a formula V: A method for synthesizing a compound, wherein R is an ester group, a carboxylic acid group, an amide group or a cyano group.
本发明采用如下技术方案，一种式V化合物的制备方法，包括如下反应步骤：The present invention adopts the following technical scheme, a method for preparing a compound of formula V, comprising the following reaction steps:
步骤(1)、式I化合物与维尔斯迈尔试剂反应，制得式II所示化合物； Step (1), reacting the compound of formula I with Vilsmeier reagent to obtain a compound of formula II;
步骤(2)、将步骤(1)制备得到的式II所示化合物水解得到式III化合物；Step (2), hydrolyzing the compound of formula II prepared in step (1) to obtain a compound of formula III;
步骤(3)、将步骤(2)制备得到的式III化合物在碱存在条件下与甲硫醇钠进行取代反应得到式IV；Step (3), subjecting the compound of formula III prepared in step (2) to a substitution reaction with sodium methyl mercaptan in the presence of a base to obtain a compound of formula IV;
步骤(4)、将步骤(3)制备得到的式IV化合物氧化制得式V化合物，其中，式I、式II、式III、式IV和式V的结构如下： 其中R为酯基，羧酸，酰胺或氰基，R1和R2分别独立的选自任选取代的烷基，优选任选取代的C1-C4烷基，X为卤素，优选氟、氯、溴和碘。Step (4), oxidizing the compound of formula IV prepared in step (3) to obtain a compound of formula V, wherein the structures of formula I, formula II, formula III, formula IV and formula V are as follows: Wherein R is an ester group, a carboxylic acid, an amide or a cyano group, R1 and R2 are independently selected from optionally substituted alkyl groups, preferably optionally substituted C1 - C4 alkyl groups, and X is a halogen, preferably fluorine, chlorine, bromine and iodine.
本发明的有益效果：Beneficial effects of the present invention:
1、本发明制备式V化合物的反应条件温和，工艺绿色环保，使用式V化合物合成苯唑草酮可以降低苯唑草酮原药的合成成本。1. The reaction conditions for preparing the compound of formula V in the present invention are mild, the process is green and environmentally friendly, and the use of the compound of formula V to synthesize benzathine can reduce the synthesis cost of benzathine technical.
2、本发明式V化合物合成过程中的原料易得，反应收率高，易于工业化。2. The raw materials used in the synthesis of the compound of formula V of the present invention are easily available, the reaction yield is high, and industrialization is easy.
具体实施方式 Detailed ways
在下文中，详细地描述本发明的实施例。然而，这些实施例是示范性的，本发明不限于此，且本发明是由权利要求的范围定义。Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the present invention is not limited thereto, and the present invention is defined by the scope of the claims.
如本文中所使用，当未另外提供具体定义时，下列用在说明书和权利要求书中的术语具有如下含义。As used herein, the following terms used in the specification and claims have the following meanings when specific definitions are not otherwise provided.
本发明中的“酯基”是指-COOR0；其中R0指任选取代的烷基，任选取代芳基或杂芳基；The "ester group" in the present invention refers to -COOR 0 ; wherein R 0 refers to an optionally substituted alkyl group, an optionally substituted aryl group or a heteroaryl group;
本发明中的“酰胺基”是指-CONRaRb；其中Ra，Rb为相同或不同的氢，任选取代的烷基，任选取代的芳基或杂芳基；The term "amide group" in the present invention refers to -CONR a R b ; wherein R a and R b are the same or different hydrogen, optionally substituted alkyl, optionally substituted aryl or heteroaryl;
本发明中的烷基或烷烃是指直链或支链烷基，优选C1-C10烷基，具体地例如，甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基及癸基等，更有选C1-C4烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。The alkyl or alkane in the present invention refers to a straight chain or branched chain alkyl, preferably a C1 - C10 alkyl, specifically, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, more preferably a C1 - C4 alkyl, for example, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl.
本发明中的芳基优选为苯基或萘基。The aryl group in the present invention is preferably a phenyl group or a naphthyl group.
