CN106748718B - Preparation process of ketoprofen - Google Patents
Preparation process of ketoprofen Download PDFInfo
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- CN106748718B CN106748718B CN201611114323.9A CN201611114323A CN106748718B CN 106748718 B CN106748718 B CN 106748718B CN 201611114323 A CN201611114323 A CN 201611114323A CN 106748718 B CN106748718 B CN 106748718B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
Abstract
The invention discloses a preparation process of ketoprofen, which takes benzoyl chloride and acetanilide as initial raw materials and prepares the ketoprofen through the steps of acylation, deprotection, hydrolysis, diazotization reduction, Darzens reaction, oxidation and the like. The method has the advantages of cheap and easily-obtained raw materials, easy realization of the process, no dangerous process for reaction, high yield, mild reaction conditions, simple and convenient operation and low requirement on equipment.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation process of ketoprofen.
Background
Ketoprofen (Ketoprofen, KP), also known as Ketoprofen, ibuprofen, eubufen, or Profenid, chemically α -methyl-3-benzoylphenylacetic acid [ 2- (3-Benzoylphenyl) propanoic acid [ CAS: 22071-15-4 ] ], is an excellent 2-arylpropionic acid nonsteroidal anti-inflammatory analgesic drug developed by R bone-Poulenc chemists of R bone-Poulenc, house, Messer, and Moutounier in 1967.
Prior to the present invention, many methods for synthesizing ketoprofen have been reported. We refer to patents CN: 95109877.2; journal of chinese medical industry, 2004,35 (9): 520-521; journal of pharmaceutical chemistry, chinese, 2000, 36: 127-128. The reported synthesis process is carefully studied, and a new preparation process of ketoprofen is designed and developed.
(1) The specific route of patent CN:95109877.2 is as follows:
A:1、
2、OH-1，3、H+
B:1、NaNO2,HBF4,2、18-C-6/CHCl3,Cu2O,H3PO2
the process is carried out by α -halogeno-propionylation (or propionylation and halogenation), ketal, rearrangement, hydrolysis, diazotization deamination reaction to obtain ketoprofen product with total yield of 49.8%, wherein the unique point is that amino (protection) is introduced to enhance the meta-position positioning function of carbonyl, thus obviously improving the yield of 1, 2-aryl migration rearrangement.
(2) The Chinese journal of pharmaceutical chemistry, 2000, 36: 127-128. The specific route is as follows:
the process uses m-bromobenzoic acid as a raw material, and comprises acylation, Grignard reaction, Darzens reaction, decarboxylation and oxidation reaction to obtain ketoprofen with a total yield of 32%. The method is characterized in that darzens reaction is applied, aldehyde is synthesized by decarboxylation, and then ketoprofen is synthesized by oxidation. The key of the process is the synthesis of 3-acetyl benzophenone. The process route is short, but the grignard reaction is used, so the danger is high. At the same time, the yield of the route is low.
(3) Journal of chinese medical industry of literature 2004,35 (9): 520-521. The specific route is as follows:
the process takes nitroacetophenone as a raw material, and prepares the ketoprofen through carbonyl protection, condensation, deprotection, reduction, diazotization reduction and synthesis of 3-acetyl benzophenone, and finally Darzens reaction, hydrolysis, decarboxylation and oxidation one-pot method. The yield of the process reaches 44.6 percent. Compared with the two processes, the process route is greatly improved, but the raw materials used in the process are expensive, the reaction route is long, and the total yield is low.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides a preparation process of ketoprofen, which comprises the steps of selecting benzoyl chloride and acetanilide as raw materials, acylating with acetyl chloride, deprotecting, diazotizing, reducing and synthesizing to obtain 3-acetyl benzophenone, and finally reacting with Darzens, hydrolyzing, decarboxylating and oxidizing by a one-pot method to obtain the ketoprofen.
