CN103304512A - Preparation method for febuxostat - Google Patents
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- CN103304512A CN103304512A CN2013102200031A CN201310220003A CN103304512A CN 103304512 A CN103304512 A CN 103304512A CN 2013102200031 A CN2013102200031 A CN 2013102200031A CN 201310220003 A CN201310220003 A CN 201310220003A CN 103304512 A CN103304512 A CN 103304512A
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Abstract
The invention discloses a preparation method for febuxostat. The preparation method for febuxostat comprises the following steps of: by using 4-hydroxybenzonitrile and thioacetamide as raw materials, and reacting in hydrochloric acid solution to prepare 4-hydroxythiobenzamide; carrying out a reaction on 4-hydroxythiobenzamide and 2-chloroacetoacetic acid ethyl ester to prepare 2-(4-hydroxylphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester; carrying out a reaction on the obtained compound and hexamine in the mixed acid system of methanesulfonic acid and trifluoroacetic acid to prepare 2-(3-formyl-4-hydroxylphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester; synthesising 2-(3-nitrile-4-isobutoxylphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester from the compound, hydroxylamine hydrochloride, potassium carbonate, iso-butyl bromide and the like in a polar protonic solvent via a one-pot method; and finally hydrolyzing in an alkaline condition to obtain the target product, namely, febuxostat. The total yield of the preparation method for febuxostat disclosed by the invention is increased to 66%, the separation steps are reduced, any extremely toxic substance is not involved, and the environmental pollution is less.
Description
Technical field
The invention belongs to the chemical pharmaceutical field, relate in particular to the preparation method of Febuxostat.
Background technology
Febuxostat (English name: Febuxostat, chemical name: 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid), it is a kind of selectivity xanthine oxidase inhibitor of Japanese Teijin company exploitation, xanthine oxidoreductase enzyme (XOR) is shown preferably inhibition activity, but can not act on other relevant enzyme in purine and the pyrimidine metabolic approach simultaneously, can not affect the eubolism of purine and pyrimidine.Compare other treatment gout medicine, the Febuxostat side effect still less, therefore, Febuxostat is subject to people as third generation anti-gout drugs after Zyloric and probenecid and pays close attention to widely.
Synthesis technique about Febuxostat has had a lot of documents and patent report:
Patent EP 0513379 has reported take 4-chloro-3-nitrobenzonitrile as raw material, generate itrile group with the Hydrochloride Hydroxylamine Oximation dehydration, it is at the N of hydrogenchloride, generate 3-nitro-4-hydroxyl thiobenzamide with the thioacetamide reaction in dinethylformamide (DMF) solution, generate thiazole ring with the cyclization of 2-chloroacetyl acetacetic ester again, the Williamson etherification reaction occurs under sodium hydride catalysis with isobutane bromide, its product generates amido through hydrogen reducing, amido and Sodium Nitrite generation diazotization reaction, the Sandmeyer reaction occurs under cuprous cyanide and potassium cyanide condition generate itrile group, at last hydrolysis obtains final product.
Patent JP10045733 has reported take 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester as raw material; under the effect of vulkacit H and polyphosphoric acid, obtain compound 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester; itself and Hydrochloride Hydroxylamine Oximation dehydration reaction generate 2-(3-itrile group-4-isobutoxy-phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester; at last hydrolysis obtains final product; the intermediate that per step of the method generates all needs to have increased the manipulation strength of actual industrial production through the silicagel column purifying.
Patent WO066803A1 has reported the synthetic of relevant intermediate 4-hydroxyl thiobenzamide.In hydrogen bromide or hydrochloride aqueous solution, react generation intermediate 4-hydroxyl thiobenzamide with 4-hydroxy-phenylformonitrile and thioformamide; Patent IN201000610-I3 has reported the synthetic of intermediate 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester.Take 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester and vulkacit H as raw material, reaction generates 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester in polyphosphoric acid and methanesulfonic.
