WO2019080682A1 - 一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法 - Google Patents

一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法

Info

Publication number
WO2019080682A1
WO2019080682A1 PCT/CN2018/106953 CN2018106953W WO2019080682A1 WO 2019080682 A1 WO2019080682 A1 WO 2019080682A1 CN 2018106953 W CN2018106953 W CN 2018106953W WO 2019080682 A1 WO2019080682 A1 WO 2019080682A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methoxymethyl
hydroxyphenyl
weight
methoxymethoxy
Prior art date
Application number
PCT/CN2018/106953
Other languages
English (en)
French (fr)
Inventor
赵云丽
于治国
孟琳
Original Assignee
沈阳药科大学
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 沈阳药科大学 filed Critical 沈阳药科大学
Publication of WO2019080682A1 publication Critical patent/WO2019080682A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • the present invention relates to the field of pharmaceutical synthesis, and in particular, to a method for synthesizing 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one.
  • Tumor is one of the major diseases that endanger human health and ranks second in all kinds of disease mortality.
  • the continuous deterioration of the environment has led to an increase in the incidence of cancer.
  • Pharmacological studies have confirmed that curcuminoid compounds have a wide range of biological activities, and have significant preventive and therapeutic effects on various physiological diseases such as cancer, neurological diseases, cardiovascular diseases, metabolic diseases, and inflammation. Among them, anti-cancer activity has attracted much attention. Curcumin can inhibit the growth of a variety of tumor cells, has a wide anti-cancer spectrum, and has few toxic and side effects.
  • curcumin As the third-generation cancer chemopreventive drug.
  • 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one is a curcuminoid compound having good antitumor activity extracted from mistletoe, and Compared with curcumin, it has higher bioavailability, better stability and better anticancer activity: it has a good inhibitory effect on various cancer cell lines.
  • the IC50 of breast cancer SKBr3 cell line can reach 1.7 nmol/L.
  • a promising anti-tumor drug candidate. This compound is represented by Structural Formula 1.
  • 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one is only naturally occurring and can only be obtained by extraction, separation and purification of mistletoe, and purity exists.
  • the object of the present invention is to synthesize a curcumin analog 1,7-di-(4-hydroxyphenyl)-heptane which has superior activity for the treatment of breast cancer with p-hydroxyphenylpropionic acid and p-hydroxybenzaldehyde as starting materials. -1,4-dien-3-one, and its activity is superior to the natural product curcumin.
  • the present invention is implemented as follows:
  • a method for synthesizing 1,7-bis-(4-hydroxyphenyl)-heptane-1,4-dien-3-one, with 3-(4-hydroxyphenyl)propionic acid and 4-hydroxybenzene Formaldehyde is the raw material, and the steps are as follows:
  • step (1) includes the following steps:
  • the reaction temperature of the step (1) is +20 to +80 ° C, and the reaction time is 2 to 4 hours;
  • the weight-to-volume ratio (g/mL) of 3-(4-hydroxyphenyl)propionic acid to methanol or ethanol in the step (1) is 1:2.5-10;
  • the reaction temperature of the step (2) is +40 to +65 ° C, the reaction time is 4 to 5 h, and N,N-diisopropylethylamine is used as a catalyst;
  • the weight-to-volume ratio (g/mL) of methyl 3-(4-hydroxyphenyl)propionate to bromomethyl methyl ether or chloromethyl methyl ether in step (2) is 1:0.5-1.3; catalyst and 3
  • the weight-to-volume ratio of methyl (4-hydroxyphenyl)propionate is 1: 12.2-2.7.
  • the reaction temperature of the step (3) is 0 to +35 ° C, and the reaction time is 1.5 to 2.5 h;
  • the weight ratio (g/g) of methyl 3-(4-(methoxymethyl)phenyl)propanoate and the lithium aluminum hydride in the step (3) is 1:0.4-1.5;
  • the reaction temperature of the step (4) is -80 to -60 ° C, and the reaction time is 2 to 8 h;
  • the weight-to-volume ratio (g/mL) of 3-(4-(methoxymethyl)phenyl)propan-1-ol to oxalyl chloride in the step (4) is: 1:0.7-1.4; 3-(4- (Methoxymethyl)phenyl)propan-1-ol and dimethyl sulfoxide weight-to-volume ratio (g/mL): 1:1.1-2.2; 3-(4-(methoxymethyl)phenyl ⁇ -1-ol and triethylamine weight-to-volume ratio (g / mL): 1:3.1-6.2;
  • Step (2) includes the following steps:
  • the reaction temperature of the step (1) is +40 to +65 ° C, and the reaction time is 4 to 5 hours;
  • the weight-to-volume ratio (g/mL) of 4-hydroxybenzaldehyde to N,N-diisopropylethylamine in the step (1) is: 1:1.16-2.76; the weight of 4-hydroxybenzaldehyde and anhydrous potassium carbonate
