CN101585767B - Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate - Google Patents
Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate, comprising the steps of adding an alkali metal hydroxide in an alcohol solvent, dripping N-methyl-N-methoxyl-2-[4-(4-chlorobutyryl)phenyl]-2-methacrylamide alcohol solvent in the solvent, reacting for 10-30h at 20-50 DEG C to obtain N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide;refluxing the N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide in an alkaline alcohol solvent for 20-40h and adjusting pH to be 3 so as to obtain 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid; reacting the 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid in an inorganic acid for 20-30h at 60-100 DEG C and recrystallizing to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid; and finally adding the 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid in the hydrochloric acid solution of absolute alcohol, and reacting for 3h at 60 DEG C to obtain the target product. The preparation method has high product yield, little pollution and applicable industrial product.
Description
Technical field
The present invention relates to the method for a kind of Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester.
Background technology
Anaphylactic disease is human common disease, like allergic rhinitis, chronic sudden rubella, spring fever etc.Fexofenadine hydrochloride is a Claritin of new generation; With like product Vagran (astemizole; Owing to be prone to cause cardiac toxic, cancelled from American market in 1999), cetirizine, LT etc. compare, fexofenadine has the advantage that effect is fast, curative effect is high, toxic side effect is little.2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester is the key intermediate of synthetic fexofenadine hydrochloride.
It is the method that raw material passes through friedel-crafts acylation reaction Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid methyl esters or 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ethyl ester that U.S. Pat 6242606B1 discloses with 2-methyl-2-phenylpropionic acid methyl esters or 2-methyl-2-phenylpropionic acid ethyl ester; In two kinds of products of this method gained a large amount of meta-isomer impurity are arranged all; And these impurity are difficult to separate, and product purity is reduced greatly.
Application number be the Indian patent application file of 2004CH00206 disclose with aforesaid method make between the position with the hydrolysis of contraposition mixture of products and Cyclopropanated after again the fractionation; Obtain open loop again behind pure 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid, esterification to prepare the method for 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ethyl ester; This method steps is many; Fractionation efficient is low, and productive rate only has about 40%.
Publication number is that the patent application document of US2002007068 (A1) also discloses similar method for splitting, and the same step of this method is many, and it is low to split efficient, and productive rate only has 28%.
Publication number is that the patent application document of WO2005019175 (A1) discloses with α; The alpha-alpha-dimethyl phenyl acetic acid methyl esters is the method for raw material Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid methyl esters; This method need experience steps such as the protection, contraposition acylations of esterification, reduction, alcoholic extract hydroxyl group, Cyclopropanated, oxidation, Trimetylene open loop, esterification; Productive rate lower (about 30%) not only, and the use of potassium permanganate can bring bigger environmental pollution in the reaction.
People [Giacomo, B.D. such as Giacomo B.D.; Coletta, D.; Natalini B.; Ni, M.H.; Pellicciari R.Farmaco; 1999,54 (9): 685～690.] disclosed with α, alpha-alpha-dimethyl phenyl acetic acid is that not only step is many for the method for raw material Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid methyl esters; Productive rate is low; Only have 27%, and the use of compounds such as lithium aluminum hydride, diazomethane has increased the danger of operating in the reaction, makes this method be inappropriate for suitability for industrialized production.
Summary of the invention
The technical problem that the present invention will solve is the deficiency to above-mentioned prior art, provides not contain meta-isomer in a kind of product, and productive rate is high, pollutes for a short time, is suitable for the compound method of 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid ester of suitability for industrialized production.
The structure of synthetic 2-of the present invention [4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester is as follows:
Wherein, R is methyl, ethyl or 2-ethylhexyl.
Its synthetic route is shown in the following figure:
(III) in the said synthesis route is that N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide adopts prior art for preparing, and the present invention is that starting raw material begins preparation with N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide (III) more then.
