CN101497567A - Preparation of 3-(3,4-dihydroxyphenyl)-acrylic acid 2-(3,4-dihydroxyphenyl)-ethyl ester and derivative phenyl acrylic acid phenyl alkyl ester compound - Google Patents

Preparation of 3-(3,4-dihydroxyphenyl)-acrylic acid 2-(3,4-dihydroxyphenyl)-ethyl ester and derivative phenyl acrylic acid phenyl alkyl ester compound Download PDF

Info

Publication number
CN101497567A
CN101497567A CNA2009101150024A CN200910115002A CN101497567A CN 101497567 A CN101497567 A CN 101497567A CN A2009101150024 A CNA2009101150024 A CN A2009101150024A CN 200910115002 A CN200910115002 A CN 200910115002A CN 101497567 A CN101497567 A CN 101497567A
Authority
CN
China
Prior art keywords
acid
structural formula
benzene
mmol
allyl
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CNA2009101150024A
Other languages
Chinese (zh)
Other versions
CN101497567B (en
Inventor
张治针
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to CN2009101150024A priority Critical patent/CN101497567B/en
Publication of CN101497567A publication Critical patent/CN101497567A/en
Application granted granted Critical
Publication of CN101497567B publication Critical patent/CN101497567B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Abstract

The invention discloses a method for preparing a benzolene propionic acid benzene alkyl ester compound, particularly a method for preparing a caffeic acid 3,4-dihydroxyl phenethyl ester. The preparation method has the advantages of single reaction product obtained in each step, less byproducts, easy separation and purification, high yield of target products and suitability for the industrialized production.

Description

Coffic acid 3, the preparation method of 4-dihydroxy-benzene ethyl ester and derivative benzene allyl acid benzene hydrocarbon base ester compound thereof
Technical field
The invention belongs to pharmaceutical field, relate to a kind of benzene allyl acid benzene hydrocarbon base ester compound, particularly coffic acid 3, the preparation method of 4-dihydroxy-benzene ethyl ester.
Background technology
Amani MD et al.Phytochemistry, 2000; 55:927-931 obtains a kind of new benzene allyl acid benzene hydrocarbon base ester cpds open first the separation from plant, it is coffic acid 3,4-dihydroxy-benzene ethyl ester (chemical name: 3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester, be called for short CADPE), and chemical structure, but do not disclose its biological activity.
Chinese patent application (publication number CN1879672A) discloses coffic acid 3,4-dihydroxy-benzene ethyl ester has anti-tumor activity, when share with traditional chemotherapeutics, coffic acid 3,4-dihydroxy-benzene ethyl ester also can obviously increase the curative effect of chemotherapeutics and reduce the toxicity of chemotherapeutics.
Recently, English Patent (publication number GB2431876A, 2007) discloses the application of this compound aspect manufacturing makeup and treatment tetter; The Korea S scholar proves coffic acid 3 with nude mice, 4-dihydroxy-benzene ethyl ester has the restraining effect of highly significant to the human body kidney, its effect is expressed relevant with tumor-blood-vessel growth with reduction signal transmitter and the active and inhibition vascular endothelial growth factor (VEGF) of transcribing agonist 3 (STAT3) and HIF-lalpha, and this compound does not have toxicity [Jung et al to normal cell, Carcinogenesis, 2007; 28:1780-1787].
Chinese patent application (publication number CN1879672A) also discloses preparation coffic acid 3 under coupling reagent dicyclohexylcarbodiimide (DDC) katalysis, the method for 4-dihydroxy-benzene ethyl ester, but this byproduct of reaction is many, the target compound separation difficulty, and yield is low.Remove this, the research of CADPE derivative be yet there are no report.Therefore, be necessary further to study coffic acid 3,4-dihydroxy-benzene ethyl ester and to its preparation method with benzene allyl acid benzene hydrocarbon base ester compound of similar mother nucleus structure, be coffic acid 3, the research and development of 4-dihydroxy-benzene ethyl ester and derivative thereof lay the foundation.
Summary of the invention
The technical problem to be solved in the present invention provides coffic acid 3, the preparation method of 4-dihydroxy-benzene ethyl ester and derivative benzene allyl acid benzene hydrocarbon base ester compound thereof.
Coffic acid 3,4-dihydroxy-benzene ethyl ester and derivative benzene allyl acid benzene hydrocarbon base ester compound thereof have the structure shown in the structural formula (1):
Figure A200910115002D00061
Wherein, m is 0,1,2,3,4 or 5,
Each R 1Represent hydroxyl, methyl, methoxyl group or acetoxyl group independently of one another,
L represents C 1-C 3Alkyl,
T is 0,1,2,3 or 4,
Each R 2Represent hydroxyl, methyl, methoxyl group or acetoxyl group independently of one another.
