Synthetic method of fluoroquinolone drug intermediate

Abstract

The present invention provides a fluoroquinolone drug intermediate synthesis method, which comprises: 1) contacting 2, 4-dichloro-5-fluorobenzoyl chloride with a compound represented by a formula I to prepare a compound represented by a formula III, and further reacting to prepare a compound represented by a formula V. The synthesis route is as follows: # imgabs0 # or 2) contacting 2, 4-dichloro-5-fluorobenzoyl chloride with a compound represented by a formula II to prepare a compound represented by a formula V; the synthesis route is as follows: # imgabs 1 #, wherein the definition of substituent groups is as defined in the specification.

Description

Technical Field

[0001] The invention relates to a method for preparing a fluoroquinolone drug intermediate, and in particular to a method for preparing an intermediate of norfloxacin, ciprofloxacin and enrofloxacin. Background Art

[0002] Fluoroquinolones are a class of chemically synthesized antibacterial drugs that have been developing rapidly since their introduction. They have become the first choice for clinical combination therapy due to their broad antibacterial spectrum, strong antibacterial activity, convenient administration, few adverse reactions, and no cross-resistance with other antibiotics. Quinolone drugs have become a hot topic for research and development. Many literatures have reported the synthesis methods of this class of drugs, but they generally have shortcomings such as long steps, low yields, and large amounts of three wastes. Therefore, people have been working tirelessly to seek synthesis methods with simpler operations, higher yields, and more environmentally friendly processes.

[0003] Norfloxacin is a third-generation quinolone antibacterial drug with a broad-spectrum antibacterial effect. Ciprofloxacin is a new generation of quinolone highly active antibacterial drugs developed, which has the characteristics of broad spectrum, high efficiency, and low toxicity and side effects, especially effective against pathogens resistant to multiple antibiotics. Enrofloxacin is a synthetic third-generation quinolone antibacterial drug and a special quinolone antibacterial drug for livestock, poultry and aquatic products. The above three drugs all have broad-spectrum antibacterial activity and strong permeability, have a strong killing effect on Gram-negative bacteria, and also have good antibacterial effects on Gram-positive bacteria and mycoplasmas. Their structural formulas are as follows:

[0004]

[0005] Patent CN104292159A reports that norfloxacin is synthesized by the following method: first synthesizing the main ring carboxylate of fluoroquinolone, and then directly condensing the piperazine to obtain the target product. The synthesis of ciprofloxacin and enrofloxacin is similar, and the reaction is as follows:

[0006]

[0007] Combined with existing literature reports, the synthesis methods of the above fluoroquinolone drugs all involve key intermediates with similar structures. Such intermediates can be represented by the general structural formula V as follows:

[0008]

[0009] Wherein, R is H, alkyl or aromatic, and Y is OR a , SR b , NR c R d ,OSO2R f , Ra , R b , R c , R d , R e is H, an alkyl group or an aromatic group.

[0010] Patent CN104292159A reports that the compound of formula V is prepared by reacting 2,4-dichloro-5-fluorobenzoyl chloride with N,N-dimethylaminoacrylate in the presence of an acid-binding agent, and then reacting the 2,4-dichloro-5-fluorobenzoyl chloride with cyclopropylamine and ethylamine in an organic solvent to undergo an amine exchange reaction.

[0011] The preparation of the compound of formula V involves a key material: N, N-dimethylaminoacrylate. The prior art reports on the preparation method of N, N-dimethylaminoacrylate include: using propargyl alcohol as a raw material for preparation, and the reaction formula is as follows:

[0012]

[0013] (See patent CN103570623A). In the above method, the cost of the raw material propargyl alcohol is high. At the same time, there is a reaction equilibrium relationship in the amine exchange and it involves the recovery of dimethylamine, which increases the industrial production cost.

[0014] There are also reports that methyl methoxyacrylate is used as a raw material to react with amines to prepare the product (see patent JP2013006781A). The above method also has the problems of high raw material costs; and the amine exchange has a reaction equilibrium relationship and involves the recovery of dimethylamine, which increases the industrial production cost.

