A process for the preparation of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole

Abstract

The present application relates to the field of organic chemistry, in particular to the use of silicon compounds in cyclization reactions, and provides a preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, which comprises: subjecting 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine to a cyclization reaction in the presence of a silicon compound and an amide compound to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. The silicon compound or / and the amide provided by the present application can be used as a cyclization reagent to efficiently perform cyclization synthesis, and has higher comprehensive benefits compared with other methods in the prior art.

Description

[0001] This application is a divisional application of patent application filed on February 7, 2021, with application number 202110180140.1 and invention title "Use of silicon compounds in cyclization reactions". Technical Field

[0002] This invention relates to the field of organic chemistry, and in particular to the use of silicon compounds in cyclization reactions. Background Technology

[0003] 2-Chloro-5-chloromethylpyridine (CCMP) is an important intermediate for the best-selling pesticides such as imidacloprid, acetamiprid, thiamethoxam, and acetamiprid, as well as the breast cancer treatment drug Abemaciclib (Bemaciclib, LY-2835219), chemically named N-[5-[(4-ethyl-1-piperazinyl)methyl]2-pyridyl]-5-fluoro-4-[4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl]-2-pyrimidinylamine. Currently, there are three main synthetic routes for 2-chloro-5-chloromethylpyridine using cyclization: the benzylamine method, the cyclopentadiene method, and the morpholine method. Most domestic manufacturers primarily use the cyclopentadiene method, where the cyclization step reaction equation is as follows:

[0004]

[0005] The cyclization step typically uses phosphorus oxychloride (Fine & Specialty Chemicals, 18(1), 47-49; 2010) or phosphorus pentachloride (US5229519), as well as triphosgene or phosgene as the cyclization reagent. Phosphorus-containing reagents have high cyclization yields and are inexpensive, but they generate large amounts of phosphorus-containing wastewater with a COD of approximately 150,000-200,000 ppm. With an annual CCMP production of nearly 10,000 tons, this would generate 60,000 tons of phosphorus-containing wastewater. Cycling with phosgene is highly toxic and has poor safety, therefore few companies use this reagent.

[0006] 5-Chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole is a key intermediate in sitagliptin for diabetes, with an annual demand exceeding 200 tons. Its cyclization step is as follows, using phosphorus oxychloride as the cyclization reagent. This step also suffers from the aforementioned problems: the use of phosphorus-containing reagents generates a large amount of phosphorus-containing wastewater, approximately 5 tons of phosphorus-containing wastewater per ton of product. During the reaction, pyrophosphate caking occurs, leading to difficulty or even halting of stirring, which is highly detrimental to operation, and the actual yield in scale-up production has consistently been low.

[0007]

[0008] Phosphorus-containing wastewater can cause environmental harm. When it enters water bodies, it can lead to eutrophication and disrupt the ecological balance. Its discharge has always been a major problem. Existing technologies are either difficult to treat to standard or too costly.

[0009] Therefore, there is an urgent need in this field for a low-cost and efficient cyclization method to prepare 2-chloro-5-chloromethylpyridine and 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, which would allow for the convenient recycling and utilization of byproducts in an economical and environmentally friendly manner, and effectively reduce phosphorus-containing wastewater generated during the production process, thereby reducing environmental harm. Summary of the Invention

[0010] In view of the shortcomings of the prior art described above, the object of the present invention is to provide the use of silicon compounds in cyclization reactions to solve the problems in the prior art.

[0011] To achieve the above and other related objectives, the present invention provides a method for preparing 2-chloro-5-chloromethylpyridine, comprising: subjecting 4-aldehyde-4,5-dichloropentanonitrile to a cyclization reaction in the presence of a silicon compound and an amide compound to provide 2-chloro-5-chloromethylpyridine, the reaction equation being as follows:

[0012]

[0013] The silicon compound is selected from one or more combinations of compounds with the chemical structural formulas shown below:

[0014]

[0015] Among them, R 3 R 4 R 5 Each is independently selected from H, Ph, C1-C4 alkyl, Cl, or Br;

[0016] Y is selected from O, or it does not exist;

[0017] n is selected from 0, 1, 2, 3, 4 or 5;

[0018] X is selected from Cl or Br.

[0019] In some embodiments of the present invention, in the compound of formula V, R 3 R 4 R 5 Each is independently selected from H, C1-C2 alkyl, Cl, or Br;

[0020] n is selected from 0 or 1;

[0021] X is selected from Cl or Br.

[0022] In some embodiments of the present invention, the silicon compound is selected from one or more combinations of methyltrichlorosilane, diethyldichlorosilane, dimethyldichlorosilane, trimethylmonochlorosilane, 1,2-dimethyl-1,1,2,2-tetrachlorodisilane, silicon tetrachloride, dimethyldibromosilane, trimethylbromosilane, and 1,3-dichloro-1,1,3,3-tetramethylsiloxane.

