CN103044479A - Synthetic method for bactericide of silthiopham - Google Patents

Abstract

The invention relates to a method for synthesizing the fungicide silthiocarb, which comprises: mixing methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate and allylamine in a solvent- Medium reflux reaction for 5-15 hours, after the reaction is completed, it is lowered to room temperature, washed with water, and the organic phase is dried, concentrated, and recrystallized; Extraction, drying, concentration, and recrystallization of the organic phase; the molar ratio of the 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate to allylamine is 1: 1-2. The method has the characteristics of cheap and easy-to-obtain raw materials, mild reaction conditions, high reaction yield, etc., and is suitable for large-scale production.

Description

The synthetic method of fungicide silthiocarb

technical field

The invention belongs to the technical field of organic synthesis, and specifically relates to a fungicide N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide (silthiocarbamide) resolve resolution.

Background technique

Sithiopyram is a fungicide developed by Monsanto Corporation of the United States for the prevention and treatment of wheat take-all, and has a significant effect on the control of wheat take-all. However, its popularization and application are limited due to the problems of raw material supply and harsh reaction conditions in the current synthesis process.

U.S. Patent US005486621A reports its synthesis method, which uses 2-butanone, sulfur, cyanoacrylate, etc. as starting materials to synthesize the target product, but the total yield is less than 10%. Moreover, the steps of the synthesis method are long, and the separation of each intermediate is difficult. US Patent US006140511A reports an improved synthesis method, but the synthesis of the important intermediate 3-(trimethylsilyl) propynamide involved in the method encounters great challenges. Although this patent provides a variety of synthesis methods, the synthesis methods involved are either difficult to obtain raw materials, or require the use of strong bases sensitive to water and air such as butyllithium or amide lithium, which are difficult to popularize and apply; in addition, due to the The intermediate has a relatively high boiling point, and its separation and purification have also encountered difficulties. Document Organic Process Research & Development 6 (2002), 357-366 has reported new synthetic route, and this synthetic method has synthesized target product with mercaptobutanone, methyl methoxyacrylate as starting material, although this process yield has It has been improved, but the reaction conditions are harsh, and air-sensitive dangerous raw materials such as butyllithium or lithium amide (LDA) are still needed, so it is difficult to produce on a large scale.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the prior art and provide a fungicide N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide (silthiocarbamide) The synthesis method has the characteristics of cheap and easy-to-obtain raw materials, mild reaction conditions, high reaction yield, etc., and is suitable for large-scale production.

To achieve the above object, the present invention adopts the following technical solutions:

A method for synthesizing the fungicide silthiocarb, the method comprising: refluxing 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylic acid methyl ester and allylamine in solvent one (Occurrence of amine exchange reaction) 5-15h, after the reaction is completed, cool down to room temperature, wash with water, dry the organic phase, concentrate, and recrystallize; Dichloromethane extraction, the organic phase is dried, concentrated and recrystallized; For 1:1-2, the synthetic route is as follows:

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Specifically, the solvent one is one or a mixture of two or more of halogenated hydrocarbons, alcohols, aromatic hydrocarbons and polar aprotic solvents; the amount of solvent one added is generally 5-10 times the mass of the reactants. In the described solvent one, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, isopropanol, etc.; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, etc.; polar non- Protic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.

The 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylic acid methyl ester is preferably prepared by the following method: 3-mercaptobutanone and 3-(trimethylsilyl ) methyl propiolate under the protection of inert gas (such as nitrogen, etc.) and under the action of alkali catalyst, reflux reaction in solvent two for 5-20h. It can be obtained by analysis and separation; or after the reaction is completed, the solvent 2 is evaporated under negative pressure, and then lowered to room temperature, washed with water, extracted with dichloromethane, and the organic phase is washed, dried, concentrated, and separated by column chromatography; the 3-mercapto The molar ratio of butanone to methyl 3-(trimethylsilyl)propiolate is 1:0.5-1; the synthetic route is as follows:

。

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The alkali catalyst is preferably one or a mixture of two or more of alkali metal carbonates, alkali metal hydrides and alkali metal alkoxides; the second solvent is preferably halogenated hydrocarbons, alcohols, aromatic hydrocarbons and One or a mixture of two or more polar aprotic solvents; the amount of the catalyst is generally 0.2-2 times the mass of 3-(trimethylsilyl) propiolate; the solvent two The amount added is generally 5-10 times the mass of the reactants. Alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, etc. . In the solvent two, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, isopropanol, etc.; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, etc.; polar non- Protic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.

