CN111635375B - Method for synthesizing thiothiazole - Google Patents
Method for synthesizing thiothiazole Download PDFInfo
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- CN111635375B CN111635375B CN202010640062.4A CN202010640062A CN111635375B CN 111635375 B CN111635375 B CN 111635375B CN 202010640062 A CN202010640062 A CN 202010640062A CN 111635375 B CN111635375 B CN 111635375B
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- CRTCWNPLKVVXIX-UHFFFAOYSA-N 5-(2-Hydroxyethyl)-4-methylthiazole acetate Chemical compound CC(=O)OCCC=1SC=NC=1C CRTCWNPLKVVXIX-UHFFFAOYSA-N 0.000 claims abstract description 14
- XCVQNYJZRZFRNT-UHFFFAOYSA-N methyl 2-(2-acetyloxyethyl)-2-chloro-3-oxobutanoate Chemical compound CC(=O)C(CCOC(=O)C)(C(=O)OC)Cl XCVQNYJZRZFRNT-UHFFFAOYSA-N 0.000 claims abstract description 14
- GQJDXGUXGNLKLO-UHFFFAOYSA-N 2-(4-methyl-2-sulfanylidene-3h-1,3-thiazol-5-yl)ethyl acetate Chemical compound CC(=O)OCCC=1SC(=S)NC=1C GQJDXGUXGNLKLO-UHFFFAOYSA-N 0.000 claims abstract description 12
- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 claims abstract description 9
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims abstract description 7
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 claims abstract description 7
- LQKQGYIKTRJVJF-UHFFFAOYSA-N (3-chloro-4-oxopentyl) acetate Chemical compound CC(=O)OCCC(Cl)C(C)=O LQKQGYIKTRJVJF-UHFFFAOYSA-N 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- -1 3-bromo-3-chloropropyl acetate tetrahydrofuran Chemical compound 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 abstract description 10
- HISQISXHXBZBOC-UHFFFAOYSA-N CC(OCCC(Cl)Br)=O Chemical compound CC(OCCC(Cl)Br)=O HISQISXHXBZBOC-UHFFFAOYSA-N 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000000605 extraction Methods 0.000 description 13
- 230000001105 regulatory effect Effects 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 description 3
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- PUBJPJACIBRCNA-UHFFFAOYSA-N 2,3-dichloro-2-methyloxolane Chemical compound CC1(Cl)OCCC1Cl PUBJPJACIBRCNA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- RHPQWKWGKXPZNT-UHFFFAOYSA-N methyl 4-acetyloxy-2-chlorobutanoate Chemical compound COC(=O)C(Cl)CCOC(C)=O RHPQWKWGKXPZNT-UHFFFAOYSA-N 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis, and discloses a method for synthesizing thiothiazole, which comprises the steps of preparing 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester by methyl acetoacetate and 3-bromo-3-chloropropyl acetate under alkaline conditions; hydrolyzing 4-acetoxy-2-acetyl-2-chlorobutyric acid methyl ester under an acidic condition to prepare 3-chloro-3-acetoacetic alcohol acetate; a step of preparing 2-mercapto-4-methyl-5- (. Beta. -acetoxyethyl) -thiazole from 3-chloro-3-acetylpropanol acetate and ammonium dithiocarbamate under acidic conditions; a step of preparing 4-methyl-5- (beta-acetoxyethyl) -thiazole by adding an oxidant into 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole under an acidic condition; a step of preparing 4-methyl-5- (beta-hydroxyethyl) -thiazole from 4-methyl-5- (beta-acetoxyethyl) -thiazole under alkaline conditions. The synthesis method has mild overall reaction conditions and simple post-treatment, and is suitable for pilot plant test and industrial production.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for synthesizing thiothiazole.
Background
The thiothiazole, which is chemically known as 4-methyl-5- (beta-hydroxyethyl) -thiazole, is a rare spice, has the fragrance of nuts, beans, milk, egg smell and meat, and can be used in nuts, milk-flavored meats and flavoring essences.
