[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2022257519A1 - 一种制备羟基酪醇的工艺 - Google Patents

一种制备羟基酪醇的工艺 Download PDF

Info

Publication number
WO2022257519A1
WO2022257519A1 PCT/CN2022/080320 CN2022080320W WO2022257519A1 WO 2022257519 A1 WO2022257519 A1 WO 2022257519A1 CN 2022080320 W CN2022080320 W CN 2022080320W WO 2022257519 A1 WO2022257519 A1 WO 2022257519A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
catalyst
hydroxytyrosol
preparing
reaction
Prior art date
Application number
PCT/CN2022/080320
Other languages
English (en)
French (fr)
Inventor
刘小红
王凡
王康
Original Assignee
南京斯贝源医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京斯贝源医药科技有限公司 filed Critical 南京斯贝源医药科技有限公司
Publication of WO2022257519A1 publication Critical patent/WO2022257519A1/zh

Links

Images

Classifications

    • 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
    • C07C37/01—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D317/54—Radicals substituted by oxygen atoms

Definitions

  • the invention belongs to the field of organic synthesis, and in particular relates to a process for preparing hydroxytyrosol.
  • Hydroxytyrosol is a natural polyphenol compound with strong antioxidant activity, mainly in the form of esters in olive fruits and leaves.
  • Hydroxytyrosol has a variety of biological and pharmacological activities, the main functions are: (1) prevent cancer, promote late cancer recovery and improve the effect of chemotherapy; (2) prevent and treat cardiovascular and cerebrovascular diseases, the effect is better than similar drugs; (3) Improve the function of the endocrine system, promote metabolism, and promote wound healing; (4) Eliminate free radicals in the body, prevent brain failure, and delay aging; (5) Enhance skin elasticity and moisture, wrinkle and anti-aging.
  • the details are as follows.
  • A the synthesis technique of hydroxytyrosol
  • This route uses eugenol as the starting material to prepare hydroxytyrosol.
  • the reaction process needs to be carried out at -78°C, the reaction conditions are harsh, and the reaction process also requires reagents such as sodium borohydride with a high price.
  • This route uses methyl 3,4-dihydroxyphenylacetate as the starting material, and the starting material is expensive, while using relatively expensive reagents such as sodium borohydride, and the process cost is relatively high.
  • the specific route is as follows:
  • This route uses 3,4-dimethoxyphenylacetic acid as the starting material, and the starting material is expensive, and simultaneously uses relatively expensive reagents such as dibutyl aluminum hydride, and the process cost is relatively high.
  • the route uses 3,4-dimethoxyphenylacetic acid as the starting material to prepare hydroxytyrosol through esterification, reduction, and demethylation reactions.
  • Genotoxic reagents such as methyl sulfate and boron trifluoride are used in the reaction process. and other highly toxic reagents.
  • the price of starting materials is high, reagents such as aluminum triiodide and sodium borohydride are expensive, and the overall process cost is relatively high.
  • the applicant has searched and sorted out the synthetic method of the key intermediate piperonyl alcohol of hydroxytyrosol, which mainly contains the following: route 1, the method [5-7] for preparing piperonyl alcohol by bromopipercycline; route 2, by safrole Method for preparing pepper ethanol [8-10] ; route 3, method for preparing pepper ethanol from pepper acetic acid [11-13] .
  • route 1 the method [5-7] for preparing piperonyl alcohol by bromopipercycline
  • route 2 by safrole Method for preparing pepper ethanol [8-10]
  • route 3 method for preparing pepper ethanol from pepper acetic acid [11-13] .
  • the specific content is as follows:
  • route 1 metal magnesium is used in the reaction process, the cost is high, anhydrous and oxygen-free conditions are required, and the operating conditions are harsh.
  • the raw material of safrole in route 2 is expensive, requires -78°C, and the reaction conditions are harsh.
  • route 3 reagents and raw materials with higher prices such as lithium hydride and pepper alcohol are used.
  • route 1 uses boron tribromide, which is a highly toxic reagent and has a high price.
  • Use expensive metal sodium in route 2 and the high temperature of 170 °C is needed in the reaction process.
  • the present invention proposes a process for preparing hydroxytyrosol, the process is mainly divided into two steps, in step 1, the Friedel-Crafts alkylation reaction of piperonyl ring and ethylene oxide directly prepares piperonyl alcohol, The process route is short, the raw materials are easy to obtain, ethylene oxide belongs to a large chemical product, the cost is low, and the yield is high; in step 2, pepper ethanol is hydrolyzed under the action of a solid acid catalyst to prepare hydroxytyrosol, and the purity is higher than 98%. To avoid highly toxic reagents, and to complete at close to room temperature.
  • the process for preparing hydroxytyrosol in the present invention combines two-step reactions, and has the characteristics of low cost, mild reaction conditions, simple aftertreatment, safety and environmental protection, and the like.
  • reaction route is as follows:
  • a kind of technique for preparing hydroxytyrosol of the present invention comprises the following steps:
