A method for synthesizing an intermediate of fluoroquinolone drugs

Abstract

This invention provides a method for synthesizing intermediates of fluoroquinolone drugs, comprising the following steps: 1) reacting 2,4-dichloro-5-fluorobenzoyl chloride with a compound of formula I to obtain formula III, and then further reacting to obtain formula V, the synthetic route being as follows: or 2) reacting 2,4-dichloro-5-fluorobenzoyl chloride with a compound of formula II to obtain formula V; the synthetic route being as follows: wherein, the substituents are defined as defined in the specification.

Description

Technical Field

[0001] This invention relates to a method for preparing intermediates of fluoroquinolone drugs, specifically a method for preparing intermediates of norfloxacin, ciprofloxacin, and enrofloxacin. Background Technology

[0002] Fluoroquinolones are a class of chemically synthesized antibacterial drugs that have seen rapid development since their introduction. Due to their broad antibacterial spectrum, strong antibacterial activity, convenient administration, few adverse reactions, and lack of cross-resistance with other antibiotics, they have become the first choice for combination therapy in clinical practice. Quinolone drugs have become a hot research topic, and numerous literatures have reported synthetic methods for these drugs. However, these methods generally suffer from drawbacks such as lengthy procedures, low yields, and significant waste generation. Therefore, researchers have been continuously striving to find simpler, higher-yield, and more environmentally friendly synthetic methods.

[0003] Norfloxacin is a third-generation quinolone antibiotic with broad-spectrum antibacterial activity. Ciprofloxacin is a newly developed, highly active quinolone antibiotic with broad-spectrum activity, high efficacy, and low toxicity, especially effective against pathogens resistant to multiple antibiotics. Enrofloxacin is a synthetic third-generation quinolone antibiotic, specifically designed for livestock, poultry, and aquaculture. All three drugs possess broad-spectrum antibacterial activity and strong penetrability, exhibiting strong bactericidal activity against Gram-negative bacteria and good antibacterial activity against Gram-positive bacteria and mycoplasma. Their structural formulas are as follows:

[0004]

[0005] According to patent CN104292159A, norfloxacin is synthesized by the following method: first, a fluoroquinolone main ring carboxylate is synthesized, and then directly condensed to obtain the target product. The synthesis of ciprofloxacin and enrofloxacin is similar, and the reaction is as follows:

[0006]

[0007] Based on existing literature, the synthetic methods for the above-mentioned fluoroquinolone drugs all involve key intermediates with similar structures. These intermediates can be represented by the general structural formula V as follows:

[0008]

[0009] Where 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 It can be H, alkyl, or aromatic.

[0010] Patent CN104292159A reports the preparation of the above-mentioned compound V by reacting 2,4-dichloro-5-fluorobenzoyl chloride with N,N-dimethylaminoacrylate in the presence of an acid binder, followed by an amine exchange reaction with cyclopropylamine and ethylamine in an organic solvent.

[0011] The preparation of compound V involves a key ingredient: N,N-dimethylaminoacrylate. Existing technical reports on the preparation method of N,N-dimethylaminoacrylate include: preparation using propynyl alcohol as a raw material, with the following reaction formula:

[0012]

[0013] (See patent CN103570623A). The above method has high raw material costs of propynyl alcohol. At the same time, amine exchange involves a reaction equilibrium relationship and the recovery of dimethylamine, which increases the industrial production cost.

