CN109438189B - Synthetic method of 3, 4-dihydroxy phenethyl alcohol - Google Patents
Synthetic method of 3, 4-dihydroxy phenethyl alcohol Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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Abstract
The embodiment of the invention discloses a method for synthesizing 3, 4-dihydroxy phenethyl alcohol, which comprises the steps of firstly taking a compound I as a raw material, and obtaining a compound II under the action of a catalyst for later use; then reacting the compound II prepared in the step one with strong acid, and extracting and concentrating to obtain a compound III; then dissolving the compound III in a solvent, and starting to react under the action of a catalyst to prepare a compound IV; finally, the compound IV is subjected to diazotization reaction and acidic hydrolysis to generate the 3, 4-dihydroxy phenethyl alcohol. The embodiment of the invention provides a method for synthesizing 3, 4-dihydroxy phenethyl alcohol, which has moderate raw material price, is easy to carry out large-scale production, has the product purity of more than 99 percent and has the overall yield of more than 78 percent. The synthesis method has simple reaction conditions, has no special requirements on equipment, is easy to realize in industrial production, and can completely recycle the organic solvent in the whole preparation method process.
Description
Technical Field
The embodiment of the invention relates to the technical field of chemical industry, and particularly relates to a synthetic method of 3, 4-dihydroxy phenethyl alcohol.
Background
The 3, 4-dihydroxy phenethyl alcohol has wide application range and good effect on human bodies, such as the synthesis of cardiovascular medicaments, the application as a safe and efficient antioxidant, the anti-aging effect on the beneficial parts of the skeletal system, the anti-cancer effect and the like. However, the existing 3, 4-dihydroxy phenylethanol has the problems of more product impurities and low overall yield in the synthesis process, which brings difficulty to industrial production and application, so that a method for synthesizing 3, 4-dihydroxy phenylethanol with high product purity and high overall yield is needed.
Disclosure of Invention
The embodiment of the invention aims to provide a method for synthesizing 3, 4-dihydroxy phenethyl alcohol, which effectively solves the problems of more impurities and low overall yield of the existing product.
In order to achieve the above object, an embodiment of the present invention provides a method for synthesizing 3, 4-dihydroxy phenethyl alcohol, including the following steps:
taking a compound I as a raw material, and obtaining a compound II under the action of a catalyst for later use;
step two, reacting the compound II prepared in the step one with strong acid, and extracting and concentrating to obtain a compound III;
dissolving a compound III in a solvent, and then starting to react under the action of a catalyst to prepare a compound IV;
step four, carrying out diazotization reaction and acid hydrolysis on the compound IV to generate the 3, 4-dihydroxy phenethyl alcohol;
the structural formulas of the compound I, the compound II, the compound III, the compound IV and the compound V are respectively as follows:
the synthetic route of the invention is as follows:
in some embodiments, the first step comprises adding the compound i and a catalyst into an ethyl acetate solution in sequence to perform a reaction, heating and stirring during the reaction, and after the reaction is finished, washing with water and concentrating to obtain a compound ii.
In some more specific embodiments, the temperature is increased from 20-25 ℃ to 70-100 ℃ during the reaction, the catalyst is selected from any one of concentrated sulfuric acid, p-toluenesulfonic acid and diphenylamine triflate (DPAT), and/or the molar ratio of compound i to catalyst is 1: 0.01-0.1; the mass-volume ratio of the compound I to the ethyl acetate is 1: 3-5 w/v.
In some embodiments, the second step comprises dissolving the compound II prepared in the first step into an acetic acid solution, then dropwise adding the solution into a dilute nitric acid solution at the temperature of 0-15 ℃, raising the temperature to room temperature after the dropwise adding is finished, continuing the reaction, and adding water and ethyl acetate after the reaction is finished, extracting and concentrating to obtain the compound III.
In some specific embodiments, the concentration of the acetic acid solution is 70% to 99% by mass, the concentration of the dilute nitric acid solution is 40% to 68% by mass, and the ratio of the compound ii to the dilute nitric acid solution to the acetic acid solution is 1: 0.4-0.8: 1.5-2.5 w/v/v.
In some embodiments, the third step includes dissolving the compound iii obtained in the second step in a solvent, reacting under the action of a catalyst to obtain a crude compound iv after the reaction is completed, washing Pd/C during the reaction, recovering Pd/C for recycling, mixing the crude compound iv with petroleum ether, pulping, filtering, and drying to obtain the compound iv.
In some more specific embodiments, the catalyst is Pd/C, the solvent comprises any one of methanol, ethanol, dioxane, ethyl acetate, and dichloromethane, and the molar ratio of compound iii to catalyst is 1: 0.01-0.05, wherein the mass-volume ratio of the compound III to the solvent is 1: 5-10w/v of the total weight of the composition,
and reacting the compound III under the action of a catalyst Pd/C at the temperature of 15-30 ℃ and the pressure of 1-4MPa, filtering after the reaction is finished, concentrating the filtrate, and recovering the solvent to obtain a crude compound IV.