  • the ratio (g/g) is: 1:5.6-13.6; the weight-to-volume ratio (g/mL) of 4-hydroxybenzaldehyde to bromomethyl methyl ether or chloromethyl methyl ether is 1:0.6-1.6;
  • the reaction temperature of the step (2) is +20 to +65 ° C, and the reaction time is 1 to 4 hours;
  • the weight-to-volume ratio (g/mL) of 4-(methoxymethyl)benzaldehyde to acetone in the step (2) is: 1:10-40; 4-(methoxymethyl)benzaldehyde and 1-
  • the weight ratio (g/g) of (triphenylphosphine)-2-propanone is: 1:1.2-2.4;
  • Step (3) includes the following steps:
  • the reaction temperature of the step (1) is -80 to -60 ° C, the reaction time is 1.5 to 2.5 h, and lithium N,N-diisopropylamide is used as a base;
  • the reaction temperature of the step (2) is 0 to +65 ° C, and the reaction time is 30 min to 1 h;
  • Weight-to-volume ratio of (1E,4E)-1,7-bis(4-(methoxymethoxy)phenyl)hepta-1,4-dien-3-one to hydrochloric acid in step (2) (g) /mL) is: 1:5-30; (1E, 4E)-1,7-bis(4-(methoxymethoxy)phenyl)heptan-1,4-dien-3-one and The weight ratio (g/g) of toluenesulfonic acid was 1:0.1-0.3.
  • the invention provides a novel preparation method for preparing 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one, which is simple and easy to operate.
  • the high yield and high purity fill the gap in the efficient preparation of this compound.
  • the invention uses 3-(4-hydroxyphenyl)propionic acid and 4-hydroxybenzaldehyde as raw materials to synthesize 1,7-di-(4-hydroxyphenyl)-heptane-1,4- by a total of 8 steps. Dien-3-one, the specific route is as follows.
  • 3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in methanol (40 mL), and concentrated with concentrated sulfuric acid (0.4 mL), and reacted at 35 ° C for 4 h. After adding 10 mL of water, the pH was adjusted to 6 with saturated sodium bicarbonate, and extracted with EtOAc EtOAc (EtOAc) Methyl hydroxyphenyl) propionate.
  • Lithium tetrahydrogen aluminum (1.5 g, 40.18 mmol) was dispersed in tetrahydrofuran (50 mL) under ice-water bath, and methyl 3-(4-(methoxymethyl)phenyl)propanoate was slowly added dropwise with stirring.
  • Oxalyl chloride (1 mL, 10.33 mmol) was added to 50 mL of dichloromethane, the system was cooled to below -60 ° C, dimethyl sulfoxide (1.6 mL, 20.66 mmol) was dissolved in 20 mL of dichloromethane and slowly added dropwise.
  • dimethyl sulfoxide 1.6 mL, 20.66 mmol
  • 3-(4-(methoxymethyl)phenyl)propan-1-ol 1.5 g, 7.65 mmol
  • Triethylamine (4.6 mL, 30.61 mmol) was slowly added dropwise, stirred for 0.5 h, warmed to 0 ° C, 30 mL of water was added, and the solution was separated, the organic layer was taken, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The dichloromethane was removed under reduced pressure to give 3-(4-(methoxymethyl)phenyl)propanal.
  • 3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in ethanol (40 mL), and concentrated with concentrated sulfuric acid (0.4 mL), and reacted at 35 ° C for 4 h, and concentrated to remove some methanol under reduced pressure. After adding 10 mL of water, the pH was adjusted to 6 with saturated sodium bicarbonate, and extracted with EtOAc EtOAc (EtOAc) Ethyl hydroxyphenyl) propionate.
  • EtOAc EtOAc
  • Lithium tetrahydrogen aluminum (1.5 g, 40.18 mmol) was dispersed in tetrahydrofuran (50 mL) under ice-water bath, and methyl 3-(4-(methoxymethyl)phenyl)propanoate B was slowly added dropwise with stirring.
  • Oxalyl chloride (2 mL, 20.66 mmol) was added to 50 mL of dichloromethane, the system was cooled to below -60 ° C, dimethyl sulfoxide (3.2 mL, 41.32 mmol) was dissolved in 40 mL of dichloromethane and slowly added dropwise.
  • dimethyl sulfoxide 3.2 mL, 41.32 mmol
  • 3-(4-(methoxymethyl)phenyl)propan-1-ol 1.5 g, 7.65 mmol
  • Triethylamine (9.2 mL, 61.22 mmol) was slowly added dropwise, stirred for 0.5 h, warmed to 0 ° C, then water (60 mL) was added and the mixture was partitioned. The organic layer was taken and washed three times with 20 mL of saturated brine and dried over anhydrous sodium sulfate. The dichloromethane was removed under reduced pressure to give 3-(4-(methoxymethyl)phenyl)propanal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及药物合成领域，涉及一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法。一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法，以3-(4-羟基苯基)丙酸和4-羟基苯甲醛为原料，其步骤是：(一)3-(4-羟基苯基)丙酸为原料，经过酯化、甲基保护、还原、氧化得3-(4-(甲氧基甲基)苯基)丙醛；(二)4-羟基苯甲醛经过醚化、羟醛缩合反应得4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮；(三)将4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮和3-(4-(甲氧基甲氧基)苯基)丙醛进行羟醛缩合，再与盐酸反应，得到1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮。该方法简单，易操作，收率高，纯度高。

