A three-step process for the preparation of a ketoprofen generic compound

Abstract

The application relates to the field of medicine synthesis, in particular to a three-step preparation method of a ketoprofen general compound. The ketoprofen general compound is prepared through three-step reactions of deamination, deesterification and acid hydrolysis from a prepared compound of formula IV, wherein R1 is -CONR4R5, -COX1, -COOR2 or -CN at the ortho position or the para position of an amine group, R2, R3, R4 and R5 are the same or different and are H or C1-C6 alkyl, and X1 is F, Cl, Br or I. The reaction is suitable for industrial production.

Description

Technical Field

[0001] This application is a divisional application of Chinese invention patent application number 201810970369.3, filed on August 24, 2018, entitled "An intermediate of ketoibuprofen and its preparation method and application". This invention relates to the field of pharmaceutical synthesis, specifically to a three-step preparation method of a general formula compound of ketoibuprofen. Background Technology

[0002] Ketoprofen, also known as "ketoprofen," was first launched in France in 1973 and officially entered China in the 1980s. It is now available in various dosage forms, including oral tablets, patches, and films, and is widely used both domestically and internationally. This drug is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, antipyretic, and analgesic effects. It is mainly used to treat rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout. Its analgesic effect is superior to similar drugs and has a longer duration of action. It has few side effects; adverse reactions generally include gastrointestinal discomfort, skin rash, headache, and tinnitus.

[0003] The chemical name of ketoiprofen is 3-benzoyl-α-methylphenylacetic acid, and its structural formula is as follows:

[0004]

[0005] In the existing technology, there are four main commonly used methods for preparing ketoibuprofen:

[0006] 1. Ketoibuprofen was prepared from 3-methylbenzoic acid via a 6-step reaction.

[0007] European patent application EP0209905 (applicant: NIPPON PETROCHEMICALS COMPANY, LIMITED, application date: July 24, 1986) discloses a method for preparing ketoibuprofen from 3-methylbenzoic acid via a 6-step reaction:

[0008]

[0009] This method has the following drawbacks:

[0010] (1) Step 3 of this method involves replacing one hydrogen atom on the methyl group of (3-(methyl)phenyl)(phenyl) ketone with a bromine atom under the action of elemental bromine, thus preparing (3-(bromomethyl)phenyl)(phenyl) ketone. However, in actual operation, this step is often accompanied by many side reactions, resulting in the final product containing (3-(bromomethyl)phenyl)(phenyl) ketone, (3-(dibromomethyl)phenyl)(phenyl) ketone, and (3-(tribromomethyl)phenyl)(phenyl) ketone simultaneously, and is difficult to purify.

[0011] (2) The reaction reagent KCN used in step 4 of this method is a highly toxic compound;

[0012] (3) The MeI used in step 5 of this method is a highly toxic compound;

[0013] (4) In step 5 of this method, the two hydrogens at the -CN ortho C of the reactant 2-(3-benzoylphenyl)acetonitrile may be replaced by methyl groups. Therefore, the final product obtained by this reaction contains both 2-(3-benzoylphenyl)propionitrile and 2-methyl-2-(3-benzoylphenyl)propionitrile, and is difficult to purify.

[0014] 2. Ketoibuprofen was prepared from neopentanoic anhydride of 2-(3-benzoylphenyl)acetic acid via a 5-step reaction.

[0015] French patent application FR2659968 (applicant: CENTRE NAT RECH SCIENT, application date: March 21, 1990) discloses a method for preparing ketoibuprofen from 2-(3-benzoylphenyl)acetic acid neopentyl anhydride via a 5-step reaction:

[0016]

[0017] This method has the following drawbacks:

[0018] (1) Steps 2 and 3 of this method need to be carried out at -40℃, and the reaction conditions are harsh;

[0019] (2) The MeI used in step 4 of this method is a highly toxic compound.

[0020] 3. Ketoibuprofen was prepared from 1-bromo-3-vinylbenzene via a 5-step reaction.

