CN102010317B - Method for synthesizing felbinac and derivatives thereof - Google Patents
Method for synthesizing felbinac and derivatives thereof Download PDFInfo
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- CN102010317B CN102010317B CN 201010529499 CN201010529499A CN102010317B CN 102010317 B CN102010317 B CN 102010317B CN 201010529499 CN201010529499 CN 201010529499 CN 201010529499 A CN201010529499 A CN 201010529499A CN 102010317 B CN102010317 B CN 102010317B
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- QRZAKQDHEVVFRX-UHFFFAOYSA-N OC(Cc(cc1)ccc1-c1ccccc1)=O Chemical compound OC(Cc(cc1)ccc1-c1ccccc1)=O QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 2
Abstract
The invention provides a method for synthesizing felbinac and derivatives thereof. In the method, 1-bromine-4-chlorobenzene and phenylboric acid are taken as raw materials and subjected to Suzuki-Miyaura coupling reaction, products and the derivatives of cyanoacetic acid are subjected to palladium-catalyzed decarboxylation coupling reaction, and hydrolysis is performed to produce the felbinac; and the derivatives of the 1-bromine-4-chlorobenzene and the derivatives of the phenylboric acid are taken as raw materials and subjected to the Suzuki-Miyaura coupling reaction, products and the derivatives of the cyanoacetic acid are subjected to the palladium-catalyzed decarboxylation coupling reaction, and the hydrolysis is performed to produce the derivatives of the felbinac. The synthesizing method is simple, and easy to operate and has low cost and high yield, and only inorganic salt and carbon dioxide are produced in the synthesizing process, so that the synthesizing method is safe, environmentally-friendly and suitable for industrialized production, and meets the requirement of green chemistry.
Description
Technical field
The present invention relates to the compou nd synthesis field, be specifically related to the method for a kind of felbinac and derivative thereof.
Background technology
The chemistry of felbinac is by name: 2-(biphenyl-4-yl) acetic acid.Its chemical formula is:
Felbinac derivative is:
Wherein R, R ' represent alkyl or the alkoxyl group that any position replaces.
Felbinac (Felbinac) is Japanese Lederle[strain] in the medicine with " Napageln " ointment exploitation listing in 1986, the multinational pharmacopeia such as Japan, the U.S. have been listed at present in, it is one of outstanding NSAID (non-steroidal anti-inflammatory drug), be mainly used in treating modification sacroiliitis, scapulohumeral periarthritis, tenosynovitis, peritendinitis, myalgia, wound swelling, pain etc.
Present existing felbinac synthetic method is a lot, mainly contain Zhengzhou University's journal (natural science edition), 1999,31 (3): 76-78, Chinese patent CN200610004076.7, Chinese patent CN200710052668.0, Chinese patent CN200710169102.6.These method stepss are more, complex operation.
Summary of the invention
The problem that the present invention solves is to provide the method for a kind of synthetic felbinac and derivative thereof, 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 felbinac may further comprise the steps:
A) 1-bromo-4-chlorobenzene and phenylo boric acid are dissolved in the water-ethanol mixed solvent, in the presence of alkali metal compound or alkaline earth metal compound, under palladium catalyst and the urea seeding of non-phosphine part benzene, the Suzuki-Miyaura linked reaction occuring in the room temperature, generates the 4-chlordiphenyl;
B) 4-chlordiphenyl and cyanoacetic acid salt
Be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, the decarboxylation linked reaction occur obtain 2-(biphenyl-4-yl) acetonitrile, M represents basic metal or alkaline-earth metal;
C) 2-(biphenyl-4-yl) acetonitrile is hydrolyzed, generates felbinac.
As preferably, described a) in the ratio of phenylo boric acid and the amount of substance of 1-bromo-4-chlorobenzene be 1.1~1.4.
As preferably, described a) in the ratio of alkali metal compound or alkaline earth metal compound and the amount of substance of 1-bromo-4-chlorobenzene be 1.5~3.
As preferably, described alkali metal compound is at least a in alkaline carbonate, alkali metal hydroxide or the alkali metal alcoholates, and described alkaline earth metal compound is at least a in alkaline earth metal carbonate, alkaline earth metal hydroxides or the alkaline-earth alkoxides.
