CN113461493A - Preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane - Google Patents
Preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane 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
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
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- C—CHEMISTRY; METALLURGY
- 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
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
Abstract
The invention discloses a preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane, which takes 4-hydroxyacetophenone and phenol as raw materials, takes acid as a catalyst, and is added with a weakly alkaline nitrogen-containing compound as an auxiliary agent for reaction to prepare the 1,1, 1-tri (4-hydroxyphenyl) ethane. According to the invention, a small amount of nitrogen-containing compound with alkalescence is added in the reaction process, so that the conversion rate of 4-hydroxyacetophenone can be improved, an ideal effect can be achieved even under the condition that the dosage of phenol is only slightly higher than the theoretical demand, the dosage of phenol raw materials is obviously reduced, and the difficulty of post-treatment is greatly reduced.
Description
Technical Field
The invention relates to a preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane, belonging to the field of organic synthesis.
Background
1,1, 1-tri (4-hydroxyphenyl) ethane (THPE) is used as a typical trifunctional phenolic compound, widely used as a cross-linking agent and a branching agent for various polymers, and also used as an intermediate for preparing an antioxidant. The polymer with the structure introduced with the 1,1, 1-tri (4-hydroxyphenyl) ethane can improve a plurality of important properties, such as solvent resistance, heat resistance, hardness, cohesiveness and the like, and the hyperbranched polymer with the structure introduced with the 1,1, 1-tri (4-hydroxyphenyl) ethane can expand the application field thereof.
1,1, 1-tris (4-hydroxyphenyl) ethane is generally produced from 4-hydroxyacetophenone and phenol under acidic conditions, and a production process of 1,1, 1-tris (4-hydroxyphenyl) ethane has been reported to have a high content of bisphenol as a by-product and a complicated purification process, resulting in a low overall yield.
The main and side reactions in the synthesis process of 1,1, 1-tri (4-hydroxyphenyl) ethane are as follows:
main reaction:
side reaction:
one of the problems reported in patent CN1053918A in the synthesis of 1,1, 1-tris (4-hydroxyphenyl) ethane is the low yield, only 70-80%. The product contains impurities such as iso-THPE, 1, 1-bis (hydroxyphenyl) ethane isomer, phenol, 4-hydroxyacetophenone, chloride and the like. Since the presence of these impurities makes the post-treatment process of 1,1, 1-tri (4-hydroxyphenyl) ethane abnormally complicated, how to reduce the impurity content from the source is one of the effective solutions for optimizing the production process. In patent CN105541561A, concentrated hydrochloric acid and concentrated sulfuric acid are used as catalysts, zinc sulfide or zinc chloride is used as a cocatalyst, the yield is improved, but the dosage of phenol is 5-20 times of that of 4-hydroxyacetophenone, the problem of overlarge dosage of phenol is not solved, and zinc salt is introduced in the patent method, so that a small amount of zinc ions can be remained in subsequent products, and the product quality is influenced.
Disclosure of Invention
In view of the above problems in the prior art, the present invention is directed to a method for preparing 1,1, 1-tris (4-hydroxyphenyl) ethane.
In the process of preparing 1,1, 1-tri (4-hydroxyphenyl) ethane, the invention discovers that the preparation process which is usually adopted and takes 4-hydroxyacetophenone and phenol as raw materials under acidic conditions needs to add phenol with the amount far exceeding the reaction requirement so as to ensure the conversion rate of the 4-hydroxyacetophenone. When the dosage of the phenol is insufficient, the content of the bisphenol as a byproduct, namely 1, 1-bis (hydroxyphenyl) ethane is increased, and when the dosage of the phenol is excessive, the residual phenol in the system is increased, and the two conditions can cause the increase of the separation difficulty.
In the process of research for solving the problems, the invention unexpectedly discovers that the conversion rate of 4-hydroxyacetophenone can be improved by adding a small amount of nitrogen-containing compound with alkalescence in the reaction process, a more ideal effect can be achieved even under the condition that the dosage of phenol is only slightly higher than the theoretical demand, the dosage of phenol raw materials is obviously reduced, and the difficulty of post-treatment is greatly reduced.
The technical scheme adopted by the invention is as follows:
the invention provides a preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane, which takes 4-hydroxyacetophenone and phenol as raw materials, takes acid as a catalyst, and adds a weakly alkaline nitrogen-containing compound as an auxiliary agent for reaction to prepare the 1,1, 1-tri (4-hydroxyphenyl) ethane.
Further, the acid is a catalyst, can be an inorganic acid or an organic acid, and is selected from one or a combination of at least two of methanesulfonic acid, p-toluenesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and concentrated phosphoric acid; preferably methanesulfonic acid and/or p-toluenesulfonic acid.