[0015] 3-Methoxyacrylate and N, N-dimethylacrylate are important intermediates or raw materials in the field of pharmaceutical chemicals. At present, the synthesis method of methyl 3-methoxyacrylate is based on the main raw materials. The main methods are: 1) Vinyl methyl ether / vinyl ethyl ether photochemical dehydrochlorination method: the raw material vinyl methyl ether has a low flash point, few sources, and difficult transportation. Although phosgene can be replaced by diphosgene or triphosgene, the experimental results show that solid phosgene is not effective; 2) Acrylonitrile and methanol method: It is necessary to use precious metal catalysts, which increases the cost of raw materials, is not easy to recycle, and produces heavy metal pollution to the environment; 3) It is reported that methyl propiolate is used as a raw material, and methanol is catalyzed in the presence of a catalyst for addition reaction, and methyl 3-methoxyacrylate is obtained with a yield of 71%. The cost of the starting raw material methyl propiolate is high, which limits large-scale industrial production. Summary of the invention

[0016] In view of the defects of the prior art in synthesizing the compound of formula V and its raw materials, the present invention first discloses a new synthesis route of methoxyacrylate and N,N-dimethylacrylate, so that the synthesis cost of methoxyacrylate and N,N-dimethylacrylate is reduced, and the synthesis cost of the compound of formula V is also reduced.

[0017] Specifically, the present invention first provides a method for preparing a compound of formula I, and the synthetic route thereof is as follows:

[0018]

[0019] wherein X is halogen; wherein R is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0020] The present invention also provides a method for preparing the compound of formula II, and the synthetic route thereof is as follows:

[0021]

[0022] Wherein, X is halogen; Y is OR a , SR b , NR c R d ,OSO2R f ;

[0023] Among them, R, R a , R b , R c , R d , R e is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0024] The present invention also discloses a method for synthesizing a fluoroquinolone drug intermediate of formula V, and the synthesis route thereof is as follows:

[0025] 1) 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula I to obtain a compound of formula III, and the compound of formula III is further reacted to obtain a compound of formula V. The synthetic route is as follows:

[0026]

[0027] or

[0028] 2) 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula II to obtain formula V, and its synthesis route is as follows:

[0029]

[0030] in,

[0031] X is halogen; Y is OR a , SR b , NR c R d ,OSO2R f ;

[0032] R, Ra , R b , R c , R d , R e is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0033] The present invention also particularly provides a compound of the following formula A, Wherein, Z is chlorine or bromine.

[0034] Beneficial Effects

[0035] The route of the present invention has at least the following technical advantages:

[0036] 1) It overcomes the disadvantages of expensive raw materials, complicated reaction balance and recovery of dimethylamine in the prior art of N,N-dimethylaminoacrylate;

[0037] 2) The new route of synthesizing acrylates using dichloropropylene as raw material has lower synthesis cost and more industrial advantages than the propynyl alcohol route.

[0038] 3) The cost of preparing the compound of formula V by the method of the present invention is reduced, the process route is simpler, and the yield is high. DETAILED DESCRIPTION

[0039] 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.

[0040] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0041] 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.

[0042] When the compounds of the present invention are capable of existing in tautomeric forms, the above and below references to

[0043] The compounds described are to be understood as also comprising the corresponding tautomeric forms, even if these are not explicitly mentioned in each case.

[0044] If the compounds of the formula I according to the invention have functional groups which can be ionized, they can also be used in the form of their agriculturally acceptable salts or mixtures thereof.

[0045] The term "alkyl" as used herein (and in other groups containing alkyl, for example the alkyl moiety of an alkoxy group, the moiety of a haloalkyl group, the alkyl moiety of an arylalkyl group) 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, in particular 1 to 3 carbon atoms. Examples of C1-C4-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C1-C6-alkyl radicals are, in addition to the radicals mentioned for C1-C4-alkyl radicals, 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.

[0046] The term "optionally substituted" means that the relevant group may be substituted by a substituent or may not be substituted.

[0047] 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.

[0048] Halogen is usually fluorine, chlorine, bromine or iodine in the present invention, preferably fluorine, bromine or chlorine. Accordingly, this also applies to halogens combined with other structures, such as haloalkyl. Haloalkyl preferably has a chain length of 1 to 6 carbon atoms, more preferably a chain length of 1 to 4 carbon atoms. Haloalkyl examples, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl; preferably fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, difluorochloromethyl and dichlorofluoromethyl.