Described 3-(trimethylsilyl) methyl propiolate is preferably prepared by the following method: methyl propiolate and trimethylchlorosilane are protected with an organic base catalyst in an inert gas (such as nitrogen, etc.) Reflux reaction (condensation reaction) in solvent 3 for 3-12 hours under the action, after the reaction is completed, cool down to room temperature, wash with water, dry the organic phase, concentrate, and separate by column chromatography; or evaporate the solvent under negative pressure after the reaction is completed 3. Cool down to room temperature, wash with water, extract with dichloromethane, dry the organic phase, concentrate, and separate by column chromatography; the molar ratio of methyl propiolate to trimethylchlorosilane is 1:1- 2; the synthetic route is as follows

。

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The organic base catalyst is preferably an organic amine; the solvent three is preferably one or a mixture of two or more of halogenated hydrocarbons, aromatic hydrocarbons and polar aprotic solvents. The amount of the catalyst used is generally 0.2-2 times the mass of methyl propiolate; the amount of the solvent added is generally 5-10 times the mass of the reactant. The organic amines, such as triethylamine, morpholine, piperazine, etc.; the solvent three, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; aromatic hydrocarbons such as toluene, xylene, chlorine Benzene, etc.; polar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, etc.

Detailed ways

Figure 1 is the ¹ H-NMR spectrum of methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate obtained by the method of the present invention, ¹ H NMR (400MHz, CDCl ₃ ) δ: 3.84 (s, 3H); 2.35 (s, 3H); 2.30 (s, 3H); 0.31 (s, 9H);

Figure 2 is the ¹³ C-NMR spectrum of methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate obtained by the method of the present invention, ¹³ C NMR (100MHz, CDCl ₃ ) δ: 165.1; 144.5; 138.6; 138.0; 136.6; 51.0; 13.7; 13.4; 0.0. GC-MS: m/z 242.0 (M ⁺ , 2%); 227 (100); 197 (34); 179 (29);

Figure 3 is the ¹ H-NMR spectrum of N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide obtained by the method of the present invention, Mp: 85-87°C ; ¹ H NMR (300MHz, CDCl ₃ ) δ: 5.97-5.86 (m, 1H); 5.67 (br s, 1H); 5.26(apparent dq, J =17.1, 1.4 Hz, 1H); 5.19(apparent dq, J =10.2, 1.2, 1H); 4.04 (t, J =5.8, 2H), 2.34(s, 3H); 2.16(s, 3H); 0.30(s, 9H). GC-MS: m/z 267 (M+, 2%); 252 (100); 211 (10), 194 (7). Anal. Calcd for C ₁₃ H ₂₁ NOSSi: C, 58.38; H, 7.91; N, 5.24; S, 11.99. Found: C, 58.20; H, 8.05; N, 5.30;

Detailed ways

The present invention will be further described by the following examples, but the protection scope of the present invention is not limited thereto.

Example 1

A kind of synthetic method of bactericide silthiocarb, the method comprises the following steps:

1) Preparation of methyl 3-(trimethylsilyl)propiolate

Put 0.84g (10mmol) of methyl propiolate and 1.41g (13mmol) of trimethylchlorosilane into a three-necked reaction flask containing 5mL of dichloromethane, and slowly add dropwise 5mL of 1.0g (10mmol) of triethylamine The dichloromethane mixed solution was added, and the reaction system was heated to reflux for 3 hours under the protection of nitrogen atmosphere. After the reaction was completed, it was lowered to room temperature, then 5 mL of water was added to stir and mix evenly, and the layers were allowed to stand. After the water phase was separated, the organic phase was dried with anhydrous sodium sulfate and filtered. The mobile phase with a volume ratio of 1:20-50 to petroleum ether was separated by silica gel column chromatography to obtain 1.4 g of light yellow liquid methyl 3-(trimethylsilyl)propiolate, with a yield of 89%.

