CN1680266A - Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid - Google Patents
Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid Download PDFInfo
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- CN1680266A CN1680266A CN 200510042319 CN200510042319A CN1680266A CN 1680266 A CN1680266 A CN 1680266A CN 200510042319 CN200510042319 CN 200510042319 CN 200510042319 A CN200510042319 A CN 200510042319A CN 1680266 A CN1680266 A CN 1680266A
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Abstract
A catalytic synthesis of 4-trifluoromethane-acetosalicylic acid is carried out by mixing by mass ratio of 4-trifluoromethane-salicylic acid and acetylating reagent=1:0.5-3, adding sulfur phosphorus mixed acid or solid sodium acid sulfate or solid potassium fluoride-aluminum oxide compound into material by acetylating reagent: sulfur phosphorus mixed acid or solid sodium acid sulfate or solid potassium fluoride=100:0.5-10 or by acetylating reagent: solid potassium fluoride-aluminum oxide compound=100:10-35, refluxing reacting at 50-90deg.C, adding reacting mixture into ice water, laying aside, filtering, obtaining white powdery solid, purifying by re-crystallizing, drying and obtaining pure product.
Description
Technical field
The present invention relates to medicine, relate in particular to the acetysalicylic process for catalytic synthesis of a kind of 4-trifluoromethyl.
Background technology
At present, can substitute acetysalicylic research report relevant for 4-trifluoromethyl acetylsalicylic acid abroad, this report gets 4-trifluoromethyl acetylsalicylic acid respectively and acetylsalicylic acid carries out drug test to small white mouse and big white mouse respectively, found that 4-trifluoromethyl acetylsalicylic acid not only can play the curative effect identical with acetylsalicylic acid, and used dosage is littler, side effect is compared also much smaller with acetylsalicylic acid.In addition, relevant report finds that 4-trifluoromethyl acetylsalicylic acid also has good curative effect on some other relative disease of treatment.Believe that in the near future 4-trifluoromethyl acetylsalicylic acid will substitute the antipyretic analgesic medicine that acetylsalicylic acid becomes a new generation, thereby brings considerable social benefit and economic benefit.
Up to the present, the 4-trifluoromethyl acetysalicylic synthetic on, abroad in the sixties in last century, announced that by the U.S. employing vitriol oil is the acetysalicylic patent specification of Catalyst Production 4-trifluoromethyl, but this method catalyst system therefor can not reclaim, and not only environmental pollution is serious, and reaction unit is had very strong corrodibility, shortened the work-ing life of equipment, made the corresponding rising of production cost.And domestic still finding no about acetysalicylic patent of 4-trifluoromethyl and bibliographical information.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide a kind of catalyzer of employing recyclable, do not have environmental pollution and little, the acetysalicylic process for catalytic synthesis of 4-trifluoromethyl that reduces production costs production unit corrodibility.
Purpose of the present invention can realize by following technical measures:
The chemical formula of medicine of the present invention is C
10H
7F
3O
4, structural formula is:
Its chemical name is a 4-trifluoromethyl acetylsalicylic acid.
Earlier with raw material according to 4-trifluoromethyl Whitfield's ointment: acetylation reagent=1: the 0.5-3 mass ratio mixes, again with mixture of sulfuric phosphoric acid or solid sulphuric acid hydrogen sodium or solid Potassium monofluoride-alumina compound according to acetylation reagent: mixture of sulfuric phosphoric acid or solid sulphuric acid hydrogen sodium=100: 0.5-10 mass ratio or according to acetylation reagent: solid Potassium monofluoride-alumina compound=100: the 10-35 mass ratio joins in the raw material, back flow reaction under 50-90 ℃ of temperature; Again reaction mixture is joined in the frozen water and leave standstill, filter and obtain the white powder solid; At last with getting pure product after recrystallization method purification, the drying.
Purpose of the present invention also can realize by following technical measures:
Described acetylation reagent is an acetic anhydride; Described reflux time is 10-90 minute; Described mixture of sulfuric phosphoric acid is meant sulfuric acid: phosphoric acid=1: the mixed solution that the 1-3 mass ratio is formed; Described Potassium monofluoride-alumina compound be prepared as existing public technology, the used Potassium monofluoride-alumina compound of the present invention be that chemical institute of reference literature Zhongshan University should change be that clock increases training, Zhou Jianneng is published in the " KF/Al on the first phase in 1998 the chemistry circular
2O
3The research of N-ethyl carbazole method is synthesized in catalysis " preparation method described in the literary composition makes.
Best reflux time when the present invention adopts mixture of sulfuric phosphoric acid to be catalyzer is 20-40 minute; Best reflux time when adopting sodium pyrosulfate to be catalyzer is 30-60 minute; Best reflux time when adopting Potassium monofluoride-alumina compound to be catalyzer is 40-60 minute.