As preferably, described a) in the ratio of water and the volume of ethanol of water-ethanol the solvent mixture be 1: 2~2: 1.
As preferably, the volume milliliter number of described water-ethanol the solvent mixture is 0.5~2 with the ratio of the mmole number of 1-bromo-4-chlorobenzene.
As preferably, described a) in the consumption of palladium catalyst count the 0.05%mol~0.2%mol of the amount of substance of 1-bromo-4-chlorobenzene with palladium.
As preferably, described a) in the ratio of non-phosphine part benzene urea and the amount of substance of palladium catalyst be 1: 1~3: 1.
As preferably, described 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 reaction times a) is 1h~3h.
As preferably, described b) cyanoacetic acid salt is 1.1~1.5 with the ratio of the amount of substance of 4-chlordiphenyl in.
As preferably, described b) the volume milliliter number of solvent is 0.5~2 with the ratio of the mmole number of 4-chlordiphenyl in.
As preferably, described b) consumption of palladium catalyst is counted the 01%mol~04%mol of the amount of substance of 4-chlordiphenyl in palladium.
As preferably, described b) organophosphorus ligand is 1: 1~3: 1 with the ratio of palladium catalyst amount of substance in.
As preferably, 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, TRIGLYME, 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 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.
As preferably, described c) be 2-(biphenyl-4-yl) acetonitrile in strong acid aqueous solution, reflux generation hydrolysis reaction obtains felbinac.
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 2-(biphenyl-4-yl) acetonitrile, 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 2-(biphenyl-4-yl) acetonitrile in strong alkali aqueous solution, solubility promoter ethanol exists lower, behind the reflux generation hydrolysis reaction with the protonated felbinac 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, the amount of substance of described highly basic is 2 times to 5 times of amount of substance of 2-(biphenyl-4-yl) acetonitrile, and the concentration of highly basic is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, the volume of described solubility promoter ethanol is 1/10 to 1/2 of 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 felbinac derivative shown in a kind of synthesis type I may further comprise the steps:
A) 1-bromo-4-chlorobenzene derivative
With the phenylo boric acid derivative
Be dissolved in the water-ethanol mixed solvent, in the presence of alkali metal compound or alkaline earth metal compound, under palladium catalyst and the urea seeding of non-phosphine part benzene, the Suzuki-Miyaura linked reaction occur in the room temperature, generate 4-chlordiphenyl derivative
R represents alkyl or the alkoxyl group that any position replaces, alkyl or alkoxyl group that any position of R ' expression replaces;
B) 4-chlordiphenyl derivative and cyanoacetic acid salt
Be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, the decarboxylation linked reaction occur obtain 2-(biphenyl-4-yl) acetonitrile derivative
M represents basic metal or alkaline-earth metal;
As preferably, described a) in the ratio of phenylo boric acid derivative and the amount of substance of 1-bromo-4-chlorobenzene derivative be 1.1~1.4.
As preferably, described a) in the ratio of alkali metal compound or alkaline earth metal compound and the amount of substance of 1-bromo-4-chlorobenzene derivative be 1.5~3.
As preferably, described alkali metal compound is at least a in alkaline carbonate, alkali metal hydroxide or the alkali metal alcoholates, and described alkaline earth metal compound is at least a in alkaline earth metal carbonate, alkaline earth metal hydroxides or the alkaline-earth alkoxides.
As preferably, described a) in the ratio of water and the volume of ethanol of water-ethanol the solvent mixture be 1: 2~2: 1.
As preferably, the volume milliliter number of described water-ethanol the solvent mixture is 0.5~2 with the ratio of the mmole number of 1-bromo-4-chlorobenzene derivative.
As preferably, described a) in the consumption of palladium catalyst count the 0.05%mol~0.2%mol of the amount of substance of 1-bromo-4-chlorobenzene derivative with palladium.
As preferably, described a) in the ratio of non-phosphine part benzene urea and the amount of substance of palladium catalyst be 1: 1~3: 1.
As preferably, described 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 reaction times a) is 1h~3h.
As preferably, described b) cyanoacetic acid salt is 1.1~1.5 with the ratio of the amount of substance of 4-chlordiphenyl derivative in.