[0049] In the present invention, "aromatic group" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, especially naphthyl, but not limited thereto. The aryl group may be substituted by an alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester group, etc., but not limited thereto.

[0050] 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 starting at position 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, indolinyl, 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 the carbon with the free valence are named by adding "sub" to the name of the corresponding monovalent radical, e.g., a pyridyl radical having two points of attachment is a pyridylidene radical. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.

[0051] The "cycloalkyl" of the present invention is preferably C3-C8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0052] The present invention first provides a method for preparing a compound of formula I, which comprises the following steps: a compound of formula VI is subjected to oxidation and esterification in an organic solvent to obtain a compound of formula I, and the synthetic route is as follows:

[0053]

[0054] wherein X is halogen; wherein R is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0055] In the preparation method of the compound of formula I, a catalyst is preferably added to the oxidation reaction, wherein the catalyst is a metal catalyst or / and TEMPO (2,2,6,6-tetramethylpiperidinyl oxide) and its derivatives, wherein the metal catalyst is one of the simple substances or salts of copper, nickel, iron, cobalt, vanadium, chromium, manganese, tungsten, osmium, molybdenum, ruthenium, palladium, platinum, silver, potassium, gold, and cerium. The metal catalyst salt is a single metal salt or a salt composed of multiple metals, wherein the single metal salt and the salt composed of multiple metals include salts formed by single metals or multiple metals and anions, wherein the anions include fluoride ions, chloride ions, bromide ions, iodide ions, oxygen ions, sulfide ions, sulfate ions, nitrate ions, molybdate ions, acetate ions, phosphate ions, hydroxide ions, etc., wherein the multiple metal salts include (NH4)3[FeMo6O 24 H6]·7H2O, (TBA)3FeMo6O 18 (OH)6, etc., but not limited thereto. Wherein TBA refers to tetrabutylammonium ion. TEMPO (2,2,6,6-tetramethylpiperidinyl oxide) and its derivatives are exemplified by, but not limited thereto, 4-OH-TEMPO, 4-Methoxy-TEMPO, 4-Carboxy-TEMPO.

[0056] The above-mentioned oxidation reaction is carried out in the presence of an oxidant, and the oxidant is selected from air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sulfuryl chloride, thionyl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, thiourea or urea of ​​hydrogen peroxide, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, peroxyformic acid, peracetic acid, peroxydichloroacetic acid, peroxydifluoro or trifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfonate, nitrous acid, nitrogen dioxide, sodium nitrite; nitric acid, sodium nitrate, ammonium cerium nitrate; substituted and unsubstituted nitrobenzene; meta-chlorobenzoic acid; preferably air and sodium chlorate. The molar ratio of the compound of formula VI to the oxidant is 1:1.0-1.5. The amount of the catalyst is 0.1%-10% of the molar amount of the compound of formula VI. The oxidation reaction temperature is 10°C to 100°C, preferably 30°C to 50°C; the oxidation reaction time is 3-10h, preferably 5-7h.

[0057] In the preparation method of the compound of formula I, the esterification reaction is carried out in the presence of an acid, wherein the acid is selected from one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and a solid superacid, preferably sulfuric acid.

[0058] The oxidation reaction described in the preparation method of the compound of formula I is carried out in a solvent, wherein the solvent is one or two of acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, toluene, cyclohexane and water, preferably DCE and water;

[0059] The present invention also provides a method for preparing a compound of formula II, which specifically comprises the following steps: preparing a compound of formula II by etherification reaction or amination reaction of a compound of formula I, and the synthesis route thereof is as follows:

[0060]

[0061] Wherein, X is halogen; Y is OR a , SR b , NR c R d ,OSO2R f ;

[0062] Among them, R, R a , R b , R c , R d , R e is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0063] During the preparation of the compound of formula II,

[0064] When Y is OR a , SR b or OSO2R f When the compound of formula I and L-OR a , L-SR b or L-OSO2R f The compound of formula II is prepared by etherification reaction. Wherein L is a metal, preferably sodium, potassium or magnesium, and L-ORa is preferably sodium alkyl alcohol or potassium alkyl alcohol, and more preferably one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide and potassium isopropoxide. b It is sodium alkylthiolate or potassium alkylthiolate, and more preferably sodium methylthiolate, sodium ethylthiolate, sodium propylthiolate, potassium methylthiolate, potassium ethylthiolate and potassium propylthiolate. f It is one of sodium methanesulfonate, sodium p-toluenesulfonate and sodium trifluoromethanesulfonate. The compound of formula I and L-OR a , L-SR b or L-OSO2R f During the etherification reaction, compound I reacts with L-OR a , L-SR b or L-OSO2Rf The molar ratio is 1:1.0-1.5.

