1-hydroxyalkyl-5-sulfydryl-1, 2, 4-triazole-3-formic acid compound as well as preparation method and application of 1-hydroxyalkyl-5-sulfydryl-1, 2, 4-triazole-3-formic acid compound

Abstract

The invention provides a 1-hydroxyalkyl-5-sulfydryl-1, 2, 4-triazole-3-formic acid compound as well as a preparation method and application of the 1-hydroxyalkyl-5-sulfydryl-1, 2, 4-triazole-3-formic acid compound. The preparation method comprises the following steps: by taking a hydroxyalkyl hydrazine compound 2 as a raw material, sequentially carrying out condensation reaction, addition cyclization reaction and dehydrogenation reaction to obtain a 1-hydroxyalkyl-5-sulfydryl-1, 2, 4-triazole-3-formic acid compound 1. The compound 1 provided by the invention has the following remarkable characteristics and advantages: (1) the compound 1 provided by the invention is novel in structure and diversified in function; (2) the compound is simple in preparation method, high in yield, less in three wastes, safe to operate and suitable for mass production; and (3) the new compound 1 with multiple functional groups can be used for synthesizing other compounds with important value through further functional group conversion reaction, such as a bactericide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorphenyl)-2-hydroxypropyl]-1, 2, 4-triazole-3-thione (prothioconazole). # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a class of 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds, and a preparation method and application thereof. Background Art

[0002] The present invention provides a novel 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, whose structural formula is as follows:

[0003]

[0004] These novel compounds 1, which have not been reported in the literature, are a class of multifunctional substances. After further functional group transformation, compound 1 is expected to be used to synthesize a variety of derivatives with different chemical properties, physical properties and biological activities.

[0005] For example, compound 1 can be used to produce end products with practical application value, such as the fungicide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole).

[0006] CN105949137 makes a relatively detailed analysis and comparison of several currently known technologies for preparing prothioconazole and discloses a more optimal synthesis method. The method successfully solves various problems of previous methods by using the strategy of preparing 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazono}acetic acid as an intermediate. However, the intermediate compound has some product separation problems in mass production due to the cis-trans isomerism of the hydrazono C=N double bond.

[0007] The actual fungicidal application of prothioconazole has been disclosed in patents such as WO9616048, WO9918086, WO9918087, and WO9918088. Summary of the invention

[0008] The first object of the present invention is to provide a novel 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, the structural formula of which is as follows:

[0009]

[0010] Among them, R 1 , R 2 , R 3 , R 4Each of them is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C1-C18 alkenyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C6-C14 aryl, unsubstituted or substituted C1-C13 heteroaryl, unsubstituted or substituted C7-C18 aralkyl, unsubstituted or substituted C8-C18 aralkenyl, unsubstituted or substituted C7-C18 aryloxyalkyl;

[0011] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0012] Preferably, R 1 , R 2 , R 3 , R 4 Each is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n is an integer of 1-2.

[0013] More preferably, R 1 is hydrogen, unsubstituted or substituted C7 aralkyl, R 2 is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 , R 4 It is hydrogen, n=1.

[0014] More preferably, R 1 is o-chlorobenzyl, R 2 is 1-chlorocyclopropyl, R 3 , R 4 is hydrogen, n=1 or R 1 , R 2 , R 3 , R 4 It is hydrogen, n=1.

[0015] The second object of the present invention is to provide a method for preparing a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, comprising the following steps: (a) condensing a hydroxyalkyl hydrazine compound 2 with glyoxylic acid or glyoxylate; (b) subjecting the condensation product to addition cyclization with thiocyanic acid or thiocyanate under the action of acid A; (c) subjecting the addition cyclization product to dehydrogenation under the action of an oxidant to obtain a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, which is represented by the following equation:

[0016]

[0017] Among them, R 1 , R 2 , R 3 , R 4Each of them is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C1-C18 alkenyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C6-C14 aryl, unsubstituted or substituted C1-C13 heteroaryl, unsubstituted or substituted C7-C18 aralkyl, unsubstituted or substituted C8-C18 aralkenyl, unsubstituted or substituted C7-C18 aryloxyalkyl;

[0018] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0019] Preferably, R 1 , R 2 , R 3 , R 4 Each is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n is an integer of 1-2.

