CN103435564A - Preparation method of tebuconazole - Google Patents
Preparation method of tebuconazole Download PDFInfo
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Abstract
The invention discloses a preparation method of tebuconazole. The preparation method using p-chlorobenzaldehyde and pinacolone as initial raw materials comprises the following steps of: obtaining 2-(4-chlorobenzene ethyl)-2-tertiary butyl ethylene oxide through condensation reaction, hydrogenation reaction and epoxidation reaction in sequence; obtaining tebuconazole through ring-opening reaction of 2-(4-chlorobenzene ethyl)-2-tertiary butyl ethylene oxide and triazole under the co-catalysis of organic amine and crown ether. A catalysis technology of a composite catalyst which is composed of organic amine and crown ether is adopted, so that the isomer byproducts in the ring-opening reaction are greatly reduced, the ring-opening yield is improved to 92.8% from 80% of the conventional process, the product quality is improved to 98.5% or higher from 95%, and the total yield (in terms of p-chlorobenzaldehyde) is improved to 82% or higher from 65% of the conventional process.
Description
Technical field
The invention belongs to the organic synthesis field, be specifically related to a kind of preparation method of tebuconazole.
Background technology
Tebuconazole; chemistry (RS)-1-(4-chloro-phenyl-by name)-4; 4-dimethyl-3-(1H-1; 2; 4 triazol-1-yl methyl) penta-3-alcohol, structure is as shown in formula I, and tebuconazole is a kind of efficient, wide spectrum, interior absorption triazole species sterilization pesticide; have protection, treat, root out three large functions, fungicidal spectrum is wide, the lasting period is long.
The study on the synthesis of relevant tebuconazole is a lot, wherein, mainly with being starting raw material to chloromethane aldehyde, through steps such as condensation, shortening, epoxidation reaction and ring-opening reactions, prepares tebuconazole.The people such as Tan Chengxia have reported that take 4-chloro-benzaldehyde and pinacolone is raw material, through condensation, hydrogenation, epoxidation and ring-opening reaction synthesizing fungicide tebuconazole (colleges and universities' chemical engineering journal, 2007,21(6), 1030-1033).It is basic catalyst and employing CO that this synthetic method has been selected strong basic ion exchange resin in Aldol condensation reaction
2in and the alkaline matter in system, make 4,4-dimethyl-1-(4-rubigan)-yield of 1-penten-3-one reaches 98.3%, purity reaches 97.4%; Utilize two kinds of isomer thermodynamic stability differences of 1,2,4-triazole in ring-opening reaction, under the strong basic ion exchange resin effect, used catalyst n, N-dimethyl-4-aminopyridine, make the purity of tebuconazole reach 98.2%, and yield reaches more than 67%.
China's full-text database of dissertations has been reported and take 4-chloro-benzaldehyde as starting raw material, addition open loop four-step reaction by aldol condensation, selective catalytic hydrogenation, sulfur ylide epoxidation, propylene oxide, synthesized tebuconazole, yield is the high your lordship of 48%(. tebuconazole synthetic and to the prevention effect [D] of wheat hypochnus. and China Agricultural University, 2002.DOI:10.7666/d.y450784).Wherein, the ring-opening reaction operation is as follows: in four-hole boiling flask, load onto distillation and temperature regulating device, add 18mL propyl carbinol, 13g 1,2 of benzene recrystallization, the potassium hydroxide powder of 4-triazole, 2.5g86%, be heated to 100 ℃, after reaction 2h, is warming up to 110 ℃.Add 45g2-(to chlorobenzene ethyl)-the 2-tertiary butyl-oxyethane, after slowly heating up 1 hour, be warming up to 133 ℃.Isothermal reaction 4h, in reaction process, azeotropic steams the water that reaction generates.Reaction is cooled to 80 ℃ after finishing, and with distilled water, is washed till neutrality, and anhydrous sodium sulfate drying spends the night.Slough solvent under decompression, obtain the tawny mashed prod.Methyl alcohol: hexanaphthene (1:2) recrystallization, obtain product 43g, with 2-(to chlorobenzene ethyl)-the 2-tertiary butyl-oxyethane calculates, productive rate 79%.This method high temperature is synthetic, solvent method of purification sewage quantity is large, and reaction yield is not high, and product content is low.