[0014] There are also reports of using methyl methoxyacrylate as a raw material to react with amines to prepare it (see patent JP2013006781A). The above methods also have the problems of high raw material costs; and the amine exchange involves a reaction equilibrium relationship and 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 pharmaceutical and chemical industries. Currently, the main methods for synthesizing 3-methoxyacrylate based on the main raw materials include: 1) Photochemical deHClization of vinyl methyl ether / vinyl diethyl ether: Vinyl methyl ether has a low flash point, is scarce, and is difficult to transport. Although phosgene can be replaced by diphosgene or triphosgene, experimental results show that solid phosgene is not effective; 2) Acrylonitrile and methanol method: This requires the use of precious metal catalysts, increasing the cost of raw materials, is not easy to recycle, and causes heavy metal pollution to the environment; 3) It has been reported that methyl propargylate is used as a raw material, and methanol is added under a catalyst to obtain 3-methoxyacrylate in 71% yield. However, the high cost of the starting material methyl propargylate limits large-scale industrial production. Summary of the Invention

[0016] To address the shortcomings of existing synthetic V compounds and their raw materials, this invention first discloses a new route for the synthesis of methoxyacrylates and N,N-dimethylacrylates, thereby reducing the synthesis cost of methoxyacrylates and N,N-dimethylacrylates, and simultaneously lowering the synthesis cost of V compounds.

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

[0018]

[0019] Wherein, X is a halogen; and R is H, an optionally substituted alkyl group, an optionally substituted aromatic group, or an optionally substituted heteroaryl group.

[0020] This invention also provides a method for preparing a compound of formula II, the synthetic route of which is as follows:

[0021]

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

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

[0024] This invention also discloses a method for synthesizing a fluoroquinolone drug intermediate of formula V, the synthetic route of which is as follows:

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

[0026]

[0027] or

[0028] 2) Formula V is prepared by contacting 2,4-dichloro-5-fluorobenzoyl chloride with a compound of formula II. The synthetic route is as follows:

[0029]

[0030] in,

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

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

[0033] The present invention also specifically provides a compound of formula A, Where Z represents chlorine or bromine.

[0034] Beneficial effects

[0035] The approach of this invention has at least the following technical advantages:

[0036] 1) It overcomes the shortcomings of existing technologies for N,N-dimethylaminoacrylate, such as expensive raw materials, complicated reaction equilibrium of dimethylamine, and recycling.

[0037] 2) The new route for synthesizing alternative acrylates using dichloropropylene as a raw material has lower synthesis costs and greater industrial advantages compared to the propynyl alcohol route.

[0038] 3) The method of the present invention reduces the cost of preparing compound V, simplifies the process route, and increases the yield. Detailed Implementation

[0039] To make the objectives, 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 only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort 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 "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0040] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0041] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0042] When the compounds of the present invention can exist in tautomer form, the meanings stated above and below shall apply where applicable.

[0043] The term "compound" should be understood to also include the corresponding tautomers, even if these tautomers are not explicitly mentioned in each case.

[0044] If the compounds of Formula I described in this invention have functional groups that can be ionized, they can also be used as agricultural salts or mixtures thereof.

[0045] As used herein, the term "alkyl" (and in other groups containing alkyl, such as the alkyl moiety of alkoxy, haloalkyl, and alkyl moiety of arylalkyl) generally refers to a straight-chain or branched alkyl group having 1-20 carbon atoms, often 1-6 carbon atoms, preferably 1-4 carbon atoms, and especially 1-3 carbon atoms. Examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl). Examples of C1-C6 alkyl groups, in addition to those mentioned for C1-C4 alkyl groups, include 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 "optional substitution" means that the relevant group may or may not be substituted by a substituent.

[0047] When a group is substituted, the substituent can be alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, amide, ester, alkoxy, and halogen, but is not limited thereto. For example, when an alkyl group is substituted with a halogen, a haloalkyl group is formed, but is not limited thereto.

[0048] In this invention, the halogen is typically fluorine, chlorine, bromine, or iodine, preferably fluorine, bromine, or chlorine. Correspondingly, this also applies to halogens combined with other structures, such as alkyl halogens. Alkyl halogens preferably have a chain length of 1 to 6 carbon atoms, more preferably a chain length of 1 to 4 carbon atoms. Examples of alkyl halogens include 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 this invention, "aromatic group" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl, especially naphthyl, but not limited thereto. The aryl group can be substituted by alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, amide, ester, etc., but is not limited thereto.