[0020] More preferably, R 1 is hydrogen, unsubstituted or substituted C7 aralkyl, R 2 is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 , R 4 It is hydrogen, n=1.

[0021] More preferably, R 1 is o-chlorobenzyl, R 2 is 1-chlorocyclopropyl, R 3 , R 4 is hydrogen, n=1 or R 1 , R 2 , R 3 , R 4 It is hydrogen, n=1.

[0022] The m=0-2, specifically 0, 0.5, 1, 1.5, 2 or any value within the range thereof.

[0023] The HX is a hydrohalic acid, sulfuric acid or phosphoric acid, and the hydrohalic acid is hydrochloric acid or hydrobromic acid, preferably hydrochloric acid.

[0024] The glyoxylic acid is glyoxylic acid or its hydrate. The glyoxylate is an alkali metal salt or ammonium salt of glyoxylic acid. The alkali metal is preferably lithium, sodium or potassium. The ammonium is NR 5 R 6 R 7 R 8 , where R 5 ,R 6 ,R 7 ,R 8are independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl, specifically R 5 ,R 6 ,R 7 ,R 8 It is methyl and n-butyl.

[0025] The thiocyanate is an alkali metal thiocyanate, an alkaline earth metal salt or an ammonium salt. The alkali metal is preferably lithium, sodium or potassium. The alkaline earth metal is preferably magnesium or calcium. The ammonium is NR 5 R 6 R 7 R 8 , where R 5 ,R 6 ,R 7 ,R 8 are independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl, specifically R 5 ,R 6 ,R 7 ,R 8 It is methyl and n-butyl.

[0026] The acid A is a protonic acid; the acid A is a hydrohalic acid, sulfuric acid, phosphoric acid, or a carboxylic acid; the carboxylic acid is an alkyl carboxylic acid or an aryl carboxylic acid, and the alkyl carboxylic acid and the aryl carboxylic acid include substituted alkyl carboxylic acids and aryl carboxylic acids; the acid A is preferably hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or benzenesulfonic acid.

[0027] The oxidant is one or more of ferric chloride, hydrogen peroxide, nitric acid, air and oxygen, preferably oxygen and hydrogen peroxide.

[0028] The process of preparing compound 1 using compound 2 as a raw material can be carried out in a step-by-step or one-pot reaction.

[0029] The third object of the present invention is to provide an application of a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, wherein the compound 1 undergoes a decarboxylation reaction under the action of a catalyst to obtain a 2-hydroxyalkyl-1,2,4-triazole-3-thione compound 3, which is expressed as follows:

[0030]

[0031] Where R 1 , R 2 , R 3 , R 4Each of them is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C1-C18 alkenyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C6-C14 aryl, unsubstituted or substituted C1-C13 heteroaryl, unsubstituted or substituted C7-C18 aralkyl, unsubstituted or substituted C8-C18 aralkenyl, unsubstituted or substituted C7-C18 aryloxyalkyl;

[0032] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0033] Preferably, R 1 , R 2 , R 3 , R 4 Each is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n is an integer of 1-2.

[0034] More preferably, R 1 is hydrogen, unsubstituted or substituted C7 aralkyl, R 2 is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 , R 4 It is hydrogen, n=1.

[0035] More preferably, R 1 is o-chlorobenzyl, R 2 is 1-chlorocyclopropyl, R 3 , R 4 is hydrogen, n=1 or R 1 , R 2 , R 3 , R 4 It is hydrogen, n=1.

[0036] The catalyst is acid B, including one or more of Bronsted acid and Lewis acid. The Bronsted acid is such as sulfuric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid, etc. The Lewis acid is such as ferric chloride, aluminum chloride, boron trifluoride, etc. Preferably, hydrochloric acid, p-toluenesulfonic acid, ferric chloride.