Summary of the invention
The invention discloses a kind of preparation method of tebuconazole, this preparation method can improve the purity of yield and the end product tebuconazole of reaction simultaneously.
A kind of preparation method of tebuconazole, comprise the steps:
(1), under the effect of alkali, 4-chloro-benzaldehyde and pinacolone generation condensation reaction, after reacting completely, obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one through aftertreatment;
Described 4, the structure of 4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one is as shown in formula II:
(2) under the effect of hydrogenation catalyst, step (1) obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one and hydrogen generation hydrogenation, after reacting completely, obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-propione through aftertreatment;
Described 4, the structure of 4-dimethyl-1-(4-chloro-phenyl-)-propione is as shown in formula III:
(3) under the effect of mineral alkali, step (2) obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-propione and sulphur drone salt initial ring oxidizing reaction, after reacting completely, obtain 2-(4-chlorobenzene ethyl)-2-tertiary butyl oxyethane through aftertreatment;
The structure of described sulphur drone salt is as shown in formula IV:
(cH
3)
3s
+cH
3so
4 - (IV);
The structure of described 2-(4-chloro-phenyl-)-2-tertiary butyl oxyethane is as shown in formula V:
(4), under the effect of organic amine and crown ether, ring-opening reaction occurs in the 2-that step (3) obtains (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane and triazole in organic solvent, after reacting completely, through aftertreatment, obtains described tebuconazole.
In the ring-opening reaction of step (4), triazole can react with 1 and 2 of the ethylene oxide group of 2-(4-chlorobenzene ethyl)-2-tertiary butyl oxyethane simultaneously, therefore likely generate two kinds of isomer, the composite catalyst that ring-opening reaction in the present invention has adopted organic amine and crown ether to form carries out catalysis, greatly reduced the generation of isomer by product, open loop selectivity rate improves greatly, and productive rate and the purity of the tebuconazole obtained are greatly improved.
In step (1), described alkali is for pulling out the H of pinacolone α position, and the alkali be well known to those skilled in the art, be preferably sodium hydroxide, the sodium hydroxide low price, and also when using sodium hydroxide, reaction yield is higher.
In step (1), the mole dosage of described pinacolone and 4-chloro-benzaldehyde gets final product about equally, and the consumption of described alkali is excessive, and as preferably, the mol ratio of 4-chloro-benzaldehyde and alkali is 1:1.5～3.
In step (1), reaction is carried out in solvent, and solvent is preferably alcoholic solvent, and while carrying out in alcoholic solvent, the productive rate of reaction is higher, and described alcoholic solvent is preferably methyl alcohol.The consumption of solvent, without strict especially requirement, can fully dissolve the reaction raw materials 4-chloro-benzaldehyde to get final product, and general 1g 4-chloro-benzaldehyde solvent load used is roughly the 5mL left and right.
In step (1), temperature of reaction is generally carried out under the reflux temperature of solvent.
In step (1), the reaction degree of carrying out can be by the TLC(thin-layer chromatography) or HPLC monitored, the reaction times is about 4～10 hours, reaction can be carried out fully.
In step (1), aftertreatment comprises: reaction solution is cooled to 0 ℃ of left and right, and insulation is separated out solid, and it is described 4 that filtration can obtain, 4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one.
In step (2), described hydrogenation catalyst can be selected the catalyzer for double-bond hydrogenation well-known to those skilled in the art, as preferably, described hydrogenation catalyst is red aluminum solutions (dihydro two-(2 methoxy ethoxy) sodium aluminate solution), while adopting red aluminium, can optionally make carbon-carbon double bond reduce, and avoid carbonyl to be reduced.
The mol ratio of described red aluminium and 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one is 1:2～4.
