A synthetic method of 5-hydroxyethyl-4-methylthiazole

Abstract

The present invention uses a thiol compound, paraformaldehyde, and hydrazine hydrate as raw materials to prepare 5-hydroxyethyl-4-methylthiazole in a one-pot process. This method is simple to operate and requires only a few steps, avoiding the multi-step, intensive reaction processes of existing technologies that can easily lead to byproducts and impurities. The product system is simple to purify, achieving high purity and a stable process.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing 5-hydroxyethyl-4-methylthiazole. Background Art

[0002] 5-Hydroxyethyl-4-methylthiazole (also known as 4-methyl-5-(β-hydroxyethyl)thiazole, 4-methyl-5-hydroxyethylthiazole, and thiothiazole) has a variety of properties and uses, making it an important chemical product, pharmaceutical intermediate, and food additive. For example, it is a key intermediate in the synthesis of the sedative and hypnotic drug clomethiazole hydrochloride and can also be used in the synthesis of vitamin B1. It is also a commonly used food additive in its own right, used in beverages, candies, baked goods, dairy products, and more.

[0003] The existing technology is mainly divided into the following routes for the synthesis of 5-hydroxyethyl-4-methylthiazole:

[0004] (1) Thioformamide method: This method uses 3-acetyl propanol as the starting material, undergoes a 3-halogenation reaction, reacts with thioformamide to form a ring, and then undergoes a dehalogenation reaction to obtain the product. The raw materials of this method can also directly use 3-halogenated raw materials or their derivatives, such as 3-chloro-3-acetyl propyl acetate, 2,3-dichloro-2-methyltetrahydrofuran, and 3-bromo-3-acetyl propanol. However, the synthesis yield of this method is low, and the halogenation and dehalogenation reactions of this method are prone to introduce unwanted impurities. In addition, this method is difficult to industrialize due to the poor stability of thioformamide and the difficulty in preparation.

[0005] (2) Thiourea method, which uses stable thiourea instead of unstable thioformamide to overcome the defects of the above route. This method uses 3-halogen-3-acetylpropanol or its similar derivatives to react with thiourea to prepare 2-amino-5-hydroxyethyl-4-methylthiazole, and then removes the amino group by sodium nitrite and acid system to obtain 5-hydroxyethyl-4-methylthiazole. This method also has a yield of only about 48%-70%, and the steps involve reactions such as halogenation and nitrous acid diazotization, which often lead to undesirable side reactions. However, this method also has its own defects, such as the diazotization reaction and the reduction of diazonium salts with sodium dihydrogen phosphite, which cause significant environmental pollution and are difficult to put into production.

[0006] (3) Dithiocarbamic acid method: This method uses 3-halogen-3-acetylpropanol or its similar derivatives to react with dithiocarbamic acid or its salt to prepare 2-mercapto-5-hydroxyethyl-4-methylthiazole, and then removes the mercapto group through concentrated sulfuric acid and hydrogen peroxide oxidation reaction to obtain 5-hydroxyethyl-4-methylthiazole. The reaction also involves a violent oxidation reaction, which easily leads to by-products and impurities. The nitric acid oxidation in this process produces wastewater and waste gas, which are detrimental to the process operation and the environment, and are also not conducive to its industrial production.

[0007] Whether used in the pharmaceutical or food industries, 5-hydroxyethyl-4-methylthiazole must be free of unwanted impurities, requiring extremely high standards for purity and impurity levels. Existing synthesis methods involve drastic reactions, such as halogenation, diazotization, and oxidation, which can easily produce undesirable byproducts, including toxic and hazardous impurities. For example, the document "Synthesis, Aroma Characteristics, and Impurity Analysis of 4-Methyl-5-hydroxyethylthiazole" discloses: "The purity of spice-grade products exceeds 99.7%, and even products used as pharmaceutical and chemical intermediates have a purity exceeding 99%. Even with such high purity, the aroma exhibits three distinct aromas: meaty, soy, and milky." "The formation of thiothiazole by-product impurities is caused by a variety of factors, including its structural characteristics, reaction conditions, and side reactions of the raw materials. These by-products also have diverse effects on aroma. Meat-flavored products are greatly influenced by the various low-molecular sulfur-containing compounds introduced into the reaction. After different refining and special post-treatment, their bean, nutty, and milky aromas are fully revealed, forming the uniqueness and diversity of their aroma." It is obvious that the purity of 5-hydroxyethyl-4-methylthiazole has a very important impact on its application.

