阅读说明：本技术 一种曲法罗汀3＂-叔丁基-4＇-（2-羟基乙氧基）-4＂-吡咯烷-1-基[1，1＇；3＇，1＂]-三联苯-4-羧酸的制备方法 (A trematopsin 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl [1, 1'; process for preparing 3 ', 1' ] -terphenyl-4-carboxylic acid ) 是由 吴溧明 陈国华 于 2021-09-18 设计创作，主要内容包括：一种曲法罗汀3″-叔丁基-4′-(2-羟基乙氧基)-4″-吡咯烷-1-基[1,1′；3′,1″]-三联苯-4-羧酸的制备方法公开了曲法罗汀3″-叔丁基-4′-(2-羟基乙氧基)-4″-吡咯烷-1-基[1,1′；3′,1″]-三联苯-4-羧酸的制备方法。所述方法包括以下步骤：①化合物1在碱作用下水解得到中间体2；②化合物3与化合物5在钯催化剂、膦配体和碱的作用下发生反应得到中间体4,反应液不经后处理直接与中间体2在钯催化剂、膦配体和碱的作用下进行Suzuki偶联反应一锅法制备曲法罗汀。其主要优点是物料易得、操作简便、安全性好、成本较低、收率高且副产物少,有利于工业化生产。(Tretinoin 3 '-tert-butyl-4' - (2-hydroxyethoxy) -4 '-pyrrolidin-1-yl [1, 1'; 3', 1 ″)]Process for the preparation of-terphenyl-4-carboxylic acid trefaritine 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl [1, 1'; 3', 1 ″)]A method for preparing (E) -terphenyl-4-carboxylic acid. The method comprises the following steps: hydrolyzing a compound 1 under the action of alkali to obtain an intermediate 2; ② the compound 3 and the compound 5 react under the action of palladium catalyst, phosphine ligand and alkali to obtain an intermediate 4, and the reaction liquid directly carries out Suzuki coupling reaction with the intermediate 2 under the action of palladium catalyst, phosphine ligand and alkali to prepare the trafavudine by a one-pot method without post-treatment. The method has the main advantages of easily obtained materials, simple and convenient operation, good safety, lower cost, high yield and less by-products, and is beneficial to industrial production.)

1. A method for preparing trebrogliptin 3 '-tert-butyl-4' - (2-hydroxyethoxy) -4 '-pyrrolidin-1-yl [1, 1'; a process for 3', 1 "] -terphenyl-4-carboxylic acid, characterized in that it comprises the following steps:

(1) hydrolyzing the compound 1 under the action of alkali to generate an intermediate 2;

(2) the compound 3 and the compound 5 react under the action of a palladium catalyst, a phosphine ligand and alkali to obtain an intermediate 4, and the reaction liquid directly carries out Suzuki coupling reaction with the intermediate 2 under the action of the palladium catalyst, the phosphine ligand and the alkali in one-pot method to prepare the trafavudine without post-treatment.

The reaction route of the synthesis method is as follows:

2. in the process of claim 1, compound 1 is characterized by R₁Represents hydrogen, a substituted or unsubstituted straight or branched chain alkanoyl group having 1 to 10 carbon atoms, a substituted or unsubstituted straight or branched chain alkenylacyl group having 1 to 10 carbon atoms, a substituted or unsubstituted straight or branched chain alkynoyl group having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkylacyl group, a substituted or unsubstituted arylacyl group, a substituted or unsubstituted heterocycloyl group, a substituted or unsubstituted heteroarylacyl group or an alkanoyl group having 1 to 10 carbon atoms containing a heteroatom; y represents cyano (-CN), amide (-CONR)₂R₃) A carboxyl group or an ester group (-COOR)₂)；R₂And R₃Each represents hydrogen, substituted or unsubstituted straight or branched alkyl of 1 to 10 carbon atoms, substituted or unsubstituted straight or branched alkenyl of 1 to 10 carbon atoms, substituted or unsubstituted straight or branched alkynyl of 1 to 10 carbon atoms, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or 1 to 10 carbon alkyl containing a heteroatom, R₂And R₃May be the same or different; x represents fluorine, chlorine, bromine, iodine, mesylate, trifluromethylAn ester group, a benzenesulfonate group, a p-toluenesulfonate group.

3. The process conditions of claims 1-2, characterized in that: the base used for hydrolysis of compound 1 is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, preferably sodium hydroxide; the molar ratio of the compound 1 to the alkali is 1: 1-20.