Further, the nitrogen-containing compound with weak alkalinity is selected from nitrogen-containing compounds with a pKb value of 0.1-10, preferably imidazole, alcamines, pyridine and aniline nitrogen-containing compounds, more preferably any one or a combination of at least two of N-methylimidazole, aniline, 1, 8-diazabicycloundecen-7-ene, trioctyl ammonium, 4-dimethylaminopyridine and triethanolamine, and most preferably 4-dimethylaminopyridine and/or 1, 8-diazabicycloundecen-7-ene.
Further, the molar ratio of the 4-hydroxyacetophenone to the phenol is 1: 2-1: 6, preferably 1: 2.2-1: 4;
preferably, the molar ratio of the acid to the 4-hydroxyacetophenone is 1: 300-1: 10, preferably 1: 100-1: 20;
preferably, the molar ratio of the weakly basic nitrogen-containing compound to the 4-hydroxyacetophenone is 1:5000 to 1:100, preferably 1:1000 to 1: 100.
Further, the reaction is preferably carried out in an inert gas atmosphere (such as nitrogen), and the reaction temperature is 0-120 ℃, preferably 45-90 ℃; the reaction time is 1-24 h, preferably 4-12 h;
sampling the reaction solution, detecting and analyzing by gas chromatography: the conversion rate of 4-hydroxyacetophenone is more than 99%, the selectivity of 1,1, 1-tri (4-hydroxyphenyl) ethane is more than 97%, the selectivity of impurity 1, 1-bis (hydroxyphenyl) ethane is less than 2%, and the selectivity of iso-THPE is less than 1%.
As a preferable scheme, the preparation method provided by the invention comprises the following steps: heating phenol to 45-90 ℃ under the inert gas atmosphere to completely melt the phenol, then stirring and adding an acid catalyst and a weakly alkaline nitrogen-containing compound, keeping the internal temperature at 0-120 ℃, stirring for 0.25-2 h, slowly adding 4-hydroxyacetophenone within 30-180 min, and reacting for 1-24 h at 0-120 ℃ after the addition is finished.
Further, after the reaction is completed, the post-treatment processes such as distillation, filtration, drying, adsorption, or recrystallization are also included, which are conventional operations in the art. As a preferred scheme, the post-treatment method adopted by the invention comprises the following steps: after the reaction is finished, cooling the system to 25-35 ℃, adding dichloroethane with the mass of 0.5-2 times of that of 4-hydroxyacetophenone, stirring for 0.5-4 h, distilling off dichloromethane at 50-55 ℃, filtering at 55-65 ℃, and drying the filter cake at 55-65 ℃ in vacuum for 3-6 h to obtain a 1,1, 1-tris (4-hydroxyphenyl) ethane crude product;
the crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane is obtained from the post-treatment process, part of reaction byproducts enter dichloromethane distillation residual liquid, the purity of the crude product is 92-99 wt%, and the yield is more than 90 wt%.
The invention further provides a purification method of the crude product of the 1,1, 1-tri (4-hydroxyphenyl) ethane. As a preferred scheme, the purification method adopted by the invention comprises the following steps:
1) heating and dissolving the crude product of the 1,1, 1-tri (4-hydroxyphenyl) ethane in a solvent A, then adding water, cooling to 25-35 ℃, stirring for 0.1-3 h, and separating and drying the precipitated solid;
2) and heating the dried solid to dissolve in a solvent B, adding sodium borohydride and active carbon, stirring for 0.1-3 h, filtering out the active carbon, adding water for recrystallization, separating and drying the separated solid again after crystals are completely separated out, and obtaining the purified 1,1, 1-tris (4-hydroxyphenyl) ethane product.
Further, in the step 1) of the purification method, the solvent A is C1-C5 alcohol, preferably methanol or ethanol;
preferably, the dosage of the solvent A is 0.25-2 times, preferably 0.5-1.5 times of the mass of the crude product of the 1,1, 1-tris (4-hydroxyphenyl) ethane;
preferably, the mass ratio of the solvent A to the water is 2: 1-1: 2, preferably 10: 7-10: 9;
preferably, the temperature for heating and dissolving the crude product of 1,1, 1-tris (4-hydroxyphenyl) ethane in the solvent A is 40-60 ℃.
Further, in the step 2) of the purification method, the solvent B is C1-C5 alcohol, preferably methanol or ethanol;
preferably, the amount of the solvent B is 0.25 to 2 times, preferably 0.5 to 1.5 times, the mass of the crude product of the 1,1, 1-tris (4-hydroxyphenyl) ethane in the step 1);
preferably, the adding amount of the sodium borohydride is 3-10 g of sodium borohydride per 1000mL of solvent B, and the adding amount of the activated carbon is 2-8 g of activated carbon per 1000mL of solvent B.
Further, in the purification method step 2), the temperature for heating and dissolving the dried solid in the solvent B is 50-80 ℃;
preferably, the mass ratio of the solvent B to the water is 0.25-2, preferably 0.5-1.
