Preparation method of 2-chloro-4-methylsulfonyl m-xylene

Abstract

The invention discloses a preparation method of 2-chloro-4-methylsulfonyl m-xylene, the preparation route is as follows: # imgabs0 #, and the definition of R is as defined in the specification. The method is short in synthetic route, high in yield and mild in process condition, and has a relatively good popularization prospect.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing 2-chloro-4-methylsulfonyl-m-xylene. Technical Background

[0002] 2-Chloro-4-methylsulfonyl-m-xylene is an important intermediate of pharmaceutical compounds. The usual synthetic route for the synthesis of this compound is to use 4-bromo-m-xylene as a raw material for sulfonylation reaction. This route overcomes the problem of poor selectivity of the traditional sulfonylation reaction using m-xylene as a raw material by adding bromine to the benzene ring of m-xylene, thereby improving the yield of 2-chloro-4-methylsulfonyl-m-xylene and reducing the synthesis cost. However, this route has the following defects: first, there are many synthetic steps and the route is long; second, there is a by-product of chlorination at the meta-position of the methyl group in the chlorination reaction in the fourth step of the route. Since the product and the by-product are very close in related properties, such as boiling point, it is very difficult to remove the by-product impurities; third, when palladium / carbon is used in the fifth step of the route for catalytic hydrogenation debromination, the synthesis cost is high and there are by-products of dechlorination.

[0003] The conventional route for synthesizing 2-chloro-4-methylsulfonyl-m-xylene in the prior art is as follows:

[0004] Summary of the invention

[0005] Aiming at the defects of the prior art in preparing 2-chloro-4-methylsulfonyl-meta-xylene, such as a long route, many by-products, difficult post-treatment, high preparation cost, harsh process conditions and the like, the present invention provides a method for preparing 2-chloro-4-methylsulfonyl-meta-xylene with a short synthetic route, high yield and mild process conditions.

[0006] In order to achieve the above object, the present invention provides a method for preparing 2-chloro-4-methylsulfonyl-m-xylene, which specifically comprises the following steps:

[0007] Step (1), compound II is subjected to a sulfonylation reaction with a sulfonating agent in the presence of an acidic catalyst to obtain compound III;

[0008] Step (2), compound III is hydrolyzed in the presence of an acidic catalyst to obtain compound V;

[0009] Step (3), compound V is subjected to chlorination reaction with a chlorination agent to obtain compound I;

[0010] Its synthetic route is as follows:

[0011]

[0012] in,

[0013] R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C 1 -C 6 alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl.

[0014] Wherein, the compound of formula II can be prepared by reacting 2-hydroxy-m-xylene and chloroformate in the presence of a base, and its synthesis route is as follows:

[0015]

[0016] wherein R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C 1 -C 6 alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl.

[0017] The beneficial effects of the present invention are:

[0018] 1. The reaction selectivity of the present invention is high, the reaction conditions are mild, the reaction raw materials are easily available, the reaction operation is simple, and it is easy to industrialize.

[0019] 2. The synthesis of compound V of the present invention can be obtained by a one-pot reaction, which reduces the number of operation steps and is more suitable for industrial production.

[0020] 3. Compound V of the present invention is synthesized into compound I through substitution reaction. The synthesis conditions are simple and the reaction is directed synthesis, thus overcoming the defect of the prior art that the chlorination step will produce by-products. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0022] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0023] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0024] In the present invention, halogen means fluorine, chlorine, bromine and iodine.

[0025] The methanesulfonic acid acylate of the present invention refers to one of methanesulfonic acid chloride, methanesulfonic acid bromide or methanesulfonic acid fluoride.

[0026] The term "alkyl" as used herein (and in other groups containing alkyl, e.g. the alkyl part of arylalkyl, the alkyl part of heteroarylalkyl) denotes in each case a straight-chain or branched alkyl group having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and in particular 1 to 3 carbon atoms. 1 -C 4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl). 1 -C 6 Examples of alkyl groups except C 1 -C 4 In addition to the groups mentioned for alkyl, there are n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. 1 -C 10 Examples of alkyl groups except C 1 -C 6 In addition to the groups mentioned for the alkyl group, there are n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, nonyl, decyl, 2-propylheptyl and 3-propylheptyl, but are not limited thereto.

[0027] In the present invention, "aryl" refers to a monocyclic or bicyclic benzene-based aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl, but is not limited thereto.