[0023] In some embodiments of the present invention, the chemical structural formula of the amide compound is selected from RCONR. 1 R 2 Wherein, R is selected from hydrogen, saturated or unsaturated C1-C8 aliphatic groups, substituted or unsubstituted phenyl groups, R 1 R 2 Each is independently selected from saturated or unsaturated C1-C8 aliphatic groups, phenyl groups, or R and R 1 , or R and R 2 Together with the atoms attached to them, they form five- or six-membered heterocyclic groups. Preferably, the amide compound is selected from one or more combinations of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-diethylpropionamide, N,N-dimethylpropionamide, N,N-diphenylformamide, N,N-diphenylacetamide, N,N-diphenylformamide, N,N-diphenylacetamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolinone.

[0024] And / or, in the cyclization reaction, the molar ratio of the compound of formula I to the amide compound is 1:0.1-1.5;

[0025] And / or, the cyclization reaction is carried out in the presence of a solvent, preferably an aprotic solvent, more preferably an aromatic hydrocarbon solvent;

[0026] And / or, the reaction temperature of the cyclization reaction is 70–150°C;

[0027] And / or, in the cyclization reaction, the molar ratio of the compound of formula I to the silicon compound is 1:0.5-2.0;

[0028] And / or, the post-treatment of the cyclization reaction includes: quenching with water, adjusting the pH of the system, solid-liquid separation, and desolvation of the organic phase.

[0029] In some embodiments of the present invention, the method further includes reacting a solid under alkaline conditions to provide a silicon oxide compound, wherein the silicon oxide compound is preferably selected from silicates.

[0030] Another aspect of the present invention provides a method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, comprising: subjecting 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine to a cyclization reaction in the presence of a silicon compound and an amide compound to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, the reaction equation being as follows:

[0031]

[0032] The silicon compound is selected from one or more combinations of compounds with the chemical structural formulas shown below:

[0033]

[0034] Among them, R 3 R 4 R 5 Each is independently selected from H, Ph, C1-C4 alkyl, Cl, or Br;

[0035] Y is selected from O, or it does not exist;

[0036] n is selected from 0, 1, 2, 3, 4 or 5;

[0037] X is selected from Cl or Br.

[0038] In some embodiments of the present invention, in the compound of formula V, R 3 R 4 R 5 Each is independently selected from H, C1-C2 alkyl, Cl, or Br;

[0039] n is selected from 0 or 1;

[0040] X is selected from Cl or Br.

[0041] In some embodiments of the present invention, the silicon compound is selected from one or more combinations of methyltrichlorosilane, diethyldichlorosilane, dimethyldichlorosilane, trimethylmonochlorosilane, 1,2-dimethyl-1,1,2,2-tetrachlorodisilane, silicon tetrachloride, dimethyldibromosilane, trimethylbromosilane, and 1,3-dichloro-1,1,3,3-tetramethylsiloxane.

[0042] In some embodiments of the present invention, the chemical structural formula of the amide compound is selected from RCONR. 1 R 2 Wherein, R is selected from hydrogen, saturated or unsaturated C1-C8 aliphatic groups, substituted or unsubstituted phenyl groups, R 1 R 2 Each is independently selected from saturated or unsaturated C1-C8 aliphatic groups, phenyl groups, or R and R 1, or R and R 2 Together with the atoms attached to them, they form a five- or six-membered heterocyclic group. Preferably, the amide compound is selected from one or more combinations of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-diethylpropionamide, N,N-dimethylpropionamide, N,N-diphenylformamide, N,N-diphenylacetamide, N,N-diphenylformamide, N,N-diphenylacetamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolinone.

[0043] And / or, in the cyclization reaction, the molar ratio of the compound of formula III to the amide compound is 1:0.1-1.5;

[0044] And / or, the cyclization reaction is carried out in the presence of a solvent, preferably an aprotic solvent, more preferably an aromatic hydrocarbon solvent;

[0045] And / or, the reaction temperature of the cyclization reaction is 70–150°C;

[0046] And / or, in the cyclization reaction, the molar ratio of the compound of formula III to the silicon compound is 1:0.5-2.0;

[0047] And / or, the post-treatment of the cyclization reaction includes: quenching with water, adjusting the pH of the system, solid-liquid separation, and desolvation of the organic phase.

[0048] In some embodiments of the present invention, the method further includes reacting a solid under alkaline conditions to provide a silicon oxide compound, wherein the silicon oxide compound is preferably selected from silicates. Detailed Implementation

[0049] To make the inventive objectives, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to embodiments. Those skilled in the art can easily understand other advantages and effects of this invention from the content disclosed in this specification.

[0050] Based on extensive practical research, the inventors of this invention have developed a novel and highly efficient cyclization synthesis method using silicon compounds and / or amides as cyclization reagents. This cyclization synthesis method has higher overall benefits compared to other methods in the prior art, and this invention was completed on this basis.

[0051] In this application, aliphatic groups generally refer to groups containing only carbon and hydrogen atoms, typically referring to the group remaining after a corresponding hydrocarbon loses one hydrogen atom. Aliphatic groups can be saturated or unsaturated, i.e., they can correspond to alkyl, alkenyl, alkynyl, etc.