In step (2), the pressure of described hydrogen is 0.5～1.0MPa, and hydrogen, in this pressure range, can make reaction have higher transformation efficiency and selectivity, and hypertonia can improve danger, and reduces the selectivity of reaction.
In step (2), when described hydrogenation carries out in alcoholic solvent, there is higher transformation efficiency, described alcoholic solvent is preferably methyl alcohol, the consumption of methyl alcohol, without strict especially requirement, can fully dissolve 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one to get final product.
In step (2), the temperature of described hydrogenation is 10～67 ℃, is preferably 60～67 ℃.
In step (2), the degree that reaction is carried out can be monitored by TLC or HPLC, and the reaction times is about 10～15 hours.
In step (3), described mineral alkali is for pulling out the hydrogen evolution sulfur ylide on the methyl of sulphur drone salt, so with carbonyl initial ring oxidizing reaction, described mineral alkali is preferably potassium hydroxide, the potassium hydroxide low price, and can with described sulphur drone salt, react well.
In step (3), the preparation method of described sulphur drone salt is well known to those skilled in the art, and can adopt dimethyl sulphide and methyl-sulfate reaction to prepare; As preferably, described sulphur drone salt obtains by dimethyl sulphide, sulfuric acid and methyl alcohol reaction, adopts this kind of method, has avoided the use of hypertoxic methyl-sulfate, the operation safe environmental protection.
In step (3), in described epoxidation reaction, sulphur drone salt is directly used with the state of solution, described 4, and 4-dimethyl-1-(4-chloro-phenyl-)-propione is 1～3:1 with the ratio of the amount of substance of sulphur drone salt.
In step (3), the temperature of described epoxidation reaction is 30～40 ℃.
In step (3), the degree that reaction is carried out can be monitored by TLC or HPLC, and the reaction times is about 5～10 hours.
In step (3), described aftertreatment is the intensification precipitation.
In step (4), described organic amine is preferably pyridine, triethylamine, DIPEA, triethylenediamine, N, N-dimethyl-4-aminopyridine or DMAP, pyridine more preferably, when selecting pyridine, the transformation efficiency of reaction is higher.
In step (4), described crown ether is preferably 15-hat (ether)-5,18-is preced with (ether)-6; Described crown ether is 18-hat-6 more preferably, can further improve the selectivity of reaction; As further preferred, when 18-hat-6 is used with pyridine simultaneously, reaction has best selectivity, and transformation efficiency is higher.
In step (4), as preferably, the mol ratio of described organic amine and crown ether is 2～3:1; The mol ratio of described crown ether and 4,4-dimethyl-1-(4-chloro-phenyl-)-propione is 0.1～0.5:1.
In step (4), when described organic solvent is selected polar solvent, reaction efficiency is higher, and as preferably, described organic solvent is dimethyl sulfoxide (DMSO); The consumption of described organic solvent, without strict especially requirement, can fully dissolve 4,4-dimethyl-1-(4-chloro-phenyl-)-propione to get final product.
In step (4), as preferably, the temperature of reaction of described ring-opening reaction is 110～130 ℃, and excess Temperature can make the elective reduction of reaction, and temperature is too low, can reduce the transformation efficiency of reaction.
In step (4), described triazole and described 4, the mol ratio of 4-dimethyl-1-(4-chloro-phenyl-)-propione is 1.5～2.5:1.
In step (4), also need to add a certain amount of sodium hydroxide in reaction process, the amount of sodium hydroxide, without strict especially requirement, gets final product about equally with the molar weight of 4,4-dimethyl-1-(4-chloro-phenyl-)-propione.
In step (4), described aftertreatment comprises: with the hexanaphthene extraction, water is washed, and after the organic phase cooling obtained, can separate out the tebuconazole product.
Compared with the existing technology, beneficial effect of the present invention is embodied in:
(1) hydrogenation reaction adopts red aluminium hydrogenation catalyst catalysis new technology, and safe, nonflammable, selectivity is good, greatly reduces the generation of by product, makes the hydrogenation yield bring up to 99% from 94%, and hydrogenation products content is brought up to more than 97%.