Description

一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法 技术领域
本发明涉及药物合成领域，具体地，本发明涉及一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法。
背景技术
肿瘤是危害人类健康的主要疾病之一,居各类疾病死亡率的第二位。近年来环境的不断恶化引发肿瘤发病率不断升高,寻找一种安全、高效的肿瘤预防与治疗药物迫在眉睫。药理研究证实，姜黄素类化合物有着广泛的生物活性，对癌症、神经性疾病、心血管疾病、代谢疾病、炎症等多种生理疾病有着显著的预防和治疗效果。其中，抗癌活性备受关注，姜黄素可以抑制多种肿瘤细胞的生长，抗癌谱广，毒副作用小，可作为抗突变剂以及抗促癌剂，对肿瘤的发生、发展多阶段均有明显的抑制效果，对同一肿瘤同时发挥多种效能，且研究表明，姜黄素类化合物对多药耐药性具有良好的逆转效果。美国国立肿瘤研究所己将姜黄素列为第3代癌化学预防药。
1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮是一种在槲寄生中提取到的具有较好抗肿瘤活性的姜黄素类化合物，并与姜黄素对比，其生物利用度更高、稳定性更好，抗癌活性更好：对多种癌细胞株具有良好的抑制作用，乳腺癌SKBr3细胞株IC50更能达到1.7nmol/L，是一种极具前景的抗肿瘤药物候选物。该化合物为结构式1表示。
Figure PCTCN2018106953-appb-000001
目前，1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮仅天然存在，仅能通过对槲寄生的提取、分离、纯化获得，存在着纯度低、含量少、提纯难、价格昂贵等缺点，因此，研究开发一条简单的合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法、使其能够化学合成乃至大规模生产非常重要。
发明内容
本发明目的在于以对羟基苯丙酸和对羟基苯甲醛作为起始原料，合成出对乳腺癌治疗具有优越活性的姜黄素类似物1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮，并且其活性优越于天然产物姜黄素。
本发明是这样实现的：
一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法，以3-(4-羟基苯基)丙酸和4-羟基苯甲醛为原料，其步骤是：
(一)3-(4-羟基苯基)丙酸为原料，经过酯化、甲基保护、还原、氧化得3-(4-(甲氧基甲基)苯基)丙醛；
(二)4-羟基苯甲醛经过醚化、羟醛缩合反应得4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮；
(三)将4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮和3-(4-(甲氧基甲氧基)苯基)丙醛进行羟醛缩合，再与盐酸反应，得到1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮。
具体地，步骤(一)包括如下步骤：
(1)以3-(4-羟基苯基)丙酸和甲醇或乙醇进行酯化反应得到3-(4-羟基苯基)丙酸甲酯或3-(4-羟基苯基)丙酸乙酯；
(2)将3-(4-羟基苯基)丙酸甲酯与溴甲基甲醚或氯甲基甲醚反应添加甲氧甲基保护基得到甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯；
(3)将甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯用四氢锂铝还原得到3-(4-(甲氧基甲基)苯基)丙-1-醇；
(4)将3-(4-(甲氧基甲基)苯基)丙-1-醇与草酰氯、二甲基亚砜反应氧化，以三乙胺游离出产物，得到3-(4-(甲氧基甲基)苯基)丙醛。
步骤(1)的反应温度为+20～+80℃，反应时间为2～4h；
步骤(1)中3-(4-羟基苯基)丙酸与甲醇或乙醇的重量体积比(g/mL)为：1：2.5-10；
步骤(2)的反应温度为+40～+65℃，反应时间为4～5h，使用N,N-二异丙基乙胺作为催化剂；
步骤(2)中3-(4-羟基苯基)丙酸甲酯与溴甲基甲醚或氯甲基甲醚的重量体积比(g/mL)为：1：0.5-1.3；催化剂与3-(4-羟基苯基)丙酸甲酯的重量体积比为：1：1.2-2.7。
步骤(3)的反应温度为0～+35℃，反应时间为1.5～2.5h；
步骤(3)中甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯与四氢锂铝的重量比(g/g)为：1：0.4-1.5；
步骤(4)的反应温度为-80～-60℃，反应时间为2～8h；
步骤(4)中3-(4-(甲氧基甲基)苯基)丙-1-醇与草酰氯的重量体积比(g/mL)为：1：0.7-1.4；3-(4-(甲氧基甲基)苯基)丙-1-醇与二甲基亚砜重量体积比(g/mL)：1：1.1-2.2；3-(4-(甲氧基甲基)苯基)丙-1-醇与三乙胺重量体积比(g/mL)：1：3.1-6.2；
步骤(二)包括如下步骤：
(1)将4-羟基苯甲醛在无水碳酸钾或N,N-二异丙基乙胺的催化下与溴甲基甲醚或氯甲基甲醚反应得到羟基保护的4-(甲氧基甲基)苯甲醛；
