CN106749057A - Intermediate compound and method for synthesizing prothioconazole - Google Patents

Abstract

The invention discloses a synthetic method of an intermediate compound and prothioconazole, wherein the method comprises: combining 5,5'-dithio-bis(1,2,4-triazole) with 2-(1- Chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol undergoes a substitution reaction to obtain the key intermediate compound; then the target product prothioconazole is obtained through reduction. The synthesis process of the invention has high conversion rate and selectivity, and the synthesis raw materials are cheap and easy to obtain, thereby reducing the production cost. Moreover, the process reaction conditions adopted in the present invention are mild and easy to control, the operation is simple, the product is easy to purify, and the product can be obtained by direct recrystallization. Among them, the control method of intermediates in each step is simple and accurate, the product yield is high, the atom economy is good, and cumbersome post-processing is avoided, which has great competitive advantages and industrial production and utilization value. At the same time, the use of raw materials such as strong alkali is avoided, and the three wastes are extremely low, which is in line with the concept of green chemistry.

Description

A kind of synthetic method of intermediate compound and prothioconazole

technical field

The invention belongs to the field of organic synthesis, and in particular relates to a synthetic method of an intermediate compound and prothioconazole.

Background technique

Prothioconazole is a demethylation inhibitor (DMIs), and its mechanism of action is to inhibit the demethylation reaction of l4-position of lanosterol, the precursor of sterol in fungi. Prothioconazole not only has good systemic activity, excellent protection, treatment and eradication activities, but also has a long duration. The results of a large number of field efficacy tests show that prothioconazole not only has good safety for crops, but also has a good effect on disease prevention and treatment, and has a significant increase in yield. Compared with triazole fungicides, prothioconazole has a broader spectrum Bactericidal activity.

Prothioconazole is currently mainly used to prevent and control many diseases of cereal crops such as wheat, barley, rape, peanut, rice and bean crops. Prothioconazole has a good control effect on almost all wheat diseases, such as powdery mildew, sheath blight, fusarium wilt, leaf spot, rust, sclerotinia, net spot, moire of wheat and barley Wait. Prothioconazole can also control soil-borne diseases of rapeseed and peanuts, such as sclerotinia, and major foliar diseases, such as gray mold, black spot, brown spot, blackleg and rust.

According to the different sources of sulfur atoms, the preparation strategies of prothioconazole can be divided into two categories. The first type of strategy for preparing prothioconazole is to use hydroxytriazole compound as a key intermediate and react with sulfur to obtain prothioconazole (US4913727). Sulfur serves as a source of sulfur atoms for the prothioconazole compound in such reactions. The key intermediate of the method can be prepared by substitution reaction of triazole with chloride (US4913727) or epoxy compound (US5146001) as the starting material. This substitution reaction will produce a considerable amount of regioisomers at the same time, which need to be removed by purification, resulting in a poor yield (51-53%). The key intermediate can also be prepared by reacting chloroketone with triazole as a raw material, and then reacting with Grignard reagent. This method also has the problem of regioselectivity.

US Patent No. 5,789,430 discloses a method for preparing prothioconazole by direct reaction of compound and sulfur. The reaction takes N-methylpyrrolidone as a solvent at 200°C for 44 hours to obtain prothioconazole with a yield of 20%. US5789430 also discloses an improved method for preparing prothioconazole by reacting a compound with sulfur. The improved method is to use n-BuLi to dehydrogenate the compound in THF solvent, and then react with sulfur, so that the yield of prothioconazole is greatly improved (93%), but this technical solution requires anhydrous, oxygen-free and ultra-low temperature reaction Equipment and conditions, while requiring the use of more than two equivalents of highly dangerous n-BuLi reagents, the cost of this technical solution is high, and the operation is unsafe, which is not conducive to industrial production.

In addition, this technical solution is also troubled by its own chemical regioselectivity, for example: (1) improper control in the hydrogen extraction process of key intermediates using n-BuLi will lead to the production of regioisomeric impurities 11; (2) in the If the regioisomers are not completely separated and purified during the preparation of key intermediates, regioisomeric impurities will result. These high requirements of separation and purification not only produce a large amount of three wastes, but also greatly increase the cost.

