CN116444398A - Preparation method of ketoprofen intermediate formula III - Google Patents

Preparation method of ketoprofen intermediate formula III Download PDF

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CN116444398A
CN116444398A CN202310455020.7A CN202310455020A CN116444398A CN 116444398 A CN116444398 A CN 116444398A CN 202310455020 A CN202310455020 A CN 202310455020A CN 116444398 A CN116444398 A CN 116444398A
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reaction
formula
compound
ketoprofen
identically
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CN116444398B (en
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高照波
刘声民
王长发
郭必豹
郑辉
胡剀
梅义将
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Zhejiang Raybow Pharmaceutical Co ltd
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Zhejiang Raybow Pharmaceutical Co ltd
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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
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of a ketoprofen intermediate formula III. The compound of the formula III is prepared by the three steps of reaction of D-A reaction, oxidation reaction and substitution reaction of the compound of the formula I',wherein X is 2 Andortho-or para-to the nitro group, R 1 is-CONR 4 R 5 、‑COX 1 、‑COOR 2 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 ‑C 6 Alkyl of X 1 、X 2 Identically or differently F, cl, br or I. The reaction is suitable for industrial production.

Description

Preparation method of ketoprofen intermediate formula III
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of a ketoprofen intermediate formula III, which is a divisional application of Chinese patent application No. 201810970369.3 and 2018.08.24, namely a ketoprofen intermediate and a preparation method and application thereof.
Background
Ketoprofen (Ketoprofen), the name "Ketoprofen", was first marketed in 1973 in France and then formally entered China in the 80 s, and various dosage forms such as tablets, patches, films and the like have been developed and are 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, rheumarthritis, osteoarthritis, ankylosing spondylitis and gout. The analgesic effect is superior to that of similar medicines and the maintenance time is long. The traditional Chinese medicine composition has small toxic and side effects, and adverse reactions are generally intestinal discomfort, stomach discomfort, rash, headache and tinnitus.
Ketoprofen has the chemical name of 3-benzoyl-alpha-methyl phenylacetic acid and has the structural formula shown in the specification:
in the prior art, there are mainly the following 4 commonly used processes for the preparation of ketoprofen:
1. preparation of ketoprofen by 6-step reaction with 3-methylbenzoic acid as raw material
In European patent application EP0209905 (applicant: NIPPON PETROCHEMICALS COMPANY, LIMITED, application date: 24 of 1986) a process for preparing ketoprofen from 3-methylbenzoic acid by a 6-step reaction is disclosed:
this method has the following disadvantages:
(1) In the method, step 3 is (3- (methyl) phenyl) (phenyl) methanone, one hydrogen on methyl is replaced by one bromine under the action of bromine simple substance, and the (3- (bromomethyl) phenyl) (phenyl) methanone is prepared. However, in the actual operation process, this 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 at the same time, and is difficult to purify;
(2) The reagent KCN used in the step 4 of the method is a highly toxic compound;
(3) The MeI used in the step 5 of the method is a highly toxic compound;
(4) In this method, two hydrogens on the-CN ortho-C of reactant 2- (3-benzoylphenyl) acetonitrile in step 5 are possibly substituted by methyl, so that the reaction product finally obtained by the reaction contains 2- (3-benzoylphenyl) propionitrile and 2-methyl-2- (3-benzoylphenyl) propionitrile at the same time, and the purification is difficult.
2. 2- (3-benzoyl phenyl) acetic acid pivalic anhydride is used as raw material to prepare ketoprofen through 5 steps of reaction
In French patent application FR2659968 (applicant: CENTRE NAT RECH SCIENT, application date: 21 of 1990) a process for preparing ketoprofen from 2- (3-benzoylphenyl) acetic acid pivalic anhydride by a 5-step reaction is disclosed:
this method has the following disadvantages:
(1) The steps 2 and 3 of the method are required to be carried out in an environment of-40 ℃ and have harsh reaction conditions;
(2) The MeI used in the step 4 of the method is a highly toxic compound.
3. Preparation of ketoprofen from 1-bromo-3-vinylbenzene by 5-step reaction
In European patent EP0282065 (applicant: NIPPON PETROCHEMICALS CO LTD, application day: 1988, month 03, 10) a process for preparing ketoprofen from 1-bromo-3-vinylbenzene by a 5-step reaction is disclosed:
this method has the following disadvantages:
(1) Step 4 of the method is required in PdCl 2 Is carried out under the catalysis of the catalyst, and the market price of the palladium reagent is higher;
(2) In the method, in the step 5, potassium permanganate is used as an oxidant, and the manganese-containing compound easily causes serious pollution to the environment, so that solid waste treatment of manganese is needed in the later period.
