A method for synthesizing intermediate α-chloroacetyl-γ-butyrolactone and a method for synthesizing thiothiazole

Abstract

The present invention provides a kind of intermediate α-chloroacetyl-γ-butyrolactone synthesis method and thiothiazole synthesis method, with α-acetyl-γ-butyrolactone as raw material, using cheap, safe trichloroisocyanuric acid as chlorination reagent, α-chloroacetyl-γ-butyrolactone is synthesized by chlorination reaction, and the prepared α-chloroacetyl-γ-butyrolactone is applied to prepare thiothiazole. The present invention uses trichloroisocyanuric acid as chlorinating agent, and compared with the traditional chlorination process using chlorine for chlorination process, the chlorination reaction is stable, has good selectivity, is easy to use, and has high safety. The chlorination byproduct of the method is cyanuric acid, which can be recycled and reused, and compared with chlorine, there is no need to process a large amount of hydrochloric acid and hypochlorous acid produced after the reaction, which reduces the burden of three wastes treatment and has the prospect of industrialized production.

Description

[0001] This application is a divisional application with an application date of December 17, 2021, an application number of 202111553319.3, and an invention name of "A method for the synthesis of an intermediate α-chloroacetyl-γ-butyrolactone and a method for the synthesis of thiothiazole". Technical Field

[0002] The invention relates to the technical field of thiothiazole synthesis, and in particular to a synthesis method of an intermediate alpha-chloroacetyl-gamma-butyrolactone and a synthesis method of thiothiazole. Background Art

[0003] 5-Hydroxyethyl-4-methylthiazole (4-methyl-5-(β-hydroxyethyl)-thiazole, referred to as thiothiazole) is a commonly used spice. Depending on the production conditions, it includes meat-flavored, bean-flavored and milk-flavored products, and is mainly used for flavoring meat, condiments and seafood. In addition, thiothiazole is the main raw material for the production of B vitamins, anti-inflammatory and blood-activating drugs. As an important industrial raw material, thiothiazole has great potential in the domestic and international markets. There are many existing processes for synthesizing thiothiazole, and the main ones are as follows:

[0004] (1) Using methyl acetoacetate (a) and 3-bromo-3-chloropropyl acetate (b) as raw materials, react under strong alkaline conditions to obtain 4-acetoxy-2-acetyl-2-chlorobutyric acid methyl ester (c), the intermediate (c) is hydrolyzed to obtain 3-chloro-3-acetyl propanol acetate (d), (d) and ammonium dithiocarbamate are prepared under acidic conditions to obtain intermediate (e), intermediate e is oxidized to obtain 4-methyl-5-(β-acetoxyethyl)-thiazole, and finally converted under alkaline conditions to obtain the target product (g) (as shown in Formula 1). This process route has many steps, the raw material 3-bromo-3-chloropropyl acetate (b) is expensive and has limited sources, the hydrolysis reaction of the intermediate (c) is accompanied by many side reactions, the reaction efficiency is reduced, and the subsequent purification process is complicated. In addition, the sodium hydride used in this route has high chemical reactivity, is not easy to store, and has certain dangers.

[0005]

[0006] Formula 1. Synthesis of thiothiazole using ethyl acetoacetate as raw material

[0007] (2) 2,3-dichloro-2-methyl-4,5-dihydrofuran (h) or the corresponding dibromo compound is used as a raw material and reacted with thioformamide to obtain the target product (g) (as shown in Formula 2). Although this method has a simple process flow, its raw material 2,3-dichloro-2-methyl-4,5-dihydrofuran (h) is difficult to obtain, and commercially available products have not yet been developed in China. Therefore, this route is not suitable for industrial production.

[0008]

[0009] Formula 2. Synthesis of thiothiazole using 2,3-dichloro-2-methyl-4,5-dihydrofuran as raw material

[0010] (3) Using ethyl acetate (m) and γ-butyrolactone (n) as raw materials and sodium metal as a condensation agent, α-acetyl-γ-butyrolactone (i) is prepared, which is then chlorinated to obtain α-chloroacetyl-γ-butyrolactone (j), which is then hydrolyzed to obtain the key intermediate 3-chloro-4-oxo-1-pentanol (k), which is then reacted with a thioformamide derivative to obtain a 5-hydroxyethyl-4-methylthiazole derivative (l), and finally the target product (g) is obtained (as shown in Formula 3).

