CN102010323A - Method for synthesizing ibuprofen and analogues thereof - Google Patents
Method for synthesizing ibuprofen and analogues thereof Download PDFInfo
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Abstract
The invention provides a method for synthesizing ibuprofen and analogues thereof. In the method, 1-halogenated-4-isobutylbenzene and cyanogen acetate derivatives are taken as raw materials for synthesizing the ibuprofen; halogenated benzene derivatives and the cyanogen acetate derivatives are taken as raw materials for synthesizing the analogues of the ibuprofen; and the raw materials for synthesizing the ibuprofen and the raw materials for synthesizing the analogues of the ibuprofen are subjected to a palladium catalyzed decarboxylation coupling reaction, a methylation reaction and a hydrolysis reaction to synthesize the ibuprofen and the analogues thereof respectively. The synthesizing method is simple, and easy to operate and has wide raw material sources and low cost, and only inorganic salt and carbon dioxide are produced in the synthesizing process, so that the method is safe and environmentally-friendly, meets the requirement of green chemistry, and is suitable for industrialized production.
Description
Technical field
The present invention relates to the synthetic field of compound, be specifically related to the method for a kind of Ibuprofen BP/EP and analogue thereof.
Background technology
The chemistry of Ibuprofen BP/EP is by name: 2-(4-isobutyl phenenyl) propionic acid.Its chemical formula is:
Similar compounds has with it:
Ketoprofen sutoprofen Lilly 53838
Ibuprofen BP/EP (Ibuprofen) early than 1968 in Britain's listing, has been listed multinational pharmacopeia such as Britain, the U.S. at present, is one of outstanding non-steroidal anti-inflammatory analgesics, is mainly used in treatment of arthritis, pain, gout, dysmenorrhoea, high fever illness such as bring down a fever.With Ketoprofen, sutoprofen and the Lilly 53838 of Ibuprofen BP/EP similar also all be the non-steroidal anti-inflammatory analgesic.
Present existing Ibuprofen BP/EP synthetic method is a lot, mainly contains Chinese patent CN88102150, Chinese patent CN92106667.8, Chinese patent CN200910042425.8.The prior synthesizing method step is too many in these methods, though the synthetic method step that occurs is simplified in the recent period, use the CO (carbon monoxide converter) gas of severe toxicity, inadequately safety.
Summary of the invention
The problem that the present invention solves is to provide the method for a kind of synthetic Ibuprofen BP/EP and analogue thereof, avoids using hypertoxic raw material, and is easy, easy to operate.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A kind of method of synthetic Ibuprofen BP/EP may further comprise the steps:
A) compound shown in 1-bromo-4-isobutyl-benzene and the formula I is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula II,
M represents basic metal or alkaline-earth metal among the formula I;
B) compound shown in the formula II is hydrolyzed, generates Ibuprofen BP/EP.
As preferably, described b) be compound shown in the formula II in strong acid aqueous solution, reflux generation hydrolysis reaction generates Ibuprofen BP/EP.
As preferably, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
As preferably, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula II, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
As preferably, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
As preferably, described b) be compound shown in the formula II in strong alkali aqueous solution, solubility promoter ethanol exists down, behind the reflux generation hydrolysis reaction with the protonated Ibuprofen BP/EP that obtains of strong acid.
As preferably, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
As preferably, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula II, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume.
As preferably, the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid, and described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
As preferably, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
A kind of method of synthetic Ibuprofen BP/EP may further comprise the steps:
A) 1-halo-4-isobutyl-benzene, be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis with compound shown in the formula III, the decarboxylation linked reaction takes place obtain compound shown in the formula IV, 1-halo-4-isobutyl-benzene is 1-chloro-4-isobutyl-benzene or 1-bromo-4-isobutyl-benzene
M represents basic metal or alkaline-earth metal in the formula III;
B) with compound shown in the formula IV and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production II, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base;
C) compound shown in the formula II is hydrolyzed, generates Ibuprofen BP/EP.
As preferably, b) described in methyl halide be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate.
As preferably, b) described in highly basic hydride be at least a in sodium hydride, potassium hydride KH or the hydrolith.
As preferably, b) described in solvent be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
As preferably, described c) be compound shown in the formula II in strong acid aqueous solution, reflux generation hydrolysis reaction generates Ibuprofen BP/EP.
As preferably, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
As preferably, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula II, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
As preferably, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
As preferably, described c) be compound shown in the formula II in strong alkali aqueous solution, solubility promoter ethanol exists down, behind the reflux generation hydrolysis reaction with the protonated Ibuprofen BP/EP that obtains of strong acid.
As preferably, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
As preferably, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula II, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume.
As preferably, the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid, and described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
As preferably, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
More than in the method for two kinds of synthetic Ibuprofen BP/EPs, following common preferred version is arranged:
As preferably, compound shown in the described formula I and compound shown in 1-bromo-4-isobutyl-benzene or the formula III are 1.1～1.5 with the ratio of the amount of substance of 1-halo-4-isobutyl-benzene.
