CN113264814A - Process for preparing hydroxytyrosol - Google Patents
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- CN113264814A CN113264814A CN202110650112.1A CN202110650112A CN113264814A CN 113264814 A CN113264814 A CN 113264814A CN 202110650112 A CN202110650112 A CN 202110650112A CN 113264814 A CN113264814 A CN 113264814A
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- 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
- C07C37/055—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 the substituted group being bound to oxygen, e.g. ether group
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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Abstract
The invention discloses a process for preparing hydroxytyrosol; the process uses piperonyl cycloxapride as an initial material, and firstly performs Friedel-crafts alkylation reaction with ethylene oxide to prepare piperonyl alcohol, and then performs catalytic hydrolysis reaction on the piperonyl alcohol to prepare hydroxytyrosol. The preparation process of hydroxytyrosol disclosed by the invention has the characteristics of easily available and cheap raw materials, simple operation process, safety, environmental friendliness and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a process for preparing hydroxytyrosol.
Background
Hydroxytyrosol is a natural polyphenol compound, has strong antioxidant activity, and is mainly present in the fruits, branches and leaves of olives in the form of esters.
Hydroxytyrosol has various biological and pharmacological activities, and has the following main effects: (1) preventing cancer, promoting cancer later stage recovery and improving chemotherapy effect; (2) preventing and treating cardiovascular and cerebrovascular diseases, and has better effect than similar medicines; (3) improving endocrine system function, promoting metabolism, and promoting wound healing; (4) eliminating free radicals in vivo, preventing cerebral failure, and delaying aging; (5) improving skin elasticity and moistening skin, removing wrinkle, and resisting aging.
Data research shows that the planting area of domestic olive is small, the yield of olive oil in 2018 in China is 4.5 ten thousand tons, the yield only accounts for 1.5 percent of the total global yield, and hydroxytyrosol obtained by extraction has high cost and small yield. The domestic hydroxytyrosol is mainly derived from chemical synthesis, and the research on the preparation of hydroxytyrosol by a chemical synthesis method has practical significance.
The applicant investigated (A) the synthesis of hydroxytyrosol, (B) the synthesis of piperonyl alcohol, which is a key intermediate, and (C) the preparation of hydroxytyrosol from piperonyl alcohol, as follows.
A. Synthetic process of hydroxytyrosol
The applicant investigated the main synthesis processes of hydroxytyrosol, of which there are four types, respectively listed in CN103038203B[1]、CN103420804B[2]、CN104030894B[3]、CN106866384B[4]The details are as follows:
guangdong-south Sha Longsha Co Ltd[1]In 2010, a process for preparing hydroxytyrosol from eugenol is provided, which comprises the following specific contents:
the method takes eugenol as an initial raw material to prepare hydroxytyrosol, the reaction process needs to be carried out at-78 ℃, the reaction condition is harsh, and reagents such as sodium borohydride and the like with higher price are also needed in the reaction process.
Roller coaster [2]In 2013, a process for preparing hydroxytyrosol by using methyl 3, 4-dihydroxyphenylacetate as a raw material is disclosed, and the specific route is as follows:
the route takes 3, 4-dihydroxy methyl phenylacetate as a starting material, the starting material is expensive, and simultaneously, sodium borohydride and other reagents with higher price are used, so that the process cost is higher.
Wake chemical Co Ltd, Germany[3]In 2014, a process for preparing hydroxytyrosol by using 3, 4-dimethoxy methyl phenylacetate as a raw material is disclosed, and the specific route is as follows:
the route takes 3, 4-dimethoxy phenylacetic acid as a starting material, the starting material is expensive, simultaneously, reagents with higher price such as dibutyl aluminum hydride and the like are used, and the process cost is higher.