[0050] In this invention, "heteroaryl" encompasses: 5- to 10-membered aromatic monocyclic rings and aromatic fused rings, wherein the aromatic monocyclic ring contains one or more (e.g., 1 to 4, or in some embodiments, 1 to 3) heteroatoms selected from N, O, and S, and the remaining atoms are carbon; and the aromatic fused ring contains one or more (e.g., 1 to 4, or in some embodiments, 1 to 3) heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon, wherein at least one heteroatom is present in the aromatic ring. For example, a heteroaryl includes a 5- to 10-membered heterocyclic alkyl aromatic ring fused with a 5- to 10-membered cycloalkyl or heterocyclic alkyl ring. For the fusion in which only one ring contains one or more heteroatoms, in a bicyclic heteroaryl ring system, 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 (self-assigned linking position numbering 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, thiophene, benzothiophenyl, furanyl, benzofuranyl, benzimidazolinyl, indolinyl, pyrazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Divalent groups derived from monovalent heteroaryl groups ending in "-" by removing a hydrogen atom from a free carbon atom are named by adding "-" to the name of the corresponding monovalent group; for example, a pyridyl group with two linking points is a pyridinyl subgroup. Heteroaryl groups do not encompass aryl, cycloalkyl, or heterocyclic alkyl groups, or do not overlap with aryl, cycloalkyl, or heterocyclic alkyl groups, as defined herein.

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

[0052] This invention first provides a method for preparing a compound of formula I, comprising the following steps: a compound of formula VI is prepared by oxidation and esterification in an organic solvent to obtain a compound of formula I. The synthetic route is as follows:

[0053]

[0054] Wherein, X is a halogen; and R is H, an optionally substituted alkyl group, an optionally substituted aromatic group, or an optionally substituted heteroaryl group.

[0055] In the preparation method of the compound of Formula I above, the oxidation reaction preferably involves the addition of a catalyst. The catalyst is a metal catalyst and / or TEMPO (2,2,6,6-tetramethylpiperidine oxide) and its derivatives. The metal catalyst is one of the elements 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 multi-metal salt, including salts formed by a single metal or multi-metal and anion. The anions include fluoride, chloride, bromide, iodide, oxygen, sulfide, sulfate, nitrate, molybdate, acetate, phosphate, hydroxide, etc. The multi-metal salt includes (NH4)3[FeMo6O] 24 H6]·7H2O、(TBA)3FeMo6O 18 (OH)6, etc., but not limited to these. TBA refers to tetrabutylammonium ion. Examples of TEMPO (2,2,6,6-tetramethylpiperidine oxide) derivatives include, but are not limited to, 4-OH-TEMPO, 4-Methoxy-TEMPO, 4-Carboxy-TEMPO.

[0056] The oxidation reaction described above is carried out in the presence of an oxidizing agent, which is selected from air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, thioyl chloride, thionyl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, hydrogen peroxide, thiourea or urea, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromic acid, sodium hypobromite, bromic acid, sodium bromate, peroxyformic acid, peracetic acid, peroxydichloroacetic acid, perdifluoroacetic acid or trifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfate, nitrous acid, nitrogen dioxide, sodium nitrite; nitric acid, sodium nitrate, cerium ammonium nitrate; substituted and unsubstituted nitrobenzenes; per-m-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 used is 0.1%-10% of the molar amount of the compound of formula VI. The oxidation reaction temperature is 10℃ to 100℃, preferably 30℃ to 50℃; the oxidation reaction time is 3-10h, preferably 5-7h.

[0057] In the preparation method of the compound of Formula I above, the esterification reaction is carried out in the presence of an acid, which is selected from one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and solid superacid, with sulfuric acid being preferred.