US2013005985 discloses a method for preparing prothioconazole by using a Grignard reagent such as i-PrMgCl instead of n-BuLi to extract hydrogen from the compound and then vulcanize it. This method solves the dangerous problem of using n-BuLi reagent, but this technical scheme still needs anhydrous anaerobic and ultra-low temperature reaction equipment and conditions, needs to use Grignard reagent greater than two equivalents simultaneously, and productive rate drops significantly (from n- 93% of BuLi dropped to 68%).

Contents of the invention

The purpose of this section is to outline some aspects of embodiments of the invention and briefly describe some preferred embodiments. Some simplifications or omissions may be made in this section, as well as in the abstract and titles of this application, to avoid obscuring the purpose of this section, the abstract and titles, and such simplifications or omissions should not be used to limit the scope of the invention.

In view of the above-mentioned and/or existing technical blanks for synthesizing prothioconazole, the present invention is proposed.

Therefore, one of the objects of the present invention is to provide an intermediate compound which can be used in the synthesis of prothioconazole.

In order to solve the above-mentioned technical problems, the present invention provides the following technical scheme: a kind of intermediate compound, its chemical structural formula is:

Another object of the present invention is to solve the deficiencies of the prothioconazole synthesis method in the prior art, improve the conversion rate of each step, reduce by-products, simplify reaction conditions, reduce energy consumption, shorten reaction time, improve atom utilization, Reduce the three wastes.

In order to solve the above-mentioned technical problems, the present invention provides the following technical scheme: a synthetic method of prothioconazole, comprising, using 1,2,4-triazole as a raw material to obtain mercapto-1,2,4- Triazole; mercapto-1,2,4-triazole is oxidized to form 5,5'-dithio-bis(1,2,4-triazole); and 2-(1-chlorocyclopropyl )-3-chloro-1-(2-chlorophenyl)-2-propanol undergoes a substitution reaction to obtain the intermediate compound as claimed in claim 1; the target product prothioconazole is obtained through reduction.

As a preferred version of the synthesis method of prothioconazole of the present invention, wherein: the 1,2,4-triazole is used as a raw material to obtain mercapto-1,2,4-triazole through sulfur oxidation, Including, dissolving 1,2,4-triazole in an organic solvent, adding sulfur with a molar ratio of 1:3 to 1:6 to 1,2,4-triazole, heating to 100-180°C, and reacting 2 to 8 hours, cooled to room temperature, filtered, the filtrate was washed with saturated sodium chloride, extracted with ethyl acetate, the organic phase was separated, dried, and the ethyl acetate was distilled off to obtain mercapto-1,2,4-triazole; Among them, the organic solvent is one or more of DMF or toluene or DMSO; wherein, the solid desiccant used for drying is anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina one or more of.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the heating is to 100-180°C, and the temperature is preferably 110-160°C.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the reaction takes 2 to 8 hours, and the reaction time is preferably 3 to 6 hours.

As a preferred version of the synthesis method of prothioconazole in the present invention, wherein: the mercapto-1,2,4-triazole is oxidized to form 5,5'-dithio-bis(1,2 , 4-triazole), including dissolving mercapto-1,2,4-triazole in DCM, adding pyridine, controlling the temperature at -2°C to 6°C, stirring, adding benzenesulfonyl chloride, and removing after reaction DCM, add water and ethyl acetate to the residue, filter after reaction, and wash with water and ethyl acetate, dry the solid product obtained by filtration to obtain solid compound (Ⅴ) namely 5,5'-dithio-bis(1 , 2,4-triazole); Wherein, the solid desiccant used for drying is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the reaction temperature is preferably 0°C to 4°C.