(2)以4-(甲氧基甲基)苯甲醛与丙酮或1-(三苯基膦)-2-丙酮进行羟醛缩合反应得到4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮；
步骤(1)的反应温度为+40～+65℃，反应时间为4～5h；
步骤(1)中4-羟基苯甲醛与N,N-二异丙基乙胺的重量体积比(g/mL)为：1：1.16-2.76；4-羟基苯甲醛与无水碳酸钾的重量比(g/g)为：1：5.6-13.6；将4-羟基苯甲醛与溴甲基甲醚或氯甲基甲醚的重量体积比(g/mL)为：1：0.6-1.6；
步骤(2)的反应温度为+20～+65℃，反应时间为1～4h；
步骤(2)中的4-(甲氧基甲基)苯甲醛与丙酮的重量体积比(g/mL)为：1：10-40；4-(甲氧基甲基)苯甲醛与1-(三苯基膦)-2-丙酮的重量比(g/g)为：1：1.2-2.4；
步骤(三)包括如下步骤：
(1)将4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮和3-(4-(甲氧基甲氧基)苯基)丙醛进行羟醛缩合，得到(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮；
(2)将(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮与盐酸或对甲苯磺酸反应，得到1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮。
步骤(1)的反应温度为-80～-60℃，反应时间为1.5～2.5h，使用N，N-二异丙基氨基锂作为碱催化；
步骤(1)中3-(4-(甲氧基甲氧基)苯基)丙醛和4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮的重量比(g/g)为：1：1-1.2；N，N-二异丙基氨基锂与4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮的重量体积比(g/mL)为：1：5-6；
步骤(2)的反应温度为0～+65℃，反应时间为30min～1h；
步骤(2)中(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮与盐酸的重量体积比(g/mL)为：1：5-30；(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮与对甲苯磺酸的重量比(g/g)为：1：0.1-0.3。
本发明所提供了一种全新的制备1，7-二-(4-羟基苯基)-庚烷-1，4-二烯-3-酮的新的合成方法，该方法简单，易操作，收率高，纯度高，填补了有效制备这个化合物的空白。
具体实施方式
下面结合实施例对本发明进一步说明。
本发明以3-(4-羟基苯基)丙酸和4-羟基苯甲醛为原料，经过共8步反应合成1，7-二-(4-羟基苯基)-庚烷-1，4-二烯-3-酮，具体路线如下。
Figure PCTCN2018106953-appb-000002
实施例1
1、制备3-(4-羟基苯基)丙酸甲酯
将3-(4-羟基苯基)丙酸(8g，48.14mmol)溶于甲醇(40mL)中，滴加浓硫酸(0.4mL)催化，在35℃下反应4h，减压浓缩除去部分甲醇，加入10mL水，用饱和碳酸氢钠调节pH至6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，得3-(4-羟基苯基)丙酸甲酯。
2、制备甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯
搅拌下将3-(4-羟基苯基)丙酸甲酯(3g，16.66mmol)和N，N-二异丙基乙胺(3.5mL，21.65mmol)溶于无水二氯甲烷(50mL)中，搅拌30min，加入丙酮50mL，滴加溴甲基甲醚(1.7mL，21.65mmol)，加热回流5h，冷却至室温，用稀盐酸(20mL，1.0mol/L)洗涤，用水20mL洗涤2次，用无水硫酸钠干燥，减压浓缩，柱色谱纯化，得甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯。 1H NMR(600MHz,MeOD)δ7.10(d,J＝8.5Hz,1H),6.94–6.90(m,1H),5.12(s,1H),4.86(d,J＝2.1Hz,1H),3.62(s,2H),3.42(s,1H),2.84(t,J＝7.6Hz,1H),2.58(t,J＝7.6Hz,1H).
3、制备3-(4-(甲氧基甲基)苯基)丙-1-醇
在冰水浴下，将四氢铝锂(1.5g，40.18mmol)分散于四氢呋喃(50mL)中，搅拌下缓慢滴加甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯(3g，13.39mmol)，室温下搅拌2h，缓缓滴加乙酸乙酯10mL，加入10mL水淬灭反应，用稀盐酸调节pH到6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次， 用无水硫酸钠干燥，减压除去乙酸乙酯，得到3-(4-(甲氧基甲基)苯基)丙-1-醇。 1H NMR(600MHz,CDCl 3)δ7.11(d,J＝8.6Hz,2H),6.96(d,J＝8.6Hz,2H),5.15(s,2H),3.66(t,J＝6.4Hz,2H),3.48(s,3H),2.68–2.63(m,2H),1.90–1.82(m,2H).