In some more specific embodiments, the crude compound iv is reacted with petroleum ether in a ratio of 1: 20 in mass ratio.
In some embodiments, the fourth step includes dissolving the compound iv in a concentrated aqueous acid solution, then dropwise adding an aqueous solution of sodium nitrite, keeping the temperature for a zero-degree reaction, extracting with an organic solvent after the reaction is finished, collecting the organic phase, drying the organic phase, concentrating to obtain a crude compound v, then dissolving the crude compound v in a solvent, and crystallizing and filtering to obtain the 3, 4-dihydroxybenzene ethanol.
In some specific embodiments, thin layer chromatography is adopted to detect whether a compound IV is dissolved into a concentrated acid aqueous solution and then completely reacts with a sodium nitrite aqueous solution, the temperature is raised to 50-100 ℃ after the reaction is completely finished, the pH value of a reaction solution is adjusted after the reaction is finished, organic solvents are used for multiple extraction, organic phases are combined, the organic phases are dried and then concentrated to recover the solvents to obtain a crude compound V, the crude compound V is dissolved into the solvents, the temperature is lowered to-20 ℃ and stirred, crystals are precipitated and then filtered to obtain the 3, 4-dihydroxy phenylethanol, and/or the concentrated acid aqueous solution comprises concentrated hydrochloric acid with the mass percentage concentration of 37% or concentrated sulfuric acid with the mass percentage concentration of 98%, and the mass percentage concentration of the sodium nitrite aqueous solution is 20-40%; dissolving the crude compound V into a solvent by dissolving the crude compound V into any one of methanol, ethanol, dichloromethane, ethyl acetate, toluene or acetone, wherein the molar mass ratio of the compound IV to sodium nitrite to concentrated acid solution is 1: 1.01-1.1: 2.5-4.
Compared with the prior art, the embodiment of the invention has the advantages that: the embodiment of the invention provides a synthesis method of 3, 4-dihydroxy phenethyl alcohol, which has the advantages of relatively mild reaction conditions, convenient post-treatment, easy realization of large-scale production and relatively high yield, and the product is obtained by a crystallization method with the purity of more than 99 percent. The synthesis method has simple reaction conditions, has no special requirements on equipment, is easy to realize in industrial production, and can completely recycle the organic solvent in the whole preparation method process.
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
In the following description and in the claims, the terms "include" and "comprise" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description which follows is a preferred embodiment of the invention, but is made for the purpose of illustrating the general principles of the invention and not for the purpose of limiting the scope of the invention. The scope of the present invention is defined by the appended claims.
In order to overcome the defects in the prior art, the application provides a method for synthesizing 3, 4-dihydroxy phenethyl alcohol, which comprises the following steps:
(1) adding 4-hydroxyphenylethanol and a catalyst into ethyl acetate in sequence, heating and stirring for a certain reaction time, finishing the reaction, washing with water, concentrating and recovering the solvent to obtain a compound II, namely a white solid, wherein the yield is more than or equal to 98%, and the purity is more than or equal to 98%. The temperature is 20-100 ℃; the catalyst is selected from one of the following solvents: concentrated sulfuric acid, p-toluenesulfonic acid, diphenylamine triflate (DPAT), and the like; the reaction time is 2-8h, and the molar ratio of the 4-hydroxyphenylethanol to the catalyst is 1: 0.01-0.1; the mass-volume ratio of the compound (I) to the ethyl acetate is 1: 3-5 w/v.
(2) Dissolving the 4- (2-acetoxyl-ethyl) phenol obtained in the step (1) in acetic acid, dropwise adding the solution into a dilute nitric acid solution at a low temperature, heating to room temperature for reacting for a period of time after dropwise adding is finished, stopping the reaction after the raw materials disappear, adding water and ethyl acetate for extraction, and concentrating the 3-nitro-4-hydroxy-phenyl ethyl acetate shown in the formula (III) to obtain a yellow oily liquid, wherein the yield is more than or equal to 90%, and the purity is more than or equal to 97%. The reaction temperature is 0-15 ℃; the concentration of the dilute nitric acid is 40-68%; the reaction time is 1-3 hours; the mass-volume ratio of the 4- (2-acetoxyl-ethyl) phenol to the dilute nitric acid to the acetic acid is 1: 0.4-0.8: 1.5-2.5 w/v/v.
