Synthesis process of metconazole

Abstract

The invention belongs to the technical field of chemical engineering, and particularly relates to a metconazole synthesis process which comprises the following steps: under the catalysis of alkali, performing condensation dehydration reaction on p-aminobenzaldehyde and cyclopentanone in a polar solvent to obtain a compound a; in the presence of alkali and a methylation reagent, carrying out methylation reaction on the compound a in an organic solvent to obtain a compound b; under the action of a specific catalyst, the compound b and a sulfur ylide reagent are subjected to an epoxidation reaction in an organic solvent to obtain a compound c; cyclopentanone and p-aminobenzaldehyde are taken as initial raw materials, metconazole is synthesized through important intermediates such as 5-(4-aminobenzylidene)-2, 2-dimethyl cyclopentanone (compound b) and the like, carbonyl alpha site is sealed by double bonds, methylation side reaction of the alpha site is avoided, and the method has the advantages of being short in route, high in yield, economical, green, good in product quality, suitable for industrial production and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical industry, and in particular relates to a synthesis process of metconazole. Background Art

[0002] Metconazole is a new type of triazole fungicide developed by Kureha Chemical Co., Ltd. of Japan. It has the advantages of high efficiency, low toxicity, broad spectrum and low environmental pollution. Its mechanism of action is to exert fungicidal effect by inhibiting C-14 demethylase of plant pathogens. It is mainly used for the prevention and control of diseases caused by dwarf rust, leaf rust, yellow rust, crown rust, powdery mildew, glumes blight, septoria and Fusarium foetida in gramineous crops. Metconazole is now widely used in cereals and rapeseed in Europe, cereals in North America, and soybeans in Latin America. In addition, it is also used in corn, rice, cotton, potatoes, grapes, pears and other vegetables. The common name of metconazole in English is metconazole, and its chemical name is 5-(4-chlorophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol. Its pure product is a white crystalline mixture of cis and trans, and the cis activity is high. Metconazole compound products have achieved good results in foreign markets, including compound products of metconazole with pyraclostrobin, metalaxyl, fluopicolide, and boscalid. Currently, only two companies in China have registered metconazole products, and the market share of metconazole is very small, with great room for growth.

[0003] The currently reported synthetic route of metconazole mainly passes through two important intermediates: 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone or 5-(4-chlorobenzyl)-1-hydroxymethyl-2,2-dimethylcyclopentane-1-ol (geminal diol), the structure of which is as follows:

[0004] Methiconazole is prepared via the route of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone. In the preparation step of epoxy, trimethyl sulfoxide halide needs to be used in combination with strong bases such as sodium hydrogen. Oxysulfur ylide raw materials such as trimethyl sulfoxide bromide are expensive and difficult to prepare, while the cheap sulfur ylide is too active and easily undergoes carbonyl α-methylation side reaction with 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone. Epoxidation reactions are mostly carried out in polar aprotic solvents. Studies have reported that there are huge risks in using sodium hydrogen in combination with solvents such as N,N-dimethylformamide, and the industrial use of sodium hydrogen also has the danger of combustion and explosion. In addition, the yield of epoxy intermediates synthesized by the step-by-step method is extremely low. There are multiple reports of using the "one-pot method" to prepare metconazole. Although the yield has improved, it is still low, resulting in high route costs. There are also disadvantages such as difficulty in solvent recovery and large amount of wastewater.

[0005]

[0006] The preparation of metconazole via the route of 5-(4-chlorobenzyl)-1-hydroxymethyl-2,2-dimethylcyclopentane-1-ol (geminal diol) generally has the disadvantages of long route, low yield, and lack of industrialization prospects. The geminal diol intermediate needs to be acylated with p-toluenesulfonyl chloride first, and then reacted with triazole to obtain metconazole. The ratio of cis-form of metconazole synthesized by this route is high, which has the advantage of selective synthesis of cis-form.

