CN101412699A - Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate - Google Patents
Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate Download PDFInfo
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Abstract
The invention provides a method for preparing 2-(3-formaldehyde base-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate. The method uses para-cyano-phenol and thioacetamide as raw materials which are reacted with each other to obtain 4-hydroxy-thiobenzamide, and the obtained product is reacted with 2-chloro acetylacetic ether to obtain 2-(4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate, and then is reacted with urotropine to obtain the 2-(3-formaldehyde base-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of a kind of 2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester.
Background technology
2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester is the important intermediate in anti-antihyperuricemic disease drug Febustat (Febuxostat) building-up process, and its structure is as shown in the formula shown in (1).
JP1045733 and JP11060552 have reported the synthetic method of formula I compound, with 4-hydroxybenzonitrile and thioacetamide is raw material, in polyphosphoric acid, carry out the Hantzch reaction and obtain 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester with the 2-chloroacetyl acetacetic ester, be reflected at 85 ℃, shown in II.Formula II compound and urotropine carry out Duff-Bills reaction in 80 ℃ in polyphosphoric acid then, obtain formula I compound after treatment.
Among the preparation method that this synthetic route provided, the yield of formula II compound is lower, only is 46%, is 70% by the yield of formula II compound formula I compound, and this makes preparation cost increase undoubtedly; And in the two-step reaction of preparation I compound, all used polyphosphoric acid, in aftertreatment, can produce a large amount of three wastes materials.
Document The chemistry of Hereocyclic compounds:Thiazole and itsderivative, 1979, put down in writing preparation technology with thioamide analog compound synthetizing thiazolium lopps derivative at 34 (1): 165, wherein mention, adopt ethanol, 1, the 4-dioxane can obtain the similar thiazole ring analog derivative with formula II as solvent during thiophosphoric anhydride catalysis, yield reaches as high as 85%.
In addition, according to summary, can learn that the mechanism of Hantzsch reaction is as follows to above-mentioned document:
In addition, described Duff-Bills reaction is that phenolic compound is introduced a kind of method of aldehyde radical on an ortho position or a position.In document JP 1045733 with PPA as solvent, yield still can (70%), but aftertreatment is loaded down with trivial details, three wastes material generation is big, and PPA is mobile poor, produces in enormous quantities relatively more difficult.
Pertinent literature Tetrehedron 1968,24:5001 and J.Org.Chem, 1972,37 (24): 3972 report Duff-Bills use acetic acid, boric acid/glycerine, trifluoroacetic acid as reaction solvent more, wherein be generally about 50% as the yield of solvent with acetic acid, boric acid/glycerine, yield higher (95%) when trifluoroacetic acid is made solvent, but be mainly the product of phenolic hydroxyl group contraposition.
The reaction mechanism of Duff-Bills is as follows:
Summary of the invention:
The object of the present invention is to provide the synthetic method of a kind of 2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester.
In the preparation method shown in the documents JP1045733, thioacetamide and 4-hydroxybenzonitrile reaction generate the 4-hydroxyl-thiobenzamide shown in the formula III, and it carries out cyclization with the 2-chloroacetyl acetacetic ester again and obtains thiazole ring.
The key of synthetizing thiazolium ring is the stability of thioamides in reaction process, and thioamides is unstable under acidic condition usually.Based on theoretical investigation and actual analysis result, the contriver thinks that the major cause that the Hantzsch reaction yield is low shown in the document JP 1045733 has been to use this acid solvent of PPA, cause the hydroxyl of 4-shown in the formula III-thiobenzamide to decompose, thereby caused yield to reduce.
In document JP 1045733 and the described preparation technology of JP11060552,4-hydroxybenzonitrile and thioacetamide are after acid solvent PPA reaction obtains 4-hydroxyl thiobenzamide, directly add 2-chloroacetyl acetacetic ester continuation reaction without separating, finally obtain 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, yield only is 46%.Though 4-hydroxybenzonitrile and thioacetamide are to generate 4-hydroxyl thiobenzamide in acid solvent PPA, this is reflected at mild conditions and can finishes, and for example, it is under the temperature about 40 ℃.And follow-up obtain the higher temperature of reaction of process need of 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester with 4-hydroxyl thiobenzamide and the reaction of 2-chloroacetyl acetacetic ester, for example 70 ℃.When temperature raise, it is unstable that above-mentioned product 4-hydroxyl thiobenzamide will become in sour environment, and it decomposes easily.This might be the lower reason of yield.
