Ketone ibuprofen intermediate and preparation method and application thereof
阅读说明：本技术 一种酮基布洛芬中间体及其制备方法和应用 (Ketone ibuprofen intermediate and preparation method and application thereof ) 是由 高照波 刘声民 王长发 郭必豹 郑辉 胡剀 梅义将 于 2018-08-24 设计创作，主要内容包括：本发明涉及医药合成领域,具体涉及一种酮基布洛芬中间体及其制备方法和应用。本发明以对或邻硝基卤苯或其混合物为原料,先与苯乙腈经狄尔斯-阿尔德反应形成异恶唑化合物,后依次经氧化反应、取代反应、还原反应、脱氨基、脱酯基和酸性水解反应制备得到酮洛芬。反应式如下：<Image he="487" wi="700" file="DDA0001775989480000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,X<Sub>2</Sub>或<Image he="150" wi="310" file="DDA0001775989480000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>位于硝基或者氨基的邻位或者对位,R<Sub>1</Sub>为-CONR<Sub>4</Sub>R<Sub>5</Sub>、-COX<Sub>1</Sub>、-COOR<Sub>2</Sub>或-CN,R<Sub>2</Sub>、R<Sub>3</Sub>、R<Sub>4</Sub>、R<Sub>5</Sub>、R<Sub>6</Sub>相同或不相同地为H或C<Sub>1</Sub>-C<Sub>6</Sub>的烷基,X<Sub>1</Sub>、X<Sub>2</Sub>相同或不同地为F、Cl、Br或I。(The invention relates to the field of medicine synthesis, and particularly relates to a ketoprofen intermediate, and a preparation method and application thereof. The invention takes p-or o-nitro halogen benzene or the mixture thereof as raw material, and the raw material and benzyl cyanide are firstly subjected to Diels-Alder reaction to form isoxazolizationAnd the ketoprofen is prepared by sequentially carrying out oxidation reaction, substitution reaction, reduction reaction, deamination, transesterification and acidic hydrolysis on the compound. The reaction formula is as follows: wherein, X 2 Or In ortho-or para-position to the nitro or amino group, R 1 is-CONR 4 R 5 、‑COX 1 、‑COOR 2 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Are, identically or not, H or C 1 ‑C 6 Alkyl of (A), X 1 、X 2 Identical or different F, Cl, Br or I.)
1. A ketoprofen intermediate compound of formula III or IV, having the following structural formula:
wherein the content of the first and second substances,
2. A preparation method of a compound shown in a formula III is characterized in that the compound is prepared by a substitution reaction of a compound shown in a formula II,
wherein R is1、R2、R3、R4、R5、R6Is as defined in claim 1, X2Is F, Cl, Br or I.
3. The preparation method of claim 2, wherein the compound of formula II is prepared by oxidation of the compound of formula I,
wherein, X2Is as defined in claim 2.
4. The method according to claim 3, wherein the reactant of the oxidation reaction is O3、Na2Cr2O7、KMnO4、O2/Co(OAc)2、H2CrO4Jones reagent, dilute sulfuric acid, active MnO2PDC reagent, O2/V2O5、NaBO3-4H2O/AcOH, TFD reagent, DMO reagent, sodium perborate, epoxyketone, oxone or RuCl3/H2O2。
5. A preparation method of a compound shown in a formula IV is characterized in that the compound is prepared from a compound shown in a formula III through a reduction reaction,
wherein the content of the first and second substances,in ortho-or para-position to the amino group, R1is-CONR4R5、-COX1、-COOR6or-CN, R2、R3、R4、R5、R6Are, identically or not, H or C1-C6Alkyl of (A), X1Is F, Cl, Br or I.
6. Use according to claim 5, wherein the reagent of the reduction reaction is Fe/AcOH, Fe/HCl, Zn/HCl, Sn/HCl, Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2Or Pd (OH)2/H2。
7. The process of claim 3, wherein the compound of formula I is prepared by reacting a compound of formula I' with phenylacetonitrile in a Dels-Alder reaction of the formula:
wherein, X2Is as defined in claim 2.
