A method for preparing a 4,5-dihydroisoxazole-3-carboxylic acid compound

Abstract

The application discloses a preparation method of a 4,5-dihydroisoxazole-3-carboxylic acid compound, and a synthetic route of the 4,5-dihydroisoxazole-3-carboxylic acid compound is as follows: wherein definitions of R1, R2, X and n are as defined in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of 4,5-dihydroisoxazole-3-carboxylic acid compounds. BACKGROUND

[0002] 4,5-dihydroisoxazole compounds are a kind of compounds with good biological activity and potential medicinal value. Among them, 4,5-dihydroisoxazole-3-carboxylic acid compounds such as 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester (monophenyl oxazole acid ethyl ester) and 5,5-diphenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester (diphenyl oxazole acid ethyl ester) can be used as herbicide safeners. At present, the methods for synthesizing diphenyl oxazole acid ethyl ester and monophenyl oxazole acid ethyl ester have problems such as long route, low yield or use of expensive raw materials, etc. For example, the synthesis route of diphenyl oxazole acid ethyl ester provided in patent CN108440435A (as shown below) has a yield of about 34% (Example 1) in the cyclization step of diphenyl ethylene and chloro oximyl acetic acid ethyl ester.

[0003]

[0004] A synthesis method of a monophenyl oxazole acid ethyl ester intermediate is reported in the literature (Katrin Thommes, Olefin Cyclopropanations via Sequential Atom Transfer Radical Addition-Dechlorination Reactions, Chimia. 2010; 64 (3): 188-190) (as shown below), which obtains 1-phenyl-2-carboxylic acid ethyl ester cyclopropane through two steps, the first step is Ru-catalyzed atom transfer radical addition, and the second step is dechlorination.

[0005]

[0006] This route uses a relatively expensive ruthenium catalyst, increasing the preparation cost of the compound. SUMMARY

[0007] In view of the defects such as low yield and need for expensive metal catalysts in the preparation of 4,5-dihydroisoxazole-3-carboxylic acid compounds in the prior art, the present application provides a method with simple preparation method, high yield and low production cost.

[0008] Specifically, the present application provides a preparation method of a compound of formula I, which comprises the following steps:

[0009] Step one, the compound of formula III is reacted with dichloroacetic acid or its ester and magnesium metal in the presence of DMF and / or DMAC to prepare the compound of formula II.

[0010] Step 2: Compound I is prepared from compound II in the presence of acid and sodium nitrite.

[0011] Its synthetic route is as follows:

[0012]

[0013] in,

[0014] X is selected from optionally substituted alkyl groups, optionally substituted alkoxy groups, cyano groups, ester groups, nitro groups, amide groups, halogens, and haloalkyl groups;

[0015] R1 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic and optionally substituted aryl;

[0016] R2 is selected from hydrogen or optionally substituted alkyl groups;

[0017] n is a natural number selected from 0 to 5, with 0, 1, 2 and 3 being particularly preferred.

[0018] Beneficial effects of the present invention

[0019] 1. In the synthetic route of this invention, stilbene first reacts with ethyl dichloroacetate to generate a three-membered ring derivative, and then reacts with sodium nitrite to generate an isoxazole ring. The yield of the two steps can reach 96%, which greatly improves the yield.

[0020] 2. This invention adopts a reaction route that is completely different from the existing technology and carries out the reaction through a different reaction mechanism. This invention does not require expensive catalysts, the raw materials are readily available, the reaction conditions are mild, and it is more suitable for industrial production. Detailed Implementation

[0021] 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. In addition, to better illustrate the present invention, numerous specific details are given in the following detailed embodiments. Those skilled in the art should understand that the present invention can be implemented without certain specific details. In some embodiments, raw materials, excipients, methods, means, etc., well known to those skilled in the art, are not described in detail in order to highlight the main points of the present invention.

[0022] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated active ingredient and not to exclude other possible active ingredients.

[0023] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0024] The term "halogen" in this invention refers to fluorine, chlorine, bromine, and iodine.