Given this, the present invention mainly adopts following two kinds of measures that described Hantzsch reaction is improved:
React in two steps: promptly obtain the 4-hydroxyl-thiobenzamide shown in the formula III with thioacetamide and 4-hydroxybenzonitrile reaction at first individually; And then with formula III compound and 2-chloroacetyl acetacetic ester in nonacid environment, ethanol or 1 for example, cyclization obtains the 2-shown in the formula II (4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester in the 4-dioxane.Can avoid formula III compound self decomposing in reaction process like this, increase the yield of formula II compound, owing to do not re-use polyphosphoric acid, also reduce the discharging of three wastes materials simultaneously.
In addition, react about the Duff-Bills described in the background technology, behind combining with theoretical analysis and practical study result, the contriver thinks, acetic acid, the reason that boric acid system yield is lower may be that its acidity is strong inadequately, after adopting trifluoroacetic acid, yield can significantly improve, though its para-selectivity is stronger, but the synthetic route that the present invention relates to adopts raw material 2-(4-hydroxy phenyl)-4-methyl-5 thiazole ethyl formate contraposition to have the thiazole ring substituting group, replaces aldehyde compound so can estimate unique ortho position that obtains.
Particularly, synthetic method provided by the invention is, with 4-hydroxybenzonitrile and thioacetamide is that raw material reaction obtains the formula III compound, products therefrom not purified directly and the 2-chloroacetyl acetacetic ester react and obtain formula II compound, and then react in trifluoroacetic acid with urotropine and to obtain formula I compound.
In the process that obtains the formula III compound, 4-hydroxybenzonitrile and thioacetamide react in being connected with the organic solvent of hydrogen chloride gas, and described organic solvent comprises one or more following solvent: DMF, ethanol, methyl alcohol etc.Because the products therefrom yield is the highest in DMF, solvent is also recyclable, so preferably use DMF as reaction solvent.Temperature of reaction is 20～80 ℃, and the reaction times is 24～48 hours.
In the process that obtains formula II compound, it is characterized in that formula III compound and 2-chloroacetyl acetacetic ester react in organic solvent, organic solvent comprises one or more following solvents: ethanol, methyl alcohol, ethyl acetate, dioxane, because ethanol is made solvent yield height, help reducing production costs, so preferred alcohol, temperature of reaction are 60～80 ℃.
In the process that obtains formula I compound, it is characterized in that formula II compound and urotropine react in trifluoroacetic acid.Temperature of reaction is 80～120 ℃, because reaction is more complete in the time of 100 ℃, and does not have impurity to produce, so preferred 100 ℃, the reaction times is 12～24 hours.
The present invention is through having following advantage to the improvement of technology: 1. yield significantly improves, and the yield of compound shown in the preparation formula I is increased to about 97% by 78%, and the yield of compound shown in the preparation formula II is increased to about 70% by 46%.2. avoid the use polyphosphoric acid as reaction solvent, reduced the discharging of the three wastes.3. reacting used DMF, trifluoroacetic acid can recovery set usefulness, has reduced production cost.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
In the following example, unified with (1) expression 2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester for simplicity, (2) expression 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, (3) expression 4-hydroxyl thiobenzamide.
The preparation of embodiment 1:4-hydroxyl thiobenzamide (3)
In the 5L reaction flask, with 4-hydroxybenzonitrile 400g, thioacetamide 584g adds saturated HCl/DMF solution 4000ml.In 40 ℃ of reactions 48 hours, TLC showed that reaction is complete substantially, was concentrated into driedly, added saturated Na
2CO
3Solution 1350ml stirred 2 hours, filtered, dry brown solid (3) 465.8g.Yield 87.6%.