Compared with the prior art, the technical scheme of the invention has the beneficial effects that:
the invention achieves the effect of improving the conversion rate of the 4-hydroxyacetophenone by controlling the addition of a small amount of nitrogen-containing compound with alkalescence in the reaction process, the byproduct bisphenol, namely the 1, 1-bis (hydroxyphenyl) ethane can be basically and completely converted into the 1,1, 1-tris (4-hydroxyphenyl) ethane due to the addition of the alkalescence nitrogen-containing compound, even if the dosage of the phenol is only slightly higher than the theoretical requirement, the ideal effect can be achieved, and only a small amount of residue exists. The reaction liquid is post-treated and purified to obtain high-quality 1,1, 1-tri (4-hydroxyphenyl) ethane product. Because the contents of 1, 1-bis (hydroxyphenyl) ethane isomer, phenol, 4-hydroxyacetophenone and other substances in the reaction solution are obviously reduced compared with the traditional method, the difficulty of post-treatment is greatly reduced, and the economical efficiency is improved.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative of the invention and are not to be construed as limiting the scope of the invention.
The main raw material source information adopted in the embodiment of the invention is as follows:
99 wt% of 4-hydroxyacetophenone, Allantin technologies, Inc.;
phenol, 99 wt%, Aladdin technologies, Inc.;
99 wt% of 4-dimethylaminopyridine, Allantin technologies, Inc.;
99 wt% of 1, 8-diazabicycloundec-7-ene, alatin technologies, inc;
methanesulfonic acid, 99 wt%, carbofuran technologies ltd;
99 wt% of methylbenzenesulfonic acid, lark technologies ltd;
dichloromethane, 99 wt%, national pharmaceutical group chemical agents ltd;
99 wt% methanol, chemical reagents of national drug group, ltd;
all others are common commercial raw materials unless otherwise specified.
Liquid chromatography conditions: waters liquid chromatograph, column Waters XBidge amide, detector ELSD detector, mobile phase acetonitrile/water 75/25, column temperature 40 ℃.
Example 1
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
282.12g of phenol (3.0mol) were added to the flask, and an inert gas (N)2) Under the atmosphere, the mixture was heated in a 60 ℃ water bath, and after phenol had completely melted, stirring was started, and 85 wt% concentrated phosphoric acid (1.96 g, 0.02mol based on phosphoric acid) and 0.18g (0.002mol) of aniline (pKb 9.34) were added, and the mixture was stirred at about 55 ℃ for 1 hour. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the flask over 60min, and after the completion of the addition, the reaction was maintained at 55 ℃ for 6 hours.
Sampling gas chromatography detection of reaction solution composition: 22.26% of phenol, 0.47% of phosphoric acid, 0.04% of aniline, 0.03% of 4-hydroxyacetophenone, 70.86% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.50% of iso-THPE, 1, 1-bis (hydroxyphenyl) ethane, 4.26% of water and 0.55% of the rest; the conversion of 4-hydroxyacetophenone was 99.91%, the selectivity of 1,1, 1-tris (4-hydroxyphenyl) ethane was 96.69%, the selectivity of 1, 1-bis (hydroxyphenyl) ethane as an impurity was 1.87%, and the selectivity of iso-THPE was 0.69%, based on the molar amount.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 100g of dichloroethane, fully stirring for 1h again, distilling 95.6g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 295.31g of crude THPE. The crude product had a purity of 95.60% and a yield of 92.22%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 400ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 320 ml of pure water, cooling to 25 ℃, continuing stirring for 1h, precipitating a light yellow solid in the solution, filtering, and drying a filter cake. And dissolving the dried product in 240ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 1.0g of activated carbon, slowly adding 2.0g of sodium borohydride, continuously stirring for 1h, filtering out the activated carbon, adding 320 ml of pure water into the liquid phase, cooling to 25 ℃, continuously stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.62%, yield 92.51% based on the mass of crude product before purification.
Example 2
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
282.12g of phenol (3.0mol) were added to the flask, and an inert gas (N)2) Under the atmosphere, the mixture was heated in a water bath at 60 ℃ until phenol was completely melted, and 8.61g (0.05mol) of p-toluenesulfonic acid and 0.41g (152.24, 0.005mol) of N-methylimidazole (pKb 7.05) were added with stirring, and the mixture was stirred at an internal temperature of about 55 ℃ for 1 hour. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the flask over 120min, and after the completion of the addition, the reaction was maintained at 55 ℃ for 6 hours.