The invention content is as follows: a preparation process of ketoprofen comprises the following steps:
the first step is as follows: preparation of 4-Acylaminobenzophenone (1):
benzoyl chloride and acetanilide are used as raw materials, acylation reaction is carried out in a solvent to synthesize the compound (1), the used catalyst is aluminum trichloride, and the solvent is selected from dichloromethane, ethyl acetate, petroleum ether, diethyl ether, carbon disulfide, nitrobenzene and chloroform;
the second step is that: preparation of 2-acetylamino-5-benzoyl-acetophenone (2):
the (1) and acetyl chloride are subjected to acylation reaction in a nonpolar solvent to synthesize the (2), the used catalyst is aluminum trichloride, and the solvent is selected from dichloromethane, ethyl acetate, petroleum ether, diethyl ether, chloroform, carbon disulfide and nitrobenzene;
the third step: preparation of 2-acetyl-4-benzoylaniline (3):
deprotecting under acidic condition to synthesize (3), selecting hydrochloric acid or sulfuric acid as acid, controlling pH below 2 and temperature at 70-80 deg.C, selecting hydrochloric acid and sulfuric acid as acid, and selecting methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran and acetonitrile as solvent;
the fourth step: preparation of 3-acetylbenzophenone (4):
diazotizing and reducing the above (3) to synthesize the compound (4), wherein a reducing agent is selected from methanol, ethanol and isopropanol, and the reduction temperature is controlled to be 70-80 degrees; diazotizing acid selected from hydrochloric acid, sulfuric acid and glacial acetic acid;
the fifth step: preparation of ketoprofen (5):
reacting the raw material (4) with ethyl chloroacetate under an alkaline condition to synthesize α -epoxy acid ester, hydrolyzing under an alkaline condition, decarboxylating under an acidic condition, and oxidizing to obtain ketoprofen (5), wherein the alkali is strong alkali such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide and the like, and the oxidant is hydrogen peroxide;
as an optimization: the step 1 specifically comprises the following operations: benzoyl chloride, acetanilide and catalyst anhydrous aluminum trichloride in the molar ratio of 1 to 1 (1.01-1.1), and the reaction time is 5-7 hr, and the temperature of friedel acylation is 0-room temperature. After the reaction, quenching the reaction with diluted hydrochloric acid.
As an optimization: the step 2 specifically operates as follows: the mol ratio of 4-acetamidobenzophenone, acetyl chloride and catalyst anhydrous aluminum trichloride is 1: 1.05:1.1, the temperature of the Friedel-crafts acylation is 0 ℃ to the reflux, and the reaction time is 5-7 h. After the reaction, quenching the reaction with ice diluted hydrochloric acid.
As an optimization: the step 3 specifically operates as follows: dissolving 2-acetamido-5-benzoyl-acetophenone in alcohol, and adding 40% diluted hydrochloric acid or diluted sulfuric acid for reflux reaction for 2-4 h. Neutralizing with saturated sodium carbonate or sodium bicarbonate to pH 9-10.
As an optimization: the step 4 specifically comprises the following operations: dissolving 2-acetyl-4-benzoylaniline in concentrated hydrochloric acid, dropwise adding sodium nitrite solution with an equal molar amount at a mass ratio of 1:4, -10 ° -5 °, wherein the temperature does not exceed-5 ° during dropwise addition, and the dropwise adding is finished after about 30 minutes, carrying out heat preservation reaction for 1-2h, then adding a reducing agent methanol, ethanol or propanol, and carrying out reaction for 2h at 60-80 °.
As an optimization: the step 5 specifically comprises the following operations: the mol ratio of the 3-acetyl benzophenone to the ethyl chloroacetate to the sodium ethoxide is 1: 1.05:1.1, dissolving in absolute ethyl alcohol, stirring at room temperature, dropwise adding an ethanol solution of sodium ethoxide, refluxing for 2-3h after dropwise adding is finished, cooling to room temperature, adding a 30% sodium hydroxide solution, stirring for 1-2h, adjusting the pH to 2 with hydrochloric acid, refluxing for decarboxylation for 1-2h, cooling to room temperature, extracting with ethyl acetate, recovering the ethyl acetate, adding glacial acetic acid, 5% molar Amberlyst 15 and 1.5 molar hydrogen peroxide into residues, and reacting for 8-10h at 90 ℃.