8. The process of claim 7, wherein the compound of formula I' is
9. A process for preparing ketoprofen compound of general formula (IV) includes such steps as deamination, deesterification and acidic hydrolysis,
wherein the content of the first and second substances,
10. A method for preparing ketoprofen general formula compounds is characterized in that the ketoprofen general formula compounds are prepared by six steps of oxidation, substitution, reduction, deamination, de-esterification and acidic hydrolysis, and the reaction formula is as follows:
wherein, X2OrIn ortho-or para-position to the nitro or amino group, R1is-CONR4R5、-COX1、-COOR2or-CN, R2、R3、R4、R5、R6Are, identically or not, H or C1-C6Alkyl of (A), X1、X2Identical or different F, Cl, Br or I.
11. The method of claim 10, wherein the reaction formula is as follows:
Technical Field
The invention relates to the field of medicine synthesis, and particularly relates to a ketoprofen intermediate, and a preparation method and application thereof.
Background
Ketoprofen (Ketoprofen), also known as "Ketoprofen", was first marketed in france in 1973, and then entered china officially in the 80 s, and various dosage forms such as oral tablets, patches, and films have been developed and widely used at home and abroad. The medicine is non-steroidal antiinflammatory and analgesic, has antiinflammatory, antipyretic, and analgesic effects, and is mainly used for treating rheumatoid arthritis, rheumatic arthritis, osteoarthritis, ankylosing spondylitis, gout, etc. It has analgesic effect superior to similar medicines and long retention time. It has less toxic side effect and adverse reaction such as intestinal and stomach discomfort or rash, headache and tinnitus.
Ketoprofen has the chemical name of 3-benzoyl- α -methylphenylacetic acid and has the following structural formula:
in the prior art, there are mainly 4 commonly used methods for the preparation of ketoprofen:
1. preparing ketoprofen by taking 3-methylbenzoic acid as raw material through 6 steps of reaction
In European patent application EP0209905 (Applicant: NIPPON PETROEMICALS COMPANY, LIMITED, filing date: 24.07.1986) a process for the preparation of ketoprofen starting from 3-methylbenzoic acid by 6 steps is disclosed:
this process has the following disadvantages:
(1) in step 3 of the method, under the action of a bromine simple substance, (3- (methyl) phenyl) (phenyl) methanone, one hydrogen on a methyl is replaced by one bromine, and then (3- (bromomethyl) phenyl) (phenyl) methanone is prepared. However, in the actual operation process, the step is often accompanied by a plurality of side reactions, so that the final product contains (3- (bromomethyl) phenyl) (phenyl) methanone, (3- (dibromomethyl) phenyl) (phenyl) methanone and (3- (tribromomethyl) phenyl) (phenyl) methanone and is difficult to purify;
(2) in the method, a reaction reagent KCN used in the step 4 is a highly toxic compound;
(3) step 5 of the method uses MeI which is a highly toxic compound;
(4) in the method, two hydrogens at the-CN ortho-position C of the reactant 2- (3-benzoylphenyl) acetonitrile in the step 5 are possibly substituted by methyl, so that a reaction product finally obtained by the reaction contains 2- (3-benzoylphenyl) propionitrile and 2-methyl-2- (3-benzoylphenyl) propionitrile simultaneously, and the purification is difficult.
2. Preparing ketoprofen by using 2- (3-benzoylphenyl) acetic acid pivalic anhydride as a raw material through 5-step reaction
In French patent application FR2659968 (Applicant: CENTRE NAT RECH SCIENT, filing date: 1990, 03, 21) a process for the preparation of ketoprofen starting from 2- (3-benzoylphenyl) acetic acid pivalic anhydride by 5 reactions is disclosed:
this process has the following disadvantages:
(1) the method needs to carry out the step 2 and the step 3 in an environment of-40 ℃, and has harsh reaction conditions;
(2) the MeI used in step 4 of the method is a highly toxic compound.
3. 1-bromo-3-vinyl benzene is used as raw material to prepare ketoprofen through 5 steps of reaction
In European patent EP0282065 (Applicant: NIPPON PETROCHEMICALS CO LTD, filing date: 03/10/1988) a process for the preparation of ketoprofen starting from 1-bromo-3-vinylbenzene by a 5-step reaction is disclosed:
this process has the following disadvantages:
(1) the method requires the step 4 of preparing PdCl2Under the catalytic action of the palladium reagent, and the market price of the palladium reagent is higher;
(2) in the step 5 of the method, potassium permanganate is used as an oxidant, and a manganese-containing compound easily causes serious pollution to the environment, so that solid waste treatment of manganese is required at the later stage.
