CN103145645B - The preparation technology of methyl mercapto thiadiazoles - Google Patents
The preparation technology of methyl mercapto thiadiazoles Download PDFInfo
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Abstract
The preparation technology of methyl mercapto thiadiazoles, relate to pharmaceutical chemistry technical field, this technique take ethyl acetate as raw material, ethyl acetate prepares methyl mercapto thiadiazoles through hydrazine, addition, ring-closure reaction, reaction solvent is not used in ethyl acetate and hydrazine hydrate reaction process, improve the hydrazine temperature of ethyl acetate and hydrazine hydrate to 104-110 DEG C simultaneously, obtain acethydrazide solution; In the addition reaction of acethydrazide solution, the methanol solution of liquefied ammonia is used to replace the methanol solution of potassium hydroxide; In the addition reaction of acethydrazide and ammonia and dithiocarbonic anhydride, first dithiocarbonic anhydride is joined in acethydrazide solution, and then add the methanol solution of liquefied ammonia.Present invention process substantially increases hydrazine speed of response, improves hydrazine reaction conversion rate, time-saving energy-saving, reduces the production cost of methyl mercapto thiadiazoles simultaneously, improves the yield of addition reaction.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, be specifically related to the preparation technology of methyl mercapto thiadiazoles.
Background technology
Methyl mercapto thiadiazoles produces Kefzol, cefcanel, cefazedone, Cephanone, cefaparole, cynnematin BL-S339, the important intermediate of the medicine such as BRL-16933, methyl mercapto thiadiazoles is pale yellow powder, due to such medicine there is antibacterial wide spectrum, good absorption, side effect are little, be particularly suited for the features such as oral absorption, be therefore widely used clinically.Its structure is as follows:
The preparation technology of current methyl mercapto thiadiazoles is through hydrazine by ethyl acetate, addition, cyclization and obtaining, concrete steps are as follows: by ethyl acetate and hydrazine hydrate in ethanolic soln at 60-70 DEG C heating reflux reaction 5 hours, again by the second alcohol and water sloughed wherein that reduces pressure, obtain acethydrazide, potassium hydroxide methanol solution is added after cooling, drip dithiocarbonic anhydride at low temperatures, stirring reaction 5-8 hour, decrease temperature crystalline, filter, filter cake uses cold methanol washing, obtain N-acetyl hydrazine dithiocarbonic acid potassium, after cryodrying, its gradation is added in the vitriol oil of low temperature, low temperature reacts, then reactant is added in frozen water, filtration obtains thiadiazoles crude product, and then carry out refining obtaining thiadiazoles finished product.But above-mentioned technique has the following disadvantages: first in ethyl acetate and hydrazine hydrate reaction process, use ethanol as reaction solvent, cause reactant concn lower, be unfavorable for that reaction is carried out, reduce speed of reaction, also need reduced pressure treatment, with removing ethanol wherein, not only time-consuming but also consume energy; Need to use potassium hydroxide and acethydrazide and dithiocarbonic anhydride to react in reaction process and form sylvite, so the potassium hydroxide that reaction uses needs a large amount of methyl alcohol to dissolve, the price of potassium hydroxide own is not low, sylvite is also dissolved in methyl alcohol, therefore can lose because being dissolved in methyl alcohol by some sylvite, therefore production cost is high, and pollutant emission is also more.
Summary of the invention
For overcoming above-mentioned the deficiencies in the prior art, after abundant research trial, the invention provides a kind of preparation technology of methyl mercapto thiadiazoles.
