CN113336633B - Synthetic method of 5-hydroxy-2-tetralone - Google Patents
Synthetic method of 5-hydroxy-2-tetralone Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 5-hydroxy-2-tetralone, which comprises the following steps: under the condition of a catalyst solvent, 3-hydroxyphenylacetic acid reacts with thionyl chloride to obtain a reaction product containing 3-hydroxyphenylacetyl chloride; recrystallizing the obtained product in normal hexane to obtain purified 3-hydroxyphenylacetyl chloride; under the condition of a catalyst solvent, 3-hydroxyphenylacetyl chloride reacts with ethylene to obtain a reaction product containing 5-hydroxy-2-tetralone; and adding hydrochloric acid to adjust the pH value of the product to 3, extracting and separating liquid under an acidic atmosphere, and performing column chromatography to obtain the purified 5-hydroxy-2-tetralone. The method has the advantages of mild reaction step conditions, simple and convenient operation, cheap and easily-obtained starting materials, short reaction steps, less three-waste pollutants, high yield, suitability for industrial large-scale production, simple reaction steps to a certain extent and contribution to subsequent reaction.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of 5-hydroxy-2-tetralone.
Background
5-hydroxy-2-tetralone is used as an important drug intermediate, and is characterized in that 5-hydroxy in the molecule is very active and can be modified in various ways, 2-carbonyl can be aminated into amino or substituted amine to perform related cyclization or substitution reaction, and saturated rings can perform various cyclization reactions. The synthesis, application and production of the compound are widely applied, developed and researched at home and abroad.
In the existing synthesis method of the intermediate 5-hydroxy-2-tetralone, 1,6-dihydroxynaphthalene is used as a raw material to react with dimethyl sulfate, the dimethyl sulfate belongs to a highly toxic substance and can generate a large amount of sulfur dioxide, which is dangerous for operators; the product and metallic sodium are subjected to reduction reaction, the metallic sodium belongs to easily explosive articles and is not beneficial to safe production, and the use of the sodium is easily influenced by the environmental humidity; finally reacting with hydrochloric acid to obtain 5-hydroxy-2-tetralone, and finally leaving methoxyl as hydroxyl.
Disclosure of Invention
The invention aims to provide a novel synthesis method of 5-hydroxy-2-tetralone, which has the advantages of mild reaction conditions, cheap and easily-obtained starting materials, short reaction steps, less pollution of three wastes generated, high yield and purity, and suitability for industrial large-scale production of rotigotine hydrochloride.
In order to achieve the purpose, the technical scheme is as follows:
a method for synthesizing 5-hydroxy-2-tetralone comprises the following steps:
(1) Under the condition of a catalyst solvent, 3-hydroxyphenylacetic acid reacts with thionyl chloride to obtain a reaction product containing 3-hydroxyphenylacetyl chloride;
(2) Recrystallizing the obtained product in normal hexane to obtain purified 3-hydroxyphenylacetyl chloride;
(3) Under the condition of a catalyst solvent, 3-hydroxyphenylacetyl chloride reacts with ethylene to obtain a reaction product containing 5-hydroxy-2-tetralone;
(4) Diluting the product with water, adding hydrochloric acid to adjust the pH of the product to 2-4, extracting and separating liquid in an acidic atmosphere, and performing column chromatography to obtain the purified 5-hydroxy-2-tetralone.
According to the scheme, the solvent in the step (1) is dichloromethane; the reactant is thionyl chloride, and the catalyst is one of N, N-dimethylformamide, dimethylaminopyridine, pyridine and triethylamine. N, N-dimethylformamide is preferred.
According to the scheme, in the step (1), because dichloromethane is used as a solvent, dropwise adding is carried out at the temperature of 50-60 ℃, preferably 55 ℃, a bumping bottle is prevented, and after dropwise adding is finished, the mixture is heated to the temperature of 80-100 ℃ for reaction, preferably 90 ℃, and the reaction time is 2-4 hours, preferably 3 hours.