4、制备3-(4-(甲氧基甲基)苯基)丙醛
将草酰氯(1mL，10.33mmol)加入50mL二氯甲烷中，将体系降温至-60℃以下，将二甲基亚砜(1.6mL，20.66mmol)溶于20mL二氯甲烷中，缓慢滴加至反应体系中，搅拌1h，将3-(4-(甲氧基甲基)苯基)丙-1-醇(1.5g，7.65mmol)溶于10mL，缓慢滴加至反应体系中，反应4h，缓慢滴加三乙胺(4.6mL，30.61mmol)，搅拌0.5h，升温至0℃，加30mL水，溶液分层，取有机层，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去二氯甲烷，得到3-(4-(甲氧基甲基)苯基)丙醛。
5、制备4-(甲氧基甲基)苯甲醛
搅拌下将4-羟基苯甲醛(2.5g，20.47mmol)和无水碳酸钾(14g，81.89mmol)溶于丙酮(100mL)中，搅拌30min，滴加溴甲基甲醚(2mL，26.61mmol)，加热回流5h，冷却至室温，用稀盐酸(20mL，1.0mol/L)洗涤，用水20mL洗涤2次，用无水硫酸钠干燥，减压浓缩，柱色谱纯化，得4-(甲氧基甲基)苯甲醛。6、制备4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮
将4-(甲氧基甲基)苯甲醛(2.0g，12.05mmol)溶于丙酮(20mL)中，搅拌至溶解，加入20％的NaOH水溶液(10mL)，在室温下反应4h，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，得4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮。 1H NMR(600MHz,MeOD)δ9.16(s,1H),7.42(d,J＝7.5Hz,2H),7.36(dd,J＝12.0,4.8Hz,4H),7.30(d,J＝7.4Hz,1H),6.95(d,J＝8.7Hz,2H),6.70(d,J＝16.3Hz,1H),6.25(d,J＝16.3Hz,1H),5.07(d,J＝6.4Hz,2H),1.90(s,3H),1.52(s,3H).
7、制备(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮
将4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮(1.5g，7.28mmol)溶于四氢呋喃(50mL)中，将体系降温至-60℃以下，滴加N，N-二异丙基氨基锂(9.47mmol)，滴加3-(4-(甲氧基甲基)苯基)丙醛(1.5g，7.28mmol)的四氢呋喃(10mL)溶液，反应2.5h，升至室温，加入20mL水，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，得(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮。
8、制备1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮
将(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮1g溶于甲醇(50mL)，加入盐酸10mL(6mol/L)室温下搅拌30min，用NaOH水溶液调pH为6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，液相制备得1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮，纯度达到99％。 1H NMR(600MHz,DMSO)δ10.03(d,J＝2.6Hz,1H),9.15(s,1H),7.58(d,J＝8.6Hz,2H),7.53(d,J＝15.9Hz,1H),7.01(d,J＝8.4Hz,2H),6.97(d,J＝16.0Hz,2H),6.80(d,J＝8.6Hz,2H),6.66(d,J＝8.5Hz,2H),6.50–6.46(m,1H),3.16(d,J＝5.3Hz,1H),2.66(t,J＝7.6Hz,2H).
实施例2
1、制备3-(4-羟基苯基)丙酸乙酯
将3-(4-羟基苯基)丙酸(8g，48.14mmol)溶于乙醇(40mL)中，滴加浓硫酸(0.4mL)催化，在35℃下反应4h，减压浓缩除去部分甲醇，加入10mL水，用饱和碳酸氢钠调节pH至6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，得3-(4-羟基苯基)丙酸乙酯。
2、制备甲基3-(4-(甲氧基甲基)苯基)丙酸乙酯
搅拌下将3-(4-羟基苯基)丙酸乙酯(3g，16.66mmol)和N，N-二异丙基乙胺(3.5mL，21.65mmol)溶于无水二氯甲烷(50mL)中，搅拌30min，加入丙酮50mL，滴加溴甲基甲醚(1.7mL，21.65mmol)，加热回流5h，冷却至室温，用稀盐酸(20mL，1.0mol/L)洗涤，用水20mL洗涤2次，用无水硫酸钠干燥，减压浓缩，柱色谱纯化，得甲基3-(4-(甲氧基甲基)苯基)丙酸乙酯。