Sampling gas chromatography detection of reaction solution composition: 21.67% of phenol, 2.02% of p-toluenesulfonic acid, 0.10% of N-methylimidazole, 0.02% of 4-hydroxyacetophenone, 70.37% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.51% of iso-THPE, 0.73% of 1, 1-bis (hydroxyphenyl) ethane, 4.19% of water and 0.39% of the rest; the conversion of 4-hydroxyacetophenone was 99.93%, the selectivity of 1,1, 1-tris (4-hydroxyphenyl) ethane was 97.40%, the selectivity of 1, 1-bis (hydroxyphenyl) ethane as an impurity was 1.35%, and the selectivity of iso-THPE was 0.70%, by mole.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 100g of dichloroethane, fully stirring for 1h again, distilling 95.9g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 301.12g of crude THPE. The crude product had a purity of 95.60% and a yield of 92.22%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 400ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 300ml of pure water, cooling to 30 ℃, continuing stirring for 1h, and precipitating light yellow solid in the solution; and drying the filter cake after filtering. And dissolving the dried product in 250ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 0.5g of activated carbon, slowly adding 1.5g of sodium borohydride, continuously stirring for 1h, filtering out the activated carbon, adding 350 ml of pure water into the liquid phase, cooling to 30 ℃, continuously stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.71% and yield 94.09% based on the mass of crude product before purification.
Example 3
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
206.89g of phenol (2.2mol) were added to the flask, inert gas (N)2) Under the atmosphere, the mixture was heated in a 100 ℃ oil bath, and after phenol was completely melted, 4.8g (0.05mol) of methanesulfonic acid and 1.2g (0.01mol) of 4-dimethylaminopyridine (pKb ═ 4.8) were added with stirring, and the mixture was stirred at about 90 ℃ for 1 hour. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the flask over 180min, and after the completion of the addition, the reaction was maintained at 90 ℃ for 2 hours.
Sampling gas chromatography detection of reaction solution composition: 5.11% of phenol, 1.38% of methanesulfonic acid, 0.34% of 4-dimethylaminopyridine, 0.01% of 4-hydroxyacetophenone, 86.43% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.59% of iso-THPE, 0.65% of 1, 1-bis (hydroxyphenyl) ethane, 4.96% of water and 0.53% of others; the conversion of 4-hydroxyacetophenone was 99.96%, the selectivity by mole for 1,1, 1-tris (4-hydroxyphenyl) ethane was 97.76%, the selectivity for 1, 1-bis (hydroxyphenyl) ethane as an impurity was 0.97%, and the selectivity for iso-THPE was 0.66%.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 120g of dichloroethane, fully stirring for 1h again, distilling 116.5g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 302.93g of crude THPE. The crude product had a purity of 96.50% and a yield of 95.49%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 300ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 280ml of pure water, cooling to 25 ℃, continuing stirring for 1h, precipitating a light yellow solid in the solution, filtering, and drying a filter cake. Dissolving the dried product in 200ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 1.0g of activated carbon, slowly adding 1.5g of sodium borohydride, continuing stirring for 1h, filtering out the activated carbon, adding 280ml of pure water into the liquid phase, cooling to 25 ℃, continuing stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.69%, yield 93.51% based on the mass of crude product before purification.
Example 4
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
376.16g of phenol (4.0mol) were added to the flask, and an inert gas (N)2) Under the atmosphere, the mixture was heated in a 50 ℃ water bath, and after phenol was completely melted, 98 wt% concentrated sulfuric acid (9.8 g, 0.1mol in terms of sulfuric acid) and 1.2g (0.01mol) of 4-dimethylaminopyridine (pKb 4.8) were added with stirring, and the mixture was stirred at about 45 ℃ for 1 hour. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the flask over 30min, and after the completion of the addition, the reaction was maintained at 45 ℃ for 12 hours.
Sampling gas chromatography detection of reaction solution composition: 35.72% of phenol, 1.87% of sulfuric acid, 0.23% of 4-dimethylaminopyridine, 0.02% of 4-hydroxyacetophenone, 57.54% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.51% of iso-THPE, 0.35% of 1, 1-bis (hydroxyphenyl) ethane, 3.30% of water and 0.46% of others; the conversion of 4-hydroxyacetophenone was 99.91%, the selectivity of 1,1, 1-tris (4-hydroxyphenyl) ethane was 97.59%, the selectivity of 1, 1-bis (hydroxyphenyl) ethane as an impurity was 0.79%, and the selectivity of iso-THPE was 0.85%, by mole.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 110g of dichloroethane, fully stirring for 1h again, distilling 106.1g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 300.32g of crude THPE. The crude product had a purity of 95.06% and a yield of 93.26%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 380ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 310 ml of pure water, cooling to 25 ℃, continuing stirring for 1h, precipitating a light yellow solid in the solution, filtering, and drying a filter cake. Dissolving the dried product in 280ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 2.0g of activated carbon, slowly adding 2.5g of sodium borohydride, continuing stirring for 1h, filtering out the activated carbon, adding 310 ml of pure water into the liquid phase, cooling to 25 ℃, continuing stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.37%, yield 91.98% based on the mass of crude product before purification.