[0021] European Patent EP0282065 (Applicant: NIPPON PETROCHEMICALS CO LTD, Application Date: March 10, 1988) discloses a method for preparing ketoibuprofen from 1-bromo-3-vinylbenzene via a 5-step reaction:

[0022]

[0023] This method has the following drawbacks:

[0024] (1) Step 4 of this method needs to be carried out under the catalysis of PdCl2, while the market price of palladium reagent is relatively high;

[0025] (2) Step 5 of this method uses potassium permanganate as an oxidant. However, manganese-containing compounds can easily cause serious environmental pollution. Therefore, solid waste treatment of manganese is required in the later stage.

[0026] In summary, existing preparation processes are not suitable for commercial-scale production of ketoibuprofen. Therefore, an improved and commercially viable process is needed to address the problems associated with existing methods and make them suitable for large-scale production. Summary of the Invention

[0027] To address the aforementioned technical problems, this invention provides a ketoibuprofen intermediate, which is used as a raw material to prepare ketoibuprofen and its general formula compounds. This eliminates the problems of high production costs, highly toxic reagents, numerous reaction byproducts, and harsh reaction conditions present in existing preparation processes, making it suitable for industrial production.

[0028] The specific process plan is as follows:

[0029] To achieve the technical objective of this invention, the following technical solution is provided:

[0030] The first aspect of this invention provides intermediate III or IV of ketoibuprofen.

[0031]

[0032] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R3, R4, R5, and R6 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0033] More preferably, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R4, and R6 are the same or different as H, methyl, ethyl, tert-butyl or isopropyl, R5 is H, methyl, tert-butyl or isopropyl, R3 is H or -CH3, and X1 is Cl or Br.

[0034] More preferably, R1 is -COOH, -CONH2, -CONHCH3, -CO(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2, -CN, -COCl or -COBr, R2 is H, methyl, ethyl, tert-butyl or isopropyl, and R3 is H or -CH3;

[0035] Most preferably, R1 is -CN, R2 is methyl or ethyl, and R3 is H or -CH3;

[0036] The second aspect of this invention provides a method for preparing intermediate III of ketoibuprofen: the above-mentioned intermediate compound III can be prepared from p- or o-nitrohalobenzene or mixtures thereof via a three-step reaction of Diels-Alder reaction (DA reaction), oxidation reaction, and substitution reaction.

[0037]

[0038] Wherein, X2 or Located at the ortho or para position of the nitro or amino group, R1 is -CONR4R5, -COX1, -COOR2 or -CN, R2, R3, R4, R5, and R6 are the same or different H or C1-C6 alkyl groups, and X1 and X2 are the same or different F, Cl, Br or I.

[0039] According to the preparation method of the compound of Formula III above, the Diels-Alder reaction can be a reaction of p- or o-nitrohalogenbenzene or a mixture thereof with phenylacetonitrile to obtain a compound of Formula I, as shown in the following reaction formula:

[0040]

[0041] X2 is located at the ortho or para position of the nitro or amino group, and X2 may be the same or different from F, Cl, Br or I, preferably chlorine or bromine.

[0042] Preferably, the above reaction formula is:

[0043]

[0044] X2 is located at the ortho or para position of the nitro or amino group, and X2 may be F, Cl, Br or I, either the same or different.

[0045] Most preferably, the above reaction formula is as follows:

[0046]

[0047] In this case, chlorine is located at the ortho or para position of the nitro group.

[0048] Based on the Diels-Alder reaction described above, the compound of formula I' can be... X2 is defined as above for a single compound or a mixture in any proportion;

[0049] According to the Diels-Alder reaction described above, the position of X2 in compound I corresponds to the position of X2 in compound I'.

[0050] Based on the Diels-Alder reaction described above, a catalyst may or may not be added;

[0051] According to the Diels-Alder reaction described above, the catalyst for the DA reaction can be a Lewis acid, preferably AlCl3, BF3, SnCl4 or TiCl4, with AlCl3 being the most preferred.