As a preferred version of the synthetic method of prothioconazole of the present invention, wherein: the chloro-1-(2-chlorophenyl)-2- The substitution reaction of propanol includes stirring and mixing the solid compound (V) with an organic solvent and potassium carbonate, heating to 20°C to 100°C, adding 2-(1-chlorocyclopropyl)-3-chloro-1 -(2-Chlorophenyl)-2-propanol intermediate compound, cooled to room temperature after reaction, suction filtered, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was separated , dried, and rotary evaporated to obtain compound (Ⅵ); wherein, the organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone or DMF; wherein, the solid compound (V) has a molar ratio of potassium carbonate of 1:2～1:4; Among them, the solid compound (V) is the same as 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol compound (Ⅱ) in moles The ratio is 1:2～1:5; wherein, the solid desiccant used for drying is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina.

As a preferred version of the synthesis method of prothioconazole of the present invention, wherein: the solid desiccant is preferably anhydrous sodium sulfate.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the heating is at 20°C to 100°C, preferably at 40°C to 80°C.

As a preferred scheme of the synthesis method of prothioconazole of the present invention, wherein: the organic solvent is, preferably DMF.

As a preferred scheme of the synthesis method of prothioconazole according to the present invention, wherein: said reduction to obtain the target product prothioconazole comprises dissolving compound (VI) in an organic solvent, adding a reducing agent, and reacting After stirring and reacting at a temperature of 20°C-60°C, recrystallize, precipitate crystals and filter to obtain the target compound prothioconazole. Wherein, the organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, and acetone; wherein, the reducing agent is one or more of TCEP, DTT, Zn, sodium borohydride, and lithium aluminum hydride.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the organic solvent is preferably methanol.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the reaction temperature is preferably 30°C-50°C.

As a preferred scheme of the synthesis method of prothioconazole in the present invention, wherein: the reducing agent is preferably metal Zn.

Beneficial effects of the present invention:

(1) The conversion rate and selectivity of the synthesis process of the present invention are high, the synthesis raw materials are cheap and easy to obtain, and the production cost is reduced.

(2) The reaction conditions are mild and easy to control, the operation is simple, the product is easy to purify, and the product can be obtained by direct recrystallization.

(3) The control method of the intermediates in each step is simple and accurate, the product yield is high, the atom economy is good, and cumbersome post-processing is avoided, which has great competitive advantages and industrial production and utilization value.

(4) The use of raw materials such as strong alkali is avoided, and the three wastes are extremely low, which is in line with the concept of green chemistry.

Description of drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the accompanying drawings that need to be used in the description of the embodiments. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For Those of ordinary skill in the art can also obtain other drawings based on these drawings without any creative effort. in:

Fig. 1 is the MS spectrum of compound IV;

Fig. 2 is the MS spectrum of compound V;

Fig. 3 is the MS spectrum of compound VI;

Fig. 4 is the MS spectrum of compound VII;

Figure 5 is the ¹ H-NMR spectrum of compound VII, wherein, ¹ H NMR (400MHz, Chloroform-d) δ11.92 (s, 1H), 7.85 (s, 1H), 7.59–7.50 (m, 1H), 7.40 –7.33(m, 1H), 7.21(tt, J=7.3, 5.3Hz, 2H), 4.79(d, J=14.6Hz, 1H), 4.50(d, J=14.6Hz, 1H), 4.27(s, 1H), 3.62(d, J=14.0Hz, 1H), 3.17(d, J=14.0Hz, 1H), 1.02-0.85(m, 2H), 0.85-0.73(m, 2H).

detailed description

In order to make the above objects, features and advantages of the present invention more comprehensible, the specific implementation of the present invention will be described in detail below in conjunction with specific examples.

In the following description, a lot of specific details are set forth in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described here, and those skilled in the art can do it without departing from the meaning of the present invention. By analogy, the present invention is therefore not limited to the specific examples disclosed below.