[0058] The oxidation reaction described in the preparation method of the compound of Formula I above 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] This invention also provides a method for preparing a compound of formula II, which specifically includes the following steps: etherification or amination of a compound of formula I to prepare a compound of formula II, and the synthetic route is as follows:

[0060]

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

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

[0063] During the preparation of the above-mentioned compound II,

[0064] When Y is OR a SR b or OSO2R f When, compound I reacts with L-OR a L-SR b Or L-OSO2R f The compound of formula II is prepared by etherification. L is a metal, preferably sodium, potassium, or magnesium, and preferably L-ORa is sodium or potassium alkyloxide, more preferably one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, and potassium isopropoxide. Preferred L-ORa... b It is sodium or potassium alkyl mercaptan, more preferably one or more of sodium methanethiol, sodium ethanethiol, sodium propanethiol, potassium methanethiol, potassium ethanethiol, and potassium propanethiol. L-OSO2R is preferred. f It is one of sodium methanesulfonate, sodium p-toluenesulfonate, and sodium trifluoromethanesulfonate. The compound of formula I is related to 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 Compound I is prepared by reacting it with an amination reagent, wherein the amination reagent is HNR. c R d The preferred reagents are benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine, and cyclopropane. The ammoniation reaction is carried out, and the ammoniation reagent can be an aqueous solution of the reagent or a salt solution of the reagent; the preferred salt solution is an aqueous solution of hydrochloride.

[0066] The reaction temperature during the preparation of the above-mentioned compound II is -10℃ to 90℃, preferably 0℃ to 70℃; the reaction time is 2-6h, preferably 3-5h.

[0067] This invention also provides a method for synthesizing a fluoroquinolone drug intermediate of formula V, comprising the following steps:

[0068] Route 1: 2,4-Dichloro-5-fluorobenzoyl chloride is reacted with a compound of formula I to obtain formula III; the compound of formula III is then reacted with an amination reagent to obtain formula V, wherein the amination reagent is HNR. c R d ;

[0069] Its synthetic route is as follows:

[0070]

[0071] Route 2) 2,4-Dichloro-5-fluorobenzoyl chloride and compound of formula II are reacted to prepare formula V;

[0072] Its synthetic route is as follows:

[0073]

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

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

[0076] In the above-mentioned route (1), 2,4-dichloro-5-fluorobenzoyl chloride and compound I are preferably reacted in the presence of an acid-binding agent to prepare compound III. The acid-binding agent is selected from organic or inorganic bases. 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 hydride, preferably sodium carbonate. The molar ratio of 4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and compound 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 2-5 h, preferably 1-3 h. The reaction is preferably carried out in an organic solvent, which is one or more selected from 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-mentioned route (1), the compound of formula III undergoes an ammoniation reaction with an ammonifying agent in an organic solvent; the ammonifying agent is HNRcRd, preferably one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine, and cyclopropane; the ammonifying agent can be an aqueous solution or a solution of its salt, preferably an aqueous solution of hydrochloride; the molar ratio of the compound of formula III to the ammonifying agent is 1:1.0-1.5; the temperature of the ammoniation reaction is -25℃ to 130℃, preferably 0℃ to 60℃; the reaction time is 1-6 h, preferably 3-4 h. 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 route (ii) above, 2,4-dichloro-5-fluorobenzoyl chloride and compound II are reacted with an acid-binding agent to prepare compound V. The acid-binding agent in the reaction is selected from organic or inorganic bases. 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 hydroxide, preferably sodium carbonate. The molar ratio of 2,4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and compound 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 2-5 hours, preferably 1-3 hours.

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

[0080] The present invention will be described in detail below through embodiments. The following embodiments include:

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

[0082] The conversion rate and selectivity of the reaction are calculated using the following formulas:

[0083] Yield = Actual mass of target product / Theoretical mass of target product × 100%

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

[0085] Example 1:

[0086] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 93.9 g of 2-chloropropenol (1.0 mol, 98%), 450 g of dichloroethane, and 5 g of TEMPO were added sequentially. The mixture was kept at 50 °C, and 424.0 g of 25% sodium chlorate aqueous solution was added dropwise over 5 hours. HPLC analysis showed that the reaction was complete, and the mixture was separated into layers to obtain 101.1 g of chloroacrylic acid, with a yield of 95.0%.