[0007] Summary of the invention

[0008] The purpose of the present invention is to overcome the above-mentioned defects of the prior art and provide a synthesis process of metconazole. The present invention uses cyclopentanone and p-aminobenzaldehyde as starting materials, and synthesizes metconazole through 6 steps of reaction through important intermediates such as 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (compound b), and uses a double bond to block the α position of the carbonyl group, thereby avoiding the methylation side reaction at the α position; at the same time, dechlorination can be avoided in the hydrogenation reduction step, and the hydrogenation reduction yield is improved. It has the advantages of short route, high yield, economic and green, good product quality, and suitability for industrial production.

[0009] The purpose of the present invention can be achieved by the following technical scheme: a synthesis process of metconazole, the process comprising the following steps: Step 1: Under the catalysis of a base, p-aminobenzaldehyde and cyclopentanone undergo condensation dehydration reaction in a polar solvent to obtain compound a; The alkali is one or more of potassium hydroxide or sodium hydroxide, preferably potassium hydroxide; The molar ratio of the base to p-aminobenzaldehyde is (0.05-0.5):1, preferably 0.1:1; The polar solvent is one or more of methanol, ethanol, isopropanol or water, preferably 50% ethanol; The condensation dehydration reaction is carried out at 50-100°C, preferably 80-90°C.

[0010] Step 2: In the presence of a base and a methylating agent, compound a undergoes a methylation reaction in an organic solvent to obtain compound b; The base is one or more of sodium hydride, sodium amide, sodium tert-butoxide, sodium tert-amyl alcoholate or sodium methoxide, preferably sodium tert-amyl alcoholate; The molar ratio of the base to compound a is (0.9-1.5):1, preferably 1.1:1; The methylating agent is one or more of dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl chloride, methyl bromide or methyl iodide, preferably methyl iodide; The organic solvent is one or more of toluene, N,N-dimethylformamide or acetone, preferably toluene.

[0011] Step 3: Under the action of a specific catalyst, compound b undergoes epoxidation reaction with a sulfur ylide reagent in an organic solvent to obtain compound c; The specific catalyst is one or more of PEG200, PEG400, PEG800 and PEG2000, preferably PEG400; The weight percentage of the catalyst added is 1% to 10% of compound b, preferably 2%; The inorganic base is one or more of potassium hydroxide and sodium hydroxide, preferably potassium hydroxide; The sulfur ylide reagent is one or more of trimethyl sulfonium chloride, trimethyl sulfonium bromide, trimethyl sulfonium methyl sulfate and trimethyl sulfonium bromide, preferably trimethyl sulfonium methyl sulfate; The organic solvent is one or more of toluene, 1,4-dioxane, dimethyl sulfide or tetrahydrofuran, preferably dimethyl sulfide.

[0012] Step 4: Compound c is subjected to ring-opening with triazole and its salt in a polar aprotic solvent to obtain compound d; The triazole and its salt are one or more of 1,2,4-triazole, 1,2,4-triazole sodium or 1,2,4-triazole potassium, preferably 1,2,4-triazole sodium; The polar aprotic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethylformamide; The ring-opening process is carried out at 50-110°C, preferably 80-90°C.

[0013] Step 5: Under a certain pressure, in the presence of a catalyst and hydrogen, compound d undergoes a hydrogenation reduction reaction in an alcohol solvent to obtain compound e; The certain pressure is 0.2-0.6 MPa, preferably 0.3 MPa; The catalyst is one or more of palladium carbon, ruthenium carbon, Raney nickel and platinum dioxide, preferably Raney nickel; The alcohol solvent is one or more of methanol, ethanol or isopropanol, preferably methanol.

[0014] Step 6: Compound e undergoes Sandmeyer reaction in an acidic aqueous solution or a polar solvent under the action of cupric chloride and nitrite to obtain metconazole.