[0011]

[0012] Formula 3. Synthesis of thiothiazole using γ-butyrolactone as raw material

[0013] At present, this process route is mainly used in China to industrially produce thiothiazole. In this technical route, α-acetyl-γ-butyrolactone (i) is used as a raw material to obtain α-chloroacetyl-γ-butyrolactone (j) through chlorination, which is a key step. α-acetyl-γ-butyrolactone (i) can be obtained from the target product by a one-pot method. This method has high product quality and low production cost, and can be industrialized. In China, Cl2 is mainly used as a chlorinating agent to chlorinate α-acetyl-γ-butyrolactone (i) to obtain the key intermediate α-chloroacetyl-γ-butyrolactone (j). Although this route has fewer steps and a simple process, a large amount of acid and alkali raw materials are involved in the production process, which greatly increases the burden of three wastes treatment and increases production costs, and does not meet the requirements of green chemistry. Moreover, Cl2 is a highly toxic chemical raw material, which has certain safety hazards in chemical production, and its use and production management are complicated. In addition, this route has very high requirements for equipment, which increases the cost of safety maintenance and equipment operation. Summary of the invention

[0014] In order to solve the problem of using Cl2 as a chlorinating agent to chlorinate α-acetyl-γ-butyrolactone (i) to obtain the key intermediate α-chloroacetyl-γ-butyrolactone (j), a large amount of acid and alkali raw materials are involved in the production process, which greatly increases the burden of three wastes treatment and production costs, and does not meet the requirements of green chemistry; and Cl2 is a highly toxic chemical raw material and has certain safety hazards in chemical production.

[0015] The present invention provides a method for synthesizing an intermediate α-chloroacetyl-γ-butyrolactone and a method for synthesizing thiothiazole, wherein α-acetyl-γ-butyrolactone is used as a raw material, and trichloroisocyanuric acid is used as a chlorination reagent, which is cheap and safe, to synthesize α-chloroacetyl-γ-butyrolactone through a chlorination reaction, and the prepared α-chloroacetyl-γ-butyrolactone is used to prepare thiothiazole. The present invention uses trichloroisocyanuric acid as a chlorinating agent, and compared with the traditional chlorination process using chlorine gas for the chlorination process, the chlorination reaction is stable, has good selectivity, is easy to use, and has high safety. The chlorination byproduct of the method is cyanuric acid, which can be recycled and reused. Compared with chlorine gas, there is no need to process a large amount of hydrochloric acid and hypochlorous acid produced after the reaction, which reduces the burden of three wastes treatment and has the prospect of industrial production.

[0016] The present invention relates to the application of trichloroisocyanuric acid in the synthesis of thiothiazole. α-acetyl-γ-butyrolactone is used as a raw material, and under the action of trichloroisocyanuric acid, α-chloroacetyl-γ-butyrolactone is obtained by chlorination, and then hydrolyzed to obtain a key intermediate 3-chloro-4-oxo-1-pentanol, which is then reacted with thioformamide to obtain a target product. The synthesis route reaction is shown in Formula 4:

[0017]

[0018] The present invention provides a method for synthesizing an intermediate α-chloroacetyl-γ-butyrolactone. α-acetyl-γ-butyrolactone is used as a raw material, trichloroisocyanuric acid is added, and α-chloroacetyl-γ-butyrolactone is obtained by chlorination. The reaction formula is shown in Formula 5:

[0019]

[0020] The synthesis method specifically comprises the following steps:

[0021] Add a certain proportion of α-acetyl-γ-butyrolactone (or a reaction solvent) to the reaction flask in sequence, start stirring, and slowly add the required amount of trichloroisocyanuric acid to the above reaction mixture at 10°C. After the addition is completed, heat the reaction mixture to the set reaction temperature, the reaction temperature is 10-80°C, preferably 25-50°C, and continue stirring to make the reaction system uniform. The reaction time is 0.5-12h, preferably 2-4h. After the reaction is completed, gas chromatography is used to detect whether α-acetyl-γ-butyrolactone is completely reacted. Cool the reaction mixture, filter and separate the by-product cyanuric acid generated by the reaction, and the filtrate is a colorless or light yellow liquid, that is, the crude product of α-chloroacetyl-γ-butyrolactone. If a reaction solvent is added to the reaction system, the filtrate after filtering and separating the by-product cyanuric acid generated by the reaction is distilled to remove the reaction solvent to obtain a colorless or light yellow liquid, that is, the crude product of α-chloroacetyl-γ-butyrolactone. The crude α-chloroacetyl-γ-butyrolactone product was detected by gas chromatography. The content of the crude α-chloroacetyl-γ-butyrolactone product was above 95%, and the crude α-chloroacetyl-γ-butyrolactone product could be directly used in the synthesis of thiothiazole.

[0022] In the above TCCA chlorination reaction of α-acetyl-γ-butyrolactone:

[0023] (1) The reaction can be carried out in the presence of a solvent or in the absence of a solvent. α-Acetyl-γ-butyrolactone is in liquid form at room temperature, and a solvent-free reaction system is preferred. When the reaction is carried out in an organic solvent, the organic solvent may be dichloromethane, 1,2-dichloroethane, ether, THF, acetonitrile, etc., preferably dichloromethane and 1,2-dichloroethane. The mass ratio of α-acetyl-γ-butyrolactone to the organic solvent is 1:1 to 10, preferably 1:3 to 6;

[0024] (2) The molar ratio of the α-acetyl-γ-butyrolactone raw material to the chlorinating agent trichloroisocyanuric acid is 1:0.33-3.0, preferably 1:0.35-0.8.

[0025] The present invention also provides a method for synthesizing thiothiazole, comprising the following steps:

[0026] Step 1: Synthesis of intermediate α-chloroacetyl-γ-butyrolactone:

[0027] The α-chloroacetyl-γ-butyrolactone is synthesized by adopting the synthesis method of the intermediate α-chloroacetyl-γ-butyrolactone.

[0028] Step 2: Synthesis of intermediate 3-chloro-4-oxo-1-pentanol:

[0029] α-Chloroacetyl-γ-butyrolactone is hydrolyzed and ring-opened to synthesize 3-chloro-4-oxo-1-pentanol. The reaction equation is shown in Formula 6:

[0030]

[0031] A certain amount of α-chloroacetyl-γ-butyrolactone is added to a reaction flask, a certain concentration of dilute acid is added thereto, and the reaction mixture is heated to reflux, the reaction temperature is 20-160° C., preferably 100-140° C., and the reaction time is 1-16 hours, preferably 3-9 hours. After the reaction is completed, gas chromatography is used to detect whether α-chloroacetyl-γ-butyrolactone is completely reacted. The reaction solution is cooled to room temperature, and the reaction pH is adjusted to 7-8 with a 5% mass fraction of NaOH aqueous solution, and the reaction is allowed to stand, and the organic phase is separated, and the aqueous phase is extracted with dichloromethane, and the extraction phase and the organic phase are mixed. After the mixed solution is dried, the solvent is removed by rotary evaporation, and then reduced pressure distillation is performed to obtain the target product intermediate 3-chloro-4-oxygen-1-pentanol, and the target product intermediate 3-chloro-4-oxygen-1-pentanol crude product is detected by gas chromatography, and the content of the target product intermediate 3-chloro-4-oxygen-1-pentanol is higher than 96.5%.

[0032] In the above synthesis reaction of 3-chloro-4-oxo-1-pentanol:

[0033] (1) In the reaction, the molar ratio of the dilute acid to the raw material α-chloroacetyl-γ-butyrolactone is 1:1-20, preferably 1:5-15;

[0034] (2) The dilute acid is an inorganic acid, preferably hydrochloric acid or sulfuric acid. If hydrochloric acid is used, the acid concentration is 2%-30%, preferably 5%-20%. If sulfuric acid is used, the acid concentration is 0.5%-98%, preferably 3%-15%.