Coffic acid 3 involved in the present invention, 4-dihydroxy-benzene ethyl ester has the structure shown in the structural formula (10),
Figure A200910115002D00071
The preparation method of benzene allyl acid benzene hydrocarbon base ester compound of the present invention comprises following reactions steps: with the acid compounds esterification of structural formula (2),
Figure A200910115002D00072
Wherein X represents C 0-C 2Alkyl, the esterification thing of generating structure formula (3),
Figure A200910115002D00073
Be reduced into the alcohol compound of structural formula (4) then,
Then
(a) with the alcohol compound of structural formula (4) and the Meldrum ' s acid-respons of structural formula (5),
Figure A200910115002D00075
The malonic acid monoester compound of generating structure formula (6),
Figure A200910115002D00076
Aldehyde compound last and structural formula (7) reacts;
Figure A200910115002D00081
Or
(b) alcohol compound of structural formula (4) and the acid compounds of structural formula (8) are reacted.
Figure A200910115002D00082
The preferred processing condition of the acid compounds carboxyl ester reaction of structural formula of the present invention (2) is: the acid compounds of structural formula (2) is dissolved in the anhydrous methanol, adds thionyl chloride (SOCl gradually under the zero degree condition 2) stir after 10-15 minute, at room temperature to place and do not stop in 7-8 hour to stir, reactant promptly gets the esterification thing of structural formula (3) through column chromatographic isolation and purification.The amount ratio of described structural formula (2) acid compounds, thionyl chloride and methyl alcohol is 1.0 (mmol): 1.2-1.3 (mmol): 2-4 (mL).
The preferred reaction conditions that the methyl compound of structural formula of the present invention (3) is reduced into the alcohol compound of structural formula (4) is: the esterification thing of structural formula (3) is dissolved in the anhydrous tetrahydro furan, progressively add tetrahydrochysene calorize lithium, room temperature is placed and was not stopped in 9-10 hour to stir, and reactant promptly gets the alcohol compound of structural formula (4) through column chromatographic isolation and purification; The amount ratio of the methyl compound of described structural formula (3), tetrahydrochysene calorize lithium and tetrahydrofuran (THF) is 1.0 (mmol): 2.0-3.0 (mmol): 10-12 (mL).
In the method for the present invention (a), preferably the alcohol compound of structural formula (4) and the Meldrum ' s acid of structural formula (5) are dissolved in dioxane, 95-110 ℃ was reacted 5-6 hour, and was cooled to room temperature afterreaction thing promptly gets structural formula (6) through column chromatographic isolation and purification malonic acid monoester compound; Meldrum ' s the acid of the alcohol compound of described structural formula (4), structural formula (5) and the amount ratio of dioxane are: 1.4-2.0 (mmol): 1.0 (mmol): 2-4 (mL).
In the method for the present invention (a), the optimum condition of the aldehyde compound reaction of the malonic acid monoester compound of structural formula (6) and structural formula (7) is: the malonic acid monoester compound of structural formula (6) and the aldehyde compound of structural formula (7) are dissolved in the pyridine, add piperidines again, stir under the room temperature after 36-48 hour, reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; The amount ratio of aldehyde compound, pyridine and the piperidines of the malonic acid monoester compound of described structural formula (6), structural formula (7) is: 1.0 (mmol): 1.3-1.6 (mmol): 1.0-1.2 (mL): 0.1-0.12 (mL).
Method of the present invention (b) can realize by chloride method, that is:
(i) with the acid compounds carboxyl chloride of structural formula (8), the chloride compounds of generating structure formula (9),
Figure A200910115002D00083
(ii) the chloride compounds of described structural formula (9) and the alcohol compound of structural formula (4) are reacted.
The preferred reaction conditions of above-mentioned chloride method reaction is, the acid compounds of structural formula (8) is dissolved in dioxane, feed argon gas, add thionyl chloride, 96-100 ℃ was reacted 3 hours down, the alcohol compound that adds structural formula (4) again, 96-100 ℃ is continued reaction 5-6 hour down, and reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; The amount ratio of alcohol compound, thionyl chloride and the dioxane of the acid compounds of described structural formula (8), structural formula (4) is 1.0 (mmol): 1.5-2.0 (mmol): 3.0-4.0 (mmol): 10-13 (mL).
Method of the present invention (b) can also be passed through N, N-carbonyl dimidazoles (CDI) and 1, and 8-diazabicylo (5,4,0) hendecene-7 (DBU) catalytic esterification method realizes.
The preferred reaction conditions of described CDI and DBU catalytic esterification method is: the acid compounds of structural formula (8) is dissolved in the tetrahydrofuran (THF), add N, the N-carbonyl dimidazoles, feed argon gas, 40-45 ℃ after stirring reaction 15-20 minute, the alcohol compound and 1 that adds structural formula (4) again, 8-diazabicylo (5,4,0) tetrahydrofuran solution of hendecene-7, mixture continues to react 20-24 hour down at 40-45 ℃, and reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; Alcohol compound, the N of the acid compounds of described structural formula (8), structural formula (4), N-carbonyl dimidazoles, 1,8-diazabicylo (5,4,0) amount ratio of hendecene-7 and tetrahydrofuran (THF) is 1.0 (mmol): 1.1-1.2 (mmol): 1.4-1.6 (mmol): 1.1-1.3 (mmol): 10-12 (mL).