According to the scheme, the reaction product in the step (1) is subjected to reduced pressure distillation at the temperature of 60 ℃ to remove excessive reactant thionyl chloride and solvent dichloromethane.
According to the scheme, n-hexane is used for dissolving in the step (2) at 70 ℃, and recrystallization is carried out at 10 ℃.
According to the scheme, the catalyst in the step (3) is anhydrous aluminum chloride; the solvent is dichloromethane. The anhydrous aluminum chloride can absorb water while being used as a catalyst, and prevents water from participating in the reaction to generate impurities.
According to the scheme, ethylene gas is slowly introduced into the step (3), and the reaction condition is-10 ℃, preferably 0 ℃, and the reaction lasts 3-6 hours, preferably 4 hours.
According to the scheme, after the reaction in the step (3) is finished, the solvent dichloromethane is removed by reduced pressure distillation.
According to the scheme, after water is added for dilution in the step (4), hydrochloric acid is added for adjusting the pH value of the product to 3, and toluene is used for extraction and liquid separation.
According to the above scheme, toluene was removed by rotary evaporation from the product after extraction and liquid separation in step (4), and a sample was dissolved with methylene chloride and subjected to silica gel column chromatography (developing solvent: V (ethyl acetate) = V (petroleum ether) = 1: 10).
The invention takes 3-hydroxyphenylacetic acid as a raw material, reacts with thionyl chloride, 3-hydroxyphenylacetyl chloride is obtained after recrystallization, then the 3-hydroxyphenylacetyl chloride reacts with ethylene, the product is subjected to silica gel column chromatography, and 5-hydroxy-2-tetralone is obtained after purification. The synthesis route of the invention is shown as the following formula:
compared with the prior art, the invention has the beneficial effects that:
the reaction steps are mild in condition, simple and convenient to operate, cheap and easily available in starting raw materials, short in reaction steps, less in generated three-waste pollutants, high in yield, suitable for industrial large-scale production, simple and convenient to a certain extent, and beneficial to subsequent reaction.
Detailed Description
The following examples further illustrate the technical solutions of the present invention, but should not be construed as limiting the scope of the present invention.
The invention relates to a method for synthesizing 5-hydroxy-2-tetralone, which comprises the following steps:
(1) Under the condition of a catalyst solvent, 3-hydroxyphenylacetic acid reacts with thionyl chloride to obtain a reaction product containing 3-hydroxyphenylacetyl chloride; the solvent is dichloromethane, the catalyst is one of N, N-dimethylformamide, dimethylaminopyridine, pyridine and triethylamine, and N, N-dimethylformamide is preferred. Dripping thionyl chloride at 50-60 ℃, preferably 55 ℃, preventing bumping in a spray bottle, heating to 80-100 ℃ after dripping, and reacting, preferably 90 ℃, for 2-4 hours, preferably 3 hours. And (3) distilling the product obtained after the reaction is finished at 60 ℃ under reduced pressure to remove excessive thionyl chloride and the solvent.
(2) Recrystallizing the obtained product in normal hexane to obtain purified 3-hydroxyphenylacetyl chloride; dissolving with n-hexane at 70 deg.C; recrystallizing at 10 ℃;
(3) Under the condition of a catalyst solvent, 3-hydroxyphenylacetyl chloride reacts with ethylene to obtain a reaction product containing 5-hydroxy-2-tetralone; the catalyst is anhydrous aluminum chloride; the solvent is dichloromethane; slowly introducing ethylene gas into the reactor, and reacting for 3 to 6 hours, preferably 4 hours at the reaction condition of-10 to 10 ℃, preferably 0 ℃; after the reaction is finished, removing a solvent dichloromethane by reduced pressure distillation;
(4) Adding water to dilute the product, adding hydrochloric acid to adjust the pH of the product to 3, and extracting and separating liquid by using toluene in an acidic atmosphere; and (3) performing extraction and liquid separation, removing toluene from the product by rotary evaporation, dissolving the sample by using dichloromethane, and performing silica gel column chromatography to obtain the purified 5-hydroxy-2-tetralone.