杂芳基：指含1个或多个N、O、S杂原子的五元环或六元环。例如吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、噻唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、哒嗪酮基、吲哚基、苯并呋喃基、苯并恶唑基、苯并噻吩基、苯并噻唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑基、苯并吡唑基、喹喔啉基等。Heteroaryl: refers to a five-membered or six-membered ring containing one or more heteroatoms of N, O, or S. For example, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinone, indolyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, quinoxalinyl, etc.
“氰基”指-CN。"Cyano" refers to -CN.
“羧酸”指-COOH。"Carboxylic acid" refers to -COOH.
当基团被取代时，取代基为烷基、卤素、-OH、NO2、-CN、氨基。When the group is substituted, the substituent is alkyl, halogen, -OH, NO2, -CN, amino.
卤素指氟、氯、溴和碘。Halogen refers to fluorine, chlorine, bromine and iodine.
本发明一方面提供一种式V化合物的制备方法，包括如下反应步骤：In one aspect, the present invention provides a method for preparing a compound of formula V, comprising the following reaction steps:
步骤(1)、式I化合物与维尔斯迈尔试剂反应，制得式II所示化合物； Step (1), reacting the compound of formula I with Vilsmeier reagent to obtain a compound of formula II;
步骤(2)、将步骤(1)制备得到的式II所示化合物水解得到式III化合物；Step (2), hydrolyzing the compound of formula II prepared in step (1) to obtain a compound of formula III;
步骤(3)、将步骤(2)制备得到的式III化合物在碱性条件下与甲硫醇钠进行取代反应得到式IV；Step (3), subjecting the compound of formula III prepared in step (2) to a substitution reaction with sodium thiomethoxide under alkaline conditions to obtain a compound of formula IV;
步骤(4)、将步骤(3)制备得到的式IV化合物氧化制得式V化合物，其中，式I、式II、式III、式IV和式V的结构如下： 其中，R为酯基，羧酸，酰胺或氰基，R1和R2分别独立的选自任选取代的烷基，优选任选取代的C1-C4烷基，X为卤素，优选氟、氯、溴和碘。Step (4), oxidizing the compound of formula IV prepared in step (3) to obtain a compound of formula V, wherein the structures of formula I, formula II, formula III, formula IV and formula V are as follows: Wherein, R is an ester group, a carboxylic acid, an amide or a cyano group, R1 and R2 are independently selected from an optionally substituted alkyl group, preferably an optionally substituted C1 - C4 alkyl group, and X is a halogen, preferably fluorine, chlorine, bromine and iodine.
其中，步骤(1)的反应式如下：
Wherein, the reaction formula of step (1) is as follows:
上述步骤(1)反应中所述的维尔斯迈尔试剂为DMF、N,N-二乙基甲酰胺、N-甲基-N-乙基甲酰胺中的一种与三氯氧磷、三溴氧磷、氯化亚砜、草酰氯中的一种反应所制得。反应温度为0-100℃，优选为10-60℃。 The Vilsmeier reagent in the reaction of step (1) is prepared by reacting one of DMF, N,N-diethylformamide, N-methyl-N-ethylformamide with one of phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, and oxalyl chloride. The reaction temperature is 0-100°C, preferably 10-60°C.
其中，上述反应步骤(2)反应式如下：
Wherein, the reaction formula of the above reaction step (2) is as follows:
步骤(2)中式II所示化合物经过水解得到式III化合物，水解优选在酸存在下水解，所述的酸为无机酸，优选硫酸、盐酸、磷酸，最优选为盐酸。水解反应是在溶剂中进行，所述的溶剂为有机溶剂、水中一种或多种，所述的有机溶剂为卤代烷烃，优选二氯甲烷、二氯乙烷中一种。In step (2), the compound represented by formula II is hydrolyzed to obtain a compound represented by formula III, and the hydrolysis is preferably carried out in the presence of an acid, wherein the acid is an inorganic acid, preferably sulfuric acid, hydrochloric acid, phosphoric acid, and most preferably hydrochloric acid. The hydrolysis reaction is carried out in a solvent, wherein the solvent is one or more of an organic solvent and water, and the organic solvent is a halogenated alkane, preferably one of dichloromethane and dichloroethane.