As preferably, described b) the volume milliliter number of solvent is 0.5~2 with the ratio of the mmole number of 4-chlordiphenyl derivative in.
As preferably, described b) consumption of palladium catalyst is counted the 0.1%mol~0.4%mol of the amount of substance of 4-chlordiphenyl derivative in palladium.
As preferably, described b) organophosphorus ligand is 1: 1~3: 1 with the ratio of palladium catalyst amount of substance in.
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, TRIGLYME, 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 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.
As preferably, described c) be 2-(biphenyl-4-yl) acetonitrile derivative in strong acid aqueous solution, reflux generation hydrolysis reaction obtains the felbinac derivative shown in the formula I.
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 2-(biphenyl-4-yl) acetonitrile derivative, 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 2-(biphenyl-4-yl) acetonitrile derivative in strong alkali aqueous solution, solubility promoter ethanol exists lower, obtains the felbinac derivative shown in the formula I 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, the amount of substance of described highly basic is 2 times to 5 times of amount of substance of 2-(biphenyl-4-yl) acetonitrile derivative, and the concentration of highly basic is counted 1mol/L to 3mol/L with hydroxide ion concentration.
As preferably, the volume of described solubility promoter ethanol is 1/10 to 1/2 of 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 present invention is take 1-bromo-4-chlorobenzene and phenylo boric acid as raw material, and through the Suzuki-Miyaura linked reaction, resultant and cyanoacetic acid derivative carry out palladium catalytic decarboxylation linked reaction, and generation felbinac again is hydrolyzed; Take 1-bromo-4-chlorobenzene derivative and phenylo boric acid derivative as raw material, through the Suzuki-Miyaura linked reaction, resultant and cyanoacetic acid derivative carry out palladium catalytic decarboxylation linked reaction, and generation felbinac derivative again is hydrolyzed.Simple synthetic method, easy to operate, cost is lower, and yield is higher, only has inorganic salt and carbon dioxide generating in the building-up process, and safety, environmental protection meet the Green Chemistry requirement, are 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 as further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
The method of a kind of synthetic felbinac provided by the invention may further comprise the steps:
A) 1-bromo-4-chlorobenzene
With phenylo boric acid
Be dissolved in the water-ethanol mixed solvent, in the presence of alkali metal compound or alkaline earth metal compound, under palladium catalyst and the urea seeding of non-phosphine part benzene, the Suzuki-Miyaura linked reaction occur in the room temperature, generate the 4-chlordiphenyl
Wherein phenylo boric acid can be 1.1~1.4 with the ratio of the amount of substance of 1-bromo-4-chlorobenzene, and more preferably 1.2.
Alkali metal compound or alkaline earth metal compound can be 1.5~3 with the ratio of the amount of substance of 1-bromo-4-chlorobenzene, and more preferably 2.
Alkali metal compound can be at least a in alkaline carbonate, alkali metal hydroxide or the alkali metal alcoholates, alkaline earth metal compound can be at least a in alkaline earth metal carbonate, alkaline earth metal hydroxides or the alkaline-earth alkoxides, more preferably salt of wormwood.
The water of water-ethanol the solvent mixture is 1: 2~2: 1 with the ratio of the volume of ethanol, more preferably 1: 1.
The volume milliliter number of water-ethanol the solvent mixture is 0.5~2 with the ratio of the mmole number of 1-bromo-4-chlorobenzene, more preferably 1.
The consumption of palladium catalyst is counted the 0.05%mol~0.2%mol of the amount of substance of 1-bromo-4-chlorobenzene, more preferably 0.1%mol with palladium.
Non-phosphine part benzene urea is 1: 1~3: 1 with the ratio of the amount of substance of palladium catalyst, more preferably 2: 1.
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, more preferably acid chloride.
Reaction times is 1h~3h, more preferably 2h.
B) 4-chlordiphenyl
With the cyanoacetic acid salt derivative
Be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, the decarboxylation linked reaction occur obtain 2-(biphenyl-4-yl) acetonitrile
M represents basic metal or alkaline-earth metal.
Wherein the cyanoacetic acid salt derivative is 1.1~1.5 with the ratio of the amount of substance of 4-chlordiphenyl, more preferably 1.2.