  • Step 1 the preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol): add piperonyl, catalyst, and then add ethylene oxide to react in the reaction flask, and the reaction temperature is -20 ⁇ 10°C, the reaction time is 0.5-1h, quenched after the reaction is completed, pickled, washed with water, concentrated and distilled to obtain peppery alcohol;
  • Step 2 the preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol): add protonic acid, the pepper alcohol obtained in step 1, a catalyst, and react at 20-60°C under nitrogen protection for 5-36h in the reaction flask, adjust The pH was adjusted to 10, washed with DCM, the pH of the aqueous layer was adjusted to 1-2, extracted with methyl tert-butyl ether, dried, decolorized, and concentrated to obtain hydroxytyrosol.
  • the catalyst is a Lewis acid
  • the Lewis acid is selected from one of AlBr 3 , AlCl 3 , FeCl 3 , SbCl 5 , SnCl 4 , BF 3 , TiCl 4 , and ZnCl 2 A combination of one or more; preferably AlCl 3 , FeCl 3 , more preferably AlCl 3 .
  • the reaction conditions are mild.
  • the reaction temperature is -15°C to -5°C, preferably -10°C to -5°C.
  • the molar ratio of piperonyl ring to catalyst is 5-10:1, preferably 5-8:1, more preferably 8:1;
  • the mol ratio of the catalyst to ethylene oxide was 1:1-5, preferably Preferably it is 1:3-3.5; when the feed ratio of ethylene oxide to catalyst is less than 3.0, the yield will decrease obviously, and when the feed (molar) ratio is 3.0-3.5, the yield will be relatively high.
  • the molar ratio of piperonyl ring, catalyst, and ethylene oxide is 5-10:1:1-5, more preferably 8:1:3-3.5.
  • ethylene oxide is added by slowly feeding ethylene oxide gas under rapid stirring.
  • the quenching reagent is 2M HCl.
  • the protonic acid is selected from any one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid.
  • the protonic acid is hydrochloric acid.
  • the catalyst is a solid strong acid or a solid superacid, selected from HND-32 solid superacid catalyst, HND-34 solid superacid catalyst, Amberlyst15 solid strong acid catalyst, HNF-5W perfluorosulfonic acid resin , NKC-9 catalytic resin any one or more.
  • the combination of protonic acid and catalyst is hydrochloric acid/Amberlyst15 solid strong acid catalyst, hydrochloric acid/HND-32 solid super acid catalyst.
  • the mass ratio of pepper to ethanol to catalyst 1: 0.001-0.02, preferably 0.002-0.01.
  • the mass ratio of pepper to ethanol and the catalyst is 1:0.01.
  • HND-32 solid superacid when used as catalyst, the mass ratio of pepper alcohol and HND-32 solid superacid catalyst is 1:0.002.
  • the reaction temperature is 20-60°C, preferably 20-30°C.
  • the invention provides a process for preparing hydroxytyrosol.
  • piperonyl cyclocycline is used as a starting material, and ethylene oxide is reacted with Friedel-Crafts alkylation to prepare pepper ethanol, and the pepper ethanol is hydrolyzed to prepare hydroxy tyrosol.
  • the process has the characteristics of low cost and high yield:
  • step 1 of the present invention reaction type, reaction substrate, catalyst are studied, and the yield of intermediate pepper ethanol is promoted to 60-70% by about 20%, and simultaneously this process raw material is easy to get, cheap, The cost is lower, and the operation process is simple, safe and environmentally friendly;
  • step 2 of the present invention the combination of protonic acid and fixed strong acid/solid superacid is used to prepare hydroxytyrosol with a purity of more than 98% and a yield of more than 85%;
  • Fig. 1 is the 1 H-NMR of hydroxytyrosol obtained in Example 8 of the present invention.
  • Embodiment 1 the preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 2 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 3 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 4 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 5 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 6 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Embodiment 7 Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)
  • Example 1 Using the feed ratio and operation of Example 1, when the Lewis acid is selected as BF 3 and ZnCl 2 , there is no product; when TiCl 4 is selected, the yield is 4.1%.
  • Adjusting the feed ratio of ethylene oxide and catalyst can find that the yield when feed ratio is 3.5 is significantly better than that of 3.0; choosing different catalysts also has a great influence on the yield of pepper ethanol, and aluminum trichloride is better than trichloride Iron, superior to other Lewis acids.
  • Embodiment 8 Preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol)
  • Embodiment 9 Preparation of 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol)
  • reaction solution was adjusted to pH 10 with 3ml NaOH solution in an ice-water bath, washed twice with 180ml DCM, the aqueous layer was adjusted to pH 1-2 with 3M HCl solution, extracted 5 times with 350ml methyl tert-butyl ether, and combined with methyl tert-butyl ether , dried over anhydrous sodium sulfate, decolorized with 5% activated carbon, concentrated by rotary evaporation to obtain an orange-yellow oil, and dried in vacuo to obtain 11.9 g. Yield 25.6%, HPLC purity: 98.686%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种制备羟基酪醇的工艺；该工艺以胡椒环为起始物料，首先与环氧乙烷发生傅克烷基化反应制备胡椒乙醇，胡椒乙醇再经催化水解反应制备羟基酪醇。本发明所公开的羟基酪醇制备工艺，具有原料易得价廉，操作过程简单，安全环保等特点。