Example 5
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
329.14g of phenol (3.5mol) were added to the flask, and an inert gas (N)2) Under the atmosphere, the mixture was heated with a 90 ℃ oil bath, and after phenol had completely melted, 1.72g (0.01mol) of p-toluenesulfonic acid, 0.6g (0.005mol) of 4-dimethylaminopyridine (pKb ═ 4.8) and 0.76g (0.005mol) of 1, 8-diazabicycloundecen-7-ene (pKb ═ 2.0) were added with stirring, and the internal temperature was maintained at about 80 ℃ for 1 hour with stirring. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the flask over 75min, and after the completion of the addition, the reaction was maintained at 80 ℃ for 4 hours.
Sampling gas chromatography detection of reaction solution composition: 29.64% of phenol, 0.37% of p-toluenesulfonic acid, 0.13% of 4-dimethylaminopyridine, 0.16% of 1, 8-diazabicycloundec-7-ene, 0.01% of 4-hydroxyacetophenone, 0.25% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 64.53% of iso-THPE, 0.56% of 1, 1-bis (hydroxyphenyl) ethane, 3.69% of water, and 0.47% of the others; the conversion of 4-hydroxyacetophenone was 99.96%, the selectivity by mole for 1,1, 1-tris (4-hydroxyphenyl) ethane was 97.55%, the selectivity for 1, 1-bis (hydroxyphenyl) ethane as an impurity was 0.89%, and the selectivity for iso-THPE was 0.85%.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 130g of dichloroethane, fully stirring for 1h again, distilling 124.9g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 301.36g of crude THPE. The crude product had a purity of 96.12% and a yield of 94.62%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 300ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 300ml of pure water, cooling to 25 ℃, continuing stirring for 1h, precipitating a light yellow solid in the solution, filtering, and drying a filter cake. And dissolving the dried product in 300ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 1.5g of activated carbon, slowly adding 2.0g of sodium borohydride, continuously stirring for 1h, filtering out the activated carbon, adding 300ml of pure water into the liquid phase, cooling to 25 ℃, continuously stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.79% and yield 93.29% based on the mass of crude product before purification.
Example 6
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
564.24g of phenol (6.0mol) were added to the flask, and an inert gas (N)2) Under the atmosphere, the mixture was heated in a 70 ℃ water bath, 17.2g (0.1mol) of p-toluenesulfonic acid and 0.15g (0.001mol) of 1, 8-diazabicycloundecen-7-ene (pKb ═ 2.0) were added after the phenol had completely melted, and the mixture was stirred at an internal temperature of about 60 ℃ for 1 hour. 136.01g (1.0mol) of 4-hydroxyacetophenone were slowly added to the autoclave over 60min, and the reaction was maintained at 60 ℃ for 6 hours after the addition.
Sampling gas chromatography detection of reaction solution composition: 52.19% of phenol, 2.40% of p-toluenesulfonic acid, 0.02% of 1, 8-diazabicycloundec-7-ene, 0.02% of 4-hydroxyacetophenone, 41.48% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.57% of iso-THPE, 0.46% of 1, 1-bis (hydroxyphenyl) ethane, 2.41% of water, and 0.45% of the others; the conversion of 4-hydroxyacetophenone was 99.88%, the selectivity by mole for 1,1, 1-tris (4-hydroxyphenyl) ethane was 96.22%, the selectivity for 1, 1-bis (hydroxyphenyl) ethane as an impurity was 1.42%, and the selectivity for iso-THPE was 1.33%.
Cooling with jacket water to reduce the internal temperature to about 25 ℃, adding 150g of dichloroethane, fully stirring for 1h again, distilling 144.1g of dichloromethane at 50-55 ℃, filtering at 55 ℃, and allowing part of reaction byproducts to enter dichloromethane distillation residual liquid. And drying the filter cake in vacuum for 6 hours to obtain 299.65g of crude THPE. The crude product was 95.08% pure with a yield of 93.07%.
A method for purifying a crude product of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 250ml of methanol into 200g of the crude product, heating in a water bath at 60 ℃ until the crude product is completely dissolved, slowly adding 220 ml of pure water, cooling to 25 ℃, continuing stirring for 1h, precipitating a light yellow solid in the solution, filtering, and drying a filter cake. Dissolving the dried product in 300ml of methanol again, heating in a water bath at 60 ℃ until the solid is completely dissolved, adding 2.0g of activated carbon, slowly adding 3.0g of sodium borohydride, continuing stirring for 1h, filtering out the activated carbon, adding 220 ml of pure water into the liquid phase, cooling to 25 ℃, continuing stirring for 1h, and recrystallizing to separate out the solid. Centrifugally separating the obtained solid, and then carrying out vacuum drying on the solid at about 60 ℃ for 3-4h to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC 99.17% and yield 91.89% based on the mass of crude product before purification.