The volume milliliter number of solvent is 0.5~2 with the ratio of the mmole number of 4-chlordiphenyl, more preferably 1.
The consumption of palladium catalyst is counted the 0.1%mol~0.4%mol of the amount of substance of 4-chlordiphenyl, more preferably 0.2%mol with palladium.
Organophosphorus ligand is 1: 1~3: 1 with the ratio of palladium catalyst amount of substance, more preferably 3: 2.
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, TRIGLYME, the dipropylene glycol diethyl ether, more preferably trimethylbenzene.
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, more preferably the dimerization allyl palladium chloride.
Organophosphorus ligand is 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 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl.
Temperature of reaction is 120 ℃~160 ℃, and more preferably 140 ℃, the reaction times is 16h~24h, more preferably 20h.
Hydrolysis reaction can have dual mode:
1. 2-(biphenyl-4-yl) acetonitrile
In strong acid aqueous solution, reflux generation hydrolysis reaction obtains felbinac.
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 2-(biphenyl-4-yl) acetonitrile, 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. 2-(biphenyl-4-yl) acetonitrile
In strong alkali aqueous solution, solubility promoter ethanol exists lower, behind the reflux generation hydrolysis reaction with the protonated felbinac 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 amount of substance of highly basic is 2 times to 5 times of amount of substance of 2-(biphenyl-4-yl) acetonitrile, and more preferably 3 times, the concentration of highly basic is counted 1mol/L to 3mol/L with hydroxide ion concentration, more preferably 1.5mol/L.
The volume of solubility promoter ethanol 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 a kind of synthetic felbinac derivative provided by the invention, can be according to the synthetic method of the felbinac that provides with the present invention identical step is synthetic, with 1-bromo-4-chlorobenzene derivative
With the phenylo boric acid derivative
Be starting raw material, with synthetic felbinac intermediate the same terms, identical preferred lower generation Suzuki-Miyaura linked reaction, obtain 4-chlordiphenyl derivative
4-chlordiphenyl derivative again with the cyanoacetic acid salt derivative, with the decarboxylation linked reaction of synthetic felbinac intermediate the same terms, the catalysis of identical preferred lower generation palladium; Obtain 2-(biphenyl-4-yl) acetonitrile derivative
Obtain felbinac derivative through hydrolysis again
The condition of hydrolysis and preferred identical with the hydrolysising condition of synthetic felbinac.
Embodiment 1:
(1) preparation 4-chlordiphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride (0.0090g, 0.04mmol), benzene urea (0.0109g, 0.08mmol), 1-bromo-4-chlorobenzene (7.66g, 40mmol), phenylo boric acid (5.85g, 48mmol), salt of wormwood (11.06g, 80mmol), 20mL water and 20mL ethanol.Stirring reaction 2h at room temperature.React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times.Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 92% after the chromatographic column separation.
(2) preparation 2-(biphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0131g, 0.036mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0444g, 0.108mmol), 4-chlordiphenyl (6.79g, 36mmol) with cyanoacetic acid sodium (4.63g, 43.2mmol).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 36mL sym-trimethylbenzene.Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Directly chromatographic column separation obtained white solid, productive rate 96% after reaction finished.
(3) preparation 2-(biphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(biphenyl-4-yl) acetonitrile (5.80g, 30mmol) and sodium hydroxide (3.60g, 90mmol), add again 60mL water and 9mL ethanol.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.Reaction stops behind the 10h, drip hydrochloric acid so that pH value of solution less than 1.With chloroform with acid extraction in organic phase, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 92% through chromatogram short column separating-purifying.
Embodiment 2:
(1) preparation 4-chloro-4 '-methyl diphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride (0.0090g, 0.04mmol), benzene urea (0.0109g, 0.08mmol), 1-bromo-4-chlorobenzene (7.66g, 40mmol), to methylphenylboronic acid (6.53g, 48mmol), salt of wormwood (11.06g, 80mmol), 20mL water and 20mL ethanol.Stirring reaction 2h at room temperature.React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times.Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 95% after the chromatographic column separation.
