CN101585764B - Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid - Google Patents
Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid Download PDFInfo
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- CN101585764B CN101585764B CN2009100994209A CN200910099420A CN101585764B CN 101585764 B CN101585764 B CN 101585764B CN 2009100994209 A CN2009100994209 A CN 2009100994209A CN 200910099420 A CN200910099420 A CN 200910099420A CN 101585764 B CN101585764 B CN 101585764B
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Abstract
The invention discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid, comprising the steps of adding an alkali metal hydroxide in an alcohol solvent, dripping the alcohol solvent of N-methyl-N-methoxyl-2-[4-(4-chlorobutyryl)phenyl]-2-methacrylamide in the alcohol solvent, reacting for 10-30h at 20-50 DEG C, evaporating the solvent to dryness, 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 organic acid in a ratio of 1: 2-8, reacting for 20-30h at 60-100 DEG C, extracting, drying, filtering and recrystallizing to obtain the product target. The invention has the advantages of a simple preparation technology,high yield and little pollution.
Description
Technical field
The present invention relates to the method for a kind of Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid.
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 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 is the important intermediate of synthetic fexofenadine hydrochloride.
Application number is to have reported with α in the Indian patent application file of 2004CH00206; Alpha-alpha-dimethyl phenyl acetic acid is the method for raw material Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid; This method needs 2-(4-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid and 2-(3-cyclopropyl carbonyl phenyl)-2 Methylpropionic acid and dicyclohexylamine reaction formation salt; Split out 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid through crystallization, acidifying, open loop again; Step is many, and it is low to split efficient, and productive rate is not very high (about 40%).
Publication number is that the application documents of WO2005019175 (A1) also disclose with α; Alpha-alpha-dimethyl phenyl acetic acid is the method for raw material Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid; This method need experience steps such as esterification, reduction, acylations, Cyclopropanated, oxidation; Not only reactions step is many, complex process, and productive rate lower (about 38%), and the use of potassium permanganate can bring bigger environmental pollution in the reaction.
Summary of the invention
The technical problem that the present invention will solve is the deficiency to above-mentioned prior art, provides a kind of reactions step few, and technology is simple, and productive rate is high, pollutes the method for little Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid.
Synthetic 2-of the present invention [4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid is the compound with following structure:
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, 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 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; Being 60 ℃～100 ℃ in temperature of reaction reacted 20～30 hours down; Reaction mixture is used dichloromethane extraction then; Drying is filtered, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal.
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 mixed solvent 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.
Temperature of reaction in the above-mentioned steps (5) is 80 ℃.
Reaction times in the above-mentioned steps (5) is 24 hours.
Raw material N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide that the present invention uses adopts prior art for preparing and gets.
Advantage of the present invention and beneficial effect: the method for Synthetic 2 of the present invention-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid is with α; Alpha-alpha-dimethyl phenyl acetic acid is a raw material; Adopt prior art to prepare N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide earlier through two steps; And then make title product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid through two-step reaction, and it is few to have reactions step, and preparation technology is simple; The advantage that productive rate is high, and the preparation process does not use potassium permanganate so environmental pollution little.
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%.
Taking by weighing above-mentioned N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide 10 grams (0.036mol) 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 8.91 grams (0.033mol) with alcohol crystal; Productive rate 92%, 79～80 ℃ of melting ranges.
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%.
Taking by weighing above-mentioned N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide 10 grams (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.
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 phenyl)-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.
Claims (8)
1. the method for Synthetic 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid, 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; Being 60 ℃～100 ℃ in temperature of reaction reacted 20～30 hours down; Reaction mixture is used dichloromethane extraction then; Drying is filtered, remove methylene dichloride after the gained residuum get product 2-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid with alcohol crystal;
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, 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 is characterized in that: the alcoholic solvent in said step (1) and (2) is methyl alcohol or 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, 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, it is characterized in that: the reaction times in the said step (4) is 18 hours.
6. the method for Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid, 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. the method for Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid, it is characterized in that: the temperature of reaction in the said step (5) is 80 ℃.
8. the method for Synthetic 2 according to claim 1-[4-(4-chlorobutyryl) phenyl]-2 Methylpropionic acid, it is characterized in that: the reaction times in the said step (5) is 24 hours.
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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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