Coffic acid 3, the preferred preparation technology of 4-dihydroxy-benzene ethyl ester is:
The preparation of (1) 3,4-dihydroxyphenyl acetic acid methyl esters: with 3, the 4-dihydroxyphenyl acetic acid is dissolved in the anhydrous methanol, 0 0After adding thionyl chloride under the C condition gradually and stirring 15 minutes, at room temperature place and do not stop in 7-8 hour to stir; Reactant will contain 3 through the mixed solvent wash-out of silica gel column chromatography with hexanaphthene and ethyl acetate (4:1), and the elutriant of 4-dihydroxyphenyl acetic acid methyl esters merges back recovery solvent and obtains 3,4-dihydroxyphenyl acetic acid methyl esters; Described 3, the amount ratio of 4-dihydroxyphenyl acetic acid, thionyl chloride and methyl alcohol is 1.0 (mmol): 1.2-1.3 (mmol): 2-4 (mL);
The preparation of (2) 3,4-dihydroxyphenyl ethanols: with described step (1) make 3,4-dihydroxyphenyl acetic acid methyl esters is dissolved in the anhydrous tetrahydro furan, progressively add tetrahydrochysene calorize lithium after, at room temperature react and do not stop in 9-10 hour to stir; Reactant is poured in 5% hydrochloric acid soln, uses ethyl acetate extraction 3 times; Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration; Acetic acid ethyl ester extract is through silica gel column chromatography, and the mixed solvent wash-out with hexanaphthene and ethyl acetate (2:1) will contain 3, and the elutriant of 4-dihydroxyphenyl ethanol merges back recovery solvent and obtains 3, the 4-dihydroxyphenyl ethanol; Described 3, the amount ratio of 4-dihydroxyphenyl acetic acid methyl esters, tetrahydrochysene calorize lithium and tetrahydrofuran (THF) is 1.0 (mmol): 2.0-3.0 (mmol): 10-12 (mL);
(3) propanedioic acid 3, the preparation of 4-dihydroxyphenyl ethanol monoesters: with Meldrum ' s acid, described step (2) make 3, the mixture of 4-dihydroxyphenyl ethanol and dioxane under 95-110 ℃ of condition reflux 5-6 hour postcooling to room temperature; Decompression and solvent recovery, residue are used 30% ethanol elution through macroporous adsorbent resin column chromatography, must fall propanedioic acid 3,4-dihydroxyphenyl ethanol monoesters; Described 3, the amount ratio of 4-dihydroxyphenyl ethanol, Meldrum ' s acid and dioxane is 1.4-2.0 (mmol): 1.0 (mmol): 2-4 (mL);
(4) coffic acid 3, the preparation of 4-dihydroxy-benzene ethyl ester: with the propanedioic acid 3 that described step (3) makes, 4-dihydroxyphenyl ethanol monoesters and 3, the 4-Dihydroxy benzaldehyde is dissolved in the pyridine, add piperidines (20mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour; The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again; The reclaim under reduced pressure ethyl acetate gets coffic acid 3,4-dihydroxy-benzene ethyl ester crude product, and this crude product is used 65% ethanol elution through macroporous adsorbent resin column chromatography, obtains coffic acid 3, the pure product of 4-dihydroxy-benzene ethyl ester.
As long as the mentioned intermediate of preparation method of the present invention can salify, the above method of the present invention just comprises the intermediate that uses salt form or free form so.
As also having hydroxyl, can further obtain the target derivative on the aforesaid method synthetic compound phenyl ring by reactions such as esterifications.
It will be appreciated by those skilled in the art that except column chromatography institute of the present invention synthetic compound can also pass through method purifying such as high-efficient liquid phase technique, solvent crystallization.
It should be appreciated by those skilled in the art that preparation method of the present invention is not limited to above-mentioned reaction, the disclosed reaction of other known technology also can make method of the present invention be achieved, and method of the present invention should advantageously comprise above-mentioned reaction.
The compound of the structural formula (1) of the present invention's preparation is preferred from the compound of structural formula (11-15):
Figure A200910115002D00101
R 1-R 23Independently represent hydrogen, hydroxyl, methoxyl group or acetoxyl group separately.