Has the advantages that: the specific advantages of the invention are as follows:
the method has the advantages of cheap and easily-obtained raw materials, easy realization of the process, no dangerous process for reaction, high yield, mild reaction conditions, simple and convenient operation and low requirement on equipment.
Compared with the prior art, the process scheme avoids the use of expensive ketoprofen zinc catalyst, avoids the Grignard reaction and avoids the use of expensive reagents.
And (III) finally, after synthesizing aldehyde through a daezens reaction, catalyzing hydrogen peroxide by Amberlyst 15 to oxidize and synthesize carboxylic acid. The process has the advantages of environmental protection, catalyst recovery and reuse and low cost.
Detailed Description
The present invention will be described in detail with reference to specific examples.
The overview is as follows: a preparation process of ketoprofen comprises the following steps:
the first step is as follows: preparation of 4-Acylaminobenzophenone (1):
benzoyl chloride and acetanilide are used as raw materials, acylation reaction is carried out in a solvent to synthesize the compound (1), the used catalyst is aluminum trichloride, and the solvent is selected from dichloromethane, ethyl acetate, petroleum ether, diethyl ether, carbon disulfide, nitrobenzene and chloroform;
the second step is that: preparation of 2-acetylamino-5-benzoyl-acetophenone (2):
the (1) and acetyl chloride are subjected to acylation reaction in a nonpolar solvent to synthesize the (2), the used catalyst is aluminum trichloride, and the solvent is selected from dichloromethane, ethyl acetate, petroleum ether, diethyl ether, chloroform, carbon disulfide and nitrobenzene;
the third step: preparation of 2-acetyl-4-benzoylaniline (3):
deprotecting under acidic condition to synthesize (3), selecting hydrochloric acid or sulfuric acid as acid, controlling pH below 2 and temperature at 70-80 deg.C, selecting hydrochloric acid and sulfuric acid as acid, and selecting methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran and acetonitrile as solvent;
the fourth step: preparation of 3-acetylbenzophenone (4):
diazotizing and reducing the above (3) to synthesize the compound (4), wherein a reducing agent is selected from methanol, ethanol and isopropanol, and the reduction temperature is controlled to be 70-80 degrees; diazotizing acid selected from hydrochloric acid, sulfuric acid and glacial acetic acid;
the fifth step: preparation of ketoprofen (5):
reacting the raw material (4) with ethyl chloroacetate under an alkaline condition to synthesize α -epoxy acid ester, hydrolyzing under an alkaline condition, decarboxylating under an acidic condition, and oxidizing to obtain ketoprofen (5), wherein the alkali is strong alkali such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide and the like, and the oxidant is hydrogen peroxide;
the step 1 specifically comprises the following operations: benzoyl chloride, acetanilide and catalyst anhydrous aluminum trichloride in the molar ratio of 1 to 1 (1.01-1.1), and the reaction time is 5-7 hr, and the temperature of friedel acylation is 0-room temperature. After the reaction, quenching the reaction with diluted hydrochloric acid.
The step 2 specifically operates as follows: the mol ratio of 4-acetamidobenzophenone, acetyl chloride and catalyst anhydrous aluminum trichloride is 1: 1.05:1.1, the temperature of the Friedel-crafts acylation is 0 ℃ to the reflux, and the reaction time is 5-7 h. After the reaction, quenching the reaction with ice diluted hydrochloric acid.
The step 3 specifically operates as follows: dissolving 2-acetamido-5-benzoyl-acetophenone in alcohol, and adding 40% diluted hydrochloric acid or diluted sulfuric acid for reflux reaction for 2-4 h. Neutralizing with saturated sodium carbonate or sodium bicarbonate to pH 9-10.
The step 4 specifically comprises the following operations: dissolving 2-acetyl-4-benzoylaniline in concentrated hydrochloric acid, dropwise adding sodium nitrite solution with an equal molar amount at a mass ratio of 1:4, -10 ° -5 °, wherein the temperature does not exceed-5 ° during dropwise addition, and the dropwise adding is finished after about 30 minutes, carrying out heat preservation reaction for 1-2h, then adding a reducing agent methanol, ethanol or propanol, and carrying out reaction for 2h at 60-80 °.