Second, "one embodiment" or "an embodiment" referred to herein refers to a specific feature, structure or characteristic that may be included in at least one implementation of the present invention. "In one embodiment" appearing in different places in this specification does not all refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

For convenience in describing the present invention, conventional and non-conventional abbreviations for various reagents are used. These abbreviations are familiar to those skilled in the art, but are listed below for clarity:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

DMSO: dimethyl sulfoxide

DCM: dichloromethane

TCEP: Tris(2-carboxyethyl)phosphine

DTT: Dithiothreitol

Example 1:

Synthesis of 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol

In a 250mL round-bottomed three-neck flask device with a constant pressure titration funnel and a condenser tube, anhydrous and anaerobic operations were carried out under nitrogen protection conditions, and 10g (0.062mol) of 2-chlorobenzyl and 50mL of THF solution were mixed and placed in a constant pressure drop In the funnel, add 1.8g (0.074mol) of magnesium chips, 10ml of THF solution and a small amount of iodine into the three-necked flask, drop in 2ml of THF solution of 2-chlorobenzyl chloride, trigger with slight heat, put the device into the ice bath and slowly Add dropwise (drop/3s) until the drop is over, and then react for 1 h after the drop is over, slowly drop the above Grignard reactant into THF (30mL) of 9.0g (0.058mol) 1-chloro-1-chloroacetylcyclopropane The solution was slowly added dropwise (drop/3s) until the drop was completed, and the reaction was continued for 1 hour after the drop was completed, and the device was kept in an ice bath. Finally, slowly add the reaction solution into saturated NH4Cl ice solution to quench the reaction, stir for 1 h, separate the organic phase with a separatory funnel, add anhydrous sodium sulfate for drying, and evaporate THF to obtain 14.45 g of compound (II) Light yellow oily liquid, the yield is 89%.

Example 2:

Synthesis of Prothioconazole

Synthesis of compound (Ⅳ)

Dissolve 5g (0.072mol) of 1,2,4-triazole in 15ml of DMF, add 6.9g (0.216mol) of sublimed sulfur, heat to 140°C, react for 3.5h, cool to room temperature, filter, and use the filtrate Wash with saturated sodium chloride, extract with ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, distill off the ethyl acetate to obtain 6.95 g of solid compound (IV), with a yield of 95%.

Synthesis of compound (Ⅴ)

3.03g (30mmol) of compound (Ⅳ) was dissolved in 30mL DCM, and 2.37g (30mmol) of redistilled pyridine was added. Under ice-bath stirring conditions, 2.64g (15mmol) benzenesulfonyl chloride was added dropwise, and the dropwise addition was completed in about 1 hour. Remove the ice-water bath and stir at room temperature for 5h. DCM was evaporated, and 15 mL of water and 10 mL of ethyl acetate were added to the residue, reacted for 1 h, filtered, and washed with appropriate amount of water and ethyl acetate. The solid product obtained by filtration was sucked dry in a vacuum oven to obtain 2.88 g of solid compound (V), with a yield of 96%.

Synthesis of compound (Ⅵ)

Stir and mix 4g (20mmol) of compound (Ⅴ), 20ml of DMF, and 5.52g (40mmol) of potassium carbonate, and heat to 50°C. Compound (II) 11.74g (42mmol) was added dropwise, and the dropwise addition was completed after 2 hours. The reaction was continued for an hour, the reaction was stopped, and the reaction was cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 11.4 g of compound (VI) was obtained with a yield of 83%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Take 5g (0.0072mol) of compound (Ⅵ) and dissolve it in 30ml of methanol, add 0.97g (0.015mol) of metal Zn, stir and react at 30°C for 3h, stop the reaction, directly recrystallize, precipitate the crystals and filter to obtain the target compound (Ⅶ) C Thiconazole 4.3g, the yield is 86%.

In the above embodiments of the present invention, the synthesis route is redesigned to reduce production costs and increase the conversion rate of each step. It uses 1,2,4-triazole as a raw material to obtain mercapto-1,2,4- Triazole, then oxidized to form a disulfide bond, and then reacted with 2-(1-chlorocyclopropane)-3- Chloro-1-(2-chlorophenyl)-2-propanol undergoes a substitution reaction and then reduced to obtain the target product prothioconazole. Its principle is expressed by chemical formula as:

Comparative Example 1:

Synthesis of Prothioconazole

Synthesis of compound (Ⅳ)

Dissolve 5g (0.072mol) of 1,2,4-triazole in 15ml of DMSO, add 11.52g (0.36mol) of sublimed sulfur, heat to 180°C, react for 5h, cool to room temperature, filter, and the filtrate is saturated with Wash with sodium chloride, extract with ethyl acetate, separate the organic phase, dry with anhydrous sodium sulfate, distill off the ethyl acetate to obtain 5.89 g of solid compound (IV), with a yield of 81%.