4. The process conditions of claims 1 to 3, characterized in that: the solvent used for hydrolyzing the compound 1 is methanol, ethanol, propanol, butanol, ethylene glycol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, sulfolane or a mixture thereof, and preferably a mixed solvent of ethanol and water; the reaction temperature is from room temperature to the boiling point of the solvent.

5. The process of claim 1, wherein compound 3, compound 5 and intermediate 2 are prepared in a one-pot process to form trafagotine, compound 5 is characterized in that R is₄And R₅Each represents hydrogen, substituted or unsubstituted, linear or branched alkyl of 1 to 3 carbon atoms, R₄And R₅May be the same or different; or R₄And R₅Together forming the final alcohol ester.

6. The process conditions of claim 1 or 5, wherein the compound 3, the compound 5 and the intermediate 2 are used for preparing the trefariptin in a one-pot method, and the molar ratio of the compound 3 to the compound 5 is 1: 1-5; the molar ratio of the intermediate 2 to the compound 3 is 1: 1-1.5; the reaction temperature is from room temperature to the boiling point of the solvent; the reaction time is 5-20 hours.

7. The process conditions of claims 1 or 5 to 6, wherein the compound 3, the compound 5 and the intermediate 2 are used for preparing trafagotine by a one-pot method, and the palladium catalyst is palladium chloride, palladium acetate, 1 ' -bis (diphenylphosphino) ferrocene palladium chloride, tetratriphenylphosphine palladium, dibenzylidene acetone palladium, methanesulfonic acid (9, 9-dimethyl-4, 5-bis diphenylphosphinoanthracene) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid [2- (dicyclohexylphosphino) biphenyl ] (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -Biphenyl-2-yl) palladium (II), chlorine (2-dicyclohexylphosphino-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), chlorine [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2-aminobiphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl) (2-amino-1, 1 ' -biphenyl-2-yl) palladium (II), chlorine (2-dicyclohexylphosphino-2 ', 4', 6 ' -triisopropyl-1), 1 '-biphenyl) [2- (2' -amino-1, 1 '-biphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2', 4', 6' -triisopropyl-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid (2-di-tert-butylphosphino-2', 4', 6' -triisopropyl-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2', 4', 6' -tri-isopropyl-1, 1 '-biphenyl) (2' -amino-1, 1' -biphenyl-2-yl) palladium (II), preferably palladium acetate; the molar ratio of the compound 3 to the palladium catalyst is 100: 0.05-10; the molar ratio of the intermediate 2 to the palladium catalyst is 100: 0.05-10.

8. The process conditions of claims 1 or 5-7 wherein compound 3, compound 5 and intermediate 2 are prepared in a one-pot process to form trafagotine, characterized in that the base used to synthesize intermediate 4 is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, potassium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundec-7-ene, preferably potassium acetate; the base used for synthesizing the trefaritine is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia water, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, preferably potassium phosphate; the molar ratio of the compound 3 to the alkali is 1: 0.5-5; the molar ratio of the intermediate 2 to the alkali is 1: 0.5-5.

9. The process conditions of claims 1 or 5-8, wherein the compound 3, the compound 5 and the intermediate 2 are used for preparing trefavudine by a one-pot method, and the method is characterized in that the solvent used for synthesizing the intermediate 4 is methanol, ethanol, propanol, butanol, ethylene glycol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, sulfolane or a mixture thereof, preferably a mixed solvent of 1, 4-dioxane and methanol; the solvent used for synthesizing the trefaritine is methanol, ethanol, propanol, butanol, ethylene glycol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, sulfolane or a mixture thereof, and preferably a mixed solvent of 1, 4-dioxane and water.

10. The process conditions of claims 1 or 5-9, wherein compound 3, compound 5 and intermediate 2 are used in a one-pot process for the preparation of trefavudine, characterized in that the phosphine ligand used is a phosphine ligand selected from the group consisting of trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, tricyclohexylphosphine, triphenylphosphine, tris (2-methylphenyl) phosphine, dimethylphenylphosphine, (2-pyridyl) diphenylphosphine, TFP, APhos, EPhos, GPhos, TriPhos, opos, XPhos, SPhos, RuPhos, XantPhos, dppf, dcpe, dmpe, BrettPhos, JohnPhos, DavePhos, TuPhos, etc., preferably triphenylphosphine; the molar ratio of the compound 3 to the phosphine ligand is 100: 0.1-20; the molar ratio of the intermediate 2 to the phosphine ligand is 100: 0.1-20.