[0025] The term "alkyl" (and in other groups containing alkyl, such as the alkyl portion of an alkoxy group, the alkyl portion of an arylalkyl group) in each case generally means 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 are 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. C1-C 10 Examples of alkyl groups, in addition to those mentioned for C1-C6 alkyl groups, include 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. The term "alkoxy" in this invention refers to an -OR group, where R is an alkyl group as defined above, typically having 1-6 carbon atoms, preferably 1-4 carbon atoms, and especially a straight-chain or branched alkyl group with 1-3 carbon atoms. Examples include methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy, or tert-butoxy, but are not limited thereto.

[0026] The term "amido" of the present application refers to a group containing "-NHCO-" or "-CONHCO-" in the group, and the amido group is, for example, -NHCOCH3, -NHCOH, -NHCOCH2CH3, -NHCOCH2CH2CH3, -NHCOCH(CH3)2, -N(COCH3)2, -CONH2, -CON(CH3)2, -CONHCH3, -CONHCH2CH3, -CON(CH2CH3)2, -CONHCH(CH3)2, -CONHCH2CH2CH3, -CONHCH2CH2CH2CH3, phthalimido, succinimido, glutarimido, maleimido, and the like, but is not limited thereto.

[0027] The term "ester" of the present application refers to a group containing "-COO-" in the group, and the ester group is, for example, -COOCH3, -COOCH2CH3, -COOCH(CH3)2, -COOCH2CH2CH3, -COOCH2CH2CH2CH3, but is not limited thereto.

[0028] The term "haloalkyl" of the present application refers to an alkyl group which is partially or completely halogenated, and the alkyl group has the meaning described above, wherein the halogen atoms are, in particular, fluorine, chlorine and / or bromine, i.e. for example chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-1,1,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 1,1,2,2-tetrachloroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoro-1-propyl, 1,1,2,3,3,3-hexafluoro-1-propyl, 1,1,1,3,3,3-hexafluoro-2-propyl, heptafluoro-1-propyl, heptafluoro-2-propyl, 2,2,3,3,4,4,4-heptafluoro-1-butyl or nonafluoro-1-butyl and the like, but is not limited thereto.

[0029] The term "cycloalkyl" of the present application refers to a monocyclic monovalent hydrocarbon group of three to eight carbon atoms, which can be saturated or contain one double bond. The cycloalkyl group can be unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy or cyano, but is not limited thereto. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl and the like, but are not limited thereto. When the cycloalkyl group contains a double bond, it can be referred to herein as a cycloalkenyl group.

[0030] The term "heterocycle" in this invention refers to a saturated or partially unsaturated carbon ring containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. Such a ring does not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples are aziridine, aziridine butane, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, tetrahydrofuran, dioxane, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane, and more preferably aziridine, aziridine butane, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane.

[0031] In this invention, "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl, especially phenyl, but not limited thereto.

[0032] The term "optional substitution" means that the relevant group may or may not be substituted by a substituent. When a group is described as optionally substituted, it is preferable to have 1-5 optional substituents, more preferably 1-3 optional substituents, and even more preferably 1 or 2 optional substituents. When a group is described as optionally substituted, and the optional substitution of the group involves more than one substituent, the more than one substituent can be the same or different. The substituent can be alkyl, halogen, cyano, nitro, aryl, cycloalkyl, heterocyclic, amide, ester, etc., but is not limited thereto.

[0033] This invention provides a method for preparing a compound of formula (I), comprising the following steps:

[0034] Step 1: Compound of Formula III is prepared by reacting it with dichloroacetic acid or its ester and metallic magnesium in the presence of DMF and / or DMAC;

[0035] Step 2: Compound I is prepared from compound II in the presence of acid and sodium nitrite.

[0036] Its synthetic route is as follows:

[0037]

[0038] in,

[0039] X is selected from one of the optionally substituted alkyl groups, optionally substituted alkoxy groups, cyano groups, ester groups, nitro groups, amide groups, halogens, and haloalkyl groups; preferably one of the optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy groups, cyano groups, ester groups, nitro groups, amide groups, fluorine, and fluorinated C1-C6 alkyl groups; particularly preferably -CH3, -C2H5, -C3H7, -C4H9, -C5H11 , -C6H 13 , -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -CN, -COO(CH3), -COO(C2H5), -COO(C3H7), -COO(C4H9), -COO(C5H 11 ), -COO(C6H 13 ), -NO2, -CO(NH2), -F, -CF3, -CHF2and CH2F;