[0028] "Arylalkyl" refers to a residue in which the aryl portion is attached to the parent structure through an alkyl residue. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl, and the like.

[0029] In the present invention, "heteroaryl" covers: 5 to 10-membered aromatic monocyclic rings, aromatic fused rings, wherein the aromatic monocyclic ring contains one or more (such as 1 to 4, or in some embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining atoms are carbon; aromatic fused rings, which contain one or more (such as 1 to 4, or in some embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms are carbon, and at least one heteroatom is present in the aromatic ring. For example, heteroaryl includes a 5 to 10-membered heterocycloalkyl aromatic ring fused to a 5 to 10-membered cycloalkyl or heterocycloalkyl ring. For the fused, bicyclic heteroaromatic ring system in which only one ring contains one or more heteroatoms, the connection point can be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to (numbering from the attachment position as 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyridazinyl, 3,4-pyridazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzimidazolinyl, indolyl, pyrazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Divalent radicals derived from a monovalent heteroaryl radical whose name ends in "radical" by removing a hydrogen atom from a carbon with a free valence are named by adding "sub" to the name of the corresponding monovalent radical, such as a pyridyl radical with two points of attachment is a pyridylene radical. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, which are defined herein.

[0030] "Heteroaralkyl" refers to a residue in which the heteroaryl portion is attached to the parent structure through an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl, and the like.

[0031] Where a group is said to be optionally substituted, preferably there are 0 to 5 optional substituents, more preferably there are 0 to 3 optional substituents, and even more preferably there are 0, 1 or 2 optional substituents. Where a group is said to be optionally substituted, and where there are more than one substituent for said optional substitution of said group, said more than one substituent may be the same or different.

[0032] The term "optionally substituted" means that the relevant group may be substituted by a substituent or may not be substituted.

[0033] When a group is substituted, the substituent may be an alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester, alkoxy and halogen, etc., but is not limited thereto. For example, when an alkyl is substituted by a halogen, a haloalkyl is formed, but is not limited thereto.

[0034] Useful solvents are, for example, aromatic hydrocarbons, such as nitrotoluene, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, ethylbenzene, chlorobenzene; aliphatic hydrocarbons, such as dichloromethane, dichloroethane, tetrachloroethane, carbon tetrachloride, nitromethane, dichloroethylene; ethers, such as methyl tert-butyl ether, tetrahydrofuran, dioxane, diethyl ether, petroleum ether, other solvents, dimethyl sulfoxide, acetonitrile.

[0035] Suitable bases for this purpose are alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; alkali metal bicarbonates, such as sodium bicarbonate and potassium bicarbonate; alkali metal phosphates, such as sodium phosphate and potassium phosphate; alkali metal hydrogenphosphates, such as sodium hydrogenphosphate and potassium hydrogenphosphate; alkali metal dihydrogenphosphates, such as sodium dihydrogenphosphate and potassium dihydrogenphosphate; nitrogen-containing organic bases, such as triethylamine; metal hydrides and alkoxides, such as sodium hydride, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide.

[0036] The present invention discloses a method for preparing 2-chloro-4-methylsulfonyl-m-xylene, which specifically comprises the following steps:

[0037] Step (1), the compound of formula II is subjected to a sulfonylation reaction with a sulfonating agent in the presence of an acidic catalyst to obtain a compound of formula III;

[0038] Step (2), compound III is hydrolyzed in the presence of an acidic catalyst to obtain compound V;

[0039] Step (3), compound V is chlorinated with a chlorinating agent to obtain compound I

[0040] The preparation route is as follows:

[0041]

[0042] wherein R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C 1 -C 6 alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl.

[0043] Preferably, in the above preparation method, step (1) and step (2) can be carried out by a one-pot reaction, wherein compound II and a sulfonating agent, preferably methanesulfonic anhydride or methanesulfonic acid acylate, are added to an organic solvent, reacted at 0-40°C for 1-5h, water is added and the temperature is raised to 60-100°C for 1-5h, then the mixture is allowed to stand for stratification, and the organic layer is treated to obtain compound V; wherein the organic solvent is preferably one of dichloroethane, carbon tetrachloride, nitrobenzene and nitromethane; preferably, an acidic catalyst is added during the reaction, and the acidic catalyst is preferably one of aluminum chloride, ferric chloride, boron trifluoride, zinc chloride, tin tetrachloride, boric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid; the molar ratio of the compound of formula II to methanesulfonic anhydride or methanesulfonic acid acylate is 1:1-3, preferably 1:1-1.5; the molar ratio of the compound of formula II to the acidic catalyst is 1:0.1-3, preferably 1:0.5-1.5.