Synthetic (the Zheng Fan of document Febuxostat; Qian Shan etc. Chinese Journal of Pharmaceuticals; 2009; 40 (10): 369-372) reported take the 4-hydroxy-phenylformonitrile as raw material; under the condition of polyphosphoric acid, react generation 4-hydroxyl thiobenzamide with thioacetamide; carry out the Duff reaction with vulkacit H again after itself and the cyclization of 2-chloroacetyl acetacetic ester and obtain 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl-5-thiazole formic acid ethyl ester; again through oxammonium hydrochloride/sodium methylate reaction; the isobutyl bromide etherification reaction; alkaline hydrolysis; make the antigout drug Febuxostat, total recovery is 28%.
The synthetic method total recovery of the Febuxostat of above-mentioned report is all lower, generally 20%～40%.Except yield is low, often use the highly toxic substances such as cuprous cyanide, potassium cyanide in the itrile group introducing in the reaction process, the introducing of aldehyde radical and thioamides is also carried out in the polyphosphoric acid of being everlasting, and has increased like this operation easier of aftertreatment, and is also unfavorable to environment.
Summary of the invention
Shortcoming for above technique exists the object of the present invention is to provide a kind of method for preparing Febuxostat (I).When introducing thioamides, use instead under the condition of thioacetamide at concentrated hydrochloric acid and carry out; When phenyl ring is introduced itrile group, use instead and under the condition of methanesulfonic and trifluoroacetic acid, introduce formyl radical first; again formyl radical is converted into itrile group; substituted cuprous cyanide; the problem of the hypertoxic hazardous substance such as potassium cyanide, polyphosphoric acid and operational difficulty; and integrated artistic is simple to operate; need not column chromatography, total recovery is higher.
Purpose of the present invention is achieved through the following technical solutions:
A kind of preparation method of Febuxostat comprises the steps:
(1) take 4-hydroxy-phenylformonitrile, thioacetamide as raw material, heat in hydrochloric acid soln, mechanical stirring was reacted 2～6 hours, and cooling crystallization filters and obtains 4-hydroxyl thiobenzamide (III);
(2) 4-hydroxyl thiobenzamide (III) is dissolved in the alcohol solvent, reflux, drip the 2-chloroacetyl acetacetic ester, react after 3～7 hours, add in the ice-water bath, leave standstill cooling crystallization, filtration drying namely gets 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (IV);
(3) with methanesulfonic and trifluoroacetic acid by volume (5～13): 1 mixes, 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (IV) is joined in the above-mentioned mixing solutions, be heated to 70～110 ℃, add vulkacit H under the mechanical stirring in batches, after reacting 6～10 hours, add saturated ice salt solution, stirring and crystallizing, filter, obtain 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (V);
(4) 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (V) is dissolved in the polar protic solvent, add behind the oxammonium hydrochloride after the room temperature reaction 1 hour, add Acetyl Chloride 98Min., heat 60～100 ℃, react stopped reaction after 2～6 hours, be cooled to room temperature, then add Anhydrous potassium carbonate, stirring at room adds isobutane bromide after half an hour, heat 80～120 ℃, react after 4～8 hours, add in the ice-water bath and cool off, stirring and crystallizing is filtered to get 2-(3-itrile group-4-isobutoxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (VI);
(5) 2-(3-itrile group-4-isobutoxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester (VI) is dissolved in the mixed solution of tetrahydrofuran (THF) and dehydrated alcohol, add inorganic alkali solution, reacted 0.5～2 hour, removal of solvent under reduced pressure, regulating the extremely a large amount of solids of pH separates out, filter, get Febuxostat crude product (I);
(6) the Febuxostat crude product is carried out recrystallization, obtain the Febuxostat elaboration.
The present invention is as follows about the concrete synthesis route of Febuxostat (I):
Preferably, the described hydrochloric acid soln of step (1) is concentrated hydrochloric acid (more than the concentration 2mol/L).