Technical Field

Tretinoin 3 '-tert-butyl-4' - (2-hydroxyethoxy) -4 '-pyrrolidin-1-yl [1, 1'; 3 ', 1' ] -terphenyl-4-carboxylic acid.

Background

Trofagotine (Trifarotene), chemical name: 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl [1, 1'; 3 ', 1' ] -terphenyl-4-carboxylic acid, a fourth alternative retinoid drug developed by the company Galderma, switzerland for the treatment of acne vulgaris, with the trade name Aklief, was approved in the us in 2019. Compared with other retinoid drugs, trefaritine has better therapeutic effects and fewer side effects.

Patent WO2006066978 discloses a method for preparing trebrogliptin, which specifically comprises: brominating 2-tert-butyl aniline under the action of tetrabutylammonium tribromide to obtain aryl bromide; b. reacting the aryl bromide with 1, 4-dibromobutane to obtain 1- (4-bromo-2-tert-butylphenyl) pyrrolidine; c, reacting 1- (4-bromo-2-tert-butylphenyl) pyrrolidine with triisopropyl borate under the action of n-butyllithium to obtain 3-tert-butyl-4-pyrrolidinophenylboronic acid; 3 '-bromo-4' -hydroxybiphenyl-4-carboxylic acid ethyl ester is subjected to nucleophilic substitution reaction to obtain 4 '- (2-acetoxyethoxy) -3' -bromobiphenyl-4-carboxylic acid ethyl ester; 3-tert-butyl-4-pyrrolidinophenylboronic acid and ethyl 4 '- (2-acetoxyethoxy) -3' -bromobiphenyl-4-carboxylate by Suzuki coupling to give 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl [1, 1'; 3', 1] -terphenyl-4-carboxylic acid ethyl ester; f. finally, the trefaritine is obtained by two-step alkaline hydrolysis. The butyl lithium and air adopted by the route for preparing the boric acid are easy to combust, and the reaction system has higher requirement on moisture, so the method is not suitable for large-scale production; hydrolysis of the ester occurs during coupling under alkaline conditions resulting in increased impurities. The total yield of 4 steps of boronization, coupling and hydrolysis is only 5.24 percent.

Disclosure of Invention

The invention aims to provide a preparation method of trematopsis in order to overcome the problems of complex operation, difficult control, high risk, more byproducts, low yield and the like in the prior art. Compared with the prior art, the method has the advantages that the intermediate 2 is obtained by hydrolysis; then, the compound 3, the compound 5 and the intermediate 2 are used for preparing the trefaritine by a one-pot method, and the method avoids the defect that arylboronic acid and arylboronic acid ester are not easy to separate. Has the advantages of simple operation, good safety, low cost, few by-products and the like. And the total yield of hydrolysis, boronation and coupling is improved from 5.24 percent to 61 percent.

The route is as follows:

hydrolyzing the compound 1 to obtain an intermediate 2, reacting the compound 3 with the compound 5 to obtain an intermediate 4, and directly carrying out Suzuki coupling on the intermediate 4 and the intermediate 2 without aftertreatment to obtain the trafavudine.

S1: the compound 1 is hydrolyzed under the action of alkali to obtain an intermediate 2.

S2 and S3: under the protection of inert gas, the compound 3 and the compound 5 react under the action of a palladium catalyst, a phosphine ligand and alkali to obtain an intermediate 4, and under the protection of inert gas, the intermediate 4 directly reacts with the intermediate 2 under the action of the palladium catalyst, the phosphine ligand and the alkali without post-treatment to obtain the taflunomide through Suzuki coupling reaction.

As a preferable scheme of the above technical scheme, the synthesis process of the intermediate 2 in S1 is as follows: adding the compound 1 into ethanol, adding a solution prepared from sodium hydroxide and water, heating for reaction, adding dilute hydrochloric acid after the reaction is finished, filtering, washing a filter cake with water, and drying under reduced pressure to obtain an intermediate 2.

More preferably, the solvent in S1 is selected from methanol, ethanol, propanol, butanol, ethylene glycol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, sulfolane, or a mixture thereof, ethanol is preferred in the present invention, and the mass-to-volume ratio of compound 1 and ethanol is 1: (3-30) g/ml.

Further preferably, the base in S1 includes lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, and sodium hydroxide is preferred in the present invention.

More preferably, the molar ratio of the compound 1 to the sodium hydroxide in S1 is 1: 1 to (1-6).