(2) prepared with methyl alcohol, sulfuric acid replacement sulfur dimethyl phthalate new technology by epoxidation reaction sulfosalt used, has realized that the green of highly toxic product substitutes, and operates safer environmental protection.
(3) ring-opening reaction adopts the composite catalyst catalysis technique that organic amine and crown ether form, and has greatly reduced the generation of isomer by product, and the open loop yield brings up to 92.8% from 80% of traditional technology, and quality product is brought up to more than 98.5% by 95%.In 4-chloro-benzaldehyde, total recovery is brought up to more than 82% from 65% of traditional technology.
Embodiment
Embodiment 1
Synthesizing of 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one: in the 500ml four-hole boiling flask, drop into 140ml methyl alcohol, 28.0g 4-chloro-benzaldehyde (dissolving), drop into the 22.0g pinacolone, sodium hydroxide 12.0g, start after finishing to stir, and slowly is warming up to 70 ℃ of backflows, insulation 5h, reaction finishes slow cooling to 0 ± 2 ℃, and insulation 0.5h, filter to obtain 43.5g4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one, productive rate is 97.6%.
Embodiment 2
4,4-dimethyl-1-(4-chloro-phenyl-)-propione synthetic: embodiment 1 is obtained 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one 43.5 drops into the hydrogenation still, add methyl alcohol 230ml simultaneously, the red aluminum solutions of red aluminum solutions 20.0g(by 70% dihydro two-(2 methoxy ethoxy) sodium aluminate and 30% toluene forms, purchased from permanent chemical materials company limited in Nanjing, trade(brand)name:
red aluminium), use successively nitrogen replacement three times, hydrogen exchange three times, slowly heat up, and starts to pass into hydrogen reaction simultaneously, controls still temperature 30-67 ℃, pressure ﹤ 1.0Mpa.Later stage temperature control 62-67 ℃, pressure 0.7-0.9Mpa reaction, when substantially constant to the still pressure, sampling HPLC analyzes.Be cooled to 35 ℃ after qualified, the emptying separating methanol, first 80 ℃ of normal pressure precipitations, change negative pressure precipitation (0.095Mpa) after insulation 0.5h, be warming up to 110 ℃ of insulation 1h, qualified to separating methanol, obtain 43.5 yellow oily solids 4,4-dimethyl-1-(4-chloro-phenyl-)-propione (productive rate 99%, purity 97%) is preserved stand-by under 20-40 ℃.
Embodiment 3(Comparative Examples 1)
4,4-dimethyl-1-(4-chloro-phenyl-)-propione synthetic: embodiment 1 is obtained 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one 43.5g drops into the hydrogenation still, adds methyl alcohol 230ml simultaneously, add Raney's nickel 8.1g simultaneously,, use successively nitrogen replacement three times, hydrogen exchange three times, slowly heat up, start to pass into hydrogen reaction simultaneously, control still temperature 10-67 ℃, pressure ﹤ 1.5Mpa.Later stage temperature control 62-67 ℃, pressure 1.2-1.5Mpa reaction, when substantially constant to the still pressure, sampling HPLC analyzes.Be cooled to 35 ℃ after qualified, the emptying separating methanol, first 80 ℃ of normal pressure separating methanols, change negative pressure precipitation (0.095Mpa) after insulation 0.5h, be warming up to 110 ℃ of insulation 1h, qualified to separating methanol, obtain 41.3g yellow oily solid 4,4-dimethyl-1-(4-chloro-phenyl-)-propione (productive rate 94%, purity is 95%) is preserved stand-by under 20-40 ℃.
Embodiment 4
The preparation of sulfosalt: drop at normal temperatures dimethyl sulphide 12.5g in the 250mL flask, methyl alcohol 13ml, stir, drip sulfuric acid 19.6g, temperature control 17-35 ℃ of about 1h drips off, after stirring at room 0.5h, slowly be warming up to 35-38 ℃, insulation reaction 2h, insulation is cooled to 30 ℃ after finishing.The sulfosalt configuration is complete.