The present invention directly pours reacting liquor while hot into after reaction is finished and leaves standstill about 0.5-3 hour in the frozen water if adopting mixture of sulfuric phosphoric acid is catalyzer, and suction filtration promptly gets the white powder solid phase prod then, and mixture of sulfuric phosphoric acid is used for chemical fertilizers production industry after reclaiming; If adopting solid sulphuric acid hydrogen sodium or solid Potassium monofluoride-alumina compound is catalyzer, filtered while hot after reaction is finished, filter residue washes with water, dry back is reused, filtrate adds in a certain amount of frozen water, left standstill about 0.5-3 hour, suction filtration promptly gets the white powder solid phase prod then, is used in this reaction through washing, dry recirculation after solid sulphuric acid hydrogen sodium and solid Potassium monofluoride-alumina compound reclaims.
The thick product of above gained is dissolved in the small amount of ethanol, removes by filter insoluble impurity, filtrate is added in the frozen water again, left standstill about 0.5-3 hour, suction filtration repeatedly for several times, is dried the pure product of white powder that promptly get then.Productive rate all can reach more than 80%, and product purity reaches more than 98%.
The present invention explores by experiment, adopting mixture of sulfuric phosphoric acid or solid sulphuric acid hydrogen sodium or solid Potassium monofluoride-alumina compound is catalyzer, high yield, highly purified 4-trifluoromethyl acetylsalicylic acid have all successfully been made, not only reduced the corrodibility of catalyzer to production unit, thereby reduced production cost, and catalyzer is all recyclable, prevented environmental pollution from the source, bring good economic benefit and social benefit, this method reaction conditions gentleness, reaction times is short, and required equipment is simple, and is easy to operate.Operation is simple for the product purifying technique, is a kind of green catalysis synthetic method that has a extensive future.
Embodiment 1:
In a there-necked flask, add 10.03g trifluoromethyl Whitfield's ointment and 14ml acetic anhydride (mass ratio of the two is 1: 0.5); and 10 sulfuric acid: the mixture of sulfuric phosphoric acid that the mass ratio of phosphoric acid=1: 1 mixes (consumption be acetylation reagent 0.5%); dress up reflux; directly put into 90 ℃ water-bath, stirring reaction 10 minutes.Directly pour reaction liquid in a certain amount of frozen water (volume ratio of reaction liquid and frozen water is about 1: 1.2) after reaction is finished, produce a large amount of white precipitates immediately, suction filtration obtains the white powder solid.
Purify: the thick product of gained is dissolved in a certain amount of dehydrated alcohol, stirring makes it to dissolve fully, filter, keep filtrate, and its adding is filled in the beaker of clean frozen water, produce white precipitate, beaker is put in leaves standstill 30 minutes in the ice-water bath, treat that solid separates out the back suction filtration fully, obtain the brilliant white solid, it is dry that this solid is put into vacuum drying oven, weighing.The gained solid masses is 10.15g, productive rate 82%.
Embodiment 2:
In a there-necked flask, add 10.03g trifluoromethyl Whitfield's ointment and 14ml acetic anhydride (mass ratio of the two is 1: 3), and 0.92g (consumption be acetylation reagent 10%) solid sulphuric acid hydrogen sodium, dress up reflux, in 50 ℃ of stirring reactions 90 minutes.The reaction finish after while hot suction filtration remove solid catalyst, filtrate is added in the frozen water, white precipitate appears, suction filtration obtains the white powder solid.
Purify: the gained solid is dissolved in saturated NaHCO
3In the solution, produce a large amount of bubbles, stirring is emitted bubble, removes by filter insolubles, filtrate is slowly poured in the beaker that fills concentrated hydrochloric acid (about 50ml) then, the limit edged stirs, and bubble is fully emitted, and beaker is placed on leaves standstill 2 hours in the ice-water bath then, treat solid separate out fully the back suction filtration, obtain the white powder solid, the 15.08g of dry back weighing, productive rate 90.9%.
Under the embodiment 3:50-90 ℃ temperature back flow reaction 10-90 minute;
In a there-necked flask, add 10.03g trifluoromethyl Whitfield's ointment and 14ml acetic anhydride (mass ratio of the two is 1: 1); and 3.75g (consumption be acetylation reagent 5%) solid Potassium monofluoride-alumina compound; dress up reflux, in 70 ℃ of stirring reactions 50 minutes.The reaction finish after while hot suction filtration remove solid catalyst, filtrate is added (volume ratio of reaction liquid and frozen water is about 1: 1.1) in the frozen water, white precipitate appears, suction filtration obtains the white powder solid.
Purify: the thick product of gained is dissolved in a certain amount of dehydrated alcohol, stirring makes it to dissolve fully, filter, keep filtrate, and its adding is filled in the beaker of clean frozen water, produce white precipitate, beaker is put in leaves standstill 3 hours in the ice-water bath, treat that solid separates out the back suction filtration fully, obtain the brilliant white solid, it is dry that this solid is put into vacuum drying oven, weighing.The gained solid masses is 10.03g, productive rate 80.89%.
Embodiment 4:
In a there-necked flask, add 10.03g trifluoromethyl Whitfield's ointment and 14ml acetic anhydride (mass ratio of the two is 1: 2); and 0.92g (consumption be acetylation reagent 35%) solid Potassium monofluoride-alumina compound; dress up reflux, in 70 ℃ of stirring reactions 80 minutes.The reaction finish after while hot suction filtration remove solid catalyst, filtrate is added in the frozen water, white precipitate appears, suction filtration obtains the white powder solid.