Preferably, the described temperature of reaction of step (1) is 50 ℃, and the reaction times is 4 hours.
Preferably, the volume ratio that the described methanesulfonic of step (3) and trifluoroacetic acid mix is (6～12): 1, and optimum ratio is 9:1.
Preferably, 90 ℃ of the described heating of step (3) were reacted 8 hours.
Preferably, the mol ratio of the described 2-of step (3) (4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester and vulkacit H is 1:(1.5～3);
Preferably, step (3) vulkacit H is to add in batches (general every minor tick half an hour).
Preferably, the temperature of the previous reaction of step (4) is 80 ℃, and the reaction times is 4 hours; The temperature of a rear reaction is 90 ℃, and the reaction times is 8 hours.
Preferably, the described polar protic solvent of step (4) is DMF, dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide.
Preferably, the described inorganic alkali solution of step (5) is barium hydroxide solution, sodium hydroxide solution, potassium hydroxide solution, magnesium hydroxide solution or lithium hydroxide solution.
Preferably, the described recrystallization of step (5) is that the Febuxostat crude product is dissolved in methylene dichloride, adds activated carbon decolorizing, filters, and is spin-dried for solvent, and the mixed solvent that adds methylene dichloride and methyl alcohol carries out recrystallization.
The present invention finds in the synthesis technique of Febuxostat: in the first step reaction, along with the increase of concentration of hydrochloric acid, yield improves, in the three-step reaction, and reaction times, temperature, the nitration mixture ratio all has considerable influence to reaction yield.Concrete data is as follows:
1, the concentration of hydrochloric acid is very large on the impact of yield in the first step, and yield increases along with the increase of concentration of hydrochloric acid, and concrete data see the following form 1.
2, in the three-step reaction, the ratio of reaction times, temperature of reaction, methanesulfonic and trifluoroacetic acid all affects larger on reaction yield, and concrete data see Table respectively 2,3,4.
In sum, what the present invention had determined that the reaction of the first step among this preparation method uses is concentrated hydrochloric acid, and considering the three-step reaction optimum reaction condition from save energy and equipment corrosion two aspects is 8 hours, 90 ℃, and V
(methanesulfonic): V (
Trifluoroacetic acid)=9:1.
Compare with the Febuxostat preparation method who has now reported, the present invention has following beneficial effect:
(1) raw materials cost is low, adopts " one kettle way " synthetic during preparation intermediate VI, has reduced operating procedure;
(2) reaction conditions is safe, gentle, does not introduce highly toxic substance, has improved simultaneously the puzzlement of the difficult treatment that the use polyphosphoric acid caused when formyl radical was introduced, and is conducive to industry's enlarging production;
(3) to need not silicagel column refining for the intermediate that generates of reaction, can be directly used in next step reaction;
(4) total recovery of reaction has brought up to 66%.
Description of drawings
Fig. 1 is that the embodiment of the invention 1 makes Febuxostat
1H-NMR figure;
Fig. 2 is that the embodiment of the invention 1 makes Febuxostat
13C-NMR figure.
Embodiment
Below in conjunction with specific embodiment the present invention is done further concrete detailed description the in detail, but embodiments of the present invention are not limited to this, the processing parameter for not indicating especially can carry out with reference to routine techniques.
Embodiment 1
A kind of preparation method of Febuxostat, concrete steps are as follows:
(1) in flask, adds 200mL concentrated hydrochloric acid (concentration 12mol/L), add thioacetamide 13.0g under the mechanical stirring, add until completely dissolved 4-hydroxy-phenylformonitrile 10.0g, 50 ℃ were stirred 4 hours, and cooling has a large amount of solids to separate out, filter, with being washed on a small quantity neutrality, dry intermediate (III) 12.3g, the yield 95.8% of getting.
(2) intermediate III 12.3g is dissolved in the dehydrated alcohol of 60mL, be heated to backflow, slowly drip 2-chloroacetyl acetacetic ester 14.2g, continue to reflux 5 hours, question response is complete, adds in the ice-water bath and cools off, a large amount of solids are separated out, filter dry yellow solid intermediate compound IV 20.4g, the yield 96.0% of getting.