In view of the above, the existing production processes are not suitable for commercial scale operations for the production of ketoprofen, and there is therefore a need for an improved and commercially viable process which solves the problems associated with the prior art processes and which makes them suitable for large scale production.
Disclosure of Invention
In order to solve the technical problems, the invention provides a ketoprofen intermediate, which is used as a raw material to prepare ketoprofen and compounds with a general formula thereof, so that the problems of high production cost, high toxic reaction reagents, a lot of reaction byproducts and harsh reaction conditions in the existing preparation process are solved, and the ketoprofen intermediate is suitable for industrial production.
The specific scheme of the process is as follows:
in order to realize the technical purpose of the invention, the invention provides the following technical scheme:
in a first aspect the invention provides intermediates iii or iv of ketoprofen,
wherein the content of the first and second substances,
More preferably, R1is-CONR4R5、-COX1、-COOR6or-CN, R2、R4、R6Identical or different H, methyl, ethyl, tert-butyl or isopropyl, R5Is H, methyl, tert-butyl or isopropyl, R3Is H or-CH3，X1Is Cl or Br;
more preferably, R1is-COOH, -CONH2、-CONHCH3、-CO(CH3)2、-CONHCH2CH3、-CON(CH2CH3)2-CN, -COCl or-COBr, R2Is H, methyl, ethyl, tert-butyl or isopropyl, R3Is H or-CH3；
Most preferably, R1is-CN, R2Is methyl or ethyl, R3Is H or-CH3；
In a second aspect, the invention provides a process for the preparation of ketoprofen intermediate III: the intermediate compound shown in formula III can be prepared by carrying out three-step reactions of Diels-Alder reaction (D-A reaction for short), oxidation reaction and substitution reaction on p-nitro halogen benzene or o-nitro halogen benzene or a mixture thereof,
wherein, X2OrIn ortho-or para-position to the nitro or amino group, R1is-CONR4R5、-COX1、-COOR2or-CN, R2、R3、R4、R5、R6Are, identically or not, H or C1-C6Alkyl of (A), X1、X2Identical or different F, Cl, Br or I.
According to the preparation method of the compound of the formula III, the Diels-Alder reaction can be a reaction of p-nitro halogen benzene or o-nitro halogen benzene or a mixture thereof with benzyl cyanide to obtain the compound of the structure of the formula I, wherein the reaction formula is as follows:
X2in ortho or para position to the nitro or amino group, X2Identically or differently, F, Cl, Br or I, preferably chlorine or bromine.
Preferably, the above reaction formula is:
wherein, X2In ortho or para position to the nitro or amino group, X2Identical or different F, Cl, Br or I.
Most preferably, the above reaction formula is as follows:
wherein the chlorine is in the ortho or para position relative to the nitro group.
The compound of formula I' may be according to the Diels-Alder reaction described aboveOf a single compound or of a mixture in any ratio, X2The definition of (1) is as above;
according to the Diels-Alder reaction described above, X in the compound of formula I2With X in the compound of formula I2The positions of the two are correspondingly consistent;
according to the Diels-Alder reaction, a catalyst may or may not be added;
the D-A reaction catalyst may be a Lewis acid, preferably AlCl, according to the Diels-Alder reaction described above3、BF3、SnCl4Or TiCl4Most preferred is AlCl3。
According to the preparation method of the compound of the formula III, the oxidation reaction can be that the benzisoxazole ring on the compound of the formula I is oxidized to obtain the compound of the formula II, and the reaction formula is as follows:
wherein, X2In ortho or para position to the nitro or amino group, X2Is F, Cl, Br or I;
preferably, the above reaction formula is as follows:
wherein, X2Is Cl or Br;
most preferably, the above reaction formula is as follows:
according to the above oxidation reaction, the compound of formula I may be
According to the above oxidation reaction, X in the compound of formula II2With X in the compound of formula I2Position ofThe positions are correspondingly consistent;
according to the above oxidation reaction, the oxidation reaction reagent may be a strong oxidizer stronger in acidity than nitric acid, preferably O3、Na2Cr2O7、KMnO4、O2/Co(OAc)2、H2CrO4Jones reagent, dilute sulfuric acid, active MnO2PDC reagent, O2/V2O5、NaBO3-4H2O/AcOH, TFD reagent, DMO reagent, sodium perborate, epoxyketone, oxone or RuCl3/H2O2More preferably O3、Na2Cr2O7、KMnO4Dilute nitric acid, dilute sulfuric acid, active MnO2TFD reagent, DMO reagent or epoxidised ketone, most preferably O3；