[0044] In step (3) of the preparation method, the chlorination reaction of compound V and a chlorination agent is carried out in an organic solvent, wherein the organic solvent is preferably one of dichloromethane, dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ether and petroleum ether, and the chlorination agent is preferably one of phosphorus oxychloride and phosphorus pentachloride. In step (3), the reaction temperature is 0 to 100° C., the reaction time is 0.5 to 3 h, and the molar ratio of compound V to the chlorination agent is 1:0.5 to 3, preferably 1:1 to 1.5.

[0045] The present invention also provides a method for preparing a compound of formula II, which comprises the following steps: 2-hydroxy-meta-xylene and chloroformate react in an organic solvent in the presence of a base to prepare the compound of formula II, the organic solvent is preferably one of dichloromethane, dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ether and petroleum ether, the base is preferably one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydride, triethylamine, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide, the reaction temperature is 0-100°C, the reaction time is 1-5h, and the molar ratio of 2-hydroxy-meta-xylene to chloroformate is 1:1-3, preferably 1:1-1.5.

[0046] Its synthetic route is as follows:

[0047]

[0048] R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C 1 -C 6alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl.

[0049] The present invention is further described below in conjunction with the examples. The raw materials in the examples can be purchased from the market unless otherwise specified, and the percentage content in the examples generally refers to the percentage content by mass. The yield in the examples is calculated according to the following formula.

[0050] Yield = actual mass of target product / theoretical mass of target product × 100%

[0051] Example 1 Synthesis of 2-chloro-4-methylsulfonyl-m-xylene

[0052]

[0053] Take 100 ml of dichloroethane, add 6.11 g of 2-hydroxy-m-xylene, 4.73 g of methyl chloroformate and 2.2 g of sodium hydroxide, react at 25°C for 2 h, add hydrochloric acid after the reaction, take the organic layer and concentrate to obtain 8.83 g of 2,6-dimethyl-phenyl methyl carbonate;

[0054] Take 150 ml of carbon tetrachloride, add 8.83 g of 2,6-dimethylphenylmethyl carbonate, 8.71 g of methanesulfonic anhydride and 4.81 g of methanesulfonic acid, react at 40°C for 1 hour, then add water and heat to 70°C for 1 hour, let stand to separate, take the organic layer, concentrate to remove the solvent, and recrystallize with methanol to obtain 9.43 g of 2-hydroxy-4-methylsulfonyl-m-xylene;

[0055] Take 150 ml of dichloroethane, add 9.43 g of 2-hydroxy-4-methylsulfonyl-m-xylene and 7.67 g of phosphorus oxychloride, react at 70°C for 2 hours, add a large amount of ice water after the reaction, take the organic layer and concentrate to obtain 10.09 g of 2-chloro-4-methylsulfonyl-m-xylene, with a total yield of 92.3%.

[0056] Example 2 Synthesis of 2-chloro-4-methylsulfonyl-m-xylene

[0057]

[0058] Take 150 ml of toluene, add 6.11 g of 2-hydroxy-m-xylene, 5.43 g of ethyl chloroformate and 6.06 g of triethylamine, react at 45 ° C for 1 hour, add hydrochloric acid after the reaction, take the organic layer and concentrate to obtain 9.52 g of 2,6-dimethyl-phenylethyl carbonate;

[0059] Take 200 ml of dichloroethane, add 9.52 g of 2,6-dimethylphenylethyl carbonate, 8.71 g of methanesulfonic anhydride and 4.81 g of methanesulfonic acid, react at 25°C for 2 h, then add water and heat to 80°C to react for 1 h, let stand to separate, take the organic layer, concentrate to remove the solvent, and recrystallize with methanol to obtain 9.23 g of 2-hydroxy-4-methylsulfonyl-m-xylene;

[0060] Take 150 ml of dioxane, add 9.23 g of 2-hydroxy-4-methylsulfonyl-m-xylene and 10.4 g of phosphorus pentachloride, react at 90°C for 1 hour, add a large amount of ice water after the reaction, take the organic layer and concentrate to obtain 9.88 g of 2-chloro-4-methylsulfonyl-m-xylene, with a total yield of 90.4%.