More preferably, the sodium hydroxide is dissolved in water in S1, and the mass-volume ratio of the sodium hydroxide to the water is 1: (2-10) g/ml.

Further preferably, the reaction temperature in S1 is from room temperature to the boiling point of the solvent.

As a preferable embodiment of the above technical solution, the synthesis process of intermediate 4 and trefarptin in S2 and S3 is as follows: under the protection of nitrogen, adding a solution prepared from a compound 3, palladium acetate, triphenylphosphine, potassium acetate, a compound 5 and methanol into 1, 4-dioxane, and heating for reaction to generate an intermediate 4. After the reaction, the reaction solution is cooled to room temperature, under the protection of nitrogen, the solution prepared from the intermediate 2, potassium phosphate and water, palladium acetate and triphenyl bony are added into the reaction solution, and the reaction solution is heated for reaction. And after the reaction is finished, adding water, acidifying with dilute hydrochloric acid until the pH value is 4-5, filtering, washing a filter cake with water, drying under reduced pressure, and recrystallizing with ethanol to obtain the trefaritine.

More preferably, the molar ratio of the compound 3 to the compound 5 in S2 is 1: 1 to (1-5).

Further preferably, the palladium catalyst in S2 is palladium chloride, palladium acetate, 1 '-bis (diphenylphosphino) ferrocene palladium chloride, tetratriphenylphosphine palladium, dibenzylideneacetone palladium, methanesulfonic acid (9, 9-dimethyl-4, 5-bisdiphenylphosphinoxanthracene) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid [2- (dicyclohexylphosphino) biphenyl ] (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-dimethoxy-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II), Chloro (2-dicyclohexylphosphino-2 ', 6' -dimethoxy-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2-aminobiphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1 '-biphenyl-2-yl) palladium (II), chloro (2-dicyclohexylphosphino-2', 4', 6' -triisopropyl-1, 1 '-biphenyl) [2- (2' -amino-1, 1 ' -Biphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ', 4', 6 ' -triisopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-di-tert-butylphosphino-2 ', 4', 6 ' -triisopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2 ', 4', 6 ' -tri-isopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), palladium acetate is preferred in the invention, and the molar ratio of the compound 3 to the palladium acetate is 100: (0.05-10).

Further preferably, the phosphine ligand in S2 is trimethyl phosphine, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tripentyl phosphine, tricyclohexyl phosphine, triphenyl phosphine, tris (2-methylphenyl) phosphine, dimethyl phenyl phosphine, (2-pyridyl) diphenyl phosphine, TFP, APhos, EPhos, GPhos, TriPhos, OPhos, XPhos, SPhos, RuPhos, XantPhos, dppf, dcpe, dmpe, Brettphos, JohnPhos, DavePhos, TuPhos, etc., and triphenylphosphine is preferred in the present invention, and the molar ratio of compound 3 to triphenyl phosphine is 100: (0.1-20).

Further preferably, in S2, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia water, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, potassium acetate is preferred in the present invention, and the molar ratio of compound 3 to potassium acetate is 1: (0.5-5).

More preferably, the compound 5 in S2 is added into methanol, and the mass-volume ratio of the compound 5 to the methanol is 1: (3-8) g/ml.

More preferably, the solvent in S2 is methanol, ethanol, propanol, butanol, ethylene glycol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, sulfolane, or a mixture thereof, preferably a mixed solvent of 1, 4-dioxane and methanol, and the mass-to-volume ratio of compound 3 and 1, 4-dioxane is 1: (2-10) g/ml.

Further preferably, the inert gas in S2 is nitrogen.

Further preferably, the reaction temperature in S2 is from room temperature to the boiling point of the solvent.

More preferably, the reaction time in S2 is 5 to 20 hours, and the reaction time in the invention is preferably 6 hours.

Further preferably, the palladium catalyst in S3 is palladium chloride, palladium acetate, 1 '-bis (diphenylphosphino) ferrocene palladium chloride, tetratriphenylphosphine palladium, dibenzylideneacetone palladium, methanesulfonic acid (9, 9-dimethyl-4, 5-bisdiphenylphosphinoxanthracene) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid [2- (dicyclohexylphosphino) biphenyl ] (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-dimethoxy-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II), Chloro (2-dicyclohexylphosphino-2 ', 6' -dimethoxy-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II), chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2-aminobiphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1 '-biphenyl-2-yl) palladium (II), chloro (2-dicyclohexylphosphino-2', 4', 6' -triisopropyl-1, 1 '-biphenyl) [2- (2' -amino-1, 1 ' -biphenyl) ] palladium (II), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ', 4', 6 ' -triisopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-di-tert-butylphosphino-2 ', 4', 6 ' -triisopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), methanesulfonic acid (2-dicyclohexylphosphino-2 ', 4', 6 ' -tri-isopropyl-1, 1 ' -biphenyl) (2 ' -amino-1, 1 ' -biphenyl-2-yl) palladium (II), palladium acetate is preferred in the invention, and the molar ratio of the intermediate 2 to the palladium acetate is 100: (0.05-10).