The prior art has more synthesis methods, and the synthesis methods mainly comprise the following steps: firstly, the alpha-acetyl-gamma-butyrolactone is used as a raw material, and 4-methyl-5- (beta-hydroxyethyl) -thiazole is obtained through chlorination, hydrolysis, decarboxylation and other reactions, so that the steps are longer, side reactions are more, the yield is lower, and gamma substitution is easy to occur in the chlorination of the alpha-acetyl-gamma-butyrolactone, so that the separation is difficult. The second is that 3-halogen-3-acetyl propanol and thioformamide are used as raw materials, the raw materials can be obtained by reacting ethyl acetoacetate with ethylene oxide under the action of an oxidant, and the raw materials are obtained by reacting the ethyl acetoacetate with the thioformamide after hydrolysis in an acidic medium, and the overall process of the reaction has lower yield and higher cost. Thirdly, 2, 3-dichloro-2-methyl-tetrahydrofuran or corresponding dibromide compound reacts with thiocarboxamide to synthesize the product, and an organic acid ester or other beam acid agent is added to be beneficial to the reaction. Although the method improves the yield, the raw material 2, 3-dichloro-2-methyl-tetrahydrofuran is high in price, and the cost is increased.
Therefore, it is an important issue for researchers to synthesize thiothiazole to increase the overall yield and reduce the cost.
Disclosure of Invention
The invention aims to provide a method for synthesizing thiothiazole, which shortens the reaction process and improves the overall yield.
To achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing thiothiazole is characterized in that the method is carried out according to the following reaction process,
The method comprises the following steps:
a. A step of preparing methyl 4-acetoxy-2-acetyl-2-chlorobutyrate from methyl acetoacetate and 3-bromo-3-chloropropyl acetate under alkaline conditions;
b, hydrolyzing 4-acetoxyl-2-acetyl-2-chlorobutyric acid methyl ester under acidic conditions to prepare 3-chloro-3-acetylpropanol acetate;
c. A step of preparing 2-mercapto-4-methyl-5- (. Beta. -acetoxyethyl) -thiazole from 3-chloro-3-acetylpropanol acetate and ammonium dithiocarbamate under acidic conditions;
d. A step of preparing 4-methyl-5- (beta-acetoxyethyl) -thiazole by adding an oxidant into 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole under an acidic condition;
e. A step of preparing 4-methyl-5- (beta-hydroxyethyl) -thiazole from 4-methyl-5- (beta-acetoxyethyl) -thiazole under alkaline conditions.
In the step a, methyl acetoacetate is dissolved in anhydrous tetrahydrofuran or anhydrous diethyl ether, under the protection of inert gas at the temperature of-5-10 ℃, 1.1-1.2 molar equivalents of 60% sodium hydrogen or 1-1.2 molar equivalents of n-butyl lithium solution are added in batches, 3-bromo-3-chloropropyl acetate tetrahydrofuran solution is added after the addition or the addition is finished, the reaction is carried out for 2-4 hours, then the temperature is raised to reflux, and the reaction is continued for 0.5-1 hour.
In the step b, 4-acetoxy-2-acetyl-2-chlorobutyrate methyl ester is added into a reaction container, 10-30% sulfuric acid is added, and after the reaction, alkali is used for neutralization and dichloromethane is used for extraction.
Further, in the step c, 3-chloro-3-acetyl propanol acetate is added into a reaction container at normal temperature, 3-10% of diluted hydrochloric acid is added, then an ammonium dithiocarbamate aqueous solution is added, stirring is started, the temperature is raised to 45-60 ℃ for reaction for 3-8 hours, after the reaction is finished, the temperature is cooled to 0-5 ℃, white solid is filtered out, and 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole is obtained after drying.
Further, in the step d, 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole is dissolved in water at normal temperature, a certain amount of 36% concentrated hydrochloric acid is added, then the temperature is raised to 40-60 ℃, hydrogen peroxide is dripped, after the detection reaction is finished, cooling is carried out, PH is regulated to be neutral, dichloromethane is used for extraction, and evaporation is carried out, thus obtaining 4-methyl-5- (beta-acetoxyethyl) -thiazole.