SHAANXI JIAHE PHARMACEUTICAL Co.,Ltd.[4]In 2016, a process for preparing hydroxytyrosol from 3, 4-dimethoxyphenylacetic acid is disclosed, and the specific route is as follows:
the method takes 3, 4-dimethoxy phenylacetic acid as a starting material, and prepares hydroxytyrosol through esterification, reduction and demethylation reactions, wherein genotoxic reagents such as methyl sulfate and the like, and highly toxic reagents such as boron trifluoride and the like are used in the reaction process. The price of the starting material is high, the price of the reagents such as aluminum triiodide, sodium borohydride and the like is high, and the overall process cost is high. B. Preparation process of key intermediate piperonyl alcohol
The applicant searches and finishes the synthesis method of the key intermediate piperonyl alcohol of hydroxytyrosol, and mainly comprises the following steps: route 1, process for preparing piperonyl alcohol from bromopiperonyl cyclane[5-7](ii) a Route 2, process for preparing piperitolethanol from safrole[8-10](ii) a Route 3, Process for preparing piperonyl alcohol from piperonyl acetic acid[11-13]. The specific contents are as follows:
route 1:
route 2:
route 3:
in the route 1, metal magnesium is used in the reaction process, so that the cost is high, anhydrous and anaerobic conditions are required, and the operation conditions are harsh. The raw material of safrole in the route 2 is expensive, needs-78 ℃ and has harsh reaction conditions. In route 3, lithium hydride, piperonyl alcohol and other relatively expensive reagents and raw materials are used.
C. Process for preparing hydroxytyrosol from piperonyl alcohol
The applicant searches and finishes the synthesis process for preparing hydroxytyrosol by hydrolyzing pepper ethanol, and the synthesis process mainly comprises the following steps: scheme 1 boron tribromide Process[14,15](ii) a Scheme 2 metallic sodium method[16]。
Route 1:
route 2:
in the process for preparing hydroxytyrosol by hydrolyzing pepper ethanol, the route 1 adopts boron tribromide, which belongs to a highly toxic reagent and is high in price. In the scheme 2, expensive metallic sodium is used, and the reaction process needs high temperature of 170 ℃.
Reference documents:
1、CN103038203B
2、CN103420804B
3、CN104030894B
4、CN106866384B
5. yellow red clouds, forest land; novel synthesis method of 3, 4-methylenedioxyphenylethylamine
6. Study on synthetic process of hydroxytyrosol
7、He,Yun et al.A Versatile Total Synthesis of 8-Oxyberberine and Oxohomoberberines[J],Chinese Journal of Chemistry,32(11),1121-1127；2014 8、Quteishat,Laith et al.An unexpected pentacarbonyl chromium complexation of acyano group of the ABC core of cephalotaxine[J].Journal of Organometallic Chemistry,776,35-42；2015
9、Romeiro,Luiz A.S.et al.Discovery of LASSBio-772,a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties[J].European Journal of Medicinal Chemistry,46(7),3000-3012；2011
10、Cabral,Lucio M.and Barreiro,Eliezer J.Synthesis of bioactive compounds from abundant natural products.13.The synthesis and analgesic properties of new spiroisochromanyl acid derivatives synthesized from natural safrole[J].Journal of Heterocyclic Chemistry,32(3),959-62；1995
11、CN 102617543
12、Xu,Xiaoming et al.Ytterbium-Catalyzed Intramolecular[3+2]Cycloaddition based on Furan Dearomatization to Construct Fused Triazoles[J].Organic Letters,22(13),5176-5181；2020
13、Jiao,Ke-Jin et al,Nickel-Catalyzed Electrochemical Reductive Relay Cross-Coupling of Alkyl Halides to Aryl Halides[J].Angewandte Chemie,International Edition,59(16),6520-6524；2020
14、CN103664536
15、Xu,Chao et al.Process research of hydroxytyrosol synthesis[J].Jingxi Huagong,27(12),1209-1212；2010
16、WO2009153374
Disclosure of Invention
Aiming at various problems in the synthesis process, the invention provides a process for preparing hydroxytyrosol, which mainly comprises two steps, wherein in the step 1, Friedel-crafts alkylation reaction is carried out on piperonyl and ethylene oxide to directly prepare piperonyl alcohol, the process route is short, the raw materials are easy to obtain, the ethylene oxide belongs to a large chemical product, the cost is low, and the yield is high; in the step 2, the pepper ethanol is hydrolyzed under the action of a solid acid catalyst to prepare the hydroxytyrosol, the purity is higher than 98 percent, and the step avoids a highly toxic reagent and is finished under the condition of being close to room temperature. The process for preparing hydroxytyrosol integrates two-step reaction, and has the characteristics of low cost, mild reaction conditions, simple post-treatment, safety, environmental protection and the like.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the process for preparing hydroxytyrosol comprises the following reaction route:
specifically, the process for preparing hydroxytyrosol comprises the following steps:
step 1, preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol): adding piperonyl butoxide and a catalyst into a reaction flask, adding ethylene oxide for reaction at the temperature of-20-10 ℃ for 0.5-1h, quenching after the reaction is finished, and carrying out acid washing, water washing, concentration and distillation to obtain piperonyl alcohol;
step 2, preparation of 3, 4-dihydroxyphenylethanol (hydroxytyrosol): adding protonic acid, the piperonyl alcohol obtained in the step (1), a catalyst and nitrogen gas into a reaction bottle, reacting for 5-36h under the protection of 20-60 ℃, adjusting the pH to 10, washing with DCM, adjusting the pH of a water layer to 1-2, extracting with methyl tert-butyl ether, drying, decoloring and concentrating to obtain hydroxytyrosol.