[0035] Step 3: Synthesis of 5-hydroxyethyl-4-methylthiazole:

[0036] 3-Chloro-4-oxo-1-pentanol reacts with thioformamide to synthesize thiothiazole. The reaction equation is shown in Formula 7:

[0037]

[0038] A certain amount of 3-chloro-4-oxygen-1-pentanol is added to a reaction flask, and a corresponding amount of dilute acid is added to the reaction system under low temperature conditions (between 0-20°C, preferably 0-5°C), stirring is maintained, and a required amount of thioformamide is added thereto. After the addition is completed, the reaction is heated to a set reaction temperature, the reaction temperature is 0-140°C, preferably 90-120°C, and the reaction time is 1-12 hours, preferably 1.5-6 hours. After the reaction is completed, gas chromatography is used to detect whether 3-chloro-4-oxygen-1-pentanol is completely reacted, and the yield is calculated. The reaction solution is cooled to room temperature, NaOH is added to adjust the pH to a corresponding value of 7-13, preferably 8-10, and the reaction is allowed to stand for stratification, and the organic phase is separated. The aqueous phase is extracted with dichloromethane, and the extract phase and the organic phase are mixed. After the mixed solution is dried, the solvent is removed by rotary evaporation, and then the target product thiothiazole is obtained by distillation under reduced pressure.

[0039] In the above-mentioned synthesis reaction of thiothiazole:

[0040] (1) The molar ratio of the raw material 3-chloro-4-oxo-1-pentanol to the acid is 1:0.01-0.6, preferably 1:0.01-0.1;

[0041] (2) The molar ratio of the raw materials 3-chloro-4-oxo-1-pentanol to thioformamide is 1:1-5, preferably 1:1.2-2;

[0042] (3) The reaction acid is hydrochloric acid or sulfuric acid, preferably sulfuric acid with a concentration of 0.5-5%.

[0043] The present invention also provides an application of trichloroisocyanuric acid as a chlorinating agent in the preparation of an intermediate α-chloroacetyl-γ-butyrolactone or thiothiazole.

[0044] Compared with the prior art, the present invention has the following technical effects:

[0045] 1. The present invention uses trichloroisocyanuric acid as a chlorinating agent for synthesizing the key intermediate α-chloroacetyl-γ-butyrolactone. The chlorination reaction conditions are mild, the chlorination position selectivity is good, the product yield and purity are high, and the next intermediate can be directly used for synthesis without purification. The process operation is simplified and the cost of the final product thiothiazole is reduced.

[0046] 2. When trichloroisocyanuric acid is used as a chlorinating agent, the byproduct generated is an insoluble white solid, which can be directly filtered, separated and recovered from the reaction mixture and recycled as a raw material for the production of trichloroisocyanuric acid. No byproduct hydrogen chloride or hydrochloric acid is produced during the chlorination process, which reduces the discharge of three wastes and is a green chlorination process.

[0047] 3. Compared with the most commonly used chlorinating agent Cl2, trichloroisocyanuric acid has good stability, low irritation, low toxicity, low safety risk, convenient operation and easy storage. Therefore, using trichloroisocyanuric acid as the chlorination agent for the key intermediate α-chloroacetyl-γ-butyrolactone, this route is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0048] The present invention is further described below in conjunction with specific embodiments.

[0049] Example 1

[0050] Weigh 38.4g of α-acetyl-γ-butyrolactone, add it to a reaction bottle equipped with stirring, thermometer and condensation reflux, stir evenly, keep the temperature at 10°C, add 25.2g of trichloroisocyanuric acid, heat the reaction to 30°C and continue stirring for 2 hours, and stop the reaction. Cool to room temperature, then filter the reaction mixture, and the filtrate is the chlorinated crude product. The crude product is distilled under reduced pressure to obtain 46.3g of α-chloroacetyl-γ-butyrolactone with a content of 98.1%, and a yield of 93.2%. The NMR data of the prepared α-chloroacetyl-γ-butyrolactone are as follows: 1 H NMR (600MHz, CDCl3): 2.483 (m, 1H), 2.572 (s, 3H), 3.214 (m, 1H), 4.385 (m, 1H), 4.454 (m, 1H).