In view of the foregoing, existing preparation processes are not suitable for commercial scale operations for the preparation of ketoprofen, and therefore, there is a need for an improved and commercially viable process that addresses the problems associated with prior art processes and 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 for preparing ketoprofen and a general formula compound thereof, so that the problems of high production cost, extremely toxic reaction reagents, more 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 achieve the technical purpose of the invention, the invention provides the following technical scheme:
in a first aspect the present invention provides an intermediate III or IV for ketoprofen,
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 4 、R 6 Identically or differently H, methyl, ethyl, tert-butyl or isopropyl, R 5 Is H, methyl, tert-butyl or isopropyl, R 3 Is H or-CH 3 ，X 1 Is Cl or Br;
more preferably, R 1 is-COOH, -CONH 2 、-CONHCH 3 、-CO(CH 3 ) 2 、-CONHCH 2 CH 3 、-CON(CH 2 CH 3 ) 2 -CN, -COCl or-COBr, R 2 Is H, methyl, ethyl, tert-butyl or isopropyl, R 3 Is H or-CH 3 ；
Most preferably, R 1 is-CN, R 2 Is methyl or ethyl, R 3 Is H or-CH 3 ；
In a second aspect, the present invention provides a process for the preparation of intermediate III of ketoprofen: the intermediate compound of the formula III can be prepared from para or ortho-nitrohalobenzene or a mixture thereof through three steps of reaction of Diels-Alder reaction (D-A reaction for short), oxidation reaction and substitution reaction,
wherein X is 2 Or (b)Ortho-or para-to nitro or amino, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 2 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 、X 2 And are identically or differently 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 para or ortho nitrohalobenzene or a mixture thereof and benzyl cyanide to obtain a compound of a structure of the formula I, wherein the reaction formula is as follows:
X 2 ortho-or para-to nitro or amino, X 2 Identically or differently F, cl, br or I, more preferably chlorine or bromine.
Preferably, the above reaction formula is:
wherein X is 2 Ortho-or para-to nitro or amino, X 2 And are identically or differently F, cl, br or I.
Most preferably, the above equation is as follows:
wherein the chlorine is located in the ortho or para position of the nitro group.
According to the Diels-Alder reaction described above, the compound of formula I' may beX is a single compound or a mixture of the compounds in any proportion 2 Is as defined above;
according to the Diels-Alder reaction, X in the compound of the formula I 2 Is shown as the formula I' and X in the compound 2 The position correspondence of (2) is consistent;
according to the diels-alder reaction described above, a catalyst may or may not be added;
according to the Diels-Alder reaction described above, the D-A reaction catalyst may be a Lewis acid, preferably AlCl 3 、BF 3 、SnCl 4 Or TiCl 4 Most preferred is AlCl 3 。
According to the preparation method of the compound shown in the formula III, the oxidation reaction can be that the benzisoxazole on the compound shown in the formula I is oxidized to obtain the compound shown in the formula II, and the reaction formula is as follows:
wherein X is 2 Ortho-or para-to nitro or amino, X 2 Is F, cl, br or I;
preferably, the above reaction formula is as follows:
wherein X is 2 Is Cl or Br;
most preferably, the above equation is as follows:
according to the oxidation reaction described above, the compound of formula I may beX is a single compound or a mixture of the compounds in any proportion 2 Is as defined above.