Examples for compounds of the present invention comprises:
3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3,4-diacetoxy phenyl)-allyl acid 2-(3,4-diacetoxy phenyl) ethyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3-methoxyl group, 4-acetoxyl group phenyl)-allyl acid 2-(3,4-diacetoxy phenyl) ethyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3-methoxyl group, 4-hydroxy phenyl) ethyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3-hydroxyl, 4-p-methoxy-phenyl) ethyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester
3-(3-hydroxyl, 4-hydroxy phenyl)-allyl acid 2-(3-hydroxyl, 4-p-methoxy-phenyl) ethyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3-methoxyl group, 4-hydroxy phenyl) ethyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3-hydroxyl, 4-p-methoxy-phenyl) ethyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3-methoxyl group, 4-hydroxy phenyl) ethyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3-hydroxyl, 4-p-methoxy-phenyl) ethyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester
3-(3-hydroxy phenyl)-allyl acid 2-(3-hydroxy phenyl) ethyl ester
3-(4-hydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2, the 3-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2, the 4-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2, the 5-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2,5-diacetyl phenyl)-allyl acid 2-(3,4-diacetoxy phenyl) ethyl ester
3-(3, the 5-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2,3,4-trihydroxy-phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2,4,5-trihydroxy-phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(2,4,6-trihydroxy-phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3,4,5-trihydroxy-phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
3-(3-hydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(4-hydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(2, the 3-dihydroxy phenyl)-allyl acid 2-(2, the 5-hydroxy phenyl) ethyl ester
3-(2, the 4-dihydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(2,4-diacetoxy phenyl)-allyl acid 2-(2,5-diacetoxy phenyl) ethyl ester
3-(2, the 5-dihydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(3, the 5-dihydroxy phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(2,3,4-trihydroxy-phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(2,4,5-trihydroxy-phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(2,4,6-trihydroxy-phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(3,4,5-trihydroxy-phenyl)-allyl acid 2-(2, the 5-dihydroxy phenyl) ethyl ester
3-(3,4,5-triacetyl oxygen base phenyl)-allyl acid 2-(2,5-diacetoxy phenyl) ethyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters
3-(3, the 4-Dimethoxyphenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters
3-(3, the 4-dihydroxy phenyl)-allyl acid (3-hydroxyl, 4-p-methoxy-phenyl) methyl esters
3-(3, the 4-dihydroxy phenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (3-methoxyl group, 4-hydroxy phenyl) methyl esters
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (3-hydroxyl, 4-p-methoxy-phenyl) methyl esters
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid (3-methoxyl group, 4-hydroxy phenyl) methyl esters
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid (3-hydroxyl, 4-p-methoxy-phenyl) methyl esters
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
3-(3, the 4-Dimethoxyphenyl)-allyl acid (3-methoxyl group, 4-hydroxy phenyl) methyl esters
3-(3, the 4-Dimethoxyphenyl)-allyl acid (3-hydroxyl, 4-p-methoxy-phenyl) methyl esters
3-(3, the 4-Dimethoxyphenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) propyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) propyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) propyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) propyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) propyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) propyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) propyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) propyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) propyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3-hydroxyl, 4-p-methoxy-phenyl) propyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) propyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) propyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 3-(3-hydroxyl, 4-p-methoxy-phenyl) propyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) allyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) allyl ester
3-(3, the 4-Dimethoxyphenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) allyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) allyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3-hydroxyl, 4-p-methoxy-phenyl) allyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) allyl ester
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) allyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) allyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) allyl ester
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) allyl ester
3-(3, the 4-dihydroxy phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3,4-diacetoxy phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3-methoxyl group, 4-acetoxyl group phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3-ethanoyl, 4-p-methoxy-phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
3-(3, the 4-Dimethoxyphenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
Preparation method of the present invention goes on foot respectively that reaction product is more single, and by product is few, and separation and purification is easy, and target product productive rate height (more than 80%) is suitable for suitability for industrialized production.
Except the coffic acid 3 that has been found that anti-tumor activity, outside the 4-dihydroxy-benzene ethyl ester, the compound of other structural formula of preparation method's synthetic of the present invention (1), its prodrug or its pharmaceutically acceptable salt process external activity screening, discovery has the activity as medicine, such as antitumor, can also further carry out experiment and clinical experiment in the animal body, thereby develop pharmaceutical composition with clinical treatment effect and clinical use value.
The compound of structural formula of the present invention (1) is acceptable salt pharmaceutically, can be by the positively charged part of compound, with have opposite electrical electronegative organic or mineral acid, for example salt of the acid group addition of hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid; Or by the electronegative part of compound, with the alkali of positive charge or the alkaline-earth metal salt that forms of sodium, potassium, calcium, magnesium for example, perhaps with the positively charged organic bases salt that for example methylamine, dimethylamine, Trimethylamine 99 became.
Figure of description
Fig. 1 CADPE synthetic route
Figure 23-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester synthetic route
Figure 33-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester synthetic route
Embodiment
Below the present invention is described in further detail.Should be understood to, these embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, the perhaps condition that provides or advise according to manufacturer.Removing other has definition or explanation, the same meaning that employed all specialties of this paper and scientific terminology and those skilled in the art are familiar with.Any in addition method similar or impartial to described content and material all can be used among the present invention.
Abbreviation of using among the embodiment or term have following implication:
SOCl 2: thionyl chloride
LiAlH 4: tetrahydrochysene calorize lithium
THF: tetrahydrofuran (THF)
MeOH: methyl alcohol
H 2SO 4: sulfuric acid
Ar: argon
CDI:N, the N-carbonyl dimidazoles
DBU:1,8-diazabicylo (5,4,0) hendecene-7
CADPE:3-(3, the 4-dihydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
One, utilizes method (a) preparation benzene allyl acid benzene hydrocarbon base ester compound
Embodiment one
The preparation of Meldrum ' s acid
In the mixture of propanedioic acid and aceticanhydride, slowly add the vitriol oil and also ceaselessly stir after most propanedioic acid dissolvings, add acetone again and maintain the temperature at 20-25 ℃.Reactant is placed on 4 ℃ of refrigerator overnight up to separating out crystallization, and the crystallization behind the suction filtration obtains Meldrum ' s acid with frozen water washing three times.The ratio of propanedioic acid, aceticanhydride, acetone and the vitriol oil that its described reaction is used is 1.0 (mol): 1.2～1.5 (mol): 1.1～1.3 (mol): 5～8 (ml).