[0065] When Y is NR c R d When the compound of formula I is subjected to an aminating reaction with an aminating agent to prepare a compound of formula II, the aminating agent is HNR c R d , preferably one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine and cyclopropylamine. The aminating reaction is carried out, and the aminating agent can be an aqueous solution thereof or a salt solution thereof, and the preferred salt solution is a hydrochloride aqueous solution.

[0066] The reaction temperature in the process of preparing the compound of formula II is -10°C to 90°C, preferably 0°C to 70°C; the reaction time is 2-6h, preferably 3-5h.

[0067] The present invention also provides a method for synthesizing a fluoroquinolone drug intermediate of formula V, which comprises the following steps:

[0068] Route 1: 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula I to obtain a compound of formula III, and the compound of formula III is reacted with an aminating agent to obtain a compound of formula V, wherein the aminating agent is HNR c R d ;

[0069] Its synthetic route is as follows:

[0070]

[0071] Route 2) 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula II to obtain a compound of formula V;

[0072] Its synthetic route is as follows:

[0073]

[0074] Wherein, X is halogen; Y is OR a , SR b , NR c R d ,OSO2R f ;

[0075] Among them, R, R a , R b , R c , R d , R e is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0076] In the above route 1), 2,4-dichloro-5-fluorobenzoyl chloride and the compound of formula I are preferably contacted in the presence of an acid binding agent to obtain formula III, wherein the acid binding agent is selected from an organic base or an inorganic base; the organic base is at least one of triethylamine, tri-n-butylamine, pyridine, and morpholine, preferably triethylamine; the inorganic base is one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium hydrogen, preferably sodium carbonate; the molar ratio of the 4-dichloro-5-fluorobenzoyl chloride, the acid binding agent, and the compound of formula I is 1:(1-2.5):(1-1.5), the reaction temperature is -25°C to 150°C, preferably -10°C to 50°C; the reaction time is 2-5h, preferably 1-3h. The reaction is preferably carried out in an organic solvent, which is one or more of DMF, NMP, DMAC, DMI, DMSO, methanol, ethanol, n-butanol, tert-butanol, isopropanol, acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, toluene and cyclohexane.

[0077] In the above route 1), the compound of formula III is reacted with an aminating agent in an organic solvent for amination reaction; the aminating agent is HNRcRd, preferably one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine and cyclopropylamine; the aminating agent can be an aqueous solution or a solution of its salt, and the salt solution is preferably a hydrochloride aqueous solution; the molar ratio of the compound of formula III to the aminating agent is 1:1.0-1.5; the temperature of the amination reaction is -25°C to 130°C, preferably 0°C to 60°C; the reaction time is 1-6h, preferably 3-4h. The organic solvent is one or more of DMF, NMP, DMAC, DMI, DMSO, methanol, ethanol, n-butanol, tert-butanol, isopropanol, acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, toluene, and cyclohexane.

[0078] In the above route 2), 2,4-dichloro-5-fluorobenzoyl chloride and the compound of formula II are reacted with an acid-binding agent to obtain a compound of formula V, wherein the acid-binding agent in the reaction is selected from an organic base or an inorganic base; the organic base is at least one of triethylamine, tri-n-butylamine, pyridine, and morpholine, preferably triethylamine; the inorganic base is one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium hydrogen, preferably sodium carbonate; the molar ratio of 2,4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and the compound of formula II is 1:(1-2.5):(1-1.5). The reaction temperature is -25°C to 150°C, preferably -10°C to 50°C; the reaction time is 2-5h, preferably 1-3h.

[0079] The present invention also provides a compound of formula A, Wherein, Z is chlorine or bromine. The compound of formula A can greatly reduce the synthesis cost of the compound of formula V as an intermediate compound.

[0080] The present invention will be described in detail below by way of examples. In the following examples:

[0081] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0082] The conversion and selectivity of the reaction were calculated by the following formula:

[0083] Yield = actual mass of target product / theoretical mass of target product × 100%

[0084] Unless otherwise specified, all raw materials used were commercially available products.

