CN102659754A - Preparation method of tiaprofenic acid - Google Patents
Preparation method of tiaprofenic acid Download PDFInfo
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- CN102659754A CN102659754A CN2012101529649A CN201210152964A CN102659754A CN 102659754 A CN102659754 A CN 102659754A CN 2012101529649 A CN2012101529649 A CN 2012101529649A CN 201210152964 A CN201210152964 A CN 201210152964A CN 102659754 A CN102659754 A CN 102659754A
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Abstract
The invention provides a preparation method of tiaprofenic acid. The method comprises the following steps of: reacting thiofuran serving as a starting raw material with propionic andydride to obtain 2-propionyl thiofuran; reacting the 2-propionyl thiofuran with bromine to obtain alpha bromo on a thiophene ring branch chain; refluxing the obtained bromo compound and ethylene glycol to obtain a bromo-ketal product; rearranging the bromo-ketal product under the action of cuprous oxide serving as a catalyst; performing a Friedel-Crafts reaction on a rearrangement product and benzoyl chloride; and hydrolyzing and acidifying to obtain tiaprofenic acid serving as a target product. The method has stable reaction conditions and high yield; a crude product obtained after reacting has high purity, is easy for purifying and operating, and is low in cost; and used reagents are conventional reagents, so that post-treatment is easy, and convenience is brought to industrial production.
Description
Technical field
The invention belongs to the medication preparation field, be specifically related to a kind of preparation method of nonsteroidal anti-inflammatory drug tiaprofenic acid.
Background technology
Tiaprofenic acid (structural formula is as follows) has another name called tiaprofenic acid, RU-15060, different thiophene ketone Ibuprofen BP/EP, chemical name 5-benzoyl--alpha-methyl-2-thiophene acetic acid.Being the verivate of thiophene propionic acid, is the NSAIDs of a novel type, is got by French Roussol-Uclaf central authorities' institute's exploitation.According to the chemical structure classification, belong to propionic non-steroid antiphlogistic.The oral property of this medicine is good, can absorb rapidly at gi tract, has analgesic, analgesia and anti-inflammatory action, can alleviate swelling, alleviates ankylosis, alleviating pain, improves joint motion.Mechanism of action is blocked inflammatory mediator for suppressing the synthetic of prostaglandin(PG), and it more effectively suppresses the synthetic of prostaglandin(PG) than diclofenac and INDOMETHACIN BP99.Its analgesic and anti-inflammatory effects is better than Ibuprofen BP/EP.Whole tolerance is good, especially the gi tract aspect.Polycentric clinically double blinding can be dwindled swelling with open consistent showing of test, this medicine, alleviates the ankylosis alleviating pain, improve and grab by strength and joint motion.Be mainly used in treatment of arthritis, rheumatic arthritis, ankylosis, post-operative pain etc. clinically.Because of its gastrointestinal reaction serious, the careful usefulness of Peptic Ulcers patient.This medicine was obtained selling license at Japanese Roussol with the trade(brand)name of Surgam in 1984.Its pharmacokinetics is: the clothes back absorbs rapidly at gi tract, about 1h Plasma Concentration peaking, and blood plasma t1/2 is 2h, plasma protein binding ratio about 98%.Mainly from urine, drain, pass through bile excretion on a small quantity.