上述反应中，步骤(3)的反应式如下：式III化合物在碱存在条件下与甲硫醇钠进行取代反应得到式IV。In the above reaction, the reaction formula of step (3) is as follows: The compound of formula III undergoes a substitution reaction with sodium thiomethoxide in the presence of a base to obtain the compound of formula IV.
上述反应中所述的碱为有机碱或无机碱；所述的无机碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾一种或多种；所述的有机碱优选甲醇钠、乙醇钠、醋酸钠、醋酸铵一种或多种；更优选为碳酸氢钠、醋酸钠、醋酸铵中一种或多种。上述反应在非质子极性溶剂中进行，所述的非极性溶剂优选六甲基磷酰三胺、二甲亚砜、四氢呋喃、乙腈、N,N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、二氧六环中任意一种或几种组合，最优选为六甲基磷酰三胺、二甲亚砜、乙腈中任意一种或几种组合。其中式III化合物、碱和甲硫醇钠的用量摩尔比为1:0.1-2:1-4，优 选1:0.1-0.5:1-3。The base described in the above reaction is an organic base or an inorganic base; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; the organic base is preferably one or more of sodium methoxide, sodium ethoxide, sodium acetate, ammonium acetate; more preferably one or more of sodium bicarbonate, sodium acetate, and ammonium acetate. The above reaction is carried out in a non-protonic polar solvent, and the non-polar solvent is preferably any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dioxane, and most preferably any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, and acetonitrile. The molar ratio of the compound of formula III, the base, and sodium methyl mercaptan is 1:0.1-2:1-4, preferably Choose 1:0.1-0.5:1-3.
上述反应中，步骤(4)的反应式如下：式IV化合物通过氧化剂氧化制得式V化合物。反应中使用的氧化剂为空气、过氧化氢、次氯酸钠、硫粉、二氧化硫、氯化亚砜、磺酰氯、浓硫酸、二氯化硫和三氧化硫中一种，优选为过氧化氢、氯化亚砜、硫粉中一种；其中，式IV化合物与氧化剂用量的摩尔比为1:0.1-5，优选为1:1-2；上述反应的反应温为10-50℃。In the above reaction, the reaction formula of step (4) is as follows: The compound of formula IV is oxidized by an oxidant to obtain a compound of formula V. The oxidant used in the reaction is one of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride and sulfur trioxide, preferably one of hydrogen peroxide, thionyl chloride and sulfur powder; wherein the molar ratio of the compound of formula IV to the oxidant is 1:0.1-5, preferably 1:1-2; and the reaction temperature of the above reaction is 10-50°C.
以下将通过实施例对本发明进行详细描述。以下实施例中反应物和产物的量通过液相色谱(Agilent HPLC 1260)测得。以下实施例中，反应的转化率和选择性通过以下公式计算：The present invention will be described in detail below through examples. The amounts of reactants and products in the following examples were measured by liquid chromatography (Agilent HPLC 1260). In the following examples, the conversion rate and selectivity of the reaction were calculated by the following formula:
转化率＝(原料投入摩尔量-产物中残留的原料摩尔量)/原料投入摩尔量×100％选择性＝目标产物的实际摩尔量/目标产物的理论摩尔量×100％Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100% Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%
实施例1化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成Example 1 Synthesis of Compound 3-Formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
1.1化合物4-溴-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯的合成
1.1 Synthesis of Compound 4-bromo-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，投入7.3g DMF(0.1mol)，降温至10℃以下，然后缓慢滴加58g三溴氧磷(0.2mol)，滴完后继续搅拌反应1小时，然后升温至20℃缓慢滴加18.2g(0.1mol)哈格曼乙酯，滴加完后保温反应2小时，中控反应完全后，旋蒸除去过量的三溴氧磷和生成的其它溶剂，得到粗产品，收率80％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 7.3 g of DMF (0.1 mol), cool to below 10°C, then slowly drop 58 g of phosphorus oxybromide (0.2 mol), continue stirring and react for 1 hour after the addition is complete, then raise the temperature to 20°C and slowly drop 18.2 g (0.1 mol) of Hageman ethyl ester, keep warm and react for 2 hours after the addition is complete. After the intermediate control reaction is complete, remove excess phosphorus oxybromide and other generated solvents by rotary evaporation to obtain a crude product with a yield of 80%.