3、制备3-(4-(甲氧基甲基)苯基)丙-1-醇
在冰水浴下，将四氢铝锂(1.5g，40.18mmol)分散于四氢呋喃(50mL)中，搅拌下缓慢滴加甲基3-(4-(甲氧基甲基)苯基)丙酸乙酯(3g，13.39mmol)，室温下搅拌2h，缓缓滴加乙酸乙酯10mL，加入10mL水淬灭反应，用稀盐酸调节pH到6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，得到3-(4-(甲氧基甲基)苯基)丙-1-醇。 1H NMR(600MHz,CDCl 3)δ7.11(d,J＝8.6Hz,2H),6.96(d,J＝8.6Hz,2H),5.15(s,2H),3.66(t,J＝6.4Hz,2H),3.48(s,3H),2.68–2.63(m,2H),1.90–1.82(m,2H).
4、制备3-(4-(甲氧基甲基)苯基)丙醛
将草酰氯(2mL，20.66mmol)加入50mL二氯甲烷中，将体系降温至-60℃以下，将二甲基亚砜(3.2mL，41.32mmol)溶于40mL二氯甲烷中，缓慢滴加至反应体系中，搅拌1h，将3-(4-(甲氧基甲基)苯基)丙-1-醇(1.5g，7.65mmol)溶于10mL，缓慢滴加至反应体系中，反应4h，缓慢滴加三乙胺(9.2mL，61.22mmol)，搅拌0.5h，升温至0℃，加60mL水，溶液分层，取有机层，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去二氯甲烷，得到3-(4-(甲氧基甲基)苯基)丙醛。
5、制备4-(甲氧基甲基)苯甲醛
搅拌下将4-羟基苯甲醛(2.5g，20.47mmol)和N，N-二异丙基乙胺(4.3mL，26.65mmol)溶于丙酮(100mL)中，搅拌30min，滴加溴甲基甲醚(2mL，26.61mmol)，加热回流5h，冷却至室温，用稀盐酸(20mL，1.0mol/L)洗涤，用水20mL洗涤2次，用无水硫酸钠干燥，减压浓缩，柱色谱纯化，得4-(甲氧基甲基)苯甲醛。
6、制备4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮
将4-(甲氧基甲基)苯甲醛(2.0g，12.05mmol)溶于四氢呋喃(20mL)中，搅拌至溶解，与1-(三苯基膦)-2-丙酮(2.41g)混合回流4h，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，得4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮。 1H NMR(600MHz,MeOD)δ9.16(s,1H),7.42(d,J＝7.5Hz,2H),7.36(dd,J＝12.0,4.8Hz,4H),7.30(d,J＝7.4Hz,1H),6.95(d,J＝8.7Hz,2H),6.70(d,J＝16.3Hz,1H),6.25(d,J＝16.3Hz,1H),5.07(d,J＝6.4Hz,2H),1.90(s,3H),1.52(s,3H).
7、制备(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮
将4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮(1.5g，7.28mmol)溶于四氢呋喃(50mL)中，将体系降温至-60℃以下，滴加N，N-二异丙基氨基锂(9.47mmol)，滴加3-(4-(甲氧基甲基)苯基)丙醛(1.5g，7.28mmol)的四氢呋喃(10mL)溶液，反应2.5h，升至室温，加入20mL水，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，得(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮。
8、制备1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮
将(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮1g溶于甲醇(50mL)，加入对甲苯磺酸(0.1g)室温下搅拌30min，用NaOH水溶液调pH为6，用20mL乙酸乙酯萃取三次，用饱和食盐水20mL洗涤三次，用无水硫酸钠干燥，减压除去乙酸乙酯，柱色谱纯化，液相制备得1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮，纯度达到99％。 1H NMR(600MHz,DMSO)δ10.03(d,J＝2.6Hz,1H),9.15(s,1H),7.58(d,J＝8.6Hz,2H),7.53(d,J＝15.9Hz,1H),7.01(d,J＝8.4Hz,2H),6.97(d,J＝16.0Hz,2H),6.80(d,J＝8.6Hz,2H),6.66(d,J＝8.5Hz,2H),6.50–6.46(m,1H),3.16(d,J＝5.3Hz,1H),2.66(t,J＝7.6Hz,2H).
可以理解的是，对本领域技术人员来说，对本发明的技术方案及发明构思加以等同替换或改变都应属于本发明所附的权利要求的保护范围。