In order to solve the problems of the technologies described above, technical scheme of the present invention is: the method for a kind of Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, and it is characterized in that: step is following:
(1) alkali metal hydroxide is joined in the alcoholic solvent, stir, make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L;
(2) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is joined in the alcoholic solvent; Stir, make that [4-(4-chlorobutyryl) phenyl]-volumetric molar concentration of 2-methyl propanamide in this alcoholic solvent is 1mol/L to N-methyl-N-methoxyl group-2-;
(3) then step (2) gained mixture is added drop-wise in step (1) the gained mixture, wherein the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is 6～10: 1;
(4) be 20～50 ℃ of following stirring reactions 10～30 hours in temperature of reaction then, evaporate to dryness alcoholic solvent after reaction finishes adds entry in residue; Use dichloromethane extraction; Drying is filtered, remove behind the methylene dichloride N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide;
(5) N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl the phenyl)-2-methyl propanamide with step (4) gained joins in the absolute alcohol solvent of alkali metal hydroxide; Make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L, the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 4～6: 1, and 20～40 hours afterreaction mixtures of back flow reaction transfer to pH=3 with hydrochloric acid; Alcoholic solvent is removed in underpressure distillation; In residue, add entry, use dichloromethane extraction, drying; Filter, remove behind the methylene dichloride 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid;
(6) 2-(4-cyclopropyl carbonyl the phenyl)-2 Methylpropionic acid with step (5) gained joins in the mineral acid; The weight ratio of mineral acid and 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid is 2～4: 1; 20～30 hours afterreaction mixtures of reaction are used dichloromethane extraction under temperature of reaction is 60 ℃～100 ℃; Drying is filtered, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal;
(7) bubbling feeds the exsiccant hydrogen chloride gas in the absolute alcohol solvent, adds 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid of step (6) gained then, and the weight ratio of absolute alcohol solvent, 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid and anhydrous hydrogen chloride is 12: 1.5: 1; After reacting 3 hours under 60 ℃, remove and desolvate; Residuum is dissolved in methylene dichloride, washing, drying; Filter, remove methylene dichloride and get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester.
Alkali metal hydroxide in above-mentioned steps (1) and (5) is Pottasium Hydroxide or sodium hydroxide.
Alcoholic solvent in above-mentioned steps (1) and (2) is methyl alcohol, ethanol or the mixture be made up of them.
Temperature of reaction in the above-mentioned steps (4) is 30 ℃.
Reaction times in the above-mentioned steps (4) is 18 hours.
Alcoholic solvent in the above-mentioned steps (5) is the trimethyl carbinol, Virahol or by the two mixture of forming.
Reaction times in the above-mentioned steps (5) is 30 hours.
Mineral acid in the above-mentioned steps (6) is that concentration is 36% concentrated hydrochloric acid.
Temperature of reaction in the above-mentioned steps (6) is 80 ℃.
Alcohol in the above-mentioned steps (7) is methyl alcohol, ethanol or 2-Ethylhexyl Alcohol.
Advantage of the present invention and beneficial effect: do not contain meta-isomer in its product of method of Synthetic 2 of the present invention-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid, and productive rate is high, pollution is little, is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail, but the present invention not only is confined to following examples.
Embodiment 1
In 250 milliliters of there-necked flasks, adding 16.00 gram (0.40mol) sodium hydroxide and 150 milliliters of anhydrous methanols stirs; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of anhydrous methanols form and are added in the there-necked flask, dropwise the back 30 ℃ of following stirring reactions 18 hours.Remove anhydrous methanol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, use anhydrous sodium sulfate drying again, filter, remove methylene dichloride under reduced pressure and get product N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide 13.00 grams (0.047mol), productive rate 95%.
In 250 milliliters of there-necked flasks, add 20.50 grams (82%; 0.30mol) Pottasium Hydroxide; 16.50 gram (0.06mol) N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide and 150 milliliters of anhydrous tertiary butanols, the back back flow reaction that stirs 30 hours.Reaction finishes the back with 5mol/L hydrochloric acid adjusting pH=3, removes the trimethyl carbinol under reduced pressure, adds 50 ml waters and 50 milliliters of methylene dichloride in the residue, and separatory, water layer are used twice of 50 milliliters of dichloromethane extraction respectively.The combined dichloromethane layer, anhydrous sodium sulfate drying filters, and removes methylene dichloride under reduced pressure and gets product 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 12.81 grams (0.055mol), 82～83 ℃ of melting ranges, productive rate 92%.
Taking by weighing above-mentioned 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 10 grams (0.043mol) joins in the 30 gram concentrated hydrochloric acids; 80 ℃ are reacted 24 hours afterreaction mixtures down and use dichloromethane extraction; Anhydrous sodium sulfate drying filters, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 10.99 grams (0.041mol) with alcohol crystal; Productive rate 95%, 79～80 ℃ of melting ranges.
In 120 gram absolute ethyl alcohols, feed 10 gram (0.27mol) anhydrous hydrogen chloride gas, the back that finishes adds 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 15 grams (0.056mol), 60 ℃ down reaction after 3 hours underpressure distillation remove and desolvate; Residuum is dissolved in methylene dichloride; Washing, drying is filtered; Remove methylene dichloride and get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ethyl ester 16.20 grams (0.055mol), productive rate 97%.