(3) intermediate compound IV 20.4g is dissolved in the mixed solution of 90mL methanesulfonic and 10mL trifluoroacetic acid, be heated to 90 ℃, mechanical stirring lower minute three times (interval half an hour) adds vulkacit H 27.9g altogether, continues reaction 8 hours, question response is complete, add 300mL ice salt solution, stirred 1 hour, have a large amount of yellow solids to separate out, filter, be washed to neutrality, dry intermediate V19.3g, the yield 85.2% of getting.
(4) intermediate V19.3g is dissolved among the DMSO of 110mL, adds oxammonium hydrochloride 9.0g, stirs 1 hour under the room temperature, then slowly add Acetyl Chloride 98Min. 10.5g, 80 ℃ were reacted cool to room temperature 4 hours down, add salt of wormwood 27.4g, reacted 30 minutes, then continue to add isobutane bromide 17.8g, be warmed up to 90 ℃ of reactions 6 hours after adding, add in the 600mL ice-water bath and cool off, have a large amount of faint yellow solids to separate out (intermediate VI), filter, dry 19.3g, the yield 84.5% of getting.
(5) intermediate VI19.3g is dissolved in the mixing solutions of 200mL tetrahydrofuran (THF) and 60mL dehydrated alcohol, slowly adds the 80mL massfraction and be 8.0% barium hydroxide solution, reacts 1 hour, regulate pH to 2～3, there are a large amount of solids to separate out, filter, the dry faint yellow solid that gets.The gained solid is dissolved in methylene dichloride, adds proper amount of active carbon and stirred 2 hours, filter, reclaim solvent and get white solid.The gained solid is added in the mixed solution of 80mL methylene dichloride and 200mL methyl alcohol, then heating for dissolving is cooled to 0 ℃ and stirred 1 hour, filters, dry 17.5g, the yield 99.3% of getting.
1H NMR (400MHz, DMSO-d
6) δ 13.47 (s, 1H), 8.30 (d, J=2.3Hz, 1H), 8.23 (dd, J=8.9,2.4Hz, 1H), 7.38 (d, J=9.0Hz, 1H), (4.01 d, J=6.5Hz, 2H), 2.66 (s, 3H), 2.10 (hept, J=6.6Hz, 1H), (1.02 d, J=6.7Hz, 6H).
13C NMR (100MHz, DMSO-d
6) δ 16.97,18.65,27.55,75.05,101.47,113.73,115.30,122.84,125.27,131.38,132.91,159.44,161.95,162.78,166.07.(sees accompanying drawing 1,2).
Embodiment 2
The difference of the present embodiment and embodiment 1 is:
In flask, add 200mL dilute hydrochloric acid (concentration 3mol/L), add thioacetamide 13.0g under the mechanical stirring, add until completely dissolved 4-hydroxy-phenylformonitrile 10.0g, 50 ℃ were stirred 4 hours, and cooling has a large amount of solids to separate out, filter, with being washed on a small quantity neutrality, dry 9.8g, the yield of 4-hydroxyl thiobenzamide is 76.6%.
Embodiment 3
The difference of the present embodiment and embodiment 1 is:
Intermediate compound IV 20.4g is dissolved in the trifluoroacetic acid of 110mL methanesulfonic and 10mL; be heated to 90 ℃; mechanical stirring lower minute three times (interval half an hour) adds vulkacit H 27.9g altogether, continues reaction 8 hours, adds 300mL ice salt solution; stirred 1 hour; there are a large amount of yellow solids to separate out, filter, be washed to neutrality; the dry 16.7g that gets, the yield of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is 74.9%.