The synthetic route of present tiaprofenic acid, conclude and get up to mainly contain five:
(1) publication number is the compound method that the Chinese patent document of CN101177423 discloses a kind of non-steroidal antiphlogiston tiaprofenic acid; With the thiophene is raw material, carries out acylation reaction with Benzoyl chloride 99min. earlier and generates benzoyl ketone, again under manganic catalysis; The reaction of methyl-malonic ester generation one-electron oxidation; Generate corresponding radical, radical and the substitution reaction of thiphene ring generation radical are introduced many carbonyl functional groups on the ring then, generate corresponding
Substituent, the substitution product hydrolysis, the decarboxylation that obtain obtain the title product tiaprofenic acid.But it is apt to deteriorate that this route uses manganic to grow as the catalyzer time of in air, shelving, and catalytic effect is not good, and the reaction of second step is very incomplete, and catalyst levels is big, and the route overall yield is lower than 10%.Reaction formula is as follows:
。
(2) scientific and technical literature " synthesizing of tiaprofenic acid " (Zheng Gengxiu, Ji Yaowu, Huang Zhixin; [J] Chinese Medicine magazine, 1991,22 (3): 97-97) disclose a kind of compound method of tiaprofenic acid; Use thiophene to be raw material; Generate acetyl thiophene with acetic anhydride earlier, use the Darzens reaction of acetyl thiophene to obtain rearrangement product Alpha-Methyl 2-thiophene acetic acid again, the Friedel-Crafts acylations obtains title product.The 4th step of this method oxidizing reaction productive rate is very low, and overall yield is lower than 10%, and the reaction cost height is not suitable for suitability for industrialized production.In the product that obtains owing to exist phenylformic acid impurity to be difficult to purifying.Reaction formula is as follows:
。
(3) European patent EP 07171840 discloses a kind of compound method method of tiaprofenic acid, uses thiophene to be raw material, and what acylation reaction adopted is that the chloroformyl ethyl formate obtains the 2-acetyl thiophene, at Grignard reagent C H
3The Grignard reaction takes place down and obtains Alpha-Methyl-alpha-hydroxy-2-thiophene acetic acid in the MgI effect, under the effect of arsenic chloride, sloughs water molecules and obtains midbody Alpha-Methyl 2-thiophene acetic acid, and last Friedel-Crafts reaction obtains the title product tiaprofenic acid.This method uses the chloroformyl ethyl formate to be starting raw material, be difficult for producing and cost higher, two steps were adopted a large amount of aluminum trichloride (anhydrous)s; Operation condition is harsh, and environmental pollution is serious, and adopting methyl iodide is the Ge Shi method of raw material; Raw materials cost is high; Condition is harsh, needs strict explosion-proof equipment, and total recovery is lower than 14.3%.Reaction formula is as follows:
(4) patent DT2055264 discloses a kind of compound method method of tiaprofenic acid; With 5-benzoyl--2-thiophene-formaldehyde; Compound that elder generation and the reaction of methyl-sulfide methylmethane obtain and sulfur oxychloride generation cancellation, replacement; Substitution product carries out carbonyl-protection earlier and obtains the transesterify thing with trimethoxy-methane again and under acidic conditions, slough the carbonyl-protection base then, and the gained compound promptly gets the tiaprofenic acid title product through hydrolysis, acidifying.Whole piece route raw material is difficult to obtain or is difficult to produce and the cost height, and reactions step is many, and operational path is long, and total recovery is lower than 10%, is inappropriate for suitability for industrialized production.
(5) scientific and technical literature " tiaprofenic acid synthetic " (Sun Min, Cai advances, Zhou Wen etc.; [J] Chinese Journal of Pharmaceuticals, 2006,37 (12): 796-797) disclose a kind of compound method of filling in ketoprofen acid; Use thiophene to be raw material, obtain 2-propionyl group thiophene with the propionic anhydride reaction, this step productive rate is more than 90%; But it is raw material that second step of committed step is adopted iodine and triethyl orthoformate; Under the cuprous effect of catalyst oxidation, obtain rearrangement product alpha-methyl-2-thiophene acetic acid ethyl ester, hydrolysis obtains corresponding acid, and last and Benzoyl chloride 99min. is paid the gram acylation reaction and obtained title product.This second step of method uses Red copper oxide very low as catalyst efficient, and uses a large amount of Iod Rs still incomplete.In addition, owing to exist phenylformic acid to be difficult to eliminate, influence quality product in the product that reaction obtains, this route total recovery is lower than 30%, and suitability for industrialized production has quite difficulty.
In sum, prepare tiaprofenic acid according to literature method and have following defective: reaction raw materials is difficult to preserve, or reaction yield is low, or big for environment pollution, or severe reaction conditions, or reaction cost is high, so all can't be used for suitability for industrialized production.
Summary of the invention
Technical problem:The present invention is directed to the preparation tiaprofenic acid and exist reaction raw materials to be difficult to preserve, or reaction yield is low, or big for environment pollution, or severe reaction conditions, or defective such as reaction cost height, a kind of new tiaprofenic acid preparation method has been proposed.