[0037] The decarboxylation reaction can be carried out in a batch reactor or a continuous flow reactor.

[0038] As an example, a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1 (R 1 is o-chlorobenzyl, R 2 is 1-chlorocyclopropyl, R 3 , R 4is hydrogen, n=1) can be further converted to prepare the fungicide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole).

[0039] The present invention has the following significant features:

[0040] (1) Compound 1 provided by the present invention has a novel structure and diverse functions;

[0041] (2) The preparation method of the compound is simple, has high yield, less waste, safe operation, and is suitable for mass production;

[0042] (3) This new compound 1 with multifunctional groups can be used to synthesize other valuable compounds through further functional group transformation reactions.

[0043] (4) The new compound 1 was successfully used to prepare the fungicide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole), solving various problems of the existing preparation methods.

[0044] Definition of noun:

[0045] The compounds described in this application are interpreted as including the compounds and their stereoisomers, tautomers, isotopic compounds or their pesticide-acceptable salts or esters. The stereoisomers, tautomers, isotopic compounds or their pesticide-acceptable salts are obtained by conventional technical means in the art, and play the same or similar effects in vivo and in vitro with substantially the same mechanism of action as the compounds.

[0046] The term "stereoisomer" refers to isomers produced by different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers, wherein configurational isomers include geometrical isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometrical isomers may exist in the present compound. Optical isomers refer to substances with identical molecular structures, similar physical and chemical properties, but different optical rotations. The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are defined as IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Atoms with an excess of one configuration (relative to the other) result in that configuration being present in higher amounts, preferably an excess of about 85% 90%, more preferably an excess of about 95% 99%, and even more preferably an excess of greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0047] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0048] The term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number is different from the atomic weight or mass number of the largest amount of atoms found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine and iodine include, but are not limited to: 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, 80Br and 125I. Compounds containing other isotopes of these and / or other atoms are within the scope of the present invention. Isotope-labeled compounds of the present invention may be prepared using general methods known to those of ordinary skill in the art.

[0049] The term "pesticide-acceptable salt" refers to a salt obtained by reacting the 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound of the present application with a chemically acceptable base, wherein the chemically acceptable base may be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.); the pesticide-acceptable salt may also be a salt obtained by reacting the 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound of the present application with a chemically acceptable acid, wherein the chemically acceptable acid may be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid, etc.). Furthermore, the salt acceptable as a pesticide may be a potassium salt, a sodium salt, an ammonium salt, a calcium salt, a pyridinium salt, a choline salt, a hydrochloride, a phosphate, an acetate, a benzenesulfonate or an oxalate.

[0050] The term "pesticide acceptable ester" refers to an ester formed between a carboxyl group on the 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound of the present application and an alcohol, a thioester formed between a mercapto group and an acylating agent, or an ester formed between a hydroxyl group and an acylating agent.

[0051] The halogen mentioned herein means fluorine, chlorine, bromine and iodine.

[0052] The term "substituted" as used herein means that one or more hydrogen atoms on a carbon atom or a nitrogen atom are independently substituted by the following groups: specifically, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio ... C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 haloalkylcarbonyloxy, C1-C6 alkylsulfonyloxy, C1-C6 haloalkylsulfonyloxy, C2-C7 alkoxycarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 alkylcarbonyl amino, C2-C7 haloalkylcarbonylamino, C2-C7 alkoxycarbonylamino, C2-C7 haloalkoxycarbonylamino, C2-C7 alkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C1-C6 alkylamino, C1-C6 haloalkylamino, C2-C6 alkenylamino, C2-C6 haloalkenylamino, C2-C6 alkynylamino, C2-C6 haloalkynylamino, C3-C9 cycloalkylamino, C3-C9 halocycloalkylamino, C3-C The following may be selected from the group consisting of: C3-C7 alkenylaminocarbonyl, C3-C7 haloalkenylaminocarbonyl, C3-C7 alkynylaminocarbonyl, C3-C7 haloalkynylaminocarbonyl, C4-C10 cycloalkylaminocarbonyl, C4-C10 halocycloalkylaminocarbonyl, amino, carbamoyl, sulfamoyl, cyano, nitro, hydroxy, carboxyl, phenyl which may have a substituent, a heterocyclic group which may have a substituent, a benzyl group which may have a substituent, a phenylcarbonyl group which may have a substituent, and a phenylamino group which may have a substituent.