[0040] R1is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; preferably hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy-C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted heterocyclyl, Particularly preferred are -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -C6H 13 , -CH2OCH3, -CH2OC2H5, -CH2OC3H7, -CH2OC4H9, -CH2CH2OCH3, -CH2CH2OC2H5, -CH2CH2OC3H7, -CH2CH2OC4H9, -C3H6OCH3, -C3H6OC2H5, -C3H6OC3H7, -C4H8OCH3, -C4H8OC2H5, -C5H 10 OCH3, , -CN, -COO(CH3), -COO(C2H5), -COO(C3H7), -COO(C4H9), -COO(C5H

[0041] R2is selected from the group consisting of hydrogen, optionally substituted alkyl; preferably one of hydrogen, methyl and ethyl;

[0042] n is selected from the group consisting of natural numbers from 0 to 5, particularly preferably 0, 1, 2 and 3.

[0043] Preferably, in the above-mentioned preparation method, step one comprises adding the compound of formula III, metallic magnesium, dichloroacetic acid or its ester, DMF and / or DMAC into a solvent, and reacting for 1-8h at -10-100°C.

[0044] More preferably, one of the compound of formula III, metallic magnesium, dichloroacetic acid or its ester, DMF and / or DMAC is added into the reaction system in batches or dropwise in step one, which can prevent the reaction from being too fast.

[0045] Preferably, the molar ratio of magnesium, the compound of formula III and dichloroacetic acid or its ester in step one is 1-5:1:1-3, and the amount of DMF and / or DMAC added is 1-100 equivalents of the compound of formula III. The solvent used in step one can be one or more of DMF, DMAC, diethyl ether, tetrahydrofuran, acetonitrile, DMSO, toluene, isopropyl ether, 1,4-dioxane and methyl tert-butyl ether; when the solvent used in step one is DMF and / or DMAC, the magnesium, the compound of formula III and dichloroacetic acid or its ester are added to the solvent system of DMF and / or DMAC respectively for reaction. Preferably, after the reaction in step one is completed, the reaction mixture is poured into acid water for quenching, and the organic layer is taken out or extracted with toluene, and then the solvent is removed to obtain the compound of formula II.

[0046] In step two of the above preparation method, the compound of formula II, an acid and sodium nitrite are added to an appropriate amount of solvent, and the mixture is reacted at 0-100°C for 1-8h to obtain the compound of formula I. The solvent used is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane, tetrahydrofuran, 1,4-dioxane, diethyl ether, isopropyl ether, methyl tert-butyl ether and toluene, the acid is an inorganic acid or an organic acid, and the inorganic acid is preferably one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; the organic acid is preferably one or more of formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid.

[0047] In the following examples, the experimental methods used are conventional methods unless otherwise specified; the reagents and materials used in the following examples are commercially available unless otherwise specified.

[0048] Example 1 Synthesis of ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate

[0049]

[0050] Take 50ml of ethyl acetate, add 3.74g of ethyl 2-phenylcyclopropane carboxylate, 0.39g of concentrated hydrochloric acid and 1.52g of sodium nitrite, and react at 5°C for 3h. After the reaction is completed, water is added, and the ethyl acetate layer is concentrated to remove the solvent to obtain 4.24g of ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate with a total yield of 96.7% and a purity of 99.8%.

[0051] Take 50ml of ethyl acetate, add 3.74g of ethyl 2-phenylcyclopropane carboxylate, 0.39g of concentrated hydrochloric acid and 1.52g of sodium nitrite, and react at 5°C for 3h. After the reaction is completed, water is added, and the ethyl acetate layer is concentrated to remove the solvent to obtain 4.24g of ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate with a total yield of 96.7% and a purity of 99.8%.

[0052] 1H NMR (300 MHz, CDCl3) δ 7.27-7.43 (m, 5H), δ 5.77-5.83 (t, 1H), δ 4.34-4.41 (q, 2H), δ 3.60-3.71 (q, 1H), δ 3.19-3.28 (q, 1H), δ 1.37-1.42 (t, 3H)

[0053] Example 2 Synthesis of 5-methyl-5-p-tolyl-4,5-dihydroisoxazole-3-carboxylic acid

[0054]

[0055] Take 50 ml DMF, add 2.64 g of 1-isopropenyl-4-methylbenzene, 2.58 g of dichloroacetic acid, 1.5 g of magnesium is added in batches, and the reaction is carried out at 80°C for 1 h. After the reaction is completed, it is cooled to room temperature and quenched by pouring into an aqueous hydrochloric acid solution. After extraction with toluene, the organic layer is concentrated to remove the solvent to obtain 3.73 g of 2-methyl-2-p-tolylcyclopropane carboxylic acid.