[0052] In this application, "alkyl" generally refers to a saturated aliphatic group, which can be straight-chain or branched. For example, C1-C20 alkyl generally refers to an alkyl group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Specifically, the alkyl group can be, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, etc.

[0053] In this application, "heterocyclic group" generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon, and has at least one heteroatom selected from N, O, or S in its structure. The heterocyclic group can be unsubstituted or substituted, and can be five-membered or six-membered.

[0054] The first aspect of this invention provides a method for preparing 2-chloro-5-chloromethylpyridine, comprising: subjecting 4-aldehyde-4,5-dichloropentanonitrile to a cyclization reaction in the presence of a silicon compound and an amide compound to provide 2-chloro-5-chloromethylpyridine, the reaction equation being as follows:

[0055]

[0056] The silicon compound is selected from one or more combinations of compounds with the chemical structural formulas shown below:

[0057]

[0058] Among them, R 3 R 4 R 5 Each is independently selected from H, Ph, C1-C4 alkyl, Cl, or Br;

[0059] Y is selected from O, or it does not exist;

[0060] n is selected from 0, 1, 2, 3, 4 or 5;

[0061] X is selected from Cl or Br.

[0062] In a specific embodiment of the present invention, in compound V, R 3 R 4 R 5 Each is independently selected from H, C1-C2 alkyl, Cl, or Br.

[0063] In another specific embodiment of the present invention, in compound V, n is selected from 0 and 1.

[0064] In another specific embodiment of the present invention, in compound V, X is selected from Cl or Br.

[0065] In another specific embodiment of the present invention, the silicon compound is selected from one or more combinations of methyltrichlorosilane, diethyldichlorosilane, dimethyldichlorosilane, trimethylmonochlorosilane, 1,2-dimethyl-1,1,2,2-tetrachlorodisilane, silicon tetrachloride, dimethyldibromosilane, trimethylbromosilane, and 1,3-dichloro-1,1,3,3-tetramethylsiloxane.

[0066] In the above cyclization reaction, the amount of silicon compound used relative to compound I can be appropriately adjusted to ensure the conversion rate and allow the reaction to proceed fully in the forward direction. For example, in the above cyclization reaction, the molar ratio of compound I to silicon compound can be 1:0.5-2.0, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1.0, 1:1.0-1.1, 1:1.1-1.2, 1:1.2-1.3, 1:1.3-1.4, 1:1.4-1.5, 1:1.5-1.6, 1:1.6-1.7, 1:1.7-1.8, 1:1.8-1.9, or 1:1.9-2.0.

[0067] In the above cyclization reactions, amide compounds are usually used as cyclizing agents, and the chemical structural formula of the amide compound can typically be RCONR. 1 R 2 Wherein, R is selected from hydrogen, saturated or unsaturated C1-C8 aliphatic groups, substituted or unsubstituted phenyl groups, R 1 R 2 Each is independently selected from saturated or unsaturated C1-C8 aliphatic groups, phenyl groups, or R and R 1 , or R and R 2Together with the atoms attached to them, they form five- or six-membered heterocyclic groups. For example, the amide compound can be one or more combinations of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-diethylpropionamide, N,N-dimethylpropionamide, N,N-diphenylformamide, N,N-diphenylacetamide, N,N-diphenylformamide, N,N-diphenylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolinone, etc. The amount of the amide compound used can be appropriately adjusted relative to the compound of Formula I to ensure the conversion rate of the reaction and to allow the reaction to proceed fully in the forward direction. For example, in the above cyclization reaction, the molar ratio of compound I to amide compound can be 1:0.1-1.5, 1:0.1-0.2, 1:0.2-0.3, 1:0.3-0.4, 1:0.4-0.5, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1.0, 1:1.0-1.1, 1:1.1-1.2, 1:1.2-1.3, 1:1.3-1.4, or 1:1.4-1.5.

[0068] In the above-described cyclization reactions, the reaction is typically carried out in the presence of a solvent. The reaction solvent used is usually an aprotic solvent and can be a good solvent for the reaction system. The type and amount of suitable reaction solvent should be adjustable by those skilled in the art. For example, in the above-described cyclization reactions, the reaction solvent can be selected from aromatic hydrocarbon solvents, etc. In a specific embodiment of the present invention, in the above-described cyclization reactions, the reaction solvent can be selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, etc. As another example, in the above-described cyclization reactions, the weight of the reaction solvent can be 1 to 8 times, 1 to 2 times, 2 to 4 times, or 4 to 8 times the weight of the reaction substrate.

[0069] In the above-described cyclization reaction, the reaction can be carried out at temperatures ranging from room temperature to the boiling point of the solvent, preferably under heating conditions. For example, the reaction temperature in the above-described cyclization reaction can be 70–150°C, 70–80°C, 80–90°C, 90–100°C, 100–110°C, 110–120°C, 120–130°C, 130–140°C, or 140–150°C. Those skilled in the art can adjust the reaction time according to the reaction progress. For example, the reaction progress in the above-described cyclization reaction can be determined by methods such as TLC or chromatography. Furthermore, the reaction time in the above-described cyclization reaction can be 1–20 h, 1–2 h, 2–4 h, 4–6 h, 6–8 h, 8–12 h, or 12–20 h.