The step 5 specifically comprises the following operations: the mol ratio of the 3-acetyl benzophenone to the ethyl chloroacetate to the sodium ethoxide is 1: 1.05:1.1, dissolving in absolute ethyl alcohol, stirring at room temperature, dropwise adding an ethanol solution of sodium ethoxide, refluxing for 2-3h after dropwise adding is finished, cooling to room temperature, adding a 30% sodium hydroxide solution, stirring for 1-2h, adjusting the pH to 2 with hydrochloric acid, refluxing for decarboxylation for 1-2h, cooling to room temperature, extracting with ethyl acetate, recovering the ethyl acetate, adding glacial acetic acid, 5% molar Amberlyst 15 and 1.5 molar hydrogen peroxide into residues, and reacting for 8-10h at 90 ℃.
Example 1.preparation of 4-Acylaminobenzophenone (1).
140g of benzoyl chloride and 148g of acetanilide, dissolving in 400g of chloroform, adding 145g of aluminum trichloride, reacting at room temperature for 8 hours, after the reaction is finished, slowly pouring the reaction solution into 500 ml of ice water of dilute hydrochloric acid, pouring while violently stirring, separating liquid, drying an organic layer with anhydrous sodium sulfate, and recovering a solvent under reduced pressure, wherein the organic layer is prepared from the following components in parts by weight: recrystallization from ethyl acetate 1:1 gave 222g of intermediate 4-acetylaminobenzophenone (1) in 93% yield.
Example 2.2 preparation of acetylamino-5-benzoyl-acetophenone (2)
120g of 4-acetamidobenzophenone and 67g of aluminum trichloride are dissolved in 400g of ethyl acetate, 40g of acetyl chloride is slowly dripped in ice bath, dripping is completed in 30 minutes, after dripping is completed, the mixture reacts for 6 hours at room temperature, the reaction is completed, the reaction solution is slowly poured into 150 ml of ice water of dilute hydrochloric acid, stirring and liquid separation are carried out while pouring, the organic layer is dried by anhydrous sodium sulfate, and the solvent and petroleum ether are recovered under reduced pressure: recrystallization from ethyl acetate 5:3 gave 139g of 2-acetylamino-5-benzoyl-acetophenone (2) in 94% yield.
EXAMPLE 3 preparation of 2-acetyl-4-benzoylaniline (3)
139g of 2-acetamido-5-benzoyl-acetophenone is dissolved in 200ml of ethanol, 100 ml of 40% diluted hydrochloric acid is added, heating and refluxing are carried out for 2h, after the reaction is finished, the solution is cooled to room temperature, and sodium carbonate solution is dropwise added under ice bath until the solution is alkaline. Extracting with ethyl acetate, drying with anhydrous sodium sulfate, and recovering solvent under reduced pressure, wherein the weight ratio of petroleum ether: recrystallization from ethyl acetate 1:1 gave 109.6g of 2-acetyl-4-benzoylaniline (3) in 98% yield.
EXAMPLE 4.3 preparation of Acetylbenzophenone (4)
60g of 2-acetyl-4-benzoylaniline, 200g of concentrated hydrochloric acid, cooling to-10 ℃ in an ice bath, dropwise adding a sodium nitrite solution (17g is dissolved in 50 ml of deionized water), wherein the temperature is not more than-5 ℃ in the dropwise adding process, the dropwise adding is finished after about 30 minutes, the temperature is kept for 1-2 hours, after the reaction is finished, 50 ml of propanol is added, the reaction is carried out for 2 hours at the temperature of 60-80 ℃, after the reaction is finished, 200g of ethyl acetate is extracted, the ethyl acetate is washed to be neutral, anhydrous sodium sulfate is dried, the filtration is carried out, the solvent is recovered under reduced pressure, and the 3-acetylbenzophenone is obtained by reduced pressure distillation (0.1Mpa, 155-inch) at 48g, and.