Technical scheme:The preparation method of tiaprofenic acid of the present invention is specific as follows: be starting raw material with the thiophene; Obtain 2-propionyl group thiophene with the propionic anhydride reaction earlier, α bromination product and terepthaloyl moietie backflow that 2-propionyl group thiophene and bromine reaction obtain on the thiphene ring side chain obtain bromo ketal product, and bromo ketal product is reset in the cuprous effect of catalyst oxidation; Obtain rearrangement product and Benzoyl chloride 99min. and carry out the Friedel-Crafts reaction; Hydrolysis, acidifying promptly get the title product tiaprofenic acid, specifically comprise the steps:
(1) 2-propionyl group thiophene is synthetic: with thiophene and propionic anhydride reflux under Vanadium Pentoxide in FLAKES and phosphoric acid catalyzed, acidylate obtains 2-propionyl group thiophene, and reaction formula is following:
(2) alpha-brominated-2-propionyl group thiophene is synthetic: the 2-propionyl group thiophene that step (1) reaction is obtained is in non-aqueous organic solvent; Under Catalyzed by Anhydrous Aluminium Chloride, react under the condition of ice bath with bromine; Obtain alpha-brominated-2-propionyl group thiophene, reaction formula is following:
(3) 2-(1-bromotrifluoromethane)-2-thiotolene-1; Synthesizing of 3-dioxolane: step (2) is reacted alpha-brominated-2-propionyl group thiophene and the alkane diol compound reflux generation ketal reaction that obtains; Obtain 2-(1-bromotrifluoromethane)-2-thiotolene-1; The 3-dioxolane, reaction formula is following:
(4) alpha-methyl-2-thiophene acetic acid is synthetic: with step (3) reaction product 2-(1-bromotrifluoromethane)-2-thiotolene-1; 3-dioxolane reflux under the cuprous catalysis of catalyst oxidation changes into rearrangement product; The rearrangement product that obtains hydrolysis under the sodium hydroxide alkali solution effects; Obtain alpha-methyl-2-thiophene acetic acid, reaction formula is following:
;
(5) tiaprofenic acid is synthetic: step (4) reaction product alpha-methyl-2-thiophene acetic acid is carried out the Friedel-Crafts reaction with Benzoyl chloride 99min. mol ratio 1:1 under condition of ice bath under the lewis acidic effect.
Preparing method of the present invention, the feed ratio of said thiophene of step (1) and propionic anhydride is thiophene: propionic anhydride=1:1.25 (mol ratio).
Preparing method of the present invention, it is 10% that the said catalyzer aluminum trichloride (anhydrous) of step (2) accounts for 2-propionyl group thiophene weight percent.
Preparing method of the present invention, the said non-aqueous organic solvent of step (2) is any one or a few the combination in anhydrous diethyl ether, chloroform or the methylene dichloride, preferred anhydrous diethyl ether.
Preparing method of the present invention, the feed ratio of step (2) said 2-propionyl group thiophene and bromine is 2-propionyl group thiophene: bromine=1:1 (mol ratio).
Preparing method of the present invention, the said alkane diol compound of step (3) is a terepthaloyl moietie, 1, the combination of any one or a few in ammediol, the NSC 6366, preferred terepthaloyl moietie.
Preparing method of the present invention, the said Lewis acid of step (5) is an aluminum chloride, selecting chloroform for use is solvent.
Each step reaction according to the invention is all carried out under normal condition, and pressure is normal pressure, and TR is-10 ℃ ~ 150 ℃, easy handling.
Beneficial effect:The compound method of tiaprofenic acid provided by the invention has following advantage: stable reaction conditions, and productive rate is high, and the bullion purity that obtains after the reaction is high, is easy to purifying and obtains the pure article of highly purified tiaprofenic acid, HPLC>99.6%.
Cost is low, and easy handling, agents useful for same are conventional reagent, and aftertreatment is simple, is convenient to suitability for industrialized production.
Embodiment
Below through embodiment concrete process step of the present invention is described, but not limited by embodiment.
Employed in the present invention term except as otherwise noted, generally has the implication of those of ordinary skills' common sense.
Below in conjunction with specific embodiment and comparable data the present invention is described in further detail.Should be understood that these embodiment just in order to demonstrate the invention, but not limit scope of the present invention by any way.