Description

一种制备羟基酪醇的工艺 技术领域
本发明属于有机合成领域，具体涉及一种制备羟基酪醇的工艺。
背景技术
羟基酪醇是一种天然多酚类化合物，具有很强的抗氧化活性，主要以酯类的形式存在于橄榄的果实和枝叶中。
羟基酪醇具有多种生物和药理活性，主要作用有：(1)预防癌症，促进癌症后期恢复和提高化疗效果；(2)预防与治疗心脑血管疾病，效果优于同类药品；(3)提高内分泌系统功能，促进新陈代谢，促进伤口愈合；(4)消除体内自由基，防止脑衰，延缓衰老；(5)增强皮肤弹性和润泽，除皱抗衰老。
资料调研显示，国内橄榄种植面积较小，2018年全国橄榄油产量4.5万吨，仅占全球总产量的1.5％，依靠提取获得羟基酪醇成本较高，产量较小。国内羟基酪醇的主要来源于化学合成，研究以化学合成法制备羟基酪醇具有现实意义。
申请人调研了羟基酪醇合成的工艺资料(A)，关键中间体胡椒乙醇合成的工艺资料(B)以及由胡椒乙醇制备羟基酪醇的工艺资料(C)，具体介绍如下。A、羟基酪醇的合成工艺
申请人调研了羟基酪醇的主要合成工艺，主要有四种，分别收录于CN103038203B [1]、CN103420804B [2]、CN104030894B [3]、CN106866384B [4]详细内容如下：
广东南沙龙沙有限公司 [1]于2010年提出了一种以丁子香酚制备羟基酪醇的工艺，具体内容如下：
Figure PCTCN2022080320-appb-000001
该路线以丁子香酚为起始原料制备羟基酪醇，反应过程需要在-78℃进行，反应条件苛刻，同时反应过程还需要价格较高的硼氢化钠等试剂。
凌霄 [2]等人于2013年公布了一种以3,4-二羟基苯乙酸甲酯为原料制备羟基酪醇的工艺，具体路线如下：
Figure PCTCN2022080320-appb-000002
该路线以3，4-二羟基苯乙酸甲酯为起始物料，起始物料价格昂贵同时使用了硼氢化钠等价格较高的试剂，工艺成本较高。
德国瓦克化学股份公司 [3]于2014年公布了3，4-二甲氧基苯乙酸甲酯为原料制备羟基酪醇的工艺，具体路线如下：
Figure PCTCN2022080320-appb-000003
该路线以3，4-二甲氧基苯乙酸为起始物料，起始物料价格昂贵同时使用了二丁基氢化铝等价格较高的试剂，工艺成本较高。
陕西嘉禾药业有限公司 [4]于2016年公布了一种由3，4-二甲氧基苯乙酸制备制备羟基酪醇的工艺，具体路线如下：
Figure PCTCN2022080320-appb-000004
该路线以3，4-二甲氧基苯乙酸为起始物料，经酯化，还原，脱甲基反应制备羟基酪醇，反应过程中使用了硫酸甲酯等基因毒性试剂，三氟化硼等剧毒试剂。起始物料价格较高，三碘化铝、硼氢化钠等试剂价格昂贵，整体工艺成本较高。B、关键中间体胡椒乙醇制备工艺
申请人就羟基酪醇的关键中间体胡椒乙醇的合成方法进行了检索整理，主要有以下几种：路线1、由溴代胡椒环制备胡椒乙醇的方法 [5-7]；路线2、由黄樟素制备胡椒乙醇的方法 [8-10]；路线3、胡椒乙酸制备胡椒乙醇的方法 [11-13]。具体内容如下：
Figure PCTCN2022080320-appb-000005
路线1中反应过程使用了金属镁，成本较高，需要无水无氧条件，操作条件苛刻。路线2中黄樟素原料价格昂贵，需要-78℃，反应条件苛刻。路线3中使用氢化锂、胡椒乙醇等价格较高的试剂与原料。
C、由胡椒乙醇制备羟基酪醇工艺
申请人就胡椒乙醇水解制备羟基酪醇的合成工艺进行了检索整理主要有以下几种：路线1、三溴化硼法 [14,15]；路线2、金属钠法 [16]。
Figure PCTCN2022080320-appb-000006
文献报道胡椒乙醇水解制备羟基酪醇的工艺中，路线1采用了三溴化硼，三溴化硼属于剧毒试剂，价格较高。路线2中使用价格昂贵的金属钠，反应过程需要170℃的高温。
参考文献：
1、CN103038203B
2、CN103420804B
3、CN104030894B
4、CN106866384B
5、黄红霞,林原；3,4-亚甲二氧基苯乙胺的合成新方法
6、许超等,羟基酪醇合成工艺研究