Example 1
Adding 1.52g (10 mmol) of 3-hydroxyphenylacetic acid and magnetons into a 50mL three-neck flask, installing a condenser pipe and a dropping funnel, placing the instrument into an oil bath kettle, setting the temperature to be 55 ℃, adding 10mL of dichloromethane and 0.5mLN, N-dimethylformamide, starting stirring and the condenser pipe, then adding a mixed solution of 2mL of thionyl chloride and 8mL of dichloromethane into the dropping funnel, starting dropwise addition when the temperature is raised to 55 ℃, slowly dropwise adding the solution into a reactor, controlling the dropwise addition speed to be 0.1mL/s, resetting the heating temperature to be 90 ℃ after the dropwise addition is finished, stirring for reacting for 3 hours, and preparing for starting purification after the TLC detection determines that the reaction is complete.
And (3) after the liquid in the reactor is cooled to room temperature, taking the liquid out of the reactor in an eggplant-shaped bottle, carrying out reduced pressure rotary evaporation on the substances in the eggplant-shaped bottle at the temperature of 60 ℃, removing redundant thionyl chloride and dichloromethane, adding 30mL of n-hexane after the rotary evaporation is finished, dissolving the product at the temperature of 70 ℃, cooling and separating out at the temperature of 10 ℃ after all the products are dissolved, and separating liquid to obtain brown liquid, wherein the weight of the brown liquid is 1.64g.
20mL of dichloromethane is added into a 100mL three-neck flask, 1.64g of 3-hydroxyphenylacetyl chloride and 1.0g of anhydrous aluminum chloride are added and stirred to be completely dissolved, the device is placed in a cold well, the temperature is adjusted to be 5 ℃, the flow of an ethylene generator is adjusted to be 0.01m3/h, ethylene is introduced into the solution, and the reaction lasts for 4h until the reaction is completely determined by TLC detection. The system was purged with nitrogen for 10 min. Finally, the solvent is removed by rotary evaporation under reduced pressure at the temperature of 55 ℃ to obtain the product.
Diluting the product with 50mL of distilled water, adding 3mL of hydrochloric acid to adjust the pH value of the product to 3, extracting the product for three times by using 10mL of toluene solution in batches, removing toluene by rotary evaporation at 95 ℃ under reduced pressure of 30mL of toluene solution dissolving the product, adding 20mL of dichloromethane to dissolve the product to prepare a sample, and performing silica gel column chromatography (developing agent: V (ethyl acetate) = V (petroleum ether) = 1: 10) to obtain 1.15g of the compound 5-hydroxy-2-tetralone.
Finally, the total yield of the three-step reaction is 71.0 percent (molar yield) by calculation, the weight of the product is 1.15g, and the HPLC purity is 96.1 percent.
Example 2
Adding 1.52g (10 mmol) of 3-hydroxyphenylacetic acid and magnetons into a 50mL three-neck flask, installing a condenser tube and a dropping funnel, placing the instrument into an oil bath kettle, setting the temperature to be 55 ℃, adding 10mL of dichloromethane and 0.5mL of dimethylamino pyridine, starting stirring and the condenser tube, then adding a mixed solution of 2mL of thionyl chloride and 8mL of dichloromethane into the dropping funnel, starting dropping when the temperature is raised to 55 ℃, slowly dropping the solution into a reactor, controlling the dropping speed to be 0.1mL/s, resetting the heating temperature to be 90 ℃ after dropping is finished, stirring for reacting for 3 hours, and preparing to start purification after the completion of the reaction is determined by TLC detection.
And (3) after the liquid in the reactor is cooled to room temperature, taking the liquid out of the reactor in an eggplant-shaped bottle, carrying out reduced pressure rotary evaporation on the substances in the eggplant-shaped bottle at the temperature of 60 ℃, removing redundant thionyl chloride and dichloromethane, adding 30mL of n-hexane after the rotary evaporation is finished, dissolving the product at the temperature of 70 ℃, cooling and separating out at the temperature of 10 ℃ after all the products are dissolved, and separating liquid to obtain brown liquid, wherein the weight of the brown liquid is 1.52g.