[0052] According to the preparation method of the compound of formula III above, the oxidation reaction can be performed by oxidizing the benzoxazole ring on the compound of formula I to obtain the compound of formula II, as shown in the following reaction formula:

[0053]

[0054] Wherein, X2 is located at the ortho or para position of the nitro or amino group, and X2 is F, Cl, Br or I;

[0055] Preferably, the above reaction formula is as follows:

[0056]

[0057] Where X2 is Cl or Br;

[0058] Most preferably, the above reaction formula is as follows:

[0059]

[0060] Based on the above oxidation reaction, the compound of formula I can be... X2 is a single compound or a mixture in any proportion, and is defined as above.

[0061] According to the above oxidation reaction, the position of X2 in the compound of formula II corresponds to the position of X2 in the compound of formula I;

[0062] According to the above oxidation reaction, the oxidizing reagent can be a strong oxidizing agent with acidity stronger than nitric acid, preferably O3, Na2Cr2O7, KMnO4, O2 / Co(OAc)2, H2CrO4, Jones reagent, dilute sulfuric acid, active MnO2, PDC reagent, O2 / V2O5, NaBO3-4H2O / AcOH, TFD reagent, DMO reagent, sodium perborate, epoxidized ketone, potassium persulfate double salt or RuCl3 / H2O2, more preferably O3, Na2Cr2O7, KMnO4, dilute nitric acid, dilute sulfuric acid, active MnO2, TFD reagent, DMO reagent or epoxidized ketone, and most preferably O3;

[0063] Based on the above oxidation reaction, the oxidation reaction solvent can be the solvent that best matches the strong oxidizing agent used; most preferably, when the strong oxidizing agent used is O3, the reaction solvent used is DMF / H2O;

[0064] According to the above substitution reaction, the oxidation reaction temperature can be 20-60℃, and most preferably 40℃;

[0065] According to the above substitution reaction, the oxidation reaction time can be 0.8-1.2 hours, and most preferably 1.0 hour;

[0066] According to the preparation method of the compound of formula III described above, the substitution reaction can be performed by replacing the -X2 group on the compound of formula II with the compound of formula II' in the presence of a base to obtain the compound of formula III, as shown in the following reaction formula:

[0067]

[0068] Among them, X2 and Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R3, R4, R5, and R6 are H or C1-C6 alkyl groups, and X2 and X1 are F, Cl, Br or I.

[0069] Preferably, the above reaction formula is as follows:

[0070]

[0071] Among them, X2 and Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1 or -CN, R2, R3, R4, R5, and R6 are the same or different H or C1-C6 alkyl groups, and X2 and X1 are F, Cl, Br or I.

[0072] Preferably, the above reaction formula is as follows:

[0073]

[0074] Among them, X2 and Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6, or -CN; R2, R3, R4, R5, and R6 are the same or different, namely H, methyl, ethyl, tert-butyl, or isopropyl; and X2 and X1 are the same or different, namely Cl or Br.

[0075] More preferably, the above reaction formula is as follows:

[0076]

[0077] Among them, X2 and Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6, or -CN; R2, R3, R4, R5, and R6 are either methyl or ethyl, and X2 and X1 are either Cl or Br, respectively.

[0078] Most preferably, the above reaction formula is as follows:

[0079]

[0080] Among them, Cl and Located at the ortho or para position of the nitro group.

[0081] Based on the above substitution reaction, the compound of formula II can be... A single compound or a mixture in any proportion; X2 is defined as above.

[0082] According to the above substitution reaction, in the compound of formula III The position corresponds to the position of X2 in compound II.

[0083] According to the above substitution reaction, the base can be a Brønsted base, preferably a carbonate, phosphate, oxide, hydroxide, alkoxide, phenolic salt, amine, metal amine, 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, and most preferably sodium carbonate.