The preparation of embodiment 2:2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (2)
4-hydroxyl thiobenzamide (3) 465.8g and dehydrated alcohol 2.8L are added in the 5L reaction flask, be heated to 60 ℃, drip 2-chloroacetyl acetacetic ester 560g, refluxed then 2 hours.Stir then down and be cooled to 10 ℃, filtration, washing with alcohol, dry yellow solid (2) 721.1g, yield 80.6%.
The preparation of embodiment 3:2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (1)
(2) 120g, urotropine 63.8g and trifluoroacetic acid 660ml are added in the 3L reaction flask, be heated to 100 ℃ of reactions 24 hours, then reaction solution is concentrated into driedly, add entry 2L and stirred 5 hours, filtering drying gets 126.5g yellow solid (1), yield 95.3%.
The preparation of embodiment 4:4-hydroxyl thiobenzamide (3)
In the 1L reaction flask, with 4-hydroxybenzonitrile 40g, thioacetamide 58.4g adds saturated HCl/ methanol solution 400ml.In 20 ℃ of reactions 48 hours, TLC showed that reaction is complete substantially, was concentrated into driedly, added saturated Na
2CO
3Solution to pH be 7～8, stirred 2 hours, filter, dry brown solid (3) 38g.Yield 71.5%.
The preparation of embodiment 5:2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (2)
4-hydroxyl thiobenzamide (3) 38g and dehydrated alcohol 200ml are added in the 500ml reaction flask, be heated to 80 ℃, drip 2-chloroacetyl acetacetic ester 45.7g, refluxed then 2 hours.Stir then down and be cooled to 10 ℃, filtration, washing with alcohol, dry yellow solid (2) 46.7g, yield 70.5%.
The preparation of embodiment 6:2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (1)
(2) 46.7g, urotropine 24.8g and trifluoroacetic acid 250ml are added in the 500ml reaction flask, be heated to 80 ℃ of reactions 24 hours, then reaction solution be concentrated into driedly, add entry 800ml and stirred 5 hours, filtering drying gets 43.9g orange/yellow solid (1), yield 85%.
The preparation of embodiment 7:4-hydroxyl thiobenzamide (3)
In the 1L reaction flask, with 4-hydroxybenzonitrile 40g, thioacetamide 58.4g adds saturated HCl/ ethanolic soln 400ml.In 80 ℃ of reactions 48 hours, TLC showed that reaction is complete substantially, was concentrated into driedly, added saturated Na
2CO
3Solution is regulated pH to 7～8, stirred 2 hours, filtration, dry brown solid (3) 41g.Yield 77.1%.
The preparation of embodiment 8:2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (2)
With 4-hydroxyl thiobenzamide (3) 41g and 1,4-dioxane 300ml adds in the 500ml reaction flask, is heated to 80 ℃, drips 2-chloroacetyl acetacetic ester 49g, refluxes then 2 hours.Stir then down and be cooled to 10 ℃, filtration, washing with alcohol, dry yellow solid (2) 49.3g, yield 69%.
The preparation of embodiment 9:2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (1)
(2) 49.3g, urotropine 26.2g and trifluoroacetic acid 270ml are added in the 500ml reaction flask, be heated to 120 ℃ of reactions 24 hours, then reaction solution be concentrated into driedly, add entry 800ml and stirred 5 hours, filtering drying gets 35.8g yellow solid (1), yield 65.5%.
The preparation of embodiment 10:4-hydroxyl thiobenzamide (3)
In the 1L reaction flask, with 4-hydroxybenzonitrile 40g, thioacetamide 58.4g adds saturated HCl/ methanol solution 200ml and saturated HCl/DMF solution 200ml.In 40 ℃ of reactions 48 hours, reaction solution was concentrated into dried, adds saturated Na
2CO
3Solution to pH be 7～8, stirred 2 hours, filter, dry brown solid (3) 36g.Yield 37.7%.