Claims (10)

  1. 一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法，其特征在于，包括如下步骤：
    (一)3-(4-羟基苯基)丙酸为原料，经过酯化、甲基保护、还原、氧化得3-(4-(甲氧基甲基)苯基)丙醛；
    (二)4-羟基苯甲醛经过醚化、羟醛缩合反应得4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮；
    (三)将4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮和3-(4-(甲氧基甲氧基)苯基)丙醛进行羟醛缩合，再与盐酸反应，得到1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮。
  2. 如权利要求1所述的合成方法，其特征在于，步骤(一)包括如下反应：
    (1)以3-(4-羟基苯基)丙酸和甲醇或乙醇进行酯化反应得到3-(4-羟基苯基)丙酸甲酯或3-(4-羟基苯基)丙酸乙酯；
    (2)将3-(4-羟基苯基)丙酸甲酯与溴甲基甲醚或氯甲基甲醚反应添加甲氧甲基保护基得到甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯；
    (3)将甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯用四氢锂铝还原得到3-(4-(甲氧基甲基)苯基)丙-1-醇；
    (4)将3-(4-(甲氧基甲基)苯基)丙-1-醇与草酰氯、二甲基亚砜反应氧化，以三乙胺游离出产物，得到3-(4-(甲氧基甲基)苯基)丙醛。
  3. 如权利要求2所述的合成方法，其特征在于，步骤(1)中，3-(4-羟基苯基)丙酸与甲醇或乙醇的重量体积比(g/mL)为：1：2.5-10，其反应温度为+20～+80℃，反应时间为2～4h。
  4. 如权利要求2所述的合成方法，其特征在于，步骤(2)中，反应温度为+40～+65℃，反应时间为4～5h，使用N,N-二异丙基乙胺作为催化剂；3-(4-羟基苯基)丙酸甲酯与溴甲基甲醚或氯甲基甲醚的重量体积比(g/mL)为：1：0.5-1.3；催化剂与3-(4-羟基苯基)丙酸甲酯的重量体积比为：1：1.2-2.7。
  5. 如权利要求2所述的合成方法，其特征在于，步骤(3)中甲基3-(4-(甲氧基甲基)苯基)丙酸甲酯与四氢锂铝的重量比(g/g)为：1：0.4-1.5。
  6. 如权利要求2所述的合成方法，其特征在于，步骤(4)中，步骤(4)中3-(4-(甲氧基甲基)苯基)丙-1-醇与草酰氯的重量体积比(g/mL)为：1：0.7-1.4；3-(4-(甲氧基甲基)苯基)丙-1-醇与二甲基亚砜重量体积比(g/mL)：1：1.1-2.2；3-(4-(甲氧基甲基)苯基)丙-1-醇与三乙胺重量体积比(g/mL)：1：3.1-6.2，反应温度为-80～-60℃，反应时间为2～8h。
  7. 如权利要求1-6任何一项所述的合成方法，其特征在于，步骤(二)包括如下反应：
    (1)将4-羟基苯甲醛在无水碳酸钾或N,N-二异丙基乙胺的催化下与溴甲基甲醚或氯甲基甲醚反应得到羟基保护的4-(甲氧基甲基)苯甲醛；
    (2)以4-(甲氧基甲基)苯甲醛与丙酮或1-(三苯基膦)-2-丙酮进行羟醛缩合反应得到4-(4-(甲氧基甲基)苯基)丁-3-烯-2-酮。
  8. 如权利要求7所述的合成方法，其特征在于，
    步骤(1)中4-羟基苯甲醛与N,N-二异丙基乙胺的重量体积比(g/mL)为：1：1.16-2.76；4-羟基苯甲醛与无水碳酸钾的重量比(g/g)为：1：5.6-13.6；将4-羟基苯甲醛与溴甲基甲醚或氯甲基甲醚的重量体积比(g/mL)为：1：0.6-1.6，反应温度为+40～+65℃，反应时间为4～5h；
    步骤(2)的4-(甲氧基甲基)苯甲醛与丙酮的重量体积比(g/mL)为：1：10-40；4-(甲氧基甲基)苯甲醛与1-(三苯基膦)-2-丙酮的重量比(g/g)为：1：1.2-2.4，反应温度为+20～+65℃，反应时间为1～4h。
  9. 如权利要求1-8任何一项所述的合成方法，其特征在于，步骤(三)包括如下反应：
    (1)将4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮和3-(4-(甲氧基甲氧基)苯基)丙醛进行羟醛缩合，得到(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮；
    (2)将(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮1g与盐酸或对甲苯磺酸反应，得到1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮。
  10. 如权利要求9所述的合成方法，其特征在于，步骤(1)中3-(4-(甲氧基甲氧基)苯基)丙醛和4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮的重量比(g/g)为：1：1-1.2；N，N-二异丙基氨基锂与4-(4-(甲氧基甲氧基)苯基)丁-3-烯-2-酮的重量体积比(g/mL)为：1：5-6；反应温度为-80～-60℃，反应时间为1.5～2.5h，使用N，N-二异丙基氨基锂作为碱催化；步骤(2)中(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮与盐酸的重量体积比(g/mL)为：1：5-30；(1E，4E)-1,7-双(4-(甲氧基甲氧基)苯基)庚-1,4-二烯-3-酮与对甲苯磺酸的重量比(g/g)为：1：0.1-0.3；反应温度为0～+65℃，反应时间为30min～1h。
PCT/CN2018/106953 2017-10-25 2018-09-21 一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法 WO2019080682A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711006268.6 2017-10-25
CN201711006268.6A CN107721836A (zh) 2017-10-25 2017-10-25 一种合成1,7‑二‑（4‑羟基苯基）‑庚烷‑1,4‑二烯‑3‑酮的方法