[0053] The alkyl group includes straight-chain alkyl groups and branched-chain alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl and the like.

[0054] The cycloalkyl group refers to C3-C8 cycloalkyl and cycloheteroalkyl groups. Cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Cycloheteroalkyl groups include glycidyl, tetrahydrofuranyl, dioxanyl and tetrahydropyrrolyl.

[0055] The aryl group includes phenyl, naphthyl, anthracenyl and phenanthrenyl.

[0056] The heteroaryl group includes a group containing at least one aromatic ring, and one or more carbon atoms in the aromatic ring are replaced by heteroatoms such as nitrogen, oxygen, sulfur, etc. Common heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and fused ring indolyl, quinolyl, carbazolyl, purinyl, etc.

[0057] The aralkyl group refers to an alkyl group in which one or more hydrogen atoms are replaced by an aryl group, such as benzyl.

[0058] The aromatic alkenyl group refers to an alkenyl group in which one or more hydrogen atoms are replaced by an aromatic group, such as a styryl group.

[0059] The aryloxyalkyl group refers to an alkyl group in which one or more hydrogen atoms are replaced by an aryloxy group, such as a phenoxymethyl group.

[0060] The alkali metals are lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr). The alkaline earth metals are beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), and radium (Ra).

[0061] It should also be pointed out that the definition of the number of carbon atoms in a carbon chain herein does not include carbon atoms in substituents. For example, the "unsubstituted or substituted C6-C14 aromatic group" mentioned herein also falls within the scope of the present invention if the aromatic ring contains substituents of multiple carbon atoms, resulting in a total carbon number exceeding 14. DETAILED DESCRIPTION

[0062] The following embodiments are clear and complete descriptions of the technical solutions of the present invention; it is obvious that the embodiments described are only part of the embodiments of the present invention, not all of them. 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.

[0063] The continuous flow reaction device used in Example 7 is a silicon carbide microchannel reactor, and the one used is a microchannel reactor made of silicon carbide made by Jinde, model JD-A-20. The microchannel reactor is composed of 6 identical reaction modules connected in series (each module has a liquid holding capacity of 20 ml); the first to fifth are reaction modules, with a total liquid holding capacity of 100 ml and a set temperature of 150°C; the sixth module is a cooling module, with a temperature set at 45°C; the outlet of the sixth module is connected to a back pressure valve and then to a receiving bottle.

[0064] Example 1: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0065] Add 13.7g 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol and 100mL acetonitrile to a 250mL reaction bottle, add 4g 50% glyoxylic acid aqueous solution dropwise, and stir at room temperature for 2 hours. Add 50ml water and 4.6g ammonium thiocyanate, then add 8g hydrochloric acid dropwise, and stir at room temperature for 6 hours. Let stand to separate. Cool the reaction solution to 0°C, add 15g hydrogen peroxide dropwise, and keep warm for 5 hours. Separate the layers, concentrate, add toluene, wash with water, and desolventize to obtain 18.8g solid product (yield 97%). 1 H NMR(δ,DMSO-d6): 14.518(m,1H), 7.584-7.565(m,1H), 7.410-7.391(m,1H), 7.276-7.245(m,2H),5.068(s,1H),4.657-4.628(d,1H) ),4.473-4.444(d,1H),3.385(s,1H),3.314-3.244(m,2H),1.014-0.988,0.827-0.794,0.755-0.699(m,4H); MS: m / z=387.9([M+1] + ).