[0051] Weigh 40.5g of α-chloroacetyl-γ-butyrolactone and 30mL of 5% dilute sulfuric acid, add them into a reaction bottle equipped with stirring, thermometer and condensation reflux, heat the reaction mixture to 100°C under stirring, stir and reflux for 3h, and stop the reaction. After cooling the reaction mixture, adjust the pH of the reaction mixture to 7-8 with a 5% NaOH aqueous solution. Let the reaction mixture stand and separate the organic phase. The aqueous phase is extracted three times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. After the mixed solution is dried, the solvent is removed, and then the product 32.3g of 3-chloro-4-oxy-1-pentanol with a content of 97.9% is obtained by vacuum distillation, and the yield is 92.6%. The NMR data of the prepared 3-chloro-4-oxy-1-pentanol are as follows: HRMS ESI (m / z): [M+H] + calcd.for C5H 10 ClO2 + :137.0364,found:137.0365.

[0052] Weigh 27.0g 3-chloro-4-oxo-1-pentanol and 30mL 5% dilute sulfuric acid, add them to a reaction bottle equipped with a stirrer, a thermometer and a condenser reflux device in turn, keep the temperature low, stir evenly, slowly add 20g thioformamide, heat the reaction to a temperature of 110°C, continue stirring for 3 hours, until the reaction is complete, and cool the reaction solution to room temperature. Adjust the pH of the reaction mixture to 9 with a 5% NaOH aqueous solution. Let the reaction mixture stand and separate the organic layer. The aqueous phase is extracted 3 times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. Dry the mixed organic phase, remove the solvent dichloromethane, and distill under reduced pressure (0.1MPa), collect the 109-111°C fraction, and obtain 5-hydroxyethyl-4-methylthiazole product, a total of 26.4g, gas chromatography analysis content of 92.7%, yield 86.5%. HRMS ESI (m / z): [M+H] +calcd.for C6H 10 NOS + :144.0478,found:144.0480.

[0053] Example 2

[0054] Weigh 39g of α-acetyl-γ-butyrolactone and dissolve it in 100mL of dichloromethane, add it to a reaction bottle equipped with stirring, thermometer, condensation reflux, stir evenly, keep the temperature at 10°C, add 28.0g of trichloroisocyanuric acid, heat the reaction to 30°C and continue stirring for 2 hours until the reaction is complete, filter, remove the solvent, and analyze the crude product of α-chloroacetyl-γ-butyrolactone by gas chromatography, the content is 88.5%, 52.8g, and the yield is 94.4%. The NMR data of the prepared α-chloroacetyl-γ-butyrolactone are as follows: 1 H NMR (600MHz, CDCl3): 2.483 (m, 1H), 2.572 (s, 3H), 3.214 (m, 1H), 4.385 (m, 1H), 4.454 (m, 1H).

[0055] Weigh the above 40.5g of α-chloroacetyl-γ-butyrolactone crude product, 45mL of 5% by mass of dilute sulfuric acid, and add them into a reaction bottle equipped with stirring, thermometer and condensation reflux, heat the mixture to 110°C under stirring, stir and reflux for 5h, and detect by gas chromatography until α-chloroacetyl-γ-butyrolactone is completely reacted. After cooling the reaction mixture, adjust the pH of the reaction mixture to 7-8 with a 5% by mass NaOH aqueous solution. Let the reaction mixture stand and separate the organic phase. The aqueous phase is extracted three times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. After the mixed solution is dried, the solvent is removed, and then the 3-chloro-4-oxy-1-pentanol product is obtained by reduced pressure distillation. The crude product content of 3-chloro-4-oxy-1-pentanol is 85.2% by gas chromatography analysis, 32.3g, and the yield is 91.4%.