(2) preparation 2-(4 '-methyl diphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0131g, 0.036mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0444g, 0.108mmol), 4-chloro-4 '-methyl diphenyl (7.30g, 36mmol) with cyanoacetic acid sodium (4.63g, 43.2mmol).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 36mL sym-trimethylbenzene.Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Directly chromatographic column separation obtained white solid, productive rate 96% after reaction finished.
(3) preparation 2-(4 '-methyl diphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4 '-methyl diphenyl-4-yl) acetonitrile (6.22g, 30mmol) and sodium hydroxide (3.60g, 90mmol), add again 60mL water and 9mL ethanol.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.Reaction stops behind the 10h, drip hydrochloric acid so that pH value of solution less than 1.With chloroform with acid extraction in organic phase, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 92% through chromatogram short column separating-purifying.
Embodiment 3:
(1) preparation 2-methyl-4-chloro biphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride (0.0090g, 0.04mmol), benzene urea (0.0109g, 0.08mmol), 2-methyl isophthalic acid-bromo-4-chlorobenzene (8.22g, 40mmol), phenylo boric acid (5.85g, 48mmol), salt of wormwood (11.06g, 80mmol), 20mL water and 20mL ethanol.Stirring reaction 2h at room temperature.React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times.Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 92% after the chromatographic column separation.
(2) preparation 2-(2-methyl diphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0131g, 0.036mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0444g, 0.108mmol), 2-methyl-4-chloro biphenyl (7.30g, 36mmol) with cyanoacetic acid sodium (4.63g, 43.2mmol).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 36mL sym-trimethylbenzene.Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Directly chromatographic column separation obtained white solid, productive rate 94% after reaction finished.
(3) preparation 2-(2-methyl diphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(2-methyl diphenyl-4-yl) acetonitrile (6.22g, 30mmol), add again 60mL1.5mol/L sulfuric acid.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, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 94% through chromatogram short column separating-purifying.
Embodiment 4:
(1) preparation 4-chloro-4 '-methoxyl biphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride (0.0090g, 0.04mmol), benzene urea (0.0109g, 0.08mmol), 1-bromo-4-chlorobenzene (7.66g, 40mmol), to methoxyphenylboronic acid (7.29g, 48mmol), salt of wormwood (11.06g, 80mmol), 20mL water and 20mL ethanol.Stirring reaction 2h at room temperature.React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times.Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 96% after the chromatographic column separation.
(2) preparation 2-(4 '-methoxyl biphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride (0.0131g, 0.036mmol), 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl (0.0444g, 0.108mmol), 4-chloro-4 '-methoxyl biphenyl (7.87g, 36mmol) with cyanoacetic acid sodium (4.63g, 43.2mmol).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 36mL sym-trimethylbenzene.Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h.Directly chromatographic column separation obtained white solid, productive rate 93% after reaction finished.
(3) preparation 2-(4 '-methoxyl biphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4 '-methoxyl biphenyl-4-yl) acetonitrile (6.70g, 30mmol) and sodium hydroxide (3.60g, 90mmol), add again 60mL water and 9mL ethanol.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.Reaction stops behind the 10h, drip hydrochloric acid so that pH value of solution less than 1.With chloroform with acid extraction in organic phase, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 90% through chromatogram short column separating-purifying.
