1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds, preparation method therefor, and use thereof

Abstract

Provided in the present invention are 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds, a preparation method therefor, and use thereof. Hydroxyalkylhydrazine compound 2, as a starting material, is subjected to a condensation reaction, an addition-cyclization reaction, and a dehydrogenation reaction in sequence to obtain 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1. The present invention has the following significant features and advantages: (1) the compound 1 provided by the present invention has a novel structure and various functions; (2) the preparation method for the compound features simple and convenient process, high yield, low degree of three waste generation, safe operation, and suitability for mass production; (3) the new compound 1 having a multifunctional group can be used to synthesize other compounds having important value by means of a further functional group conversion reaction, such as a bactericide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole).

Description

A class of 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a class of 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds, their preparation methods, and applications. Background Technology

[0002] This invention provides a novel class of 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds 1, the structural formula of which is shown below:

[0003] These novel compounds, 1, which have not been previously reported in the literature, represent a class of multifunctional compounds. With further functional group transformations, compound 1 is expected to be used to synthesize a wide variety of derivatives with different chemical, physical, and biological properties.

[0004] For example, compound 1 can be used to produce end products with practical applications, such as the fungicide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole).

[0005] CN105949137 provides a detailed analysis and comparison of several known techniques for preparing prothioconazole and discloses a superior synthetic method. This method successfully solves various problems of previous methods by using 2-{2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]hydrazine}acetic acid as an intermediate. However, due to the cis-trans isomerism of the hydrazine C=N double bond in this intermediate compound, some product separation problems exist in large-scale production.

[0006] The actual bactericidal applications of prothioconazole have been disclosed by patents such as WO9616048, WO9918086, WO9918087, and WO9918088.

[0007] Summary of the Invention

[0008] The primary objective of this invention is to provide a novel class of 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compounds 1, the structural formula of which is shown below:

[0009] Among them, R 1 R 2 R 3 R 4Independently, they are 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 arylene, and unsubstituted or substituted C7-C18 aryloxyalkyl.

[0010] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0011] Preferably, R 1 R 2 R 3 R 4 Each of the following is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n = 1-2 integers.

[0012] More preferably, R 1 It is a hydrogen-containing, unsubstituted or substituted C7 aralkyl group, R 2 It is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 R 4 It is hydrogen, n=1.

[0013] More preferably, R 1 o-chlorobenzyl, R 2 It is 1-chlorocyclopropyl, R 3 R 4 For hydrogen, n = 1 or R 1 R 2 R 3 R 4 It is hydrogen, n=1.

[0014] The second objective of this invention is to provide a method for preparing 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, comprising the following steps: (a) condensing hydroxyalkylhydrazine compound 2 with glyoxylic acid or glyoxylate; (b) cyclizing the condensation product with thiocyanate or thiocyanate under the action of acid A; (c) dehydrogenating the cyclization product under the action of an oxidant to obtain 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, represented by the following equation:

[0015] Among them, R 1 R 2 R 3 R 4Independently, they are 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 arylene, and unsubstituted or substituted C7-C18 aryloxyalkyl.

[0016] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0017] Preferably, R 1 R 2 R 3 R 4 Each of the following is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n = 1-2 integers.

[0018] More preferably, R 1 It is a hydrogen-containing, unsubstituted or substituted C7 aralkyl group, R 2 It is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 R 4 It is hydrogen, n=1.

[0019] More preferably, R 1 o-chlorobenzyl, R 2 It is 1-chlorocyclopropyl, R 3 R 4 For hydrogen, n = 1 or R 1 R 2 R 3 R 4 It is hydrogen, n=1.

[0020] The m = 0-2, specifically 0, 0.5, 1, 1.5, 2 or any value within the interval thereof.

[0021] HX is a hydrohalic acid, sulfuric acid, or phosphoric acid, and the hydrohalic acid is hydrochloric acid or hydrobromic acid, preferably hydrochloric acid.