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 a cyano 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].AngewandteChemie,International Edition,59(16),6520-6524；2020
14、CN103664536
15、Xu,Chao et al.Process research of hydroxytyrosolsynthesis[J].JingxiHuagong,27(12),1209-1212；2010
16、WO2009153374
发明内容
针对以上合成工艺中的诸多问题，本发明提出了一种制备羟基酪醇的工艺，该工艺主要分为两步，步骤1中胡椒环与环氧乙烷发生傅克烷基化反应直接制备胡椒乙醇，工艺路线短，原料易得，环氧乙烷属于大化工产品，成本低，收率高；步骤2中胡椒乙醇在固体酸催化剂作用下，水解制备羟基酪醇，纯度高于98％，该步骤中避免了剧毒试剂，且在接近室温的条件下完成。本发明制备羟基酪醇的工艺，综合两步反应，具有成本低，反应条件温和，后处理简单，安全环保等特点。
本发明解决其技术问题采用的技术方案是：
本发明的一种制备羟基酪醇的工艺，反应路线如下：
Figure PCTCN2022080320-appb-000007
具体的，本发明一种制备羟基酪醇的工艺，包括如下步骤：
步骤1，5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备：向反应瓶中加入胡椒环，催化剂，再加入环氧乙烷反应，反应温度为-20～10℃，反应时间0.5-1h，反应结束后猝灭，经酸洗，水洗，浓缩，蒸馏，得到胡椒乙醇；
步骤2，3,4-二羟基苯乙醇(羟基酪醇)的制备：向反应瓶中加入质子酸、步骤1所得的胡椒乙醇、催化剂、氮气保护下20～60℃，反应5-36h，调节pH至10，DCM洗涤，水层调节pH至1-2，甲基叔丁基醚萃取，干燥，脱色，浓缩得羟基酪醇。
作为本申请的优选技术方案，所述步骤1中，催化剂为路易斯酸，所述路易斯酸选自AlBr 3、AlCl 3、FeCl 3、SbCl 5、SnCl 4，BF 3、TiCl 4、ZnCl 2中一种或多种的组合；优选为AlCl 3、FeCl 3，更优选为AlCl 3。采用卤化物作为催化剂，反应条件温和。
作为本申请的优选技术方案，所述步骤1中，反应温度为-15℃～-5℃,优选为-10℃～-5℃。
作为本申请的优选技术方案，所述步骤1中，胡椒环与催化剂的摩尔比为5-10：1，优选为5-8：1，更优选为8：1；胡椒环既作为反应试剂又作为反应溶 剂，当胡椒环与催化剂投料(摩尔)比小于5时，反应过程中反应液变得粘稠不利于搅拌；所述催化剂与环氧乙烷的摩尔比为1：1-5，更优选为1：3-3.5；当环氧乙烷与催化剂投料比小于3.0时，收率明显降低，投料(摩尔)比3.0～3.5时，收率相对较高。
作为本申请的优选技术方案，所述步骤1中，胡椒环、催化剂、环氧乙烷的摩尔比为5-10：1：1-5，更优选为8：1：3-3.5。
作为本申请的优选技术方案，所述步骤1中，环氧乙烷通过在快速搅拌下缓慢通入环氧乙烷气体的方式加入。
作为本申请的优选技术方案，所述步骤1中，猝灭试剂为2M HCl。
作为本申请的优选技术方案，所述步骤2中，质子酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸中的任一种或多种。
优选的，所述质子酸为盐酸。
作为本申请的优选技术方案，所述催化剂为固体强酸或固体超强酸，选自HND-32固体超强酸催化剂、HND-34固体超强酸催化剂、Amberlyst15固体强酸催化剂、HNF-5W全氟磺酸树脂、NKC-9催化树脂任一种或多种。
优选的，质子酸与催化剂的组合为盐酸/Amberlyst15固体强酸催化剂、盐酸/HND-32固体超强酸催化剂。
作为本申请的优选技术方案，所述步骤2中，胡椒乙醇、催化剂质量比＝1：0.001-0.02，优选为0.002-0.01。
其中，当以Amberlyst15固体强酸催化剂为催化剂时，胡椒乙醇、催化剂质量比为1：0.01。