Comparative example 1
Reference example 1 method for the synthesis of 1,1, 1-tris (4-hydroxyphenyl) ethane: the difference is that weakly alkaline nitrogen-containing compound 4-dimethylamino pyridine is not added, after the reaction is carried out for 6 hours at 55 ℃ after the charging is finished, a sample is taken for gas chromatography to detect the composition of the reaction solution: 33.34% of phenol, 0.46% of methanesulfonic acid, 7.45% of 4-hydroxyacetophenone, 48.11% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.54% of iso-THPE, 5.77% of 1, 1-bis (hydroxyphenyl) ethane, 3.24% of water and 1.09% of the rest; the conversion of 4-hydroxyacetophenone was 77.41%, the selectivity to 1,1, 1-tris (4-hydroxyphenyl) ethane was 83.78%, the selectivity to 1, 1-bis (hydroxyphenyl) ethane as an impurity was 13.38%, and the selectivity to iso-THPE was 0.94%, by mole.
Comparative example 2
Reference example 1 method for the synthesis of 1,1, 1-tris (4-hydroxyphenyl) ethane: except that 4-dimethylaminopyridine was replaced with an equimolar amount of glycine (glycine has two pKb values, pKb1 ═ 11.65 and pKb2 ═ 4.4), and after keeping at 55 ℃ for 6 hours after the addition was complete, the reaction mixture composition was checked by gas chromatography, by sampling: 32.88% of phenol, 0.46% of methanesulfonic acid, 0.04% of glycine, 7.33% of 4-hydroxyacetophenone, 47.99% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.59% of iso-THPE, 6.46% of 1, 1-bis (hydroxyphenyl) ethane, 3.24% of water and 1.01% of the rest; the conversion of 4-hydroxyacetophenone was 77.92%, the selectivity to 1,1, 1-tris (4-hydroxyphenyl) ethane was 82.48%, the selectivity to 1, 1-bis (hydroxyphenyl) ethane as an impurity was 14.77%, and the selectivity to iso-THPE was 1.03%, based on the molar amount.
Comparative example 3
Reference example 1 method for the synthesis of 1,1, 1-tris (4-hydroxyphenyl) ethane: except that 4-dimethylaminopyridine was replaced with an equimolar amount of lithium hydroxide (pKb ═ 0.2), and after completion of the addition and maintaining at 55 ℃ for 6 hours, the reaction mixture was sampled and examined by gas chromatography for composition: 33.68% of phenol, 0.46% of methanesulfonic acid, 0.01% of glycine, 7.46% of 4-hydroxyacetophenone, 48.26% of 1,1, 1-tris (4-hydroxyphenyl) ethane, 0.55% of iso-THPE, 5.50% of 1, 1-bis (hydroxyphenyl) ethane, 3.24% of water and 0.84% of the rest; the conversion of 4-hydroxyacetophenone was 77.23%, the selectivity by mole for 1,1, 1-tris (4-hydroxyphenyl) ethane was 84.72%, the selectivity for 1, 1-bis (hydroxyphenyl) ethane as an impurity was 12.85%, and the selectivity for iso-THPE was 0.97%.
Comparative example 4
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
adding 54.0mol of phenol and 100g of zinc chloride into a reaction kettle, stirring to uniformly mix, slowly adding 6.5mol of 4-hydroxyacetophenone within 40min, heating to 60 ℃ after the addition is finished, slowly adding 100ml of concentrated hydrochloric acid within 60min under the temperature condition, and stirring to react for 8h after the addition is finished. Sampling gas chromatography to detect the composition of the reaction liquid at the bottom of the tower: 63.75% of phenol, 0.59% of hydrogen chloride, 1.66% of zinc sulfide, 0.50% of 4-hydroxyacetophenone, 28.87% of 1,1, 1-tri (4-hydroxyphenyl) ethane, 0.59% of iso-THPE, 0.81% of 1, 1-bis (hydroxyphenyl) ethane, 2.92% of water and 0.31% of the rest; the conversion of 4-hydroxyacetophenone was 96.45%, the selectivity of 1,1, 1-tris (4-hydroxyphenyl) ethane was 93.59%, the selectivity of 1, 1-bis (hydroxyphenyl) ethane as an impurity was 3.51%, and the selectivity of iso-THPE was 1.90% by mole;
after the reaction is finished, carrying out post-treatment according to the method of example 1 until the crude product of the 1,1, 1-tri (4-hydroxyphenyl) ethane is obtained, and purifying to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity 99.12% by HPLC analysis, yield 85.37% and zinc ion remaining 12 ppm.
