CN101585768B - 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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- CN101585768B CN101585768B CN2009100994177A CN200910099417A CN101585768B CN 101585768 B CN101585768 B CN 101585768B CN 2009100994177 A CN2009100994177 A CN 2009100994177A CN 200910099417 A CN200910099417 A CN 200910099417A CN 101585768 B CN101585768 B CN 101585768B
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 17
- VBTJEFSCACXENO-UHFFFAOYSA-N 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=C(C(=O)CCCCl)C=C1 VBTJEFSCACXENO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 85
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- -1 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester Chemical class 0.000 claims description 13
- 230000001476 alcoholic effect Effects 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 230000005587 bubbling Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- 238000004821 distillation Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- ULWORPZJUIFPIC-UHFFFAOYSA-N methyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate Chemical class COC(=O)C(C)(C)C1=CC=C(C(=O)CCCCl)C=C1 ULWORPZJUIFPIC-UHFFFAOYSA-N 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- NQQITLVKOMJPDY-UHFFFAOYSA-N ethyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=C(C(=O)CCCCl)C=C1 NQQITLVKOMJPDY-UHFFFAOYSA-N 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- 229960000354 fexofenadine hydrochloride Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- LOWWEULESZKQRF-UHFFFAOYSA-N 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(=O)C1CC1 LOWWEULESZKQRF-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical class ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241001425575 Vagrans Species 0.000 description 1
- WXIUBYCJAAEOFL-UHFFFAOYSA-N [S].ClOCl Chemical class [S].ClOCl WXIUBYCJAAEOFL-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical class Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 229960004754 astemizole Drugs 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- OFYSAFPKXXTYLU-UHFFFAOYSA-N ethyl 2-methyl-2-phenylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=CC=C1 OFYSAFPKXXTYLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- WITYUUTUSPKOAB-UHFFFAOYSA-N methyl 2-methyl-2-phenylpropanoate Chemical class COC(=O)C(C)(C)C1=CC=CC=C1 WITYUUTUSPKOAB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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, extracting, drying, and filtering to obtain N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide; adding the N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide in an inorganic acid, reacting for 20-30h at 60 DEG C, extracting, drying, filtering, crystallizing by ethanol to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid; infusing HCl gas in the alcohol solvent, then adding the 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid, washing by water, drying and filtering to obtain the target product. The synthetic method of the invention has high yield, little pollution and applicable industrial production.
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 Xin-Dai Claritin; With like product Vagran (astemizole; Owing to be prone to cause cardiac toxic; Cancelled from American market in 1999), cetirizine, LT etc. compare, fexofenadine hydrochloride 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 has about 40% approximately.
U.S. Patent application file 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 has about 28% approximately.
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 about 30%) not only, and the use of potassium permanganate can bring bigger environmental pollution in the reaction.
[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 be the method for raw material Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid methyl esters not only step is many, productive rate low (having 27% approximately); 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, and a kind of meta-isomer that do not contain is provided, and productive rate is high, pollutes for a short time, is suitable for the method for Synthetic 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid ester of suitability for industrialized production.
Synthetic 2-of the present invention [4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, its structure 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, the volumetric molar concentration of alkali metal hydroxide in 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, [4-(4-chlorobutyryl) phenyl]-volumetric molar concentration of 2-methyl propanamide in 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 ℃ in temperature of reaction then and reacted 10～30 hours down that evaporate to dryness alcoholic solvent after reaction finishes adds entry in residue; Use dichloromethane extraction; Drying is filtered, remove behind the methylene dichloride product 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 mineral acid; The weight ratio of mineral acid and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 2～8: 1; 20～30 hours afterreaction mixtures of reaction are used dichloromethane extraction under temperature of reaction is 60 ℃～100 ℃; Dry; Filter, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal;
(6) bubbling feeds the exsiccant hydrogen chloride gas in the absolute alcohol solvent, adds 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid of step (5) 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; 60 ℃ are reacted down after 3 hours except that desolvating; 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 the above-mentioned steps (1) 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.
Mineral acid in the above-mentioned steps (5) is that concentration is 36% concentrated hydrochloric acid.
The weight ratio of the mineral acid in the above-mentioned steps (5) and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 3: 1.
The temperature of reaction of above-mentioned steps (5) is 80 ℃.
Reaction times in the above-mentioned steps (5) is 24 hours.
Alcoholic solvent in the above-mentioned steps (6) is methyl alcohol, ethanol or 2-Ethylhexyl Alcohol.
Advantage of the present invention and beneficial effect: the method for Synthetic 2 of the present invention-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid has and does not contain meta-isomer and need not to split operation, and productive rate is high, pollutes for a short time, is suitable for the advantage of 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%.Take by weighing above-mentioned N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide
10 grams (0.036mol) join 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 8.91 grams (0.033mol) with alcohol crystal; Productive rate 92%, 79～80 ℃ of melting ranges.In 120 gram absolute ethyl alcohols, feed 10 gram (0.27mol) exsiccant 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%.Take by weighing above-mentioned N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl benzene)-2-methyl propanamide 10
Gram (0.036mol) 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 8.72 grams (0.032mol) with alcohol crystal; Productive rate 90%, 79～80 ℃ of melting ranges.In 120 gram anhydrous methanols, feed 10 gram (0.27mol) exsiccant 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%.
Taking by weighing above-mentioned N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl benzene)-2-methyl propanamide 10 grams (0.036mol) joins in the 80 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 8.72 grams (0.032mol) with alcohol crystal; Productive rate 90%, 79～80 ℃ of melting ranges.In the anhydrous 2-Ethylhexyl Alcohol of 120 grams, feed 10 gram (0.27mol) exsiccant 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 mineral acid; The weight ratio of mineral acid and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 2～8: 1; 20～30 hours afterreaction mixtures of reaction are used dichloromethane extraction under temperature of reaction is 60 ℃～100 ℃; Dry; Filter, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal;
(6) bubbling feeds the exsiccant hydrogen chloride gas in the absolute alcohol solvent, adds 2-[4-(4-chlorobutyryl) the phenyl]-2 Methylpropionic acid of step (5) 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; 60 ℃ are reacted down after 3 hours except that desolvating; 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 (5) is that concentration is 36% concentrated hydrochloric acid.
2. the method for Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the alkali metal hydroxide in the said step (1) is Pottasium Hydroxide or sodium hydroxide.
3. the method for Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester 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 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 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. according to the method for the said Synthetic 2 of claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the weight ratio of the mineral acid in the said step (5) and N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide is 3: 1.
7. according to the method for the said Synthetic 2 of claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the temperature of reaction in the said step (5) is 80 ℃.
8. according to the method for the said Synthetic 2 of claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the reaction times in the said step (5) is 24 hours.
9. according to the method for the said Synthetic 2 of claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid ester, it is characterized in that: the alcohol in the said step (6) is methyl alcohol, ethanol or 2-Ethylhexyl Alcohol.
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| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine 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 |
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| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine 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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