1H-NMR(MeOH-d 4，600MHz)δ?1.77(6H，s，-CH 3)，3.85(2H，s，-CH 2-)；
13C-NMR(MeOH-d 4，150MHz)δ?27.7(q，-CH 3)，37.0(t，-CH 2-)，107.6(s，O-C-O)，165.7(s，-C＝O)。
Embodiment two
The preparation of CADPE: synthetic route is referring to accompanying drawing 1
1) 3, the preparation of 4-dihydroxyphenyl acetic acid methyl esters: with 3,4-dihydroxyphenyl acetic acid (336.3 grams, 2.0mol) be dissolved in the 4000mL anhydrous methanol, (174.0mL 2.4mol) and after stirring 15 minutes, at room temperature places and did not stop in 7-8 hour to stir to add thionyl chloride under 0 ℃ of condition gradually.Reactant gets residue behind concentrating under reduced pressure, its residue is through the mixed solvent wash-out of silica gel column chromatography with hexanaphthene and ethyl acetate (4:1), the Fractional Collections elutriant, under ultraviolet lamp, detect each component with thin-layer chromatography (TLC), to contain 3, the elutriant of 4-dihydroxyphenyl acetic acid methyl esters merges back recovery solvent and obtains 3,4-dihydroxyphenyl acetic acid methyl esters (332.2 grams, yield 91.2%).
1H-NMR(MeOH-d 4，600MHz)δ?3.45(2H，s，H-7)，3.64(3H，s，OCH 3)，6.55(1H，dd，J＝2.0/8.0Hz，H-6)，6.69(1H，d，J＝8.0Hz，H-5)，6.70(1H，d，J＝2.0Hz，H-2)；
13C-NMR(MeOH-d 4，150MHz)δ?41.6(t，C-7)，52.9(q，OCH 3)，116.8(d，C-5)，117.8(d，C-2)，122.1(d，C-6)，127.4(s，C-1)，145.9(s，C-4)，146.7(s，C-3)，175.0(s，C-8)。
2) 3, the preparation of 4-dihydroxyphenyl ethanol: with 3,4-dihydroxyphenyl acetic acid methyl esters (109.3 grams, 600mmol) be dissolved in the 6000mL anhydrous tetrahydro furan, branch add tetrahydrochysene calorize lithium (45.52 grams, 1.2mol) after, at room temperature react and do not stop in 9-10 hour to stir.Reactant is poured in the 3000mL5% hydrochloric acid soln, uses ethyl acetate extraction 3 times.Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration.Acetic acid ethyl ester extract is through silica gel column chromatography, mixed solvent wash-out with hexanaphthene and ethyl acetate (2:1), the Fractional Collections elutriant, under ultraviolet lamp, detect each component with thin-layer chromatography (TLC), to contain 3, the elutriant of 4-dihydroxyphenyl ethanol merges back recovery solvent and obtains 3,4-dihydroxyphenyl ethanol (85.6 grams, yield 92.5%).
1H-NMR(MeOH-d 4，600MHz)δ?2.66(2H，t，J＝7.2Hz，H-7)，3.69(2H，t，J＝7.2Hz，H-8)，6.53(1H，dd，J＝2.0/8.0Hz，H-6)，6.71(1H，J＝2.0Hz，H-2)，6.73(1H，d，J＝8.0Hz，H-5)；
13C-NMR(MeOH-d 4，150MHz)δ?39.6(t，C-7)，64.8(t，C-8)，116.8(d，C-5)，117.5(d，C-2)，121.8(d，C-6)，132.2(s，C-1)，144.5(s，C-4)，146.1(s，C-3)。
3) propanedioic acid 3, the preparation of 4-dihydroxyphenyl ethanol monoesters: with Meldrum ' s acid (72.05 grams, 500mmol), 3, the 4-dihydroxyphenyl ethanol (53.94 grams, 350mmol) and the mixture of dioxane (1000mL) naturally cooling after under the 95-110 ℃ of condition reflux 5-6 hour.The reactant decompression and solvent recovery, its residue gets propanedioic acid 3 through macroporous adsorbent resin column chromatography (using 30% ethanol elution) separation and purification, 4-dihydroxyphenyl ethanol monoesters (72.88 grams, yield 86.7%).
1H-NMR(MeOH-d 4，600MHz)δ?2.79(2H，t，J＝6.7Hz，H-7)，3.23(2H，s，H-10)，4.24(2H，t，J＝6.7Hz，H-8)，6.66(1H，dd，J＝1.7/8.1Hz，H-6)，6.78(1H，d，J＝1.7Hz，H-2)，6.80(1H，d，J＝8.1Hz，H-5)；
13C-NMR(MeOH-d 4，150MHz)δ?34.6(t，C-7)，45.0(t，C-10)，67.3(t，C-8)，117.1(d，C-5)，117.7(d，C-2)，122.1(d，C-6)，131.9(s，C-1)，143.8(s，C-4)，145.2(s，C-3)，172.2(s，C-9)，174.7(s，C-11)。
4) preparation of CADPE: with propanedioic acid 3,4-dihydroxyphenyl ethanol monoesters (48.04 grams, 200mmol) with 3,4-Dihydroxy benzaldehyde (41.4 grams, 300mmol) be dissolved in pyridine (pyridine, 200mL), add piperidines (20mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour.The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again.The reclaim under reduced pressure ethyl acetate gets the thick product of CADPE, and this thick product separates the pure product of CADPE that obtain (54.7 grams, yield 86.5%) through macroporous adsorbent resin column chromatography (using 65% ethanol elution).