In the step e, 4-methyl-5- (beta-acetoxyethyl) -thiazole is put into a reaction bottle at normal temperature, toluene is added, 5-15% sodium hydroxide solution is added, and stirring is carried out until the reaction is completed, so that 4-methyl-5- (beta-hydroxyethyl) -thiazole is obtained.
The beneficial effects of the invention are as follows:
1. compared with the prior reaction taking alpha-acetyl-gamma-butyrolactone as a raw material, the preparation method saves one step of reaction steps and saves the reaction time.
2. The invention has the overall yield reaching more than 50 percent, and has lower cost and avoids more side reactions.
3. The method has mild overall reaction conditions and simple post-treatment, and is suitable for pilot plant test and industrial production.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments.
Example 1
11.6G (0.1 mol) of methyl acetoacetate is dissolved in 300ml of anhydrous tetrahydrofuran, 4.8g (0.12 mol) of 60% sodium hydrogen is added in batches under the protection of nitrogen at 0 ℃, then 21.5g (0.1 mol) of 3-bromo-3-chloropropyl acetate in 50ml of tetrahydrofuran is added dropwise, after the addition is finished, the reaction is continued for 2 hours, and then the temperature is raised to reflux reaction for 0.5-1 hour. After the reaction is detected by GC-MS, the temperature is reduced to 0 ℃, a sufficient amount of 5% dilute hydrochloric acid is slowly dripped, the PH is regulated to be neutral, diethyl ether is used for extraction, then diethyl ether is distilled off to obtain 24g of crude 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester, the content of the 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester detected by GC-MS is 95%, the 2.8% of 4-acetoxyl-2-acetyl-2-bromobutyrate methyl ester is further contained, the content of disubstituted impurities is less than 1%, the content of halogen-free impurities is less than 1%, no further purification is needed, and the crude 4-acetoxyl-2-chlorobutyrate methyl ester is directly put into the next reaction.
24G of the crude product 4-acetoxyl-2-acetyl-2-chlorobutyrate prepared above and 20% sulfuric acid are added into a 500ml reaction bottle, reflux is carried out, after the reaction is finished and the reaction is neutralized by sodium carbonate, dichloromethane is used for extraction, and 18g of 3-chloro-3-acetoacetate crude product is obtained by reduced pressure distillation, thus the purification is not needed, and the next step is carried out.
At normal temperature, 18g of 3-chloro-3-acetyl propanol acetate and 200ml of water are added into a 500ml reaction bottle, 20 drops of 10% diluted hydrochloric acid are dripped into the bottle by a dropper, then 11g of ammonium dithiocarbamate 50ml of aqueous solution is dripped into the bottle, stirring is started, the temperature is raised to 55 ℃ for reaction for 3 hours, the reaction is completed, the temperature is cooled to 0 ℃, white solid is filtered out, and 20g of 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole pure product with the content of 98.8% is obtained after drying.
At normal temperature, 20g of 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole are dissolved in water, 20ml of 36% concentrated hydrochloric acid is added, then the temperature is raised to 48 ℃, 30ml of 35% hydrogen peroxide is dripped, after the detection reaction is finished, the mixture is cooled, the PH is regulated to be neutral, dichloromethane is used for extraction, and decompression evaporation is carried out, thus 16g of 4-methyl-5- (beta-acetoxyethyl) -thiazole with the content of 96.8% is obtained.
At normal temperature, 16g of 4-methyl-5- (beta-acetoxyethyl) -thiazole are put into a 250ml reaction bottle, toluene is added for dissolution, 10% sodium hydroxide solution is added for 100ml, stirring is carried out until the reaction is completed, the pH is regulated to be slightly acidic, dichloromethane is used for extraction, 13g of 4-methyl-5- (beta-hydroxyethyl) -thiazole crude product is obtained through reduced pressure distillation, and 11g of 100% pure product is obtained through rectification and purification.