[0085] Embodiment 1:

[0086] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 93.9 g (1.0 mol, 98%) of 2-chloropropenol, 450 g of ethylene dichloride, and 5 g of TEMPO were added in sequence, and the mixture was kept at 50°C. 424.0 g of a 25% aqueous sodium chlorate solution was added dropwise for 5 h. The reaction of the raw materials was complete after HPLC detection. The mixture was separated by stratification and desolventization to obtain 101.1 g of chloroacrylic acid with a yield of 95.0%.

[0087] The product of the previous step was added with 210 g methanol and 7 g concentrated sulfuric acid, and refluxed for 8 h. HPLC detected that the raw material had reacted completely, and the solvent was removed to obtain 108.8 g methyl chloroacrylate, with a yield of 95.1%;

[0088] Embodiment 2:

[0089] The difference from Example 1 is that sodium hypochlorite is used instead of sodium chlorate, and other molar ratios remain unchanged. The reaction produces 108.6 g of methyl chloroacrylate with a yield of 90.1%.

[0090] Embodiment 3:

[0091] The difference from Example 1 is that sodium chlorite is used instead of sodium chlorate, and other molar ratios remain unchanged. The reaction produces 109.4 g of methyl chloroacrylate with a yield of 90.8%.

[0092] Embodiment 4:

[0093] The difference from Example 1 is that o-nitrotoluene replaces sodium chlorate, TEMPO is omitted, and other molar ratios remain unchanged. The reaction produces 107.3 g of methyl chloroacrylate with a yield of 89.1%.

[0094] Embodiment 5:

[0095] The difference from Example 1 is that hydrogen peroxide replaces sodium chlorate, cuprous iodide replaces TEMPO, and other molar ratios remain unchanged. The reaction produces 103.0 g of methyl chloroacrylate with a yield of 85.5%.

[0096] Embodiment 6:

[0097] The difference from Example 1 is that oxygen replaces sodium chlorate, Fe(NO3)3·9H2O and KCl replace TEMPO, and other molar ratios remain unchanged. The reaction produces 104.4 g of methyl chloroacrylate with a yield of 86.6%.

[0098] Example 7

[0099] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 123.0 g (1.0 mol, 98%) of methyl chloroacrylate and 200 g of methanol were added in sequence, the temperature was kept at 20°C, 189.5 g of 30% sodium methoxide solution was slowly added dropwise, and the mixture was stirred for 3 h. HPLC detected that the raw material reaction was complete, and the solvent was removed to obtain 101.7 g of methyl methoxyacrylate, with a yield of 95.5%;

[0100] Example 8

[0101] The difference from Example 7 is that sodium methylthiolate is used instead of sodium methoxide, and other molar ratios remain unchanged. The reaction produces 122.3 g of methyl meththioacrylate with a yield of 92.5%.

[0102] Example 9

[0103] The difference from Example 7 is that sodium p-toluenesulfonate replaces sodium methoxide, and other molar ratios remain unchanged. The reaction produces 235.8 g of methyl 3-toluenesulfonate acrylate with a yield of 92.0%.

[0104] Example 10

[0105] The difference from Example 7 is that isopropyl chloroacrylate is used instead of methyl chloroacrylate, and other molar ratios remain unchanged. The reaction produces 118.2 g of isopropyl methoxyacrylate with a yield of 82.0%.

[0106] Embodiment 11

[0107] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 123.0 g (1.0 mol, 98%) of methyl chloroacrylate and 150 g of NMP were added in sequence, the temperature was kept at 60°C, 124.0 g of a 40% aqueous solution of dimethylamine was slowly added dropwise, and the mixture was stirred for 3 h. HPLC detected that the reaction of the raw materials was complete, the mixture was washed with water, extracted with EA, and desolventized to obtain 124.4 g of the product N,N-methyl dimethacrylate, with a yield of 96.3%;

[0108] Example 12

[0109] The difference from Example 11 is that cyclopropylamine is used instead of dimethylamine, and other molar ratios remain unchanged. The reaction produces 114.1 g of N-cyclopropyl methyl acrylate with a yield of 80.8%.

