CN111592451A - Preparation method of 4- (4-phenylbutoxy) benzoic acid - Google Patents
Preparation method of 4- (4-phenylbutoxy) benzoic acid Download PDFInfo
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- CN111592451A CN111592451A CN202010586546.5A CN202010586546A CN111592451A CN 111592451 A CN111592451 A CN 111592451A CN 202010586546 A CN202010586546 A CN 202010586546A CN 111592451 A CN111592451 A CN 111592451A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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Abstract
The invention relates to a preparation method of 4- (4-phenylbutoxy) benzoic acid, which is specifically carried out according to the following steps: a. under the catalysis of alkali, gamma-chlorobenzene butanone reacts with p-hydroxybenzoate to generate a compound 3; b. the compound 2 is catalytically reduced to generate a compound 4; c. the compound 4 is hydrolyzed to obtain 4- (4-phenylbutoxy) benzoic acid. The preparation method of the 4- (4-phenylbutoxy) benzoic acid has the advantages that the adopted raw materials are low in price and easy to obtain; short synthetic route, novel route, no pollution and high yield.
Description
Technical Field
The invention relates to the field of drug synthesis, and relates to a preparation method of 4- (4-phenylbutoxy) benzoic acid.
Background
4- (4-Phenylbutoxy) benzoic acid (4- (4-Phenylbutoxy) benzoic acid), formula: c17H18O3Belongs to a medical intermediate, and is an important intermediate of novel anti-asthma drug pranlukast.
The synthesis of 4- (4-phenylbutoxy) benzoic acid is described in literature in a few ways, and the main methods are:
the synthesis method has complex process and many steps, the toxicity of the raw material benzene and the intermediate product 4-phenyl-1-butyl bromide is high, and simultaneously, the used aluminum trichloride as a catalyst can generate a large amount of waste water, is difficult to treat and has high cost.
The synthesis method for synthesizing p-phenylbutoxy benzoic acid by taking the phenylbutanol as the starting material comprises the following steps:
although the synthesis method is not complex, the used starting materials of the phenylbutanol and the 4-chloro (or fluoro or bromo or iodo) benzonitrile are expensive and high in cost, and if the 4-bromoxynil is used, the high-toxicity pungent and malodorous hydrobromic acid is generated, so that the synthesis method is not suitable for large-scale industrial production.
The benzene butanol is used as a starting material, and the synthetic route is as follows:
the synthesis method comprises a synthesis method of the benzene butanol, the benzene butanol is expensive and can be prepared by itself, the processes are multiple, the process is complex, the cost is high, and the method is not suitable for large-scale industrial production.
Disclosure of Invention
The invention provides a preparation method of 4- (4-phenylbutoxy) benzoic acid, which adopts cheap and easily-obtained raw materials; the synthesis route is short, the route is novel, and the yield is high; and (4) a dangerous process is avoided.
The method specifically comprises the following steps:
a. reacting the compound 1 with the compound 2 under the catalysis of alkali to generate a compound 3;
b. under the catalysis of metal, the compound 3 is reduced by catalytic hydrogenation to generate a compound 4;
c. hydrolyzing the compound 4 to generate a compound 5, namely completing the preparation of 4- (4-phenylbutoxy) benzoic acid;
wherein the content of the first and second substances,
the compound 1 is gamma-chlorobenzene butanone;
the compound 2 is 4-hydroxybenzeneformate;
compound 3 is 4- (4-oxo-4-phenylbutoxy) benzoate;
compound 4 is 4- (4-phenylbutoxy) benzoate;
compound 5 is 4- (4-phenylbutoxy) benzoic acid;
the reaction formula of the step a is as follows:
R＝C1-C5alkyl, benzyl;
the reaction formula of the step b is as follows:
R，R1is C1-C5Alkyl, benzyl, when R is benzyl, R1Is hydrogen;
the reaction formula of the step c is as follows:
R1is C1-C5An alkyl group.
The specific process of the step a is as follows: dissolving the compounds 1 and 2 in a solvent, adding solid alkali, heating and refluxing, cooling, filtering and concentrating to obtain a compound 3; wherein the molar ratio of the compound 1 to the compound 2 to the alkali is 1: 0.8-1.2: 2-5; the alkali is triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide; the solvent is acetone, dichloromethane, DMF or tetrahydrofuran.