According to the oxidation reaction, X in the compound of formula II 2 Is shown as the formula I, and X in the compound 2 The position correspondence of (2) is consistent;
according to the above oxidation reaction, the oxidizing agent may be a strong oxidizing agent having an acidity stronger than that of nitric acid, preferably O 3 、Na 2 Cr 2 O 7 、KMnO 4 、O 2 /Co(OAc) 2 、H 2 CrO 4 Jones reagent, dilute sulfuric acid, active MnO 2 PDC reagent, O 2 /V 2 O 5 、NaBO 3 -4H 2 O/AcOH, TFD reagent, DMO reagent, sodium perborate, epoxyketone, potassium persulfate double salt or RuCl 3 /H 2 O 2 More preferably O 3 、Na 2 Cr 2 O 7 、KMnO 4 Dilute nitric acid, dilute sulfuric acid, active MnO 2 TFD reagent, DMO reagent or epoxidised ketone, most preferably O 3 ；
According to the above oxidation reaction, the oxidation reaction solvent may be a solvent that is most compatible with the strong oxidizing agent used; most preferably, when the strong oxidizing agent used is O 3 The reaction solvent used is DMF/H 2 O；
According to the substitution reaction described above, the oxidation reaction temperature may be 20-60 ℃, most preferably 40 ℃;
according to the substitution reaction described above, the oxidation reaction time may be 0.8 to 1.2 hours, most preferably 1.0 hour;
according to the above process for preparing the compound of formula III, the substitution reaction may be-X on the compound of formula II 2 The group is substituted by a compound of formula II' in the presence of a base to obtain a compound of formula III, wherein the reaction formula is as follows:
wherein X is 2 Andin the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 2 、X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein X is 2 Andin the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 2 、X 1 Is F, cl, br or I;
more preferably, the above reaction formula is as follows:
wherein X is 2 Andin the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H, methyl, ethyl, tert-butyl, isopropyl, X 2 、X 1 And are the same or different Cl or Br.
More preferably, the above equation is as follows:
wherein X is 2 Andin the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently methyl, ethyl, X 2 、X 1 And are the same or different Cl or Br.
Most preferably, the above equation is as follows:
wherein Cl andin the ortho or para position to the nitro group.
According to the substitution reaction, the compound of the formula II can beAnd->Single compounds or mixtures thereof in any proportion, X 2 Is as defined above.
According to the substitution reaction, the compound of the formula IIIIs identical to the position X in the compound of formula II 2 Is consistent with the corresponding position.
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 t-butoxide, potassium t-butoxide, sodium hydroxide or potassium hydroxide, most preferably sodium carbonate;
according to the substitution reaction, the solvent for the substitution reaction can be alcohols, low molecular esters, halogenated alkanes, ketones, ethers, organic amines, benzene, C 1 -C 4 Preferably 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 substitution reaction described above, 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 of the formula IV can be prepared from a compound of a formula III through a reduction reaction,
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H, methyl, ethyl, tert-butyl or isopropyl, X 1 Is Cl or Br;
more preferably, the above equation is as follows:
wherein,,in the ortho or para position to the amino group, R 1 is-CN, R 2 Is methyl or ethyl, R 3 Is H or-CH 3 ；
Most preferably, the above equation is as follows:
according to the above reduction reaction, the compound of formula III may beOr (b)Or a mixture of the same in any ratio.
According to the above reduction reaction, in the compound of formula IV,is the same as that in the compound of formula IIIIs identical in position.
The reduction reagent can be Fe/AcOH, fe/HCl, zn/HCl, sn/HCl, pd/H 2 、Pt/H 2 、Ni/H 2 、PtO 2 /H 2 、Pd-C/H 2 Or Pd (OH) 2 /H 2 Preferably Fe/AcOH, fe/HCl, zn/HCl, sn/HCl, pd/H 2 、Pd-C/H 2 、Pt/H 2 、Ni/H 2 、PtO 2 /H 2 Or Pd (OH) 2 /H 2 More preferably Fe/AcOH, fe/HCl, pd/H 2 Most preferably Pd/H 2 ；
According to the above reduction reaction, the reduction reaction solvent may be alcohols, alcohols/water, alkylbenzenes, low molecular esters, benzene or low molecular esters/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 above reduction reaction, 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;
in a fourth aspect, the invention provides a method for preparing a ketoprofen compound of formula VII.
The intermediate compound of the formula IV can be subjected to deamination, deesterification and acid hydrolysis to prepare the ketoprofen general formula compound with the structure of the formula VII,
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 4 、R 6 Identically or differently H or C 1 -C 6 Alkyl of R 3 Is H or-CH 3 ，R 5 Is H or C other than ethyl 1 -C 6 Alkyl of X 1 Is F, cl, br or I;
according to the above process for the preparation of the compounds of formula VII, the deamination may be-NH on the compounds of formula IV 2 The group is removed to obtain the compound with the structure of the formula V,
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein,,in the ortho or para position to the amino group, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H, methyl, ethyl, tert-butyl or isopropyl, X 1 Is Cl or Br;
more preferably, the above equation is as follows:
wherein,,located at amino groupsOrtho-or para-position of R 1 is-CN, R 2 Is methyl or ethyl, R 3 Is H or-CH 3 ；
Most preferably, the above equation is as follows:
according to the deamination reaction described above, the compound of formula IV may beOr (b)R is a single compound or a mixture of the compounds in any proportion 1 、R 2 、R 3 Is as defined above.