[0056] Take 50 ml of acetic acid, add 3.73 g of 2-methyl-2-p-tolylcyclopropane carboxylic acid, 0.42 g of sulfuric acid, and 1.38 g of sodium nitrite, and react at 40°C for 2 h. After the reaction is completed, water is added, and after extraction with toluene, the organic layer is concentrated to remove the solvent to obtain 4.22 g of 5-methyl-5-p-tolyl-4,5-dihydroisoxazole-3-carboxylic acid with a total yield of 96.2% and a purity of 99.4%.

[0057] Example 3 Synthesis of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5-dihydroisoxazole-3-carboxylic acid methyl ester

[0058]

[0059] Take 250 ml of acetonitrile, add 16.68 g of 1,3-dimethoxy-5-(1-methoxymethyl-vinyl)-benzene, 4.0 g of magnesium, and 10.6 g of DMAC. At 50°C, drop 11.44 g of dichloroacetic acid methyl ester in acetonitrile solution into the mixture. After 2 h of reaction, cool to room temperature, quench by pouring into an aqueous sulfuric acid solution, extract with toluene, and take the organic layer to concentrate and remove the solvent to obtain 22.08 g of 2-(3,5-dimethoxy-phenyl)-2-methoxymethyl-cyclopropane carboxylic acid methyl ester.

[0060] Take 80 ml of tetrahydrofuran, 5.52 g of 2-(3,5-dimethoxy-phenyl)-2- methoxymethyl-cyclopropane carboxylic acid methyl ester, 0.38 g of nitric acid and 2.07 g of sodium nitrite, 50 °C for 1.5 h, after the reaction is completed, add water, toluene extraction after taking the organic layer concentrated to remove the solvent to obtain 5.93 g of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, the total yield is 95.9%, the purity is 99.3%.

[0061] Example 4 synthesis of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5- dihydroisoxazole-3-carboxylic acid methyl ester

[0062] Take 80 ml of tetrahydrofuran, 5.52 g of 2-(3,5-dimethoxy-phenyl)-2- methoxymethyl-cyclopropane carboxylic acid methyl ester (synthesis sample of example 3), 0.36 g of acetic acid and 2.07 g of sodium nitrite, 50 °C for 1.5 h, after the reaction is completed, add water, toluene extraction after taking the organic layer concentrated to remove the solvent to obtain 5.36 g of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, the total yield of synthesis is 86.6%, the purity is 98.1%.

[0063] Example 5 synthesis of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5- dihydroisoxazole-3-carboxylic acid methyl ester

[0064] Take 80 ml of tetrahydrofuran, 5.52 g of 2-(3,5-dimethoxy-phenyl)-2- methoxymethyl-cyclopropane carboxylic acid methyl ester (synthesis sample of example 3), 0.36 g of acetic acid and 2.07 g of sodium nitrite, 50 °C for 1.5 h, after the reaction is completed, add water, toluene extraction after taking the organic layer concentrated to remove the solvent to obtain 5.36 g of 5-(3,5-dimethoxy-phenyl)-5-methoxymethyl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, the total yield of synthesis is 86.6%, the purity is 98.1%.

[0065] Example 6 synthesis of 5-cyclohexyl-5-(3,4,5-trimethyl-phenyl)-4,5- dihydroisoxazole-3-carboxylic acid isopropyl ester

[0066]

[0067] Take 100 ml of toluene, add 4.57 g of 5-(1-cyclohexyl-vinyl)-1,2,3-trimethylbenzene, 3.42 g of isopropyl dichloroacetate, 17.4 g of DMAC, 2.2 g of magnesium is added in batches at 5 °C, after the reaction for 3 h, pour into aqueous sulfuric acid solution to quench, take the organic layer, concentrate to remove the solvent to obtain 6.37 g of 2-cyclohexyl-2-(3,4,5-trimethyl-phenyl)- cyclopropane carboxylic acid isopropyl ester.