As a preferred technical scheme, in the step 1, the catalyst is Lewis acid, and the Lewis acid is selected from AlBr3、AlCl3、FeCl3、SbCl5、SnCl4，BF3、TiCl4、ZnCl2A combination of one or more of the foregoing; preferably AlCl3、FeCl3More preferably AlCl3. The halide is used as a catalyst, and the reaction condition is mild.
As a preferred technical scheme of the application, in the step 1, the reaction temperature is-15 ℃ to-5 ℃, and preferably-10 ℃ to-5 ℃.
As a preferred technical scheme of the present application, in the step 1, the molar ratio of the piperonyl radicals to the catalyst is 5-10: 1, preferably 5 to 8: 1, more preferably 8: 1; the piperonyl butoxide is used as a reaction reagent and a reaction solvent, and when the feeding (molar) ratio of the piperonyl butoxide to a catalyst is less than 5, a reaction solution becomes viscous in the reaction process and is not beneficial to stirring; the molar ratio of the catalyst to ethylene oxide is 1: 1-5, more preferably 1: 3-3.5; when the feeding ratio of the ethylene oxide to the catalyst is less than 3.0, the yield is obviously reduced, and when the feeding (molar) ratio is 3.0-3.5, the yield is relatively high.
In the preferred technical scheme of the application, in the step 1, the molar ratio of the piperonyl, the catalyst and the ethylene oxide is 5-10: 1: 1-5, more preferably 8: 1: 3-3.5.
In the preferred embodiment of the present application, in step 1, ethylene oxide is added by slowly introducing ethylene oxide gas under rapid stirring.
In a preferred embodiment of the present invention, in step 1, the quenching reagent is 2M HCl.
In a preferred embodiment of the present invention, in step 2, the protonic acid is selected from one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid.
Preferably, the protic acid is hydrochloric acid.
As a preferred technical scheme of the application, the catalyst is solid strong acid or solid super acid and is selected from any one or more of HND-32 solid super acid catalyst, HND-34 solid super acid catalyst, Amberlyst15 solid strong acid catalyst, HNF-5W perfluorosulfonic acid resin and NKC-9 catalytic resin.
Preferably, the combination of protonic acid and catalyst is hydrochloric acid/Amberlyst 15 solid strong acid catalyst, hydrochloric acid/HND-32 solid super acid catalyst.
In a preferred embodiment of the present invention, in the step 2, the mass ratio of piperonyl alcohol to the catalyst is 1: 0.001-0.02, preferably 0.002-0.01.
Wherein, when Amberlyst15 solid strong acid catalyst is used as the catalyst, the mass ratio of the piperonyl alcohol to the catalyst is 1: 0.01.
wherein, when HND-32 solid super acid is used as a catalyst, the mass ratio of the piperonyl alcohol to the HND-32 solid super acid catalyst is 1: 0.002.
as a preferred technical scheme of the application, in the step 2, the reaction temperature is 20-60 ℃, preferably 20-30 ℃.
Advantageous effects
The invention provides a process for preparing hydroxytyrosol, which takes piperonyl butoxide as a starting material, prepares piperonyl alcohol by Friedel-crafts alkylation reaction with ethylene oxide, and prepares hydroxytyrosol by hydrolysis of the piperonyl alcohol. The process has the characteristics of low cost, high yield and the like:
(1) in the step 1, the reaction type, the reaction substrate and the catalyst are researched, the yield of the intermediate piperonyl alcohol is improved from about 20% to 60-70%, and meanwhile, the process has the advantages of easily available raw materials, low price, lower cost, simple operation process, safety and environmental protection;
(2) in the step 2 of the invention, the protonic acid and the fixed strong acid/solid super acid are used in combination to prepare the hydroxytyrosol, the purity is more than 98 percent, and the yield is more than 85 percent;
(3) avoids using virulent reagents such as boron bromide and the like, has low cost and mild reaction conditions, and is safer and more environment-friendly.