Synthesis of compound (Ⅴ)

3.03g (30mmol) of compound (Ⅳ) was dissolved in 30mL DCM, and 3.16g (40mmol) of redistilled pyridine was added. Under the condition of stirring at 6°C, 3.53g (20mmol) of benzenesulfonyl chloride was added dropwise, and the dropwise addition was completed in about 1 hour. Stir at room temperature for 4h. DCM was evaporated, and 20 mL of water and 20 mL of ethyl acetate were added to the residue, reacted for 1 h, filtered, and washed with appropriate amount of water and ethyl acetate. The solid product obtained by filtration was sucked dry in a vacuum oven to obtain 2.49 g of solid compound (V), with a yield of 83%.

Synthesis of compound (Ⅵ)

Stir and mix 4g (20mmol) of compound (V), 40ml of acetonitrile, 8.28g (60mmol) of potassium carbonate, and heat to 80°C. 21.24g (80mmol) of compound (II) was added dropwise, and the dropwise addition was completed after 2h, and the reaction was continued for 4h, then the reaction was stopped, and cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 10.7 g of compound (VI) was obtained with a yield of 78%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Take 5g (0.0072mol) of compound (Ⅵ) and dissolve it in 30ml of ethanol, add 1.98g (0.0079mol) of TCEP, stir and react at 50°C for 3h, stop the reaction, directly recrystallize, precipitate crystals and filter to obtain the target compound (Ⅶ) propylsulfide Conazole 4.1g, the yield is 82%.

Comparative example 2:

Synthesis of Prothioconazole

Synthesis of compound (Ⅳ)

Dissolve 5g (0.072mol) of 1,2,4-triazole in 20ml of toluene, add 9.22g (0.288mol) of sublimed sulfur, heat to 100°C, react for 10h, cool to room temperature, filter, and the filtrate is saturated with Wash with sodium chloride, extract with ethyl acetate, separate the organic phase, dry with anhydrous sodium sulfate, distill off the ethyl acetate to obtain 4.07 g of solid compound (IV), with a yield of 56%.

Synthesis of compound (Ⅴ)

3.03g (30mmol) of compound (Ⅳ) was dissolved in 30mL DCM, and 3.16g (40mmol) of redistilled pyridine was added. Under the condition of stirring at -2°C, 3.53 g (20 mmol) of benzenesulfonyl chloride was added dropwise, and the dropwise addition was completed in about 1 hour. Stir at room temperature for 5h. DCM was evaporated, and 20 mL of water and 20 mL of ethyl acetate were added to the residue, reacted for 1 h, filtered, and washed with appropriate amount of water and ethyl acetate. The solid product obtained by filtration was sucked dry in a vacuum oven to obtain 2.1 g of solid compound (V), with a yield of 70%.

Synthesis of compound (Ⅵ)

Stir and mix 4g (20mmol) of compound (Ⅴ), 40ml of acetone, and 11.04g (80mmol) of potassium carbonate, and heat to 30°C. Compound (II) 21.24g (60mmol) was added dropwise, and the dropwise addition was completed after 2h, and the reaction was continued for 4h, then the reaction was stopped, and cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 7.0 g of compound (VI) was obtained with a yield of 51%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Dissolve 5g (0.0072mol) of compound (Ⅵ) in 30ml of acetone, add 0.55g (0.0144mol) of sodium borohydride, stir and react at 20°C for 5h, stop the reaction, recrystallize directly, precipitate the crystals and filter to obtain the target compound (Ⅶ) Prothioconazole 2.72g, the yield is 55%.