As preferably, the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of 1-bromo-4-isobutyl-benzene or 1-halo-4-isobutyl-benzene.
As preferably, the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of 1-bromo-4-isobutyl-benzene or 1-halo-4-isobutyl-benzene with palladium.
As preferably, described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance.
As preferably, described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
As preferably, palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
As preferably, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
As preferably, temperature of reaction is 120 ℃～160 ℃, and the reaction times is 16h～24h.
The method of Ibuprofen BP/EP analogue shown in a kind of synthesis type VII may further comprise the steps:
A) compound shown in bromobenzene derivative shown in the formula V and the formula I is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula VI,
Benzoyl between R ' expression among the formula V, to thiophene-2-formyl radical or m-phenoxy, M represents basic metal or alkaline-earth metal among the formula I;
B) compound shown in the formula VI is hydrolyzed the Ibuprofen BP/EP analogue shown in the production VII
It is characterized in that described b) be compound shown in the formula VI in strong acid aqueous solution, reflux generation hydrolysis reaction, the Ibuprofen BP/EP analogue shown in the production VII.
As preferably, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
As preferably, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula VI, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
As preferably, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
As preferably, described b) be compound shown in the formula VI in strong alkali aqueous solution, solubility promoter ethanol exists down, obtains the Ibuprofen BP/EP analogue shown in the formula VII with strong acid is protonated behind the reflux generation hydrolysis reaction.
As preferably, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
As preferably, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula VI, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume.
As preferably, the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid, and described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
As preferably, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
The method of Ibuprofen BP/EP analogue shown in a kind of synthesis type VII may further comprise the steps:
A) compound shown in halogeno-benzene derivative shown in the formula VIII and the formula III is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula IX,
Represent chlorine or bromine among the formula VIII, benzoyl between R ' expression, to thiophene-2-formyl radical or m-phenoxy, M represents basic metal or alkaline-earth metal in the formula III;
B) with compound shown in the formula IX and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production VI, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base;
C) compound shown in the formula VI is hydrolyzed the Ibuprofen BP/EP analogue shown in the production VII
As preferably, b) described in methyl halide be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate.
As preferably, b) described in highly basic hydride be at least a in sodium hydride, potassium hydride KH or the hydrolith.
As preferably, b) described in solvent be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
As preferably, described c) be compound shown in the VI in strong acid aqueous solution, reflux generation hydrolysis reaction, the Ibuprofen BP/EP analogue shown in the production VII.
As preferably, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
As preferably, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the VI, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
As preferably, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
As preferably, described c) be compound shown in the VI in strong alkali aqueous solution, solubility promoter ethanol exists down, obtains the Ibuprofen BP/EP analogue shown in the formula VII with strong acid is protonated behind the reflux generation hydrolysis reaction.
As preferably, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
As preferably, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the VI, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume.
As preferably, the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid, and described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
As preferably, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
More than in the method for two kinds of synthetic Ibuprofen BP/EP analogues, following common preferred version is arranged:
As preferably, compound shown in the described formula I and compound shown in bromobenzene derivative or the formula III are 1.1～1.5 with the ratio of the amount of substance of halogeno-benzene derivative.
As preferably, the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of bromobenzene derivative or halogeno-benzene derivative.
As preferably, the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of bromobenzene derivative or halogeno-benzene derivative with palladium.
As preferably, described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance.
As preferably, described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
As preferably, palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
As preferably, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
As preferably, temperature of reaction is 120 ℃～160 ℃, and the reaction times is 16h～24h.
The present invention is the raw material of synthetic Ibuprofen BP/EP with 1-halo-4-isobutyl-benzene and cyanoacetic acid salt derivative, with halogeno-benzene derivative and cyanoacetic acid salt derivative is the raw material of synthetic Ibuprofen BP/EP analogue, the two all passes through palladium catalytic decarboxylation linked reaction, methylation reaction and hydrolysis reaction, Ibuprofen BP/EP and analogue thereof have been synthesized respectively, simple synthetic method, easy to operate, raw material sources are extensive, cost is lower, have only inorganic salt and carbon dioxide generating in the building-up process, safety, environmental protection, meet the Green Chemistry requirement, be fit to suitability for industrialized production.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment the preferred embodiment of the invention is described, but should be appreciated that these describe just to further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
The method of synthetic Ibuprofen BP/EP of the present invention may further comprise the steps:
1-halo-4-isobutyl-benzene and cyanoacetic acid salt derivative are dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula X,
1-halo-4-isobutyl-benzene cyanoacetic acid salt derivative X
X represents chlorine or bromine, and R represents methyl or hydrogen, and M represents basic metal or alkaline-earth metal.
The cyanoacetic acid salt derivative can be 1.1～1.5 with the ratio of the amount of substance of 1-halo-4-isobutyl-benzene, and more preferably 1.2.