Drawings
FIG. 1 shows hydroxytyrosol obtained in example 8 of the present invention1H-NMR。
Detailed Description
The following non-limiting description of the present invention is provided in connection with several preferred embodiments. The reagents or instruments used are not indicated by manufacturers, and are regarded as conventional products which can be purchased in the market.
Example 1: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
At room temperature, 880.5g (7.21mol, 8eq) of piperonyl butoxide and 120.0g (0.901mol, 1.0eq) of aluminum trichloride are added into a four-necked flask, and the temperature is reduced to-10 ℃ to-5 ℃. 139.0g (3.155mol, 3.5eq) of ethylene oxide were introduced in the form of a gas and the reaction was continued for 1h after the addition. Adding 1L dichloromethane and 1.5L 2M hydrochloric acid solution into the reaction solution, stirring at room temperature for 30min, separating, washing DCM organic layer with 1M hydrochloric acid solution for 2 times, washing with water for 3 times, drying with anhydrous sodium sulfate, and filtering. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 102.0g, yield: 68.1%, HPLC purity: 98.305 percent.
Example 2: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
733.8g (6.009mol, 8eq) of piperonyl butoxide and 100.0g (0.751mol, 1.0eq) of aluminum trichloride are added into a four-necked flask at room temperature, and the temperature is reduced to-10 ℃ to-5 ℃. 99.3g (2.253mol, 3.0eq) of ethylene oxide were passed in as a gas and the reaction was continued for 1h after the addition was complete. The reaction solution was added with 800ml of dichloromethane, 1.2L of 2M hydrochloric acid solution and stirred at room temperature for 30min, the organic layer was separated, washed with 1M hydrochloric acid solution for 2 times, washed with water for 3 times, dried over anhydrous sodium sulfate and filtered. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 73.2g, yield: 58.7%, HPLC purity: 97.565 percent.
Example 3: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
542.1g (4.439mol, 8eq) of piperonyl butoxide and 90.0g (0.555mol, 1.0eq) of ferric trichloride are added into a four-necked flask at room temperature, and the temperature is reduced to-10 ℃ to-5 ℃. 85.5g (1.942mol, 3.5eq) of ethylene oxide were passed in as a gas and the reaction was continued for 1h after the addition was complete. The reaction solution was added with 800ml of dichloromethane, 1.2L of 2M hydrochloric acid solution and stirred at room temperature for 30min, the organic layer was separated, washed with 1M hydrochloric acid solution for 2 times, washed with water for 3 times, dried over anhydrous sodium sulfate and filtered. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 19.0g, yield: 20.6%, HPLC purity: 98.119 percent.
Example 4: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
At room temperature, 481.8g (3.946mol, 8eq) of piperonyl butoxide and 80.0g (0.493mol, 1.0eq) of ferric trichloride are added into a four-necked flask, and the temperature is reduced to-10 ℃ to-5 ℃. 65.2g (1.480mol, 3.0eq) of ethylene oxide were introduced in gaseous form and the reaction was continued for 1h after the addition was complete. 600ml of dichloromethane and 1.0L of 2M hydrochloric acid solution are added into the reaction solution, stirred at room temperature for 30min, separated, and the DCM organic layer is washed with 1M hydrochloric acid solution for 2 times, washed with water for 3 times, dried by anhydrous sodium sulfate and filtered. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 14.8g, yield: 18.1%, HPLC purity: 98.645 percent.
Example 5: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
183.4g (1.502mol, 4eq) of piperonyl butoxide and 50.0g (0.376mol, 1.0eq) of aluminum trichloride are added into a four-necked flask at room temperature, and the temperature is reduced to-10 ℃ to-5 ℃. 57.9g (1.314mol, 3.5eq) of ethylene oxide were passed in as a gas and the reaction was continued for 1h after the addition was complete. The reaction solution was added with 0.5L of dichloromethane and 0.75L of 2M hydrochloric acid solution and stirred at room temperature for 30min, the organic layer of the solution was separated, washed with 1M hydrochloric acid solution for 2 times, washed with water for 3 times, dried over anhydrous sodium sulfate and filtered. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 27.2g, yield: 43.6%, HPLC purity: 98.155 percent.