In following examples, the various conditioned disjunction methods of not describing in detail are normal condition as known in the art or method.
Synthesizing of embodiment 1 2-propionyl group thiophene
In the 250mL eggplant-shape bottle, once add 32mL (0.4mol) thiophene, 64mL (0.5mol) propionic anhydride, 4mL phosphoric acid and 0.8g (6mmol) Vanadium Pentoxide in FLAKES, oil bath is heated to 95-100 ℃ of refluxed.Behind the reaction 20min, the clarification system begins deepening, and along with the prolongation in reaction times, the system color becomes chocolate gradually, and in bottle, constantly has " white cigarette " to generate.Stopped reaction behind the 6h-8h, system is cooled to room temperature, adds 100mL water and stirs 20min, uses the 3x50mL dichloromethane extraction, merges organic layer; Organic layer shows alkaline with stirring 1h under 15% the NaOH solution 100mL room temperature to system upper water solution, washes with the 4x50mL saturated common salt again.Anhydrous sodium sulfate drying spends the night, and filters, and removes solvent under reduced pressure and obtains the 62.1g brown liquid; With the product rectifying that obtains, collect 92 ℃ cut 54.2g.The product structure formula is:
, productive rate is 96.8%.
Synthesizing of embodiment 2 alpha-brominated-2-propionyl group thiophene
Add 14g (0.1mol) 2-propionyl group thiophene in the exsiccant 250mL eggplant-shape bottle, purified ether solvent 60mL.Cryosel is bathed and is made system temperature reduce to 0 ℃, adds the agent of 1.4g (0.01mol) Catalyzed by Anhydrous Aluminium Chloride.Stir and drip 8g (0.1mol) bromine down, drip 2 bromines when dripping bromine earlier, treat to drip remaining bromine more rapidly after color takes off to the greatest extent in the system.The bromine that drip this moment becomes colorless rapidly, and the hydrogen bromide of generation absorbs with 10% sodium hydroxide.10min drips complete, and this moment, system was an incarnadine.Continuation is reacted 30min under this temperature.Stopped reaction is poured into system in the 200mL ice-water bath, this moment system become by incarnadine faint yellow, stirred for several minute.Use saturated sodium bicarbonate to be washed till the upper strata and be alkalescence, use the 3x50mL saturated aqueous common salt to be washed till the upper strata again and be neutrality.Drying is filtered, and steams to desolventize to obtain product 20.2g.Product structure is:
productive rate be 92.3%, HPLC>98%.
1H-NMR（300MHz，CDCl
3）δ：7.14~7.84（3H，m，-Ar），5.11~5.18（H，d，C
H-Br），1.83~1.94(3H，d，-C
H 3)。
Embodiment 3 2-(1-bromotrifluoromethane)-2-(2-thiotolene)-1,3-dioxolane synthetic
In 500mL exsiccant there-necked flask, add the alpha-brominated 2-propionyl group of 44.0g (0.2mol) thiophene, 240mL toluene and 4.4g tosic acid, oil bath is warming up to 140 ℃ of vigorous reflux.Begin to add 2 normal terepthaloyl moietie behind the temperature-stable.This temperature refluxed reaction 12h, stopped reaction.System is washed with the 3x40mL saturated common salt after being cooled to room temperature.The upper strata is dry; Filter; Steaming desolventizes, and obtains faint yellow oily thing 52.4g, and product structure is:
; Productive rate 99.3%, HPLC>99%.
Synthesizing of embodiment 4 alpha-methyl-2s-thiophene acetic acid
Add 52.8g (0.2mol) compound 2-(1-bromotrifluoromethane)-2-(2-thiotolene)-1 in the dry eggplant type of the 500mL bottle, the 3-dioxolane adds cuprous 5.28g of catalyst oxidation (0.06mol) and 240mL hexanaphthene, and oil bath is heated to 85 ℃ of refluxed.Stopped reaction behind the reaction 12h shelves system to room temperature, filters, and filtrating is washed with the 120mL saturated common salt.Organic layer is dry, and steaming desolventizes, and obtains faint yellow oily thing 52.9g.Be equipped with toward 1L and add 400mL methyl alcohol in the eggplant type bottle of this oily matter, stir dissolving down.Oil bath is warming up to 75 ℃, treats to add 20% sodium hydroxide solution 160mL behind the temperature-stable, and this moment, system became blood red rapidly.Stopped reaction behind the 30min is shelved room temperature with system.Steam and remove methanol solvate, wash with the 3x80mL chloroform, water layer is transferred pH to 2-3 with concentrated hydrochloric acid, uses the 3x80mL chloroform extraction again, merges organic layer.Organic layer is washed with the 3x100mL saturated common salt, drying, and steaming desolventizes and obtains faint yellow oily thing 28.4g.Product structure is
; Productive rate is 91.0%, HPLC>98%.