The volume milliliter number of solvent can be 0.5～2 with the ratio of the mmole number of 1-halo-4-isobutyl-benzene, and more preferably 1.Solvent can be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether, more preferably trimethylbenzene.
The consumption of palladium catalyst can be the 0.1%mol～0.4%mol of the amount of substance of 1-halo-4-isobutyl-benzene, more preferably 0.2%mol in palladium.Palladium catalyst can be at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium, more preferably dimerization allyl palladium chloride.
Organophosphorus ligand can be 1: 1 with the ratio of palladium catalyst amount of substance～and 3: 1, more preferably 3: 2.Organophosphorus ligand can be triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene, more preferably 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene.
Temperature of reaction is 120 ℃～160 ℃, and more preferably 140 ℃, the reaction times is 16h～24h, more preferably 20h.
(1) when R is methyl, X can only be bromine, and promptly 1-halo-4-isobutyl-benzene is a 1-bromo-4-isobutyl-benzene, and M is preferably potassium, and reaction obtains compound shown in the formula II, is hydrolyzed then, obtains Ibuprofen BP/EP.
(2) when R is hydrogen, X is a chlorine or bromine, and promptly 1-halo-4-isobutyl-benzene is 1-chloro-4-isobutyl-benzene or 1-bromo-4-isobutyl-benzene, and M is preferably sodium, and reaction obtains compound shown in the formula IV; With compound shown in the formula IV and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production II, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base, are hydrolyzed then, obtain Ibuprofen BP/EP.
Wherein methyl halide can be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate, more preferably methyl iodide.
Highly basic hydride can be at least a in sodium hydride, potassium hydride KH or the hydrolith, more preferably sodium hydride.
Solvent can be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether, more preferably dimethyl formamide.
Hydrolysis reaction can have dual mode:
1. compound shown in the formula II is in strong acid aqueous solution, and reflux generation hydrolysis reaction generates Ibuprofen BP/EP.
Wherein strong acid can be in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid at least a, sulfuric acid more preferably.
The amount of substance of strong acid is 2 times to 5 times of amount of substance of compound shown in the formula II, and more preferably 3 times, the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration, more preferably 1.5mol/L.
Temperature of reaction can be 100 ℃～150 ℃, and more preferably 120 ℃, the reaction times can be 5h～15h, more preferably 10h.
2. compound shown in the formula II is in strong alkali aqueous solution, and solubility promoter ethanol exists down, behind the reflux generation hydrolysis reaction with the protonated Ibuprofen BP/EP that obtains of strong acid.
Wherein highly basic can be in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate at least a, sodium hydroxide more preferably.
The alkaline amount of substance is 2 times to 5 times of amount of substance of compound shown in the formula II, and more preferably 3 times, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration, more preferably 1.5mol/L.
Solubility promoter alcoholic acid volume can be 1/10 to 1/2 of strong alkali aqueous solution volume, and more preferably 3/10.
The strong acid of protonated usefulness can be in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid at least a, hydrochloric acid more preferably, and the strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance, more preferably 1.2 times.
Temperature of reaction can be 100 ℃～150 ℃, and more preferably 120 ℃, the reaction times is 5h～15h, more preferably 10h.
The method of synthetic Ibuprofen BP/EP analogue of the present invention may further comprise the steps:
Halogeno-benzene derivative and cyanoacetic acid salt derivative are dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula XI,
Halogeno-benzene derivative cyanoacetic acid salt derivative XI
X represents chlorine or bromine, and R represents methyl or hydrogen, benzoyl between R ' expression, to thiophene-2-formyl radical or m-phenoxy, and M represents basic metal or alkaline-earth metal.
The cyanoacetic acid salt derivative can be 1.1～1.5 with the ratio of the amount of substance of halogeno-benzene derivative, and more preferably 1.2.
The volume milliliter number of solvent can be 0.5～2 with the ratio of the mmole number of halogeno-benzene derivative, and more preferably 1.Solvent can be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether, more preferably trimethylbenzene.
The consumption of palladium catalyst can be the 0.1%mol～0.4%mol of the amount of substance of halogeno-benzene derivative, more preferably 0.2%mol in palladium.Palladium catalyst can be at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium, more preferably dimerization allyl palladium chloride.
Organophosphorus ligand can be 1: 1 with the ratio of palladium catalyst amount of substance～and 3: 1, more preferably 3: 2.Organophosphorus ligand can be triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene, more preferably 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene.
Temperature of reaction is 120 ℃～160 ℃, and more preferably 140 ℃, the reaction times is 16h～24h, more preferably 20h.
(1) when R is methyl, X can only be bromine, and promptly the halogeno-benzene derivative is the bromobenzene derivative, and M is preferably potassium, and reaction obtains compound shown in the formula VI, is hydrolyzed then, obtains the Ibuprofen BP/EP analogue shown in the formula VII.