[0084] According to the above substitution reaction, the solvent for the substitution reaction can be alcohols, low molecular weight esters, haloalkanes, ketones, ethers, organic amines, benzene, C1-C4 alkylbenzenes, acetonitrile, or acetic acid, preferably methanol, ethyl acetate, ethanol, chloroform, acetonitrile, dichloromethane, acetone, diethyl ether, triethylamine, pyridine, ethylenediamine, acetic acid, chlorobenzene, N,N-dimethylaniline, N,N-dimethylformamide, glycerol, ethylene glycol, tetrahydrofuran, toluene, or benzene, more preferably methanol, ethyl acetate, ethanol, chloroform, dichloromethane, acetone, pyridine, N,N-dimethylaniline, N,N-dimethylformamide, tetrahydrofuran, toluene, or benzene, and most preferably N,N-dimethylformamide;

[0085] According to the above substitution reaction, the substitution reaction temperature can be 50-100℃, and most preferably 80℃;

[0086] According to the above substitution reaction, the substitution reaction time can be 0.2-0.8 hours, and most preferably 0.5 hours;

[0087] The third aspect of this invention provides a method for preparing intermediate compound of formula IV:

[0088] The intermediate compound of formula IV can be prepared from the compound of formula III by a reduction reaction.

[0089]

[0090] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R3, R4, R5, and R6 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0091] Preferably, the above reaction formula is as follows:

[0092]

[0093] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, or -CN, R2, R3, R4, R5, and R6 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br, or I.

[0094] Preferably, the above reaction formula is as follows:

[0095]

[0096] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, or -CN; R2, R3, R4, R5, and R6 are the same or different H, methyl, ethyl, tert-butyl, or isopropyl; and X1 is Cl or Br.

[0097] More preferably, the above reaction formula is as follows:

[0098]

[0099] in, Located at the ortho or para position of an amino group, R1 is -CN, R2 is methyl or ethyl, and R3 is H or -CH3;

[0100] Most preferably, the above reaction formula is as follows:

[0101]

[0102] Based on the above reduction reaction, the compound of formula III can be...

[0103] A single compound or a mixture in any proportion.

[0104] Based on the reduction reaction described above, in the compound of formula IV, The position of the compound in Formula III The positions are consistent.

[0105] The reducing reagent can be Fe / AcOH, Fe / HCl, Zn / HCl, Sn / HCl, Pd / H2, Pt / H2, Ni / H2, PtO2 / H2, Pd-C / H2 or Pd(OH)2 / H2, preferably Fe / AcOH, Fe / HCl, Zn / HCl, Sn / HCl, Pd / H2, Pd-C / H2, Pt / H2, Ni / H2, PtO2 / H2 or Pd(OH)2 / H2, more preferably Fe / AcOH, Fe / HCl, Pd / H2, and most preferably Pd / H2;

[0106] According to the above reduction reaction, the solvent for the reduction reaction can be an alcohol, an alcohol / water mixture, an alkylbenzene, a low molecular weight ester, benzene, or a low molecular weight ester / water mixture, 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, and most preferably methanol;

[0107] According to the above reduction reaction, the reduction reaction temperature can be 15-35℃, and most preferably 25℃;

[0108] According to the above reduction reaction, the reduction reaction time can be 3.5-6.5 hours, and most preferably 5 hours;

[0109] The fourth aspect of this invention provides a method for preparing a ketoiprofen compound of formula VII.

[0110] The aforementioned intermediate compound of formula IV can be prepared into the ketoiprofen compound of formula VII via a three-step reaction involving deamination, deesterification, and acidic hydrolysis.

[0111]

[0112] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R4, and R6 are the same or different H or C1-C6 alkyl groups, R3 is H or -CH3, R5 is H or C1-C6 alkyl groups other than ethyl groups, and X1 is F, Cl, Br or I.

[0113] According to the preparation method of compound VII described above, the deamination reaction can be performed by removing the -NH2 group from compound IV to obtain compound V.

[0114]

[0115] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, or -CN, R2, R3, R4, and R5 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br, or I.

[0116] Preferably, the above reaction formula is as follows:

[0117]

[0118] in, Located at the ortho or para position of the amino group, R1 is -CONR4R5, -COX1, or -CN; R2, R3, R4, and R5 are the same or different, being H, methyl, ethyl, tert-butyl, or isopropyl; and X1 is Cl or Br.

