CN1143624A - Process for synthesizing ketoprofen - Google Patents
Process for synthesizing ketoprofen Download PDFInfo
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- CN1143624A CN1143624A CN 95109877 CN95109877A CN1143624A CN 1143624 A CN1143624 A CN 1143624A CN 95109877 CN95109877 CN 95109877 CN 95109877 A CN95109877 A CN 95109877A CN 1143624 A CN1143624 A CN 1143624A
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- amino
- benzophenone
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- ketoprofen
- propionylization
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Abstract
A ketoprofen is synthesized from 2-amino-benzophenone, or 4-amino-benzophenone, or their amino-protecting compound through alpha-halopropionylating (or first propionylating and then halogenating), ketalization, rearrangement, hydrolysis, diazo removing amino and synthesizing ketoprofen. The process features low cost, no need of separating isomer generated in reaction, high yield and high purity of product.
Description
The present invention relates to a kind of new synthetic process of Ketoprofen BP 93.
Ketoprofen BP 93 (ketoprofen) is the non-steroidal anti-inflammatory analgesic, and is stronger than Ibuprofen BP/EP to the mitigation of pain, and effect is faster.The sixties by the exploitation of French Phone-Poulenc company, subsequently, particularly Japan is to the synthetic number of research projects of having done of Ketoprofen BP 93.In the existing Ketoprofen BP 93 synthetic method, the raw material that has is difficult to obtain; The synthetic route that has is long, and yield is low; The synthetic agent costliness that has; Impurity is difficult in the product that has separates, and causes cost to raise.
In order to overcome the deficiencies in the prior art, the invention provides a kind of is starting raw material with 2 (4)-amino-benzophenone, and its raw material is cheap and easy to get, and is easy to operate, product purity height, the Ketoprofen BP 93 new synthetic process that cost is low.
Technical scheme of the present invention is: with 2-amino-benzophenone or 4-amino-benzophenone and their amido protecting compound thereof is starting raw material; Through α-halogenation propionylization (or halogenation after the first propionylization), ketal, rearrangement, hydrolysis, diazonium deaminizating, synthetic Ketoprofen BP 93.
Because the introducing of amino (protection) is played activation to phenyl ring, and plays adjacency pair position positioning action, make the 1.2-virtue move and reset the yield height.
Characteristics of the present invention also are: acidylate gained isomer need not separate, and all can a few step reactions synthesize target product through the back.
Chemical equation:
One, be raw material with 2-amino-benzophenone
Two, be raw material with 4-amino-benzophenone
The invention has the advantages that: used starting raw material is cheap and easy to get; Through the reaction of five steps, reactions steps is few; Reaction gained isomer need not separate, and all can synthesize target product, and operating procedure is simple; Synthetic agent that need not be valuable and poisonous reagent, cost is low, pollution is few; The yield height, good product purity.
Embodiment
One, routine 1:2-amino-benzophenone route
(1) alpha-brominated propionylization:
Aluminum chloride 13.5g (0.101mol) is joined in an amount of dithiocarbonic anhydride,, reduce to room temperature then in 40 ℃ of insulations 15 minutes, add 2-acetylaminohydroxyphenylarsonic acid benzophenone 20g (0.084mol) in half an hour, dropping to 2-bromo propionyl chloride 12.3ml (0.10mol) in the said mixture below 10 ℃ in batches, temperature rising reflux 2 hours, cooling is in the impouring frozen water, tell organic layer, washing, reclaim under reduced pressure is dithiocarbonic anhydride to the greatest extent, drying, get isomer mixture 28.8g altogether, yield 92%.
(2) ketal, rearrangement
With the tosic acid of top propionyl product 20g (0.53mol) and ethylene glycol 7.9ml (0.14mol) and an amount of toluene and catalytic amount, stirring and refluxing is divided water-yielding stratum by water trap simultaneously; toluene layer returns, and continues to reflux 14 hours, after the cooling; pour among the ordinary water 150ml, tell organic layer, be washed to neutrality; reclaim under reduced pressure toluene about 2/3; add freshly prepd Ketoprofen BP 93 acid zinc 2g, back flow reaction 1.5 hours, reclaim under reduced pressure toluene; cooling then; add 40%NaOH solution 70ml, ethanol is an amount of, refluxes 3 hours; cooling; filter, filtrate is transferred PH=2 with 10% hydrochloric acid, filters; dry rearrangement product-isomer mixture 12.0g, the yield 84.5% of getting.
(3) diazonium deaminizating
At 0～5 ℃, with the above-mentioned rearrangement product of 10g (0.37mol), 2.85g Sodium Nitrite, 120ml 3N NaOH solution, 50ml water stirs half an hour, drips 90ml 18% hydrochloric acid in-10 ℃ then in 1 hour, filter, diazonium salt, in-10 ℃--join 12.3ml50%H under 5 ℃
3PO
2In, be stirred to room temperature, use benzene extraction then, behind the pressure reducing and steaming benzene, use the alcohol-water recrystallization, white powder 6.09g (deducted Ketoprofen BP 93 acid zinc conversion product) yield 64%mp93～95 ℃.
Total recovery: to 2-acetylaminohydroxyphenylarsonic acid benzophenone yield is 49.8%.