(2) when R is hydrogen, X is a chlorine or bromine, and promptly the halogeno-benzene derivative is chlorobenzene derivative or bromobenzene derivative, and M is preferably sodium, and reaction obtains compound shown in the formula IX; With compound shown in the formula IX and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production VI, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base, are hydrolyzed then, obtains the Ibuprofen BP/EP analogue shown in the formula VII.
Wherein methyl halide can be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate, more preferably methyl iodide.
Highly basic hydride can be at least a in sodium hydride, potassium hydride KH or the hydrolith, more preferably sodium hydride.
Solvent can be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether, more preferably dimethyl formamide.
Hydrolysis reaction can have dual mode:
1. compound shown in the formula VI is in strong acid aqueous solution, reflux generation hydrolysis reaction, the Ibuprofen BP/EP analogue shown in the production VII.
Wherein strong acid can be in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid at least a, sulfuric acid more preferably.
The amount of substance of strong acid is 2 times to 5 times of amount of substance of compound shown in the formula VI, and more preferably 3 times, the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration, more preferably 1.5mol/L.
Temperature of reaction can be 100 ℃～150 ℃, and more preferably 120 ℃, the reaction times can be 5h～15h, more preferably 10h.
2. compound shown in the formula VI is in strong alkali aqueous solution, and solubility promoter ethanol exists down, obtains the Ibuprofen BP/EP analogue shown in the formula VII with strong acid is protonated behind the reflux generation hydrolysis reaction.
Wherein highly basic can be in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate at least a, sodium hydroxide more preferably.
The alkaline amount of substance is 2 times to 5 times of amount of substance of compound shown in the formula VI, and more preferably 3 times, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration, more preferably 1.5mol/L.
Solubility promoter alcoholic acid volume can be 1/10 to 1/2 of strong alkali aqueous solution volume, and more preferably 3/10.
The strong acid of protonated usefulness can be in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid at least a, hydrochloric acid more preferably, and the strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance, more preferably 1.2 times.
Temperature of reaction can be 100 ℃～150 ℃, and more preferably 120 ℃, the reaction times is 5h～15h, more preferably 10h.
Embodiment 1:
(1) preparation 2-(4-isobutyl phenenyl) propionitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene (0.0693g, 0.120mmol), 1-bromo-4-isobutyl-benzene (8.52g, 40mmol) and 2-cyanopropionic acid potassium (6.58g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 96%.
(2) preparation 2-(4-isobutyl phenenyl) propionic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4-isobutyl phenenyl) propionitrile (5.62g, 30mmol) and sodium hydroxide (3.60g 90mmol), adds 60mL water and 9mL ethanol again.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h, dripping hydrochloric acid makes pH value of solution less than 1.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 88%.
Embodiment 2:
(1) preparation 2-(4-isobutyl phenenyl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0493g, 0.120mmol), 1-chloro-4-isobutyl-benzene (6.75g, 40mmol) and cyanoacetic acid sodium (5.14g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 97%.
(2) preparation 2-(4-isobutyl phenenyl) propionitrile
In a 150ml round-bottomed flask that magneton is housed, add 2-(4-isobutyl phenenyl) acetonitrile (6.24g, 36mmol), NaH (0.86g, 36mmol) and 80mLDMF.In ice-water bath, stir after 10 minutes, slowly drip methyl iodide (5.11g, 36mmol).Dropwise the back and round-bottomed flask is covered, remove ice-water bath, at room temperature stirring reaction 2h with lid.After reaction finishes solution in the round-bottomed flask is transferred in the 500mL separating funnel, added the 150mL ethyl acetate, organic phase with 150mL water extracting twice, is extracted once with the 150mL saturated aqueous common salt again.Extracted the back organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, removed solvent ethyl acetate, obtained weak yellow liquid, productive rate 79% after separating through simple and easy chromatographic column again with the decompression rotatory evaporator.
(3) preparation 2-(4-isobutyl phenenyl) propionic acid
(5.62g 30mmol), adds 60mL1.5mol/L sulfuric acid again to add 2-(4-isobutyl phenenyl) propionitrile in a clean 100mL round-bottomed flask that magneton is housed.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 90%.
Raw material 1-halo-4-isobutyl-benzene can be by halogeno-benzene
(X represents chlorine or bromine) and isobutyryl chloride
Under the catalysis of Lewis acid aluminum chloride the Fu Shi acylation reaction taking place obtains
Obtain 1-halo-4-isobutyl-benzene through reduction again
Embodiment 3:
(1) preparation 2-(3-benzoyl phenyl) propionitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene (0.0693g, 0.120mmol), 3-bromophenyl benzophenone (10.44g, 40mmol) and 2-cyanopropionic acid potassium (6.58g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 91%.