其中，当以HND-32固体超强酸为催化剂时，胡椒乙醇、HND-32固体超强酸催化剂质量比为1：0.002。
作为本申请的优选技术方案，所述步骤2中，所述反应温度为20-60℃，优选20-30℃。
有益效果
本发明提供的一种制备羟基酪醇的工艺，该工艺以胡椒环为起始物料，与环氧乙烷经傅克烷基化反应制备胡椒乙醇，胡椒乙醇经水解制备羟基酪醇。该工艺具有成本低，收率高等特点：
(1)本发明步骤1中，对反应类型、反应底物、催化剂进行研究，将中间体胡椒乙醇的收率由20％左右提升至60-70％，同时该工艺原料易得、价格低廉，成本更低，且操作过程简单，安全环保；
(2)本发明步骤2中，将质子酸和固定强酸/固体超强酸组合使用，制备羟基酪醇，纯度在98％以上，收率在85％以上；
(3)避免使用溴化硼等剧毒试剂，成本低，反应条件温和且更加安全环保。
附图说明
图1是本发明实施例8所得羟基酪醇的 1H-NMR。
具体实施方式
以下结合数个较佳实施案例对本发明技术方案坐进一步非限制性的说明。所用试剂或者仪器设备未注明生产厂商的，均视为可以通过市场购买的常规产品。
实施例1：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入880.5g(7.21mol，8eq)胡椒环，120.0g(0.901mol，1.0eq)三氯化铝，降温至-10℃至-5℃。以气体形式通入139.0g(3.155mol，3.5eq)环氧乙烷，加入完毕继续反应1h。反应液加入1L二氯甲烷，1.5L 2M盐酸溶液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：102.0g，收率：68.1％，HPLC纯度：98.305％。
实施例2：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入733.8g(6.009mol，8eq)胡椒环，100.0g(0.751mol，1.0eq)三氯化铝，降温至-10℃至-5℃。以气体形式通入99.3g(2.253mol，3.0eq)环氧乙烷，加入完毕继续反应1h。反应液加入800ml二氯甲烷，1.2L 2M盐酸溶液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：73.2g，收率：58.7％，HPLC纯度：97.565％。
实施例3：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入542.1g(4.439mol，8eq)胡椒环，90.0g(0.555mol，1.0eq)三氯化铁，降温至-10℃至-5℃。以气体形式通入85.5g(1.942mol，3.5eq)环氧乙烷，加入完毕继续反应1h。反应液加入800ml二氯甲烷，1.2L 2M盐酸溶 液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：19.0g，收率：20.6％，HPLC纯度：98.119％。
实施例4：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入481.8g(3.946mol，8eq)胡椒环，80.0g(0.493mol，1.0eq)三氯化铁，降温至-10℃至-5℃。以气体形式通入65.2g(1.480mol，3.0eq)环氧乙烷，加入完毕继续反应1h。反应液加入600ml二氯甲烷，1.0L 2M盐酸溶液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：14.8g，收率：18.1％，HPLC纯度：98.645％。
实施例5：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入183.4g(1.502mol，4eq)胡椒环，50.0g(0.376mol，1.0eq)三氯化铝，降温至-10℃至-5℃。以气体形式通入57.9g(1.314mol，3.5eq)环氧乙烷，加入完毕继续反应1h。反应液加入0.5L二氯甲烷，0.75L 2M盐酸溶液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：27.2g，收率：43.6％，HPLC纯度：98.155％。