Example 5 ketoprofen (5)
44g of 3-acetyl benzophenone and 24g of ethyl chloroacetate, dissolving in 100 ml of ethanol, dropwise adding an ethanol solution (100 ml, 15g of sodium ethoxide) of sodium ethoxide under stirring, refluxing for 2-3h after dropwise adding is finished, cooling to room temperature, adding a 30% sodium hydroxide solution (100 ml), stirring for 2h, adjusting the pH to 2 with hydrochloric acid, refluxing for decarboxylation for 2h, extracting to room temperature and 80 ml of ethyl acetate, washing to be neutral, recovering ethyl acetate under reduced pressure, adding 10 ml of glacial acetic acid, 2g of Amberlyst 15,40 ml of hydrogen peroxide, and reacting at 90 ℃ for 10 h. After the reaction is finished, cooling to room temperature, filtering, adjusting the pH of the filtrate to 9-10 by using 20% sodium hydroxide, extracting by using 20 ml of ethyl acetate, adjusting the pH of the aqueous phase to 2 by using 6mol of hydrochloric acid, extracting by using 50 ml of ethyl acetate, washing by using water to be neutral, drying by using anhydrous sodium sulfate, filtering, adding 10 ml of petroleum ether into the filtrate for recrystallization, filtering, and drying a filter cake to obtain 41g of white crystalline powder with the yield of 83%.
The specific advantages of the invention are as follows: firstly, the raw materials are cheap and easy to obtain, and the process is easy to realize. Secondly, the reaction has no dangerous process and high yield. Thirdly, the reaction condition is mild, the operation is simple and convenient, and the requirement on equipment is low.
The present invention is not limited to the above-mentioned preferred embodiments, and any other products in various forms can be obtained by anyone in the light of the present invention, but any changes in the shape or structure thereof, which have the same or similar technical solutions as those of the present application, fall within the protection scope of the present invention.
Claims (6)
1. A preparation process of ketoprofen is characterized by comprising the following steps: the method comprises the following steps:
the first step is as follows: preparation of 4-acetamidobenzophenone:
benzoyl chloride and acetanilide are used as raw materials, and are subjected to acylation reaction in a solvent to synthesize 4-acetamido benzophenone, the used catalyst is aluminum trichloride, and the solvent is dichloromethane, ethyl acetate, petroleum ether, diethyl ether, carbon disulfide, nitrobenzene and chloroform;
the second step is that: preparation of 2-acetamido-5-benzoyl-acetophenone:
the 4-acetamidobenzophenone and acetyl chloride are subjected to acylation reaction in a nonpolar solvent to synthesize 2-acetamido-5-benzoyl-acetophenone, the used catalyst is aluminum trichloride, and the solvent is selected from dichloromethane, ethyl acetate, petroleum ether, diethyl ether, chloroform, carbon disulfide and nitrobenzene;
the third step: preparation of 2-acetyl-4-benzoylaniline:
deprotecting under acidic condition to synthesize 2-acetyl-4-benzoylaniline, selecting acid hydrochloric acid or sulfuric acid, controlling pH below 2, controlling temperature at 70-80 deg.C, and selecting methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, and acetonitrile as solvent;
the fourth step: preparation of 3-acetylbenzophenone:
diazotizing and reducing the 2-acetyl-4-benzoyl aniline to synthesize 3-acetyl benzophenone, wherein a reducing agent is selected from methanol, ethanol and isopropanol, and the reduction temperature is controlled at 70-80 ℃; diazotizing acid selected from hydrochloric acid, sulfuric acid and glacial acetic acid;
the fifth step: preparation of ketoprofen:
the 3-acetyl benzophenone reacts with ethyl chloroacetate under alkaline conditions to synthesize α -epoxy acid ester, the hydrolysis is carried out under alkaline conditions, decarboxylation is carried out under acidic conditions, ketoprofen is prepared by oxidation, the alkali is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide and the oxidant is hydrogen peroxide.