Comparative example 5
The synthesis method of 1,1, 1-tri (4-hydroxyphenyl) ethane comprises the following steps:
referring to comparative example 4, except that the amount of phenol was reduced from 54.0mol to 19.5mol, the molar ratio of phenol to 4-hydroxyacetophenone of this comparative example was adjusted to 3: 1, after reacting for 8 hours, sampling gas chromatography to detect the composition of a reaction solution at the bottom of the tower: 25.60% of phenol, 1.29% of hydrogen chloride, 3.63% of zinc sulfide, 7.97% of 4-hydroxyacetophenone, 46.97% of 1,1, 1-tri (4-hydroxyphenyl) ethane, 1.09% of iso-THPE, 7.05% of 1, 1-bis (hydroxyphenyl) ethane, 5.55% of water and 0.85% of the rest; the conversion of 4-hydroxyacetophenone was 76.46%, the selectivity by mole for 1,1, 1-tris (4-hydroxyphenyl) ethane was 80.58%, the selectivity for 1, 1-bis (hydroxyphenyl) ethane as an impurity was 1.87%, and the selectivity for iso-THPE was 16.09%;
after the reaction is finished, carrying out post-treatment according to the method of example 1 until the crude product of the 1,1, 1-tri (4-hydroxyphenyl) ethane is obtained, and purifying to obtain a purified 1,1, 1-tri (4-hydroxyphenyl) ethane product; purity by HPLC analysis 95.22%, yield 63.18%, 15ppm zinc ion remained.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (9)
1. The preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane is characterized in that 4-hydroxyacetophenone and phenol are used as raw materials, acid is used as a catalyst, and a weakly alkaline nitrogen-containing compound is added as an auxiliary agent to react to prepare the 1,1, 1-tri (4-hydroxyphenyl) ethane.
2. The method according to claim 1, wherein the acid is an inorganic acid or an organic acid selected from any one of or a combination of at least two of methanesulfonic acid, p-toluenesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid, and concentrated phosphoric acid; preferably methanesulfonic acid and/or p-toluenesulfonic acid.
3. The preparation method according to claim 1 or 2, wherein the nitrogen-containing compound with weak basicity is selected from nitrogen-containing compounds with a pKb value of 0.1-10, preferably imidazole, alcamines, pyridines, aniline nitrogen-containing compounds, more preferably N-methylimidazole, aniline, 1, 8-diazabicycloundecen-7-ene, trioctylammonium, 4-dimethylaminopyridine, triethanolamine, or any one or a combination of at least two thereof, and most preferably is 4-dimethylaminopyridine and/or 1, 8-diazabicycloundecen-7-ene.
4. The preparation process according to any one of claims 1 to 3, characterized in that the molar ratio of 4-hydroxyacetophenone to phenol is 1:2 to 1:6, preferably 1:2.2 to 1: 4;
preferably, the molar ratio of the acid to the 4-hydroxyacetophenone is 1: 300-1: 10, preferably 1: 100-1: 20;
preferably, the molar ratio of the weakly basic nitrogen-containing compound to the 4-hydroxyacetophenone is 1:5000 to 1:100, preferably 1:1000 to 1: 100.
5. The method according to any one of claims 1 to 4, wherein the reaction is carried out in an inert gas atmosphere at a temperature of 0 to 120 ℃, preferably 45 to 90 ℃; the reaction time is 1-24 h, preferably 4-12 h.
6. The preparation method of any one of claims 1 to 5, wherein after the reaction is finished, the temperature of the system is reduced to 25-35 ℃, dichloroethane with 0.5-2 times of the mass of 4-hydroxyacetophenone is added and stirred for 0.5-4 h, dichloromethane is distilled out at 50-55 ℃, the dichloromethane is filtered at 55-65 ℃, and the filter cake is dried in vacuum at 55-65 ℃ for 3-4h to obtain the crude product of 1,1, 1-tris (4-hydroxyphenyl) ethane.
7. The method according to any one of claims 1 to 6, wherein the step of purifying the crude 1,1, 1-tris (4-hydroxyphenyl) ethane comprises:
1) heating and dissolving the crude product of the 1,1, 1-tri (4-hydroxyphenyl) ethane in a solvent A, then adding water, cooling to 25-35 ℃, stirring for 0.1-3 h, and separating and drying the precipitated solid;
2) and heating the dried solid to dissolve in a solvent B, adding sodium borohydride and active carbon, stirring for 0.1-3 h, filtering out the active carbon, adding water for recrystallization, separating and drying the separated solid again after crystals are completely separated out, and obtaining the purified 1,1, 1-tris (4-hydroxyphenyl) ethane product.
8. The process according to any one of claims 1 to 7, wherein in step 1) of the purification process, the solvent A is a C1-C5 alcohol, preferably methanol or ethanol;
preferably, the dosage of the solvent A is 0.25-2 times, preferably 0.5-1.5 times of the mass of the crude product of the 1,1, 1-tris (4-hydroxyphenyl) ethane;
preferably, the mass ratio of the solvent A to the water is 2: 1-1: 2, preferably 10: 7-10: 9;
preferably, the temperature for heating and dissolving the crude product of 1,1, 1-tris (4-hydroxyphenyl) ethane in the solvent A is 40-60 ℃.