实施例6：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
室温下，向四颈瓶中加入336.9g(3.004mol，8eq)胡椒环，50.0g(0.376mol，1.0eq)三氯化铝，降温至-10℃至-5℃。以气体形式通入33.1g(0.751mol，2.0eq)环氧乙烷，加入完毕继续反应1h。反应液加入0.5L二氯甲烷，0.75L 2M盐酸溶液室温搅拌30min，分液，DCM有机层分别以1M盐酸溶液洗涤2次，水洗3次，无水硫酸钠干燥，过滤。滤液减压蒸馏收胡椒环，收集115-120℃馏分，得胡椒乙醇：24.5g，收率：39.3％，HPLC纯度：98.359％。
实施例7：5-羟甲基苯并-1,3-二恶环戊烷(胡椒乙醇)的制备
采用实施例1投料比与操作，当选用路易斯酸为BF 3、ZnCl 2时，无产物；当选用TiCl 4时，收率为4.1％。
调整环氧乙烷与催化剂的投料比可以发现，投料比3.5时的收率显著优于3.0时；选择不同的催化剂对胡椒乙醇收率的影响也很大，三氯化铝优于三氯化铁， 优于其他路易斯酸。
实施例8：3,4-二羟基苯乙醇(羟基酪醇)的制备
室温下向四口瓶中加入55.0g(0.331mol，1.0eq)胡椒乙醇，134.2g(1.324mol，4.0eq)36％盐酸，Amberlyst15固体强酸催化剂0.55g，氮气保护下20-30℃反应36h。反应结束，过滤，滤液以3ml NaOH溶液在冰水浴下调节pH至10，以150ml DCM洗涤2次，水层以3M HCl溶液调节pH至1-2，300ml甲基叔丁基醚萃取5次，合并甲基叔丁基醚，无水硫酸钠干燥，5％活性炭脱色，旋转蒸发浓缩得橙黄色油状物，真空干燥得43.4g。收率85.1％，HPLC纯度：98.858％。
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).
实施例9：3,4-二羟基苯乙醇(羟基酪醇)的制备
室温下向四口瓶中加入80.0g(0.481mol，1.0eq)胡椒乙醇，195.2g(1.926mol，4.0eq)36％盐酸，HND-32固体超强酸催化剂0.16g，氮气保护下20-30℃反应28h。反应结束，过滤，滤液以3ml NaOH溶液在冰水浴下调节pH至10，以150ml DCM洗涤2次，水层以3M HCl溶液调节pH至1-2，300ml甲基叔丁基醚萃取5次，合并甲基叔丁基醚，无水硫酸钠干燥，5％活性炭脱色，旋转蒸发浓缩得橙黄色油状物，真空干燥得64.8g。收率87.3％，HPLC纯度：98.566％。
对比例1：3,4-二羟基苯乙醇(羟基酪醇)的制备
室温下向四口瓶中加入60.0g(0.361mol，1.0eq)胡椒乙醇，182.6g(1.083mol，3.0eq)48％氢溴酸，氮气保护下升温至20-30℃，反应12h，TLC监控原料消失，反应结束。反应液以3mlNaOH溶液在冰水浴下调节pH至10，以200mlDCM洗涤2次，水层以3MHCl溶液调节pH至1-2，400ml甲基叔丁基醚萃取5次，合并甲基叔丁基醚，无水硫酸钠干燥，5％活性炭脱色，旋转蒸发浓缩得橙黄色油状物，真空干燥得6.5g，收率11.6％，HPLC纯度：98.232％。
对比例2：3,4-二羟基苯乙醇(羟基酪醇)的制备
室温下向四口瓶中加入50.0g(0.301mol，1.0eq)胡椒乙醇，122.0g(1.204mol，4.0eq)36％盐酸，氮气保护下升温至50-60℃，反应6h，反应TLC监控原料消失时，反应结束。反应液以3mlNaOH溶液在冰水浴下调节pH至10，以180mlDCM洗涤2次，水层以3MHCl溶液调节pH至1-2，350ml甲基叔丁基醚萃取5次， 合并甲基叔丁基醚，无水硫酸钠干燥，5％活性炭脱色，旋转蒸发浓缩得橙黄色油状物，真空干燥得11.9g。收率25.6％，HPLC纯度：98.686％。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求为保护范围。