The specific process of the step b is as follows: mixing the compound 3 prepared in the step a, a catalyst and a solvent, stirring and reacting for 1-5 hours at the temperature from room temperature to reflux under the condition of 1-5 atmospheric pressure hydrogen atmosphere, filtering to remove the catalyst after the reaction is finished, and concentrating the solvent to obtain a compound 4; wherein the mass ratio of the catalyst to the compound 3 is (0.05-0.2) to 1; the catalyst is palladium, palladium carbon or palladium acetate; the solvent is dichloromethane, methanol, ethanol, ethyl acetate or tetrahydrofuran.
The specific process of the step c is as follows: dissolving the compound 4 prepared in the step b in a solvent, adding alkali, heating and refluxing for 1-5 hours, and after the reaction is finished, carrying out acid acidification and recrystallization to obtain a compound 1, namely, the preparation of the 4- (4-phenylbutoxy) benzoic acid is finished, wherein the molar ratio of the alkali to the compound 5 is (1-2) to 1; the alkali is sodium hydroxide or potassium hydroxide; the solvent is one or a combination of methanol, ethanol, isopropanol or water in any proportion.
The invention provides a synthesis process of p-phenylbutoxy benzoic acid, the synthesis route has simple steps and convenient operation, and avoids the generation of a highly toxic intermediate, namely phenyl bromide and a large amount of wastewater in the synthesis process, so that the synthesis process is environment-friendly, saves the production cost, has higher purity of the p-phenylbutoxy benzoic acid synthesized by the process, and is suitable for large-scale industrial production.
Detailed Description
In order to enhance the understanding of the present invention, the present invention will be described in further detail with reference to the following examples, which are provided for the purpose of illustration only and are not intended to limit the scope of the present invention.
Examples
This example provides a method for the preparation of 4- (4-phenylbutoxy) benzoic acid, in particular according to the following procedure, the compound γ -chlorobenzone ketone being prepared according to literature procedures.
1. Synthesis of compound 3 a: 4- (4-oxo-4-phenylbutoxy) benzoic acid methyl ester
Weighing 9.1 g of gamma-chlorobenzene butanone and 8.4 g of methyl p-hydroxybenzoate, dissolving the gamma-chlorobenzene butanone and the methyl p-hydroxybenzoate with 100 ml of DMF, adding 27.6 g of potassium carbonate, stirring, heating, stirring at 100 ℃ for 5 hours, cooling, filtering, concentrating the filtrate under reduced pressure, dissolving dichloromethane, washing with 1N sodium hydroxide, separating an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a white solid, and directly using the white solid for the next reaction.
The reaction formula is as follows:
2. synthesis of compound 3 b: 4- (4-oxo-4-phenylbutoxy) benzyl benzoate
According to the method of the step 1, benzyl p-hydroxybenzoate is used as a raw material to obtain 4- (4-oxo-4-phenylbutoxy) benzyl benzoate, and the benzyl 4- (4-oxo-4-phenylbutoxy) benzyl benzoate is directly used for the next reaction.
The reaction formula is as follows:
3. synthesis of compound 4 a: 4- (4-Phenylbutoxy) benzoic acid methyl ester
Weighing 10.0 g of methyl 4- (4-oxo-4-phenylbutoxy) benzoate, dissolving the methyl 4- (4-oxo-4-phenylbutoxy) benzoate in 50 ml of ethanol, adding 1.0 g of 10% palladium carbon, reacting at 70 ℃ for 3 hours under a hydrogen atmosphere with the pressure of 5 kg, cooling, filtering, and concentrating the filtrate under reduced pressure to obtain 9.1 g of white solid with the yield of 96%.
The reaction formula is as follows:
4. synthesis of compound 4 b: 4- (4-Phenylbutoxy) benzoic acid
According to the same method as that of step 3, 4- (4-oxo-4-phenylbutoxy) benzyl benzoate was used as a starting material, and recrystallization was carried out with isopropanol to obtain a white solid, with a yield of 87%.