[0022] 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 8Each of the following is independently hydrogen, a non-substituted or substituted alkyl group, a non-substituted or substituted aralkyl group, or a non-substituted or substituted aryl group, specifically as R 5 ,R 6 ,R 7 ,R 8 It is methyl or n-butyl.

[0023] The thiocyanate is an alkali metal salt, alkaline earth metal salt, or ammonium salt of thiocyanate. 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 Each of the following is independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl, specifically as R 5 ,R 6 ,R 7 ,R 8 It is methyl or n-butyl.

[0024] Acid A is a protic acid; acid A is a hydrohalic acid, sulfuric acid, phosphoric acid, or carboxylic acid; carboxylic acid is an alkyl carboxylic acid or an aryl carboxylic acid, and the alkyl carboxylic acid or aryl carboxylic acid includes substituted alkyl carboxylic acids or aryl carboxylic acids; acid A is preferably hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or benzenesulfonic acid.

[0025] The oxidant is one or more of ferric chloride, hydrogen peroxide, nitric acid, air, and oxygen, preferably oxygen or hydrogen peroxide.

[0026] The process of preparing compound 1 from compound 2 can be carried out in steps or in a one-pot reaction.

[0027] A third objective of this invention is to provide an application of compound 1, 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid, wherein compound 1 undergoes a decarboxylation reaction under the action of a catalyst to yield compound 3, 2-hydroxyalkyl-1,2,4-triazole-3-thione, as represented by the following equation:

[0028] Where R 1 R 2 R 3 R 4Independently, they are 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 arylene, and unsubstituted or substituted C7-C18 aryloxyalkyl.

[0029] n is an integer from 1 to 4, such as 1, 2, 3, 4.

[0030] Preferably, R 1 R 2 R 3 R 4 Each of the following is independently hydrogen, unsubstituted or substituted C1-C18 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted C7-C18 aralkyl, and n = 1-2 integers.

[0031] More preferably, R 1 It is a hydrogen-containing, unsubstituted or substituted C7 aralkyl group, R 2 It is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 R 4 It is hydrogen, n=1.

[0032] More preferably, R 1 o-chlorobenzyl, R 2 It is 1-chlorocyclopropyl, R 3 R 4 For hydrogen, n = 1 or R 1 R 2 R 3 R 4 It is hydrogen, n=1.

[0033] The catalyst is acid B, including one or more of Bronsted acids and Lewis acids. Bronsted acids include sulfuric acid, hydrochloric acid, acetic acid, and p-toluenesulfonic acid. Lewis acids include ferric chloride, aluminum trichloride, and boron trifluoride. Hydrochloric acid, p-toluenesulfonic acid, and ferric chloride are preferred.

[0034] The decarboxylation reaction can be carried out in a batch reactor or a continuous flow reactor.

[0035] As an example, 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1 (R) was prepared by the present invention. 1 o-chlorobenzyl, R 2 It is 1-chlorocyclopropyl, R 3 R 4(If the hydrogen content is 1, n=1) can be further converted to prepare the bactericide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole).

[0036] This invention has the following significant features:

[0037] (1) Compound 1 provided by the present invention has a novel structure and diverse functions;

[0038] (2) The preparation method of this compound is simple, has a high yield, produces little waste, is safe to operate, and is suitable for mass production;

[0039] (3) This type of new compound 1 with multifunctional groups can be used to synthesize other compounds of important value through further functional group transformation reactions.

[0040] (4) The new compound 1 was successfully used in the preparation of the fungicide 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazole-3-thione (prothioconazole), which solved various problems of the existing preparation methods.

[0041] Definition of the noun:

[0042] The compounds described in this application are interpreted as including the compounds themselves, their stereoisomers, tautomers, isotopic compounds, or pesticide-acceptable salts or esters thereof. The stereoisomers, tautomers, isotopic compounds, or pesticide-acceptable salts of the compounds are obtained using conventional techniques in the art and exert the same or similar effects in vitro and in vivo through substantially the same mechanism of action as the compounds themselves.