[0070] In the above-described cyclization reaction, those skilled in the art can choose appropriate methods to post-process the product obtained from the reaction. For example, this may include: quenching with water, adjusting the pH of the system, solid-liquid separation, and solvent removal from the organic phase to provide 2-chloro-5-chloromethylpyridine. After the reaction is complete, the reaction system can be quenched with water, and the pH of the system can be appropriately adjusted (e.g., adjusted to a weakly acidic to weakly basic state, more specifically, pH = 6–8). Solid-liquid separation is then performed, and the organic phase obtained in the liquid phase is further purified to provide 2-chloro-5-chloromethylpyridine. The 2-chloro-5-chloromethylpyridine product can be further purified to provide 2-chloro-5-chloromethylpyridine with higher purity. Suitable purification methods should be known to those skilled in the art; for example, methods such as distillation can be used.

[0071] The method for preparing 2-chloro-5-chloromethylpyridine provided by this invention may further include: reacting a solid phase (obtained through solid-liquid separation) under alkaline conditions to provide a silicon oxide compound. The solid phase mainly includes a silyl ether polymer generated during the cyclization reaction for preparing 2-chloro-5-chloromethylpyridine, which can be hydrolyzed under alkaline conditions to form the corresponding silicon oxide compound.

[0072] In the above methods for preparing silicon oxides, the silicon oxides vary depending on the substituents in the silicon compound used in the cyclization reaction. For example, when R in the silicon compound... 3 R 4 R 5 When both are independently selected from Cl and Br, the resulting silicon oxide compound can be a silicate; when R in the silicon compound... 3 R 4 R 5 One of them is selected from Ph or C1-C4 alkyl, and the remaining R 3 R 4 R 5 When two of them are independently selected from Cl and Br, the resulting silicon oxide compound can be a phenyl silicate or an alkyl silicate; when R 3 R 4 R 5 Two of them are independently selected from C1-C4 alkyl groups, and the remaining R 3 R 4 R 5 When one of them is selected from Cl or Br, the resulting silicon oxide compound can be a polydialkylsiloxane; when R 3 R 4 R 5 When each molecule is independently selected from C1-C4 alkyl groups, the resulting silicon oxide can be a hexaalkyldisil ether. The resulting silicate typically corresponds to the cation included under alkaline conditions. For example, when the alkaline conditions include Na... +Under alkaline conditions, the aforementioned silicate can be sodium silicate, and phenyl silicates or alkyl silicates can be sodium phenyl silicate or sodium alkyl silicate, respectively. For example, alkaline conditions can be provided by suitable alkaline compounds, which can also be suitable sodium salts (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, etc.), thereby providing conditions including Na... + Alkaline conditions.

[0073] In the above-described method for preparing silicon oxide compounds, the amount of basic compound used is essentially equal to or in excess of the silyl ether polymer, thereby ensuring the conversion rate of the reaction and allowing the reaction to proceed fully in the forward direction. For example, in the above-described method for preparing silicon oxide compounds, the equivalent ratio of the silyl ether polymer to the basic compound can be 1:0.5-5, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1, 1:1-1.1, 1:1.1-1.2, 1:1.2-1.5, 1:1.5-2, 1:2-3, 1:3-4, or 1:4-5.

[0074] In the above-described method for preparing silicon oxide compounds, the reaction can be carried out at temperatures ranging from room temperature to the boiling point of the solvent. The reaction temperature can typically be adjusted appropriately based on the reaction pressure of the reaction system to obtain a faster reaction rate. For example, the reaction temperature in the above-described method for preparing silicon oxide compounds can be 100–150°C, 100–105°C, 105–110°C, 110–120°C, 120–130°C, 130–140°C, or 140–150°C. Furthermore, the reaction pressure can be atmospheric pressure or a pressurized condition ≤5 bar. Those skilled in the art can adjust the reaction time according to the reaction progress. For example, the cyclization reaction progress can be determined using methods such as TLC or chromatography in the above-described method for preparing silicon oxide compounds. Furthermore, the reaction time in the above-described method for preparing silicon oxide compounds can be 0.5–10 h, 0.5–1 h, 1–2 h, 2–4 h, 4–6 h, or 6–10 h.

[0075] In the above-described method for preparing silicon oxide compounds, those skilled in the art can choose a suitable method to post-process the product obtained from the reaction. For example, by fully contacting the solid with an aqueous solution of an alkaline compound, an aqueous solution of silicon oxide compounds can be provided.

[0076] A second aspect of the present invention provides a method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, comprising: subjecting 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine to a cyclization reaction in the presence of a silicon compound and an amide compound to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, the reaction equation being as follows:

[0077]

[0078] The silicon compound is selected from one or more combinations of compounds with the chemical structural formulas shown below:

[0079]

[0080] Among them, R 3 R 4 R 5 Each is independently selected from H, Ph, C1-C4 alkyl, Cl, or Br;

[0081] Y is selected from O, or it does not exist;

[0082] n is selected from 0, 1, 2, 3, 4 or 5;

[0083] X is selected from Cl or Br.