[0066] Example 2: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0067] In a 250mL reaction bottle, add 15.6g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride, 100mL of acetic acid and 20ml of water, dropwise add 11.5g of 50% sodium glyoxylate aqueous solution, and stir at room temperature for 3 hours. Add 20g of water and 5.7g of sodium thiocyanate, then dropwise add 7.5g of concentrated sulfuric acid, and stir at room temperature for 8 hours. Let stand to separate. The reaction solution is cooled to -5°C, air is introduced, and the reaction is kept warm for 7 hours. Layer, concentrate, add toluene, wash with water, and desolventize to obtain 19g of solid product (yield 98%).

[0068] Example 3: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0069] Add 23.4g 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinopropan-2-ol hydrochloride, 120mL water and 20ml acetonitrile to a 250mL reaction bottle, cool to 10°C, dropwise add 60g 10% glyoxylic acid aqueous solution, and stir for 3 hours. Filter and wash with water. Add the solid wet product obtained by washing with water and 150ml acetic acid to another 250mL reaction bottle, add 8.5g sodium thiocyanate, then dropwise add 12.6g sodium bisulfate, and stir at room temperature for 10 hours. Let stand and separate. Cool the reaction solution to -10°C, introduce oxygen, and keep warm for 10 hours. Separate and concentrate, add toluene, wash with water, and desolventize to obtain 25.5g solid product (yield 98.5%).

[0070] Example 4: Synthesis of 1-(2-hydroxyethyl)-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0071] Add 15.7g 2-2-hydrazineethanol and 100mL acetonitrile to a 500mL reaction bottle, add 22.1g glyoxylic acid monohydrate, and stir at room temperature for 1 hour. Add 100ml water and 25.3g potassium thiocyanate, then dropwise add 31.6g hydrochloric acid, and stir at room temperature for 8 hours. The reaction solution is cooled to -10°C, 59g ferric chloride hexahydrate is added in batches, and the reaction is kept warm for 5 hours. Layer, concentrate, add toluene, wash with water, and desolventize to obtain 35.9g solid product (yield 95%). 1 H NMR (δ, DMSO-d6): 14.247 (s, 1H), 4.704 (s, 1H), 4.167-4.144 (t, 2H), 3.761-3.737 (t, 2H); MS: m / z=189.9 ([M+1] + )

[0072] Example 5: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione

[0073] In a 250 mL hydrothermal kettle, 20 g of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid and 100 mL of toluene were added, and 0.5 g of p-toluenesulfonic acid was added, and the temperature was raised to 130° C. and kept for 3 hours. After cooling, washing with water, and desolventizing, 17.6 g of solid product was obtained (yield 99%). 1H NMR(δ,CDCl3):12.300(s,1H),7.856(s,1H),7.549-7.544,7.534-7.530(dd ,1H),7.377-7.374,7.362-7.358(dd,1H),7.242-7.183(m,2H),4.802-4.77 3(d,1H),4.510-4.481(d,1H),4.212(s,1H),3.621-3.594(d,1H),3.193-3. 166(d,1H),0.943-0.922(m,1H),0.885-0.767(m,3H); MS: m / z=343.9([M+1] + ).

[0074] Example 6: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione

[0075] Add 30g of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid and 100mL of Hisol (100 solvent oil) into a 250mL reaction bottle, dropwise add 0.5g of 10% FeCl3 solution, heat to 150°C, and keep warm for 2 hours. Cool, wash with water, and desolventize to obtain 26.6g of solid product (yield 99%).

[0076] Example 7: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione

[0077] A 40% tert-butyl alcohol solution of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid was added with hydrochloric acid to adjust the pH to 2. The solution was input into the first module of the Kind microchannel reactor at a speed of 50 ml / min by an infusion pump; at the same time, a 5% hydrochloric acid aqueous solution was input into the third reaction module at 0.5 ml / min. The reaction mixture was collected in a receiving bottle after passing through a cooling module and a back pressure valve. The collected reaction mixture was concentrated, washed with toluene, and desolventized to obtain a solid product (yield 98%).

