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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- phenylbutoxy
- benzoic acid
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- XWCWFMQMZZPALR-UHFFFAOYSA-N 4-(4-phenylbutoxy)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCCCCC1=CC=CC=C1 XWCWFMQMZZPALR-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 229940126214 compound 3 Drugs 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 4
- 239000002994 raw material Substances 0.000 abstract description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000001308 synthesis method Methods 0.000 description 6
- -1 4- (4-Phenylbutoxy) benzoic acid (4- (4-Phenylbutoxy) benzoic acid) Chemical compound 0.000 description 5
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Natural products C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 229960002903 benzyl benzoate Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- LDZLXQFDGRCELX-UHFFFAOYSA-N 4-phenylbutan-1-ol Chemical compound OCCCCC1=CC=CC=C1 LDZLXQFDGRCELX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- PARZUJYSRABXOU-UHFFFAOYSA-N methyl 4-(4-oxo-4-phenylbutoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OCCCC(=O)C1=CC=CC=C1 PARZUJYSRABXOU-UHFFFAOYSA-N 0.000 description 3
- HQRWWHIETAKIMO-UHFFFAOYSA-N 1-phenylbutan-1-ol Chemical compound CCCC(O)C1=CC=CC=C1 HQRWWHIETAKIMO-UHFFFAOYSA-N 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- HXAOFLQZQYZBAL-UHFFFAOYSA-N methyl 4-(4-phenylbutoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OCCCCC1=CC=CC=C1 HXAOFLQZQYZBAL-UHFFFAOYSA-N 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- XPBQQAHIVODAIC-UHFFFAOYSA-N 4-bromobutylbenzene Chemical compound BrCCCCC1=CC=CC=C1 XPBQQAHIVODAIC-UHFFFAOYSA-N 0.000 description 1
- MOZDKDIOPSPTBH-UHFFFAOYSA-N Benzyl parahydroxybenzoate Chemical compound C1=CC(O)=CC=C1C(=O)OCC1=CC=CC=C1 MOZDKDIOPSPTBH-UHFFFAOYSA-N 0.000 description 1
- 239000005489 Bromoxynil Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 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 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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