Embodiment 5
The preparation of 2-(4-chlorobenzene ethyl)-2-tertiary butyl oxyethane: in the sulfosalt configured to embodiment 4, drop into embodiment 2 synthetic 4, 4-dimethyl-1-(4-chloro-phenyl-)-propione 43.5g, control temperature at 30 ℃, drop into again KOH, stir 10min, naturally heat up, control temperature at 38-42 ℃, insulation 6h sampling, be cooled to 30 ℃ after qualified, add water 10ml washing, temperature is controlled at 35-38 ℃, stir, standing, divide water, after three washings, first normal pressure precipitation, slowly rise to 110 ℃, after the normal pressure precipitation finishes, be cooled to 90 ℃, add a small amount of water precipitation 0.5h that starts to reduce pressure, (productive rate is 98.7% to obtain 44.2g2-(4-chlorobenzene ethyl)-2-tertiary butyl oxyethane, purity is 98.5%).Sampling, moisture, thioether≤0.5% are qualified.
Embodiment 6
Synthesizing of tebuconazole: in the 500ml flask, drop into triazole 23.5g, sheet alkali 20g, dimethyl sulfoxide (DMSO) 300mL, pyridine 5.3g and 8.0g18-hat-6, stir the 10min dissolved solids, after temperature-stable, be warming up to 80 ℃ and start to drip the synthetic 2-of embodiment 5 (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane 44.2g, during dropping temperature be controlled at≤115 ℃, approximately within 1 hour, drip off, continue to heat up, to 118-122 ℃ of insulation 5h, insulation finishes, then be cooled to 110 ℃ and add water and hexanaphthene, material is warming up to 70 ℃ of backflow 0.5h, 65 ℃ of insulations are standing, after dividing water, wash twice to material pH<8, layering obtains organic layer, slow cooling to room temperature filter 52.1g tebuconazole product (purity is 98%, productive rate is 92.8%), comprehensive yield 83.0%.Resulting tebuconazole is contrasted with standard substance by HPLC, and retention value is consistent.
Embodiment 7(Comparative Examples 2)
Synthesizing of tebuconazole: in the 500ml flask, drop into triazole 23.5g, sheet alkali 20g, dimethyl sulfoxide (DMSO) 300mL, pyridine 5.3g and 6.5g15-hat-5, stir the 10min dissolved solids, after temperature-stable, be warming up to 80 ℃ and start to drip the synthetic 2-of embodiment 5 (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane 44.2, during dropping temperature be controlled at≤115 ℃, approximately within 1 hour, drip off, continue to heat up, to 118-122 ℃ of insulation 5h, insulation finishes, then be cooled to 110 ℃ and add water and hexanaphthene, material is warming up to 70 ℃ of backflow 0.5h, 65 ℃ of insulations are standing, after dividing water, wash twice to material pH<8, layering obtains organic layer, slow cooling to room temperature filter 48.9g tebuconazole product (purity is 95%, productive rate is 87%), comprehensive yield 73.8%.Resulting tebuconazole is contrasted with standard substance by HPLC, and retention value is consistent.
Embodiment 8(Comparative Examples 3)
Synthesizing of tebuconazole: in the 500ml flask, drop into triazole 26g, sheet alkali 20g, dimethyl sulfoxide (DMSO) 300mL, triethylamine 6.5g and 8.0g18-hat-6, stir the 10min dissolved solids, after temperature-stable, be warming up to 80 ℃ and start to drip the synthetic 2-of embodiment 5 (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane 44.2g, during dropping temperature be controlled at≤115 ℃, approximately within 1 hour, drip off, continue to heat up, to 118-122 ℃ of insulation 5h, insulation finishes, then be cooled to 110 ℃ and add water and hexanaphthene, material is warming up to 70 ℃ of backflow 0.5h, 65 ℃ of insulations are standing, after dividing water, wash twice to material pH<8, layering obtains organic layer, slow cooling to room temperature filter 47.8g tebuconazole product (purity is 95%, productive rate is 85%), comprehensive yield 73.7%.Resulting tebuconazole is contrasted with standard substance by HPLC, and retention value is consistent.