[0043] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may be present in this compound. Optical isomers refer to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in 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. Having an excess of atoms in one configuration (relative to another) results in a higher quantity of that configuration, preferably an excess of about 85% to 90%, more preferably an excess of about 95% to 99%, and even more preferably an excess greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0044] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0045] The term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. 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. The isotopically labeled compounds of the present invention can be prepared using general methods well known to those skilled in the art.

[0046] 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 this application with a chemically acceptable base. The chemically acceptable base can 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.). Alternatively, the pesticide-acceptable salt can be a salt obtained by reacting the 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound of this application with a chemically acceptable acid. The chemically acceptable acid can 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 salts acceptable as pesticides can be potassium salts, sodium salts, ammonium salts, calcium salts, pyridine salts, choline salts, hydrochloride salts, phosphates, acetates, benzenesulfonates, or oxalates.

[0047] The term "pesticide-acceptable ester" refers to an ester formed by the carboxyl group and an alcohol, a thioester formed by the mercapto group and an acylation reagent, or an ester formed by the hydroxyl group and an acylation reagent on the 1-hydroxyalkyl-5-mercapto-1,2,4-triazol-3-carboxylic acid compound of this application.

[0048] The halogens mentioned in the text refer to fluorine, chlorine, bromine, and iodine.

[0049] The term "non-substituted or substituted" in this text refers to substitution where one or more hydrogen atoms on a carbon or 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-C 6-Halogenated alkylthioyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkylcarbonyloxy, C2-C7 alkylcarbonyloxy, C1-C6 alkylsulfonyloxy, C1-C6 alkylsulfonyloxy, C2-C7 alkoxycarbonyl, 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 7-C10 alkenylaminocarbonyl, C3-C7 haloalkenylaminocarbonyl, C3-C7 alkynylaminocarbonyl, C3-C7 haloalkynylaminocarbonyl, C4-C10 cycloalkylaminocarbonyl, C4-C10 halocycloalkylaminocarbonyl, amino, carbamoyl, aminosulfonyl, cyano, nitro, hydroxyl, carboxyl, phenyl (which may have substituents), heterocyclic (which may have substituents), benzyl (which may have substituents), phenylcarbonyl (which may have substituents), and phenylamino (which may have substituents).

[0050] The alkyl group includes straight-chain alkyl and branched-chain alkyl, such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, etc.

[0051] The term "cycloalkyl" refers to C3-C8 cyclocarbonyl and cycloheteroalkyl groups. Examples of cyclocarbonyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. Examples of cycloheteroalkyl groups include glycidyl, tetrahydrofuranyl, dioxanecyclol, and tetrahydropyrroleyl.

[0052] The aryl groups include phenyl, naphthyl, anthracene, and phenanthrene.

[0053] The aforementioned heteroaryl group comprises a group containing at least one aromatic ring, wherein one or more carbon atoms in the aromatic ring are substituted by heteroatoms such as nitrogen, oxygen, and sulfur. Common heteroaryl groups include pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and fused-ring indole, quinolinyl, carbazole, and purine groups.

[0054] The term aryl refers to an alkyl group in which one or more hydrogen atoms are replaced by an aryl group, such as benzyl.

[0055] The term "aryl group" refers to an alkenyl group in which one or more hydrogen atoms are replaced by an aryl group, such as styrene.

[0056] The term "aryloxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by aryloxy groups, such as phenoxymethyl.

[0057] The alkali metals mentioned 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).

[0058] It should also be noted that the definition of the number of carbon atoms in the carbon chain in this article does not include carbon atoms in substituents. For example, the case of "non-substituted or substituted C6-C14 aryl" mentioned in this article, where the total number of carbon atoms exceeds 14 due to the presence of substituents with multiple carbon atoms in the aromatic ring, is also within the scope of this invention. Detailed Implementation

[0059] The following embodiments clearly and completely describe the technical solutions of the present invention; obviously, the embodiments described are only some embodiments of the present invention, and 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.