1.2化合物4-溴-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
1.2 Synthesis of compound 4-bromo-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入30g化合物4-溴-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯(0.1mol)和100g DCM(二氯甲烷)，加入10g 36.5％的盐酸和50g水室温搅拌2小时，反应结束后静置分层，旋干有机相得到目标化合物4-溴-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯，收率96％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 30 g of the compound 4-bromo-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100 g of DCM (dichloromethane) were added, and then 10 g of 36.5% hydrochloric acid and 50 g of water were added and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was allowed to stand and the layers were separated. The organic phase was dried to obtain the target compound 4-bromo-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester in a yield of 96%.
1.3化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
1.3 Synthesis of compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入27.2g化合物4-溴-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯(0.1mol)和100g六甲基磷酰三胺，再加入8.4g的碳酸氢钠(0.1mol)，室温下缓慢滴加70g 20％的甲硫醇钠溶液(0.2mol)，滴加完保温反应0.5小时，中控反应完全，反应液中加入100g DCM，100g水，萃取分层，旋干有机相，得到目标化合物，收率90％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 27.2g of the compound 4-bromo-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester (0.1mol) and 100g of hexamethylphosphoric triamide, then add 8.4g of sodium bicarbonate (0.1mol), slowly add dropwise 70g of 20% sodium methyl mercaptan solution (0.2mol) at room temperature, keep warm for 0.5 hours, and the reaction is complete. Add 100g of DCM and 100g of water to the reaction solution, extract and separate the layers, spin-dry the organic phase to obtain the target compound with a yield of 90%.
1.4化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成
1.4 Synthesis of compound 3-formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入24g化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯(0.1mol)，200g DCM，室温下缓慢滴加12g氯化亚砜(0.1mol)，滴加结束后升温至40℃反应3小时，取样中控反应完全，得到目标化合物(1H NMR(400MHz,CDCl3)δ＝10.65(s,1H),7.91(d,J＝8.6,1H),7.22(d,J＝8.6,1H),4.38(q,J＝7.1,2H),2.84(s,3H),2.48(s,3H),1.40(t,J＝7.1,3H)，收率92％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 24 g of the compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester (0.1 mol) and 200 g of DCM were added, and 12 g of thionyl chloride (0.1 mol) was slowly added dropwise at room temperature. After the addition was completed, the temperature was raised to 40°C and the reaction was carried out for 3 hours. The reaction was controlled to be complete during sampling to obtain the target compound ( 1 H NMR (400 MHz, CDCl 3 )δ＝10.65(s,1H),7.91(d,J＝8.6,1H),7.22(d,J＝8.6,1H),4.38(q,J＝7.1,2H),2.84(s,3H),2.48(s,3H),1.40(t,J＝7.1,3H), with a yield of 92%.
实施例2化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成Example 2 Synthesis of Compound 3-Formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
2.1化合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯的合成
2.1 Synthesis of Compound 4-Chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，投入7.3g DMF(0.1mol)，降温至10℃以下，然后缓慢滴加26g草酰氯(0.2mol)，滴完后继续搅拌反应0.5小时，然后升温至60℃缓慢滴加18.2g(0.1mol)哈格曼乙酯，滴加完后保温反应2小时，中控反应完全后，得到粗产品，收率79％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 7.3 g of DMF (0.1 mol), cool to below 10°C, then slowly drop 26 g of oxalyl chloride (0.2 mol), continue stirring and react for 0.5 hours after the addition is complete, then raise the temperature to 60°C and slowly drop 18.2 g (0.1 mol) of Hageman ethyl ester, keep warm and react for 2 hours after the addition is complete. After the intermediate control reaction is complete, a crude product is obtained with a yield of 79%.