[0078] Example 8: Synthesis of 2-(2-hydroxyethyl)-1,2,4-triazole-3-thione

[0079] 35.9 g of 1-(2-hydroxyethyl)-5-mercapto-1,2,4-triazole-3-carboxylic acid and 100 mL of acetic acid were added to a 250 mL reaction bottle, the temperature was raised to reflux, and the reaction was performed for 5 hours. The mixture was cooled, washed with water, and desolventized to obtain 23 g of a solid product (yield 98%). 1 HNMR (δ, CDCl3): 12.208 (s, 1H), 7.946 (s, 1H), 4.377-4.354 (t, 2H), 3.866-3.842 (t, 2H); MS: m / z=145.9 ([M+1] + )

[0080] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. 1-Hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, the structural formula is as follows: in, R 1 , R 2 , R 3 , R 4 Each of them is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C1-C18 alkenyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C6-C14 aryl, unsubstituted or substituted C1-C13 heteroaryl, unsubstituted or substituted C7-C18 aralkyl, unsubstituted or substituted C8-C18 aralkenyl, unsubstituted or substituted C7-C18 aryloxyalkyl; n is an integer of 1 to 4.

2. The compound according to claim 1, characterized in that R 1 , R 2 , R 3 , R 4 are independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, n=an integer of 1-2; R 1 Preferably, hydrogen, unsubstituted or substituted C7 aralkyl, R 2 is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 , R 4 It is hydrogen, n=1.

3. The compound according to claim 2, characterized in that R 1 is o-chlorobenzyl, R 2 is 1-chlorocyclopropyl, R 3 , R 4 is hydrogen, n=1; or R 1 , R 2 , R 3 , R 4 It is hydrogen, n=1.

4. A method for preparing a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, comprising the following steps: (a) a hydroxyalkyl hydrazine compound 2 is condensed with glyoxylic acid or glyoxylate; (b) the condensation product is subjected to addition cyclization with thiocyanic acid or thiocyanate under the action of acid A; (c) the addition cyclization product is dehydrogenated under the action of an oxidant to obtain a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, which is represented by the following equation: in, R 1 , R 2 , R 3 , R 4 , n is defined as in claim 1; m＝0-2； HX is hydrohalic acid, sulfuric acid or phosphoric acid; The acid A is a protonic acid.

5. The method according to claim 4, characterized in that HX is a hydrohalic acid; glyoxylic acid is glyoxylic acid or its hydrate; glyoxylate is an alkali metal salt or an ammonium salt; thiocyanate is an alkali metal salt, an alkaline earth metal salt or an ammonium salt of thiocyanate; the acid A is a hydrohalic acid, sulfuric acid, phosphoric acid, or a carboxylic acid; the oxidant is one or more of ferric chloride, hydrogen peroxide, nitric acid, air, and oxygen; and m=0 or 1.

6. The method according to claim 5, characterized in that HX is hydrochloric acid; glyoxylic acid is its hydrate; glyoxylic acid alkali metal salt is preferably glyoxylic acid sodium salt; thiocyanate is thiocyanate alkali metal salt, preferably thiocyanate sodium salt; acid A is hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid; the oxidant is oxygen and hydrogen peroxide.

7. The method according to any one of claims 4 to 6, characterized in that: The process of preparing compound 1 using compound 2 as a raw material can be carried out in a step-by-step or "one-pot" reaction.

8. An application of a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, comprising the steps of subjecting the compound 1 to a decarboxylation reaction under the action of a catalyst to obtain a 2-hydroxyalkyl-1,2,4-triazole-3-thione compound 3, which is represented by the following equation: in, R 1 , R 2 , R 3 , R 4 , n is defined as in claim 1; The catalyst is acid B.

9. The use according to claim 8, characterized in that: The acid B is one or more of Bronsted acid and Lewis acid; preferably sulfuric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid, ferric chloride, aluminum chloride, and boron trifluoride.

10. The use according to any one of claims 8-9, characterized in that: The decarboxylation reaction can be carried out in a batch reactor or a continuous flow reactor.

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