According to the deamination reaction, the deamination reagent may be CO/H + 、H 2 S、H 2 S/H + 、Na 2 S/H + 、K 2 S/H + 、HI、HI/H + 、NaI/H + 、KI/H + 、HNO 2 、HNO 2 /H + 、NaNO 2 /H + 、KNO 2 /H + 、H 2 SO 3 、H 2 SO 3 /H + 、Na 2 SO 3 /H + 、K 2 SO 3 /H + 、KBH 4 、NaBH 4 、FeSO 4 Or LiAlH 4 Preferably CO/HCl, H 2 S、H 2 S/HCl、Na 2 S/HCl、K 2 S/HCl、HI、HI/HCl、NaI/HCl、KI/HCl、HNO 2 、HNO 2 /HCl、NaNO 2 /HCl、KNO 2 /HCl、H 2 SO 3 、H 2 SO 3 /HCl、Na 2 SO 3 /HCl、K 2 SO 3 /HCl、KBH 4 、NaBH 4 、FeSO 4 Or LiAlH 4 More preferably H 2 S、H 2 S/HCl、Na 2 S/HCl、K 2 S/HCl、HNO 2 、HNO 2 /HCl、NaNO 2 /HCl、KNO 2 /HCl、H 2 SO 3 、H 2 SO 3 /HCl、Na 2 SO 3 HCl or K 2 SO 3 HCl, more preferably HNO 2 、HNO 2 /HCl、NaNO 2 HCl or KNO 2 HCl, most preferably NaNO 2 /HCl；
According to the above deamination reaction, the deamination reaction solvent may be alcohols, alcohols/water, alkylbenzenes, 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 of the formula VII, the de-esterification reaction is that the ester group on the compound of the formula V is removed to obtain the compound of the structure of the formula VI,
wherein R is 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein R is 1 is-CONR 4 R 5 、-COX 1 、-COOR 5 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
Preferably, the above reaction formula is as follows:
wherein R is 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H, methyl, ethyl, tert-butyl or isopropyl, X 1 Is F, cl, br or I.
More preferably, the above equation is as follows:
wherein R is 1 is-CN, R 2 Is methyl or ethyl, R 3 Is H or-CH 3 ；
Most preferably, the above equation 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 de-esterification reaction, the base may be a bronsted base, preferably a carbonate, a phosphate, an oxide, a hydroxide, an alkoxide, a phenoxide, an amine, a metal amide, a fluoride or guanidine, more preferably potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, triethylamine or potassium hydroxide, most preferably sodium carbonate;
according to the above-mentioned transesterification reaction, the transesterification reactionThe solvent can be alcohols, low molecular esters, halogenated alkanes, ketones, ethers, organic amines, benzene, water, C 1 -C 4 Preferably 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 compounds of formula VII, the acidic hydrolysis is carried out on-R on the compounds of formula VI 1 Hydrolyzing the group into carboxyl in the presence of acid to obtain a compound with a structure of a formula VII,
wherein R is 1 is-CONR 4 R 5 、-COX 1 、-COOR 6 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein R is 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 Is F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein R is 1 is-CONR 4 R 5 、-COX 1 -CN，R 2 、R 3 、R 4 、R 5 Identically or differently H, methyl, ethyl, tert-butyl or isopropyl, X 1 Is Cl or Br;
more preferably, the above equation is as follows:
wherein R is 1 is-CN, R 3 Is H or-CH 3 ；
Most preferably, the above equation is as follows:
according to the above acidic hydrolysis, the acid may be an acid having an acidity stronger than ketoprofen, preferably HClO 4 、HI、HBr、HCl、HNO 3 、H 2 SeO 4 、H 2 SO 4 、HClO 3 、H 2 C 2 O 4 、H 2 SO 3 、H 3 PO 4 、CH 3 COCOOH、HNO 2 HF or HCOOH, more preferably HClO 4 、HCl、HNO 3 、H 2 SO 4 Most preferred is H 2 SO 4 ；
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 ketoprofen general formula compound with a structure of formula VII by six steps of oxidation, substitution, reduction, deamination, deesterification and acid hydrolysis of the compound with the structure of formula I,
wherein X is 2 Or (b)Ortho-or para-to nitro or amino, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 2 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 、X 2 And are identically or differently F, cl, br or I.