Example 3

Synthesis of compound (Ⅵ)

Stir and mix 6g (30mmol) of compound (Ⅴ), 30ml of DMF, and 12.42g (90mmol) of potassium carbonate, and heat to 60°C. 17.61 g (63 mmol) of compound (II) was added dropwise, and the dropwise addition was completed after 2 hours. The reaction was continued, stopped, and cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 17.31 g of compound (VI) was obtained with a yield of 84%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Dissolve 6.25g (0.009mol) of compound (Ⅵ) in 30ml of methanol, add 1.21g (0.019mol) of metal Zn, stir and react at 40°C for 3h, stop the reaction, directly recrystallize, precipitate the crystals and filter to obtain the target compound (Ⅶ) Prothioconazole 5.5g, the yield is 88%.

Example 4

Synthesis of compound (Ⅵ)

Stir and mix 6g (30mmol) of compound (Ⅴ), 30ml of DMF, and 12.42g (90mmol) of potassium carbonate, and heat to 80°C. 17.61 g (63 mmol) of compound (II) was added dropwise, and the dropwise addition was completed after 2 hours. The reaction was continued, stopped, and cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 16.49 g of compound (VI) was obtained with a yield of 80%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Take 6.25g (0.009mol) of compound (VI) and dissolve it in 30ml of methanol, add 0.97g (0.015mol) of metal sodium borohydride, stir and react at 50°C for 3h, stop the reaction, directly recrystallize, precipitate the crystals and filter to obtain the target compound ( VII) Prothioconazole 5.06g, the yield is 81%.

Example 5

Synthesis of compound (Ⅵ)

Stir and mix 6g (30mmol) of compound (V), 30ml of DMF, and 12.42g (90mmol) of potassium carbonate, and heat to 100°C. 17.61 g (63 mmol) of compound (II) was added dropwise, and the dropwise addition was completed after 2 hours. The reaction was continued, stopped, and cooled to room temperature. Suction filtration, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and the product obtained by rotary evaporation. 11.54 g of compound (VI) was obtained with a yield of 56%.

Synthesis of Target Compound (Ⅶ) Prothioconazole

Dissolve 6.25g (0.009mol) of compound (Ⅵ) in 30ml of methanol, add 0.97g (0.015mol) of metal TECP, stir and react at 20°C for 3h, stop the reaction, recrystallize directly, precipitate the crystals and filter to obtain the target compound (Ⅶ) Prothioconazole 3.44g, the yield is 55%.

Embodiment 3～5 reaction principle is:

In above-mentioned embodiment 1～5, produced the key intermediate compound of synthesis target compound, its chemical structural formula is:

Based on the data provided in the above examples, it can be seen that the synthesis method of prothioconazole provided by the present invention can obtain relatively excellent yields.

In the specific examples, Examples 1 and 2 all adopt the preferred solutions provided by the present invention regarding the selection of organic solvents, temperature control ranges and reducing agents, so the yield of the target compound at each stage is relatively excellent. In contrast, Comparative Example 1 basically followed the preferred scheme, but in the synthesis route, the preferred scheme of temperature or reducing agent provided by the present invention was not used in the synthesis of individual target compounds, and the corresponding yields were not ideal. In Comparative Example 2, the synthesis of target compounds in each step did not adopt the preferred ranges of the present invention regarding reaction time, reaction temperature, organic solvent and reducing agent selection.

The specific mechanism is as follows:

From the point of view of reaction temperature and reaction time, if the reaction temperature is too high and the reaction time is too long, when the reaction balance target product accounts for the main proportion, the reaction will continue, and the balance will be further advanced, which will increase the by-products; If the temperature and the reaction time are too short, the reaction cannot be fully carried out, and a better chemical balance cannot be presented, so that a better specific yield of the target product can be obtained. The present invention provides a preferred control range through the design of the synthetic route and the matching design of the reaction temperature and reaction time for the synthesis of the target product in each step.