[0015] The cupric chloride salt is one or more of cupric chloride and cuprous chloride, preferably cuprous chloride; The nitrite compound is one of sodium nitrite and tert-butyl nitrite, preferably sodium nitrite; The molar ratio of the nitrite compound to the compound e is (1-1.5):1, preferably 1.1:1; The acidic aqueous solution or polar solvent is one or more of hydrochloric acid aqueous solution, sulfuric acid aqueous solution and acetonitrile, preferably hydrochloric acid aqueous solution.

[0016] The invention has the following beneficial effects: high yield, high product quality, simple operation, economic and green, and is suitable for industrial production.

[0017] The technical effects achieved by the present invention are: The invention uses cyclopentanone and p-aminobenzaldehyde as starting materials, and synthesizes metconazole through 6 steps of reaction via important intermediates such as 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (compound b), and uses a double bond to block the α position of the carbonyl group, thereby avoiding a methylation side reaction at the α position; meanwhile, dechlorination can be avoided in the hydrogenation reduction step, thereby improving the yield of the hydrogenation reduction, and has the advantages of a short route, a high yield, being economical and green, having a good product quality, being suitable for industrial production, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a synthetic process route diagram of metconazole disclosed in the present invention; Figure 2 This is the hydrogen nuclear magnetic spectrum (1H NMR) of metconazole obtained in the examples of the present invention. DETAILED DESCRIPTION

[0019] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the accompanying drawings.

[0020] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0021] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure or characteristic that may be included in at least one implementation of the present invention. The phrase "in a preferred embodiment" that appears in different places in this specification does not refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

[0022] Example 1 Preparation of 2-(4-aminobenzylidene)cyclopentanone (Compound a) Cyclopentanone (85 g, 1 mol), potassium hydroxide (6 g, 0.09 mol) and 50% ethanol (700 mL) were added to a 2L reaction bottle in sequence, and the temperature was naturally raised to 85°C. p-Chlorobenzaldehyde (130 g, 0.9 mol) and 50% ethanol solution (300 mL) were heated and dissolved, and p-Chlorobenzaldehyde ethanol solution was prepared and dripped into the reaction bottle under heat preservation for 3 hours. After the dripping, the reaction was kept warm for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, toluene and water were added and stirred for 30 minutes, and the liquid was separated by standing. The aqueous phase was extracted once with toluene, and the organic phases were combined. The organic phases were washed with water, washed with saturated brine and dried over anhydrous sodium sulfate in sequence, and the solvent was evaporated under reduced pressure to obtain 167.3 g of the product 2-(4-aminobenzylidene)cyclopentanone, with a purity of 97.2% and a yield of 96.5% (based on p-Chlorobenzaldehyde).

[0023] 1H NMR (400MHz, Chloroform-d) δ 7.43(d,J=8.1Hz,2H),7.35(d,J=8.2Hz,2H), 7.31(d,J=2.8Hz,1H),3.00–2.87(m,1H),2.76(dtd,J= 13.9, 7.2, 6.8, 3.5Hz, 1H), 2.34 (q,J=9.8, 8.2Hz, 2H), 1.57–1.43(m,1H). Example 2 Preparation of 2-(4-aminobenzylidene)cyclopentanone (Compound a) Cyclopentanone (85 g, 1 mol), sodium hydroxide (4 g, 0.1 mol) and 50% ethanol (700 mL) were added to a 2L reaction bottle in sequence, and the temperature was naturally raised to 80°C. p-Chlorobenzaldehyde (130 g, 0.9 mol) and 50% ethanol solution (300 mL) were heated and dissolved, and p-Chlorobenzaldehyde ethanol solution was prepared and dripped into the reaction bottle under heat preservation for 2 hours. After the dripping, the reaction was kept warm for 1.5 hours. After the reaction was completed, the solvent was removed under reduced pressure, ethyl acetate and water were added and stirred for 30 minutes, and the liquid was separated by standing. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined. The organic phases were washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate in sequence, and the solvent was evaporated under reduced pressure to obtain 165.2 g of the product 2-(4-aminobenzylidene)cyclopentanone, with a purity of 96.8% and a yield of 95.8% (based on p-Chlorobenzaldehyde).