[0119] More preferably, the above reaction formula is as follows:

[0120]

[0121] in, Located at the ortho or para position of an amino group, R1 is -CN, R2 is methyl or ethyl, and R3 is H or -CH3;

[0122] Most preferably, the above reaction formula is as follows:

[0123]

[0124] Based on the above deamination reaction, the compound of formula IV can be...

[0125] A single compound or a mixture in any proportion, with R1, R2, and R3 defined as above.

[0126] Based on 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 +The preferred solvents are KBH4, NaBH4, FeSO4, or LiAlH4, preferably 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, FeSO4, or LiAlH4, more preferably H2S, H2S / HCl, Na2S / HCl, K2S / HCl, HNO2, HNO2 / HCl, NaNO2 / HCl, KNO2 / HCl, H2SO3, H2SO3 / HCl, Na2SO3 / HCl, or K2SO3 / HCl, more preferably HNO2, HNO2 / HCl, NaNO2 / HCl, or KNO2 / HCl, and most preferably NaNO2 / HCl.

[0127] According to the above deamination reaction, the solvent for the deamination reaction can be an alcohol, an alcohol / water mixture, an alkylbenzene, benzene, a low molecular weight ester, or a low molecular weight ester / water mixture. Preferably, it is methanol, ethanol, isopropanol, n-butanol, toluene, ethylbenzene, benzene, methanol / water, ethanol / water, isopropanol / water, n-butanol / water, ethyl acetate, or ethyl acetate / water mixture. More preferably, it is toluene, benzene, methanol, ethanol, or isopropanol. Most preferably, it is ethanol.

[0128] According to the above deamination reaction, the deamination reaction temperature can be 0-15℃, and most preferably 5℃;

[0129] According to the above deamination reaction, the deamination reaction time can be 0.5-1.5 hours, and most preferably 1 hour.

[0130] According to the preparation method of compound VII described above, the deesterification reaction involves the removal of the ester group from compound V to obtain compound with structure VI.

[0131]

[0132] Wherein, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R3, R4, and R5 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0133] Preferably, the above reaction formula is as follows:

[0134]

[0135] Wherein, R1 is -CONR4R5, -COX1, -COOR5 or -CN, R2, R3, R4, and R5 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0136] Preferably, the above reaction formula is as follows:

[0137]

[0138] Wherein, R1 is -CONR4R5, -COX1 or -CN, R2, R3, R4, and R5 are the same or different H, methyl, ethyl, tert-butyl or isopropyl, and X1 is F, Cl, Br or I.

[0139] More preferably, the above reaction formula is as follows:

[0140]

[0141] Wherein, R1 is -CN, R2 is methyl or ethyl, and R3 is H or -CH3;

[0142] Most preferably, the above reaction formula is as follows:

[0143]

[0144] According to the above-described deesterification reaction, the deesterification reaction is carried out in the presence of a base;

[0145] According to the above deesterification reaction, the base can be a Brønsted base, preferably a carbonate, phosphate, oxide, hydroxide, alkoxide, phenolic salt, amine, metal amine, 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, and most preferably sodium carbonate;

[0146] According to the above-described deesterification reaction, the solvent for the deesterification reaction can be an alcohol, a low molecular weight ester, a haloalkanes, a ketone, an ether, an organic amine, benzene, water, a C1-C4 alkylbenzene, acetonitrile, or acetic acid. Preferably, it is methanol, ethyl acetate, ethanol, chloroform, acetonitrile, dichloromethane, acetone, diethyl ether, triethylamine, pyridine, ethylenediamine, acetic acid, chlorobenzene, N,N-dimethylaniline, N,N-dimethylformamide, glycerol, water, ethylene glycol, tetrahydrofuran, toluene, or benzene. More preferably, it is methanol, ethyl acetate, ethanol, chloroform, dichloromethane, water, acetone, pyridine, N,N-dimethylaniline, N,N-dimethylformamide, tetrahydrofuran, toluene, or benzene. Most preferably, it is methanol / water.