[0056] Weigh the above 27.0g 3-chloro-4-oxy-1-pentanol crude product and 50mL 5% dilute sulfuric acid, add them into a reaction bottle equipped with stirring, thermometer and condenser reflux device in turn, keep low temperature, stir evenly, slowly drop 13g thioformamide therein, heat the reaction to 100°C, continue stirring for 3 hours, until the reaction is complete, and cool the reaction solution to room temperature. Use a 5% NaOH aqueous solution to adjust the pH of the reaction mixture to 9. Let the reaction mixture stand and separate the organic layer. The aqueous phase is extracted 3 times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. Dry the mixed organic phase, remove the solvent dichloromethane, and distill under reduced pressure (0.1MPa), collect the 109-111°C fraction, and obtain 5-hydroxyethyl-4-methylthiazole product, a total of 25.4g, gas chromatography analysis content of 91.5%, yield 96.4%.

[0057] Example 3

[0058] Weigh 39g of α-acetyl-γ-butyrolactone and dissolve it in 100mL of 1,2-dichloroethane. Add it to a reaction bottle equipped with stirring, thermometer, condensation and reflux, stir evenly, keep the temperature at 10°C, add 28g of trichloroisocyanuric acid, heat the reaction to 30°C and continue stirring for 2 hours until the reaction is complete, filter, remove the solvent, and the gas chromatography analysis shows that the content is 87.1%, and 51.9g of α-chloroacetyl-γ-butyrolactone crude product is obtained, with a yield of 91.3%. The NMR data of the prepared α-chloroacetyl-γ-butyrolactone are as follows: 1 H NMR (600MHz, CDCl3): 2.483 (m, 1H), 2.572 (s, 3H), 3.214 (m, 1H), 4.385 (m, 1H), 4.454 (m, 1H).

[0059] Weigh the above 40.5g of α-chloroacetyl-γ-butyrolactone crude product, 30mL of 10% by mass of dilute sulfuric acid, and add them into a reaction bottle equipped with stirring, thermometer and condensation reflux, heat the mixture to 100°C under stirring, stir and reflux for 4h, and detect by gas chromatography until α-chloroacetyl-γ-butyrolactone is completely reacted. After cooling the reaction mixture, adjust the pH of the reaction mixture to 7-8 with a 5% by mass NaOH aqueous solution. Let the reaction mixture stand and separate the organic phase. The aqueous phase is extracted three times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. After the mixed solution is dried, the solvent is removed, and then the 3-chloro-4-oxygen-1-pentanol product is obtained by reduced pressure distillation. The crude product content of 3-chloro-4-oxygen-1-pentanol is 72.6% by gas chromatography analysis, 33.1g, and the yield is 81.1%.

[0060] Weigh the above 27.0g 3-chloro-4-oxy-1-pentanol crude product and 100mL 5% dilute sulfuric acid, add them into a reaction bottle equipped with a stirrer, a thermometer and a condenser reflux device in turn, keep the temperature low, stir evenly, slowly drop 13g thioformamide therein, heat the reaction to a temperature of 100°C, continue stirring for 3 hours, until the reaction is complete, and cool the reaction solution to room temperature. Use a 5% NaOH aqueous solution to adjust the pH of the reaction mixture to 9. Let the reaction mixture stand and separate the organic layer. The aqueous phase is extracted 3 times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. Dry the mixed organic phase, remove the solvent dichloromethane, and distill under reduced pressure (0.1MPa), collect the 109-111°C fraction, and obtain 5-hydroxyethyl-4-methylthiazole product, a total of 20.4g, gas chromatography analysis content of 92.8%, yield 92.1%.