Example 6: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
At room temperature, 336.9g (3.004mol, 8eq) of piperonyl butoxide and 50.0g (0.376mol, 1.0eq) of aluminum trichloride were added into a four-necked flask and the temperature was reduced to-10 ℃ to-5 ℃. 33.1g (0.751mol, 2.0eq) of ethylene oxide were introduced in the form of a gas and the reaction was continued for 1h after the addition was complete. The reaction solution was added with 0.5L of dichloromethane and 0.75L of 2M hydrochloric acid solution and stirred at room temperature for 30min, the organic layer of the solution was separated, washed with 1M hydrochloric acid solution for 2 times, washed with water for 3 times, dried over anhydrous sodium sulfate and filtered. Distilling the filtrate under reduced pressure to collect piperonyl alcohol, and collecting 115-120 deg.C fraction to obtain piperonyl alcohol: 24.5g, yield: 39.3%, HPLC purity: 98.359 percent.
Example 7: preparation of 5-hydroxymethylbenzo-1, 3-dioxacyclopentane (piperonyl alcohol)
By adopting the feeding ratio and operation of example 1, when the Lewis acid is selected as BF3、ZnCl2When no product is produced; when TiCl is selected4The yield thereof was found to be 4.1%.
The feed ratio of the ethylene oxide to the catalyst is adjusted to find that the yield is obviously better than that of 3.0 when the feed ratio is 3.5; the influence of different catalysts on the yield of the piperonyl alcohol is great, and the aluminum trichloride is superior to the ferric trichloride and the other Lewis acid.
Example 8: preparation of 3, 4-dihydroxyphenylethanol (hydroxytyrosol)
55.0g (0.331mol, 1.0eq) of piperonyl ethanol, 134.2g (1.324mol, 4.0eq) of 36% hydrochloric acid, 0.55g of Amberlyst15 solid strong acid catalyst and a nitrogen protection reaction at 20-30 ℃ for 36h are added into a four-mouth bottle at room temperature. After the reaction, filtering, adjusting the pH of the filtrate to 10 with 3ml of NaOH solution in an ice water bath, washing with 150ml of DCM for 2 times, adjusting the pH of the water layer to 1-2 with 3M HCl solution, extracting with 300ml of methyl tert-butyl ether for 5 times, combining the methyl tert-butyl ether, drying with anhydrous sodium sulfate, decoloring with 5% activated carbon, concentrating by rotary evaporation to obtain orange yellow oily matter, and drying in vacuum to obtain 43.4 g. Yield 85.1%, HPLC purity: 98.858 percent.
1H NMR(DMSO-D6)δ,ppm:8.060(s,1H),6.875-6.846(m,1H),6.725-6.710(m,1H),5.989(s,2H),2.976-2.946(m,2H),2.848-2.818(m,2H).
Example 9: preparation of 3, 4-dihydroxyphenylethanol (hydroxytyrosol)
80.0g (0.481mol, 1.0eq) of piperonyl alcohol, 195.2g (1.926mol, 4.0eq) of 36% hydrochloric acid, 0.16g of HND-32 solid super acidic catalyst and the reaction at 20-30 ℃ for 28h under the protection of nitrogen are added into a four-mouth bottle at room temperature. After the reaction, filtering, adjusting the pH of the filtrate to 10 with 3ml of NaOH solution in an ice water bath, washing with 150ml of DCM for 2 times, adjusting the pH of the water layer to 1-2 with 3M HCl solution, extracting with 300ml of methyl tert-butyl ether for 5 times, combining the methyl tert-butyl ether, drying with anhydrous sodium sulfate, decoloring with 5% activated carbon, concentrating by rotary evaporation to obtain an orange-yellow oily substance, and drying in vacuum to obtain 64.8 g. Yield 87.3%, HPLC purity: 98.566 percent.
Comparative example 1: preparation of 3, 4-dihydroxyphenylethanol (hydroxytyrosol)
60.0g (0.361mol, 1.0eq) of piperonyl ethanol and 182.6g (1.083mol, 3.0eq) of 48% hydrobromic acid are added into a four-mouth bottle at room temperature, the temperature is raised to 20-30 ℃ under the protection of nitrogen, the reaction is carried out for 12h, TLC monitors that the raw materials disappear, and the reaction is finished. Adjusting the pH of a reaction solution to 10 by using 3ml of NaOH solution in an ice water bath, washing the reaction solution for 2 times by using 200ml of DCM, adjusting the pH of a water layer to 1-2 by using 3M of HCl solution, extracting 400ml of methyl tert-butyl ether for 5 times, combining methyl tert-butyl ether, drying by using anhydrous sodium sulfate, decoloring by using 5% of activated carbon, concentrating by rotary evaporation to obtain an orange-yellow oily substance, and drying in vacuum to obtain 6.5g of the orange-yellow oily substance with the yield of 11.6% and the HPLC purity: 98.232 percent.