Purify: the gained solid is dissolved in saturated NaHCO
3In the solution, produce a large amount of bubbles, stirring is emitted bubble, removes by filter insolubles, filtrate is slowly poured in the beaker that fills concentrated hydrochloric acid (about 45ml) then, the limit edged stirs, and bubble is fully emitted, and beaker is placed on leaves standstill 1 hour in the ice-water bath then, treat solid separate out fully the back suction filtration, obtain the white powder solid, the 15.07g of dry back weighing, productive rate 90.6%.
Embodiment 5:
In a there-necked flask, add 10g trifluoromethyl Whitfield's ointment and 14ml acetic anhydride (quality of the two is 1: 1.5); and 10 sulfuric acid: the mixture of sulfuric phosphoric acid that the mass ratio of phosphoric acid=1: 3 mixes (consumption be acetylation reagent 10%); dress up reflux; directly put into 70 ℃ water-bath, stirring reaction 40 minutes.Directly pour reaction liquid in a certain amount of frozen water (volume ratio of reaction liquid and frozen water is about 1: 1.3) after reaction is finished, produce a large amount of white precipitates immediately, suction filtration obtains the white powder solid.
Purify: the thick product of gained is dissolved in a certain amount of dehydrated alcohol, stirring makes it to dissolve fully, filter, keep filtrate, and its adding is filled in the beaker of clean frozen water, produce white precipitate, beaker is put in leaves standstill 60 minutes in the ice-water bath, treat that solid separates out the back suction filtration fully, obtain the brilliant white solid, it is dry that this solid is put into vacuum drying oven, weighing.The gained solid masses is 10.1g, and productive rate is 82.1.
Claims (4)
1, the acetysalicylic process for catalytic synthesis of a kind of 4-trifluoromethyl is characterized in that:
A. earlier with raw material according to 4-trifluoromethyl Whitfield's ointment: the mass ratio of acetylation reagent=1: 0.5-3 mixes, again with mixture of sulfuric phosphoric acid or solid sulphuric acid hydrogen sodium or solid Potassium monofluoride-alumina compound according to acetylation reagent: mixture of sulfuric phosphoric acid or solid sulphuric acid hydrogen sodium=100: 0.5-10 mass ratio or according to acetylation reagent: solid Potassium monofluoride-alumina compound=100: the 10-35 mass ratio joins in the raw material, back flow reaction under 50-90 ℃ of temperature;
B. again reaction mixture is joined in the frozen water and leave standstill, filter and obtain the white powder solid;
C. at last with getting pure product after recrystallization method purification, the drying.
2, the acetysalicylic process for catalytic synthesis of a kind of 4-trifluoromethyl according to claim 1 is characterized in that described acetylation reagent is an acetic anhydride.
3, the acetysalicylic process for catalytic synthesis of a kind of 4-trifluoromethyl according to claim 1 is characterized in that described reflux time is 10-90 minute.
4, the acetysalicylic process for catalytic synthesis of a kind of 4-trifluoromethyl according to claim 1 is characterized in that described mixture of sulfuric phosphoric acid is meant sulfuric acid: phosphoric acid=1: the mixed solution that the 1-3 mass ratio is formed.
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|---|---|---|---|
| CNB2005100423191A CN1308282C (en) | 2005-01-11 | 2005-01-11 | Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid |
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| CNB2005100423191A CN1308282C (en) | 2005-01-11 | 2005-01-11 | Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid |
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| CN1680266A true CN1680266A (en) | 2005-10-12 |
| CN1308282C CN1308282C (en) | 2007-04-04 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101580469B (en) * | 2009-07-06 | 2011-07-27 | 成都顺道医药开发有限公司 | Preparation method of officinal 4-trifluoromethyl acetylsalicylic acid |
| CN101503355B (en) * | 2009-01-21 | 2012-05-09 | 吉林天强制药有限公司 | Synthetic refinement of triflusal |
| CN102617338A (en) * | 2012-02-29 | 2012-08-01 | 常州市阳光药业有限公司 | Preparation method of p-trifluoromethyl salicylic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4096252A (en) * | 1976-06-10 | 1978-06-20 | J. Uriach & Cia S.A. | 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents |
| KR100503267B1 (en) * | 2002-09-17 | 2005-07-22 | (주)리드젠 | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid |
-
2005
- 2005-01-11 CN CNB2005100423191A patent/CN1308282C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503355B (en) * | 2009-01-21 | 2012-05-09 | 吉林天强制药有限公司 | Synthetic refinement of triflusal |
| CN101580469B (en) * | 2009-07-06 | 2011-07-27 | 成都顺道医药开发有限公司 | Preparation method of officinal 4-trifluoromethyl acetylsalicylic acid |
| CN102617338A (en) * | 2012-02-29 | 2012-08-01 | 常州市阳光药业有限公司 | Preparation method of p-trifluoromethyl salicylic acid |
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| CN1308282C (en) | 2007-04-04 |
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