(2) preparation 2-(3-benzoyl phenyl) propionic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(3-benzoyl phenyl) propionitrile (7.06g, 30mmol) and sodium hydroxide (3.60g 90mmol), adds 60mL water and 9mL ethanol again.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h, dripping hydrochloric acid makes pH value of solution less than 1.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 92%.
Embodiment 4:
(1) 2-(3-benzoyl phenyl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0493g, 0.120mmol), 3-chloro-phenyl-benzophenone (8.67g, 40mmol) and cyanoacetic acid sodium (5.14g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 85%.
(2) preparation 2-(3-benzoyl phenyl) propionitrile
In a 150ml round-bottomed flask that magneton is housed, add 2-(3-benzoyl phenyl) acetonitrile (7.96g, 36mmol), NaH (0.86g, 36mmol) and 80mLDMF.In ice-water bath, stir after 10 minutes, slowly drip methyl iodide (5.11g, 36mmol).Dropwise the back and round-bottomed flask is covered, remove ice-water bath, at room temperature stirring reaction 2h with lid.After reaction finishes solution in the round-bottomed flask is transferred in the 500mL separating funnel, added the 150mL ethyl acetate, organic phase with 150mL water extracting twice, is extracted once with the 150mL saturated aqueous common salt again.Extracted the back organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, removed solvent ethyl acetate, obtained weak yellow liquid, productive rate 77% after separating through simple and easy chromatographic column again with the decompression rotatory evaporator.
(3) preparation 2-(3-benzoyl phenyl) propionic acid
(7.06g 30mmol), adds 60mL1.5mol/L sulfuric acid again to add 2-(3-benzoyl phenyl) propionitrile in a clean 100mL round-bottomed flask that magneton is housed.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 91%.
Embodiment 5:
(1) preparation 2-(4-(thiophene-2-formyl radical) phenyl) propionitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene (0.0693g, 0.120mmol), 4-bromophenyl thiophene-2-ketone (10.68g, 40mmol) and 2-cyanopropionic acid potassium (6.58g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 90%.
(2) preparation 2-(4-(thiophene-2-formyl radical) phenyl) propionic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4-(thiophene-2-formyl radical) phenyl) propionitrile (7.24g, 30mmol) and sodium hydroxide (3.60g 90mmol), adds 60mL water and 9mL ethanol again.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h, dripping hydrochloric acid makes pH value of solution less than 1.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 87%.
Embodiment 6:
(1) preparation 2-(4-(thiophene-2-formyl radical) phenyl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0493g, 0.120mmol), 4-chloro-phenyl-thiophene-2-ketone (8.91g, 40mmol) and cyanoacetic acid sodium (5.14g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 83%.
(2) preparation 2-(4-(thiophene-2-formyl radical) phenyl) propionitrile
In a 150ml round-bottomed flask that magneton is housed, add 2-(4-(thiophene-2-formyl radical) phenyl) acetonitrile (8.18g, 36mmol), NaH (0.86g, 36mmol) and 80mLDMF.In ice-water bath, stir after 10 minutes, slowly drip methyl iodide (5.11g, 36mmol).Dropwise the back and round-bottomed flask is covered, remove ice-water bath, at room temperature stirring reaction 2h with lid.After reaction finishes solution in the round-bottomed flask is transferred in the 500mL separating funnel, added the 150mL ethyl acetate, organic phase with 150mL water extracting twice, is extracted once with the 150mL saturated aqueous common salt again.Extracted the back organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, removed solvent ethyl acetate, obtained weak yellow liquid, productive rate 77% after separating through simple and easy chromatographic column again with the decompression rotatory evaporator.
(3) preparation 2-(4-(thiophene-2-formyl radical) phenyl) propionic acid
(7.24g 30mmol), adds 60mL1.5mol/L sulfuric acid to propionitrile again to add 2-(4-(thiophene-2-formyl radical) phenyl) in a clean 100mL round-bottomed flask that magneton is housed.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 86%.
Embodiment 7:
(1) preparation 2-(3-Phenoxyphenyl) propionitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene (0.0693g, 0.120mmol), 1-bromo-3-phenoxy group benzene (9.96g, 40mmol) and 2-cyanopropionic acid potassium (6.58g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 97%.
(2) preparation 2-(3-Phenoxyphenyl) propionic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(3-Phenoxyphenyl) propionitrile (6.70g, 30mmol) and sodium hydroxide (3.60g 90mmol), adds 60mL water and 9mL ethanol again.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h, dripping hydrochloric acid makes pH value of solution less than 1.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 90%.
Embodiment 8:
(1) preparation 2-(3-Phenoxyphenyl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0146g, 0.040mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0493g, 0.120mmol), 1-chloro-3-phenoxy group benzene (8.19g, 40mmol) and cyanoacetic acid sodium (5.14g, 48mmol).Cover and scribble the vacuum grease grinding port plug, be connected on the Shi Lanke vacuum line, drain the air in the container and fill nitrogen with, repeat 3 times, under the nitrogen that flows backwards, add the 40mL sym-trimethylbenzene.Cover stopper after adding again, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Reaction finishes directly chromatographic column separation of back, obtains weak yellow liquid, productive rate 96%.