Claims (10)

  1. 一种制备羟基酪醇的工艺，其特征在于，包括如下步骤：
    步骤1，胡椒乙醇的制备：向反应瓶中加入胡椒环、催化剂，再通入环氧乙烷气体反应，反应温度为-20～10℃，反应时间0.5-1h，反应结束后猝灭，再经酸洗、水洗、浓缩、蒸馏，得到关键中间体胡椒乙醇；
    步骤2，羟基酪醇的制备：向反应瓶中加入质子酸、步骤1所得的胡椒乙醇、催化剂、氮气保护下20～60℃，反应5-36h；反应结束后调节pH至10±0.5，DCM洗涤，水层调节pH至1-2，再以甲基叔丁基醚萃取，干燥，脱色，浓缩得羟基酪醇。
  2. 根据权利要求1所述的制备羟基酪醇的工艺，其特征在于，步骤1中，所述催化剂为路易斯酸，选自AlBr 3、AlCl 3、FeCl 3、SbCl 5、SnCl 4，BF 3、TiCl 4、ZnCl 2中一种或多种的组合，优选为AlCl 3、FeCl 3，更优选为AlCl 3。
  3. 根据权利要求1或2所述的制备羟基酪醇的工艺，其特征在于，步骤1中，所述反应温度为-10～-5℃。
  4. 根据权利要求1所述的制备羟基酪醇的工艺，其特征在于，步骤1中，胡椒环与催化剂的摩尔比为5～10:1，优选为5～8：1。
  5. 根据权利要求1或4所述的制备羟基酪醇的工艺，其特征在于，步骤1中，所述催化剂与环氧乙烷的摩尔比为1:1～5，优选为1:3～3.5。
  6. 根据权利要求1所述的制备羟基酪醇的工艺，其特征在于，步骤2中，所述质子酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸中的任一种或多种。
  7. 根据权利要求6所述的制备羟基酪醇的工艺，其特征在于，所述质子酸为盐酸。
  8. 根据权利要求1所述的制备羟基酪醇的工艺，其特征在于，步骤2中，所述催化剂为固体强酸或固体超强酸，选自HND-32固体超强酸催化剂、HND-34固体超强酸催化剂、Amberlyst15固体强酸催化剂、HNF-5W全氟磺酸树脂、NKC-9催化树脂任一种或多种。
  9. 根据权利要求8所述的制备羟基酪醇的工艺，其特征在于，所述催化剂为HND-32固体超强酸催化剂或Amberlyst15固体强酸催化剂。
  10. 根据权利要求1所述的制备羟基酪醇的工艺，其特征在于，质子酸与催化剂的组合为盐酸/Amberlyst15固体强酸催化剂，或盐酸/HND-32固体超强酸催化剂。
PCT/CN2022/080320 2021-06-10 2022-03-11 一种制备羟基酪醇的工艺 WO2022257519A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110650112.1A CN113264814B (zh) 2021-06-10 2021-06-10 一种制备羟基酪醇的工艺
CN202110650112.1 2021-06-10

Publications (1)

Publication Number Publication Date
WO2022257519A1 true WO2022257519A1 (zh) 2022-12-15

Family

ID=77234800

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/080320 WO2022257519A1 (zh) 2021-06-10 2022-03-11 一种制备羟基酪醇的工艺

Country Status (2)

Country Link
CN (1) CN113264814B (zh)
WO (1) WO2022257519A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116730824A (zh) * 2023-08-11 2023-09-12 山东国邦药业有限公司 一种2,4,5-三氟苯乙酸的合成方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264814B (zh) * 2021-06-10 2022-07-26 南京斯贝源医药科技有限公司 一种制备羟基酪醇的工艺

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009153374A1 (es) * 2008-06-20 2009-12-23 Universidad De Granada Procedimiento para la preparación de hidroxitirosol y 3-(3,4-dihidroxifenil)propanol a partir de metilendioxibencenos
CN103038203A (zh) * 2010-07-06 2013-04-10 广州龙沙研究开发中心 用于制备羟基酪醇的方法
CN103080056A (zh) * 2010-07-15 2013-05-01 广州龙沙研究开发中心 使用有机金属化合物制备羟基酪醇的方法
CN103420804A (zh) * 2013-05-24 2013-12-04 凌霄 一种制备高纯度羟基酪醇的方法
CN103664536A (zh) * 2012-09-17 2014-03-26 天津科技大学 一种羟基酪醇的合成方法
CN104030894A (zh) * 2013-03-05 2014-09-10 瓦克化学股份公司 用于制备羟基酪醇的方法
CN106866384A (zh) * 2016-12-29 2017-06-20 陕西嘉禾药业有限公司 一种羟基酪醇的制备方法
CN108250175A (zh) * 2018-02-05 2018-07-06 杭州更蓝生物科技有限公司 一种佳乐麝香的合成工艺
CN113264814A (zh) * 2021-06-10 2021-08-17 南京斯贝源医药科技有限公司 一种制备羟基酪醇的工艺