[0147] According to the preparation method of compound VII described above, the acidic hydrolysis reaction involves the hydrolysis of the -R1 group on compound VI to a carboxyl group in the presence of acid to obtain a compound with the structure of formula VII.

[0148]

[0149] Wherein, R1 is -CONR4R5, -COX1, -COOR6 or -CN, R2, R3, R4, and R5 are H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0150] Preferably, the above reaction formula is as follows:

[0151]

[0152] Wherein, R1 is -CONR4R5, -COX1 or -CN, R2, R3, R4 and R5 are the same or different H or C1-C6 alkyl groups, and X1 is F, Cl, Br or I.

[0153] Preferably, the above reaction formula is as follows:

[0154]

[0155] Where R1 is -CONR4R5 or -COX1-CN, R2, R3, R4, and R5 are the same or different H, methyl, ethyl, tert-butyl, or isopropyl, and X1 is Cl or Br;

[0156] More preferably, the above reaction formula is as follows:

[0157]

[0158] Where R1 is -CN and R3 is H or -CH3;

[0159] Most preferably, the above reaction formula is as follows:

[0160]

[0161] According to the above acidic hydrolysis reaction, the acid can be an acid with stronger acidity than ketoibuprofen, preferably HClO4, HI, HBr, HCl, HNO3, H2SeO4, H2SO4, HClO3, H2C2O4, H2SO3, H3PO4, CH3COCOOH, HNO2, HF or HCOOH, more preferably HClO4, HCl, HNO3, H2SO4, and most preferably H2SO4;

[0162] Based on the above acidic hydrolysis reaction, the concentration of the acid can be 80%;

[0163] According to the above acidic hydrolysis reaction, the reaction time can be 5-9 hours, and most preferably 7 hours;

[0164] In conjunction with the second, third, and fourth aspects mentioned above, this invention provides a method for preparing a ketoiprofen compound of formula VII from a compound of formula I via a six-step reaction involving oxidation, substitution, reduction, deamination, deesterification, and acidic hydrolysis.

[0165]

[0166] Wherein, X2 or Located at the ortho or para position of the nitro or amino group, R1 is -CONR4R5, -COX1, -COOR2 or -CN, R2, R3, R4, R5, and R6 are the same or different H or C1-C6 alkyl groups, and X1 and X2 are the same or different F, Cl, Br or I.

[0167] Preferably, the above reaction formula is as follows:

[0168]

[0169] Wherein, X2 or Located at the ortho or para position of the nitro or amino group, R1 is -CONR4R5, -COX1 or -CN, R2, R3, R4, R5, and R6 are the same or different H or C1-C6 alkyl groups, and X1 and X2 are the same or different Cl or Br.

[0170] More preferably, the above reaction formula is as follows:

[0171]

[0172] Wherein, X2 or Located at the ortho or para position of nitro or amino, R1 is -CONR4R5, -COX1 or -CN, R2, R3, R4, R5, and R6 are the same or different hydrogen, methyl, ethyl, tert-butyl, or isopropyl, and X1 and X2 are the same or different Cl or Br.

[0173] More preferably, the above reaction formula is as follows:

[0174]

[0175] Wherein, X2 or Located at the ortho or para position of the nitro or amino group, R1 is -CN, R2 is methyl or ethyl, R3 is H or -CH3, and X2 is Cl or Br;

[0176] Most preferably, the above reaction formula is as follows:

[0177]

[0178] The ketoiprofen intermediate provided by this invention has the following advantages in preparing ketoiprofen and its general formula compounds: it eliminates the safety hazards existing in existing preparation processes, reduces the requirements for reaction conditions, has fewer accompanying side reactions, the product is easy to separate and purify, and it is low-cost and has a high yield. Therefore, the ketoiprofen intermediate provided by this invention has high industrial application and economic value. Detailed Implementation

[0179] To better understand the content of this invention, the following detailed description, in conjunction with specific embodiments, illustrates a ketoibuprofen intermediate, its preparation method, and its applications. It should be understood that these embodiments are merely for further detailing the features of the invention and are not intended to limit the scope of the invention or the scope of the claims.

