CN115819370A - Synthetic method of 4-methyl-5- (beta-hydroxyethyl) -thiazole - Google Patents
Synthetic method of 4-methyl-5- (beta-hydroxyethyl) -thiazole Download PDFInfo
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- CN115819370A CN115819370A CN202211707506.7A CN202211707506A CN115819370A CN 115819370 A CN115819370 A CN 115819370A CN 202211707506 A CN202211707506 A CN 202211707506A CN 115819370 A CN115819370 A CN 115819370A
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- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000010189 synthetic method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 49
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims abstract description 39
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 30
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 26
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 claims abstract description 22
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 claims abstract description 22
- FYWDUQCSMYWUHV-UHFFFAOYSA-N 3-chloro-5-hydroxypentan-2-one Chemical compound CC(=O)C(Cl)CCO FYWDUQCSMYWUHV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- CBEZEZZIXCULJW-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methyl-3h-1,3-thiazole-2-thione Chemical compound CC=1NC(=S)SC=1CCO CBEZEZZIXCULJW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000011230 binding agent Substances 0.000 claims abstract description 16
- CYCRRRIREKXQTK-UHFFFAOYSA-N 3-acetyl-3-chlorooxolan-2-one Chemical compound CC(=O)C1(Cl)CCOC1=O CYCRRRIREKXQTK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000460 chlorine Substances 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000005935 nucleophilic addition reaction Methods 0.000 claims abstract description 6
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 17
- 229910000831 Steel Inorganic materials 0.000 claims description 16
- 239000010959 steel Substances 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 238000007086 side reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 description 5
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- -1 thiazole compound Chemical class 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ZIHZGZMCAYJNFA-UHFFFAOYSA-N 5-bromo-5-chloropentanoic acid Chemical compound OC(=O)CCCC(Cl)Br ZIHZGZMCAYJNFA-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000013372 meat Nutrition 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
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
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- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a synthesis method of 4-methyl-5- (beta-hydroxyethyl) -thiazole, which comprises the following steps: (1) Under the action of an acid-binding agent, carrying out chlorination reaction on the alpha-acetyl-gamma-butyrolactone and chlorine; (2) Under the action of hydrochloric acid solution, the obtained alpha-acetyl-alpha chloro-gamma-butyrolactone is subjected to ring-opening hydrolysis reaction; (3) In the presence of dimethyl carbonate, carbon disulfide and ammonia gas undergo nucleophilic addition reaction; (4) Under the action of hydrochloric acid solution, the obtained 3-chloro-4-oxo-1-pentanol and the obtained ammonium dithiocarbamate undergo condensation reaction; (5) Under the action of concentrated sulfuric acid, oxidizing the obtained 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole by using hydrogen peroxide, adding ammonia water for neutralization reaction, and rectifying to obtain the 4-methyl-5- (beta-hydroxyethyl) -thiazole. The invention simplifies the hydrolysis process, has less side reaction, simple operation, mild reaction process, high product yield up to over 96 percent and low production cost.
Description
Technical Field
The invention belongs to the field of thiazoie synthesis, and particularly relates to a synthesis method of 4-methyl-5- (beta-hydroxyethyl) -thiazole.
Background
4-methyl-5- (. Beta. -hydroxyethyl) -thiazole, also known as thiazoie, is a pale yellow liquid, non-volatile, having the unpleasant odor of the thiazole compound, but at very dilute concentrations it has a pleasant fragrance and is able to form, with HCl, a hydrochloride salt which is soluble in water and alcohol. The thiazothiazole is a basic structural ring for forming vitamin VB1, is an important intermediate for synthesizing the vitamin VB1, also has the fragrance of nut beans, milk, egg fishy smell, meat and the like, and can be used as spice and essence.