[0024] 1H NMR (400MHz, Chloroform-d) δ 7.41(d,J=8.0Hz,2H),7.33(d,J = 8.1Hz, 2H), 7.29(d,J=2.7Hz,1H),2.98–2.85(m,1H),2.74(dtd,J= 13.8, 7.1, 6.7, 3.4Hz, 1H), 2.32 (q,J=9.7, 8.1Hz, 2H), 1.55–1.41(m,1H). Example 3 Preparation of 2-(4-aminobenzylidene)cyclopentanone (Compound a) Cyclopentanone (85 g, 1 mol), potassium carbonate (13.8 g, 0.1 mol) and anhydrous ethanol (700 mL) were added to a 2L reaction bottle in sequence and heated to reflux temperature. p-Chlorobenzaldehyde (130 g, 0.9 mol) was dissolved in anhydrous ethanol (300 mL), and after being configured into a p-chlorobenzaldehyde ethanol solution, it was slowly added dropwise to the reaction bottle, and the dropping time was controlled to 4 hours. After the dropwise addition, the reflux reaction was continued for 3 hours, and the reaction was cooled to room temperature after the reaction was completed. After the solvent was removed under reduced pressure, dichloromethane and water were added and stirred for 30 minutes, and the liquid was allowed to stand for separation. The aqueous phase was extracted once with dichloromethane, and the organic phases were combined, and the organic phases were washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate in sequence. The solvent was evaporated under reduced pressure to obtain 168.5 g of the product 2-(4-aminobenzylidene)cyclopentanone, with a purity of 96.5% and a yield of 96.1% (based on p-chlorobenzaldehyde).

[0025] 1H NMR (400MHz, Chloroform-d) δ 7.45(d,J=8.2Hz,2H),7.37(d,J = 8.3Hz, 2H), 7.33(d,J=2.9Hz,1H),3.02–2.89(m,1H),2.78(dtd,J= 14.0, 7.3, 6.9, 3.6Hz, 1H), 2.36 (q,J=9.9, 8.3Hz, 2H), 1.59–1.45(m,1H). Example 4 Preparation of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (Compound b) 2-(4-aminobenzylidene)cyclopentanone (167.3 g, 0.868 mol), sodium tert-amyl alcohol (110 g, 0.96 mol) and toluene (1.5 L) were added to a 2 L reaction bottle, stirred at room temperature for 30 min, and methyl iodide (187 g, 1.3 mol) was added dropwise within 1 h. After the addition was complete, the temperature was raised to 50 ° C and stirred for 4 h. After the reaction was completed, the mixture was cooled to room temperature, stirred with a large amount of water, allowed to stand for stratification, and the aqueous phase was extracted with toluene once. The organic phases were combined, washed with water until pH ≈ 8, and toluene was evaporated under reduced pressure. The mixture was recrystallized from methanol to obtain 173.9 g of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone with a purity of 99.2% and a yield of 92.3%.

[0026] 1H NMR(400MHz,Chloroform-d) δ 7.47 (d,J=8.2Hz,2H),7.43–7.31(m,3H),2.86(td, J=7.3,2.7Hz,2H),1.86(t,J=7.3Hz,2H),1.13(s,6H). Example 5 Preparation of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (Compound b) 2-(4-aminobenzylidene)cyclopentanone (compound a) (167.3 g, 0.868 mol) was dissolved in anhydrous ethanol (1.5 L), and potassium hydroxide (50 g, 0.89 mol) and tert-amyl alcohol (1.5 L) were added. After stirring at room temperature for 30 minutes, iodomethane (187 g, 1.3 mol) was slowly added dropwise to the reaction mixture, and the dropwise addition rate was controlled to keep the reaction temperature at room temperature. After the dropwise addition, the reaction was continued to stir for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, a large amount of water was added and stirred, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with ethyl acetate, the organic phases were combined, the organic phases were washed with water until pH ≈ 8, and the ethyl acetate was evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized from methanol to obtain 175.2 g of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone with a purity of 99.0% and a yield of 91.5%.