(3) Dissolving 4-hydroxy-3-nitro-phenyl ethyl acetate in a solvent, carrying out normal-temperature reaction under certain pressure by using a catalyst Pd/C, stopping the reaction after the raw materials completely disappear, filtering, washing Pd/C, recovering Pd/C for recycling, concentrating the filtrate and recovering the solvent to obtain 3-amino-4-hydroxy-phenyl ethyl acetate shown in a formula (IV), and then using ethyl acetate/petroleum ether as a solvent, wherein the weight ratio of the ethyl acetate/petroleum ether is 1: pulping the mixed solution of 15-20, filtering and drying to obtain light yellow solid, wherein the yield is more than or equal to 95 percent and the purity is more than or equal to 98 percent. The solvent is selected from one of the following solvents: methanol, ethanol, dioxane, ethyl acetate, dichloromethane, etc.; the molar ratio of the 4-hydroxy-3-nitro-ethyl phenylacetate to the Pd/C catalyst is 1: 0.01-0.05; the mass-volume ratio of the compound II to the solvent is 1: 5-10 w/v; the pressure of the hydrogen is 1-4 bar; the recycling frequency of the Pd/C is 5-20 times.
(4) Dissolving 3-amino-4-hydroxy-phenyl ethyl acetate in concentrated acid aqueous solution, reducing the temperature to about zero, dropwise adding sodium nitrite aqueous solution within a certain time, keeping the temperature to react at zero, heating the solution after the reaction is completely detected by thin-layer chromatography, stopping the reaction after the reaction is carried out for a certain time, adjusting the pH of the reaction solution, extracting the reaction solution for multiple times by using an organic solvent, combining organic phases, drying the organic phases, concentrating and recovering the solvent to obtain dark red oily liquid, dissolving the crude product in the solvent, cooling the crude product to-20 ℃, stirring the solution, separating out crystals, and filtering the crystals to obtain the pure 3, 4-dihydroxy benzene ethanol shown in the formula (V), wherein the pure product is colorless transparent solid, the yield is more than or equal to 85 percent, and the purity is more than or equal to 99 percent. The concentrated acid aqueous solution is selected from one of the following: 37% concentrated hydrochloric acid and 98% concentrated sulfuric acid; the dropping time of the sodium nitrite is 10-30 min; the mass fraction of the sodium nitrite aqueous solution is 20-40%; the temperature rise temperature is 50-100 ℃; the temperature-rising reaction time is 1-3 h; the solvent for dissolving the crude product is selected from one of the following solvents: methanol, ethanol, dichloromethane, ethyl acetate, toluene, acetone, etc.; the molar mass ratio of the compound (IV) to the sodium nitrite is 1: 1.01-1.1: 2.5-4.
The technical solution of the present invention is further described below with reference to several exemplary embodiments.
Example 1
Adding 10g of 4-hydroxybenzene ethanol and 71mg of concentrated sulfuric acid into 30mL of ethyl acetate in sequence, heating to 80 ℃, stirring for 4h, adding 20mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering the ethyl acetate to obtain 12.8g of compound (I), namely 4- (2-acetoxy-ethyl) phenol, of a white solid, wherein the purity is 98.2%, and the yield is 98.1%.
Dissolving 12.8g of 4- (2-acetoxyl-ethyl) phenol in 23mL of 75% acetic acid, dropwise adding the solution into 6.3mL of 60% dilute nitric acid solution at 10 ℃, heating to room temperature to react for 2 hours after the dropwise addition, stopping the reaction, adding 50mL of water and 50mL of ethyl acetate to extract, separating an organic phase, extracting an aqueous phase twice with 50mL of ethyl acetate, combining the organic phase, washing the organic phase once with 50mL of water, washing the aqueous phase once with 50mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 14.5g of 3-nitro-4-hydroxy-phenyl ethyl acetate shown in the formula (III), wherein the purity is 97.5%, and the yield is 90.6%.
Dissolving 14.5g of 3-nitro-4-hydroxy-phenyl ethyl acetate in 100mL of ethanol, adding 10% of Pd/C, setting the pressure to be 1bar, reacting at 25 ℃ for 4 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C and directly using the Pd/C for the next reduction, concentrating the filtrate to recover ethanol to obtain 3-amino-4-hydroxy-phenyl ethyl acetate shown in formula (IV), and then using 10mL of ethyl acetate/petroleum ether to obtain 1: the mixed solution of 20 is pulped, filtered and dried to obtain light yellow solid 12.3g, the purity is 96.1 percent, and the yield is 97.8 percent.