[0061] Example 3 Synthesis of 2-chloro-4-methylsulfonyl-m-xylene

[0062]

[0063] Take 150 ml of acetonitrile, add 6.11 g of 2-hydroxy-m-xylene, 4.73 g of methyl chloroformate and 4.24 g of sodium carbonate, react at 0°C for 3 h, add hydrochloric acid after the reaction, extract with dichloroethane, and concentrate the organic layer to obtain 8.74 g of 2,6-dimethyl-phenyl methyl carbonate;

[0064] Take 200 ml of dichloroethane, add 8.74 g of 2,6-dimethylphenylmethyl carbonate, 8.71 g of methanesulfonic anhydride and 5.29 g of methanesulfonic acid, react at 10°C for 3 h, then add water and heat to 90°C to react for 1 h, let stand to separate, take the organic layer, concentrate to remove the solvent, and recrystallize with methanol to obtain 8.77 g of 2-hydroxy-4-methylsulfonyl-m-xylene;

[0065] Take 150 ml of acetonitrile, add 8.77 g of 2-hydroxy-4-methylsulfonyl-m-xylene and 7.67 g of phosphorus oxychloride, react at 40°C for 2 hours, add a large amount of ice water after the reaction, extract with dichloroethane, and concentrate the organic layer to obtain 9.38 g of 2-chloro-4-methylsulfonyl-m-xylene, with a total yield of 85.8%.

[0066] Example 4 Synthesis of 2-chloro-4-methylsulfonyl-m-xylene

[0067]

[0068] Take 100 ml of tetrahydrofuran, add 6.11 g of 2-hydroxy-m-xylene, 6.43 g of isopropyl chloroformate and 2.74 g of sodium methoxide, react at 60°C for 1 hour, add hydrochloric acid after the reaction, take the organic layer and concentrate to obtain 10.21 g of 2,6-dimethylphenylisopropyl carbonate;

[0069] Take 150 ml of dichloroethane, add 10.21 g of 2,6-dimethylphenylisopropyl carbonate, 8.71 g of methanesulfonic anhydride and 5.72 g of trifluoroacetic acid, react at 30°C for 1 hour, then add water and heat to 70°C for 1 hour, let stand to separate, take the organic layer, concentrate to remove the solvent, and recrystallize with methanol to obtain 9.38 g of 2-hydroxy-4-methylsulfonyl-m-xylene;

[0070] Take 150 ml of toluene, add 9.38 g of 2-hydroxy-4-methylsulfonyl-m-xylene and 7.62 g of phosphorus oxychloride, react at 60°C for 2 hours, add a large amount of ice water after the reaction, take the organic layer and concentrate to obtain 10.04 g of 2-chloro-4-methylsulfonyl-m-xylene, with a total yield of 91.8%.

[0071] Example 5 Synthesis of 2-chloro-4-methylsulfonyl-m-xylene

[0072]

[0073] Take 100 ml of toluene, add 6.11 g of 2-hydroxy-m-xylene, 7.83 g of phenyl chloroformate and 4.25 g of sodium bicarbonate, react at 80°C for 1 hour, add hydrochloric acid after the reaction, take the organic layer and concentrate to obtain 11.87 g of 2,6-dimethylphenyl carbonate;

[0074] Take 150 ml of dichloroethane, add 11.87 g of 2,6-dimethylphenyl carbonate, 8.71 g of methanesulfonic anhydride and 7.50 g of trifluoromethanesulfonic acid, react at 25°C for 3 h, then add water and heat to 60°C to react for 2 h, let stand to separate, take the organic layer, concentrate to remove the solvent, and recrystallize with methanol to obtain 9.40 g of 2-hydroxy-4-methylsulfonyl-m-xylene;

[0075] Take 200 ml of tetrahydrofuran, add 9.40 g of 2-hydroxy-4-methylsulfonyl-m-xylene and 8.43 g of phosphorus oxychloride, react at 50°C for 2 hours, add a large amount of ice water after the reaction, extract with dichloroethane, and concentrate the organic layer to obtain 10.06 g of 2-chloro-4-methylsulfonyl-m-xylene, with a total yield of 92.0%.