(2) preparation 2-(3-Phenoxyphenyl) propionitrile
In a 150ml round-bottomed flask that magneton is housed, add 2-(3-Phenoxyphenyl) acetonitrile (7.53g, 36mmol), NaH (0.86g, 36mmol) and 80mLDMF.In ice-water bath, stir after 10 minutes, slowly drip methyl iodide (5.11g, 36mmol).Dropwise the back and round-bottomed flask is covered, remove ice-water bath, at room temperature stirring reaction 2h with lid.After reaction finishes solution in the round-bottomed flask is transferred in the 500mL separating funnel, added the 150mL ethyl acetate, organic phase with 150mL water extracting twice, is extracted once with the 150mL saturated aqueous common salt again.Extracted the back organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, removed solvent ethyl acetate, obtained weak yellow liquid, productive rate 81% after separating through simple and easy chromatographic column again with the decompression rotatory evaporator.
(3) preparation 2-(3-Phenoxyphenyl) propionic acid
(6.70g 30mmol), adds 60mL1.5mol/L sulfuric acid again to add 2-(3-Phenoxyphenyl) propionitrile in a clean 100mL round-bottomed flask that magneton is housed.After adding round-bottomed flask is fixed in the oil cauldron, connects the condensing reflux pipe and open water of condensation, temperature is reached 120 ℃ of reflux stir hydrolysis.Stop behind the reaction 10h.With chloroform with acid extraction in organic phase, remove solvent chloroform with Rotary Evaporators again, thick product separates through the chromatogram short column purifies, and obtains white solid, productive rate 92%
More than the method for a kind of synthetic Ibuprofen BP/EP provided by the present invention and analogue thereof is described in detail.Used specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (82)
1. the method for a synthetic Ibuprofen BP/EP is characterized in that, may further comprise the steps:
A) compound shown in 1-bromo-4-isobutyl-benzene and the formula I is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula II,
M represents basic metal or alkaline-earth metal among the formula I;
B) compound shown in the formula II is hydrolyzed, generates Ibuprofen BP/EP.
2. method according to claim 1 is characterized in that, compound shown in the described formula I is 1.1～1.5 with the ratio of the amount of substance of 1-bromo-4-isobutyl-benzene.
3. method according to claim 1 is characterized in that, the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of 1-bromo-4-isobutyl-benzene.
4. method according to claim 1 is characterized in that, the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of 1-bromo-4-isobutyl-benzene with palladium.
5. method according to claim 1 is characterized in that, described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance.
6. according to each described method in the claim 1 to 5, it is characterized in that described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
7. according to each described method in the claim 1 to 5, it is characterized in that palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
8. according to each described method in the claim 1 to 5, it is characterized in that, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
9. according to each described method in the claim 1 to 5, it is characterized in that temperature of reaction is 120 ℃～160 ℃, the reaction times is 16h～24h.
10. according to each described method in the claim 1 to 5, it is characterized in that described b) be compound shown in the formula II in strong acid aqueous solution, reflux generation hydrolysis reaction generates Ibuprofen BP/EP.
11. method according to claim 10 is characterized in that, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
12. method according to claim 11 is characterized in that, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula II, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
13. method according to claim 10 is characterized in that, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
14., it is characterized in that described b according to each described method in the claim 1 to 5) be compound shown in the formula II in strong alkali aqueous solution, solubility promoter ethanol exists down, behind the reflux generation hydrolysis reaction with the protonated Ibuprofen BP/EP that obtains of strong acid.
15. method according to claim 14 is characterized in that, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
16. method according to claim 15 is characterized in that, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula II, and alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
17. method according to claim 16 is characterized in that, described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume.
18. method according to claim 16 is characterized in that, the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid, and described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
19. method according to claim 14 is characterized in that, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
20. the method for a synthetic Ibuprofen BP/EP is characterized in that, may further comprise the steps:
A) 1-halo-4-isobutyl-benzene, be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis with compound shown in the formula III, the decarboxylation linked reaction takes place obtain compound shown in the formula IV, 1-halo-4-isobutyl-benzene is 1-chloro-4-isobutyl-benzene or 1-bromo-4-isobutyl-benzene
M represents basic metal or alkaline-earth metal in the formula III;
B) with compound shown in the formula IV and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production II, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base;
C) compound shown in the formula II is hydrolyzed, generates Ibuprofen BP/EP.
21. method according to claim 20 is characterized in that, compound shown in the described formula III is 1.1～1.5 with the ratio of the amount of substance of 1-halo-4-isobutyl-benzene.
22. method according to claim 20 is characterized in that, the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of 1-halo-4-isobutyl-benzene.
23. method according to claim 20 is characterized in that, the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of 1-halo-4-isobutyl-benzene with palladium.