Dissolving 12.3g of 3-amino-4-hydroxy-phenyl ethyl acetate in 19g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dropwise adding 15.2g of 30% sodium nitrite aqueous solution within 20min, keeping the temperature for reaction at zero for 30min, heating to 80 ℃, reacting for 2 times, stopping the reaction, adjusting the pH of the reaction solution to 5-6 by using saturated sodium bicarbonate, extracting the aqueous phase twice by using 100mL of dichloromethane, discarding the dichloromethane layer, extracting the aqueous phase for 3 times by using 100mL of ethyl acetate, combining the organic phases, drying, concentrating and recovering the ethyl acetate to obtain 10g of dark red oily liquid, dissolving the crude product in 4mL of 95% industrial ethanol, reducing the temperature to-20 ℃, stirring, separating out a large amount of transparent crystals, and carrying out cold filtration to obtain 7.8g of the pure 3, 4-dihydroxy phenethyl alcohol shown in the formula (V) and a colorless transparent solid, the product is light yellow liquid at normal temperature, the purity is 99.2 percent, and the yield is 80.3 percent.
Example 2
Adding 20g of 4-hydroxybenzene ethanol and 280mg of p-toluenesulfonic acid into 60mL of ethyl acetate in sequence, heating to 85 ℃, stirring for 3 hours, adding 20mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering the ethyl acetate to obtain 25.1g of compound (I)4- (2-acetoxy-ethyl) phenol, white solid with the purity of 98.2 percent and the yield of 96.2 percent.
Dissolving 25.1g of 4- (2-acetoxyl-ethyl) phenol in 50mL of 78% acetic acid, dropwise adding the solution into 12.4mL of 60% dilute nitric acid solution at 15 ℃, heating to room temperature to react for 2 hours after the dropwise addition, stopping the reaction, adding 100mL of water and 100mL of ethyl acetate to extract, separating an organic phase, extracting an aqueous phase twice with 100mL of ethyl acetate, combining the organic phase, washing once with 100mL of water, washing once with 100mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 29.2g of ethyl 3-nitro-4-hydroxy-phenylacetate shown in the formula (III), and obtaining yellow oily liquid with the purity of 97.4% and the yield of 93.1%.
Dissolving 29.2g of 3-nitro-4-hydroxy-phenylacetic acid ethyl ester in 200mL of ethanol, adding 2.9g of 10% Pd/C, setting the pressure to be 2bar, reacting at 25 ℃ for 3 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C, directly using the Pd/C for the next reduction, concentrating the filtrate to recover ethanol to obtain 3-amino-4-hydroxy-phenylacetic acid ethyl ester shown in the formula (IV), and then using 20mL of ethyl acetate/petroleum ether to obtain 1: the mixed solution of 20 is pulped, filtered and dried to obtain light yellow solid 24.8g, the purity is 96.6 percent, and the yield is 97.9 percent.
Dissolving 24.8g of 3-amino-4-hydroxy-phenyl ethyl acetate in 37g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dripping 23g of 40% sodium nitrite aqueous solution in 30 minutes, keeping the temperature for reaction for 30 minutes at zero, heating to 70 ℃, reacting for 2 times, stopping the reaction, adjusting the pH of the reaction solution to be between 5 and 6 by using saturated sodium bicarbonate, extracting an aqueous phase twice by using 200mL of dichloromethane, discarding a dichloromethane layer, extracting the aqueous phase for 3 times by using 200mL of ethyl acetate, merging organic phases, drying, concentrating and recovering ethyl acetate to obtain 19g of dark red oily liquid, dissolving a crude product in 9mL of 95% industrial ethanol, reducing the temperature to-20 ℃, stirring, separating out a large number of transparent crystals, carrying out cold filtration to obtain 16.7g of a pure product of 3, 4-dihydroxy benzene ethanol shown in a formula (V), and obtaining a colorless transparent solid, the product is light yellow liquid at normal temperature, the purity is 99.6 percent, and the yield is 85.2 percent.
Example 3
Adding 100g of 4-hydroxybenzene ethanol and 1.4g of p-toluenesulfonic acid into 300mL of ethyl acetate in sequence, heating to 78 ℃, stirring for 4 hours, adding 100mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering the ethyl acetate to obtain 126g of compound (I)4- (2-acetoxy-ethyl) phenol with the purity of 98.1% and the yield of 96.6%.
Dissolving 126g of 4- (2-acetoxyl-ethyl) phenol in 250mL of 85% acetic acid, dropwise adding the mixture into 62mL of 55% dilute nitric acid solution at 15 ℃, heating to room temperature for reacting for 2 hours after dropwise adding, stopping the reaction, adding 500mL of water and 500mL of ethyl acetate for extraction, separating an organic phase, extracting an aqueous phase twice with 500mL of ethyl acetate, combining the organic phases, washing once with 200mL of water, washing once with 200mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 145g of 3-nitro-4-hydroxy-phenyl ethyl acetate shown in the formula (III), wherein the purity of the 3-nitro-4-hydroxy-phenyl ethyl acetate is 97.3%, and the yield of the 3-nitro-4-hydroxy-phenyl ethyl acetate is 92.1%.