The preparation of embodiment 11:2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (2)
In 4-hydroxyl thiobenzamide (3) 36g and dehydrated alcohol 100ml and 1.4-dioxane 100ml adding 500ml reaction flask, be heated to 80 ℃, drip 2-chloroacetyl acetacetic ester 45.7g, refluxed then 2 hours.Stir then down and be cooled to 10 ℃, filtration, washing with alcohol, dry yellow solid (2) 41g, yield 65.6%.
The preparation of embodiment 12:2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester (1)
In (2) 41g, urotropine 21.8g and trifluoroacetic acid 20ml and Glacial acetic acid 200ml adding 500ml reaction flask, be heated to 100 ℃ of reactions 24 hours, then reaction solution be concentrated into driedly, add entry 700ml and stirred 5 hours, filtering drying gets 32g orange/yellow solid (1), yield 70.6%.
Claims (11)
1, the preparation method of a kind of 2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, the reaction process of this method is as follows:
With 4-hydroxybenzonitrile and thioacetamide is raw material, reaction obtains the 4-hydroxyl thiobenzamide shown in the formula III, gained formula III compound and the reaction of 2-chloroacetyl acetacetic ester obtain the 2-shown in the formula II (4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, formula II compound obtains the 2-shown in the formula I (3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester with the urotropine reaction more then, it is characterized in that:
Among the described preparation technology, 4-hydroxyl thiobenzamide and 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester is successively synthetic separately step by step, promptly separately synthetic earlier 4-hydroxyl thiobenzamide, be raw material further Synthetic 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester in nonacid environment with it then, avoid the latter's self decomposing in reaction process.
2. preparation method according to claim 1, it is characterized in that, 4-hydroxybenzonitrile and thioacetamide react in being connected with the organic solvent of hydrogen chloride gas, generate 4-hydroxyl thiobenzamide, and described organic solvent is selected from one or more following solvent: DMF, ethanol, methyl alcohol.
3. preparation method according to claim 2 is characterized in that described solvent is DMF.
4. according to claim 2 or 3 described preparation methods, it is characterized in that the condition that described 4-hydroxybenzonitrile and thioacetamide react is, temperature of reaction is 20～80 ℃, and the reaction times is 24～48 hours.
5. preparation method according to claim 1, it is characterized in that, described 4-hydroxyl thiobenzamide and 2-chloroacetyl acetacetic ester react in organic solvent and obtain 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester, and described organic solvent is selected from one or more following solvents: ethanol, methyl alcohol, ethyl acetate, dioxane.
6. preparation method according to claim 5 is characterized in that described organic solvent is an ethanol.
7. according to claim 5 or 6 described preparation methods, it is characterized in that the condition that described 4-hydroxyl thiobenzamide and 2-chloroacetyl acetacetic ester react is, temperature of reaction is 60～80 ℃, and the reaction times is 24～48 hours.
8. preparation method according to claim 1, it is characterized in that, 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester and urotropine react Synthetic 2-(3-carboxaldehyde radicals-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester in acid organic solvent, described acid organic solvent is selected from trifluoroacetic acid, acetic acid or its combination.
9. preparation method according to claim 8 is characterized in that, described acid organic solvent is a trifluoroacetic acid.
10. according to Claim 8 or 9 described preparation methods, it is characterized in that the condition that described 2-(4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester and urotropine react is, temperature of reaction is 80～120 ℃, and the reaction times is 12～24 hours.
11. preparation method according to claim 10 is characterized in that, described temperature of reaction is 100 ℃.