24. method according to claim 20 is characterized in that, described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance.
25. according to each described method in the claim 20 to 24, it is characterized in that described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
26. according to each described method in the claim 20 to 24, it is characterized in that palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
27. according to each described method in the claim 20 to 24, it is characterized in that, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
28., it is characterized in that temperature of reaction is 120 ℃～160 ℃ according to each described method in the claim 20 to 24, the reaction times is 16h～24h.
29. according to each described method in the claim 20 to 24, it is characterized in that, b) described in methyl halide be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate.
30. according to each described method in the claim 20 to 24, it is characterized in that, b) described in highly basic hydride be at least a in sodium hydride, potassium hydride KH or the hydrolith.
31. according to each described method in the claim 20 to 24, it is characterized in that, b) described in solvent be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
32., it is characterized in that described c according to each described method in the claim 20 to 24) be compound shown in the formula II in strong acid aqueous solution, reflux generation hydrolysis reaction generates Ibuprofen BP/EP.
33. method according to claim 32 is characterized in that, described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
34. method according to claim 33 is characterized in that, the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula II, and the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
35. method according to claim 32 is characterized in that, temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
36., it is characterized in that described c according to each described method in the claim 20 to 24) be compound shown in the formula II in strong alkali aqueous solution, solubility promoter ethanol exists down, behind the reflux generation hydrolysis reaction with the protonated Ibuprofen BP/EP that obtains of strong acid.
37. method according to claim 36 is characterized in that, described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate.
38. according to the described method of claim 37, it is characterized in that, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula II, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
39., it is characterized in that described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume according to the described method of claim 38.
40., it is characterized in that the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid according to the described method of claim 38, described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
41. method according to claim 36 is characterized in that, described temperature of reaction is 100 ℃～150 ℃, and the reaction times is 5h～15h.
42. the method for Ibuprofen BP/EP analogue is characterized in that shown in the synthesis type VII, may further comprise the steps:
A) compound shown in bromobenzene derivative shown in the formula V and the formula I is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula VI,
Benzoyl between R ' expression among the formula V, to thiophene-2-formyl radical or m-phenoxy, M represents basic metal or alkaline-earth metal among the formula I;
B) compound shown in the formula VI is hydrolyzed the Ibuprofen BP/EP analogue shown in the production VII
43., it is characterized in that compound shown in the described formula I is 1.1～1.5 with the ratio of the amount of substance of bromobenzene derivative according to the described method of claim 42.
44., it is characterized in that the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of bromobenzene derivative according to the described method of claim 42.
45., it is characterized in that the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of bromobenzene derivative with palladium according to the described method of claim 42.
46., it is characterized in that described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance according to the described method of claim 42.
47. according to each described method in the claim 42 to 46, it is characterized in that described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
48. according to each described method in the claim 42 to 46, it is characterized in that palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
49. according to each described method in the claim 42 to 46, it is characterized in that, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
50., it is characterized in that temperature of reaction is 120 ℃～160 ℃ according to each described method in the claim 42 to 46, the reaction times is 16h～24h.
51., it is characterized in that described b according to each described method in the claim 42 to 46) be compound shown in the formula VI in strong acid aqueous solution, reflux generation hydrolysis reaction, the Ibuprofen BP/EP analogue shown in the production VII.
52., it is characterized in that described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid according to the described method of claim 51.
53., it is characterized in that the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula VI according to the described method of claim 51, the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
54., it is characterized in that temperature of reaction is 100 ℃～150 ℃ according to the described method of claim 51, the reaction times is 5h～15h.
55. according to each described method in the claim 42 to 46, it is characterized in that, described b) be compound shown in the formula VI in strong alkali aqueous solution, solubility promoter ethanol exists down, obtains the Ibuprofen BP/EP analogue shown in the formula VII with strong acid is protonated behind the reflux generation hydrolysis reaction.
56., it is characterized in that described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate according to the described method of claim 55.
57. according to the described method of claim 55, it is characterized in that, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula VI, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
58., it is characterized in that described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume according to the described method of claim 57.
59., it is characterized in that the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid according to the described method of claim 57, described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
60., it is characterized in that described temperature of reaction is 100 ℃～150 ℃ according to the described method of claim 55, the reaction times is 5h～15h.
61. the method for Ibuprofen BP/EP analogue is characterized in that shown in the synthesis type VII, may further comprise the steps:
A) compound shown in halogeno-benzene derivative shown in the formula VIII and the formula III is dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, and the decarboxylation linked reaction takes place obtain compound shown in the formula IX,
Represent chlorine or bromine among the formula VIII, benzoyl between R ' expression, to thiophene-2-formyl radical or m-phenoxy, M represents basic metal or alkaline-earth metal in the formula III;
B) with compound shown in the formula IX and methyl halide CH
3X is dissolved in the solvent, reacts in the presence of highly basic hydride, and compound shown in the production VI, X are chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base;
C) compound shown in the formula VI is hydrolyzed the Ibuprofen BP/EP analogue shown in the production VII
62., it is characterized in that described cyanoacetic acid salt is 1.1～1.5 with the ratio of the amount of substance of halogeno-benzene derivative according to the described method of claim 61.