[0060] The continuous flow reactor used in Example 7 was a silicon carbide microchannel reactor, specifically a Jinde silicon carbide microchannel reactor, model JD-A-20. The microchannel reactor consisted of six identical reaction modules connected in series (each module had a liquid holding capacity of 20 ml); the first to fifth modules were reaction modules with a total liquid holding capacity of 100 ml and a set temperature of 150°C; the sixth module was a cooling module with a set temperature of 45°C; the outlet of the sixth module was connected to a back pressure valve and then to a receiving bottle.

[0061] Example 1: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0062] 13.7 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinoprop-2-ol and 100 mL of acetonitrile were added to a 250 mL reaction flask, followed by the dropwise addition of 4 g of 50% glyoxylic acid aqueous solution. The mixture was stirred at room temperature for 2 hours. 50 mL of water and 4.6 g of ammonium thiocyanate were added, followed by the dropwise addition of 8 g of hydrochloric acid. The mixture was stirred at room temperature for 6 hours. The mixture was allowed to stand to separate into layers. The reaction solution was cooled to 0 °C, and 15 g of hydrogen peroxide was added dropwise. The reaction was maintained at this temperature for 5 hours. The layers were separated, concentrated, and toluene was added. The mixture was washed with water and dissolved to obtain 18.8 g of solid product (97% yield). 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] + ).

[0063] Example 2: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0064] In a 250 mL reaction flask, add 15.6 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinoprop-2-ol hydrochloride, 100 mL of acetic acid, and 20 mL of water. Add 11.5 g of 50% sodium glyoxylate aqueous solution dropwise and stir at room temperature for 3 hours. Add 20 g of water and 5.7 g of sodium thiocyanate, followed by 7.5 g of concentrated sulfuric acid. Stir at room temperature for 8 hours. Allow to stand for separation. Cool the reaction solution to -5 °C, purge with air, and maintain the reaction temperature for 7 hours. Separate the layers, concentrate, add toluene, wash with water, and remove solvent to give 19 g of solid product (98% yield).

[0065] Example 3: Synthesis of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazol-3-carboxylic acid

[0066] In a 250 mL reaction flask, add 23.4 g of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-hydrazinoprop-2-ol hydrochloride, 120 mL of water, and 20 mL of acetonitrile. Cool to 10 °C, and add 60 g of 10% glyoxylic acid aqueous solution dropwise. Stir at this temperature for 3 hours. Filter and wash with water. In another 250 mL reaction flask, add the wet solid obtained after washing with water and 150 mL of acetic acid, then add 8.5 g of sodium thiocyanate, followed by dropwise addition of 12.6 g of sodium bisulfate. Stir at room temperature for 10 hours. Allow to stand for phase separation. Cool the reaction solution to -10 °C, introduce oxygen, and maintain the reaction temperature for 10 hours. Separate the layers, concentrate, add toluene, wash with water, and remove solvent to obtain 25.5 g of solid product (yield 98.5%).

[0067] Example 4: Synthesis of 1-(2-hydroxyethyl)-5-mercapto-1,2,4-triazole-3-carboxylic acid

[0068] In a 500 mL reaction flask, 15.7 g of 2-2-hydrazinoethanol and 100 mL of acetonitrile were added, followed by 22.1 g of glyoxylic acid monohydrate. The mixture was stirred at room temperature for 1 hour. Then, 100 mL of water and 25.3 g of potassium thiocyanate were added, followed by dropwise addition of 31.6 g of hydrochloric acid. The mixture was stirred at room temperature for 8 hours. The reaction solution was cooled to -10 °C, and 59 g of ferric chloride hexahydrate was added in portions. The reaction mixture was kept at this temperature for 5 hours. The layers were separated, concentrated, and toluene was added. The mixture was washed with water and dissolved to obtain 35.9 g of solid product (95% yield). 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] + )

[0069] Example 5: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazol-3-thione

[0070] 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 to a 250 mL hydrothermal reactor, along with 0.5 g of p-toluenesulfonic acid. The mixture was heated to 130 °C and reacted for 3 hours. After cooling, the mixture was washed with water and dissolved to obtain 17.6 g of solid product (99% yield). 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] + ).