According to the above oxidation reaction, the oxidation reaction solvent may be a solvent that most closely matches the strong oxidant used; most preferably, when the strong oxidant used is O3The reaction solvent is DMF/H2O；
According to the substitution reaction described above, the oxidation reaction temperature may be 20 to 60 ℃, most preferably 40 ℃;
according to the above substitution reaction, the oxidation reaction time may be 0.8 to 1.2 hours, most preferably 1.0 hour;
according to the above process for the preparation of the compound of formula III, the substitution may be by-X on the compound of formula II2The group is substituted by a compound of formula II' in the presence of a base to obtain a compound of formula III:
wherein, X2And
More preferably, the above reaction formula is as follows:
wherein, X2And
more preferably, the above reaction formula is as follows:
wherein, X2Andin ortho-or para-position to the amino group, R1is-CONR4R5、-COX1、-COOR6or-CN, R2、R3、R4、R5、R6Identical or different H, methyl, ethyl, tert-butyl, isopropyl, X2、X1Identical or different are Cl or Br.
More preferably, the above reaction formula is as follows:
wherein, X2And
Most preferably, the above reaction formula is as follows:
wherein Cl and
According to the above substitution reaction, the compound of formula II may beAnd
According to the above substitution reaction, in the compound of the formula III
According to the substitution reaction described above, the base may be a bronsted base, preferably a carbonate, phosphate, oxide, hydroxide, alkoxide, phenoxide, amine, metal amide, fluoride or guanidine, more preferably potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide, most preferably sodium carbonate;
according to the above substitution reaction, the substitution reaction solvent may be an alcoholClass, low molecular ester, halogenated alkane, ketone, ether, organic amine, benzene, C1-C4Preferably methanol, ethyl acetate, ethanol, chloroform, acetonitrile, dichloromethane, acetone, diethyl ether, triethylamine, pyridine, ethylenediamine, acetic acid, chlorobenzene, N-dimethylaniline, N-dimethylformamide, glycerol, ethylene glycol, tetrahydrofuran, toluene or benzene, more preferably methanol, ethyl acetate, ethanol, chloroform, dichloromethane, acetone, pyridine, N-dimethylaniline, N-dimethylformamide, tetrahydrofuran, toluene or benzene, most preferably N, N-dimethylformamide;
according to the above substitution reaction, the substitution reaction temperature may be 50 to 100 ℃, most preferably 80 ℃;
according to the above substitution reaction, the substitution reaction time may be 0.2 to 0.8 hours, most preferably 0.5 hours;
in a third aspect, the invention provides a process for the preparation of an intermediate compound of formula iv:
the intermediate compound shown in the formula IV can be prepared from a compound shown in the formula III through a reduction reaction,
wherein the content of the first and second substances,
More preferably, the above reaction formula is as follows:
wherein the content of the first and second substances,
More preferably, the above reaction formula is as follows:
wherein the content of the first and second substances,
more preferably, the above reaction formula is as follows:
wherein the content of the first and second substances,
Most preferably, the above reaction formula is as follows:
according to the above reduction reaction, the compound of formula III may be
According to the above reduction reaction, in the compound of formula IV,
The reduction reagent can be Fe/AcOH, Fe/HCl, Zn/HCl, Sn/HCl, Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2Or Pd (OH)2/H2Preferably Fe/AcOH, Fe/HCl, Zn/HCl, Sn/HCl, Pd/H2、Pd-C/H2、Pt/H2、Ni/H2、PtO2/H2Or Pd (OH)2/H2More preferably Fe/AcOH, Fe/HCl, Pd/H2Most preferably Pd/H2；
According to the above reduction reaction, the reduction reaction solvent may be an alcohol, an alcohol/water, an alkylbenzene, a low molecular ester, benzene, or a low molecular ester/water, preferably methanol, ethanol, isopropanol, n-butanol, toluene, benzene, methanol/water, ethanol/water, isopropanol/water, n-butanol/water, ethyl acetate/water, ethylbenzene, or ethyl acetate, more preferably toluene, benzene, methanol, ethanol, ethyl acetate/water, isopropanol, or ethyl acetate, most preferably methanol;
according to the reduction reaction described above, the reduction reaction temperature may be 15-35 ℃, most preferably 25 ℃;
according to the above reduction reaction, the reduction reaction time may be 3.5 to 6.5 hours, most preferably 5 hours;
the fourth aspect of the invention provides a preparation method of ketoprofen general formula compound with a structure shown in formula VII.