[0027] 1H NMR (400MHz, Chloroform-d) δ 7.45 (d, J=8.2Hz, 2H), 7.39–7.30 (m,3H), 2.84 (td, J=7.2, 2.6Hz, 2H), 1.84 (t, J=7.2Hz, 2H), 1.11 (s, 6H). Example 6 Preparation of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (Compound b) 2-(4-aminobenzylidene)cyclopentanone (compound a) (167.3 g, 0.868 mol) was dissolved in dimethyl sulfoxide (DMSO) (1.5 L), followed by the addition of potassium carbonate (120 g, 0.87 mol) and tert-amyl alcohol (1.5 L). After stirring at room temperature for 30 minutes, iodomethane (187 g, 1.3 mol) was slowly added dropwise to the reaction mixture, and the dropwise addition rate was controlled to keep the reaction temperature at room temperature. After the dropwise addition, the reaction was continued to stir for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, a large amount of water was added and stirred, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane, the organic phases were combined, the organic phases were washed with water until pH ≈ 8, and dichloromethane was removed under reduced pressure to obtain a crude product. The crude product was recrystallized from methanol to obtain 174.5 g of 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone with a purity of 99.1% and a yield of 91.9%.

[0028] 1H NMR (400MHz, Chloroform-d) δ 7.46 (d, J=8.2Hz, 2H), 7.40–7.31 (m,3H), 2.85 (td, J=7.3, 2.7Hz, 2H), 1.85 (t, J=7.3Hz, 2H), 1.12 (s, 6H). Example 7 Preparation of 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane (Compound C) 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (173.9 g, 0.801 mol), PEG400 (3.5 g), dimethyl sulfate (162 g, 1.26 mol), potassium hydroxide (132 g, 2 mol) and dimethyl sulfide (800 mL) were added to a 2L reaction bottle, and the temperature was naturally raised to 40 degrees and stirred for reaction for 12 hours. After the reaction was completed, water was added and stirred, and the mixture was allowed to stand for separation. The aqueous phase was extracted once with dimethyl sulfide, the organic phases were combined, and dimethyl sulfide was evaporated to obtain 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane, which was directly used in the next reaction.

[0029] Example 8 Preparation of 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane (Compound C) 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (compound b) (173.9 g, 0.801 mol) was dissolved in anhydrous ethanol (1.5 L), and sodium hydroxide (48 g, 1.2 mol) and tert-amyl alcohol (1.5 L) were added. After stirring at room temperature for 30 minutes, dimethyl sulfate (162 g, 1.26 mol) was slowly added dropwise to the reaction mixture, and the dropwise addition rate was controlled to keep the reaction temperature at room temperature. After the dropwise addition, the reaction was continued to stir for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, a large amount of water was added and stirred, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with ethyl acetate, the organic phases were combined, the organic phases were washed with water until pH ≈ 8, and the ethyl acetate was evaporated under reduced pressure to obtain 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane, which was directly used in the next step reaction.

[0030] Example 9 Preparation of 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane (Compound C) 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (compound b) (173.9 g, 0.801 mol) was dissolved in dimethyl sulfoxide (DMSO) (1.5 L), followed by the addition of potassium hydroxide (132 g, 2 mol) and tert-amyl alcohol (1.5 L). After stirring at room temperature for 30 minutes, dimethyl sulfate (162 g, 1.26 mol) was slowly added dropwise to the reaction mixture, and the dropwise addition rate was controlled to keep the reaction temperature at room temperature. After the dropwise addition, the reaction was continued to stir for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, a large amount of water was added and stirred, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane, the organic phases were combined, the organic phases were washed with water until pH ≈ 8, and the dichloromethane was removed under reduced pressure to obtain 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane, which was directly used in the next step.