Embodiment 9(Comparative Examples 4)
Synthesizing of tebuconazole: in the 500ml flask, drop into triazole 26g, sheet alkali 20g, dimethyl sulfoxide (DMSO) 300mL, triethylamine 6.5g and 6.5g15-hat-5, stir the 10min dissolved solids, after temperature-stable, be warming up to 80 ℃ and start to drip the synthetic 2-of embodiment 5 (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane 44.2g, during dropping temperature be controlled at≤115 ℃, approximately within 1 hour, drip off, continue to heat up, to 118-122 ℃ of insulation 5h, insulation finishes, then be cooled to 110 ℃ and add water and hexanaphthene, material is warming up to 70 ℃ of backflow 0.5h, 65 ℃ of insulations are standing, after dividing water, wash twice to material pH<8, layering obtains organic layer, slow cooling to room temperature filter 45.0g tebuconazole product (purity is 95%, productive rate is 80%), comprehensive yield 69.4%.Resulting tebuconazole is contrasted with standard substance by HPLC, and retention value is consistent.
Claims (10)
1. the preparation method of a tebuconazole, is characterized in that, comprises the steps:
(1), under the effect of alkali, 4-chloro-benzaldehyde and pinacolone generation condensation reaction, after reacting completely, obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one through aftertreatment;
Described 4, the structure of 4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one is as shown in formula II:
(2) under the effect of hydrogenation catalyst, step (1) obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-1-penten-3-one and hydrogen generation hydrogenation, after reacting completely, obtain 4,4-dimethyl-1-(4-chloro-phenyl-)-propione through aftertreatment;
Described 4, the structure of 4-dimethyl-1-(4-chloro-phenyl-)-propione is as shown in formula III:
(3) under the effect of mineral alkali; step (2) obtain 4; 4-dimethyl-1-(4-chloro-phenyl-)-propione and sulphur drone salt initial ring oxidizing reaction, after reacting completely, obtain 2-(4-chlorobenzene ethyl)-2-tertiary butyl oxyethane through aftertreatment;
The structure of described sulphur drone salt is suc as formula shown in (IV):
(CH
3)
3s
+cH
3so
4 - (IV);
The structure of described 2-(4-chloro-phenyl-)-2-tertiary butyl oxyethane is as shown in formula V:
(4), under the effect of organic amine and crown ether, ring-opening reaction occurs in the 2-that step (3) obtains (4-chlorobenzene ethyl)-2-tertiary butyl oxyethane and triazole in organic solvent, after reacting completely, through aftertreatment, obtains described tebuconazole.
2. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (1), described alkali is sodium hydroxide.
3. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (2), described hydrogenation catalyst is red aluminium.
4. according to the preparation method of claim 1 or 3 described tebuconazole, it is characterized in that, in step (2), the pressure of described hydrogen is 0.5～1.0MPa.
5. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (3), described mineral alkali is potassium hydroxide.
6. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (3), described sulphur drone salt obtains by dimethyl sulphide, sulfuric acid and methyl alcohol reaction.
7. the preparation method of tebuconazole according to claim 1, it is characterized in that, in step (4), described organic amine is pyridine, triethylamine, N, N-diisopropylethylamine, triethylenediamine, N, N-dimethyl-4-aminopyridine or DMAP.
8. according to the preparation method of claim 1 or 7 described tebuconazole, it is characterized in that, in step (4), described crown ether is 15-hat-5 or 18-hat-6.
9. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (4), the mol ratio of described organic amine and crown ether is 2～5:1.
10. the preparation method of tebuconazole according to claim 1, is characterized in that, in step (4), described organic solvent is dimethyl sulfoxide (DMSO).
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| CN105348057A (en) * | 2015-12-14 | 2016-02-24 | 上海生农生化制品有限公司 | Synthetic method of tebuconazole intermediate |
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