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109081769A (zh) * 2017-06-13 2018-12-25 苏州蘅盛生物医药科技有限公司 羟基酪醇的合成工艺
CN110128246B (zh) * 2019-06-10 2022-07-26 杭州志源生物科技有限公司 一种羟基酪醇的制备方法
CN112457171B (zh) * 2020-12-14 2021-05-14 深圳市迪克曼科技开发有限公司 一种羟基酪醇的合成方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009153374A1 (es) * 2008-06-20 2009-12-23 Universidad De Granada Procedimiento para la preparación de hidroxitirosol y 3-(3,4-dihidroxifenil)propanol a partir de metilendioxibencenos
CN103038203A (zh) * 2010-07-06 2013-04-10 广州龙沙研究开发中心 用于制备羟基酪醇的方法
CN103080056A (zh) * 2010-07-15 2013-05-01 广州龙沙研究开发中心 使用有机金属化合物制备羟基酪醇的方法
CN103664536A (zh) * 2012-09-17 2014-03-26 天津科技大学 一种羟基酪醇的合成方法
CN104030894A (zh) * 2013-03-05 2014-09-10 瓦克化学股份公司 用于制备羟基酪醇的方法
CN103420804A (zh) * 2013-05-24 2013-12-04 凌霄 一种制备高纯度羟基酪醇的方法
CN106866384A (zh) * 2016-12-29 2017-06-20 陕西嘉禾药业有限公司 一种羟基酪醇的制备方法
CN108250175A (zh) * 2018-02-05 2018-07-06 杭州更蓝生物科技有限公司 一种佳乐麝香的合成工艺
CN113264814A (zh) * 2021-06-10 2021-08-17 南京斯贝源医药科技有限公司 一种制备羟基酪醇的工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XU CHAO, GAO JUN-CHAO,ZHANG JIAN,JIANG SHEN-DE: "Process Research of Hydroxytyrosol Synthesis", FINE CHEMICALS, vol. 27, no. 12, 31 December 2010 (2010-12-31), pages 1209 - 1212, XP093014160, ISSN: 1003-5214, DOI: 10.13550/j.jxhg.2010.12.011 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116730824A (zh) * 2023-08-11 2023-09-12 山东国邦药业有限公司 一种2,4,5-三氟苯乙酸的合成方法
CN116730824B (zh) * 2023-08-11 2023-10-17 山东国邦药业有限公司 一种2,4,5-三氟苯乙酸的合成方法

Also Published As

Publication number Publication date
CN113264814A (zh) 2021-08-17
CN113264814B (zh) 2022-07-26

Similar Documents

Publication Publication Date Title
WO2022257519A1 (zh) 一种制备羟基酪醇的工艺
CN101786942B (zh) 2,4-二氯-10,11-二氢-5H-二苯并[a,d]环庚烯-5-醇的制备方法
CN113248432B (zh) 高收率制备罗沙司他中间体的新方法
CN113773204A (zh) 一种氟代苯胺的制备方法
CN113045389B (zh) 一种9,9-双(甲氧基甲基)芴的合成方法
CN103360264A (zh) 茚达特罗氨基片段5,6-二乙基-2,3-二氢-1h-茚-2-胺盐酸盐的合成方法
CN101575348A (zh) 一种β-甘油磷酸钠的合成方法
CN112939738B (zh) 一种3，5-二羟基戊苯的制备方法
CN111100042B (zh) 一种2-甲氧基-5-磺酰胺基苯甲酸的制备方法
CN102936205B (zh) 一种他喷他多的合成方法
CN107573230A (zh) 一种对溴甲基苯丙酸的合成方法
CN111116493B (zh) 一种制备Apabetalone的方法、中间体及其中间体的制备方法
CN113262816B (zh) 一种催化体系及其用于合成苯并[1,2-b:4,5-b’]二苯并呋喃的方法
CN109942382B (zh) 一种香兰醇醚的合成方法
CN110128246A (zh) 一种羟基酪醇的制备方法
CN101270048B (zh) 1-氯-2-甲基-4-乙酰氧基-2-丁烯的合成方法
CN110790734A (zh) 一种苯并呋喃-2-(3h)-酮的制备方法
CN114524767B (zh) 立他司特中间体5,7-二氯-1,2,3,4-四氢异喹啉盐酸盐的合成方法
CN116082163B (zh) 一种3’,4’-二氟-2’-胺基联苯的制备方法
CN111302930B (zh) 一种对苯丁氧基苯甲酸的制备方法
CN113121578B (zh) 苯并硼唑类化合物的制备方法
CN112266360B (zh) 一种高纯度组胺二盐酸盐的合成方法
CN111825688B (zh) 一种6-叔丁基-3’,3’,3-三甲基吡喃[3,2-a]咔唑的制备方法
CN112321430A (zh) 一种环己基乙烯的制备方法
CN112694497A (zh) 一种4-异丙基磺酰基苯硼酸的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22819124

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22819124

Country of ref document: EP

Kind code of ref document: A1