[0068] Take 80 ml of acetonitrile, add 6.37 g of 2-cyclohexyl-2-(3,4,5-trimethyl-phenyl)- cyclopropanecarboxylic acid isopropyl ester, 0.92 g of formic acid, 1.38 g of sodium nitrite, and react at 70°C for 1 h. After the reaction is completed, add water, extract with toluene, and then concentrate the organic layer to remove the solvent to obtain 6.38 g of 5-cyclohexyl-5-(3,4,5-trimethyl-phenyl)- 4,5-dihydroisoxazole-3-carboxylic acid isopropyl ester, with a total yield of 89.2% and a purity of 98.3%.

[0069] Example 7 Synthesis of 5,5-diphenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester

[0070]

[0071] Take 80 ml of DMF, add 3.60 g of diphenyl ethylene, 3.14 g of ethyl dichloroacetate, and add 0.98 g of magnesium in batches at 60°C. After reacting for 2 h, cool to room temperature, pour into an aqueous hydrochloric acid solution to quench, extract with toluene, and then concentrate the organic layer to remove the solvent to obtain 5.22 g of 2,2-diphenyl-cyclopropanecarboxylic acid ethyl ester.

[0072] Take 80 ml of acetone, add 5.22 g of 2,2-diphenyl-cyclopropanecarboxylic acid ethyl ester, 0.68 g of trifluoroacetic acid, and 1.8 g of sodium nitrite, and react at 25°C for 3 h. After the reaction is completed, add water, extract with toluene, and then concentrate the organic layer to remove the solvent to obtain 5.70 g of 5,5-diphenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester, with a total yield of 96.5% and a purity of 99.5%.

[0073] 1H NMR (300 MHz, DMSO) δ 7.26-7.44 (m, 10H), δ 4.19-4.26 (q, 2H), δ 3.60-3.71 (q, 1H), δ 3.90 (s, 2H), δ 1.21-1.26 (t, 3H)

[0074] Example 8 Synthesis of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5- dihydroisoxazole-3-carboxylic acid methyl ester

[0075]

[0076] Take 400 ml of tetrahydrofuran, add 21.52 g of 5-fluoro-4-nitro-2-(1-pyridin-3-yl- vinyl)-benzonitrile, 11.44 g of methyl dichloroacetate, and 29.2 g of DMF, and add 7.2 g of magnesium in batches at 50°C. After reacting for 2 h, cool to room temperature, pour into an aqueous hydrochloric acid solution to quench, extract with toluene, and then concentrate the organic layer to remove the solvent to obtain 25.92 g of 2-(2-cyano-4-fluoro-5-nitro-phenyl)-2-pyridin-3-yl- cyclopropanecarboxylic acid methyl ester.

[0077] To 100 ml of ether, 6.48 g of 2-(2-cyano-4-fluoro-5-nitro-phenyl)-2-pyridin-3- ylcyclopropanecarboxylic acid methyl ester, 1.17 g of phosphoric acid, 1.93 g of sodium nitrite, and 30°C for 1 h, after the reaction, add water, and take the organic layer to concentrate to obtain 6.68 g of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, total yield 90.2%, purity 98.9%.

[0078] Example 9 Synthesis of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5- dihydroisoxazole-3-carboxylic acid methyl ester

[0079] To 100 ml of ether, 6.48 g of 2-(2-cyano-4-fluoro-5-nitro-phenyl)-2-pyridin-3- ylcyclopropanecarboxylic acid methyl ester (synthesis sample of Example 8), 1.08 g of oxalic acid, 1.93 g of sodium nitrite, and 30°C for 1 h, after the reaction, add water, and take the organic layer to concentrate to obtain 6.03 g of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, total yield of synthesis 81.4%, purity 97.4%.