) to prepare methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate

Put 1.56g (15mmol) of 3-mercaptobutanone and 1.56g (10mmol) of methyl 3-(trimethylsilyl) propiolate into a three-necked reaction flask filled with 20mL of toluene, and then add 0.5g (9mmol) After adding sodium methoxide, the reaction system was heated under reflux for 10 hours under the protection of nitrogen atmosphere. Cool down to room temperature after the reaction is over, add 10mL of water, stir evenly, let stand to separate layers, and separate the water phase; the organic phase is washed twice with 8mL saturated saline, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated with a rotary evaporator , the concentrated raffinate was separated by silica gel column chromatography to obtain 2g light yellow liquid 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-methyl carboxylate, yield 83%, and the spectrum results are shown in Figure 1 ,2.

) to prepare N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide

Add 2.4g (10mmol) methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate into a three-necked reaction flask filled with 10mL chloroform, and then drop it with a dropping funnel at room temperature Add 5 mL of chloroform solution in which 0.7 g (12 mmol) of allylamine was dissolved, dropwise, and heat the reaction system under reflux for 15 h. After the reaction was completed, it was lowered to room temperature, then 8 mL of water was added to stir and mix evenly, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. This crude product is recrystallized with normal hexane to obtain 2.3g white needle crystal N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide, yield 86%, collection of illustrative plates The results are shown in Figure 3.

Example 2

A kind of synthetic method of bactericide silthiocarb, the method comprises the following steps:

1) Preparation of methyl 3-(trimethylsilyl)propiolate

Put 0.84g (10mmol) of methyl propiolate and 2.16g (20mmol) of trimethylchlorosilane into a three-necked reaction flask containing 10mL of toluene, and slowly add dropwise a mixed solution of 5mL of toluene containing 0.9g (10mmol) of morpholine After the addition, the reaction system was heated to reflux for 8 hours under the protection of nitrogen atmosphere. After the reaction was completed, it was lowered to room temperature, then 10 mL of water was added to stir and mix well, and the layers were allowed to stand. After the water phase was separated, the organic phase was dried with anhydrous sodium sulfate and filtered. The mobile phase with a volume ratio of 1:20-50 to petroleum ether was separated by silica gel column chromatography to obtain 1.2 g of light yellow liquid methyl 3-(trimethylsilyl)propiolate with a yield of 77%.

) to prepare methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate

Put 1.04g (10mmol) of 3-mercaptobutanone and 1.56g (10mmol) of methyl 3-(trimethylsilyl)propiolate into a three-necked reaction flask containing 30mL of N,N-dimethylformamide , then add 1.4g (10mmol) of potassium carbonate, after the addition is complete, the reaction system is heated to reflux for 20 hours under the protection of a nitrogen atmosphere. After the reaction was completed, the solvent N,N-dimethylformamide was evaporated under negative pressure, cooled to room temperature, washed with 10mL of water, extracted with 30mL of dichloromethane, and the organic phase was washed twice with 8mL of saturated saline, anhydrous sodium sulfate Dry, filter, the filtrate is concentrated with a rotary evaporator, and the concentrated residue is separated by silica gel column chromatography to obtain 1.5g light yellow liquid 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-methyl carboxylate , The yield is 62%%. The results of the spectrum are shown in Figures 1 and 2.

) to prepare N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide

Add 2.4g (10mmol) of methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate into a three-necked reaction flask filled with 15mL of toluene, and then drop it with a dropping funnel at room temperature Add 5mL of toluene solution in which 1.14g (20mmol) of allylamine was dissolved, dropwise, and heat the reaction system under reflux for 5h. After the reaction was completed, it was lowered to room temperature, then 8 mL of water was added to stir and mix evenly, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. This crude product is recrystallized with n-hexane to obtain 2.4g white needle crystal N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide, yield 90%, collection of illustrative plates The results are shown in Figure 3.