At present, the synthesis process of 4-methyl-5- (beta-hydroxyethyl) -thiazole mainly has the defects of high raw material cost, more side reactions, difficult purification and unsuitability for industrial large-scale batch production, for example, an invention patent with the publication number of CN111635375A discloses a synthesis method of thiazothiazole, which takes methyl acetoacetate and 3-bromo-3-chloropropylacetate as raw materials to prepare 4-acetoxy-2-acetyl-2-methyl chlorobutyrate under the alkaline condition, and the thiazothiazole is obtained by acid hydrolysis, condensation, oxidation and alkaline hydrolysis, wherein the reaction equation is shown as follows:
in the synthesis process, the 3-bromo-3-chloropropylacetic acid ester is high in raw material cost, and needs to undergo two-step hydrolysis reaction, so that the side reactions are more, the product yield is influenced, and the product purification difficulty is improved. Therefore, how to develop a novel synthesis method of 4-methyl-5- (beta-hydroxyethyl) -thiazole with high yield and low cost, which is suitable for industrial large-scale production, is a technical problem to be solved urgently.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole.
The technical scheme of the invention is summarized as follows:
a method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole comprises the following steps:
(1) Under the action of an acid-binding agent, carrying out chlorination reaction on the alpha-acetyl-gamma-butyrolactone and chlorine to generate alpha-acetyl-alpha chloro-gamma-butyrolactone; the reaction equation is shown in formula I:
(2) Under the action of hydrochloric acid solution, the alpha-acetyl-alpha chloro-gamma-butyrolactone carries out ring-opening hydrolysis reaction to generate 3-chloro-4-oxo-1-pentanol; the reaction equation is shown in formula II:
(3) In the presence of dimethyl carbonate, carbon disulfide and ammonia gas undergo nucleophilic addition reaction to generate ammonium dithiocarbamate; the reaction equation is shown in formula III:
(4) Under the action of hydrochloric acid solution, 3-chloro-4-oxo-1-pentanol and ammonium dithiocarbamate are subjected to condensation reaction to generate 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole; the reaction equation is shown in formula IV:
(5) Under the action of concentrated sulfuric acid, oxidizing 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole by using hydrogen peroxide, adding ammonia water for neutralization reaction, and rectifying to obtain 4-methyl-5- (beta-hydroxyethyl) -thiazole; the reaction equation is shown in formula V:
further, the acid-binding agent is one of sodium bicarbonate and sodium acetate.
Further, the acid-binding agent is sodium bicarbonate, and the reaction equation in the step (1) is as follows:
further, the synthesis method of the 4-methyl-5- (beta-hydroxyethyl) -thiazole comprises the following steps:
(1) Adding water into a chlorination reaction kettle at 10-20 ℃, adding an acid-binding agent and alpha-acetyl-gamma-butyrolactone in a stirring state, opening a liquid chlorine steel bottle valve, slowly introducing chlorine into the chlorination reaction kettle, carrying out stirring reaction, closing the liquid chlorine steel bottle valve after the reaction end point is reached, continuing stirring for 1h, standing for layering for 3-6h, and separating out a light yellow oil layer to obtain the alpha-acetyl-alpha chloro-gamma-butyrolactone for later use;
(2) Adding water and a hydrochloric acid solution into a hydrolysis kettle, adding the alpha-acetyl-alpha chloro-gamma-butyrolactone obtained in the step (1) under a stirring state, stirring and reacting for 1h at 70-75 ℃, then heating to 80-90 ℃, carrying out reflux reaction for 3h at constant temperature, then cooling to 25-50 ℃, completing hydrolysis reaction, and obtaining a 3-chloro-4-oxo-1-pentanol solution for later use after neutralization;