Above-mentioned raw materials N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide adopts prior art for preparing: (1) with 98.4 gram (0.6mol) α, alpha-alpha-dimethyl phenyl acetic acid is dissolved in 400 milliliters of toluene, and 0 ℃ drips 131 milliliters of sulfur oxychlorides down; 100 milliliters of toluene and excessive sulfur oxychloride are removed in the back underpressure distillation that finishes of stirring at room reaction back flow reaction 2 hours again after 15 hours, reaction, add 184.6 gram (1.34mol) salt of wormwood; 58.5 gram (0.6mol) N, O-dimethyl hydroxylamine hydrochloride and 300 ml waters, stirring at room reaction 4 hours; After finishing, reaction in reaction mixture, drips 200 milliliters of 2N hydrochloric acid; Separatory, organic phase are used 2N hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying after-filtration successively; Toluene is removed in underpressure distillation; Residuum distill N-methyl-N-methoxyl group-α, alpha-alpha-dimethyl phenylacetamide 111.8 gram (0.54mol), productive rate 90%;
(2) 64 gram (0.48mol) aluminum chlorides are dissolved in 200 milliliters of ethylene dichloride, drip 34 gram (0.24mol) 4-chlorobutanoylchlorides under the room temperature and be dissolved in the solution that 60 milliliters of ethylene dichloride form, room temperature reaction drips 41.4 gram (0.20mol) N-methyl-N-methoxyl group-α again after 1 hour; The alpha-alpha-dimethyl phenylacetamide is dissolved in the solution that 50 milliliters of ethylene dichloride form, and dropwises the back room temperature reaction 16 hours, after reaction finishes reaction mixture is slowly poured in 200 milliliters of 2N hydrochloric acid of frozen water refrigerative; Separatory; Water layer extracts with ethylene dichloride, merges organic phase, washes and washes with saturated sodium bicarbonate solution respectively; Dry; Filter, remove solvent and get product N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide 66.3 grams (purity 80%), productive rate 85%; Embodiment 2～3 also together.
Embodiment 2
In 250 milliliters of there-necked flasks, add 20.50 grams (82%; 0.30mol) Pottasium Hydroxide and 150 milliliters of anhydrous methanols stir; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of anhydrous methanols form and are added in the there-necked flask, after dropwising, 20 ℃ of following stirring reactions 30 hours.Remove anhydrous methanol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, use anhydrous sodium sulfate drying again, filter, remove methylene dichloride under reduced pressure and get product N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide 12.38 grams (0.045mol), productive rate 90%.
In 250 milliliters of there-necked flasks, add 14.40 gram (0.36mol) sodium hydroxide, 16.50 gram (0.06mol) N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propionyl and 150 milliliters of anhydrous isopropyl alcohols, the back back flow reaction that stirs 40 hours.Reaction finishes the back with 5mol/L hydrochloric acid adjusting pH=3, removes Virahol under reduced pressure, adds 50 ml waters and 50 milliliters of methylene dichloride in the residue, and separatory, water layer are used twice of 50 milliliters of dichloromethane extraction respectively.The combined dichloromethane layer, anhydrous sodium sulfate drying filters, and removes methylene dichloride under reduced pressure and gets product 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 12.25 grams (0.053mol), 82～83 ℃ of melting ranges, productive rate 88%.
Taking by weighing above-mentioned 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 10 grams (0.043mol) joins in the 20 gram concentrated hydrochloric acids; 100 ℃ are reacted 20 hours afterreaction mixtures down and use dichloromethane extraction; Anhydrous sodium sulfate drying filters, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 10.41 grams (0.039mol) with alcohol crystal; Productive rate 90%, 79～80 ℃ of melting ranges.
In 120 gram anhydrous methanols, feed 10 gram (0.27mol) anhydrous hydrogen chloride gas, the back that finishes adds 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 15 grams (0.056mol), 60 ℃ down reaction after 3 hours underpressure distillation remove and desolvate; Residuum is dissolved in methylene dichloride; Washing, drying is filtered; Remove methylene dichloride and get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid methyl esters 15.53 grams (0.055mol), productive rate 98%.
Embodiment 3
In 250 milliliters of there-necked flasks, add 20.00 gram (0.50mol) sodium hydroxide and 150 milliliters of absolute ethyl alcohols; Stir; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of absolute ethyl alcohols form and are added in the there-necked flask, after dropwising, 50 ℃ of following stirring reactions 30 hours.Remove absolute ethyl alcohol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, anhydrous sodium sulfate drying filters, and removes methylene dichloride under reduced pressure and gets product N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide 12.65 grams (0.046mol), productive rate 92%.
In 250 milliliters of there-necked flasks, add 20.50 grams (82%; 0.30mol) Pottasium Hydroxide; 20.63 gram (0.075mol) N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide and 150 milliliters of anhydrous isopropyl alcohols, the back back flow reaction that stirs 20 hours.Reaction finishes the back with 5mol/L hydrochloric acid adjusting pH=3, removes Virahol under reduced pressure, adds 50 ml waters and 50 milliliters of methylene dichloride in the residue, and separatory, water layer are used twice of 50 milliliters of dichloromethane extraction respectively.The combined dichloromethane layer, anhydrous sodium sulfate drying filters, and removes methylene dichloride under reduced pressure and gets product 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 15.49 grams (0.067mol), 82～83 ℃ of melting ranges, productive rate 89%.