Further preferably, the phosphine ligand in S3 is trimethyl phosphine, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tripentyl phosphine, tricyclohexyl phosphine, triphenyl phosphine, tris (2-methylphenyl) phosphine, dimethyl phenyl phosphine, (2-pyridyl) diphenyl phosphine, TFP, APhos, EPhos, GPhos, TriPhos, OPhos, XPhos, SPhos, RuPhos, XantPhos, dppf, dcpe, dmpe, Brettphos, JohnPhos, DavePhos, TuPhos, etc., and triphenylphosphine is preferred in the present invention, and the molar ratio of intermediate 2 to triphenyl phosphine is 100: (0.1-20).

More preferably, the molar ratio of the intermediate 2 to the compound 3 in S3 is 1: 1 to 1.5.

Further preferably, in S3, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, palladium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, palladium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, palladium phosphate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia water, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, potassium phosphate is preferred in the present invention, and the molar ratio of intermediate 2 to potassium phosphate is 1: (0.5-5).

More preferably, the potassium phosphate in S3 is dissolved in water, and the mass volume ratio of the potassium phosphate to the water is 1: (3-8) g/ml.

Further preferably, the inert gas in S3 is nitrogen.

Further preferably, the reaction temperature in S3 is from room temperature to the boiling point of the solvent.

More preferably, the reaction time in S3 is 5 to 20 hours, and 10 hours is preferred in the invention.

Detailed Description

The following examples further illustrate the invention but the invention is not limited thereto.

Example (b):

EXAMPLE 1 preparation of intermediate 2

Adding compound 1(10g, 24.6mmol) into 60ml ethanol, adding sodium hydroxide (2.4g, 59mmol) water (10ml), heating to 50 deg.C for reaction for 3h, adding diluted hydrochloric acid to acidify to pH 2, filtering, washing filter cake with water, and drying under reduced pressure at 50 deg.C. 7.9g of intermediate 2 are obtained with a yield of 95%.

EXAMPLE 2 preparation of intermediate 4 and Triflunomide

A solution of compound 3(4.6g, 16.3mmol), palladium acetate (0.08g, 0.36mmol), triphenylphosphine (0.186g, 0.72mmol), potassium acetate (3.5g, 36mmol) and tetrahydroxydiboron (2.4g, 26.7mmol) in methanol (15ml) was added to 1, 4-dioxane (50ml) under nitrogen and heated to 80 ℃ for 6h to give intermediate 4. The reaction mixture was cooled to room temperature, and a solution of intermediate 2(5g, 14.8mmol), palladium acetate (0.08g, 0.36mmol), triphenylphosphine (0.186g, 0.72mmol) and potassium phosphate (6.3g, 29.6mmol) in water (20ml) was added under nitrogen, and the mixture was heated to 100 ℃ for 10 hours. Cooling the reaction solution to room temperature, adding water, acidifying with dilute hydrochloric acid until the pH is 4-5, filtering, washing the filter cake with water, and drying at 50 ℃ under reduced pressure. Recrystallization of the solid from 60ml ethanol gave 4.5g of trefaritine in 65% yield.

The structure identification data are as follows:

¹H NMR(500MHz，DMSO-d₆)δ7.99(d，J＝8.1Hz，2H)，7.81(d，J＝8.2Hz，2H)，7.70-7.62(m，2H)，7.59(d，J ＝1.9Hz，1H)，7.53-7.38(m，2H)，7.22(d，J＝8.5Hz，1H)，4.82(s，1H)，4.10(t，J＝5.2Hz，2H)，3.72(t，J＝5.2Hz， 2H)，2.95(d，J＝5.6Hz，4H)，1.88(q，J＝3.9，2.6Hz，4H)，1.42(s，9H).

HRMS(ESI+)：460.25143[M+H]⁺. The molecular formula is as follows: c₂₉H₃₃NO₄。