2.2化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
2.2 Synthesis of compound 4-chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入26g(0.1mol)化合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯和100g DCM，加入10g 36.5％盐酸和50g水室温搅拌2小时，反应结束后静置分层，旋干有机相得到目标化合物，收率96％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 26 g (0.1 mol) of the compound 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic acid ethyl ester and 100 g DCM, add 10 g 36.5% hydrochloric acid and 50 g water and stir at room temperature for 2 hours. After the reaction is completed, let the mixture stand and separate the layers. The organic phase is spin-dried to obtain the target compound with a yield of 96%.
2.3化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
2.3 Synthesis of compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入23g(0.1mol)化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯和100g DMSO，再加入8.2g的醋酸钠(0.1mol)，室温下缓慢滴加70g 20％的甲硫醇钠溶液(0.2mol)，滴加完保温反应0.5小时，中控反应完全，反应液中加入100g DCM，100g水，萃取分层，旋干有机相，得到目标化合物，收率82％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23 g (0.1 mol) of the compound 4-chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 100 g DMSO were added, and then 8.2 g of sodium acetate (0.1 mol) was added, and 70 g of 20% sodium methyl mercaptan solution (0.2 mol) was slowly added dropwise at room temperature. After the addition was completed, the mixture was kept warm for 0.5 hours. When the reaction was complete, 100 g DCM and 100 g water were added to the reaction solution. The layers were extracted and separated, and the organic phase was spin-dried to obtain the target compound with a yield of 82%.
2.4化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成
2.4 Synthesis of compound 3-formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入24g(0.1mol)化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯，200g DCE(二氯乙烷)，室温下缓慢滴加12g(0.1mol)氯化亚砜，滴加结束后升温至40℃反应3小时，取样中控反应完全，得到目标化合物，收率92％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 24 g (0.1 mol) of the compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 200 g DCE (dichloroethane), and slowly add 12 g (0.1 mol) of thionyl chloride at room temperature. After the addition is completed, raise the temperature to 40°C and react for 3 hours. Take samples to control the reaction completion and obtain the target compound with a yield of 92%.
实施例3化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成Example 3 Synthesis of Compound 3-Formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
3.1化合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯的合成
3.1 Synthesis of Compound 4-Chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，投入7.3g DMF(0.1mol)，降温至10℃以下，然后缓慢滴加60g(0.4mol)三氯氧磷，滴完后继续搅拌反应0.5小时，然后升温至60℃缓慢滴加18.2g(0.1mol)哈格曼乙酯，滴加完后保温反应2小时，中控反应完全后，旋蒸除去多余的三氯氧磷，得到粗产品，收率83％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 7.3 g of DMF (0.1 mol), cool to below 10°C, then slowly drop 60 g (0.4 mol) of phosphorus oxychloride, continue stirring and react for 0.5 hour after the addition is complete, then raise the temperature to 60°C and slowly drop 18.2 g (0.1 mol) of Hageman ethyl ester, keep warm and react for 2 hours after the addition is complete. After the intermediate control reaction is complete, remove excess phosphorus oxychloride by rotary evaporation to obtain a crude product with a yield of 83%.
3.2化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
3.2 Synthesis of Compound 4-Chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入26g(0.1mol)化合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯和100g DCM，加入10g 36.5％盐酸和50g水室温搅拌2小时，反应结束后静置分层，旋干有机相得到目标化合物，收率96％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 26 g (0.1 mol) of the compound 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic acid ethyl ester and 100 g DCM, add 10 g 36.5% hydrochloric acid and 50 g water and stir at room temperature for 2 hours. After the reaction is completed, let the mixture stand and separate the layers. The organic phase is spin-dried to obtain the target compound with a yield of 96%.