Two, example 2:
With 4-amino-benzophenone is raw material:
(1) acetyl protection amino
20g (0.102mol) 4-amino-benzophenone gradation is dissolved in the aceticanhydride, in stirring at room after half an hour, in the impouring frozen water, dry 4-acetylaminohydroxyphenylarsonic acid benzophenone 23.6g, yield 97%.
(2) alpha-brominated propionylization
FERRIC CHLORIDE ANHYDROUS 16.4g is joined an amount of 1, in the 2-ethylene dichloride, in 45 ℃ of insulations 15 minutes, gradation added 20g (0.084mol) 4-acetylaminohydroxyphenylarsonic acid benzophenone, drips alpha-brominated propionyl chloride 12.3ml (0.101mol) in 10～15 ℃, 20 ℃ are incubated 2 hours, in the impouring frozen water, tell organic layer, steam is towards the intact ethylene dichloride of gold-plating, cooling is filtered to such an extent that isomer mixture is total to 27.3g, yield 87.2%.
(3) ketal, rearrangement
Tosic acid stirring and refluxing dehydration with above-mentioned propionyl product 20g (0.053mol) and ethylene glycol 7.8ml (0.14mol) and an amount of toluene and catalytic amount; continue to reflux 17 hours; after the cooling, pour among the ordinary water 140ml, tell organic layer and be washed to neutrality; the most of toluene of reclaim under reduced pressure; add Zinic stearas 1g (1.59mmol), back flow reaction 1.5 hours, reclaim under reduced pressure toluene; cooling; add 35%NaOH liquid 70ml, ethanol is an amount of, refluxes 3 hours; cooling; filter, filtrate is transferred PH=2-3 with 10% hydrochloric acid, filters; get isomer mixture 11.8g altogether, yield 83%.
(4) diazonium deaminizating
With the aqueous solution of the fluorborate solution of the above-mentioned rearrangement product of 10g (0.037mol) and Sodium Nitrite 2.85g in-5～-10 ℃ parallel join fill that small amounts is cuprous, 18-hat-6 (0.003mol), chloroform 80ml, 12.3ml 50%H
3PO
2Mixed solution in, stir, be warming up to room temperature naturally, with benzene extraction three times, cold wash behind pressure reducing and steaming chloroform and the benzene, is used the alcohol-water recrystallization, must white powder 6.4g, MP93-95 ℃, yield 68%, total recovery: for 4-amino-benzophenone is 47.6%.
Claims (6)
1, a kind of synthesis technique of Ketoprofen BP 93; it is characterized in that: with 2-amino-benzophenone or 4-amino-benzophenone and their amido protecting compound thereof is starting raw material, through α-halogenation propionylization (or halogenation after the first propionylization), ketal, rearrangement, hydrolysis, diazonium deaminizating, synthetic Ketoprofen BP 93.
2, as the said technology of claim 1.It is characterized in that said alpha-halogen propionyl reagent is preferably alpha-brominated propionyl chloride.
3, as the said technology of claim 1, it is characterized in that said alpha-halogen propionylization, or the isomer mixture of halogenation gained after the propionylization, need not separate, can be directly used in several steps reactions in back.
4, as the said technology of claim 1, it is characterized in that said diazonium deaminizating, can in the presence of Red copper oxide, phase-transfer catalyst PEG-400 or 18 hats-6, carry out.
5, as the said technology of claim 1, when it is characterized in that being starting raw material with 2-amino-benzophenone and amido protecting compound thereof, its technology is: (representing with reaction formula)
6, as the said technology of claim 1, when it is characterized in that being starting raw material with 4-amino-benzophenone and amido protecting compound thereof, its technology is for being: (representing with reaction formula)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95109877 CN1143624A (en) | 1995-08-24 | 1995-08-24 | Process for synthesizing ketoprofen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95109877 CN1143624A (en) | 1995-08-24 | 1995-08-24 | Process for synthesizing ketoprofen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1143624A true CN1143624A (en) | 1997-02-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95109877 Pending CN1143624A (en) | 1995-08-24 | 1995-08-24 | Process for synthesizing ketoprofen |
Country Status (1)
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| CN (1) | CN1143624A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2808020A1 (en) | 2006-04-21 | 2014-12-03 | The Government Of The United States, As Represented by The Secretary Of Health And Human Services | Beta-Amyloid Pet Imaging Agents |
| CN105037059A (en) * | 2015-06-16 | 2015-11-11 | 青岛科技大学 | Preparation method of alpha-(4-substituted phenyl)isobutyric acid |
| CN106748723A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation method of Ketoprofen |
| CN106748718A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation technology of Ketoprofen |
-
1995
- 1995-08-24 CN CN 95109877 patent/CN1143624A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2808020A1 (en) | 2006-04-21 | 2014-12-03 | The Government Of The United States, As Represented by The Secretary Of Health And Human Services | Beta-Amyloid Pet Imaging Agents |
| CN105037059A (en) * | 2015-06-16 | 2015-11-11 | 青岛科技大学 | Preparation method of alpha-(4-substituted phenyl)isobutyric acid |
| CN106748723A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation method of Ketoprofen |
| CN106748718A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation technology of Ketoprofen |
| CN106748718B (en) * | 2016-12-07 | 2020-03-10 | 江苏工程职业技术学院 | Preparation process of ketoprofen |
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