20mL of dichloromethane is added into a 100mL three-neck flask, 1.52g of 3-hydroxyphenylacetyl chloride and 1.0g of anhydrous aluminum chloride are added and stirred to be completely dissolved, the device is placed in a cold well, the temperature is adjusted to be 5 ℃, the flow of an ethylene generator is adjusted to be 0.05m3/h, ethylene is introduced into the solution, and the reaction lasts for 4h until the reaction is completely determined by TLC detection. The system was purged with nitrogen for 10 min. Finally, the solvent is removed by rotary evaporation under reduced pressure at the temperature of 55 ℃ to obtain the product.
Diluting the product with 50mL of distilled water, adding 3mL of hydrochloric acid to adjust the pH value of the product to 3, extracting the product for three times by using 10mL of toluene solution in batches, carrying out reduced pressure rotary evaporation on 30mL of toluene solution dissolving the product at 95 ℃ to remove toluene, carrying out rotary drying on the product, adding 20mL of dichloromethane to dissolve the product to prepare a sample, carrying out silica gel column chromatography (developing agent: V (ethyl acetate) = V (petroleum ether) = 1: 10) on the product after the product is dried in a rotary manner, and obtaining 1.02g of the compound 5-hydroxy-2-tetralone.
Finally, the total yield of the three-step reaction is 62.2 percent (mol yield), the weight of the product is 1.02g, and the HPLC purity is 97.7 percent.
Example 3
1.52g (10 mmol) of 3-hydroxyphenylacetic acid and magnetons are added into a 50mL three-neck flask, a condenser pipe and a dropping funnel are installed, the instrument is placed in an oil bath kettle, the temperature is set to be 55 ℃, 10mL of dichloromethane and 0.5mL of pyridine are added, stirring and the condenser pipe are started, then 2mL of mixed solution of thionyl chloride and 8mL of dichloromethane are added into the dropping funnel, the dropping is started when the temperature is raised to 55 ℃, the solution is slowly dropped into a reactor, the dropping speed is controlled to be 0.1mL/s, after the dropping is finished, the heating temperature is reset to be 90 ℃, the stirring reaction is carried out for 3 hours, and after the completion of the reaction is determined by TLC detection, the purification is ready to be started.
And (3) after the liquid in the reactor is cooled to room temperature, taking the liquid out of the reactor in an eggplant-shaped bottle, carrying out reduced pressure rotary evaporation on the substances in the eggplant-shaped bottle at the temperature of 60 ℃, removing redundant thionyl chloride and dichloromethane, adding 30mL of n-hexane after the rotary evaporation is finished, dissolving the product at the temperature of 70 ℃, cooling and separating out at the temperature of 10 ℃ after all the products are dissolved, and separating liquid to obtain brown liquid, wherein the weight of the brown liquid is 1.56g.
20mL of dichloromethane is added into a 100mL three-neck flask, 1.56g of 3-hydroxyphenylacetyl chloride and 1.0g of anhydrous aluminum chloride are added and stirred to be completely dissolved, the device is placed in a cold well, the temperature is adjusted to be 5 ℃, the flow of an ethylene generator is adjusted to be 0.01m3/h, ethylene is introduced into the solution, and the reaction lasts for 4h until the reaction is completely determined by TLC detection. The system was purged with nitrogen for 10 min. Finally, the solvent is removed by rotary evaporation under reduced pressure at the temperature of 55 ℃ to obtain the product.