3.3化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
3.3 Synthesis of compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入23g(0.1mol)化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯和100g乙腈，再加入4.2g(0.05mol)的碳酸氢钠，室温下缓慢滴加70g(0.2mol)20％的甲硫醇钠溶液，滴加完保温反应0.5小时，中控反应完全，反应液中加入100g DCM，100g水，萃取分层，旋干有机相，得到目标化合物，收率90％。 In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 23 g (0.1 mol) of the compound 4-chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 100 g of acetonitrile were added, and then 4.2 g (0.05 mol) of sodium bicarbonate was added, and 70 g (0.2 mol) of 20% sodium methyl mercaptan solution was slowly added dropwise at room temperature. After the addition was completed, the reaction was kept warm for 0.5 hours. The reaction was completed in the intermediate control. 100 g of DCM and 100 g of water were added to the reaction solution, and the layers were extracted and separated. The organic phase was spin-dried to obtain the target compound with a yield of 90%.
3.4化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成
3.4 Synthesis of compound 3-formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入24g(0.1mol)化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯，200g DCE，40℃下缓慢滴加23g(0.2mol)30％的过氧化氢，滴加结束后保温反应2小时，取样中控反应完全，得到目标化合物，收率90％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 24 g (0.1 mol) of the compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 200 g DCE, and slowly add 23 g (0.2 mol) of 30% hydrogen peroxide at 40°C. After the addition is completed, keep the reaction warm for 2 hours. Take a sample to control the reaction completion and obtain the target compound with a yield of 90%.
实施例4化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成Example 4 Synthesis of Compound 3-Formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
4.1化合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯的合成
4.1 Synthesis of Compound 4-Chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，投入7.3g DMF(0.1mol)，降温至10℃以下，然后缓慢滴加60g(0.4mol)三氯氧磷，滴完后继续搅拌反应0.5小时，然后升温至60℃缓慢滴加18.2g(0.1mol)哈格曼乙酯，滴加完后保温反应2小时，中控反应完全后，旋蒸除去多余的三氯氧磷，得到粗产品，收率83％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 7.3 g of DMF (0.1 mol), cool to below 10°C, then slowly drop 60 g (0.4 mol) of phosphorus oxychloride, continue stirring and react for 0.5 hour after the addition is complete, then raise the temperature to 60°C and slowly drop 18.2 g (0.1 mol) of Hageman ethyl ester, keep warm and react for 2 hours after the addition is complete. After the intermediate control reaction is complete, remove excess phosphorus oxychloride by rotary evaporation to obtain a crude product with a yield of 83%.
4.2化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
4.2 Synthesis of Compound 4-Chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入26g(0.1mol)化 合物4-氯-3-((二甲氨基)亚甲基)-2-甲基环六-1,4-二烯-1-甲酸乙酯和100g DCM，加入10g 36.5％盐酸和50g水室温搅拌2小时，反应结束后静置分层，旋干有机相得到目标化合物，收率96％。In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 26 g (0.1 mol) of The product 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexa-1,4-diene-1-carboxylic acid ethyl ester and 100g DCM were added with 10g 36.5% hydrochloric acid and 50g water, and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was allowed to stand and the layers were separated. The organic phase was dried to obtain the target compound with a yield of 96%.
4.3化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯的合成
4.3 Synthesis of Compound 4-Methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic Acid Ethyl Ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入23g(0.1mol)化合物4-氯-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯和100g乙腈，再加入5.3g(0.05mol)的碳酸钠，室温下缓慢滴加70g(0.2mol)20％的甲硫醇钠溶液，滴加完保温反应0.5小时，中控反应完全，反应液中加入100g DCM，100g水，萃取分层，旋干有机相，得到目标化合物，收率84％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23 g (0.1 mol) of the compound 4-chloro-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 100 g of acetonitrile were added, and then 5.3 g (0.05 mol) of sodium carbonate was added, and 70 g (0.2 mol) of 20% sodium methyl mercaptan solution was slowly added dropwise at room temperature. After the addition was completed, the mixture was kept warm for 0.5 hours. When the reaction was complete, 100 g of DCM and 100 g of water were added to the reaction solution. The layers were extracted and separated, and the organic phase was spin-dried to obtain the target compound with a yield of 84%.