[0061] Example 4

[0062] Weigh 38.4g of α-acetyl-γ-butyrolactone, add it to a reaction bottle equipped with stirring, thermometer and condensation reflux, stir evenly, keep the temperature at 10°C, add 25.2g of trichloroisocyanuric acid, heat the reaction to 50°C and continue stirring for 4 hours, and detect the raw material α-acetyl-γ-butyrolactone until the reaction is complete. Filter the reaction mixture, and the filtrate is the chlorinated crude product. The crude product is distilled under reduced pressure to obtain 33.4g of α-chloroacetyl-γ-butyrolactone with a content of 97.8%, and a yield of 67.0%. The NMR data of the prepared α-chloroacetyl-γ-butyrolactone are as follows: 1 H NMR (600MHz, CDCl3): 2.483 (m, 1H), 2.572 (s, 3H), 3.214 (m, 1H), 4.385 (m, 1H), 4.454 (m, 1H).

[0063] Take 32.5g of the α-chloroacetyl-γ-butyrolactone synthesized in the previous step, 50mL of 5% dilute sulfuric acid, and add them into a reaction bottle equipped with stirring, a thermometer and condensation reflux. Heat the reaction mixture to 100°C under stirring, stir and reflux for 8h, and detect by gas chromatography until the α-chloroacetyl-γ-butyrolactone is completely reacted. After cooling the reaction mixture, adjust the pH of the reaction mixture to 7-8 with a 5% NaOH aqueous solution. Let the reaction mixture stand and separate the organic phase. The aqueous phase is extracted three times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. After the mixed solution is dried, the solvent is removed, and then the reduced pressure distillation is performed to obtain 20.6g of 3-chloro-4-oxy-1-pentanol product with a content of 92.1%, and the yield is 71.0%.

[0064] Weigh 17.6g of the 3-chloro-4-oxy-1-pentanol synthesized in the previous step and 50mL of 5% dilute sulfuric acid, add them to a reaction bottle equipped with a stirrer, a thermometer and a condenser reflux device in turn, keep the temperature low, stir evenly, slowly drop 14g of thioformamide therein, heat the reaction to a temperature of 110°C, continue stirring for 3 hours, until the reaction is complete, and cool the reaction solution to room temperature. Use a 5% NaOH aqueous solution by mass fraction to adjust the pH of the reaction mixture to 9. Let the reaction mixture stand and separate the organic layer. The aqueous phase is extracted 3 times with an appropriate amount of dichloromethane, and the extract is mixed with the organic phase. Dry the mixed organic phase, remove the solvent dichloromethane, and distill under reduced pressure (0.1MPa), collect the 109-111°C fraction, and obtain 5-hydroxyethyl-4-methylthiazole product, a total of 15.8g, gas chromatography analysis content of 92.3%, yield 86.6%.

[0065] Example 5

[0066] Weigh 25.2g trichloroisocyanuric acid and 39g α-acetyl-γ-butyrolactone, add them to a reaction bottle equipped with stirring, thermometer, condensation reflux, stir evenly, heat the reaction to 30°C and continue stirring for 2 hours, and filter. Then add 35mL of 5% by mass sulfuric acid to the filtrate, heat the reaction to a temperature of 110°C, continue stirring for 3 hours, sample and detect the progress of the reaction until it is complete, add 100mL of 5% by mass sulfuric acid and 17g of thioformamide, continue stirring for 4 hours, until the reaction is complete, cool the reaction solution to room temperature, use a 5% by mass NaOH aqueous solution to pH 9, filter, separate the organic layer, and extract the organic layer 3 times with dichloromethane, distill the extract under reduced pressure (0.1MPa), collect 109-111°C, and obtain 28.7g of 5-hydroxyethyl-4-methylthiazole product, with a chromatographic analysis content of 93.4% and a yield of 61.5%.

[0067] The embodiments described above are only preferred embodiments of the present invention and are only used to explain the present invention, not to limit the scope of implementation of the present invention. For those skilled in the art, other implementation methods can certainly be easily made by replacement or modification based on the technical contents disclosed in this specification. Therefore, all changes and improvements made to the principles and process conditions of the present invention should be included in the scope of the patent application of the present invention.