Example 2
200G (1.72 mol) of methyl acetoacetate was dissolved in 1.5L of anhydrous tetrahydrofuran, 72g (1.80 mol) of 60% sodium hydrogen was added in portions under the protection of nitrogen at-5℃and 369.8g (1.72 mol) of 3-bromo-3-chloropropyl acetate was then added dropwise thereto, and the reaction was continued for 2 hours after the addition was completed, and then the temperature was raised to reflux for 1 hour. After the reaction is detected by GC-MS, the temperature is reduced to 0 ℃, a sufficient amount of 5% diluted hydrochloric acid is slowly dripped, the PH is regulated to be neutral, diethyl ether is used for extraction, then 240g of crude 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester is obtained after evaporation, 408g of crude 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester with 96% content is detected by GC-MS, and the further purification is not needed, and the next reaction is directly put into.
The crude product of the methyl 4-acetoxy-2-acetyl-2-chlorobutyrate 408 g prepared above is added into a 2L reaction bottle, 10 percent sulfuric acid 1.2L is added, reflux is carried out, after the reaction is finished, 10 percent sodium hydroxide solution is used for neutralization until the PH is 7, dichloromethane is used for extraction, reduced pressure distillation and purification are carried out, thus 295g of 3-chloro-3-acetoacetate with the content of 99.8 percent is obtained.
At normal temperature, 295g of 3-chloro-3-acetoacetate and 800ml of water are added into a 2L reaction bottle, 100ml of 10% dilute hydrochloric acid is dripped into the reaction bottle by a dropper, then 181.7g of 200ml of aqueous solution of ammonium dithiocarbamate is dripped into the reaction bottle, stirring is started, the temperature is raised to 50 ℃ for reaction for 8 hours, after the reaction is finished, the reaction bottle is put into brine ice, cooled to 0 ℃, white solid is filtered out, and 350g of pure 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole with 99% content is obtained by drying.
At normal temperature, 350g of 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole are dissolved in water, 200ml of 36% concentrated hydrochloric acid is added, then the temperature is raised to 45 ℃, 165ml of 35% hydrogen peroxide is dripped into the solution, after the detection reaction is finished, the solution is cooled, the pH is regulated to be neutral, dichloromethane extraction is carried out, anhydrous sodium sulfate drying and reduced pressure evaporation are carried out, and 278g of 4-methyl-5- (beta-acetoxyethyl) -thiazole with the content of 98% is obtained.
At normal temperature, 278g of 4-methyl-5- (beta-acetoxyethyl) -thiazole are put into a 2L reaction bottle, 600ml of toluene is added for dissolution, 15% sodium hydroxide solution 500 ml is added, the mixture is stirred until the reaction is completed, the pH is regulated to be slightly acidic, dichloromethane is used for extraction, and 214 g of 4-methyl-5- (beta-hydroxyethyl) -thiazole crude product is obtained through reduced pressure distillation, and the product is purified through rectification, so that the pure product with the 210 g content of 100% is obtained.
Example 3
5Kg of methyl acetoacetate is put into a 50L reaction kettle, 20L of anhydrous tetrahydrofuran is added for dissolution, 1.81kg of 60% sodium hydrogen is added in batches under the protection of nitrogen at the temperature of minus 10 to minus 5 ℃, then 8.62kg of 3-bromo-3-chloropropyl acetate is added dropwise, the reaction is continued for 8 hours after the addition is finished, and then the temperature is raised to room temperature for reaction for 2 hours. After the reaction is detected by GC-MS, the temperature is reduced to minus 5 ℃, enough 10 percent of diluted hydrochloric acid is slowly dripped, the PH is regulated to be neutral, diethyl ether is used for extraction, 9.98kg of crude 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester is obtained after the diethyl ether is distilled off, and the methyl 4-acetoxyl-2-acetyl-2-chlorobutyrate with 97 percent of content is detected by GC-MS without purification and is directly put into the next reaction.
Adding 9.98kg of the prepared crude product of 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester into a 100L reaction kettle, adding 50L of 20% sulfuric acid, refluxing, neutralizing to pH of 7 by using sodium hydroxide after the reaction is finished, extracting by using dichloromethane, and distilling under reduced pressure to obtain 7.4kg of crude product of 3-chloro-3-acetoacetate with 98% content, wherein purification is not needed, and the next step is added.