[0008] It is difficult to completely remove the impurities by simply relying on subsequent purification, and purification will cause a large amount of raw material loss, increasing time and economic costs. Therefore, for the synthesis of 5-hydroxyethyl-4-methylthiazole, the above problems have not been taken seriously and solved, and a synthetic solution that can solve the above problems is urgently needed. Summary of the Invention

[0009] In order to overcome the defects of the prior art, the present invention provides a method for synthesizing 5-hydroxyethyl-4-methylthiazole. The method comprises the following steps:

[0010] Formula I: ;

[0011] The compound of formula I is reacted with paraformaldehyde, hydrazine hydrate, and an alcohol-water solvent to synthesize 4-methyl-5-(2-acetoxyethyl)thiazole in a one-pot process. After the reaction is completed, sodium hydroxide aqueous solution is added without separation to hydrolyze, and 5-hydroxyethyl-4-methylthiazole is obtained through post-treatment.

[0012] Wherein, the molar ratio of the compound of formula I: paraformaldehyde: hydrazine hydrate is 1:1-1.1:1-1.3;

[0013] The post-treatment is as follows: the reaction solution is poured into an equal volume of ice water, half of the volume of the solvent is evaporated under reduced pressure, and then ether is added for extraction. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain the product 5-hydroxyethyl-4-methylthiazole.

[0014] Since paraformaldehyde has low solubility in alcohols but good solubility in weakly acidic and alkaline solutions, and since hydrazine hydrate is an alkaline raw material in the system, an appropriate amount of water is introduced to increase the solubility of paraformaldehyde. The alcohol solvent can be selected from commonly used alcohol solvents such as methanol and ethanol. The weight ratio of water in the alcohol-water solvent is 20-50% of the total solvent. The weight ratio can be 20%, 30%, 40%, or 50%, with 30% being preferred.

[0015] For post-treatment of the product, column chromatography can be further performed according to the purity and actual needs. Column chromatography can further improve the purity of the product. It is understood that the medium volume and half volume in the post-treatment step are not necessarily accurate values. In the actual reaction process, these two steps are approximate amounts, for example, by visual inspection.

[0016] The reaction temperature should not be too high, as long as it ensures the reaction proceeds smoothly. Excessive temperatures can easily lead to excessive release of paraformaldehyde, which can cause leakage or waste of raw materials. The reaction does not require a specific reaction time; the primary goal is to ensure the reaction proceeds without causing excessive decomposition of paraformaldehyde. The reaction temperature for the one-pot method is 60-100°C, specifically 60°C, 70°C, 80°C, 90°C, or 100°C. 80°C is preferred. The key to the reaction can be monitored by chromatography; the reaction is considered complete when no compound of Formula I is detected.

[0017] Deprotection of the acetyl protecting group is a conventional reaction in the art. The reaction proceeds stably and requires no additional attention. The hydrolysis temperature is 60-80°C. Specifically, 60°C, 70°C, and 80°C can be selected. 60°C is preferred. The amount of aqueous sodium hydroxide used is such that the molar ratio of sodium hydroxide to the compound of Formula I is 1.3-1.5:1. The reaction endpoint is also monitored by chromatography; the reaction is considered complete when no acetoxy intermediate is detected in the reaction system.

[0018] The present invention has at least the following beneficial effects:

[0019] (1) The process route of the present invention avoids the diazotization deamination step of the prior art thiourea route and the oxidative desulfhydration step of the dithiocarbamic acid method, thereby reducing the by-products caused by the violent reaction.

[0020] (2) Compared with the multi-step process route of the prior art, the one-pot method of the present invention is simple to operate, greatly reduces the process difficulty, and the raw materials and solvent residues are simple and easy to remove.

[0021] (3) The product system is simple to purify, has high purity, and a stable process route.