[0180] Example 1: Preparation of Compound II

[0181]

[0182] Compound I (13.0 g, 0.057 mol), DMF (68 ml), and water (13.6 ml) were added to a reaction flask and stirred until dissolved. Ozone was then introduced, and the reaction solution gradually lightened, exhibiting exothermic activity, with the temperature rising to approximately 40°C. After about one hour, a sample was taken for analysis. Once the raw materials disappeared, the ozone was turned off, and air or nitrogen was introduced for 10-20 minutes. An appropriate amount of ethyl acetate hydrate was added, and the mixture was stirred, allowed to stand, and allowed to separate into layers. The layers were then extracted with a small amount of ethyl acetate, and the organic layer was washed with water. The organic layer was concentrated to dryness under reduced pressure. 14.6 g of compound II was obtained, with a purity of 93.2% and a yield of 91.9%.

[0183] Example 2: Preparation of Compound III

[0184]

[0185] In a 100 ml reaction flask, compound II (10 g, 0.038 mol), DMF (50 ml), and K2CO3 (11 g, 0.080 mol) were added and stirred until homogeneous. The temperature was then raised to 80 °C. A DMF solution of methyl cyanoacetate (6.6 g, 0.066 mol) was added dropwise. After the addition was complete, the mixture was kept at 80 °C for 30 minutes. A sample was taken for testing. Once the raw material disappeared, the temperature was lowered to about 10 °C. The pH was adjusted to 1-2 with 1 N dilute HCl. Ethyl acetate was added for extraction. The organic layer was washed with an appropriate amount of water and concentrated under reduced pressure to dryness to obtain 12.1 g of compound III with a purity of 87.3% and a yield of 85%.

[0186] Example 3: Preparation of Compound IV

[0187]

[0188] Compound III (10 g, 0.03 mol), Pd / C (50 mg), and methanol (30 ml) were added to a 100 ml reaction flask, and hydrogen gas was introduced and the mixture was stirred. After reacting at 25 °C for 5 hours, samples were taken for monitoring. After the starting material disappeared, the mixture was filtered, washed with an appropriate amount of methanol, and the mother liquor was concentrated to dryness under reduced pressure to obtain 8.97 g of compound IV, with a purity of 97.2% and a yield of 96.1%.

[0189] Example 4: Preparation of Compound V

[0190]

[0191] Compound IV (10 g, 0.034 mol) and ethyl acetate (50 ml, 5 vol) were added to a 250 ml reaction flask and stirred to dissolve. Water (30 ml, 3 vol) and 98% concentrated sulfuric acid (10.2 g, 0.10 mol) were added, and the mixture was cooled to 0°C. A 20% sodium nitrite aqueous solution (12.3 g, 0.035 mol) was added dropwise at 2°C. After the addition was complete and the mixture was stirred for 30 minutes, 50% sodium hypophosphite monohydrate (14.4 g, 0.068 mol) was added at the same temperature. After the addition was complete, the mixture was stirred at 2°C for 1 hour, then slowly raised to 25°C and continued to react for another hour. Samples were taken for analysis. After the starting material disappeared, ethyl acetate was added for extraction. The organic layer was washed with water and concentrated under reduced pressure to dryness, yielding 9.46 g of compound V with a purity of 87.9% and a yield of 87.6%.

[0192] Example 5: Preparation of Compound VI

[0193]