[0110] Embodiment 13

[0111] The difference from Example 11 is that 50% ethylamine replaces 40% dimethylamine aqueous solution, and other molar ratios remain unchanged. The reaction produces 116.4 g of compound N-methyl ethacrylate with a yield of 90.1%.

[0112] Embodiment 14

[0113] The difference from Example 11 is that isopropyl chloroacrylate is used instead of methyl chloroacrylate, and the other molar ratios remain unchanged. The reaction produces 138.8 g of compound N,N-isopropyl dimethacrylate with a yield of 88.3%.

[0114] Embodiment 15

[0115] In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 144.6 g of methyl chloroacrylate and 121.2 g of triethylamine were added, the temperature was kept at 50°C, 228.6 g (1.0 mol, 99.5%) of 2,4-dichloro-5-fluorobenzoyl chloride was slowly added dropwise, and the reaction was stirred for 5 hours. HPLC detected that the reaction of the raw materials was complete, toluene and acid water were added, and the layers were extracted. The toluene phase was directly used for the next step; the temperature was kept at 10°C, 65.7 g of cyclopropylamine and 110.0 g of triethylamine were slowly added dropwise, and the reaction was stirred for 3 hours. HPLC detected that the reaction of the raw materials was complete, and the liquid was separated at rest. After desolventizing, 285.7 g of the compound of formula V-1 was obtained with a yield of 86.0%.

[0116]

[0117] Example 16

[0118] The difference from Example 15 is that diethylamine is used instead of cyclopropylamine, and the other molar ratios remain unchanged. The reaction produces 282.7 g of compound of formula V-2 with a yield of 88.3%.

[0119]

[0120] Embodiment 17

[0121] In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 169.4 g of methyl N-cyclopropylacrylate and 121.2 g of triethylamine were added, the temperature was maintained at 50°C, 228.6 g (1.0 mol, 99.5%) of 2,4-dichloro-5-fluorobenzoyl chloride was slowly added dropwise, and the reaction was stirred for 5 hours. HPLC detection showed that the raw material reaction was complete, EA (ethyl acetate) and acid water were added, the liquid was separated at a static state, and the solvent was removed to obtain 298.9 g of the compound of formula V-1 with a yield of 90.0%.

[0122] Embodiment 18

[0123] The difference from Example 17 is that N-ethyl methyl acrylate replaces N-cyclopropyl methyl acrylate, and the other molar ratios remain unchanged. The reaction produces 292.0 g of compound of formula V-2 with a yield of 91.2%.

[0124] 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 method comprises the following steps: the compound of formula VI is subjected to oxidation and esterification in an organic solvent to prepare the compound of formula I. The synthesis route is as follows: wherein X is halogen; and R is H, optionally substituted alkyl, optionally substituted aromatic or optionally substituted heteroaromatic.

2. The method for preparing the compound of formula (I) according to claim 1, characterized in that: The oxidation reaction is an oxidation reaction of the compound of formula VI with an oxidant, wherein the oxidant is selected from air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sodium p-toluenesulfonyl chloride, sulfuryl chloride, thionyl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, thiourea or urea of ​​hydrogen peroxide, hypochlorous acid, sodium hypochlorite, subchloroform The invention relates to one of sodium iodide, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, iodobenzene diacetate, performic acid, peracetic acid, peroxydichloroacetic acid, peroxydifluoroacetic acid, peroxytrifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium permonosulfate, nitrous acid, nitrogen dioxide, sodium nitrite, nitric acid, sodium nitrate, cerium ammonium nitrate, substituted and unsubstituted nitrobenzene and meta-chlorobenzoic acid; preferably, a catalyst is added to the oxidation reaction.

3. The method for preparing the compound of formula I according to claim 1, characterized in that: The esterification reaction is carried out in the presence of an acid, and the acid is selected from one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and a solid superacid.