[0031] Example 10 Preparation of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound d) 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane was dissolved in N,N-dimethylformamide (1L), 1,2,4-triazole sodium (102g, 1.04mol) was added, and the temperature was raised to 85°C and stirred for 3h. After the reaction, the solvent was removed under reduced pressure, toluene and water were added and stirred, and the mixture was allowed to stand for separation. The aqueous phase was extracted with toluene once, the organic phases were combined, toluene was removed under reduced pressure, and 60% methanol aqueous solution was added for recrystallization to obtain 218.8g of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol with a purity of 95.6% and a yield of 87.5%.

[0032] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.44 (d, J =8.2 Hz, 2H), 7.39 – 7.27 (m, 3H), 4.32 (s, 2H), 2.83 (td, J = 7.3, 2.7 Hz, 2H), 1.84 (t, J = 7.3 Hz, 2H), 1.13 (s, 3H). 0.83 (s, 3H). Embodiment 11 Preparation of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound d) 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane (50 g, 0.18 mol) was dissolved in anhydrous ethanol (500 mL), sodium hydroxide (7.2 g, 0.18 mol) was added and heated to reflux. Then, an anhydrous ethanol solution (100 mL) of 1H-1,2,4-triazole-1-methanol (20.4 g, 0.23 mol) was slowly added dropwise, and the reaction was continued under reflux for 4 hours after the addition was completed. After the reaction was completed, most of the ethanol was removed by vacuum distillation, and water (300 mL) was added to the residue and extracted with dichloromethane (200 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from a mixed solvent of ethyl acetate and petroleum ether to obtain 18.6 g of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol with a purity of 94.2% and a yield of 74.4%.

[0033] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.44 (d, J =8.2 Hz, 2H), 7.39 – 7.27 (m, 3H), 4.32 (s, 2H), 2.83 (td, J = 7.3, 2.7 Hz, 2H), 1.84 (t, J = 7.3 Hz, 2H), 1.13 (s, 3H), 0.83 (s, 3H). Example 12 Preparation of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound d) 7-(4-aminobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]heptane (100 g, 0.36 mol) was dissolved in dimethyl sulfoxide (DMSO, 1 L), and potassium carbonate (100 g, 0.72 mol) was added as a basic catalyst. Under nitrogen protection, a DMSO solution (200 mL) of 1H-1,2,4-triazole (43.2 g, 0.63 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to 110 °C and the reaction was maintained for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (1 L) was added, and it was extracted with ethyl acetate (500 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1) to obtain 102.4 g of 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol with a purity of 94.5% and a yield of 85.7%.

[0034] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.44 (d, J =8.2 Hz, 2H), 7.39 – 7.27 (m, 3H), 4.32 (s, 2H), 2.83 (td, J = 7.3, 2.7 Hz, 2H), 1.84 (t, J = 7.3 Hz, 2H), 1.13 (s, 3H), 0.83 (s, 3H). Embodiment 13 Preparation of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound e) 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (218.8 g, 0.7 mol), methanol (1.5 L), and Raney nickel (4.6 g, 0.07 mol) were added to a 2L high-pressure hydrogenation reactor. The air in the reactor was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was raised to 0.3 MPa by hydrogen, and the temperature was raised to 55°C and stirred for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated under reduced pressure to remove methanol to obtain 205.1 g of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, with a purity of 93.1% and a yield of 90.8%.