4.4化合物3-甲酰基-2-甲基-4-(甲硫基)苯甲酸乙酯的合成
4.4 Synthesis of compound 3-formyl-2-methyl-4-(methylthio)benzoic acid ethyl ester
在装有机械搅拌、温度计、冷凝管的四口瓶中，加入24g(0.1mol)化合物4-甲硫基-3-甲酰基-2-甲基环六-1,3-二烯-1-甲酸乙酯，200g DCE，40℃下缓慢滴加23g(0.2mol)30％的过氧化氢，滴加结束后保温反应2小时，取样中控反应完全，得到目标化合物，收率90％。In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, add 24 g (0.1 mol) of the compound 4-methylthio-3-formyl-2-methylcyclohexa-1,3-diene-1-carboxylic acid ethyl ester and 200 g DCE, and slowly add 23 g (0.2 mol) of 30% hydrogen peroxide at 40°C. After the addition is completed, keep the reaction warm for 2 hours. Take a sample to control the reaction completion and obtain the target compound with a yield of 90%.
根据本发明所述的制备4-甲硫基-3-醛基-2-甲基苯甲酸酯类化合物的方法可以获得较高的反应转化率和选择性。成本大大降低。The method for preparing 4-methylthio-3-aldehyde-2-methylbenzoate compounds according to the present invention can achieve higher reaction conversion rate and selectivity, and the cost is greatly reduced.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。 The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims (7)

  1. 一种式V化合物的制备方法，其特征在于，包括如下反应步骤：A method for preparing a compound of formula V, characterized in that it comprises the following reaction steps:
    步骤(1)、式Ⅰ化合物与维尔斯迈尔试剂反应，制得式II所示化合物；Step (1), reacting the compound of formula I with Vilsmeier reagent to obtain a compound of formula II;
    步骤(2)、将步骤(1)制备得到的式II所示化合物水解得到式III化合物；Step (2), hydrolyzing the compound of formula II prepared in step (1) to obtain a compound of formula III;
    步骤(3)、将步骤(2)制备得到的式III化合物在碱存在条件下与甲硫醇钠进行取代反应得到式IV；Step (3), subjecting the compound of formula III prepared in step (2) to a substitution reaction with sodium methyl mercaptan in the presence of a base to obtain a compound of formula IV;
    步骤(4)、将步骤(3)制备得到的式IV化合物通过氧化剂氧化得到式V化合物，Step (4), oxidizing the compound of formula IV prepared in step (3) with an oxidant to obtain a compound of formula V,
    其中，式I、式II、式III、式IV和式V的结构如下： 其中，R为酯基，羧酸，酰胺基或氰基，R1和R2分别独立的选自烷基，优选C1-C4烷基，X为卤素，优选氟、氯、溴和碘。Wherein, the structures of Formula I, Formula II, Formula III, Formula IV and Formula V are as follows: Wherein, R is an ester group, a carboxylic acid group, an amide group or a cyano group, R1 and R2 are independently selected from alkyl groups, preferably C1 - C4 alkyl groups, and X is a halogen, preferably fluorine, chlorine, bromine and iodine.
  2. 根据权利要求1所述的式V化合物的制备方法，其特征在于，步骤(1)中所述的维尔斯迈尔试剂是由DMF、N,N-二乙基甲酰胺、N-甲基-N-乙基甲酰胺中的一种与三氯氧磷、三溴氧磷、氯化亚砜及草酰氯中的一种制备得到；式Ⅰ化合物与维尔斯迈尔试剂反应温度为0-100℃，优选为10-60℃。The method for preparing a compound of formula V according to claim 1, characterized in that the Vilsmeier reagent described in step (1) is prepared from one of DMF, N,N-diethylformamide, N-methyl-N-ethylformamide and one of phosphorus oxychloride, phosphorus oxybromide, thionyl chloride and oxalyl chloride; the reaction temperature of the compound of formula I and the Vilsmeier reagent is 0-100°C, preferably 10-60°C.