Publications (1)

Publication Number Publication Date
WO2019080682A1 true WO2019080682A1 (zh) 2019-05-02

Family

ID=61213754

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/106953 WO2019080682A1 (zh) 2017-10-25 2018-09-21 一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法

Country Status (2)

Country Link
CN (1) CN107721836A (zh)
WO (1) WO2019080682A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107721836A (zh) * 2017-10-25 2018-02-23 沈阳药科大学 一种合成1,7‑二‑（4‑羟基苯基）‑庚烷‑1,4‑二烯‑3‑酮的方法
CN113354522B (zh) * 2021-06-09 2022-08-16 西安瑞联新材料股份有限公司 一种改进的佛尔酮合成方法
CN113861009B (zh) * 2021-11-23 2024-04-05 沈阳药科大学 单羰基姜黄素类似物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103819475A (zh) * 2014-02-11 2014-05-28 浙江新和成股份有限公司 一种西他列汀及其盐的合成方法
CN103910616A (zh) * 2014-03-20 2014-07-09 浙江工业大学 一种姜黄素衍生物及其制备与应用
CN103936577A (zh) * 2013-01-18 2014-07-23 北京大学 E-3,4-二羟苯乙烯基酮类化合物的制备方法及其作为神经保护药物的应用
CN107721836A (zh) * 2017-10-25 2018-02-23 沈阳药科大学 一种合成1,7‑二‑（4‑羟基苯基）‑庚烷‑1,4‑二烯‑3‑酮的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100532373C (zh) * 2007-05-31 2009-08-26 中国科学院广州化学研究所 (2r,3s)-环氧-9-辛烯-1-醇的全合成方法
CN101402573B (zh) * 2008-11-19 2012-07-04 厦门大学 双羟基-2-酰基苯乙酸酯及其制备方法与应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103936577A (zh) * 2013-01-18 2014-07-23 北京大学 E-3,4-二羟苯乙烯基酮类化合物的制备方法及其作为神经保护药物的应用
CN103819475A (zh) * 2014-02-11 2014-05-28 浙江新和成股份有限公司 一种西他列汀及其盐的合成方法
CN103910616A (zh) * 2014-03-20 2014-07-09 浙江工业大学 一种姜黄素衍生物及其制备与应用
CN107721836A (zh) * 2017-10-25 2018-02-23 沈阳药科大学 一种合成1,7‑二‑（4‑羟基苯基）‑庚烷‑1,4‑二烯‑3‑酮的方法

Also Published As

Publication number Publication date
CN107721836A (zh) 2018-02-23

Similar Documents

Publication Publication Date Title
WO2019080682A1 (zh) 一种合成1,7-二-(4-羟基苯基)-庚烷-1,4-二烯-3-酮的方法
JP5021549B2 (ja) 癌細胞の処理のための組成物及びその合成方法
KR101890080B1 (ko) 프로스타시클린 유도체 제조를 위한 중간체의 합성
EP2981260B1 (en) Novel analogues of epicatechin and related polyphenols
WO2020031179A1 (en) Methods for synthesis of cannabinoid compounds
CN101307024B (zh) 5-正丁基-2-乙基胺基-6-甲基嘧啶-4-基二甲基胺基磺酸酯的合成方法
KR101308258B1 (ko) 엔독시펜의 신규한 제조 방법
US20070037874A1 (en) Manufacturing process of isoflavan or isoflavene derivatives
CN101891595B (zh) 一种羟基酪醇的制备方法
CN111018928B (zh) 一种天麻素半水合物的合成方法及其应用
JP2019509293A (ja) ４−ペンタフルオロチオフェノール類化合物と調製方法及びペンタフルオロサルファー置換ベンゾピラン化合物の調製方法
CN112174823B (zh) 一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用
JP4329759B2 (ja) 新規ショウガオール系化合物および当該化合物によるチロシナーゼ活性阻害剤
JP2003327574A (ja) ショウガオール類の製造方法および合成用中間体
KR101042103B1 (ko) 도미노 알돌형 반응 및 6π―전자고리화 반응을 이용한 피라노스틸벤 화합물의 합성방법
WO2013008175A1 (fr) Procede de preparation du trans-resveratrol et de ses analogues
TWI718699B (zh) 十七碳三烯烷基對苯二酚衍生物之合成方法
KR100932071B1 (ko) 벤잘아세토페논 유도체의 제조방법
JP4345311B2 (ja) 抗酸化剤
US11434217B2 (en) Method for synthesis of lobaric acid and analog thereof
CN110669031B (zh) 天然产物异猴头菌酮j的全合成方法
CN106995366A (zh) 一种3‑氨基‑2‑羟基苯乙酮的制备新方法
CN107973706B (zh) 一个氧取代的香叶基查尔酮的合成方法
JP5023322B2 (ja) 縮合多環化合物の製造方法
Kuo et al. An efficient synthesis of a potent anti-inflammatory agent, viscolin, and its inducible nitric oxide synthase inhibitory activity

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: 18870830

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: 18870830

Country of ref document: EP

Kind code of ref document: A1