(3) Adding dimethyl carbonate and carbon disulfide into an ammoniation reaction kettle, cooling to 10-15 ℃, opening a liquid ammonia steel cylinder valve, slowly introducing ammonia gas into the ammoniation reaction kettle, stirring for reaction, closing the liquid ammonia steel cylinder valve after ammonia introduction is finished, continuing to perform heat preservation stirring reaction for 1h, adding water and stirring for 1h after the reaction is finished, standing and layering for 1h to dissolve the product ammonium dithiocarbamate into a water layer, and separating to obtain an ammonium dithiocarbamate aqueous solution for later use;
(4) Adding the 3-chloro-4-oxo-1-pentanol solution obtained in the step (2) and the ammonium dithiocarbamate solution obtained in the step (3) into a condensation reaction kettle, heating to 40-45 ℃, dropwise adding a hydrochloric acid solution for 2-3h, stirring at 60-70 ℃ for 1h after dropwise adding, cooling to 10-15 ℃, performing suction filtration and centrifugation, and washing until the pH is =7.0 to obtain 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole for later use;
(5) Adding dichloromethane and concentrated sulfuric acid catalyst into an oxidation reaction kettle, adding 2-sulfydryl-4-methyl-5- (beta-hydroxyethyl) -thiazole obtained in the step (4), dropwise adding hydrogen peroxide at 20-25 ℃ under a stirring state, continuously stirring at 20-30 ℃ to react for 2 hours after dropwise adding is finished, standing for layering for 0.5-1 hour, separating out a dichloromethane oil layer, slowly dropwise adding ammonia water for neutralization, evaporating and recovering a dichloromethane solvent to obtain a crude product of the 4-methyl-5- (beta-hydroxyethyl) -thiazole, and rectifying to obtain a pure product of the 4-methyl-5- (beta-hydroxyethyl) -thiazole.
Further, the mass fraction of the hydrochloric acid solution is 30%.
Further, in step (1): the dosage ratio of the acid binding agent, the alpha-acetyl-gamma-butyrolactone, the chlorine and the water is 1mol (200-300) mL.
Furthermore, the dosage ratio of the water and the hydrochloric acid solution in the step (2) to the alpha-acetyl-gamma-butyrolactone in the step (1) is (100-150) mL, (20-25) g:1mol.
Further, in the step (3): the dosage ratio of the dimethyl carbonate, the carbon disulfide, the ammonia gas and the water is (2-2.5) g:1mol, (100-130) g.
Furthermore, the dosage ratio of the hydrochloric acid solution in the step (4) to the alpha-acetyl-gamma-butyrolactone in the step (1) and the carbon disulfide in the step (3) is (40-50) g: 11mol.
Further, the dosage ratio of the dichloromethane, the concentrated sulfuric acid catalyst and the hydrogen peroxide in the step (5) to the alpha-acetyl-gamma-butyrolactone in the step (1) is 150g, 2-2.5 g, 200-250 g and 1mol; and in the step (5), the mass fraction of the concentrated sulfuric acid is 98%, the mass fraction of the hydrogen peroxide is 25-30%, and the mass fraction of the ammonia water is 20%.
The invention has the beneficial effects that:
the invention adopts alpha-acetyl-gamma-butyrolactone with relatively low price as a raw material, synthesizes 3-chloro-4-oxo-1-pentanol through chlorination and ring-opening hydrolysis, and performs condensation reaction with ammonium dithiocarbamate generated by nucleophilic addition reaction of carbon disulfide and ammonia gas to synthesize an intermediate 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole for the first time, and further oxidizes and neutralizes the intermediate to prepare the target product 4-methyl-5- (beta-hydroxyethyl) -thiazole, thereby reducing hydrolysis steps, few side reactions, reducing the generation of waste water and waste residue, having simple and convenient operation, mild reaction process, more than 96 percent of product yield, low production cost and laying the foundation for large-scale production.