[0076] 1H NMR (300MHz, CDCl 3 )δ7.89-7.92(d,1H),δ7.26-7.30(d,1H),δ3.10(s,3H),δ2.78(s,3H),δ2.47(s,3H)

[0077] Example 6 Synthesis of 2-hydroxy-4-methylsulfonyl-m-xylene

[0078]

[0079] Take 200 ml of dichloroethane, add 9.52 g of 2,6-dimethylphenylethyl carbonate, 8.71 g of methanesulfonic anhydride and 6.68 g of aluminum chloride, react at 25°C for 2 hours, then add water and heat to 80°C to react for 1 hour, let stand to separate the layers, take the organic layer, concentrate to remove the solvent, and obtain 7.59 g of 2-hydroxy-4-methylsulfonyl-m-xylene after recrystallization from methanol.

[0080] Example 7 Synthesis of 2-hydroxy-4-methylsulfonyl-m-xylene

[0081]

[0082] Take 200 ml of dichloroethane, add 8.74 g of 2,6-dimethylphenylmethyl carbonate, 8.71 g of methanesulfonic anhydride and 8.94 g of ferric chloride, react at 10°C for 3 hours, then add water and heat to 90°C to react for 1 hour, let stand to separate the layers, take the organic layer, concentrate to remove the solvent, and obtain 7.24 g of 2-hydroxy-4-methylsulfonyl-m-xylene after recrystallization with methanol.

[0083] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that: The steps include: Step (1), the compound of formula II is subjected to a sulfonylation reaction with a sulfonating agent in the presence of an acidic catalyst to obtain a compound of formula III; Step (2), compound III is hydrolyzed in the presence of an acidic catalyst to obtain a compound of formula V; Step (3), compound V is chlorinated with a chlorinating agent to obtain a compound of formula I The preparation route is as follows: Wherein, R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C1-C6 alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl or benzyl.

2. The preparation method according to claim 1, characterized in that Step (1) and step (2) adopt a one-pot reaction, which comprises the steps of reacting compound II and a sulfonating agent in the presence of an acidic catalyst, adding water and heating to hydrolyze the compound V after the reaction, wherein the reaction temperature of compound II and the sulfonating agent in the presence of an acidic catalyst is 0 to 40° C., the reaction time is 1 to 5 hours, and the hydrolysis reaction temperature is 60 to 100° C., and the reaction time is 1 to 5 hours; preferably, step (1) and step (2) are both reacted in the same organic solvent, and the organic solvent is preferably one of dichloroethane, carbon tetrachloride, nitrobenzene and nitromethane.

3. The preparation method according to claim 1 or 2, characterized in that The sulfonating agent is preferably methanesulfonic anhydride or methanesulfonic acid acylate.

4. The preparation method according to claims 1-3, characterized in that: The acidic catalyst in the reaction of step (1) and step (2) is preferably one of aluminum trichloride, ferric trichloride, boron trifluoride, zinc chloride, tin tetrachloride, boric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid; the molar ratio of the compound of formula II to methanesulfonic anhydride or methanesulfonic acid acylate is 1:1-3, preferably 1:1-1.5; the molar ratio of the compound of formula II to the acidic catalyst is 1:0.1-3, preferably 1:0.5-1.

5.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step (3), the chlorination reaction of compound V and a chlorination agent is carried out in an organic solvent, wherein the organic solvent is preferably one of dichloromethane, dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ether and petroleum ether, and the chlorination agent is preferably one of phosphorus oxychloride and phosphorus pentachloride. In step (3), the reaction temperature is 0 to 100° C., the reaction time is 0.5 to 3 h, and the molar ratio of compound V to the chlorination agent is 1:0.5 to 3, preferably 1:1 to 1.

5.

6. The preparation method according to any one of claims 1 to 5, characterized in that: 2-Hydroxy-m-xylene and chloroformate react in an organic solvent in the presence of a base to prepare compound II. Its synthetic route is as follows: R is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, preferably optionally substituted C1-C6 alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, most preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl.

7. The preparation method according to claim 6, characterized in that: The organic solvent is preferably one of dichloromethane, dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ether and petroleum ether; the base is preferably one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydride, triethylamine, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide; the reaction temperature is 0 to 100° C., the reaction time is 1 to 5 hours, and the molar ratio of 2-hydroxy-m-xylene to chloroformate is 1:1 to 3, preferably 1:1 to 1.5.

Images