[0087] The product from the previous step was added to 210g of methanol and 7g of concentrated sulfuric acid, and the mixture was refluxed for 8 hours. HPLC analysis showed that the reaction of the starting material was complete. The solvent was removed to obtain 108.8g of methyl chloroacrylate, with a yield of 95.1%.

[0088] Example 2:

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

[0090] Example 3:

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

[0092] Example 4:

[0093] The difference from Example 1 is that o-nitrotoluene is used instead of sodium chlorate, TEMPO is not used, and other molar ratios remain unchanged. The reaction yields 107.3 g of methyl chloroacrylate, with a yield of 89.1%.

[0094] Example 5:

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

[0096] Example 6:

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

[0098] Example 7

[0099] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 123.0 g (1.0 mol, 98%) of methyl chloroacrylate and 200 g of methanol were added sequentially. The mixture was kept at 20 °C, and 189.5 g of 30% sodium methoxide solution was slowly added dropwise. The mixture was stirred for 3 h. HPLC analysis showed that the reaction was complete. After solvent removal, 101.7 g of methyl methoxyacrylate was obtained, with a yield of 95.5%.

[0100] Example 8

[0101] The difference from Example 7 is that sodium methanethiol is used instead of sodium methoxide, while the other molar ratios remain the same. The reaction yields 122.3 g of methyl thioacrylate, with a yield of 92.5%.

[0102] Example 9

[0103] The difference from Example 7 is that sodium p-toluenesulfonate is used instead of sodium methoxide, while other molar ratios remain unchanged. The reaction yields 235.8 g of compound 3-p-toluenesulfonic acid methyl 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, while other molar ratios remain unchanged. The reaction yielded 118.2 g of the compound isopropyl methoxyacrylate, with a yield of 82.0%.

[0106] Example 11

[0107] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 123.0 g (1.0 mol, 98%) of methyl chloroacrylate and 150 g of NMP were added sequentially. The mixture was kept at 60°C, and 124.0 g of 40% dimethylamine aqueous solution was slowly added dropwise. The mixture was stirred for 3 hours. HPLC analysis showed that the reaction of the starting material was complete. The mixture was washed with water, extracted with EA, and the solvent was removed to obtain 124.4 g of the product N,N-dimethyl acrylate, with a yield of 96.3%.

[0108] Example 12

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

[0110] Example 13

[0111] The difference from Example 11 is that 50% ethylamine is used instead of 40% dimethylamine aqueous solution, while other molar ratios remain unchanged. The reaction yields 116.4 g of compound N-ethyl acrylate, with a yield of 90.1%.

[0112] Example 14

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

[0114] Example 15

[0115] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 144.6 g of methyl chloroacrylate and 121.2 g of triethylamine were added. The mixture was kept at 50°C, and 228.6 g (1.0 mol, 99.5%) of 2,4-dichloro-5-fluorobenzoyl chloride was slowly added dropwise. The mixture was stirred for 5 h, and HPLC analysis showed that the reaction of the starting material was complete. Toluene and acidic water were added, and the mixture was extracted and separated into layers. The toluene phase was directly added to the next step. The mixture was kept at 10°C, and 65.7 g of cyclopropylamine and 110.0 g of triethylamine were slowly added dropwise. The mixture was stirred for 3 h, and HPLC analysis showed that the reaction of the starting material was complete. The mixture was allowed to stand, separated, and dissolved to obtain 285.7 g of compound V-1, with a yield of 86.0%.