[0194] Add compound V (10g, 0.036mol), DMF (12ml, 1.2vol), and dimethyl sulfate (4.97g, 0.039mol) to a 250ml reaction flask, stir and heat to 90℃, slowly add triethylamine (3.8g, 0.038mol) dropwise over about 2 hours, keep the reaction at 90℃ for 1.5 hours, and take samples for testing. After the starting material disappeared, the mixture was cooled to 50°C and water (20 ml, 2.0 vol) was added. The temperature was then raised to 70°C and stirred for 1 hour. The mixture was slowly cooled to room temperature, and ethyl acetate (50 ml, 5.0 vol) was added for extraction. The organic layer was washed with water (10 ml), concentrated under reduced pressure, and then dissolved in methanol (80 ml, 8 vol). K₂CO₃ (5.2 g, 0.038 mol) and water (11.3 ml, 1.1 vol) were added, and the mixture was heated to 30-35°C and maintained at this temperature for 0.5 hours. Samples were taken for analysis. After the starting material disappeared, ethyl acetate (50 ml, 5.0 vol) was added for extraction. The organic layer was washed with water (20 ml, 2 vol), concentrated under reduced pressure, and then dissolved. A brownish-yellow oily compound of formula VI was obtained. After dissolving the compound in chloroform under reflux, the mixture was slowly cooled to 0°C to crystallize. The crystals were filtered to obtain a white solid, which was dried to give 7.16 g of compound of formula VI, with an HPLC purity of 97.2% and a yield of 82.6%.

[0195] Example 6: Preparation of Compound VII

[0196]

[0197] Compound VI (10 g, 0.042 mol) and 80% sulfuric acid solution (10.3 g, 0.084 mol) were added to a 250 ml reaction flask. The mixture was heated to reflux and maintained at this temperature for 7 hours. A sample was taken for analysis; after the starting material disappeared, the mixture was cooled to allow precipitation. After stirring at 7°C for 1 hour, the mixture was filtered, washed with a small amount of water, dried, and 10.6 g of compound VII was obtained. The HPLC purity was 94.6%, and the yield was 92.8%.

[0198] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A three-step process for the preparation of a compound of the general formula of ketoprofen characterized by, The prepared compound of formula IV is prepared by deamination, de-esterification and acid hydrolysis, ； wherein R1is -CN, R2is methyl, and R3is H, located para to the amino group; In the deamination reaction: The compound of formula IV and ethyl acetate are added and stirred to dissolve; water and concentrated sulfuric acid are added and cooled to 0°C, and 20% sodium nitrite aqueous solution is added dropwise at 2°C. After stirring for 30 minutes, 50% sodium hypophosphite monohydrate is added at the same temperature. After the dropwise addition is completed, the reaction is stirred at 2°C for 1 hour, and then the temperature is increased to 25°C and the reaction is continued for 1 hour. After the sample is detected and the raw material disappears, ethyl acetate is added for extraction. After the organic layer is washed with water, it is concentrated under reduced pressure to obtain the compound of formula V; In the de-esterification reaction: The compound of formula V, DMF and dimethyl sulfate are added and stirred to increase the temperature to 90°C. Triethylamine is added dropwise, and the reaction is continued at 90°C for 1.5 hours. After the sample is detected and the raw material disappears, the temperature is decreased to 50°C, water is added, and then the temperature is increased to 70°C and the reaction is continued for 1 hour. After the temperature is decreased to room temperature, ethyl acetate is added for extraction. After the organic layer is washed with water, it is concentrated under reduced pressure to dryness. Methanol is added and stirred to dissolve, and then K2CO3 and water are added. After heating to 30-35°C, the reaction is continued for 0.5 hours. After the sample is detected and the raw material disappears, ethyl acetate is added for extraction. After the organic layer is washed with water, it is concentrated under reduced pressure to dryness. Chloroform is added and heated to reflux to dissolve. After the temperature is decreased to 0°C, the compound of formula VI is precipitated and filtered, and then dried. In the acid hydrolysis reaction: The compound of formula VI and 80% sulfuric acid solution are added and heated to reflux. After the reaction is continued for 7 hours, the sample is detected and the raw material disappears. The temperature is then decreased to precipitate the product. After stirring at 7°C for 1 hour, the product is filtered, washed with water, and then dried to obtain the compound of formula VII.

2. The production method according to claim 1, characterized by, The deamination reaction is: .

3. The preparation method according to claim 1, characterized in that, The de-esterification reaction is: .

4. The preparation method according to claim 1, characterized in that, The acid hydrolysis reaction is: .

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