[0084] In a specific embodiment of the present invention, in compound V, R 3 R 4 R 5 Each is independently selected from H, C1-C2 alkyl, Cl, or Br.

[0085] In another specific embodiment of the present invention, in compound V, n is selected from 0 and 1.

[0086] In another specific embodiment of the present invention, in compound V, X is selected from Cl or Br.

[0087] In another specific embodiment of the present invention, the silicon compound is selected from one or more combinations of methyltrichlorosilane, diethyldichlorosilane, dimethyldichlorosilane, trimethylmonochlorosilane, 1,2-dimethyl-1,1,2,2-tetrachlorodisilane, silicon tetrachloride, dimethyldibromosilane, trimethylbromosilane, and 1,3-dichloro-1,1,3,3-tetramethylsiloxane.

[0088] In the above cyclization reaction, the amount of silicon compound used relative to compound III can be appropriately adjusted to ensure the conversion rate and allow the reaction to proceed fully in the forward direction. For example, in the above cyclization reaction, the molar ratio of compound III to silicon compound can be 1:0.5-2.0, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1.0, 1:1.0-1.1, 1:1.1-1.2, 1:1.2-1.3, 1:1.3-1.4, 1:1.4-1.5, 1:1.5-1.6, 1:1.6-1.7, 1:1.7-1.8, 1:1.8-1.9, or 1:1.9-2.0.

[0089] In the above cyclization reactions, amide compounds are usually used as cyclizing agents, and the chemical structural formula of the amide compound can typically be RCONR. 1 R 2 Wherein, R is selected from hydrogen, saturated or unsaturated C1-C8 aliphatic groups, substituted or unsubstituted phenyl groups, R 1 R 2 Each is independently selected from saturated or unsaturated C1-C8 aliphatic groups, phenyl groups, or R and R 1 , or R and R 2 Together with the atoms attached to them, they form five- or six-membered heterocyclic groups. For example, the amide compound can be one or more combinations of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-diethylpropionamide, N,N-dimethylpropionamide, N,N-diphenylformamide, N,N-diphenylacetamide, N,N-diphenylformamide, N,N-diphenylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolinone, etc. The amount of the amide compound used can be appropriately adjusted relative to the compound of Formula I to ensure the conversion rate of the reaction and to allow the reaction to proceed fully in the forward direction. For example, in the above cyclization reaction, the molar ratio of compound III to amide compound can be 1:0.1-1.5, 1:0.1-0.2, 1:0.2-0.3, 1:0.3-0.4, 1:0.4-0.5, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1.0, 1:1.0-1.1, 1:1.1-1.2, 1:1.2-1.3, 1:1.3-1.4, or 1:1.4-1.5.

[0090] In the above-described cyclization reactions, the reaction is typically carried out in the presence of a solvent. The reaction solvent used is usually an aprotic solvent and is generally a good solvent for the reaction system. The type and amount of suitable reaction solvent should be adjustable by those skilled in the art. For example, in the above-described cyclization reactions, the reaction solvent can be selected from aromatic hydrocarbon solvents, etc. In a specific embodiment of the present invention, in the above-described cyclization reactions, the reaction solvent can be selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, etc. As another example, in the above-described cyclization reactions, the weight of the reaction solvent can be 1 to 8 times, 1 to 2 times, 2 to 4 times, or 4 to 8 times the weight of the reaction substrate.

[0091] In the above-described cyclization reaction, the reaction can be carried out at temperatures ranging from room temperature to the boiling point of the solvent, preferably under heating conditions. For example, the reaction temperature in the above-described cyclization reaction can be 70–150°C, 70–80°C, 80–90°C, 90–100°C, 100–110°C, 110–120°C, 120–130°C, 130–140°C, or 140–150°C. Those skilled in the art can adjust the reaction time according to the reaction progress. For example, the reaction progress in the above-described cyclization reaction can be determined by methods such as TLC or chromatography. Furthermore, the reaction time in the above-described cyclization reaction can be 1–20 h, 1–2 h, 2–4 h, 4–6 h, 6–8 h, 8–12 h, or 12–20 h.

[0092] In the above cyclization reaction, those skilled in the art can choose appropriate methods to post-process the product obtained from the reaction. For example, this may include: quenching with water, adjusting the pH of the system, solid-liquid separation, and solvent removal from the organic phase to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. After the reaction is complete, the reaction system can be quenched with water, and the pH of the system can be appropriately adjusted (e.g., adjusted to a weakly acidic to weakly basic state, more specifically, pH = 6–8). Solid-liquid separation is then performed, and the organic phase obtained in the liquid phase is further purified to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole with higher purity. Suitable purification methods should be known to those skilled in the art; for example, methods such as distillation may be used.

[0093] The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole provided by this invention may further include: reacting a solid phase (obtained through solid-liquid separation) under alkaline conditions to provide a silicon oxide compound. The solid phase mainly includes a silyl ether polymer generated during the cyclization reaction of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, which can be hydrolyzed under alkaline conditions to form the corresponding silyl ether polymer.