Above method to a kind of synthetic felbinac provided by the present invention and derivative 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 (10)
1. the method for a synthetic felbinac is characterized in that, may further comprise the steps:
A) 1-bromo-4-chlorobenzene and phenylo boric acid are dissolved in the water-ethanol mixed solvent, in the presence of alkali metal compound or alkaline earth metal compound, under palladium catalyst and the urea seeding of non-phosphine part benzene, the Suzuki-Miyaura linked reaction occuring in the room temperature, generates the 4-chlordiphenyl;
Described alkali metal compound is at least a in alkaline carbonate, alkali metal hydroxide or the alkali metal alcoholates, and described alkaline earth metal compound is at least a in alkaline earth metal carbonate, alkaline earth metal hydroxides or the alkaline-earth alkoxides;
Described palladium catalyst is acid chloride;
Phenylo boric acid is 1.1~1.4 with the ratio of the amount of substance of 1-bromo-4-chlorobenzene; Alkali metal compound or alkaline earth metal compound are 1.5~3 with the ratio of the amount of substance of 1-bromo-4-chlorobenzene;
The consumption of palladium catalyst is counted the 0.05%mol~0.2%mol of the amount of substance of 1-bromo-4-chlorobenzene with palladium;
Non-phosphine part benzene urea is 1:1~3:1 with the ratio of the amount of substance of palladium catalyst;
Reaction times is 1h~3h;
B) 4-chlordiphenyl and cyanoacetic acid salt
Be dissolved in the solvent under palladium catalyst and organophosphorus ligand catalysis, the decarboxylation linked reaction occur obtain 2-(biphenyl-4-yl) acetonitrile, M represents basic metal;
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, TRIGLYME, the dipropylene glycol diethyl ether;
Palladium catalyst is the dimerization allyl palladium chloride;
Described organophosphorus ligand is 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl;
Temperature of reaction is 120 ℃~160 ℃, and the reaction times is 16h~24h;
Cyanoacetic acid salt is 1.1~1.5 with the ratio of the amount of substance of 4-chlordiphenyl;
The volume milliliter number of solvent is 0.5~2 with the ratio of the mmole number of 4-chlordiphenyl;
The consumption of palladium catalyst is counted the 0.1%mol~0.4%mol of the amount of substance of 4-chlordiphenyl with palladium;
Organophosphorus ligand is 1:1~3:1 with the ratio of palladium catalyst amount of substance;
C) with 2-(biphenyl-4-yl) acetonitrile in strong acid aqueous solution, reflux generation hydrolysis reaction obtains felbinac; Temperature of reaction is 100 ℃~150 ℃, and the reaction times is 5h~15h;
Perhaps with 2-(biphenyl-4-yl) acetonitrile in strong alkali aqueous solution, solubility promoter ethanol exists lower, behind the reflux generation hydrolysis reaction with the protonated felbinac that obtains of strong acid; Described temperature of reaction is 100 ℃~150 ℃, and the reaction times is 5h~15h.
2. method according to claim 1 is characterized in that, the water of described a) middle water-ethanol the solvent mixture is 1:2~2:1 with the ratio of the volume of ethanol.
3. method according to claim 1 and 2 is characterized in that, the volume milliliter number of described water-ethanol the solvent mixture is 0.5~2 with the ratio of the mmole number of 1-bromo-4-chlorobenzene.
4. method according to claim 1 is characterized in that, the strong acid in the described strong acid aqueous solution is at least a in sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or the perchloric acid.
5. method according to claim 4, it is characterized in that, the amount of substance of the strong acid in the described strong acid aqueous solution is 2 times to 5 times of amount of substance of 2-(biphenyl-4-yl) acetonitrile, and the concentration of the strong acid in the described strong acid aqueous solution is counted 1mol/L to 3mol/L with hydrogen ion concentration.
6. method according to claim 5 is characterized in that, the highly basic in the described strong alkali aqueous solution is at least a in sodium hydroxide or the potassium hydroxide.
7. method according to claim 6, it is characterized in that, the amount of substance of the highly basic in the described strong alkali aqueous solution is 2 times to 5 times of amount of substance of 2-(biphenyl-4-yl) acetonitrile, and the concentration of highly basic is counted 1mol/L to 3mol/L with hydroxide ion concentration in the described strong alkali aqueous solution.
8. method according to claim 7 is characterized in that, the volume of described solubility promoter ethanol is 1/10 to 1/2 of strong alkali aqueous solution volume.
9. method according to claim 8 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 the strong acid consumption of described protonated usefulness is 1.2 times to 1.5 times of highly basic amount of substance.