  3. 根据权利要求1所述的式V化合物的制备方法，其特征在于，步骤 (2)中水解优选在酸存在下水解，所述的酸为无机酸，优选硫酸、盐酸、磷酸，最优选为盐酸，水解反应是在溶剂中进行，所述的溶剂为有机溶剂、水中一种或多种，所述的有机溶剂为卤代烷烃，优选二氯甲烷、二氯乙烷中一种。The method for preparing the compound of formula V according to claim 1, characterized in that the steps (2) The hydrolysis is preferably carried out in the presence of an acid, wherein the acid is an inorganic acid, preferably sulfuric acid, hydrochloric acid, phosphoric acid, and most preferably hydrochloric acid. The hydrolysis reaction is carried out in a solvent, wherein the solvent is one or more of an organic solvent and water, wherein the organic solvent is a halogenated alkane, preferably one of dichloromethane and dichloroethane.
  4. 根据权利要求1所述的式V化合物的制备方法，其特征在于，步骤(3)所述的碱为有机碱或无机碱；所述的无机碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾一种或多种；所述的有机碱为甲醇钠、乙醇钠、醋酸钠、醋酸铵一种或多种；优选为碳酸氢钠、醋酸钠、醋酸铵中一种或多种。The method for preparing a compound of formula V according to claim 1, characterized in that the base in step (3) is an organic base or an inorganic base; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; the organic base is one or more of sodium methoxide, sodium ethoxide, sodium acetate, ammonium acetate; preferably one or more of sodium bicarbonate, sodium acetate, and ammonium acetate.
  5. 根据权利要求1所述的式V化合物的制备方法，其特征在于，步骤(3)的反应在非质子极性溶剂中进行，所述非极性溶剂为六甲基磷酰三胺、二甲亚砜、四氢呋喃、乙腈、N,N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、二氧六环中任意一种或几种组合，优选为六甲基磷酰三胺、二甲亚砜、乙腈中任意一种或几种组合。The method for preparing a compound of formula V according to claim 1, characterized in that the reaction in step (3) is carried out in a non-protonic polar solvent, and the non-polar solvent is any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dioxane, preferably any one or a combination of hexamethylphosphoric triamide, dimethyl sulfoxide, and acetonitrile.
  6. 根据权利要求1任一项所述的式V化合物的制备方法，其特征在于，步骤(3)中所述的式III化合物、碱和甲硫醇钠的用量摩尔比为1:0.1-2:1-4，优选1:0.1-0.5:1-3。The method for preparing a compound of formula V according to any one of claim 1, characterized in that the molar ratio of the compound of formula III, the base and the sodium methyl mercaptan in step (3) is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3.
  7. 根据权利要求1任一项所述的式V化合物的制备方法，其特征在于，步骤(4)中所述的氧化剂为空气、过氧化氢、次氯酸钠、硫粉、二氧化硫、氯化亚砜、磺酰氯、浓硫酸、二氯化硫和三氧化硫中一种，优选为过氧化氢、氯化亚砜、硫粉中一种；所述式IV化合物与氧化剂用量的摩尔比为1:0.1-5，优选为1:1-2，反应温为10-50℃。 The method for preparing a compound of formula V according to any one of claim 1, characterized in that the oxidant in step (4) is one of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride and sulfur trioxide, preferably one of hydrogen peroxide, thionyl chloride and sulfur powder; the molar ratio of the compound of formula IV to the oxidant is 1:0.1-5, preferably 1:1-2, and the reaction temperature is 10-50°C.
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JP2003327580A (en) * 2002-05-10 2003-11-19 Kureha Chem Ind Co Ltd 2-(substituted benzoyl)thiazine derivative, method for producing the same and herbicide
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