Synthesizing of embodiment 5 tiaprofenic acids
Add 26.7g (0.02mol) aluminum trichloride (anhydrous) in the 250mL eggplant type bottle, chloroform 156mL, cryosel bathe and make system temperature reduce to 0-5 ℃.Splash into 14.05g (0.1mol) Benzoyl chloride 99min. after the system of treating is stable.15min drips complete.Continue to drip alpha-methyl-2-thiophene acetic acid 15.6g (0.1mol) behind the reaction 30min.20min drips complete, and let system be warming up to room temperature naturally this moment.Stopped reaction behind the 1h is poured system in the frozen water into, uses the 3x40mL chloroform extraction, merges organic layer, washes with the 4x40mL saturated common salt again.Dry; Steaming desolventizes; Obtain off-white color solid 27.4g; Obtain white solid 24.5g behind the recrystallization, product structure is:
productive rate be 94.2%.
mp：95-98℃，HPLC：99.9%。
1H-NMR（300MHz，CDCl
3）δ：7.49~7.84（5H，m，-Ar），7.05~7.59（2H，d，C
H-C-S-C-C
H），4.06~4.11（1H，s，-C
H-），1.66~1.67（3H，s，-C
H 3），MS（m/z）：261?[M+H]
+。
Claims (7)
1. the preparation method of a tiaprofenic acid; It is characterized in that with the thiophene being starting raw material; Obtain 2-propionyl group thiophene with the propionic anhydride reaction earlier; α bromination product on the thiphene ring side chain that 2-propionyl group thiophene and bromine reaction obtain and terepthaloyl moietie reflux and obtain bromo ketal product, and bromo ketal product is reset under the cuprous effect of catalyst oxidation, and rearrangement product that obtains and Benzoyl chloride 99min. carry out the Friedel-Crafts reaction; Promptly get the title product tiaprofenic acid after hydrolysis, the acidifying, specifically comprise the steps:
1) 2-propionyl group thiophene is synthetic: with thiophene and propionic anhydride reflux under Vanadium Pentoxide in FLAKES and phosphoric acid catalyzed, acidylate obtains 2-propionyl group thiophene, and reaction formula is following:
2) alpha-brominated-2-propionyl group thiophene is synthetic: the 2-propionyl group thiophene that the step 1) reaction is obtained in non-aqueous organic solvent, under the condition of ice bath under Catalyzed by Anhydrous Aluminium Chloride with the bromine reaction, obtain alpha-brominated-2-propionyl group thiophene, reaction formula is following:
3) 2-(1-bromotrifluoromethane)-2-thiotolene-1; Synthesizing of 3-dioxolane: with step 2) react the alpha-brominated-2-propionyl group thiophene and the alkane diol compound reflux generation ketal reaction that obtain; Obtain 2-(1-bromotrifluoromethane)-2-thiotolene-1; The 3-dioxolane, reaction formula is following:
4) alpha-methyl-2-thiophene acetic acid is synthetic: with step 3) product 2-(1- bromoethyl)-2- methylthiophene-1; 3- dioxolane reflux under the cuprous catalysis of catalyst oxidation changes into rearrangement product; The rearrangement product that obtains hydrolysis under the sodium hydroxide alkali solution effects; Obtain alpha-methyl-2-thiophene acetic acid; Reaction equation is following:
5) tiaprofenic acid is synthetic: step 4) reaction product alpha-methyl-2-thiophene acetic acid is carried out the Friedel-Crafts reaction with Benzoyl chloride 99min. mol ratio 1:1 under condition of ice bath under the lewis acidic effect
2. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that in the said step 1), and the feed ratio of thiophene and propionic anhydride is thiophene: propionic anhydride=1:1.25 with mol ratio calculating.
3. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that said step 2) in, it is 10% that said catalyzer aluminum trichloride (anhydrous) accounts for 2-propionyl group thiophene weight percent.
4. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that said step 2) in, said non-aqueous organic solvent is a kind of or this two kinds the combination in anhydrous diethyl ether or chloroform or the methylene dichloride.
5. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that said step 2) in, the feed ratio of said 2-propionyl group thiophene and bromine is 2-propionyl group thiophene: bromine=1:1 with mol ratio calculating.
6. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that in the said step 3), and said alkane diol compound is a terepthaloyl moietie, 1, the combination of one or more in ammediol or the NSC 6366.
7. the preparation method of tiaprofenic acid as claimed in claim 1 is characterized in that in the said step 5), and said Lewis acid is an aluminum chloride.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501233A (en) * | 2017-10-13 | 2017-12-22 | 江苏工程职业技术学院 | A kind of synthesis technique of non-steroidal antiphlogiston tiaprofenic acid |
| CN107540654A (en) * | 2017-10-13 | 2018-01-05 | 江苏工程职业技术学院 | A kind of synthesis technique of Tiaprofenic Acid |
| CN107573320A (en) * | 2017-10-13 | 2018-01-12 | 江苏工程职业技术学院 | A kind of preparation method of Tiaprofenic Acid |
| CN107698554A (en) * | 2017-10-13 | 2018-02-16 | 江苏工程职业技术学院 | A kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4924915A (en) * | 1972-06-29 | 1974-03-05 | ||
| JPH0924915A (en) * | 1995-07-12 | 1997-01-28 | Honda Motor Co Ltd | Peeling method for temporary protective film |
| CN101177423A (en) * | 2007-12-10 | 2008-05-14 | 天津理工大学 | Method for synthesizing non-steroidal antiphlogiston tiaprofenic acid |
| CN102432591A (en) * | 2011-11-10 | 2012-05-02 | 苏州东南药物研发有限责任公司 | Novel synthesis process of nonsteroidal antiinflammatory agent, namely, 5-benzoyl-alpha-methyl-2-thiopheneacetic acid |
-
2012
- 2012-05-17 CN CN2012101529649A patent/CN102659754A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4924915A (en) * | 1972-06-29 | 1974-03-05 | ||
| JPH0924915A (en) * | 1995-07-12 | 1997-01-28 | Honda Motor Co Ltd | Peeling method for temporary protective film |
| CN101177423A (en) * | 2007-12-10 | 2008-05-14 | 天津理工大学 | Method for synthesizing non-steroidal antiphlogiston tiaprofenic acid |
| CN102432591A (en) * | 2011-11-10 | 2012-05-02 | 苏州东南药物研发有限责任公司 | Novel synthesis process of nonsteroidal antiinflammatory agent, namely, 5-benzoyl-alpha-methyl-2-thiopheneacetic acid |
Non-Patent Citations (2)
| Title |
|---|
| 郑庚修 等: "噻洛芬酸的合成", 《中国医药工业杂志》, vol. 22, no. 3, 31 December 1991 (1991-12-31), pages 97 - 98 * |
| 郑庚修 等: "噻洛芬酸的合成", 《中国医药工业杂志》, vol. 37, no. 12, 31 December 2006 (2006-12-31), pages 796 - 797 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501233A (en) * | 2017-10-13 | 2017-12-22 | 江苏工程职业技术学院 | A kind of synthesis technique of non-steroidal antiphlogiston tiaprofenic acid |
| CN107540654A (en) * | 2017-10-13 | 2018-01-05 | 江苏工程职业技术学院 | A kind of synthesis technique of Tiaprofenic Acid |
| CN107573320A (en) * | 2017-10-13 | 2018-01-12 | 江苏工程职业技术学院 | A kind of preparation method of Tiaprofenic Acid |
| CN107698554A (en) * | 2017-10-13 | 2018-02-16 | 江苏工程职业技术学院 | A kind of preparation method of non-steroidal antiphlogiston tiaprofenic acid |
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Application publication date: 20120912 |