7.4Kg of 3-chloro-3-acetoacetate and 50L of water are added into a 100L reaction bottle at normal temperature, 2L of 10% diluted hydrochloric acid is added, then 4.557kg of ammonium dithiocarbamate aqueous solution is dripped, stirring is started, the temperature is raised to 50 ℃ for reaction for 2 hours, the reaction is completed, the temperature is cooled to 0 ℃, white solid is filtered out, and 8.110kg of pure 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole with 99% content is obtained after drying.
At normal temperature, 8.11Kg of 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole is put into a 100L reaction kettle, 30L and 5L of 36% concentrated hydrochloric acid are added, 36L of 35% hydrogen peroxide is sucked in five batches by a vacuum pump, the temperature is raised to 50 ℃, after the reaction is detected, the temperature is cooled, sodium hydroxide is added to adjust the PH to be neutral, sufficient sodium sulfite is added to remove excessive hydrogen peroxide, dichloromethane is used for extraction, and the solution is evaporated to dryness under reduced pressure, so that 5.948Kg of 4-methyl-5- (beta-acetoxyethyl) -thiazole is obtained, and the content is 99%.
At normal temperature, 5.948kg of 4-methyl-5- (beta-acetoxyethyl) -thiazole is put into a 100L reaction kettle, 50L of toluene is added for dissolution, 1.54kg of sodium hydroxide is added, 10L of water is added, the mixture is stirred until the reaction is completed, the pH is regulated to be slightly acidic, dichloromethane is used for extraction, reduced pressure distillation is carried out to obtain a crude product of 4-methyl-5- (beta-hydroxyethyl) -thiazole, and 4.3kg of 100% pure product is obtained through rectification and purification.
The technical principle of the present invention is described above in connection with the specific embodiments. The description is made for the purpose of illustrating the general principles of the invention and should not be taken in any way as limiting the scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of this specification without undue burden.
Claims (1)
1. A method for synthesizing thiothiazole is characterized in that the method is carried out according to the following reaction process,
The method comprises the following steps:
In the step a, methyl acetoacetate is dissolved in anhydrous tetrahydrofuran or anhydrous diethyl ether, under the protection of inert gas at the temperature of between 5 ℃ below zero and 10 ℃, 1.1 to 1.2 molar equivalents of 60 percent sodium hydrogen or 1 to 1.2 molar equivalents of n-butyl lithium solution are added in batches, 3-bromo-3-chloropropyl acetate tetrahydrofuran solution is added after the addition or the addition is finished, the reaction is carried out for 2 to 4 hours, then the temperature is raised to reflux, and the reaction is continued for 0.5 to 1 hour;
b, adding 4-acetoxyl-2-acetyl-2-chlorobutyrate methyl ester into a reaction container, adding 10-30% sulfuric acid, neutralizing with alkali after the reaction is finished, and extracting with dichloromethane;
c, adding 3-chloro-3-acetyl propanol acetate into a reaction container at normal temperature, adding 3-10% of diluted hydrochloric acid, then adding an ammonium dithiocarbamate aqueous solution, starting stirring, heating to 45-60 ℃ for reaction for 3-8 hours, cooling to 0-5 ℃ after the reaction is finished, filtering out white solid, and drying to obtain 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole;
d, dissolving 2-mercapto-4-methyl-5- (beta-acetoxyethyl) -thiazole in water at normal temperature, adding a certain amount of 36% concentrated hydrochloric acid, heating to 40-60 ℃, dripping hydrogen peroxide, cooling after the detection reaction is finished, adjusting the PH to be neutral, extracting with dichloromethane, and evaporating to dryness to obtain 4-methyl-5- (beta-acetoxyethyl) -thiazole;
And e, at normal temperature, putting 4-methyl-5- (beta-acetoxyl ethyl) -thiazole into a reaction bottle, adding toluene, adding 5-15% sodium hydroxide solution, and stirring until the reaction is completed, thus obtaining 4-methyl-5- (beta-hydroxyethyl) -thiazole.
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