[0094] In the above methods for preparing silicon oxides, the silicon oxides vary depending on the substituents in the silicon compound used in the cyclization reaction. For example, when R in the silicon compound... 3 R 4 R 5 When both are independently selected from Cl and Br, the resulting silicon oxide compound can be a silicate; when R in the silicon compound... 3 R 4 R 5 One of them is selected from Ph or C1-C4 alkyl, and the remaining R 3 R4 R 5 When two of them are independently selected from Cl and Br, the resulting silicon oxide compound can be a phenyl silicate or an alkyl silicate; when R 3 R 4 R 5 Two of them are independently selected from C1-C4 alkyl groups, and the remaining R 3 R 4 R 5 When one of them is selected from Cl or Br, the resulting silicon oxide compound can be a polydialkylsiloxane; when R 3 R 4 R 5 When each molecule is independently selected from C1-C4 alkyl groups, the resulting silicon oxide can be a hexaalkyldisil ether. The resulting silicate typically corresponds to the cation included under alkaline conditions. For example, when the alkaline conditions include Na... + Under alkaline conditions, the aforementioned silicate can be sodium silicate, and phenyl silicates or alkyl silicates can be sodium phenyl silicate or sodium alkyl silicate, respectively. For example, alkaline conditions can be provided by suitable alkaline compounds, which can also be suitable sodium salts (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, etc.), thereby providing conditions including Na... + Alkaline conditions.

[0095] In the above-described method for preparing silicon oxide compounds, the amount of basic compound used is essentially equal to or in excess of the silyl ether polymer, thereby ensuring the conversion rate of the reaction and allowing the reaction to proceed fully in the forward direction. For example, in the above-described method for preparing silicon oxide compounds, the equivalent ratio of the silyl ether polymer to the basic compound can be 1:0.5-5, 1:0.5-0.6, 1:0.6-0.7, 1:0.7-0.8, 1:0.8-0.9, 1:0.9-1, 1:1-1.1, 1:1.1-1.2, 1:1.2-1.5, 1:1.5-2, 1:2-3, 1:3-4, or 1:4-5.

[0096] In the above-described method for preparing silicon oxide compounds, the reaction can be carried out at temperatures ranging from room temperature to the boiling point of the solvent. The reaction temperature can typically be adjusted appropriately based on the reaction pressure of the reaction system to obtain a faster reaction rate. For example, the reaction temperature in the above-described method for preparing silicon oxide compounds can be 100–150°C, 100–105°C, 105–110°C, 110–120°C, 120–130°C, 130–140°C, or 140–150°C. Furthermore, the reaction pressure can be atmospheric pressure or a pressurized condition ≤5 bar. Those skilled in the art can adjust the reaction time according to the reaction progress. For example, the cyclization reaction progress can be determined using methods such as TLC or chromatography in the above-described method for preparing silicon oxide compounds. Furthermore, the reaction time in the above-described method for preparing silicon oxide compounds can be 0.5–10 h, 0.5–1 h, 1–2 h, 2–4 h, 4–6 h, or 6–10 h.

[0097] In the above-described method for preparing silicon oxide compounds, those skilled in the art can choose a suitable method to post-process the product obtained from the reaction. For example, by fully contacting the solid with an aqueous solution of an alkaline compound, an aqueous solution of silicon oxide compounds can be provided.

[0098] This invention provides a novel application of silicon compounds in cyclization reactions and further provides methods for preparing 2-chloro-5-chloromethylpyridine and 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. Using the silicon compounds and / or amides provided by this invention as cyclization reagents allows for highly efficient cyclization synthesis. Compared with existing technologies, this method offers advantages such as high cyclization yield, low waste, environmental friendliness, and the ability to recycle byproducts. It is economically efficient, easy to operate, suitable for industrial production, and has promising prospects for industrialization.

[0099] The invention of this application will be further illustrated by the following embodiments, but this does not limit the scope of this application.

[0100] Example 1

[0101] Preparation of 2-chloro-5-chloromethylpyridine:

[0102] 1-1

[0103] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 18.3 g of N,N-dimethylformamide (DMF) were added. The temperature was raised to 100–110 °C, and 89.7 g of methyltrichlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 68.9 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.7% and a yield of 85%.

[0104] 1-2

[0105] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 18.3 g of N,N-dimethylformamide (DMF) were added. The internal temperature was raised to 100–110 °C, and 117.8 g of diethyldichlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 68.9 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.2% and a yield of 85%.

[0106] 1-3

[0107] In a glass reaction flask, 360 g of chlorobenzene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 39.2 g of N,N-dimethylacetamide (DMAC) were added. The internal temperature was raised to 120–130 °C, and 116.2 g of dimethyldichlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 72.9 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.5% and a yield of 90%.

[0108] 1-4

[0109] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 44.6 g of N-methylpyrrolidone (NMP) were added. The internal temperature was raised to 100–110 °C, and 103.2 g of trimethylchlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 65.6 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.3% and a yield of 81%.