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| CN101921243A (en) * | 2010-08-14 | 2010-12-22 | 青岛黄海制药有限责任公司 | Method for preparing 2-(3-formacyl-4-isobutoxyphenyl)-4-methyl-1,3 thiazole-5-carboxylic acid ethyl ester |
| WO2011031409A1 (en) | 2009-09-10 | 2011-03-17 | Teva Pharmaceutical Industries Ltd. | Processes for preparing febuxostat |
| CN102002017A (en) * | 2010-11-02 | 2011-04-06 | 北京赛科药业有限责任公司 | Method for preparing febuxostat intermediate |
| WO2011066803A1 (en) * | 2009-12-04 | 2011-06-09 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediate of febuxostat |
| CN102702054A (en) * | 2012-06-29 | 2012-10-03 | 晋城海斯制药有限公司 | Preparation method of p-hydroxythiobenzamide |
| CN103030605A (en) * | 2012-12-14 | 2013-04-10 | 贵州信邦制药股份有限公司 | Preparation method and detection method of febuxostat raw material |
| CN103304512A (en) * | 2013-06-04 | 2013-09-18 | 华南理工大学 | Preparation method for febuxostat |
| EP2718272A2 (en) | 2011-06-06 | 2014-04-16 | Hetero Research Foundation | Process for febuxostat |
| CN104163782A (en) * | 2013-05-17 | 2014-11-26 | 重庆圣华曦药业股份有限公司 | Preparation method of 3,4-substitituted thiobenzamide and application of 3,4-substitituted thiobenzamide in febuxostat synthesis |
| CN104418823A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Preparation method of febuxostat intermediate |
| CN104529935A (en) * | 2014-12-23 | 2015-04-22 | 浙江华义医药有限公司 | Method for synthesizing high-purity ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate |
| CN108033929A (en) * | 2017-12-27 | 2018-05-15 | 青岛黄海制药有限责任公司 | A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity |
| CN109354584A (en) * | 2018-10-15 | 2019-02-19 | 湖北理工学院 | The method of one pot process 2- (4- hydroxy phenyl) -4- methyl-1,3-thiazole-5-carboxylic acid ethyl ester |
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2007
- 2007-10-19 CN CN 200710047267 patent/CN101412699A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011031409A1 (en) | 2009-09-10 | 2011-03-17 | Teva Pharmaceutical Industries Ltd. | Processes for preparing febuxostat |
| CN102086169B (en) * | 2009-12-04 | 2014-01-15 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediates of Febuxostat |
| WO2011066803A1 (en) * | 2009-12-04 | 2011-06-09 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediate of febuxostat |
| CN101921243A (en) * | 2010-08-14 | 2010-12-22 | 青岛黄海制药有限责任公司 | Method for preparing 2-(3-formacyl-4-isobutoxyphenyl)-4-methyl-1,3 thiazole-5-carboxylic acid ethyl ester |
| CN102002017B (en) * | 2010-11-02 | 2012-09-26 | 华润赛科药业有限责任公司 | Method for preparing febuxostat intermediate |
| CN102002017A (en) * | 2010-11-02 | 2011-04-06 | 北京赛科药业有限责任公司 | Method for preparing febuxostat intermediate |
| EP2718272A2 (en) | 2011-06-06 | 2014-04-16 | Hetero Research Foundation | Process for febuxostat |
| CN102702054A (en) * | 2012-06-29 | 2012-10-03 | 晋城海斯制药有限公司 | Preparation method of p-hydroxythiobenzamide |
| CN103030605A (en) * | 2012-12-14 | 2013-04-10 | 贵州信邦制药股份有限公司 | Preparation method and detection method of febuxostat raw material |
| CN104163782A (en) * | 2013-05-17 | 2014-11-26 | 重庆圣华曦药业股份有限公司 | Preparation method of 3,4-substitituted thiobenzamide and application of 3,4-substitituted thiobenzamide in febuxostat synthesis |
| CN103304512A (en) * | 2013-06-04 | 2013-09-18 | 华南理工大学 | Preparation method for febuxostat |
| CN104418823A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Preparation method of febuxostat intermediate |
| CN104529935A (en) * | 2014-12-23 | 2015-04-22 | 浙江华义医药有限公司 | Method for synthesizing high-purity ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate |
| CN104529935B (en) * | 2014-12-23 | 2017-04-12 | 浙江华义医药有限公司 | Method for synthesizing ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate |
| CN108033929A (en) * | 2017-12-27 | 2018-05-15 | 青岛黄海制药有限责任公司 | A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity |
| CN109354584A (en) * | 2018-10-15 | 2019-02-19 | 湖北理工学院 | The method of one pot process 2- (4- hydroxy phenyl) -4- methyl-1,3-thiazole-5-carboxylic acid ethyl ester |
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