Example 3

A kind of synthetic method of bactericide silthiocarb, the method comprises the following steps:

1) Preparation of methyl 3-(trimethylsilyl)propiolate

Put 0.84g (10mmol) methyl propiolate and 1.08g (10mmol) trimethylchlorosilane into a three-necked reaction flask filled with 5mL N,N-dimethylformamide, slowly dropwise add 2.0g (20mmol) ) triethylamine 5mL N,N-dimethylformamide mixed solution, after addition, the reaction system was heated to reflux for 12 hours under the protection of nitrogen atmosphere. After the reaction, the solvent N,N-dimethylformamide was distilled off under negative pressure, then cooled to room temperature, washed with 10mL of water, extracted with 30mL of dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was Concentrate, the concentrated residue is separated by silica gel column chromatography with a mobile phase of ethyl acetate and petroleum ether with a volume ratio of 1:20-50 to obtain 1.1 g of light yellow liquid methyl 3-(trimethylsilyl)propiolate , yield 71%.

) to prepare methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate

Put 2.08g (20mmol) of 3-mercaptobutanone and 1.56g (10mmol) of methyl 3-(trimethylsilyl) propiolate into a three-necked reaction flask containing 20mL of chloroform, and then add 0.4g (17mmol) After adding sodium hydride, the reaction system was heated to reflux for 5 hours under the protection of nitrogen atmosphere. Cool down to room temperature after the reaction, add 10 mL of water and mix well, let stand to separate the layers, separate the water phase, wash the organic phase twice with 8 mL of saturated saline, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate with a rotary evaporator. The concentrated residue was separated by silica gel column chromatography to obtain 1.8g light yellow liquid 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-methyl carboxylate, yield 74%, and the results of the spectrum are shown in Figure 1 ,2.

) to prepare N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide

Add 2.4g (10mmol) of 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylic acid methyl ester into a three-necked reaction flask filled with 20mL of ethanol, and then drop it with a dropping funnel at room temperature Add 10mL of ethanol solution in which 0.7g (12mmol) of allylamine was dissolved, dropwise, and heat the reaction system under reflux for 10h. After the reaction, the solvent ethanol was evaporated under negative pressure, the residue was cooled to room temperature, washed with 8 mL of water, extracted with 20 mL of dichloromethane, the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was recrystallized with n-hexane to obtain 2.2g white needle-like crystal N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide, yield 82%, collection of illustrative plates The results are shown in Figure 3.

Example 4

A kind of synthetic method of bactericide silthiocarb, the method comprises the following steps:

1) Preparation of methyl 3-(trimethylsilyl)propiolate

Put 0.84g (10mmol) methyl propiolate and 1.41g (13mmol) trimethylchlorosilane into a three-necked reaction flask containing 15mL toluene, slowly add 5mL toluene containing 0.8g (9.5mmol) piperazine and mix After the addition of the solution, the reaction system was heated to reflux for 8 hours under the protection of a nitrogen atmosphere. After the reaction was completed, it was lowered to room temperature, then 10 mL of water was added to mix, and the layers were allowed to stand. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated with a rotary evaporator. The mobile phase of 1:20-50 was separated by silica gel column chromatography to obtain 1.3 g of light yellow liquid methyl 3-(trimethylsilyl)propiolate, with a yield of 83%.

) to prepare methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate

Put 1.56g (15mmol) of 3-mercaptobutanone and 1.56g (10mmol) of methyl 3-(trimethylsilyl) propiolate into a three-necked reaction flask filled with 20mL of ethanol, and then add 0.14g (2mmol) After adding sodium ethoxide, the reaction system was heated to reflux for 10 hours under the protection of nitrogen atmosphere. After the reaction, the solvent ethanol was evaporated under negative pressure, and the residue was cooled to room temperature, washed with 8 mL of water, extracted with 20 mL of dichloromethane, and the water phase was separated; the organic phase was washed twice with 8 mL of saturated saline, and dried over anhydrous sodium sulfate. , filtered, the filtrate was concentrated with a rotary evaporator, and the concentrated residue was separated by silica gel column chromatography to obtain 1.6g light yellow liquid 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylic acid methyl ester, The yield is 66%, and the spectrum results are shown in Figures 1 and 2.