Dissolving 145g of 3-nitro-4-hydroxy-phenyl ethyl acetate in 1000mL of ethanol, adding 14g of 10% Pd/C, setting the pressure to be 2bar, reacting at 25 ℃ for 4 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C, directly using the Pd/C for the next reduction, concentrating the filtrate, recovering ethanol to obtain 3-amino-4-hydroxy-phenyl ethyl acetate shown in formula (IV), and then using 100mL of ethyl acetate/petroleum ether to be 1: the mixed solution of 20 is pulped, filtered and dried to obtain light yellow solid 123g, the purity is 96.3 percent, and the yield is 97.8 percent.
Dissolving 123g of 3-amino-4-hydroxy-phenyl ethyl acetate in 186g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dropwise adding 114g of 40% sodium nitrite aqueous solution within 30 minutes, keeping the temperature at zero for reaction for 30 minutes, heating to 70 ℃, reacting for 2 times, stopping the reaction, adjusting the pH of the reaction solution to 5-6 by using saturated sodium bicarbonate, extracting the aqueous phase twice by using 1000mL of dichloromethane, discarding the dichloromethane layer, extracting the aqueous phase for 3 times by using 1000mL of ethyl acetate, combining the organic phases, drying, concentrating and recovering the ethyl acetate to obtain 102g of dark red oily liquid, dissolving the crude product in 45mL of 95% industrial ethanol, reducing the temperature to-20 ℃, stirring, precipitating a large amount of transparent crystals, and carrying out cold filtration to obtain 80.3g of the pure 3, 4-dihydroxybenzene ethanol shown in the formula (V) as a colorless transparent solid, the product is light yellow liquid at normal temperature, the purity is 99.5 percent, and the yield is 82.6 percent.
Example 4
Adding 20g of 4-hydroxybenzene ethanol and DPAT430mg into 60mL of ethyl acetate in sequence, heating to 80 ℃, stirring for 4 hours, adding 20mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering the ethyl acetate to obtain 24.7g of compound (I)4- (2-acetoxy-ethyl) phenol, wherein the purity is 98.2%, and the yield is 94.7%.
Dissolving 24.7g of 4- (2-acetoxyl-ethyl) phenol in 50mL of 75% acetic acid, dropwise adding the solution into 12.1mL of 60% dilute nitric acid solution at 15 ℃, heating to room temperature to react for 2 hours after the dropwise addition, stopping the reaction, adding 100mL of water and 100mL of ethyl acetate to extract, separating an organic phase, extracting an aqueous phase twice with 100mL of ethyl acetate, combining the organic phase, washing once with 100mL of water, washing once with 100mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 28.5g of ethyl 3-nitro-4-hydroxy-phenylacetate shown in the formula (III), and obtaining yellow oily liquid with the purity of 96.3% and the yield of 92.3%.
Dissolving 28.5g of ethyl 3-nitro-4-hydroxy-phenylacetate in 200mL of ethanol, adding 10% of Pd/C, setting the pressure to be 3bar, reacting at 25 ℃ for 2 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C and directly using the Pd/C for the next reduction, concentrating the filtrate to recover ethanol to obtain the ethyl 3-amino-4-hydroxy-phenylacetate shown in the formula (IV), and then using 20mL of ethyl acetate/petroleum ether to obtain the compound of 1: the mixed solution of 20 is pulped, filtered and dried to obtain light yellow solid 24.3g, the purity is 97.3 percent, and the yield is 98.3 percent.
Dissolving 24.3g of 3-amino-4-hydroxy-phenyl ethyl acetate in 36.8g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dropwise adding 22.5g of 40% sodium nitrite aqueous solution within 30 minutes, keeping the temperature at zero for reaction for 30 minutes, heating to 80 ℃, reacting for 2 times, stopping the reaction, adjusting the pH of the reaction solution to be between 5 and 6 by using saturated sodium bicarbonate, extracting the aqueous phase twice by using 200mL of dichloromethane, discarding the dichloromethane layer, extracting the aqueous phase for 3 times by using 200mL of ethyl acetate, combining organic phases, drying, concentrating and recovering ethyl acetate to obtain 19.5g of dark red oily liquid, dissolving the crude product in 9mL of 95% industrial ethanol, cooling to-20 ℃, stirring, precipitating a large amount of transparent crystals, carrying out cold filtration to obtain 16.2g of the pure 3, 4-dihydroxy phenethyl alcohol shown in the formula (V), obtaining colorless transparent solid which is light yellow liquid at normal temperature, the purity was 99.4%, and the yield was 84.4%.
Example 5
Adding 20g of 4-hydroxybenzene ethanol and 280mg of p-toluenesulfonic acid into 60mL of ethyl acetate in sequence, heating to 78 ℃, stirring for 3 hours, adding 20mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering the ethyl acetate to obtain 25.2g of compound (I)4- (2-acetoxy-ethyl) phenol, white solid with the purity of 98.1% and the yield of 96.6%.