4. A method for preparing a compound of formula II, which comprises the following steps: etherification reaction or amination reaction of a compound of formula I to prepare a compound of formula II, and the synthetic route is as follows: in, X is halogen; Y is OR a , SR b , NR c R d ,OSO2R f ; Among them, R, R a , R b , R c , R d , R e are each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

5. The method for preparing the compound of formula II according to claim 4, characterized in that: A) When Y is OR a , SR b or OSO2R f When the compound of formula I and L-OR a , L-SR b or L-OSO2R f Etherification reaction is carried out to prepare a compound of formula II, wherein L is a metal, preferably sodium, potassium or magnesium, L-OR a Preferably, it is sodium alkyl alcoholate or potassium alkyl alcoholate, more preferably one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide and potassium isopropoxide; L-SR b Preferably, it is sodium alkylthiolate or potassium alkylthiolate, more preferably one or more of sodium methylthiolate, sodium ethylthiolate, sodium propylthiolate, potassium methylthiolate, potassium ethylthiolate and potassium propylthiolate; L-OSO2R f is one of sodium methanesulfonate, sodium p-toluenesulfonate and sodium trifluoromethanesulfonate; the compound of formula I and L-OR a , L-SR b or L-OSO2R f When the etherification reaction is carried out, the compound of formula I and LO Ra , L-SR b or L-OSO2R f The molar ratio is 1:1.0-1.

5. B) When Y is NR c R d When the compound of formula I is subjected to an aminating reaction with an aminating agent to prepare a compound of formula II, the aminating agent is HNR c R d , where R c , R d Each of them is independently H, an alkyl group or an aromatic group, preferably one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine and cyclopropylamine; and the amination reaction is carried out, and the amination reagent can be an aqueous solution thereof or a salt solution thereof, and the preferred salt solution is a hydrochloride aqueous solution.

6. A method for synthesizing a fluoroquinolone intermediate of formula V, characterized in that: The steps include: Route 1, 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula I to obtain a compound of formula III, and the compound of formula III is further reacted to obtain a compound of formula V; Its synthetic route is as follows: Route 2) 2,4-dichloro-5-fluorobenzoyl chloride is contacted with a compound of formula II to obtain a compound of formula V; Its synthetic route is as follows: Wherein, X is a halogen; Y is OR a , SR b , NR c R d , OSO2R f ; wherein R, Ra, Rb, Rc, Rd, and Re are each independently selected from H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

7. The preparation method of formula V according to claim 6, characterized in that 2,4-dichloro-5-fluorobenzoyl chloride and the compound of formula I are preferably contacted in the presence of an acid-binding agent to obtain formula III, wherein the acid-binding agent is selected from an organic base or an inorganic base; the organic base is at least one of triethylamine, tri-n-butylamine, pyridine, and morpholine; the inorganic base is one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium hydrogen; the molar ratio of the 4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and the compound of formula I is 1:(1-2.5 ): (1-1.5), the reaction temperature is -25°C to 150°C, preferably -10°C to 50°C; the reaction time is 2-5h, preferably 1-3h; preferably, the reaction is carried out in an organic solvent, the organic solvent is one or more of DMF, NMP, DMAC, DMI, DMSO, methanol, ethanol, n-butanol, tert-butanol, isopropanol, acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, toluene, and cyclohexane.

8. The preparation method of formula V according to claim 6, characterized in that When Y is NRcRd, the compound of formula I is subjected to an aminating reaction with an aminating agent to prepare a compound of formula V, wherein the aminating agent is HNRcRd, wherein Rc and Rd are independently selected from H, an optionally substituted alkyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group, preferably one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine and cyclopropylamine; preferably, during the aminating reaction, the aminating agent can be an aqueous solution thereof or a salt solution thereof, and the preferred salt solution is a hydrochloride aqueous solution. The molar ratio of the compound of formula III to the aminating agent is 1:1.0-1.5; the temperature of the aminating reaction is -25°C to 130°C, preferably 0°C to 60°C; the reaction time is 1-6h, preferably 3-4h. The organic solvent is one or more of DMF, NMP, DMAC, DMI, DMSO, methanol, ethanol, n-butanol, tert-butanol, isopropanol, acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, toluene, cyclohexane and water.

9. The preparation method of formula V according to claim 6, characterized in that 2,4-dichloro-5-fluorobenzoyl chloride and a compound of formula II are reacted with an acid-binding agent to prepare a compound of formula V, wherein the acid-binding agent in the reaction is selected from an organic base or an inorganic base; the organic base is at least one of triethylamine, tri-n-butylamine, pyridine, and morpholine; the inorganic base is one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium hydrogen, preferably sodium carbonate; the molar ratio of 2,4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and the compound of formula II is 1:(1-2.5):(1-1.5).

10. A compound of formula A, in, Z is chlorine or bromine.

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