[0110] 1-5

[0111] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 18.3 g of N,N-dimethylformamide (DMF) were added. The internal temperature was raised to 100–110 °C, and 148.2 g of 1,2-dimethyl-1,1,2,2-tetrachlorodisilazane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 66.4 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.5% and a yield of 82%.

[0112] 1-6

[0113] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 21.9 g of N,N-dimethylformamide (DMF) were added. The temperature was raised to 100–110 °C, and 110.4 g of silicon tetrachloride was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of a 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 65.6 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.5% and a yield of 81%.

[0114] 1-7

[0115] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 11 g of N,N-dimethylformamide (DMF) were added. The internal temperature was raised to 100–110 °C, and 163.5 g of dimethyldibromosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 67.2 g of 2-chloro-5-chloromethylpyridine was obtained, with a GC content of 99.5% and a yield of 83%.

[0116] 1-8

[0117] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 34.7 g of N-methylpyrrolidone (NMP) were added. The temperature was raised to 100–110 °C, and 153.1 g of trimethylbromosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 64 g of 2-chloro-5-chloromethylpyridine was obtained with a GC content of 99.5% and a yield of 79%.

[0118] 1-9

[0119] In a glass reaction flask, 270 g of toluene, 90 g of 4-aldehyde-4,5-dichloropentanonitrile, and 25.6 g of N,N-dimethylformamide (DMF) were added. The internal temperature was raised to 100–110 °C, and 182.9 g of 1,3-dichloro-1,1,3,3-tetramethylsiloxane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 64.8 g of 2-chloro-5-chloromethylpyridine was obtained with a GC content of 99.6% and a yield of 80%.

[0120] 1-10

[0121] In a glass reaction flask, 200 g of toluene and 18.3 g of N,N-dimethylformamide (DMF) were added, and the internal temperature was raised to 100–110 °C. Two feedstocks were prepared: feedstock A consisted of 117.8 g of diethyldichlorosilane, and feedstock B consisted of a toluene solution of 90 g of 4-aldehyde-4,5-dichloropentanonitrile and 120 g of toluene. Feedstocks A and B were added dropwise simultaneously, maintaining reflux throughout the process. After the addition was complete, the mixture was refluxed and kept at the same temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of a 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. Desolventizing and distilling yielded 70.5 g of 2-chloro-5-chloromethylpyridine with a GC content of 99.3% and a yield of 87%.

[0122] Example 2

[0123] Preparation of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole:

[0124] 2-1

[0125] In a glass reaction flask, 360 g of toluene, 102.3 g of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine, and 18.3 g of N,N-dimethylformamide (DMF) were added. The temperature was raised to 100–110 °C, and 97.1 g of methyltrichlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 75.5 g of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole was obtained, with an HPLC purity of 99.2% and a yield of 81%.

[0126] 2-2

[0127] In a glass reaction flask, 400 g of chlorobenzene, 102.3 g of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine, and 39.2 g of N,N-dimethylacetamide (DMAC) were added. The internal temperature was raised to 120–130 °C, and 116.2 g of dimethyldichlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 82.1 g of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole was obtained, with an HPLC purity of 99.5% and a yield of 88%.

[0128] 2-3

[0129] In a glass reaction flask, 360 g of toluene, 102.3 g of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine, and 44.6 g of N-methylpyrrolidone (NMP) were added. The mixture was heated to an internal temperature of 100–110 °C, and 108.6 g of trimethylchlorosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 79.3 g of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole was obtained, with an HPLC purity of 99.6% and a yield of 85%.

[0130] 2-4

[0131] In a glass reaction flask, 400 g of toluene, 102.3 g of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine, and 14.6 g of N,N-dimethylformamide (DMF) were added. The internal temperature was raised to 100–110 °C, and 163.5 g of dimethyldibromosilane was added dropwise while maintaining reflux during the addition. After the addition was complete, the mixture was refluxed and kept at this temperature for 2 hours. The temperature was then lowered to 60 °C, and 10 g of water was added. The temperature was further lowered to 20–30 °C, and 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 76.5 g of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole was obtained, with an HPLC purity of 99.2% and a yield of 82%.

[0132] 2-5

[0133] In a glass reaction flask, 200 g of chlorobenzene and 18.3 g of N,N-dimethylformamide (DMF) were added, and the internal temperature was raised to 100–110 °C. Two feeds were prepared: feed A was 97.1 g of methyltrichlorosilane, and feed B was a solution of 102.3 g of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine / 200 g of chlorobenzene. Feeds A and B were added dropwise simultaneously, with the system kept under reflux during the addition. After the addition was complete, the system was kept under reflux for 2 hours. The temperature was lowered to 60 °C, 10 g of water was added, and the temperature was further lowered to 20–30 °C. 15 g of 30% NaOH aqueous solution was added dropwise. The pH of the aqueous phase was approximately 6–7. The mixture was filtered, and the filter cake was washed with 50 g of toluene to obtain the organic phase. After solvent removal and distillation, 78.3 g of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole was obtained, with an HPLC purity of 99.7% and a yield of 84%.