It should be noted that the above embodiments are only used to illustrate the technical solution of the present invention without limitation, although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solution of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (10)

1. an intermediate compound is characterized in that its chemical structural formula is: 2. A synthetic method for prothioconazole, characterized in that: comprising, 5,5'-dithio-bis(1,2,4-triazole) and 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propane Alcohol substitution reaction obtains the intermediate compound as claimed in claim 1; The target product, prothioconazole, was obtained through reduction. 3. according to the synthetic method of prothioconazole described in claim 2, it is characterized in that: before obtaining intermediate compound as claimed in claim 1, also comprises, Using 1,2,4-triazole as raw material to obtain mercapto-1,2,4-triazole through sulfur oxidation; Mercapto-1,2,4-triazole is oxidized to form 5,5'-dithio-bis(1,2,4-triazole). 4. according to the synthetic method of prothioconazole described in claim 3, it is characterized in that: The mercapto-1,2,4-triazole is obtained by sulfur oxidation using 1,2,4-triazole as a raw material, comprising, dissolving 1,2,4-triazole in an organic solvent, adding the same 1, 2, 4-Triazole sulfur with a molar ratio of 1:3 to 1:6, heated to 100 to 180°C, reacted for 2 to 8 hours, cooled to room temperature, filtered, the filtrate was washed with saturated sodium chloride, and washed with Extract with ethyl acetate, separate the organic phase, dry, evaporate the ethyl acetate to obtain mercapto-1,2,4-triazole; wherein, The organic solvent is one or more of DMF or toluene or DMSO; The solid desiccant used in the drying is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina. 5. The method for synthesizing prothioconazole according to claim 4, characterized in that: the heating is to 100-180°C, preferably 110-160°C. 6. The synthetic method of prothioconazole according to any one of claims 3 to 5, characterized in that: the mercapto-1,2,4-triazole is oxidized to form 5,5'-dithio-bis (1,2,4-triazole), including, Dissolve mercapto-1,2,4-triazole in DCM, add pyridine, control the temperature at -2°C to 6°C, stir, add benzenesulfonyl chloride, remove DCM after reaction, add water and ethyl acetate to the residue , filtered after the reaction, and washed with water and ethyl acetate, and the solid product obtained by filtration was dried to obtain 5,5'-dithio-bis(1,2,4-triazole); wherein, The solid desiccant used for drying is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina. 7. The synthesis method of prothioconazole according to claim 6, characterized in that: the reaction temperature is preferably 0°C to 4°C. 8. according to the synthetic method of the arbitrary described prothioconazole of claim 2～5 or 7, it is characterized in that: described 5,5'-dithio-bis(1,2,4-triazole) and 2-(1-Chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol undergoes substitution reactions including, Stir and mix the 5,5'-dithio-bis(1,2,4-triazole) with organic solvent and potassium carbonate, heat to 20°C~100°C, add 2-(1-chlorocyclopropane base)-3-chloro-1-(2-chlorophenyl)-2-propanol, cooled to room temperature after reaction, suction filtered, the filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine , separating the organic phase, drying, and rotary evaporation to obtain the intermediate compound as claimed in claim 1; wherein, The organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone or DMF; The molar ratio of 5,5'-dithio-bis(1,2,4-triazole) to potassium carbonate is 1:2～1:4; 5,5'-dithio-bis(1,2,4-triazole) with 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propane Alcohol molar ratio is 1:2～1:5; The solid desiccant used for the drying is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate or activated alumina. 9. According to the synthetic method of any one of claims 2-5 or 7, prothioconazole is characterized in that: the target product prothioconazole is obtained through reduction, comprising: Dissolving the intermediate compound as claimed in claim 1 in an organic solvent, adding a reducing agent, stirring and reacting at a reaction temperature of 20°C to 60°C, recrystallizing, and filtering out crystals to obtain the target compound prothioconazole; wherein, The organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, and acetone; The reducing agent is one or more of TCEP, DTT, Zn, sodium borohydride and lithium aluminum hydride. 10. according to the synthetic method of prothioconazole described in claim 9, it is characterized in that: described organic solvent is preferably methyl alcohol.