More preferably, the above reaction formula is as follows:
wherein X is 2 Or (b)Ortho-or para-to nitro or amino, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently H or C 1 -C 6 Alkyl of X 1 、X 2 Are identical or different Cl or Br;
more preferably, the above equation is as follows:
wherein X is 2 Or (b)Ortho-or para-to nitro or amino, R 1 is-CONR 4 R 5 、-COX 1 or-CN, R 2 、R 3 、R 4 、R 5 、R 6 Identically or differently hydrogen, methyl, ethyl, tert-butyl, isopropyl, X 1 、X 2 Are identical or different Cl or Br;
more preferably, the above equation is as follows:
wherein X is 2 Or (b)Ortho-or para-to nitro or amino, R 1 is-CN, R 2 Is methyl or ethyl, R 3 Is H or-CH 3 ，X 2 Is Cl or Br;
most preferably, the above equation is as follows:
the ketoprofen intermediate provided by the invention is used for preparing ketoprofen and the general formula compound thereof, and has the beneficial effects that: the method eliminates the potential safety hazard existing in the existing preparation process, reduces the requirement on reaction conditions, has fewer side reactions, and is easy to separate and purify the product, low in cost and high in yield. Therefore, the ketoprofen intermediate provided by the invention has very high industrial application and economic value.
Detailed Description
In order to better understand the present invention, a ketoprofen intermediate, a preparation method and application thereof provided by the present invention are described in detail below with reference to specific examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1: preparation of Compounds of formula II
The compound of formula I (13.0 g,0.057 mol), DMF (68 ml) and water (13.6 ml) were added into the flask and stirred to dissolve, then the ozone reaction was started, the reaction solution became gradually lighter, the exothermic phenomenon was observed, and the temperature was raised to about 40 ℃. After about 1 hour, sampling test center was controlled. When the raw materials disappear, turning off ozone, introducing air or nitrogen for 10-20 minutes, adding a proper amount of hydrated ethyl acetate, stirring, standing, layering, extracting with a small amount of ethyl acetate, and washing an organic layer with water. The organic layer was concentrated to dryness under reduced pressure. 14.6g of the compound of formula II are obtained, the content is 93.2% and the yield is 91.9%.
EXAMPLE 2 preparation of the Compound of formula III
A100 ml reaction flask was charged with the compound of formula II (10 g,0.038 mol), DMF (50 ml), K 2 CO 3 (11 g,0.080 mol), stirring uniformly, heating, dripping DMF solution of methyl cyanoacetate (6.6 g,0.066 mol) at 80deg.C, maintaining at 80deg.C for 30 min, sampling, detecting, controlling, cooling to 10deg.C, adjusting pH to 1-2 with 1N diluted HCl, extracting with ethyl acetate, washing the organic layer with appropriate amount of water, concentrating under reduced pressure to dryness to obtain compound of formula III 12.1g, content 87.3%, and yield 85%.
EXAMPLE 3 preparation of Compounds of formula IV
A100 ml reaction flask was charged with the compound of formula III (10 g,0.03 mol), pd/C (50 mg) and methanol (30 ml), and the reaction was stirred by passing hydrogen gas therethrough. After the reaction is carried out for 5 hours at 25 ℃, sampling detection and central control are started, after the raw materials disappear, suction filtration, proper methanol leaching and mother liquor decompression concentration are carried out, 8.97g of compound of the formula IV is obtained, the content is 97.2%, and the yield is 96.1%.
Example 4: preparation of Compounds of formula V
A250 ml reaction flask was charged with the compound of formula IV (10 g,0.034 mol) and ethyl acetate (50 ml,5 vol) and dissolved with stirring; water (30 ml,3 vol) and 98% concentrated sulfuric acid (10.2 g,0.10 mol) were added, cooled to 0 ℃, 20% aqueous sodium nitrite solution (12.3 g,0.035 mol) was added dropwise at 2℃under control, after stirring at 2℃for 30 minutes, 50% sodium phosphinate monohydrate (14.4 g,0.068 mol) was added at the same temperature, after stirring at 2℃for 1 hour after completion of the dropwise addition, the reaction was slowly raised to 25℃for further reaction for 1 hour, after sampling and detection, after disappearance of the raw material, extraction was carried out by adding ethyl acetate, washing the organic layer with water, and concentrating to dryness under reduced pressure, 9.46g of the compound of formula V was obtained, the content of which was 87.9% and the yield of which was 87.6%.