Drawings
FIG. 1 is a flow chart of the synthesis of 4-methyl-5- (. Beta. -hydroxyethyl) -thiazole of the present invention;
FIG. 2 is a flow chart of the synthesis process of 4-methyl-5- (. Beta. -hydroxyethyl) -thiazole of the present invention.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
The invention provides a synthesis method of 4-methyl-5- (beta-hydroxyethyl) -thiazole, which is characterized by comprising the following steps:
(1) Under the action of an acid-binding agent, carrying out chlorination reaction on the alpha-acetyl-gamma-butyrolactone and chlorine to generate alpha-acetyl-alpha chloro-gamma-butyrolactone, which specifically comprises the following steps: adding water into a chlorination reaction kettle at 10-20 ℃, adding an acid-binding agent and alpha-acetyl-gamma-butyrolactone in a stirring state, opening a liquid chlorine steel bottle valve, slowly introducing chlorine into the chlorination reaction kettle, carrying out stirring reaction, closing the liquid chlorine steel bottle valve after the reaction end point is reached, continuing stirring for 1h, standing for layering for 3-6h, and separating out a light yellow oil layer to obtain the alpha-acetyl-alpha chloro-gamma-butyrolactone for later use; the acid-binding agent is one of sodium bicarbonate and sodium acetate; the dosage ratio of the acid binding agent, the alpha-acetyl-gamma-butyrolactone, the chlorine and the water is 1mol (200-300) mL; the reaction equation is shown in formula I:
when the acid-binding agent is sodium bicarbonate, the reaction equation is as follows:
(2) Under the action of hydrochloric acid solution, alpha-acetyl-alpha chloro-gamma-butyrolactone is subjected to ring-opening hydrolysis reaction to generate 3-chloro-4-oxo-1-pentanol, which specifically comprises the following steps: adding water and a hydrochloric acid solution with the mass fraction of 30% into a hydrolysis kettle, adding the alpha-acetyl-alpha chloro-gamma-butyrolactone obtained in the step (1) under the stirring state, stirring and reacting for 1h at 70-75 ℃, then heating to 80-90 ℃, carrying out reflux reaction for 3h at constant temperature, cooling to 25-50 ℃, completing the hydrolysis reaction, and neutralizing to obtain a 3-chloro-4-oxo-1-pentanol solution for later use; the dosage ratio of the water and the hydrochloric acid solution in the step (2) to the alpha-acetyl-gamma-butyrolactone in the step (1) is (100-150) mL, (20-25) g:1mol; the reaction equation is shown in formula II:
(3) In the presence of dimethyl carbonate, carbon disulfide and ammonia gas undergo a nucleophilic addition reaction to generate ammonium dithiocarbamate, which specifically comprises the following steps: adding dimethyl carbonate and carbon disulfide into an ammoniation reaction kettle, cooling to 10-15 ℃, opening a liquid ammonia steel cylinder valve, slowly introducing ammonia gas into the ammoniation reaction kettle, stirring for reaction, closing the liquid ammonia steel cylinder valve after ammonia introduction is finished, continuing to perform heat preservation stirring reaction for 1h, adding water and stirring for 1h after the reaction is finished, standing and layering for 1h to dissolve the product ammonium dithiocarbamate into a water layer, and separating to obtain an ammonium dithiocarbamate aqueous solution for later use; the dosage ratio of the dimethyl carbonate, the carbon disulfide, the ammonia gas and the water is (2-2.5) g, 1mol, and (100-130) g; the reaction equation is shown in formula III:
(4) Under the action of hydrochloric acid solution, 3-chloro-4-oxo-1-pentanol and ammonium dithiocarbamate are subjected to condensation reaction to generate 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole, which specifically comprises the following steps: adding the 3-chloro-4-oxo-1-pentanol solution obtained in the step (2) and the ammonium dithiocarbamate aqueous solution obtained in the step (3) into a condensation reaction kettle, heating to 40-45 ℃, then dropwise adding a hydrochloric acid solution with the mass fraction of 30%, controlling the dropwise adding time to be 2-3h, stirring for 1h at 60-70 ℃ after the dropwise adding is finished, cooling to 10-15 ℃, performing suction filtration and centrifugation, and washing until the pH is =7.0 to obtain 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole for later use; the dosage ratio of the hydrochloric acid solution in the step (4) to the alpha-acetyl-gamma-butyrolactone in the step (1) and the carbon disulfide in the step (3) is (40-50) g:1mol; the reaction equation is shown in formula IV:
(5) Under the action of concentrated sulfuric acid, oxidizing 2-sulfydryl-4-methyl-5- (beta-ethoxyl) -thiazole by using hydrogen peroxide, adding ammonia water for neutralization reaction, and rectifying to obtain 4-methyl-5- (beta-ethoxyl) -thiazole, wherein the method specifically comprises the following steps: adding dichloromethane, a concentrated sulfuric acid catalyst with the mass fraction of 98% and the 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole obtained in the step (4) into an oxidation reaction kettle, dropwise adding hydrogen peroxide with the mass fraction of 25-30% under the stirring state at 20-25 ℃, continuously stirring and reacting for 2 hours at 20-30 ℃ after dropwise adding, standing and layering for 0.5-1 hour, separating a dichloromethane oil layer, slowly dropwise adding ammonia water with the mass fraction of 20% for neutralization, evaporating and recovering a dichloromethane solvent to obtain a crude product of the 4-methyl-5- (beta-hydroxyethyl) -thiazole, and rectifying to obtain a pure product of the 4-methyl-5- (beta-hydroxyethyl) -thiazole; the dosage ratio of the dichloromethane, the concentrated sulfuric acid catalyst and the hydrogen peroxide in the step (5) to the alpha-acetyl-gamma-butyrolactone in the step (1) is 150g, (2-2.5) g, (200-250) g to 1mol; the reaction equation is shown in formula V:
example 1
A method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole is characterized by comprising the following steps:
(1) Adding 600L of water into a chlorination reaction kettle at 15 ℃, adding 197.42kg of sodium bicarbonate and 301.11kg of alpha-acetyl-gamma-butyrolactone in a stirring state, opening a liquid chlorine steel bottle valve, slowly introducing 166.64kg of chlorine into the chlorination reaction kettle, carrying out stirring reaction, closing the liquid chlorine steel bottle valve after the reaction end point is reached, continuously stirring for 1h, flushing a pump with boiling water to discharge chlorine, standing for layering for 3h, and separating out a light yellow oil layer to obtain alpha-acetyl-alpha-chloro-gamma-butyrolactone, wherein the product yield is 98% for later use;
(2) Adding 300L of water and 48kg of 30wt% hydrochloric acid solution into a hydrolysis kettle, adding the alpha-acetyl-alpha chloro-gamma-butyrolactone obtained in the step (1) under the stirring state, stirring and reacting at 75 ℃ for 1h, heating to 85 ℃, carrying out reflux reaction at constant temperature for 3h, cooling to 30 ℃, completing hydrolysis reaction, and neutralizing to obtain 3-chloro-4-oxo-1-pentanol solution, wherein the yield of the 3-chloro-4-oxo-1-pentanol is 99% for standby;
(3) Adding 5kg of dimethyl carbonate and 178.93kg of carbon disulfide into an ammonification reaction kettle, cooling to 15 ℃, opening a liquid ammonia steel cylinder valve, slowly introducing 80.05kg of ammonia into the ammonification reaction kettle, stirring for reaction, closing the liquid ammonia steel cylinder valve after ammonia introduction is finished, continuing heat preservation stirring for reaction for 1h, adding 258kg of water and stirring for 1h after the reaction is finished, standing for layering for 1h to dissolve the product ammonium dithiocarbamate in a water layer, separating liquid to obtain an ammonium dithiocarbamate aqueous solution, wherein the yield of the ammonium dithiocarbamate is 97% for later use;
(4) Adding the 3-chloro-4-oxo-1-pentanol solution obtained in the step (2) and the ammonium dithiocarbamate aqueous solution obtained in the step (3) into a condensation reaction kettle, heating to 45 ℃, then dropwise adding 96kg of 30wt% hydrochloric acid solution, controlling the dropwise adding time to be 3h, stirring at 60 ℃ for 1h after the dropwise adding is finished, cooling to 10 ℃, performing suction filtration, centrifuging, and washing until the pH is =7.0 to obtain 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole, wherein the yield of the 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole is 96% for later use;
(5) 352.5kg of dichloromethane and 5kg of 98wt% concentrated sulfuric acid catalyst are added into an oxidation reaction kettle, and 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole obtained in the step (4) is added, and is added with 540kg of 27.5wt% hydrogen peroxide dropwise under the stirring state, after the dropwise addition is finished, the stirring reaction is continued at 25 ℃ for 2 hours, the mixture is kept still and layered for 1 hour, a dichloromethane oil layer is separated out, 20wt% ammonia water is slowly added dropwise for neutralization, a dichloromethane solvent is evaporated and recovered to obtain a crude 4-methyl-5- (beta-hydroxyethyl) -thiazole product, and after rectification, a pure 4-methyl-5- (beta-hydroxyethyl) -thiazole product is obtained, wherein the product yield is 98%.