[0035] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.32 (d, 2H), 7.21 (d, 2H), 4.29 (s, 2H), 2.35 – 2.20 (m, 2H), 2.28 (m, 1H), 1.72 – 1.68 (m, 1H), 1.47 – 1.36 (m, 1H), 1.30 – 1.12 (m, 2H), 1.04 (s, 3H), 0.77 (s, 3H). Embodiment 14 Preparation of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound e) 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (218.8 g, 0.7 mol), ethanol (1.5 L), palladium carbon (10%, 4.6 g, 0.07 mol) were added to a 2L high-pressure hydrogenation reactor. The air in the reactor was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was raised to 0.5 MPa by hydrogen, and the temperature was raised to 65°C and stirred for 10 hours. After the reaction was completed, the temperature was cooled to room temperature, filtered, and the filtrate was decompressed to remove ethanol to obtain 210.3 g of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, with a purity of 92.2% and a yield of 89.5%.

[0036] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.32 (d, 2H), 7.21 (d, 2H), 4.29 (s, 2H), 2.35 – 2.20 (m, 2H), 2.28 (m, 1H), 1.72 – 1.68 (m, 1H), 1.47 – 1.36 (m, 1H), 1.30 – 1.12 (m, 2H), 1.04 (s, 3H), 0.77 (s, 3H). Embodiment 15 Preparation of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound e) 5-(4-aminobenzylidene)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (218.8 g, 0.7 mol), isopropanol (1.5 L), and platinum oxide (4.6 g, 0.07 mol) were added to a 2L high-pressure hydrogenation reactor. The air in the reactor was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was raised to 0.4 MPa by hydrogen, and the temperature was raised to 70°C and stirred for 12 hours. After the reaction was completed, the temperature was cooled to room temperature, filtered, and the filtrate was evaporated under reduced pressure to remove isopropanol to obtain 208.5 g of 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, with a purity of 92.5% and a yield of 90.3%.

[0037] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.32 (d, 2H), 7.21 (d, 2H), 4.29 (s, 2H), 2.35 – 2.20 (m, 2H), 2.28 (m, 1H), 1.72 – 1.68 (m, 1H), 1.47 – 1.36 (m, 1H), 1.30 – 1.12 (m, 2H), 1.04 (s, 3H), 0.77 (s, 3H). Example 16 Preparation of metconazole Add 5-(4-aminophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (205.1 g, 0.636 mol) and 16% hydrochloric acid (2 L) to a 2 L reaction bottle, cool to 0-5 ° C, stir thoroughly, slowly drop sodium nitrite aqueous solution (161 g, 0.7 mol), keep warm for 1 hour, add cuprous chloride hydrochloric acid solution (1.27 mol), keep warm for 4 hours. After the reaction, adjust the pH to about 8 with liquid alkali, precipitate a large amount of solid, stir at 0-5 ° C for 1 hour, filter, wash the filter cake with water, and recrystallize the filter cake with methylcyclohexane to obtain 185.6 g of white solid with a purity of 98.4% and a yield of 89.8%.

[0038] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.97 (s, 1H), 7.29 (d, 2H), 7.18 (d, 2H), 4.32 (s, 2H), 2.39 (t, 1H), 2.29 – 2.20 (m, 1H), 2.08 (dd, 1H), 1.74 – 1.65 (m, 1H), 1.54 – 1.44 (m, 1H), 1.30 – 1.16 (m, 2H), 1.00 (s, 3H), 0.63 (s, 3H).

[0039] In summary, combined with Figure 1 and Figure 2 As shown, cyclopentanone and p-aminobenzaldehyde are used as starting materials, and through important intermediates such as 5-(4-aminobenzylidene)-2,2-dimethylcyclopentanone (compound b), through condensation reaction, reduction reaction, Sandmeyer reaction and the like, a total of 6 steps of reaction are performed to obtain metconazole with a purity of more than 98% with a total yield of 63.5%. At the same time, the α position of the carbonyl group is blocked by a double bond to avoid methylation side reaction at the α position, and dechlorination can be avoided in the hydrogenation reduction step, thereby improving the hydrogenation reduction yield. Compared with the prior art method for preparing metconazole, the method has the advantages of short route, high yield, economic and green, good product quality, and suitability for industrial production.