[0116]

[0117] Example 16

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

[0119]

[0120] Example 17

[0121] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 169.4 g of N-cyclopropyl methyl acrylate and 121.2 g of triethylamine were added. The mixture was kept at 50 °C, and 228.6 g (1.0 mol, 99.5%) of 2,4-dichloro-5-fluorobenzoyl chloride was slowly added dropwise. The mixture was stirred for 5 h, and HPLC analysis showed that the reaction was complete. Ethyl acetate and acidic water were added, and the mixture was allowed to stand before separation. The solvent was removed to obtain 298.9 g of compound V-1, with a yield of 90.0%.

[0122] Example 18

[0123] The difference from Example 17 is that N-ethyl methyl acrylate is used instead of N-cyclopropyl methyl acrylate, while other molar ratios remain unchanged. The reaction yielded 292.0 g of compound V-2, with a yield of 91.2%.

[0124] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that, The following steps are included in the preparation of compound I from compound VI by oxidation and esterification in an organic solvent. The synthetic route is as follows: ， Wherein, X is a halogen; R is an optional substituted alkyl group; The oxidation reaction is a reaction between compound VI and an oxidant, wherein the oxidant is selected from hypochlorous acid, sodium hypochlorite, sodium chlorite, or sodium chlorate; a catalyst is added to the oxidation reaction, wherein the catalyst is TEMPO (2,2,6,6-tetramethylpiperidine oxide) and its derivatives; the derivatives of TEMPO (2,2,6,6-tetramethylpiperidine oxide) are 4-OH-TEMPO, 4-Methoxy-TEMPO, or 4-Carboxy-TEMPO; the molar ratio of compound VI to oxidant is 1:1.0-1.5; the amount of catalyst used is 0.1%-10% of the molar amount of compound VI.

2. 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, which is selected from one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and solid superacids.

3. A method for preparing a compound of formula II, characterized in that, The following steps are included in the preparation of compound I from compound VI by oxidation and esterification in an organic solvent. The synthetic route is as follows: ， The oxidation reaction is a reaction between compound VI and an oxidant, wherein the oxidant is selected from hypochlorous acid, sodium hypochlorite, sodium chlorite, or sodium chlorate; a catalyst is added to the oxidation reaction, wherein the catalyst is TEMPO (2,2,6,6-tetramethylpiperidine oxide) and its derivatives; the derivatives of TEMPO (2,2,6,6-tetramethylpiperidine oxide) are 4-OH-TEMPO, 4-Methoxy-TEMPO, or 4-Carboxy-TEMPO; the molar ratio of compound VI to oxidant is 1:1.0-1.5; the amount of catalyst used is 0.1%-10% of the molar amount of compound VI; Compound II is prepared by etherification or amination of compound I, and the synthetic route is as follows: Where X is a halogen; Y is an OR a SR b NR c R d OSO2R f R is an optional substituted alkyl group; R a R b R c R d R f Each is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aromatic or optionally substituted heteroaryl.

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

5. The method for preparing the compound of formula II according to claim 3 or 4, characterized in that: A) When Y is OR a SR b or OSO2R f When, compound I reacts with L-OR a L-SR b Or L-OSO2R f The compound of formula II was prepared by etherification, where L is a metal and L-OR a Sodium or potassium alkylol; L-SR b Sodium or potassium alkylthiolate; L-OSO2R f It is one of sodium methanesulfonate, sodium p-toluenesulfonate, and sodium trifluoromethanesulfonate; the compound of formula I is related to L-OR a L-SR b Or L-OSO2R f During the etherification reaction, compound I reacts with 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 Compound I is prepared by reacting it with an amination reagent, wherein the amination reagent is HNR. c R d , where R c R d Each group can be independently H, alkyl, or aromatic; when undergoing amination, the amination reagent is its aqueous solution or a salt solution.

6. The preparation method according to claim 5, characterized in that, When Y is OR a SR b or OSO2R f When, compound I reacts with L-OR a L-SR b Or L-OSO2R f The compound of formula II was prepared by etherification, wherein L is sodium, potassium or magnesium, and L-OR a It is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, and potassium isopropoxide; L-SR b It is one or more of sodium methanethiol, sodium ethanethiol, sodium propanethiol, potassium methanethiol, potassium ethanethiol, and potassium propanethiol; B) When Y is NR c R d Compound I is prepared by reacting it with an ammoniation reagent to obtain compound II, wherein the ammoniation reagent is one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine, and cyclopropane; the ammoniation reagent is an aqueous solution of hydrochloride.