Embodiment 4
The difference of the present embodiment and embodiment 1 is:
Intermediate compound IV 20.4g is dissolved in the trifluoroacetic acid of 70mL methanesulfonic and 10mL; be heated to 90 ℃; mechanical stirring lower minute three times (interval half an hour) adds vulkacit H 27.9g altogether, continues reaction 8 hours, adds 300mL ice salt solution; stirred 1 hour; there are a large amount of yellow solids to separate out, filter, be washed to neutrality; the dry 19.4g that gets, the yield of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is 85.5%.
Embodiment 5
The difference of the present embodiment and embodiment 1 is:
Intermediate compound IV 20.4g is dissolved in the trifluoroacetic acid of 90mL methanesulfonic and 10mL; be heated to 90 ℃; mechanical stirring lower minute three times (interval half an hour) adds vulkacit H 27.9g altogether, continues reaction 6 hours, adds 300mL ice salt solution; stirred 1 hour; there are a large amount of yellow solids to separate out, filter, be washed to neutrality; the dry 15.3g that gets, the yield of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is 67.2%.
Embodiment 9,10,11 and the difference of embodiment 1 see table 2 for details.
Embodiment 12～15 sees table 3 for details with the difference of embodiment 1.
Embodiment 16～18 sees table 4 for details with the difference of embodiment 1.
Table 1. concentration of hydrochloric acid is on the impact of 4-hydroxyl thiobenzamide yield
Table 2. reaction times is on the impact of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester yield
Table 3. temperature of reaction is on the impact of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester yield
The ratio of table 4. methanesulfonic and trifluoroacetic acid is on the impact of 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester yield
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. the preparation method of a Febuxostat is characterized in that, comprises the steps:
(1) take 4-hydroxy-phenylformonitrile, thioacetamide as raw material, heat in hydrochloric acid soln, mechanical stirring was reacted 2～6 hours, and cooling crystallization filters and obtains 4-hydroxyl thiobenzamide;
(2) 4-hydroxyl thiobenzamide is dissolved in the alcohol solvent, and reflux drips the 2-chloroacetyl acetacetic ester, react after 3～7 hours, add in the ice-water bath, leave standstill cooling crystallization, filtration drying namely gets 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester;
(3) with methanesulfonic and trifluoroacetic acid by volume (5～13): 1 mixes, 2-(4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is joined in the above-mentioned mixing solutions, be heated to 70-110 ℃, add vulkacit H under the mechanical stirring in batches, after reacting 6～10 hours, add saturated ice salt solution, stirring and crystallizing, filter, obtain 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester;
(4) 2-(3-formyl radical-4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is dissolved in the polar protic solvent, add behind the oxammonium hydrochloride after the room temperature reaction 1 hour, add Acetyl Chloride 98Min., heat 60～100 ℃, react stopped reaction after 2～6 hours, be cooled to room temperature, then add Anhydrous potassium carbonate, stirring at room adds isobutane bromide after half an hour, heat 80～120 ℃, react after 4～8 hours, add in the ice-water bath and cool off, stirring and crystallizing is filtered to get 2-(3-itrile group-4-isobutoxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester;
(5) 2-(3-itrile group-4-isobutoxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester is dissolved in the mixed solution of tetrahydrofuran (THF) and dehydrated alcohol, adds inorganic alkali solution, reacts 0.5～2 hour, removal of solvent under reduced pressure, regulate pH and separate out to a large amount of solids, filter, get the Febuxostat crude product;
(6) the Febuxostat crude product is carried out recrystallization, obtain the Febuxostat elaboration.
2. preparation method according to claim 1 is characterized in that, the described hydrochloric acid soln of step (1) is concentrated hydrochloric acid.
3. preparation method according to claim 1 is characterized in that, the described temperature of reaction of step (1) is 50 ℃, and the reaction times is 4 hours.
4. preparation method according to claim 1 is characterized in that, the volume ratio that the described methanesulfonic of step (3) and trifluoroacetic acid mix is (6～12): 1, and preferred proportion is 9:1.
5. preparation method according to claim 1 is characterized in that, 90 ℃ of the described heating of step (3) were reacted 8 hours.