In the embodiment 1, alpha-acetyl-gamma-butyrolactone with relatively low price is used as a raw material, and is subjected to chlorination and ring-opening hydrolysis to synthesize 3-chloro-4-oxo-1-pentanol, and is subjected to condensation reaction with ammonium dithiocarbamate generated by nucleophilic addition reaction of carbon disulfide and ammonia gas to synthesize an intermediate 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole for the first time, and the intermediate is further oxidized and neutralized to prepare the target product 4-methyl-5- (beta-hydroxyethyl) -thiazole, so that the hydrolysis steps and side reactions are reduced, the generation of wastewater and waste residues is reduced, the operation is simple and convenient, the reaction process is mild, the product yield reaches over 96%, the production cost is low, and the safety and operability foundation is laid for large-scale production.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (10)
1. A method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole is characterized by comprising the following steps:
(1) Under the action of an acid-binding agent, carrying out chlorination reaction on the alpha-acetyl-gamma-butyrolactone and chlorine to generate alpha-acetyl-alpha chloro-gamma-butyrolactone; the reaction equation is shown in formula I:
(2) Under the action of hydrochloric acid solution, alpha-acetyl-alpha chloro-gamma-butyrolactone is subjected to ring-opening hydrolysis reaction to generate 3-chloro-4-oxo-1-pentanol; the reaction equation is shown in formula II:
(3) In the presence of dimethyl carbonate, carbon disulfide and ammonia gas undergo a nucleophilic addition reaction to generate ammonium dithiocarbamate; the reaction equation is shown in formula III:
(4) Under the action of hydrochloric acid solution, 3-chloro-4-oxo-1-pentanol and ammonium dithiocarbamate are subjected to condensation reaction to generate 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole; the reaction equation is shown in formula IV:
(5) Under the action of concentrated sulfuric acid, oxidizing 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole by using hydrogen peroxide, adding ammonia water for neutralization reaction, and rectifying to obtain 4-methyl-5- (beta-hydroxyethyl) -thiazole; the reaction equation is shown in formula V:
2. the method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to claim 1, wherein the acid-binding agent is one of sodium bicarbonate and sodium acetate.
3. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to claim 2, wherein the acid-binding agent is sodium bicarbonate.
4. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to claim 1, comprising the following steps:
(1) Adding water into a chlorination reaction kettle at 10-20 ℃, adding an acid-binding agent and alpha-acetyl-gamma-butyrolactone in a stirring state, opening a liquid chlorine steel bottle valve, slowly introducing chlorine into the chlorination reaction kettle, carrying out stirring reaction, closing the liquid chlorine steel bottle valve after the reaction end point is reached, continuing stirring for 1h, standing for layering for 3-6h, and separating out a light yellow oil layer to obtain the alpha-acetyl-alpha chloro-gamma-butyrolactone for later use;
(2) Adding water and a hydrochloric acid solution into a hydrolysis kettle, adding the alpha-acetyl-alpha chloro-gamma-butyrolactone obtained in the step (1) under a stirring state, stirring and reacting for 1h at 70-75 ℃, then heating to 80-90 ℃, carrying out reflux reaction for 3h at constant temperature, then cooling to 25-50 ℃, completing hydrolysis reaction, and obtaining a 3-chloro-4-oxo-1-pentanol solution for later use after neutralization;
(3) Adding dimethyl carbonate and carbon disulfide into an ammoniation reaction kettle, cooling to 10-15 ℃, opening a liquid ammonia steel cylinder valve, slowly introducing ammonia gas into the ammoniation reaction kettle, stirring for reaction, closing the liquid ammonia steel cylinder valve after ammonia introduction is finished, continuing to perform heat preservation stirring reaction for 1h, adding water and stirring for 1h after the reaction is finished, standing and layering for 1h to dissolve the product ammonium dithiocarbamate into a water layer, and separating to obtain an ammonium dithiocarbamate aqueous solution for later use;
(4) Adding the 3-chloro-4-oxo-1-pentanol solution obtained in the step (2) and the ammonium dithiocarbamate solution obtained in the step (3) into a condensation reaction kettle, heating to 40-45 ℃, dropwise adding a hydrochloric acid solution for 2-3h, stirring at 60-70 ℃ for 1h after dropwise adding, cooling to 10-15 ℃, performing suction filtration and centrifugation, and washing until the pH is =7.0 to obtain 2-mercapto-4-methyl-5- (beta-hydroxyethyl) -thiazole for later use;
(5) Adding dichloromethane and concentrated sulfuric acid catalyst into an oxidation reaction kettle, adding 2-sulfydryl-4-methyl-5- (beta-hydroxyethyl) -thiazole obtained in the step (4), dropwise adding hydrogen peroxide at 20-25 ℃ under a stirring state, continuously stirring at 20-30 ℃ for reacting for 2h after dropwise adding, standing for layering for 0.5-1h, separating out a dichloromethane oil layer, slowly dropwise adding ammonia water for neutralization, evaporating and recovering a dichloromethane solvent to obtain a 4-methyl-5- (beta-hydroxyethyl) -thiazole crude product, and rectifying to obtain a 4-methyl-5- (beta-hydroxyethyl) -thiazole pure product.
5. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to any of claims 1 to 4, wherein the mass fraction of the hydrochloric acid solution is 30%.
6. A method for the synthesis of 4-methyl-5- (. Beta. -hydroxyethyl) -thiazole, according to any of claims 1 to 4, characterized in that in step (1): the dosage ratio of the acid binding agent, the alpha-acetyl-gamma-butyrolactone, the chlorine gas and the water is 1mol.
7. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to claim 4, characterized in that the ratio of the water and the hydrochloric acid solution in the step (2) to the alpha-acetyl-gamma-butyrolactone in the step (1) is (100-150) mL (20-25) g:1mol.
8. The method for synthesizing 4-methyl-5- (. Beta. -hydroxyethyl) -thiazole according to claim 4 or 7, wherein in the step (3): the dosage ratio of the dimethyl carbonate, the carbon disulfide, the ammonia gas and the water is (2-2.5) g:1mol, (100-130) g.
9. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to claim 8, characterized in that the dosage ratio of the hydrochloric acid solution in the step (4) to the alpha-acetyl-gamma-butyrolactone in the step (1) and the carbon disulfide in the step (3) is (40-50) g:1mol.
10. The method for synthesizing 4-methyl-5- (beta-hydroxyethyl) -thiazole according to any one of the claims 4, 7 or 9, characterized in that the dosage ratio of dichloromethane, concentrated sulfuric acid catalyst, hydrogen peroxide and alpha-acetyl-gamma-butyrolactone in the step (1) in the step (5) is 150g (2-2.5) g (200-250) g:1mol; and in the step (5), the mass fraction of the concentrated sulfuric acid is 98%, the mass fraction of the hydrogen peroxide is 25-30%, and the mass fraction of the ammonia water is 20%.
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