Dissolving 25.2g of 4- (2-acetoxyl-ethyl) phenol in 50mL of 90% acetic acid, dropwise adding the mixture into 17mL of 50% dilute nitric acid solution at 15 ℃, heating to room temperature to react for 1 hour after the dropwise addition is finished, stopping the reaction, adding 100mL of water and 100mL of ethyl acetate to extract, separating an organic phase, extracting an aqueous phase twice with 100mL of ethyl acetate, combining the organic phase, washing once with 100mL of water, washing once with 100mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 30g of 3-nitro-4-hydroxy-phenyl ethyl acetate shown in the formula (III), wherein the purity is 90.2%, and the yield is 95.2%.
Dissolving 30g of 3-nitro-4-hydroxy-phenyl ethyl acetate in 200mL of ethanol, adding 3g of 10% Pd/C, setting the pressure to be 3bar, reacting at 25 ℃ for 2 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C, directly using the Pd/C for the next reduction, concentrating the filtrate, recovering ethanol to obtain 3-amino-4-hydroxy-phenyl ethyl acetate shown in formula (IV), and then using 20mL of ethyl acetate/petroleum ether to be 1: the mixed solution of 20 is pulped, filtered and dried to obtain light yellow solid 24.8g with the purity of 94.3 percent and the yield of 95.3 percent.
Dissolving 24.8g of 3-amino-4-hydroxy-phenyl ethyl acetate in 37.5g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dripping 23g of 40% sodium nitrite aqueous solution within 30 minutes, keeping the temperature for reaction for 30 minutes at zero, heating to 80 ℃, reacting for 2 times, stopping the reaction, adjusting the pH of the reaction liquid to be between 5 and 6 by using saturated sodium bicarbonate, extracting an aqueous phase twice by using 100mL of dichloromethane, discarding a dichloromethane layer, extracting the aqueous phase for 3 times by using 200mL of ethyl acetate, combining organic phases, drying, concentrating and recovering ethyl acetate to obtain 20g of dark red oily liquid, dissolving the crude product in 9mL of 95% industrial ethanol, reducing the temperature to-20 ℃, stirring to separate out a large number of transparent crystals, carrying out cold filtration to obtain 16.2g of a pure product of 3, 4-dihydroxy phenethyl alcohol shown in the formula (V), obtaining colorless transparent solid, and forming light yellow liquid at normal temperature, purity 90.4%, yield 82.7%.
Example 6
Adding 10g of 4-hydroxybenzene ethanol and 140mg of p-toluenesulfonic acid into 30mL of ethyl acetate in sequence, heating to 80 ℃, stirring for 3 hours, adding 20mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering ethyl acetate to obtain 12.8g of compound (I)4- (2-acetoxy-ethyl) phenol, white solid with the purity of 98.2% and the yield of 98.1%.
Dissolving 12.8g of 4- (2-acetoxyl-ethyl) phenol in 25mL of 80% acetic acid, dropwise adding the mixture into 8.6mL of 60% dilute nitric acid solution at 15 ℃, heating to room temperature to react for 3 hours after the dropwise addition is finished, stopping the reaction, adding 50mL of water and 500mL of ethyl acetate to extract, separating an organic phase, extracting an aqueous phase twice with 50mL of ethyl acetate, combining the organic phase, washing the organic phase once with 50mL of water, washing the aqueous phase once with 50mL of saturated sodium chloride, concentrating and recovering ethyl acetate to obtain 14g of ethyl 3-nitro-4-hydroxy-phenylacetate shown in the formula (III), and obtaining 14g of yellow oily liquid with the purity of 95.4% and the yield of 87.5%.
Dissolving 14g of 3-nitro-4-hydroxy-phenyl ethyl acetate in 100mL of ethanol, adding 1.4g of 10% Pd/C, setting the pressure to be 2bar, reacting at 25 ℃ for 3 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C, directly using the Pd/C for the next reduction, concentrating the filtrate and recovering ethanol to obtain 24.8g of 3-amino-4-hydroxy-phenyl ethyl acetate shown in formula (IV), yellow solid with the purity of 93.2%, and 8mL of ethyl acetate/petroleum ether being 1: pulping, filtering and drying 15 g to obtain 11.6g of light yellow solid with the purity of 98.3 percent and the yield of 95.5 percent.