6. preparation method according to claim 1 is characterized in that, the temperature of the previous reaction of step (4) is 80 ℃, and the reaction times is 4 hours; The temperature of a rear reaction is 90 ℃, and the reaction times is 8 hours.
7. preparation method according to claim 1 is characterized in that, the described polar protic solvent of step (4) is DMF, dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide.
8. preparation method according to claim 1 is characterized in that, the mol ratio of the described 2-of step (3) (4-hydroxy phenyl)-4-methyl thiazole-5-carboxyl acid ethyl ester and vulkacit H is 1:(1.5～3).
9. preparation method according to claim 1 is characterized in that, described inorganic alkali solution is barium hydroxide solution, sodium hydroxide solution, potassium hydroxide solution, magnesium hydroxide solution or lithium hydroxide solution; Described recrystallization is that the Febuxostat crude product is dissolved in methylene dichloride, adds activated carbon decolorizing, filters, and is spin-dried for solvent, and the mixed solvent that the solid that obtains adds methylene dichloride and methyl alcohol again carries out recrystallization.
10. the described preparation method of any one is characterized in that according to claim 1～9, and the described vulkacit H of step (3) adds in batches.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103910695A (en) * | 2014-04-24 | 2014-07-09 | 重庆科瑞制药(集团)有限公司 | Synthetic method of febuxostat |
| CN104478824A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Preparation method of 2-(3-cyano-4-hydroxyl) phenyl-4-methyl-5-thiazole ethyl formate |
| CN109232593A (en) * | 2018-09-04 | 2019-01-18 | 华南理工大学 | A kind of fluorescence probe and preparation method thereof detecting ferric ion |
| 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 |
| CN109574952A (en) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | A kind of synthetic method of febuxostat intermediate |
| CN110229117A (en) * | 2019-06-20 | 2019-09-13 | 福安药业集团重庆博圣制药有限公司 | A kind of novel preparation method of Febustat |
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| CN110790720A (en) * | 2019-09-09 | 2020-02-14 | 内蒙古京东药业有限公司 | New preparation method of febuxostat intermediate |
| CN111285821A (en) * | 2018-12-06 | 2020-06-16 | 重庆圣华曦药业股份有限公司 | Method for continuously preparing febuxostat |
| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
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| CN103910695A (en) * | 2014-04-24 | 2014-07-09 | 重庆科瑞制药(集团)有限公司 | Synthetic method of febuxostat |
| CN104478824A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Preparation method of 2-(3-cyano-4-hydroxyl) phenyl-4-methyl-5-thiazole ethyl formate |
| CN109574952B (en) * | 2017-09-28 | 2022-04-01 | 安徽省庆云医药股份有限公司 | Synthetic method of febuxostat intermediate |
| CN109574952A (en) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | A kind of synthetic method of febuxostat intermediate |
| CN109232593A (en) * | 2018-09-04 | 2019-01-18 | 华南理工大学 | A kind of fluorescence probe and preparation method thereof detecting ferric ion |
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| CN111285821A (en) * | 2018-12-06 | 2020-06-16 | 重庆圣华曦药业股份有限公司 | Method for continuously preparing febuxostat |
| CN110229117A (en) * | 2019-06-20 | 2019-09-13 | 福安药业集团重庆博圣制药有限公司 | A kind of novel preparation method of Febustat |
| CN110229117B (en) * | 2019-06-20 | 2023-04-18 | 福安药业集团重庆博圣制药有限公司 | Novel preparation method of febuxostat |
| CN110790720A (en) * | 2019-09-09 | 2020-02-14 | 内蒙古京东药业有限公司 | New preparation method of febuxostat intermediate |
| CN110642804A (en) * | 2019-10-17 | 2020-01-03 | 武汉光谷亚太医药研究院有限公司 | Preparation method of certain specific impurity of febuxostat |
| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
| CN114315710B (en) * | 2022-01-07 | 2024-04-26 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
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