[0134] Example 3

[0135] Preparation of aqueous solution of sodium alkylsilicate

[0136] 3-1

[0137] Add 150g of tap water to a stainless steel atmospheric pressure vessel, and add 100g of the silicon polymer obtained by filtration in Example 1-1 above while stirring. Quickly add 120g of 30% sodium hydroxide aqueous solution, which exothermics the reaction. Heat to reflux and maintain the temperature for 4 hours until the system becomes clear and free of solids. Cool to an internal temperature of 40-50 degrees Celsius, filter, and obtain 365g of a clear and colorless aqueous solution of sodium methylsilyltriol.

[0138] 3-2

[0139] In a stainless steel atmospheric pressure vessel, 150g of tap water was added, followed by 100g of the silicon polymer obtained by filtration in Examples 1-6 above, and stirred until homogeneous. 130g of a 30% sodium hydroxide aqueous solution was quickly added, resulting in an exothermic reaction. The system was heated to reflux and kept at this temperature for 4 hours until clear and free of solids. The solution was then cooled to an internal temperature of 40-50 degrees Celsius and filtered to obtain a clear, colorless water glass solution (376g). The water glass contained 28.09% SiO2, 8.87% Na2O, and had a modulus of 3.27%.

[0140] 3-3

[0141] 150g of tap water was added to a stainless steel autoclave, and 100g of the silicon polymer obtained by filtration in Examples 1-3 above was added while stirring. 8g of ammonium hydroxide catalyst was added, and 100g of 30% sodium hydroxide aqueous solution was quickly added. An exothermic phenomenon occurred. The mixture was heated to an internal temperature of 120°C and an internal pressure of approximately 1.5 bar. The system was held at this temperature for 2 hours until it became clear and free of solids. The mixture was then cooled to an internal temperature of 40-50°C and filtered to obtain 344g of a clear, colorless polydimethylsiloxane aqueous solution.

[0142] 3-4

[0143] 150g of tap water was added to a stainless steel atmospheric pressure vessel, and 100g of the silicon polymer obtained by filtration in Example 2-2 was added while stirring. 100g of a 30% sodium hydroxide aqueous solution was then quickly added. An exothermic reaction occurred. After sealing the vessel, the internal temperature was raised to 145°C, the internal pressure was approximately 2.5 bar, and the reaction time was 1 hour. The mixture was then cooled to an internal temperature of 40-50°C and filtered to obtain 346g of a clear, colorless polydimethylsiloxane aqueous solution.

[0144] Comparative Example 1

[0145] Preparation of 2-chloro-5-chloromethylpyridine:

[0146] 0.1 mol of compound CCC was dissolved in 20 mL of toluene. 2.19 g of N,N-dimethylformamide (0.03 mol) was added, and the mixture was heated in an oil bath to 90 °C. 6.15 g (0.04 mol) of phosphorus oxychloride was added dropwise, maintaining the temperature between 90-95 °C for 2 hours. The mixture was then kept at 95 °C for 30 minutes, and then cooled to 50 °C. 10 mL of water was added, followed by the dropwise addition of 10.7 g of 30% NaOH aqueous solution at 20-50 °C. The pH of the aqueous phase was approximately 8.0-10.0. After standing and separating into layers, the upper layer was the toluene phase. After solvent removal, 14.1 g of brown solid was obtained. GC internal standard analysis showed that it contained 71.6% CCMP, with a yield of 62.3%.

[0147] In summary, this invention effectively overcomes the various shortcomings of the prior art and has high industrial application value.

[0148] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, comprising: 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazine was cyclized in the presence of silicon and amide compounds to provide 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, as shown in the following reaction equation: ； The silicon compound is selected from one or more combinations of methyltrichlorosilane, diethyldichlorosilane, dimethyldichlorosilane, trimethylmonochlorosilane, 1,2-dimethyl-1,1,2,2-tetrachlorodisilane, silicon tetrachloride, dimethyldibromosilane, trimethylbromosilane, and 1,3-dichloro-1,1,3,3-tetramethylsiloxane. The amide compound is selected from one or more combinations of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-diethylpropionamide, N,N-dimethylpropionamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolinone.

2. The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole as described in claim 1, characterized in that, In the cyclization reaction, the molar ratio of compound III to amide compound is 1:0.1-1.5; And / or, the cyclization reaction is carried out in the presence of a solvent; And / or, the reaction temperature of the cyclization reaction is 70~150℃; And / or, in the cyclization reaction, the molar ratio of the compound of formula III to the silicon compound is 1:0.5-2.0; And / or, the post-treatment of the cyclization reaction includes: quenching with water, adjusting the pH of the system, solid-liquid separation, and desolvation of the organic phase.

3. The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole as described in claim 2, characterized in that, The reaction solvent is an aprotic solvent.

4. The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole as described in claim 3, characterized in that, The aprotic solvent is an aromatic hydrocarbon solvent.

5. The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole as described in claim 4, characterized in that, Also includes: The solid phase is reacted under alkaline conditions to provide silicon oxides.

6. The method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole as described in claim 5, characterized in that, The silicon oxide compound is selected from silicates.

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