Claims

1. A method for synthesizing an intermediate α-chloroacetyl-γ-butyrolactone, characterized in that: The specific steps are as follows: Using α-acetyl-γ-butyrolactone as a raw material, adding trichloroisocyanuric acid, carrying out a chlorination reaction, cooling the obtained reaction mixture, filtering and separating the by-product cyanuric acid, and obtaining α-chloroacetyl-γ-butyrolactone; the chlorination reaction system is a solvent-free reaction system; The temperature of the chlorination reaction is 30°C and the time of the chlorination reaction is 2h; The molar ratio of the α-acetyl-γ-butyrolactone to trichloroisocyanuric acid is 1:0.35-0.

8.

2. A method for synthesizing an intermediate α-chloroacetyl-γ-butyrolactone, characterized in that: The method comprises the following steps: dissolving α-acetyl-γ-butyrolactone as a raw material in an organic solvent, adding trichloroisocyanuric acid, carrying out a chlorination reaction, cooling the obtained reaction mixture, filtering and separating the by-product cyanuric acid, and removing the reaction solvent to obtain α-chloroacetyl-γ-butyrolactone; the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, ether, THF and acetonitrile; and the mass ratio of the α-acetyl-γ-butyrolactone to the organic solvent is 1:1-10; The temperature of the chlorination reaction is 30°C and the time of the chlorination reaction is 2h; The molar ratio of the α-acetyl-γ-butyrolactone to trichloroisocyanuric acid is 1:0.35-0.

8.

3. A method for synthesizing thiothiazole, characterized in that: The following steps are involved: α-chloroacetyl-γ-butyrolactone is synthesized by using the synthesis method of an intermediate α-chloroacetyl-γ-butyrolactone described in any one of claims 1 to 2; the α-chloroacetyl-γ-butyrolactone is hydrolyzed and ring-opened to synthesize 3-chloro-4-oxo-1-pentanol; and the 3-chloro-4-oxo-1-pentanol is reacted with thioformamide to synthesize thiothiazole.

4. The method for synthesizing thiothiazole according to claim 3, characterized in that: The specific steps of hydrolyzing and ring-opening α-chloroacetyl-γ-butyrolactone to synthesize 3-chloro-4-oxo-1-pentanol are as follows: Add α-chloroacetyl-γ-butyrolactone to a reaction device, then add dilute acid, start heating to a reaction temperature of 20-160° C., and a reaction time of 1-16 hours. After the reaction is completed, cool to room temperature, adjust the pH of the solution to 7-8, and allow the solution to stand for stratification into an organic phase and an aqueous phase. Extract the aqueous phase with dichloromethane, mix the extract with the organic phase, dry it, remove the solvent, and then distill under reduced pressure to obtain an intermediate 3-chloro-4-oxo-1-pentanol; The molar ratio of the dilute acid to α-chloroacetyl-γ-butyrolactone is 1:1-20, the dilute acid is hydrochloric acid or sulfuric acid, the concentration of the hydrochloric acid is 2%-20%, and the concentration of the sulfuric acid is 0.5%-15%.

5. The method for synthesizing thiothiazole according to claim 3, characterized in that: The specific steps of synthesizing thiothiazole by reacting 3-chloro-4-oxo-1-pentanol with thioformamide are as follows: Add 3-chloro-4-oxo-1-pentanol to a reaction device, add dilute acid at 0-20°C, keep stirring, then add thioformamide, start heating to the reaction temperature, the reaction temperature is 90-140°C, the reaction time is 1-12 hours, cool to room temperature after the reaction is completed, adjust the pH of the solution to 7-13, stand and separate, separate the organic phase, extract the aqueous phase with dichloromethane, mix the extract phase and the organic phase, dry the mixed solution, remove the solvent, and then distill under reduced pressure to obtain the target product thiothiazole; The molar ratio of the 3-chloro-4-oxo-1-pentanol to the dilute acid is 1:0.01-0.6; the molar ratio of the 3-chloro-4-oxo-1-pentanol to thioformamide is 1:1-5; the dilute acid is hydrochloric acid or sulfuric acid, and the concentration of the sulfuric acid is 0.5-5%.

Images