[0071] Example 6: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazol-3-thione

[0072] 30 g of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazole-3-carboxylic acid and 100 mL of Hisol (solvent oil No. 100) were added to a 250 mL reaction flask, followed by the dropwise addition of 0.5 g of 10% FeCl3 solution. The mixture was heated to 150 °C and maintained at this temperature for 2 hours. After cooling, the mixture was washed with water and the solvent was removed to obtain 26.6 g of solid product (yield 99%).

[0073] Example 7: Synthesis of 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazol-3-thione

[0074] A 40% solution of 1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-5-mercapto-1,2,4-triazol-3-carboxylic acid in tert-butanol was added to adjust the pH to 2 with hydrochloric acid. This solution was then pumped into the first module of the Jinde microchannel reactor at a rate of 50 ml / min; simultaneously, a 5% hydrochloric acid aqueous solution was pumped into the third reaction module at a rate of 0.5 ml / min. The reaction mixture was collected in a receiving flask after passing through a cooling module and a back pressure valve. The collected reaction mixture was concentrated, washed with toluene water, and solvent-removed to give a solid product (98% yield).

[0075] Example 8: Synthesis of 2-(2-hydroxyethyl)-1,2,4-triazol-3-thione

[0076] 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 flask, and the mixture was heated to reflux and reacted for 5 hours. After cooling, the mixture was washed with water and the solvent was removed to give 23 g of solid product (yield 98%). 1 H NMR (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] + )

[0077] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions 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 compounds 1, of the following structure: in, R 1 R 2 R 3 R 4 Independently, they are 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 arylene, and unsubstituted or substituted C7-C18 aryloxyalkyl. n is an integer from 1 to 4.

2. The compound of claim 1, wherein R 1 R 2 R 3 R 4 Each of the following is independently hydrogen, a non-substituted or substituted C1-C18 alkyl group, a non-substituted or substituted C3-C18 cycloalkyl group, or a non-substituted or substituted C7-C18 aralkyl group, n being an integer from 1 to 2; R 1 Preferably, it is hydrogen-based, unsubstituted or substituted C7 aralkyl, R 2 It is hydrogen, unsubstituted or substituted C3 cycloalkyl, R 3 R 4 It is hydrogen, n=1.

3. The compound of claim 2, wherein 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 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) condensation of a hydroxyalkylhydrazine compound 2 with glyoxylic acid or a glyoxylic acid salt; (b) addition-cyclization of the condensation product with thiocyanic acid or a thiocyanate salt in the presence of an acid A; (c) dehydrogenation of the addition-cyclization product in the presence of an oxidizing agent to give a 1-hydroxyalkyl-5-mercapto-l,2,4-triazole-3-carboxylic acid compound 1, which is represented by the following equations: in, R 1 , R 2 , R 3 , R 4 , n is as defined in claim 1 ; m＝0-2； HX is a hydrohalic acid, sulfuric acid, or phosphoric acid; The acid A mentioned is a protic acid.

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

6. The method of claim 5, wherein, HX is hydrochloric acid; glyoxylic acid is its hydrate; the alkali metal salt of glyoxylic acid is preferably sodium glyoxylate; thiocyanate is the alkali metal salt of thiocyanate, preferably sodium thiocyanate; acid A is hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or benzenesulfonic acid; the oxidizing agent is oxygen or hydrogen peroxide.

7. The method according to any of claims 4-6, characterized by, The process of preparing compound 1 from compound 2 can be carried out in steps or in a one-pot reaction.

8. The application of a 1-hydroxyalkyl-5-mercapto-1,2,4-triazole-3-carboxylic acid compound 1, comprising the steps of decarboxylating compound 1 in the presence of a catalyst to yield a 2-hydroxyalkyl-1,2,4-triazole-3-thione compound 3, represented by the following equation: wherein, R 1 , R 2 , R 3 , R 4 , n is as defined in claim 1 ; The catalyst is acid B.

9. 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, or boron trifluoride.

10. 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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