[0080] Example 10 Synthesis of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5- dihydroisoxazole-3-carboxylic acid methyl ester

[0081] To 100 ml of ether, 6.48 g of 2-(2-cyano-4-fluoro-5-nitro-phenyl)-2-pyridin-3- ylcyclopropanecarboxylic acid methyl ester (synthesis sample of Example 8), 1.08 g of oxalic acid, 1.93 g of sodium nitrite, and 30°C for 1 h, after the reaction, add water, and take the organic layer to concentrate to obtain 6.03 g of 5-(2-cyano-4-fluoro-5-nitro-phenyl)-5-pyridin-3-yl-4,5-dihydroisoxazole-3- carboxylic acid methyl ester, total yield of synthesis 81.4%, purity 97.4%.

[0082] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application, and are not limited thereto; those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacements for some technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing a compound of formula I, characterized in that, Includes the following steps: Step 1: Compound of Formula III is prepared by reacting it with dichloroacetic acid or its ester and metallic magnesium in the presence of DMF and / or DMAC. Step 2: Compound I is prepared from compound II in the presence of acid and sodium nitrite. Its synthetic route is as follows: in, X is selected from one of the following: optionally substituted alkyl, optionally substituted alkoxy, cyano, ester, nitro, amide, halogen, and haloalkyl; R1 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic and optionally substituted aryl; R2 is selected from hydrogen or optionally substituted alkyl groups; n is a natural number selected from 0 to 5. When the above alkyl group is substituted, the substituent is one of alkyl, cyano, nitro, aryl, cycloalkyl, heterocyclic, amide or ester group; When the above-mentioned alkoxy, alkoxy-alkyl, cycloalkyl, heterocyclic or aryl groups are substituted, the substituent is one of alkyl, halogen, cyano, nitro, aryl, cycloalkyl, heterocyclic, amide or ester.

2. The preparation method according to claim 1, characterized in that, X is selected from one of the following: optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy groups, cyano groups, ester groups, nitro groups, amide groups, fluorine groups, and fluorinated C1-C6 alkyl groups. R1 is selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy-C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted heterocyclic groups, etc. R2 is selected from one of hydrogen, methyl, and ethyl.

3. The preparation method according to claim 1 or 2, characterized in that, X is selected from -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 -C6H 13 , -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 -OC6H 13 , -CN, -COO(CH3), -COO(C2H5), -COO(C3H7), -COO(C4H9), -COO(C5H 11 -COO(C6H) 13 One of the following: -NO2, -CO(NH2), -F, -CF3, -CHF2, and CH2F; R1 is selected from -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 -C6H 13 , -CH2OCH3, -CH2OC2H5, -CH2OC3H7, -CH2OC4H9, -CH2CH2OCH3, -CH2CH2O C2H5, -CH2CH2O C3H7, -CH2CH2OC4H9, -C3H6OCH3, -C3H6O C2H5, -C3H6O C3H7, -C4H8OCH3, -C4H8O C2H5, -C5H 10 O CH3、 One of them; n is selected from 0, 1, 2, and 3.

4. The preparation method according to claim 1 is characterized in that, Step one includes adding the compound of formula III, magnesium, dichloroacetic acid or its ester, DMF and / or DMAC to a solvent and reacting at -10 to 100°C.

5. The preparation method according to claim 4, characterized in that, In step one, one of the following is added in batches or dropwise to the reaction system: compound of formula III, magnesium, dichloroacetic acid or its ester, DMF and / or DMAC.

6. The preparation method according to claim 5, characterized in that, In step one, the molar ratio of magnesium, compound of formula III, and dichloroacetic acid or its ester is 1-5:1:1-3, and the amount of DMF and / or DMAC added is 1-100 equivalents of compound of formula III.

7. The preparation method according to claim 6, characterized in that, The solvent mentioned in step one is one or more of DMF, DMAC, diethyl ether, tetrahydrofuran, acetonitrile, DMSO, toluene, isopropyl ether, 1,4-dioxane, and methyl tert-butyl ether.

8. The claim according to claim 1, characterized in that, Step two involves adding an appropriate amount of solvent to compound II, acid, and sodium nitrite, and reacting at 0-100℃ to prepare compound I.

9. The preparation method according to claim 8, characterized in that, The solvent mentioned in step two is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane, tetrahydrofuran, 1,4-dioxane, diethyl ether, isopropyl ether, methyl tert-butyl ether, and toluene; the acid mentioned in step two is an inorganic acid or an organic acid.

10. The preparation method according to claim 9, characterized in that, The inorganic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and the organic acid is one or more of formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid.

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