The preparation technology of methyl mercapto thiadiazoles provided by the invention take ethyl acetate as raw material, ethyl acetate prepares methyl mercapto thiadiazoles through hydrazine, addition, ring-closure reaction, the technical solution adopted for the present invention to solve the technical problems be ethyl acetate with hydrazine hydrate reaction process in do not use reaction solvent, improve the hydrazine temperature of ethyl acetate and hydrazine hydrate to 104-110 DEG C simultaneously, obtain acethydrazide solution; In the addition reaction of acethydrazide solution, the methanol solution of liquefied ammonia is used to replace the methanol solution of potassium hydroxide; In the addition reaction of acethydrazide and ammonia and dithiocarbonic anhydride, first joined in acethydrazide solution by dithiocarbonic anhydride, and then add the methanol solution of liquefied ammonia, the concrete technology step of the inventive method is as follows:
(1) hydrazineization reaction: add ethyl acetate and hydrazine hydrate to closed reactor, start stirring, after homo(io)thermism, be slowly warming up to 104-110 DEG C in a hour, constant temperature 2.1 hours, obtain sticky shape acethydrazide solution after cooling;
(2) addition reaction: under agitation condition, when acethydrazide solution is cooled to 10 DEG C, dithiocarbonic anhydride solution fast drop is entered in acethydrazide, when temperature of reaction rises to 25 DEG C, start the methanol solution dripping liquefied ammonia, keep temperature of reaction between 24.5-35.5 DEG C, when the rate of addition that slows down after the faint yellow ammonia salt-pepper noise of precipitation, keep reactant in yellow, the pH value of detecting reactant at any time, 7.5 are reached in after weakly alkaline until PH, be reaction end, stop the methanol solution dripping liquefied ammonia, continue to be stirred to after temperature drops to 0 DEG C, blowing suction filtration dries and obtains N-acetyl hydrazine dithiocarbonic acid ammonium,
(3) ring-closure reaction: add the vitriol oil in reactor, and control reactor temperature between 15 DEG C-17 DEG C, N-acetyl hydrazine dithiocarbonic acid ammonium addition reaction obtained evenly is sprinkled in reactor, N-acetyl hydrazine dithiocarbonic acid ammonium is 1: 3 with the molar mass ratio of the vitriol oil,, control temperature of reaction between 24.5-26.5 DEG C, after adding ammonia salt, reaction continues stirring 2.1 hours, obtains the cyclization liquid that sticky shape is white;
(4) process of cyclization liquid: drip ice cube in cyclization liquid, the sulfuric acid concentration in cyclization liquid is made to be diluted to 30%, be diluted with water to about 20% again, washing is dried by whizzer, the thiadiazoles filter cake obtained carries out low-temperature vacuum drying again, temperature is 80 DEG C, and pressure-controlling between 0.085-0.095MPa, thus obtains thiadiazoles crude product;
(5) refining: by thiadiazoles crude product through general purification, after vacuum-drying, to obtain methyl mercapto thiadiazoles finished product.
In above-mentioned hydrazineization reaction, ethyl acetate is 1: 1-1.3: 1 with the molar mass ratio of hydrazine hydrate.
In above-mentioned addition reaction, dithiocarbonic anhydride and the molar mass of acethydrazide are than 1.2: 1-1.4: 1.
Above-mentioned addition reaction temperature is preferably between 26-32 DEG C.
The advantage of employing the inventive method is:
1, do not use the reaction solvents such as ethanol in hydrazine reaction process, hydrazine temperature is increased to 104-110 DEG C simultaneously, substantially increase hydrazine speed of response, improve hydrazine reaction conversion rate, time-saving energy-saving.
2, the methanol solution of liquefied ammonia is used to replace the methanol solution of potassium hydroxide in addition reaction, thus in addition reaction, obtain N-acetyl hydrazine dithiocarbonic acid ammonium, instead of N-acetyl hydrazine dithiocarbonic acid potassium, not only reduce production cost, also improve the yield of addition reaction.
3, in addition reaction, first dithiocarbonic anhydride and acethydrazide are reacted, then the methanol solution adding liquefied ammonia reacts, such Absorbable organic halogens ground controls temperature of reaction, prevents temperature from rising too fast, generates by product, reduce addition reaction yield.