7. A method for synthesizing a fluoroquinolone drug intermediate of formula V, characterized in that, Includes the following steps: Route 1: 2,4-Dichloro-5-fluorobenzoyl chloride is reacted with compound I to obtain compound III, and compound III is further reacted to obtain compound V; Its synthetic route is as follows: ， Route 2) 2,4-Dichloro-5-fluorobenzoyl chloride and compound II are reacted to prepare compound V; Its synthetic route is as follows: ， Compound II is prepared by etherification or amination of compound I, and the synthetic route is as follows: ， The preparation method of compound I includes the following steps: compound VI is prepared by oxidation and esterification in an organic solvent to obtain compound I. The synthetic route is as follows: ， Where X is a halogen; R is an optional substituted alkyl group; Y is OR a SR b NR c R d OSO2R f Among them, R a R b R c R d R f Each of the following groups is independently selected from optional substituted alkyl, optional substituted cycloalkyl, optional substituted aromatic or optional substituted heteroaryl groups; The oxidation reaction is a reaction between compound VI and an oxidant, wherein the oxidant is selected from hypochlorous acid, sodium hypochlorite, sodium chlorite, or sodium chlorate; a catalyst is added to the oxidation reaction, wherein the catalyst is TEMPO (2,2,6,6-tetramethylpiperidine oxide) and its derivatives; the derivatives of TEMPO (2,2,6,6-tetramethylpiperidine oxide) are 4-OH-TEMPO, 4-Methoxy-TEMPO, or 4-Carboxy-TEMPO; the molar ratio of compound VI to oxidant is 1:1.0-1.5; the amount of catalyst used is 0.1%-10% of the molar amount of compound VI.

8. The method for preparing formula V according to claim 7, characterized in that, 2,4-Dichloro-5-fluorobenzoyl chloride and a compound of formula I are reacted in the presence of an acid-binding agent to prepare formula III. The acid-binding agent is selected from organic or inorganic bases; 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 hydroxide; the molar ratio of 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; the reaction time is 2-5 h; the reaction is 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.

9. The method for preparing formula V according to claim 8, characterized in that, The reaction temperature is -10℃ to 50℃; the reaction time is 1-3h.

10. The method for preparing formula V according to claim 7, characterized in that, When Y is NRcRd, compound I is prepared by ammoniation with an ammonifying agent to obtain compound V, wherein the ammonifying 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 heteroaryl group; during the ammoniation reaction, the ammonifying agent is its aqueous solution or its salt solution; the molar ratio of compound III to the ammonifying agent is 1:1.0-1.5; the temperature of the ammoniation reaction is -25℃ to 130℃; the reaction time is 1-6h; and 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.

11. The method for preparing formula V according to claim 10, characterized in that, The amination reagent is one of benzylamine, N-methylaniline, dimethylamine, methylamine, ammonia, ethylamine, and cyclopropane; when carrying out the amination reaction, the amination reagent is an aqueous solution of hydrochloride; the temperature of the amination reaction is 0°C to 60°C; and the reaction time is 3-4 hours.

12. The method for preparing formula V according to claim 7, characterized in that, Compound V is prepared by reacting 2,4-dichloro-5-fluorobenzoyl chloride and compound II with an acid-binding agent, wherein the acid-binding agent in the reaction is selected from organic or inorganic bases; 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 hydride; the molar ratio of 2,4-dichloro-5-fluorobenzoyl chloride, the acid-binding agent, and compound II is 1:(1-2.5):(1-1.5).

13. The method for preparing formula V according to claim 12, characterized in that, The acid-binding agent used in the reaction is selected from sodium carbonate.

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