The molecular formula of CADPE is C 17H 16O 6, yellowish white needle crystal, fusing point 110-111 ℃, be dissolved in methyl alcohol, ethyl acetate, in the ethanol, the ferric chloride reaction positive.Apparent blue-fluorescence under the ultraviolet lamp.
UV (MeOH, λ max) (log ε) 203 (5.06), 223 (4.45), 246 (acromions), 278 (4.40), 326 (4.46) nm.
1H-NMRMeOH-d 4，600MHz)：δ?2.80(2H，t，J＝7.1Hz，H-7′)，4.27(2H，t，J＝7.1Hz，H-8′)，6.21(1H，d，J＝15.9Hz，H-8)，6.56(1H，dd，J＝2.0/8.1Hz，H-6′)，6.70(1H，d，J＝8.1Hz，H-5′)，6.71(1H，d，J＝2.0Hz，H-2′)，6.77(1H，d，J＝8.2Hz，H-5)，6.91(1H，dd，J＝2.0/8.2Hz，H-6)，7.03(1H，d，J＝2.0Hz，H-2)，7.50(1H，d，J＝15.9Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)：δ35.7(t，C-7′)，66.6(t，C-8′)，115.3(d，C-2)，115.3(d，C-8)，116.5(d，C-5′)，116.6(d，C-5)，117.2(d，C-2′)，121.4(d，C-6′)，123.1(d，C-6)，127.8(s，C-1)，131.0(s，C-1′)，144.9(s，C-4′)，146.3(s，C-3′)，146.8(s，C-3)，147.0(d，C-7)，149.6(s，C-4)，169.4(s，C-9)。
HRESIMS：m/z339.08408[M+Na] +(calcd?for?C 17H 16NaO 10，339.08446)。
Embodiment three
The preparation of 3-(3,4-diacetoxy phenyl)-allyl acid 2-(3,4-diacetoxy phenyl) ethyl ester
With coffic acid 3, (embodiment two preparations of 4-dihydroxy-benzene ethyl ester, 1.0 gram) be dissolved in the mixed solvent (50mL) of pyridine and aceticanhydride (2:1), room temperature adds a small amount of distilled water after placing and spending the night, question response thing naturally cooling gets residue behind concentrating under reduced pressure, its residue obtains target compound (1.39 gram) through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification.
This compound molecule formula is C 25H 24O 10, colourless powder is dissolved in methyl alcohol, ethyl acetate and the chloroform.
1H-NMR data (MeOH-d 4, 600MHz) δ 2.19,2.20,2.21,2.22 (each 3H, s, OAc-3,4,3 ', 4 '), 2.96 (2H, t, J=6.8Hz, H-7 '), 4.36 (2H, t, J=6.8Hz, H-8 '), 6.42 (1H, d, J=15.9Hz, H-8), 7.03 (1H, d, J=8.0Hz, H-5), 7.12 (1H, d, J=8.2Hz, H-5 '), 7.16 (1H, d, J=2.0Hz, H-2 '), 7.18 (1H, dd, J=2.0/8.2Hz, H-6 '), 7.22 (1H, dd, J=1.8/8.0Hz, H-6), 7.26 (1H, d, J=1.8Hz, H-2), 7.60 (1H, d, J=15.9Hz, H-7);
13C-NMR(MeOH-d 4，150MHz)δ?20.6、20.6、20.7、20.7(each?q，OAc-3，4，3′，4′)，35.5(t，C-7′)，65.9(t，C-8′)，119.0(d，C-8)，122.6(d，C-2)，124.5(d，C-5′)，124.6(d，C-5)，125.1(d，C-2′)，128.1(d，C-6′)，128.2(d，C-6)，134.5(s，C-1)，138.5(s，C-1′)，142.3(s，C-4′)，143.0(s，C-3′)，146.0(d，C-7)，146.3(s，C-3)，146.6(s，C-4)，168.0(s，C-9)，169.8、169.9、170.1、170.2(each?s，OAc-3，4，3′，4′)；
HRESIMS：m/z?507.12619[M+Na] +(calcd?for?C 25H 24NaO 10，507.12672)。
Embodiment four
The preparation of 3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester
With propanedioic acid 3,4-dihydroxyphenyl ethanol monoesters (is made by embodiment two, 24.02 gram, 100mmol) with 4-hydroxy 3-methoxybenzene formaldehyde (22.82 grams, 150mmol) be dissolved in the pyridine (100mL), add piperidines (10mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour.The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again.The reclaim under reduced pressure ethyl acetate gets the thick product of target compound, this thick product through macroporous adsorbent resin column chromatography (using 70% ethanol elution) separate the pure product of target compound (28.8 gram, yield 87.2%).