Diluting the product with 50mL of distilled water, adding 3mL of hydrochloric acid to adjust the pH value of the product to 3, extracting the product for three times by using 10mL of toluene solution in batches, carrying out reduced pressure rotary evaporation on 30mL of toluene solution dissolving the product at 95 ℃ to remove toluene, carrying out rotary drying on the product, adding 20mL of dichloromethane to dissolve the product to prepare a sample, carrying out silica gel column chromatography (developing agent: V (ethyl acetate) = V (petroleum ether) = 1: 10) on the product after the product is dried in a rotary manner, and obtaining 1.04g of the compound 5-hydroxy-2-tetralone.
Finally, the total yield of the three-step reaction is 64.2 percent (mol yield) through calculation, the weight of the product is 1.04g, and the HPLC purity is 96.5 percent.
Claims (8)
1. A method for synthesizing 5-hydroxy-2-tetralone is characterized by comprising the following steps:
(1) Under the condition of a catalyst solvent, 3-hydroxyphenylacetic acid reacts with thionyl chloride to obtain a reaction product containing 3-hydroxyphenylacetyl chloride; the solvent is dichloromethane; the catalyst is one of N, N-dimethylformamide, dimethylamino pyridine, pyridine and triethylamine; dripping thionyl chloride at 50-60 ℃; after the dropwise addition, heating to 80-100 ℃ for reaction; the reaction time is 2~4 hours;
(2) Recrystallizing the obtained product in normal hexane to obtain purified 3-hydroxyphenylacetyl chloride;
(3) Under the condition of a catalyst solvent, 3-hydroxyphenylacetyl chloride and ethylene react at 5 ℃ to obtain a reaction product containing 5-hydroxy-2-tetralone;
(4) Extracting and separating liquid under an acidic atmosphere, and performing column chromatography to obtain the purified 5-hydroxy-2-tetralone.
2. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein the reaction product of step (1) is distilled under reduced pressure at 60 ℃ to remove excess reactant thionyl chloride and solvent methylene chloride.
3. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein in the step (2), n-hexane is used for dissolution at 70 ℃; recrystallization was carried out at 10 ℃.
4. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein the catalyst in the step (3) is anhydrous aluminum chloride; the solvent is dichloromethane.
5. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein ethylene gas is slowly introduced into the step (3) to react for 3~6 hours.
6. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein the solvent is removed by distillation under reduced pressure after the reaction of step (3) is completed.
7. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein the product obtained in step (4) is diluted with water and adjusted to pH 3 with hydrochloric acid, and then extracted with toluene.
8. The method for synthesizing 5-hydroxy-2-tetralone according to claim 1, wherein the purified 5-hydroxy-2-tetralone is obtained by subjecting the product obtained in step (4) after extraction and liquid separation to spin-steaming to remove toluene, dissolving the sample with dichloromethane, and performing silica gel column chromatography.
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| CN1184425A (en) * | 1995-03-20 | 1998-06-10 | 伊莱利利公司 | 5 -substituted -3 -(1, 2, 3, 6 -tetrahydro -pyridin -4 -yl) - and 3 -(piperidin -4 -yl) -1h -indoles: new 5 -HT1f agonists |
| JP4286524B2 (en) * | 2002-12-04 | 2009-07-01 | 株式会社クレハ | A method for producing 4-alkoxyphenyl-4-oxo-butyric acid and a method for producing 7-alkoxy-1-tetralones. |
| CN101468946B (en) * | 2007-12-25 | 2011-12-07 | 南通柏盛化工有限公司 | Preparation technique of 5-methoxy-2-tetralone |
| CN101768086B (en) * | 2008-12-29 | 2014-03-26 | 北京富龙康泰生物技术有限公司 | Amino methanol derivant and salt compound thereof as well as synthesizing method and medical application thereof |
| CZ2012768A3 (en) * | 2012-11-08 | 2014-05-21 | Zentiva, K.S. | Process for preparing 5-halosubstituted 6-methyl-{beta}-tetralones |
| CN106278841B (en) * | 2016-07-18 | 2018-10-09 | 浙江永太药业有限公司 | A kind of preparation method of 8- methoxyl groups -3,4- dihydro -1H-2- naphthalenones |
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