The intermediate compound shown in formula IV can be prepared into ketoprofen general formula compound with the structure shown in formula VII through three steps of reactions of deamination, deesterification and acidic hydrolysis,
wherein the content of the first and second substances,
according to the above process for the preparation of the compound of formula VII, the deamination reaction can be-NH-on the compound of formula IV2Removing the group to obtain the compound with the structure of the formula V,
wherein the content of the first and second substances,
More preferably, the above reaction formula is as follows:
wherein the content of the first and second substances,in ortho-or para-position to the amino group, R1is-CONR4R5、-COX1or-CN, R2、R3、R4、R5Identical or different H, methyl, ethyl, tert-butyl or isopropyl, X1Is Cl or Br;
more preferably, the above reaction formula is as follows:
wherein the content of the first and second substances,
Most preferably, the above reaction formula is as follows:
according to the above deamination reaction, the compound of formula IV may be
According to the above deamination reaction, the deamination reagent can be CO/H+、H2S、H2S/H+、Na2S/H+、K2S/H+、HI、HI/H+、NaI/H+、KI/H+、HNO2、HNO2/H+、NaNO2/H+、KNO2/H+、H2SO3、H2SO3/H+、Na2SO3/H+、K2SO3/H+、KBH4、NaBH4、FeSO4Or LiAlH4Preferably CO/HCl, H2S、H2S/HCl、Na2S/HCl、K2S/HCl、HI、HI/HCl、NaI/HCl、KI/HCl、HNO2、HNO2/HCl、NaNO2/HCl、KNO2/HCl、H2SO3、H2SO3/HCl、Na2SO3/HCl、K2SO3/HCl、KBH4、NaBH4、FeSO4Or LiAlH4More preferably H2S、H2S/HCl、Na2S/HCl、K2S/HCl、HNO2、HNO2/HCl、NaNO2/HCl、KNO2/HCl、H2SO3、H2SO3/HCl、Na2SO3/HCl or K2SO3HCl, more preferably HNO2、HNO2/HCl、NaNO2HCl or KNO2HCl, most preferably NaNO2/HCl；
According to the above deamination reaction, the deamination reaction solvent may be alcohols, alcohols/water, alkylbenzene, benzene, low molecular esters/water, preferably methanol, ethanol, isopropanol, n-butanol, toluene, ethylbenzene, benzene, methanol/water, ethanol/water, isopropanol/water, n-butanol/water, ethyl acetate/water, more preferably toluene, benzene, methanol, ethanol, isopropanol, most preferably ethanol;
according to the above deamination reaction, the deamination reaction temperature may be 0-15 ℃, most preferably 5 ℃;
according to the above deamination reaction, the deamination reaction time may be 0.5-1.5 hours, most preferably 1 hour.
According to the preparation method of the compound shown in the formula VII, the ester group removing reaction is that the ester group on the compound shown in the formula V is removed to obtain the compound shown in the formula VI,
wherein R is1is-CONR4R5、-COX1、-COOR6or-CN, R2、R3、R4、R5Are, identically or not, H or C1-C6Alkyl of (A), X1Is F, Cl, Br or I.
More preferably, the above reaction formula is as follows:
wherein R is1is-CONR4R5、-COX1、-COOR5or-CN, R2、R3、R4、R5Are, identically or not, H or C1-C6Alkyl of (A), X1Is F, Cl, Br or I.