The molecular formula of this compound is C 18H 18O 6, yellowish white needle crystal, is dissolved in methyl alcohol, ethyl acetate and the ethanol ferric chloride reaction positive by fusing point 119-120 ℃.
1H-NMR data (MeOD-d 4, 600MHz): δ 2.82 (2H, t, J=7.1Hz, H-7 '), 3.88 (3H, s, OCH 3-3), 4.28 (2H, t, J=7.1Hz, H-8 '), 6.31 (1H, d, J=15.9Hz, H-8), 6.57 (1H, dd, J=2.0/8.0Hz, H-6 '), (6.70 1H, d, J=8.0Hz, H-5 '), 6.71 (1H, d, J=2.0Hz, H-2 '), 6.80 (1H, d, J=8.2Hz, H-5), 7.04 (1H, dd, J=2.0/8.2Hz, H-6), 7.16 (1H, d, J=2.0Hz, H-2), 7.56 (1H, d, J=15.9Hz, H-7);
13C-NMR(MeOH-d 4，150MHz)：δ?35.6(t，C-7′)，56.5(q，OCH 3-3)，66.6(t，C-8′)，111.8(d，C-2)，115.6(d，C-8)，116.5(d，C-5′)，116.5(d，C-5)，117.2(d，C-2′)，121.4(d，C-6′)，124.2(d，C-6)，127.8(s，C-1)，131.0(s，C-1′)，144.9(s，C-4′)，146.3(s，C-3′)，146.8(s，C-7)，149.3(s，C-3)，150.5(d，C-4)，169.3(s，C-9)；
HRESIMS：m/z?353.09904[M+Na] +(calcd?for?C 18H 18NaO 6，353.10011)。
Embodiment five
The preparation of 3-(3-methoxyl group, 4-acetoxyl group phenyl)-allyl acid 2-(3,4-diacetoxy phenyl) ethyl ester
With 3-(3-methoxyl group, the 4-hydroxy phenyl)-allyl acid 2-(3, the 4-dihydroxy phenyl) ethyl ester is (by embodiment four preparations, 1.0 gram) be dissolved in the mixed solvent (50mL) of pyridine and aceticanhydride (2:1), room temperature adds a small amount of distilled water after placing and spending the night, question response thing naturally cooling gets residue behind concentrating under reduced pressure, its residue obtains target compound (1.34 gram) through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification.
This compound molecule formula is C 24H 24O 9, colourless powder is dissolved in methyl alcohol, and ethyl acetate is in the chloroform.
1H-NMR data (MeOH-d 4, 600MHz) δ 2.23,2.24,2.25 (each 3H, s, OAc-4,3 ', 4 '), 2.99 (2H, t, J=6.7Hz, H-7 '), 3.82 (3H, s, OCH 3-3), 4.38 (2H, t, J=6.7Hz, H-8 '), 6.45 (1H, d, J=16.0Hz, H-8), 7.03 (1H, d, J=8.0Hz, H-5), (7.13 1H, d, J=8.2Hz, H-5 '), 7.15 (1H, d, J=2.0Hz, H-2 '), 7.16 (1H, dd, J=1.8/8.0Hz, H-6), (7.17 1H, dd, J=2.0/8.2Hz, H-6 '), 7.27 (1H, d, J=1.8Hz, H-2), 7.59 (1H, d, J=16.0Hz, H-7);
13C-NMR(MeOH-d 4，150MHz)δ?20.6(q，OAc-4，3′，4′)，35.5(t，C-7′)，56.7(q，OCH 3-3)，66.0(t，C-8′)，112.9(d，C-2)，119.2(d，C-8)，122.5(d，C-6)，124.4(d，C-5)，124.6(d，C-5′)，125.3(d，C-2′)，128.27(d，C-6′)，134.9(s，C-1)，138.7(s，C-1′)，142.4(s，C-4′)，143.1(s，C-3′)，143.6(s，C-4)，145.8(d，C-7)，153.1(s，C-3)，168.5(s，C-9)，170.1、170.2、170.6(each?s，OAc-4，3′，4′)。
HRESIMS：m/z?479.13129[M+Na] +(calcd?for?C 24H 24NaO 9，479.13180)。
Embodiment six
The preparation of 3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester
1) 3, the preparation of 4-dimethoxyphenylacetic acid methyl esters: with 3,4-dimethoxyphenylacetic acid (19.62 grams, 100mmol) be dissolved in the 200mL anhydrous methanol, (8.7mL 120mmol) and after stirring 15 minutes, at room temperature places and did not stop in 7-8 hour to stir to add thionyl chloride under the 00C condition gradually.Reactant gets residue behind concentrating under reduced pressure, its residue obtains 3 through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification, 4-dimethoxyphenylacetic acid methyl esters (19.3 grams, yield 91.8%).
2) 3, the preparation of 4-dimethoxy benzene alcoholic acid: with 3,4-dimethoxyphenylacetic acid methyl esters (16.82 grams, 80mmol) be dissolved in the 800mL anhydrous tetrahydro furan, branch add tetrahydrochysene calorize lithium (6.07 grams, 160mmol) after, at room temperature react and do not stop in 9-10 hour to stir.Reactant is used ethyl acetate extraction 3 times to going in the 400mL5% hydrochloric acid soln.Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration.Acetic acid ethyl ester extract obtains 3 through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification, 4-dimethoxy phenylethyl alcohol (13.6 grams, yield 93.6%).