63., it is characterized in that the volume milliliter number of described solvent is 0.5～2 with the ratio of the mmole number of halogeno-benzene derivative according to the described method of claim 61.
64., it is characterized in that the consumption of described palladium catalyst is counted the 0.1%mol～0.4%mol of the amount of substance of halogeno-benzene derivative with palladium according to the described method of claim 61.
65., it is characterized in that described organophosphorus ligand is 1: 1～3: 1 with the ratio of palladium catalyst amount of substance according to the described method of claim 61.
66. according to each described method in the claim 61 to 65, it is characterized in that described solvent is at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
67. according to each described method in the claim 61 to 65, it is characterized in that palladium catalyst is at least a in palladium metal, acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladiums, dimerization allyl palladium chloride, two (dibenzalacetone) palladium.
68. according to each described method in the claim 61 to 65, it is characterized in that, described organophosphorus ligand is a triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2,4, the 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, the N-dimethyl amido) biphenyl, 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene, 9,9-dimethyl-4,5-two (di-t-butyl phosphino-) xanthene, 2-dicyclohexyl phosphorus-2 ', 6 '-diisopropoxy-1,1 '-biphenyl, (±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene, (±)-2,2 '-two-(di-p-tolyl phosphino-)-1,1 '-dinaphthalene and 1,1 '-at least a in two (diphenylphosphino) ferrocene.
69., it is characterized in that temperature of reaction is 120 ℃～160 ℃ according to each described method in the claim 61 to 65, the reaction times is 16h～24h.
70. according to each described method in the claim 61 to 65, it is characterized in that, b) described in methyl halide be at least a in methyl chloride, monobromethane, methyl iodide, trifluoromethanesulfonic acid methyl esters or the methyl tosylate.
71. according to each described method in the claim 61 to 65, it is characterized in that, b) described in highly basic hydride be at least a in sodium hydride, potassium hydride KH or the hydrolith.
72. according to each described method in the claim 61 to 65, it is characterized in that, b) described in solvent be at least a in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dme, the dipropylene glycol diethyl ether.
73., it is characterized in that described c according to each described method in the claim 61 to 65) be compound shown in the formula VI in strong acid aqueous solution, reflux generation hydrolysis reaction, the Ibuprofen BP/EP analogue shown in the production VII.
74., it is characterized in that described strong acid is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid according to the described method of claim 73.
75., it is characterized in that the amount of substance of described strong acid is 2 times to 5 times of amount of substance of compound shown in the formula VI according to the described method of claim 74, the concentration of strong acid is counted 1mol/L to 3mol/L with hydrogen ion concentration.
76., it is characterized in that temperature of reaction is 100 ℃～150 ℃ according to the described method of claim 73, the reaction times is 5h～15h.
77. according to each described method in the claim 61 to 65, it is characterized in that, described c) be compound shown in the formula VI in strong alkali aqueous solution, solubility promoter ethanol exists down, obtains the Ibuprofen BP/EP analogue shown in the formula VII with strong acid is protonated behind the reflux generation hydrolysis reaction.
78., it is characterized in that described highly basic is at least a in sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate or the potassium ethylate according to the described method of claim 77.
79. according to the described method of claim 77, it is characterized in that, 2 times to 5 times of the amount of substance that described alkaline amount of substance is a compound shown in the formula VI, alkaline concentration is counted 1mol/L to 3mol/L with hydroxide ion concentration.
80., it is characterized in that described solubility promoter alcoholic acid volume is 1/10 to 1/2 of a strong alkali aqueous solution volume according to the described method of claim 79.
81., it is characterized in that the strong acid of described protonated usefulness is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid according to the described method of claim 79, described strong acid consumption is 1.2 times to 1.5 times of highly basic amount of substance.
82., it is characterized in that described temperature of reaction is 100 ℃～150 ℃ according to the described method of claim 77, the reaction times is 5h～15h.
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| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
| CN109053491A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | Synthetic method of the acaricide cyflumetofen intermediate to tert-butyl benzene acetonitrile |
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| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
| CN101757950A (en) * | 2009-12-29 | 2010-06-30 | 中国科学技术大学 | Catalyst system and application for leading poly-fluorine phenyl in organic synthesis thereof |
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| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
| CN101757950A (en) * | 2009-12-29 | 2010-06-30 | 中国科学技术大学 | Catalyst system and application for leading poly-fluorine phenyl in organic synthesis thereof |
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| 于凤丽等，: "布洛芬合成绿色化进展", 《有机化学》 * |
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| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
| CN109053491A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | Synthetic method of the acaricide cyflumetofen intermediate to tert-butyl benzene acetonitrile |
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