Dissolving 11.6g of 3-amino-4-hydroxy-phenyl ethyl acetate in 34g of 37% concentrated hydrochloric acid solution, reducing the temperature to zero, dropwise adding 20.9g of 40% sodium nitrite aqueous solution within 30 minutes, keeping the temperature at zero for reaction for 30 minutes, heating to 100 ℃, reacting for 1 time, stopping the reaction, adjusting the pH of the reaction solution to 5-6 by using saturated sodium bicarbonate, extracting the aqueous phase twice by using 100mL of dichloromethane, discarding the dichloromethane layer, extracting the aqueous phase for 3 times by using 100mL of ethyl acetate, combining organic phases, drying, concentrating and recovering ethyl acetate to obtain 9g of dark red oily liquid, dissolving the crude product in 4mL of 95% industrial ethanol, cooling to-20 ℃, stirring, separating out a large amount of transparent crystals, cold filtering to obtain 6.5g of pure 3, 4-dihydroxy phenethyl alcohol shown in formula (V), colorless transparent solid, forming light yellow liquid at normal temperature, the purity was 96.5% and the yield was 70.9%.
Example 7
Adding 500g of 4-hydroxybenzene ethanol and 6g of p-toluenesulfonic acid into 1.5L of ethyl acetate in sequence, heating to 80 ℃, stirring for 5 hours, adding 100mL of clear water after the reaction is finished, extracting and layering, separating out an organic phase, repeating the extraction and layering for one time, concentrating the organic phase and recovering ethyl acetate to obtain 645g of compound (I)4- (2-acetoxy-ethyl) phenol, wherein the purity is 98.2%, and the yield is 98.9%.
645g of 4- (2-acetoxyl-ethyl) phenol is dissolved in 1.2L of 80% acetic acid, the mixture is dripped into 315mL of 60% dilute nitric acid solution at the temperature of 15 ℃, after the dripping is finished, the mixture is heated to room temperature to react for 2 hours, the reaction is stopped, 2.5L of water and 2.5L of ethyl acetate are added to extract, an organic phase is separated, an aqueous phase is extracted twice by 2.5L of ethyl acetate, the organic phase is combined, 500mL of water is washed once, 500mL of saturated sodium chloride is washed once and then ethyl acetate is concentrated and recovered, 790g of 3-nitro-4-hydroxy-phenylacetic acid ethyl ester shown in formula (III) is obtained, yellow oily liquid is obtained, the purity is 97.3%, and the yield is 98%.
Dissolving 790g of 3-nitro-4-hydroxy-phenyl ethyl acetate in 5L of ethanol, adding 79g of 10% Pd/C, setting the pressure at 3bar, reacting at 25 ℃ for 4 hours, completely removing the raw materials, stopping the reaction, filtering, washing the Pd/C with ethanol, recovering the Pd/C, directly using the recovered Pd/C for the next reduction, concentrating the filtrate and recovering ethanol to obtain 680g of 3-amino-4-hydroxy-phenyl ethyl acetate shown in formula (IV), and obtaining a brown yellow solid, wherein 380mL of ethyl acetate/petroleum ether is 1: pulping, filtering and drying to obtain 662g of light yellow solid with the purity of 98.5 percent and the yield of 96.6 percent.
662g of 3-amino-4-hydroxy-phenyl ethyl acetate is dissolved in 1kg of 37% concentrated hydrochloric acid solution, the temperature is reduced to zero degree, 614g of 40% sodium nitrite aqueous solution is dripped in 30 minutes, the temperature is kept at zero degree for reaction for 30 minutes, the temperature is increased to 70 ℃, the reaction is carried out for 2 times, the reaction is stopped, the pH of the reaction solution is adjusted to be between 5 and 6 by saturated sodium bicarbonate, 5L of dichloromethane is used for extracting the aqueous phase twice, the dichloromethane layer is discarded, the aqueous phase is extracted by 5L of ethyl acetate for 3 times, the organic phase is combined, the ethyl acetate is recovered after drying and concentration to obtain 530g of dark red oily liquid, the crude product is dissolved in 200mL of 95% industrial ethanol, the temperature is reduced to-20 ℃, stirring is carried out, a large amount of transparent crystals are separated out, cold filtration is carried out to obtain 440g of pure 3, 4-dihydroxy phenethyl alcohol shown in the formula (V), colorless transparent solid is light yellow liquid at normal temperature, the purity was 99.6% and the yield was 84.1%.
The combined examples 1 to 7 show that: the method for synthesizing the 3, 4-dihydroxy phenethyl alcohol has the advantages of relatively mild reaction conditions, convenient post-treatment, easy realization of enlarged production, relatively high yield, high overall yield of over 78 percent, and high purity of over 99 percent of the product obtained by a crystallization method.