Embodiment
Example 1
(1) hydrazineization reaction: 80% hydrazine hydrate of the ethyl acetate of 184kg and 127.5kg is pumped in 500L reactor, closed reactor, start stirring, after homo(io)thermism, 107 DEG C are slowly warming up in one hour, constant temperature 2.1 hours, goes in a 1000L reactor by the sticky shape acethydrazide solution obtained after cooling;
(2) addition reaction: start stirring, when acethydrazide solution is cooled to 10 DEG C, 200kg dithiocarbonic anhydride fast drop is entered in acethydrazide solution, when temperature of reaction rises to 25 DEG C, start the methanol solution dripping liquefied ammonia, rate of addition is controlled when condenser has backflow, keep temperature of reaction at about 26-32 DEG C, slow down rate of addition after separating out faint yellow ammonia salt-pepper noise, keep reaction mass in yellow, if dropping block, reaction solution can be made to be partially red, detection reaction liquid pH value at any time, be after weakly alkaline until PH=7.5, be reaction end, stop the methanol solution dripping liquefied ammonia, continue to be stirred to after temperature drops to 0 DEG C, blowing suction filtration dries and obtains 300kgN-acetyl hydrazine dithiocarbonic acid ammonium, suction filtration solution, reclaim,
(3) ring-closure reaction: add the vitriol oil in the reactor of three 500L, and control reactor temperature between 15 DEG C-17 DEG C, N-acetyl hydrazine dithiocarbonic acid ammonium addition reaction obtained evenly is sprinkled in three 500L reactors respectively, N-acetyl hydrazine dithiocarbonic acid ammonium is 1: 3 with the molar mass ratio of the vitriol oil,, control temperature of reaction at 25 DEG C, after adding ammonia salt, reaction continues stirring 2.1 hours, obtains the cyclization liquid that sticky shape is white;
(4) process of cyclization liquid: drip ice cube in cyclization liquid, the sulfuric acid concentration in cyclization liquid is made to be diluted to 30%, be diluted with water to about 20% again, washing is dried by whizzer, the thiadiazoles filter cake obtained carries out low-temperature vacuum drying again, temperature is 80 DEG C, and pressure-controlling between 0.09MPa, thus obtains thiadiazoles crude product;
(5) refining: by thiadiazoles crude product through conventional processing such as deionized water recrystallization, activated carbon decolorizings, after vacuum-drying, to obtain methyl mercapto thiadiazoles finished product 274.2kg.
Example 2
Except the molar mass of ethyl acetate and hydrazine hydrate in hydrazineization reaction is than 1.3: 1, hydrazine temperature of reaction is 104 DEG C, addition reaction temperature is 24.5 DEG C, in addition reaction, dithiocarbonic anhydride is beyond 1.2: 1 with the molar mass ratio of acethydrazide, all the other steps, with example 1, finally obtain methyl mercapto thiadiazoles finished product 269.3kg.
Example 3
Except the molar mass of ethyl acetate and hydrazine hydrate in hydrazineization reaction is than 1.2: 1, hydrazine temperature of reaction is 110 DEG C, addition reaction temperature is 35.5 DEG C, in addition reaction, dithiocarbonic anhydride is beyond 1.4: 1 with the molar mass ratio of acethydrazide, all the other steps, with example 1, finally obtain methyl mercapto thiadiazoles finished product 270.4kg.
Claims (4)
1. the preparation technology of a methyl mercapto thiadiazoles, take ethyl acetate as raw material, ethyl acetate prepares methyl mercapto thiadiazoles through hydrazine, addition, ring-closure reaction, it is characterized in that ethyl acetate with hydrazine hydrate reaction process in do not use reaction solvent, improve the hydrazine temperature of ethyl acetate and hydrazine hydrate to 104-110 DEG C simultaneously, obtain acethydrazide solution; In the addition reaction of acethydrazide solution, the methanol solution of liquefied ammonia is used to replace the methanol solution of potassium hydroxide; In the addition reaction of acethydrazide and ammonia and dithiocarbonic anhydride, first joined in acethydrazide solution by dithiocarbonic anhydride, and then add the methanol solution of liquefied ammonia, concrete technology step is as follows:
(1) hydrazineization reaction: add ethyl acetate and hydrazine hydrate to closed reactor, start stirring, after homo(io)thermism, be slowly warming up to 104-110 DEG C in a hour, constant temperature 2.1 hours, obtain sticky shape acethydrazide solution after cooling;
(2) addition reaction: under agitation condition, when acethydrazide solution is cooled to 10 DEG C, dithiocarbonic anhydride solution fast drop is entered in acethydrazide, when temperature of reaction rises to 25 DEG C, start the methanol solution dripping liquefied ammonia, keep temperature of reaction between 24.5-35.5 DEG C, when the rate of addition that slows down after the faint yellow ammonium salt crystallization of precipitation, keep reactant in yellow, the pH value of detecting reactant at any time, 7.5 are reached in after weakly alkaline until PH, be reaction end, stop the methanol solution dripping liquefied ammonia, continue to be stirred to after temperature drops to 0 DEG C, blowing suction filtration dries and obtains N-acetyl hydrazine dithiocarbonic acid ammonium,
(3) ring-closure reaction: add the vitriol oil in reactor, and control reactor temperature between 15 DEG C-17 DEG C, N-acetyl hydrazine dithiocarbonic acid ammonium addition reaction obtained evenly is sprinkled in reactor, the mol ratio of N-acetyl hydrazine dithiocarbonic acid ammonium and the vitriol oil is 1:3, control temperature of reaction between 24.5-26.5 DEG C, after adding ammonium salt, reaction continues stirring 2.1 hours, obtains the cyclization liquid that sticky shape is white;
(4) process of cyclization liquid: drip ice cube in cyclization liquid, the sulfuric acid concentration in cyclization liquid is made to be diluted to 30%, be diluted with water to about 20% again, washing is dried by whizzer, the thiadiazoles filter cake obtained carries out low-temperature vacuum drying again, temperature is 80 DEG C, and pressure-controlling between 0.085-0.095MPa, thus obtains thiadiazoles crude product;
(5) refining: by thiadiazoles crude product through general purification, after vacuum-drying, to obtain methyl mercapto thiadiazoles finished product.
2. the preparation technology of methyl mercapto thiadiazoles according to claim 1, is characterized in that the mol ratio of ethyl acetate and hydrazine hydrate in hydrazineization reaction is 1:1-1.3:1.
3. the preparation technology of methyl mercapto thiadiazoles according to claim 1, is characterized in that the mol ratio 1.2:1-1.4:1 of dithiocarbonic anhydride and acethydrazide in addition reaction.
4. the preparation technology of methyl mercapto thiadiazoles according to claim 1, is characterized in that addition reaction temperature is preferably between 26-32 DEG C.
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| CN103360337B (en) * | 2013-07-11 | 2016-04-27 | 浙江海蓝化工集团有限公司 | A kind of 2-sulfydryl-5-methyl isophthalic acid, the preparation method of 3,4-thiadiazoles |
| CN111925340A (en) * | 2019-12-16 | 2020-11-13 | 山东金城柯瑞化学有限公司 | Preparation process of methyl mercapto thiadiazole |
| CN114380770B (en) * | 2021-12-24 | 2022-12-09 | 山东艾孚特科技有限公司 | Synthesis process of methyl mercapto thiadiazole catalyzed by solid superacid |
| CN115466197A (en) * | 2022-09-14 | 2022-12-13 | 浙江新码生物医药有限公司 | Method for synthesizing acethydrazide |
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| CN102219758A (en) * | 2011-08-01 | 2011-10-19 | 山东济宁裕鑫精细材料有限公司 | Synthesis method of 2-methyl-5-sulfydryl-1,3,4-thiadiazole |
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| CN102659715A (en) * | 2012-04-17 | 2012-09-12 | 黑龙江豪运精细化工有限公司 | Preparation method of 5-methyl-2-mercapto-1,3,4-thiadiazole |
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| CN102775370A (en) * | 2011-05-11 | 2012-11-14 | 中国科学院海洋研究所 | Thiazole compound, its preparation and application |
| CN102219758A (en) * | 2011-08-01 | 2011-10-19 | 山东济宁裕鑫精细材料有限公司 | Synthesis method of 2-methyl-5-sulfydryl-1,3,4-thiadiazole |
| CN102285941A (en) * | 2011-09-01 | 2011-12-21 | 信诺美（北京）化工科技有限公司 | 2-sulfydryl-4,5-dimethyl-1,3,4,-thiadiazole and lithium salt and diplont thereof, and synthesis methods thereof |
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