[0022] (4) The system does not involve substances that seriously pollute the environment and is green and environmentally friendly. DETAILED DESCRIPTION Example

[0023] To a 500 ml flask, add 0.1 mol of the compound of Formula I, 0.11 mol of paraformaldehyde, 0.11 mol of hydrazine hydrate, and 300 ml of ethanol-water (30 wt% water content) in sequence at room temperature. With stirring, raise the temperature by 1°C / min to 80°C and allow the reaction to continue until no compound of Formula I can be detected by GC. Continue adding 0.14 mol of an aqueous solution of NaOH (30 wt% sodium hydroxide content). Maintain the temperature at 60°C and stir until no 4-methyl-5-(2-acetoxyethyl)thiazole can be detected by GC.

[0024] The reaction mixture was poured into an equal volume of ice water. Half the solvent was evaporated under reduced pressure, and then 100 ml of ether was added for extraction. The organic phase was separated. The extraction-phase separation procedure was repeated three times. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 13.8 g of the product, 5-hydroxyethyl-4-methylthiazole, with a GC purity of 99.8%. A silica gel column was prepared using 200-300 mesh silica gel with a developing solvent ratio of 50:50 (ethanol:petroleum ether). The product was passed through the column to obtain 13.6 g of the fine product, 5-hydroxyethyl-4-methylthiazole. No impurity peaks were detected by GC. 1 HNMR (500MHz, CDCl3) δ: 2.16 (s, 3H), 3.09 (t, 2H), 3.36 (s, 1H), 3.74 (t, 2H), 8.73 (s, 1H). Example

[0025] To a 500ml flask, add 0.1mol of the compound of Formula I, 0.12mol of paraformaldehyde, 0.13mol of hydrazine hydrate, and 300ml of ethanol-water (30wt%) in sequence at room temperature. With stirring, raise the temperature by 1°C / min to 80°C and allow the reaction to continue until no compound of Formula I can be detected by GC. Continue adding 0.14mol of an aqueous solution of NaOH (30wt%). Maintain the temperature at 60°C and stir until no 4-methyl-5-(2-acetoxyethyl)thiazole can be detected by GC.

[0026] The reaction mixture was poured into an equal volume of ice water. After half the solvent was evaporated under reduced pressure, 100 ml of ether was added for extraction and the organic phase was separated. The extraction-phase separation procedure was repeated three times. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 14.0 g of the product, 5-hydroxyethyl-4-methylthiazole, with a GC purity of 99.6%. A silica gel column was prepared using 200-300 mesh silica gel with a developing solvent ratio of 50:50 (ethanol:petroleum ether). The product was passed through the column to obtain 13.8 g of the fine product, with no impurity peaks detected by GC.

[0027] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for synthesizing 5-hydroxyethyl-4-methylthiazole, characterized in that: Formula I: ; The compound of formula I is reacted with paraformaldehyde, hydrazine hydrate, and an alcohol-water solvent to synthesize 4-methyl-5-(2-acetoxyethyl)thiazole in a one-pot process. After the reaction is completed, sodium hydroxide aqueous solution is added without separation to hydrolyze, and 5-hydroxyethyl-4-methylthiazole is obtained through post-treatment. Wherein, the molar ratio of the compound of formula I: paraformaldehyde: hydrazine hydrate is 1:1-1.1:1-1.3; The post-treatment is as follows: the reaction solution is poured into an equal volume of ice water, half of the solvent is evaporated under reduced pressure, and then ether is added for extraction. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain the product 5-hydroxyethyl-4-methylthiazole; The reaction temperature of the one-pot method is 60-100° C.; the weight ratio of water in the alcohol-water solvent accounts for 20-50% of the total solvent; the alcohol is selected from methanol and ethanol; and the amount of sodium hydroxide aqueous solution used is such that the molar ratio of sodium hydroxide to the compound of formula I is 1.3-1.5:

1.

2. The synthesis method according to claim 1, wherein: The post-processing also includes column chromatography purification of the product.

3. The synthesis method according to claim 1, wherein: The one-pot reaction was complete as no compound of formula I could be detected by chromatography.

4. The synthesis method according to claim 1, wherein: The hydrolysis temperature is 60-80℃.

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