Comparative example 2: preparation of 3, 4-dihydroxyphenylethanol (hydroxytyrosol)
Adding 50.0g (0.301mol, 1.0eq) of piperonyl ethanol and 122.0g (1.204mol, 4.0eq) of 36% hydrochloric acid into a four-port bottle at room temperature, heating to 50-60 ℃ under the protection of nitrogen, reacting for 6 hours, and finishing the reaction when the raw materials disappear as monitored by reaction TLC. The reaction solution is adjusted to pH 10 by 3ml of NaOH solution in an ice water bath, washed 2 times by 180ml of DCM, the water layer is adjusted to pH 1-2 by 3M of HCl solution, extracted 5 times by 350ml of methyl tert-butyl ether, the methyl tert-butyl ether is combined, dried by anhydrous sodium sulfate, decolored by 5% of activated carbon, concentrated by rotary evaporation to obtain orange yellow oily matter, and dried in vacuum to obtain 11.9 g. Yield 25.6%, HPLC purity: 98.686 percent.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept and the scope of the appended claims is intended to be protected.
Claims (10)
1. A process for the preparation of hydroxytyrosol, which comprises the steps of:
step 1, preparing piperonyl alcohol: adding piperonyl butoxide and a catalyst into a reaction flask, introducing ethylene oxide gas for reaction at the temperature of-20-10 ℃ for 0.5-1h, quenching after the reaction is finished, and carrying out acid washing, water washing, concentration and distillation to obtain a key intermediate piperonyl alcohol;
step 2, preparation of hydroxytyrosol: adding protonic acid, the piperonyl alcohol obtained in the step (1), a catalyst and nitrogen into a reaction bottle, and reacting for 5-36h at 20-60 ℃; adjusting pH to 10 + -0.5 after reaction, washing with DCM, adjusting pH of water layer to 1-2, extracting with methyl tert-butyl ether, drying, decolorizing, and concentrating to obtain hydroxytyrosol.
2. The process of claim 1, wherein in step 1 the catalyst is a lewis acid selected from AlBr3、AlCl3、FeCl3、SbCl5、SnCl4，BF3、TiCl4、ZnCl2Preferably AlCl3、FeCl3More preferably AlCl3。
3. The process for preparing hydroxytyrosol as claimed in claim 1 or 2, wherein the reaction temperature in step 1 is-10 to-5 ℃.
4. The process for preparing hydroxytyrosol as claimed in claim 1, wherein in the step 1, the molar ratio of the piperonyl radicals to the catalyst is 5-10: 1, preferably 5-8: 1.
5. the process of claim 1 or 4, wherein in step 1, the molar ratio of the catalyst to the ethylene oxide is 1:1 to 5, preferably 1:3 to 3.5.
6. The process of claim 1, wherein in step 2, the protic acid is selected from one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid.
7. The process of claim 6, wherein the protic acid is hydrochloric acid.
8. The process of claim 1, wherein in step 2, the catalyst is a solid strong acid or a solid super acid selected from one or more of HND-32 solid super acid catalyst, HND-34 solid super acid catalyst, Amberlyst15 solid strong acid catalyst, HNF-5W perfluorosulfonic acid resin, and NKC-9 catalyzed resin.
9. The process of claim 8, wherein the catalyst is a HND-32 solid super acid catalyst or Amberlyst15 solid strong acid catalyst.
10. The process of claim 1, wherein the combination of protic acid and catalyst is hydrochloric acid/Amberlyst 15 solid strong acid catalyst or hydrochloric acid/HND-32 solid super acid catalyst.
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| CN202110650112.1A CN113264814B (en) | 2021-06-10 | 2021-06-10 | Process for preparing hydroxytyrosol |
| PCT/CN2022/080320 WO2022257519A1 (en) | 2021-06-10 | 2022-03-11 | Process for preparing hydroxytyrosol |
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