Example 5: preparation of Compounds of formula VI
A250 ml reaction flask was charged with the compound of formula V (10 g,0.036 mol), DMF (12 ml,1.2 vol) and dimethyl sulfate (4.97 g,0.039 mol), stirred and warmed to 90℃and triethylamine (3.8 g,0.038 mol) was slowly added dropwise over a period of about 2 hours, incubated at 90℃for 1.5 hours, and the reaction was monitored by sampling and monitoring. After the raw materials disappear, cooling to 50deg.C, adding water (20 ml, 2.0vol), heating to 70deg.C, stirring for 1 hr, slowly cooling to room temperature, extracting with ethyl acetate (50 ml, 5.0vol), washing the organic layer with water (10 ml), concentrating under reduced pressure, adding methanol (80 ml, 8vol), stirring for dissolving, adding K 2 CO 3 (5.2 g,0.038 mol) and water (11.3 ml,1.1 vol), heating to 30-35 ℃ and keeping the temperature for 0.5 hours, sampling and detecting, when the raw material disappears, adding ethyl acetate (50 ml,5.0 vol) for extraction, washing the organic layer with water (20 ml,2 vol), concentrating under reduced pressure to dryness. The compound of formula VI is obtained as a brown yellow oil, after chloroform is added for heating and refluxing to dissolve, the temperature is slowly reduced to 0 ℃ for crystallization, white solid is obtained after filtration, and 7.16g of the compound of formula VI is obtained after drying, the HPLC content is 97.2%, and the yield is 82.6%.
Example 6: preparation of Compounds of formula VII
A250 ml reaction flask was charged with the compound of formula VI (10 g,0.042 mol) and 80% sulfuric acid solution (10.3 g,0.084 mol), heating to reflux was started, the reaction was kept for 7 hours, sampling was performed to detect, and after the raw material disappeared, cooling and material separation were started. After stirring at 7℃for 1 hour, suction filtration and a small amount of water washing, drying gave 10.6g of the compound of formula VII, with an HPLC content of 94.6% and a yield of 92.8%.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.

Claims (10)

1. A preparation method of ketoprofen intermediate formula III is characterized in that the compound of formula III is prepared by three steps of reaction of D-A, oxidation reaction and substitution reaction of the compound of formula I',
wherein X is 2 Andortho-or para-to the nitro group, R 1 is-CONR 4 R 5 、-COX 1 、-COOR 2 or-CN, R 2 、R 3 、R 4 、R 5 Identically or differently H or C 1 -C 6 Alkyl of X 1 、X 2 Identically or differently F, cl, br or I.
2. The method of claim 1, wherein X is 2 Andin para position to the nitro group, R 1 is-CN, R 3 Is H, R 2 Is H or C 1 -C 6 Is a hydrocarbon group.
3. The method of claim 1, wherein the D-a reaction has the following formula:
4. the process of claim 3, wherein the catalyst for the D-A reaction is AlCl 3 、BF 3 、SnCl 4 、TiCl 4 One of them.
5. The method according to claim 1, wherein the oxidation reaction has the following reaction formula:
6. the method according to claim 5, wherein the reagent for oxidation is O 3 、Na 2 Cr 2 O 7 、KMnO 4 Dilute nitric acid, dilute sulfuric acid, active MnO 2 TFD reagent, DMO reagent or epoxidised ketone.
7. The method according to claim 6, wherein the reagent is O 3 The reaction solvent used is DMF/H 2 O。
8. The method of claim 1, wherein the substitution reaction has the formula:
9. the method according to claim 8, wherein the substitution reaction is carried out in the presence of a base such as potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium hydroxide or potassium hydroxide.
10. The method according to claim 8 or 9, wherein the solvent for the substitution reaction is methanol, ethyl acetate, ethanol, chloroform, dichloromethane, acetone, pyridine, N-dimethylaniline, N-dimethylformamide, tetrahydrofuran, toluene or benzene.
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