) to prepare N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide

Add 2.4g (10mmol) methyl 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate into a three-necked reaction flask filled with 20mL tetrahydrofuran, and then drop it with a dropping funnel at room temperature Add 10 mL of tetrahydrofuran solution in which 0.7 g (12 mmol) of allylamine was dissolved, dropwise, and heat the reaction system under reflux for 8 h. After the reaction, the solvent tetrahydrofuran was evaporated under negative pressure, the residue was cooled to room temperature, washed with 8 mL of water, extracted with 20 mL of dichloromethane, the water phase was separated, the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was recrystallized with n-hexane to obtain 2.0g white needle-like crystal N-allyl-4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxamide, yield 75%, collection of illustrative plates The results are shown in Figure 3.

Claims (6)

1. a synthetic method of bactericide silthiocarb, characterized in that, 4,5-dimethyl-2-(trimethylsilyl) thiophene-3-formic acid methyl ester and allylamine in solvent one Refluxing reaction for 5-15 hours, after the reaction is completed, lower to room temperature, wash with water, dry, concentrate, and recrystallize the organic phase to obtain the product; , the organic phase is dried, concentrated, and recrystallized; the molar ratio of the 4,5-dimethyl-2-(trimethylsilyl)thiophene-3-carboxylate to allylamine is 1:1 -2. 2. the synthetic method of fungicide silthiocarb as claimed in claim 1, is characterized in that, described solvent one is one or two or more in halogenated hydrocarbons, alcohols, aromatic hydrocarbons and polar aprotic solvents mixture. 3. the synthetic method of bactericide silthiocarb as claimed in claim 1, is characterized in that, described 4,5-dimethyl-2-(trimethylsilyl) thiophene-3-formic acid methyl ester The following method is prepared: 3-mercaptobutanone and 3-(trimethylsilyl)propiolic acid methyl ester are refluxed in solvent two under the protection of inert gas and alkali catalyst for 5-20h, after the reaction, the drop to room temperature, washed with water, the organic phase was washed, dried, concentrated, and separated by column chromatography; It is obtained by drying, concentrating, and separating by column chromatography; the molar ratio of 3-mercaptobutanone to 3-(trimethylsilyl)propiolic acid methyl ester is 1:0.5-1. 4. the synthetic method of fungicide silthiocarb as claimed in claim 3 is characterized in that, described alkali catalyst is one or both in alkali metal carbonate, alkali metal hydride and alkali metal alkoxide A mixture of the above; the second solvent is one or a mixture of two or more of halogenated hydrocarbons, alcohols, aromatic hydrocarbons and polar aprotic solvents. 5. the synthetic method of bactericide silthiocarb as claimed in claim 3 is characterized in that, described 3-(trimethylsilyl) propiolic acid methyl ester is obtained through following method: propiolic acid Methyl ester and trimethylchlorosilane are refluxed in solvent three under the protection of inert gas and organic base catalyst for 3-12 hours. After the reaction is completed, it is cooled to room temperature, washed with water, and the organic phase is dried, concentrated, and separated by column chromatography. or after the reaction is finished, the solvent three is steamed out under negative pressure, and then lowered to room temperature, washed with water, extracted with dichloromethane, and the organic phase is dried, concentrated, and separated by column chromatography; the methyl propiolate and trimethyl The molar ratio of chlorosilane is 1:1-2. 6. the synthetic method of fungicide silthiocarb as claimed in claim 5 is characterized in that, described organic base catalyst is organic amine; Described solvent three is halogenated hydrocarbon, aromatic hydrocarbon and polar aprotic solvent one or a mixture of two or more.

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