The reaction formula is as follows:
5. synthesis of compound 5: 4- (4-Phenylbutoxy) benzoic acid
7.1 g of methyl 4- (4-phenylbutoxy) benzoate is mixed with 50 ml of 10% sodium hydroxide solution, the temperature is raised to 60 ℃, the mixture is kept and stirred for 2 hours, the mixture is cooled to room temperature, the pH value is adjusted to 2 by using 1N hydrochloric acid, white solid is separated out, the mixture is filtered, washed by water and dried, the mixture is recrystallized by using isopropanol to obtain the white solid, the drying weight is 6.2 g, and the yield is 92%.
The reaction formula is as follows:
the above embodiments should not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent transformations fall within the protection scope of the present invention.
Claims (10)
1. A preparation method of 4- (4-phenylbutoxy) benzoic acid is characterized by comprising the following steps:
a. reacting the compound 1 with the compound 2 under the catalysis of alkali to generate a compound 3;
b. under the catalysis of metal, the compound 3 is reduced by catalytic hydrogenation to generate a compound 4;
c. hydrolyzing the compound 4 to generate a compound 5, namely completing the preparation of 4- (4-phenylbutoxy) benzoic acid;
wherein the content of the first and second substances,
the compound 1 is gamma-chlorobenzene butanone;
the compound 2 is 4-hydroxybenzeneformate;
compound 3 is 4- (4-oxo-4-phenylbutoxy) benzoate;
compound 4 is 4- (4-phenylbutoxy) benzoate;
compound 5 is 4- (4-phenylbutoxy) benzoic acid;
the reaction formula of the step a is as follows:
R＝C1-C5alkyl, benzyl;
the reaction formula of the step b is as follows:
R，R1is C1-C5Alkyl, benzyl, when R is benzyl, R1Is hydrogen;
the reaction formula of the step c is as follows:
R1is C1-C5An alkyl group.
2. The method for preparing 4- (4-phenylbutoxy) benzoic acid according to claim 1, wherein the specific process of step a is as follows: dissolving the compounds 1 and 2 in a solvent, adding solid alkali, heating and refluxing, cooling, filtering and concentrating to obtain a compound 3; wherein the molar ratio of the compound 1 to the compound 2 to the alkali is 1: 0.8-1.2: 2-5.
3. The method of preparing 4- (4-phenylbutoxy) benzoic acid according to claim 2, wherein the base used in step # a is triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium bicarbonate, sodium hydroxide, or potassium hydroxide.
4. The method of claim 2, wherein the solvent used in step a is acetone, dichloromethane, DMF or tetrahydrofuran.
5. The method for preparing 4- (4-phenylbutoxy) benzoic acid according to claim 1, wherein the specific process of step b is as follows: mixing the compound 3 prepared in the step a, a catalyst and a solvent, stirring and reacting for 1-5 hours at the temperature from room temperature to reflux under the condition of 1-5 atmospheric pressure hydrogen atmosphere, filtering to remove the catalyst after the reaction is finished, and concentrating the solvent to obtain a compound 4; wherein the mass ratio of the catalyst to the compound 3 is (0.05-0.2): 1.
6. The method according to claim 5, wherein the catalyst used in step b is palladium, palladium on carbon or palladium acetate.
7. The method according to claim 5, wherein the solvent used in step b is dichloromethane, methanol, ethanol, ethyl acetate or tetrahydrofuran.
8. The method for preparing 4- (4-phenylbutoxy) benzoic acid according to claim 1, wherein the specific process of step c is as follows: and (b) dissolving the compound 4 prepared in the step (b) in a solvent, adding a base, heating and refluxing for 1-5 hours, and after the reaction is finished, acidifying and recrystallizing to finish the preparation of the 4- (4-phenylbutoxy) benzoic acid, wherein the molar ratio of the base to the compound 5 is (1-2): 1.
9. The method according to claim 8, wherein the base in step c is sodium hydroxide or potassium hydroxide.
10. The method for preparing 4- (4-phenylbutoxy) benzoic acid according to claim 8, wherein the solvent in step c is one or a combination of methanol, ethanol, isopropanol, and water.
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| CN108558916A (en) * | 2018-05-22 | 2018-09-21 | 昆山力田医化科技有限公司 | A kind of synthesis technology to benzene butoxybenzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108558916A (en) * | 2018-05-22 | 2018-09-21 | 昆山力田医化科技有限公司 | A kind of synthesis technology to benzene butoxybenzoic acid |
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