Preferably, the above reaction formula is as follows:
wherein R is1is-CONR4R5、-COX1or-CN, R2、R3、R4、R5Identical or different H, methyl, ethyl, tert-butyl or isopropyl, X1Is F, Cl, Br or I.
More preferably, the above reaction formula is as follows:
wherein R is1is-CN, R2Is methyl or ethyl, R3Is H or-CH3；
Most preferably, the above reaction formula is as follows:
according to the above-mentioned deesterification reaction, the deesterification reaction is carried out in the presence of a base;
according to the above-mentioned deesterification reaction, the base may be a bronsted base, preferably a carbonate, phosphate, oxide, hydroxide, alkoxide, phenoxide, amine, metal amide, fluoride or guanidine, more preferably potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, triethylamine or potassium hydroxide, most preferably sodium carbonate;
according to the above-mentioned deesterification reaction, the solvent for the deesterification reaction may be alcohols, low-molecular esters, halogenated alkanes, ketones, ethers, organic amines, benzene, water, C1-C4Preferably methanol, ethyl acetate, ethanol, chloroform, acetonitrile, dichloromethane, acetone, diethyl ether, triethylamine, pyridine, ethylenediamine, acetic acid, chlorobenzene, N-dimethylaniline, N-dimethylformamide, glycerol, water, ethylene glycol, tetrahydrofuran, toluene or benzene, more preferably methanol, ethyl acetate, ethanol, chloroform, dichloromethane, water, acetone, pyridine, N-dimethylaniline, N-dimethylformamide, tetrahydrofuran, toluene or benzene, most preferably methanol/water.
According to the above process for the preparation of the compound of formula VII, the acidic hydrolysis reaction is to R on the compound of formula VI1The group is hydrolyzed into carboxyl in the presence of acid to obtain a compound with a structure of a formula VII,
wherein R is1is-CONR4R5、-COX1、-COOR6or-CN, R2、R3、R4、R5Are, identically or not, H or C1-C6Alkyl of (A), X1Is F, Cl, Br or I.
More preferably, the above reaction formula is as follows:
wherein R is1is-CONR4R5、-COX1or-CN, R2、R3、R4、R5Are, identically or not, H or C1-C6Alkyl of (A), X1Is F, Cl, Br or I.
More preferably, the above reaction formula is as follows:
wherein R is1is-CONR4R5、-COX1-CN，R2、R3、R4、R5Identical or different H, methyl, ethyl, tert-butyl or isopropyl, X1Is Cl or Br;
more preferably, the above reaction formula is as follows:
wherein R is1is-CN, R3Is H or-CH3；
Most preferably, the above reaction formula is as follows:
according to the above acidic hydrolysis reaction, the acid may be an acid more acidic than ketoprofen, preferably HClO4、HI、HBr、HCl、HNO3、H2SeO4、H2SO4、HClO3、H2C2O4、H2SO3、H3PO4、CH3COCOOH、HNO2HF or HCOOH, more preferably HClO4、HCl、HNO3、H2SO4Most preferred is H2SO4；
According to the above acidic hydrolysis reaction, the concentration of the acid may be 80%;
according to the above acidic hydrolysis reaction, the reaction time may be 5 to 9 hours, most preferably 7 hours;
in combination with the second, third and fourth aspects, the invention provides a method for preparing a ketoprofen general formula compound with a structure shown in formula VII by six steps of oxidation, substitution, reduction, deamination, transesterification and acidic hydrolysis of a compound with a structure shown in formula I,
wherein, X2Or
More preferably, the above reaction formula is as follows:
wherein, X2Or
more preferably, the above reaction formula is as follows:
wherein, X2Or
more preferably, the above reaction formula is as follows:
wherein, X2Or
most preferably, the above reaction formula is as follows:
the ketoprofen intermediate provided by the invention used for preparing ketoprofen and compounds with the general formula thereof has the following beneficial effects: the potential safety hazard in the existing preparation process is eliminated, the requirement on reaction conditions is reduced, the accompanying side reaction is less, the product is easy to separate and purify, the cost is low, and the yield is high. Therefore, the ketoprofen intermediate provided by the invention has high industrial application and economic value.
Detailed Description
In order to better understand the content of the present invention, the following detailed description will be made on a ketoprofen intermediate provided by the present invention, and a preparation method and application thereof, with reference to specific examples. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
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