Taking by weighing above-mentioned 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid 10 grams (0.043mol) joins in the 40 gram concentrated hydrochloric acids; 60 ℃ are reacted 30 hours afterreaction mixtures down and use dichloromethane extraction; Anhydrous sodium sulfate drying filters, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 10.64 grams (0.040mol) with alcohol crystal; Productive rate 92%, 79～80 ℃ of melting ranges.
In the anhydrous 2-Ethylhexyl Alcohol of 120 grams, feed 10 gram (0.27mol) anhydrous hydrogen chloride gas, the back that finishes adds 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 15 grams (0.056mol), 60 ℃ down reaction after 3 hours underpressure distillation remove and desolvate; Residuum is dissolved in methylene dichloride; Washing, drying is filtered; Remove methylene dichloride and get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid 2-Ethylhexyl Alcohol ester 19.81 grams (0.052mol), productive rate 92%.
Claims (9)
1. the method for Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: preparation process is following:
(1) alkali metal hydroxide is joined in the alcoholic solvent, stir, make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L;
(2) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is joined in the alcoholic solvent; Stir, make that [4-(4-chlorobutyryl) phenyl]-volumetric molar concentration of 2-methyl propanamide in this alcoholic solvent is 1mol/L to N-methyl-N-methoxyl group-2-;
(3) then step (2) gained mixture is added drop-wise in step (1) the gained mixture, wherein the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is 6～10: 1;
(4) be 20～50 ℃ of following stirring reactions 10～30 hours in temperature of reaction then, evaporate to dryness alcoholic solvent after reaction finishes adds entry in residue; Use dichloromethane extraction; Drying is filtered, remove behind the methylene dichloride N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide;
(5) N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl the phenyl)-2-methyl propanamide with step (4) gained joins in the absolute alcohol solvent of alkali metal hydroxide; Make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L, the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 4～6: 1, and 20～40 hours afterreaction mixtures of back flow reaction transfer to pH=3 with hydrochloric acid; Alcoholic solvent is removed in underpressure distillation; In residue, add entry, use dichloromethane extraction, drying; Filter, remove behind the methylene dichloride 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid;
(6) 2-(4-cyclopropyl carbonyl the phenyl)-2 Methylpropionic acid with step (5) gained joins in the mineral acid; The weight ratio of mineral acid and 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid is 2～4: 1; 20～30 hours afterreaction mixtures of reaction are used dichloromethane extraction under temperature of reaction is 60 ℃～100 ℃; Drying is filtered, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal;
(7) bubbling feeds the exsiccant hydrogen chloride gas in the absolute alcohol solvent, adds 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid of step (6) gained then, and the weight ratio of absolute alcohol solvent, 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid and anhydrous hydrogen chloride is 12: 1.5: 1; After reacting 3 hours under 60 ℃, remove and desolvate; Residuum is dissolved in methylene dichloride, washing, drying; Filter, remove methylene dichloride and get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester;
Mineral acid in the said step (6) is that concentration is 36% concentrated hydrochloric acid.
2. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the alkali metal hydroxide in said step (1) and (5) is Pottasium Hydroxide or sodium hydroxide.
3. according to the method for the said a kind of Synthetic 2 of claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the alcoholic solvent in said step (1) and (2) is methyl alcohol, ethanol or by the two mixture of forming.
4. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the temperature of reaction in the said step (4) is 30 ℃.
5. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the reaction times in the said step (4) is 18 hours.
6. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester is characterized in that: the alcoholic solvent in the said step (5) is the trimethyl carbinol, Virahol or by the two mixture of forming.
7. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the reaction times in the said step (5) is 30 hours.
8. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the temperature of reaction in the said step (6) is 80 ℃.
9. the method for a kind of Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the alcohol in the said step (7) is methyl alcohol, ethanol or 2-Ethylhexyl Alcohol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | Novel intermediates for prepn. of antihisatminic 4-diphenylmethyl/diphenymethoxy piperidine derivatives |
| CN1308611A (en) * | 1998-07-02 | 2001-08-15 | 阿旺蒂斯制药公司 | Antihistaminic piperidine derivatives and intermediates for the preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | Novel intermediates for prepn. of antihisatminic 4-diphenylmethyl/diphenymethoxy piperidine derivatives |
| CN1308611A (en) * | 1998-07-02 | 2001-08-15 | 阿旺蒂斯制药公司 | Antihistaminic piperidine derivatives and intermediates for the preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 吕彬华 等.抗组胺药非索非那定盐酸盐的合成.《中国药物化学杂志》.2004,第14卷(第2期),第96-98页. * |
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