10. the method for a synthetic felbinac derivative is characterized in that, may further comprise the steps:
(1) preparation 4-chloro-4 '-methyl diphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride 0.04mmol, benzene urea 0.08mmol, 1-bromo-4-chlorobenzene 40mmol, to methylphenylboronic acid 48mmol, salt of wormwood 80mmol, 20mL water and 20mL ethanol; Stirring reaction 2h at room temperature; React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times; Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 95% after the chromatographic column separation;
(2) preparation 2-(4 '-methyl diphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride 0.036mmol, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl 0.108mmol, 4-chloro-4 '-methyl diphenyl 36mmol and cyanoacetic acid sodium 43.2mmol; 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 36mL sym-trimethylbenzene; Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h; Directly chromatographic column separation obtained white solid, productive rate 96% after reaction finished;
(3) preparation 2-(4 '-methyl diphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4 '-methyl diphenyl-4-yl) acetonitrile 30mmol and sodium hydroxide 90mmol, add again 60mL water and 9mL ethanol; 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; Reaction stops behind the 10h, drip hydrochloric acid so that pH value of solution less than 1; With chloroform with acid extraction in organic phase, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 92% through chromatogram short column separating-purifying;
Perhaps be:
(1) preparation 2-methyl-4-chloro biphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride 0.04mmol, benzene urea 0.08mmol, 2-methyl isophthalic acid-bromo-4-chlorobenzene 40mmol, phenylo boric acid 48mmol, salt of wormwood 80mmol, 20mL water and 20mL ethanol; Stirring reaction 2h at room temperature; React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times; Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 92% after the chromatographic column separation;
(2) preparation 2-(2-methyl diphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride 0.036mmol, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl 0.108mmol, 2-methyl-4-chloro biphenyl 36mmol and cyanoacetic acid sodium 43.2mmol; 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 36mL sym-trimethylbenzene; Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h; Directly chromatographic column separation obtained white solid, productive rate 94% after reaction finished;
(3) preparation 2-(2-methyl diphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(2-methyl diphenyl-4-yl) acetonitrile 30mmol, add again 60mL1.5mol/L sulfuric acid; 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, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 94% through chromatogram short column separating-purifying;
Perhaps be:
(1) preparation 4-chloro-4 '-methoxyl biphenyl
In a 150ml round-bottomed flask that magneton is housed, add acid chloride 0.04mmol, benzene urea 0.08mmol, 1-bromo-4-chlorobenzene 40mmol, to methoxyphenylboronic acid 48mmol, salt of wormwood 80mmol, 20mL water and 20mL ethanol; Stirring reaction 2h at room temperature; React and solution in the round-bottomed flask is transferred in the 150mL separating funnel after complete, with 80mL ethyl acetate extraction 3 times; Extracted rear organic phase and used anhydrous magnesium sulfate drying 20 minutes, filtered, with decompression rotatory evaporator desolventizing ethyl acetate, again through obtaining white solid, productive rate 96% after the chromatographic column separation;
(2) preparation 2-(4 '-methoxyl biphenyl-4-yl) acetonitrile
In a 100mL Shi Lanke bottle of crossing with oven drying that magneton is housed, add dimerization allyl palladium chloride 0.036mmol, 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-biphenyl 0.108mmol, 4-chloro-4 '-methoxyl biphenyl 36mmol and cyanoacetic acid sodium 43.2mmol; 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 36mL sym-trimethylbenzene; Cover again stopper after adding, put into 140 ℃ of oil cauldrons after the clamping, stirring reaction 20h; Directly chromatographic column separation obtained white solid, productive rate 93% after reaction finished;
(3) preparation 2-(4 '-methoxyl biphenyl-4-yl) acetic acid
In a clean 100mL round-bottomed flask that magneton is housed, add 2-(4 '-methoxyl biphenyl-4-yl) acetonitrile 30mmol and sodium hydroxide 90mmol, add again 60mL water and 9mL ethanol; 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; Reaction stops behind the 10h, drip hydrochloric acid so that pH value of solution less than 1; With chloroform with acid extraction in organic phase, use again Rotary Evaporators desolventizing chloroform, thick product obtains white solid, productive rate 90% through chromatogram short column separating-purifying.
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Non-Patent Citations (3)
Title |
---|
Rui Shang,et al..Synthesis of Aromatic Esters via Pd-Catalyzed Decarboxylative Coupling of Potassium Oxalate Monoesters with Aryl Bromides and Chlorides.《Journal of American Chemical Society》.2009,第131卷(第16期),5738-5739. * |
邓维等.铜催化交叉偶联反应研究的新进展.《有机化学》.2004,第24卷(第2期),150-165. |
铜催化交叉偶联反应研究的新进展;邓维等;《有机化学》;20041231;第24卷(第2期);150-165 * |
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