Although the invention has been described in detail with respect to the general description and the specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (7)
1. A method for synthesizing 3, 4-dihydroxy phenethyl alcohol is characterized by comprising the following steps:
taking a compound I as a raw material, and obtaining a compound II under the action of a catalyst for later use;
step two, reacting the compound II prepared in the step one with strong acid, and extracting and concentrating to obtain a compound III;
dissolving a compound III in a solvent, and then starting to react under the action of a catalyst to prepare a compound IV;
step four, carrying out diazotization reaction and acid hydrolysis on the compound IV to generate the 3, 4-dihydroxy phenethyl alcohol;
wherein the structural formulas of the compound I, the compound II, the compound III, the compound IV and the compound V are respectively as follows:
the first step comprises the steps of sequentially adding a compound I and a catalyst into an ethyl acetate solution for reaction, heating and stirring in the reaction process, and washing and concentrating after the reaction is finished to obtain a compound II; the temperature is increased from 20-25 ℃ to 70-100 ℃ in the reaction process, the catalyst is selected from any one of concentrated sulfuric acid, p-toluenesulfonic acid and diphenylamine triflate, and the molar ratio of the compound I to the catalyst is 1: 0.01 to 0.1; the mass-volume ratio of the compound I to the ethyl acetate is 1: 3-5 w/v;
and the second step comprises the steps of dissolving the compound II prepared in the first step into an acetic acid solution, dropwise adding the solution into a dilute nitric acid solution at the temperature of 0-15 ℃, heating to room temperature after dropwise adding for continuous reaction, and adding water and ethyl acetate for extraction and concentration after the reaction is finished to prepare a compound III.
2. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 1, wherein: the mass percentage concentration of the acetic acid solution is 70-99%, the mass percentage concentration of the dilute nitric acid solution is 40-68%, and the proportion of the compound II, the dilute nitric acid solution and the acetic acid solution is 1: 0.4-0.8: 1.5-2.5 w/v/v.
3. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 1, wherein: and step three, dissolving the compound III prepared in the step two in a solvent, reacting under the action of a catalyst to obtain a compound IV crude product after the reaction is finished, washing the catalyst in the reaction process, recovering the catalyst for recycling, mixing the compound IV crude product with petroleum ether, pulping, filtering and drying to obtain the compound IV.
4. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 3, characterized in that: the catalyst is Pd/C, the solvent comprises any one of methanol, ethanol, dioxane, ethyl acetate and dichloromethane, and the molar ratio of the compound III to the catalyst is 1: 0.01-0.05, wherein the mass-volume ratio of the compound III to the solvent is 1: 5-10w/v of the total weight of the composition,
and reacting the compound III under the action of a catalyst Pd/C at the temperature of 15-30 ℃ and the pressure of 1-4MPa, filtering after the reaction is finished, concentrating the filtrate, and recovering the solvent to obtain a crude compound IV.
5. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 3, characterized in that: and mixing the crude compound IV and petroleum ether according to the weight ratio of 1: 15-20 by mass ratio.
6. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 1, wherein: dissolving the compound IV into a concentrated acid aqueous solution, then dropwise adding a sodium nitrite aqueous solution, keeping the temperature to perform zero-degree reaction, extracting with an organic solvent after the reaction is finished, collecting an organic phase, drying the organic phase, concentrating to obtain a crude compound V product, dissolving the crude compound V product into the solvent, and crystallizing and filtering to obtain the 3, 4-dihydroxy phenylethanol.
7. The method of synthesizing 3, 4-dihydroxyphenylethanol according to claim 1, wherein: detecting whether a compound IV is dissolved into a concentrated acid aqueous solution and then completely reacts with a sodium nitrite aqueous solution by adopting thin layer chromatography, heating to 50-100 ℃ after the reaction is completely finished, adjusting the pH value of a reaction solution after the reaction is finished, extracting for multiple times by using an organic solvent, combining organic phases, drying the organic phases, concentrating and recovering the solvent to obtain a crude compound V, dissolving the crude compound V into the solvent, cooling to-20 ℃, stirring, separating out crystals, and filtering to obtain the 3, 4-dihydroxybenzene ethanol, wherein the concentrated acid aqueous solution comprises concentrated hydrochloric acid with the mass percentage concentration of 37% or concentrated sulfuric acid with the mass percentage concentration of 98%, and the mass percentage concentration of the sodium nitrite aqueous solution is 20-40%; dissolving the crude compound V into a solvent by dissolving the crude compound V into any one of methanol, ethanol, dichloromethane, ethyl acetate, toluene or acetone, wherein the molar mass ratio of the compound IV to sodium nitrite to concentrated acid solution is 1: 1.01-1.1: 2.5-4.
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Denomination of invention: A Synthesis Method of 3,4-Dihydroxyphenylethanol Effective date of registration: 20230426 Granted publication date: 20220712 Pledgee: Ningbo Tianjin Enterprise Service Co.,Ltd. Pledgor: NINGBO SYNTAME BIOTECHNOLOGY Co.,Ltd. Registration number: Y2023980039282 |