2. The process for preparing ketoprofen according to claim 1, characterized in that: the first step is specifically operated as follows: benzoyl chloride, acetanilide and catalyst anhydrous aluminum trichloride in the molar ratio of 1 to 1.01-1.1, the temperature of friedel-crafts acylation is 0-room temperature, the reaction time is 5-7h, and after the reaction is finished, quenching reaction is carried out by using dilute hydrochloric acid.
3. The process for preparing ketoprofen according to claim 1, characterized in that: the second step is specifically operated as follows: the mol ratio of 4-acetamidobenzophenone, acetyl chloride and catalyst anhydrous aluminum trichloride is 1: 1.05:1.1, the temperature of friedel-crafts acylation is 0 ℃ to reflux, the reaction time is 5-7h, and after the reaction is finished, the reaction is quenched by using ice dilute hydrochloric acid.
4. The process for preparing ketoprofen according to claim 1, characterized in that: the third step is specifically operated as follows: dissolving 2-acetamido-5-benzoyl-acetophenone in alcohol, adding 40% diluted hydrochloric acid or diluted sulfuric acid, refluxing for 2-4 hr, and neutralizing with saturated sodium carbonate or sodium bicarbonate until pH is 9-10.
5. The process for preparing ketoprofen according to claim 1, characterized in that: the fourth step specifically operates as follows: dissolving 2-acetyl-4-benzoylaniline in concentrated hydrochloric acid at a mass ratio of 1:4, dropwise adding an equimolar amount of sodium nitrite solution at-10 to-5 ℃, wherein the temperature does not exceed-5 ℃ in the dropwise adding process, dropwise adding the solution after 30 minutes, keeping the temperature for reaction for 1 to 2 hours after the dropwise adding is finished, and then adding a reducing agent methanol, ethanol or propanol for reaction for 2 hours at 60 to 80 ℃.
6. The process for preparing ketoprofen according to claim 1, characterized in that: the fifth step specifically operates as follows: the mol ratio of the 3-acetyl benzophenone to the ethyl chloroacetate to the sodium ethoxide is 1: 1.05:1.1, dissolving in absolute ethyl alcohol, stirring at room temperature, dropwise adding an ethanol solution of sodium ethoxide, refluxing for 2-3h after dropwise adding is finished, cooling to room temperature, adding a 30% sodium hydroxide solution, stirring for 12h, adjusting the pH to 2 by using hydrochloric acid, cooling to room temperature after refluxing for decarboxylation for 1-2h, extracting by using ethyl acetate, recovering the ethyl acetate, adding glacial acetic acid, 5% molar Amberlyst 15 and 1.5 molar hydrogen peroxide into residues, and reacting for 8-10h at 90 ℃.
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|---|---|---|---|---|
| FR2403326A1 (en) * | 1977-09-17 | 1979-04-13 | Ricorvi Sa | Benzoyl:phenyl-propionic acid prepn. - from 3-halo-benzophenone via metal complex |
| CN1143624A (en) * | 1995-08-24 | 1997-02-26 | 胡钊侠 | Process for synthesizing ketoprofen |
| CN101250103A (en) * | 2007-12-29 | 2008-08-27 | 武穴市迅达药业有限公司 | Method for synthesizing ketoprofen by using ethylbenzene as raw material |
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2016
- 2016-12-07 CN CN201611114323.9A patent/CN106748718B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2403326A1 (en) * | 1977-09-17 | 1979-04-13 | Ricorvi Sa | Benzoyl:phenyl-propionic acid prepn. - from 3-halo-benzophenone via metal complex |
| CN1143624A (en) * | 1995-08-24 | 1997-02-26 | 胡钊侠 | Process for synthesizing ketoprofen |
| CN101250103A (en) * | 2007-12-29 | 2008-08-27 | 武穴市迅达药业有限公司 | Method for synthesizing ketoprofen by using ethylbenzene as raw material |
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| Title |
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| 酮基布洛芬的合成工艺研究;吕布 等;《中国药物化学杂志》;20000620;第10卷(第2期);第127-128页 * |
| 酮洛芬的合成;胡钊侠;《中国医药工业杂志》;20040920;第35卷(第9期);520-521 * |
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