[0040] The above is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention. The structures, devices and operating methods not specifically described and explained in the present invention shall be implemented according to the conventional means in the art unless otherwise specified and limited.

Claims

1. A synthesis process of metconazole, characterized in that: The following steps are involved: Step 1: Under the catalysis of a base, p-aminobenzaldehyde and cyclopentanone undergo condensation dehydration reaction in a polar solvent to obtain compound a; Step 2: In the presence of a base and a methylating agent, compound a undergoes a methylation reaction in an organic solvent to obtain compound b; Step 3: Under the action of a specific catalyst, compound b undergoes epoxidation reaction with a sulfur ylide reagent in an organic solvent to obtain compound c; Step 4: Compound c is subjected to ring-opening with triazole and its salt in a polar aprotic solvent to obtain compound d; Step 5: Under a certain pressure, in the presence of a catalyst and hydrogen, compound d undergoes a hydrogenation reduction reaction in an alcohol solvent to obtain compound e; Step 6: Compound e undergoes Sandmeyer reaction in an acidic aqueous solution or a polar solvent under the action of cupric chloride and nitrite to obtain metconazole.

2. A synthesis process of metconazole according to claim 1, characterized in that: In step 1, the base is one or more of potassium hydroxide or sodium hydroxide, and the molar ratio of the base to p-aminobenzaldehyde is (0.05-0.5):1; the polar solvent is one or more of methanol, ethanol, isopropanol or water; and the condensation dehydration reaction is carried out at 50-100°C.

3. A synthesis process of metconazole according to claim 1, characterized in that: The base in step 2 is one or more of sodium hydride, sodium amide, sodium tert-butoxide, sodium tert-amyloxide or sodium methoxide; the molar ratio of the base to compound a is (0.9-1.5):

1.

4. A synthesis process of metconazole according to claim 1, characterized in that: The methylating agent described in step 2 is one or more of dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl chloride, methyl bromide or methyl iodide; the organic solvent is one or more of toluene, N,N-dimethylformamide or acetone.

5. A synthesis process of metconazole according to claim 1, characterized in that: The specific catalyst described in step 3 is one or more of PEG200, PEG400, PEG800 or PEG2000; the inorganic base is one or more of potassium hydroxide or sodium hydroxide; the sulfur ylide reagent is one or more of trimethyl sulfoxide chloride, trimethyl sulfoxide bromide, trimethyl sulfonium methyl sulfate or trimethyl sulfonium bromide; the organic solvent is one or more of toluene, 1,4-dioxane, dimethyl sulfide or tetrahydrofuran.

6. A synthesis process of metconazole according to claim 1, characterized in that: The weight percentage of the catalyst added in step 3 is 1% to 10% of compound b.

7. A synthesis process of metconazole according to claim 1, characterized in that: The triazole and its salt described in step 4 are one or more of 1,2,4-triazole, 1,2,4-triazole sodium or 1,2,4-triazole potassium; the polar aprotic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

8. A synthesis process of metconazole according to claim 1, characterized in that: The ring-opening process described in step 4 is carried out at 50-110°C.

9. A synthesis process of metconazole according to claim 1, characterized in that: The certain pressure described in step 5 is 0.2-0.6 MPa; the catalyst is one or more of palladium carbon, ruthenium carbon, Raney nickel or platinum dioxide; the alcohol solvent is one or more of methanol, ethanol or isopropanol.

10. A synthesis process of metconazole according to claim 1, characterized in that: The cupric chloride salt in step 6 is one or more of cupric chloride or cuprous chloride; the nitrite compound is one of sodium nitrite or tert-butyl nitrite; and the acidic aqueous solution or polar solvent is one or more of hydrochloric acid aqueous solution, sulfuric acid aqueous solution or acetonitrile.

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