9. The process according to any one of claims 1 to 8, wherein in step 2) of the purification process, the solvent B is a C1-C5 alcohol, preferably methanol or ethanol;
preferably, the amount of the solvent B is 0.25 to 2 times, preferably 0.5 to 1.5 times, the mass of the crude product of the 1,1, 1-tris (4-hydroxyphenyl) ethane in the step 1);
preferably, the adding amount of the sodium borohydride is 3-10 g of sodium borohydride per 1000mL of solvent B, and the adding amount of the active carbon is 2-8 g of active carbon per 1000mL of solvent B;
preferably, the temperature for heating and dissolving the dried solid in the solvent B is 50-80 ℃;
preferably, the mass ratio of the solvent B to the water is 0.25-2, preferably 0.5-1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113943212A (en) * | 2021-11-17 | 2022-01-18 | 烟台海川化学制品有限公司 | Preparation method of 1, 1, 1-tri (4-hydroxyphenyl) ethane |
| CN114624378A (en) * | 2022-03-22 | 2022-06-14 | 中化国际新材料(河北)有限公司 | Monitoring analysis method for process of preparing 1,1, 1-tri (4-hydroxyphenyl) ethane from 4-hydroxyacetophenone |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5672776A (en) * | 1996-09-27 | 1997-09-30 | General Electric Company | Method for purifying 1,1,1-tris(4-hydroxyphenyl)-alkanes |
| CN1178782A (en) * | 1996-09-27 | 1998-04-15 | 通用电气公司 | Purifying method for 1, 1, 1 -tri(4 -hydroxy-phenyl) paraffin |
| US5756859A (en) * | 1996-01-05 | 1998-05-26 | General Electric Company | Method for preparing and purifying 1,1,1-tris(4-hydroxyphenyl)ethane |
| US20060004214A1 (en) * | 2004-06-30 | 2006-01-05 | Gurram Kishan | Methods for preparing 1,1,1-tris(4-hydroxyphenyl)alkanes |
| US20070212899A1 (en) * | 2006-03-09 | 2007-09-13 | Fujifilm Corporation | Photosensitive resin composition and method for manufacturing semiconductor apparatus using the same |
| CN105541561A (en) * | 2016-02-04 | 2016-05-04 | 常州市天华制药有限公司 | Method for synthesizing and purifying 1,1,1-tri(4-hydroxy phenyl) ethane |
| CN112062657A (en) * | 2019-06-10 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane |
-
2021
- 2021-07-01 CN CN202110743501.9A patent/CN113461493B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5756859A (en) * | 1996-01-05 | 1998-05-26 | General Electric Company | Method for preparing and purifying 1,1,1-tris(4-hydroxyphenyl)ethane |
| US5672776A (en) * | 1996-09-27 | 1997-09-30 | General Electric Company | Method for purifying 1,1,1-tris(4-hydroxyphenyl)-alkanes |
| CN1178782A (en) * | 1996-09-27 | 1998-04-15 | 通用电气公司 | Purifying method for 1, 1, 1 -tri(4 -hydroxy-phenyl) paraffin |
| US20060004214A1 (en) * | 2004-06-30 | 2006-01-05 | Gurram Kishan | Methods for preparing 1,1,1-tris(4-hydroxyphenyl)alkanes |
| US20070212899A1 (en) * | 2006-03-09 | 2007-09-13 | Fujifilm Corporation | Photosensitive resin composition and method for manufacturing semiconductor apparatus using the same |
| CN105541561A (en) * | 2016-02-04 | 2016-05-04 | 常州市天华制药有限公司 | Method for synthesizing and purifying 1,1,1-tri(4-hydroxy phenyl) ethane |
| CN112062657A (en) * | 2019-06-10 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of 1,1, 1-tri (4-hydroxyphenyl) ethane |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113943212A (en) * | 2021-11-17 | 2022-01-18 | 烟台海川化学制品有限公司 | Preparation method of 1, 1, 1-tri (4-hydroxyphenyl) ethane |
| CN113943212B (en) * | 2021-11-17 | 2023-11-24 | 烟台海川化学制品有限公司 | Preparation method of 1, 1-tri (4-hydroxyphenyl) ethane |
| CN114624378A (en) * | 2022-03-22 | 2022-06-14 | 中化国际新材料(河北)有限公司 | Monitoring analysis method for process of preparing 1,1, 1-tri (4-hydroxyphenyl) ethane from 4-hydroxyacetophenone |
| CN114624378B (en) * | 2022-03-22 | 2024-04-05 | 中化国际新材料(河北)有限公司 | Monitoring analysis method for preparing 1, 1-tri (4-hydroxyphenyl) ethane from 4-hydroxyacetophenone |
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