3) propanedioic acid 3, the preparation of 4-dimethoxy phenylethyl alcohol monoesters: with Meldrum ' s acid (12.35 grams, 85.7mmol), 3,4-dimethoxy phenylethyl alcohol (10.93 grams, 60mmol) and the mixture of dioxane (180mL) naturally cooling after under the 95-110 ℃ of condition reflux 5-6 hour.The reactant decompression and solvent recovery, its residue gets propanedioic acid 3 through macroporous adsorbent resin column chromatography (using 30% ethanol elution) separation and purification, 4-dimethoxy phenylethyl alcohol monoesters (14.3 grams, yield 88.9%).
4) 3-(3-methoxyl group, the 4-hydroxy phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) preparation of ethyl ester: with propanedioic acid 3,4-dimethoxy phenylethyl alcohol monoesters (13.41 grams, 50mmol) with 4-hydroxy 3-methoxybenzene formaldehyde (11.41 grams, 75mmol)) be dissolved in the pyridine (50mL), add piperidines (5mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour.The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again.The reclaim under reduced pressure ethyl acetate, its residue through macroporous adsorbent resin column chromatography (using 70% ethanol elution) separate target compound (15.4 gram, yield 85.9%).
This compound molecule formula is C 20H 22O 6, the colourless powder shape is dissolved in methyl alcohol, ethyl acetate and the ethanol.
1H-NMR(MeOH-d 4，600MHz)：δ?2.81(2H，t，J＝7.0Hz，H-7′)，3.79、3.81、3.86(each?3H，s，OCH3-3，4′，3′)，4.25(2H，t，J＝7.0Hz，H-8′)，6.31(1H，d，J＝15.8Hz，H-8)，6.66(1H，dd，J＝1.8/8.0Hz，H-6′)，6.81(1H，d，J＝8.0Hz，H-5)，6.85(1H，d，J＝8.0Hz，H-5′)，6.88(1H，d，J＝1.8Hz，H-2′)，7.06(1H，dd，J＝1.9/8.0Hz，H-6)，7.18(1H，d，J＝1.9Hz，H-2)，7.53(1H，d，J＝15.8Hz，H-7)；
13C-NMR data (MeOH-d 4, 150MHz): δ 35.6 (t, C-7 '), 56.5,56.7,56.9 (each q, OCH 3-3,3 ', 4 '), 66.5 (t, C-8 '), 111.8 (d, C-2), 112.9 (d, C-5 '), 113.8 (d, C-2 '), 115.8 (d, C-8), 116.6 (d, C-5), 121.6 (d, C-6 '), 123.8 (d, C-6), 128.0 (s, C-1), 131.3 (s, C-1 '), 146.6 (s, C-4 '), 147.1 (d, C-7), 148.3 (s, C-3 '), 149.1 (s, C-3), 150.1 (s, C-4), 169.6 (s, C-9);
HRESIMS：m/z381.13061[M+Na] +(calcd?for?C 20H 22NaO 6，381.13141)。
Embodiment seven
The preparation of 3-(3, the 4-dihydroxy phenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters
With 3,4-resorcylic acid and 3,4-Dihydroxy benzaldehyde are raw material, adopt the same procedure of embodiment two to prepare 3-(3, the 4-dihydroxy phenyl)-allyl acid (3, the 4-dihydroxy phenyl) methyl esters, promptly, at first by 3, the 4-resorcylic acid prepares 3, the 4-methyl dihydroxy benzoate; Secondly with 3, the 4-methyl dihydroxy benzoate obtains 3 through the reduction of tetrahydrochysene calorize lithium, the 4-dihydroxybenzyl alcohol, and again with 3,4-dihydroxybenzyl alcohol and Meldrum ＇ s acid-respons prepare propanedioic acid 3,4-dihydroxybenzyl alcohol monoesters; At last with propanedioic acid 3,4-dihydroxybenzyl alcohol monoesters and 3,4-Dihydroxy benzaldehyde prepared in reaction obtains target compound (1.68 gram).
The molecular formula of this compound is C 16H 14O 6, yellowish white needle crystal is dissolved in methyl alcohol, ethyl acetate and the ethanol ferric chloride reaction positive.
1H-NMRMeOD-d 4，600MHz)：δ?5.12(2H，s，H-7′)，6.25(1H，d，J＝15.9Hz，H-8)，6.55(1H，dd，J＝1.9/8.1Hz，H-6′)，6.71(1H，d，J＝8.1Hz，H-5′)，6.73(1H，d，J＝1.9Hz，H-2′)，6.76(1H，d，J＝8.1Hz，H-5)，6.98(1H，dd，J＝2.0/8.1Hz，H-6)，7.05(1H，d，J＝2.0Hz，H-2)，7.51(1H，d，J＝15.9Hz，H-7)；
13C-NMR data (MeOH-d 4, 150MHz): δ 67.2 (t, C-7 '), 115.5 (d, C-2), 115.6 (d, C-8), 116.1 (d, C-5 '), 116.6 (d, C-5), 117.0 (d, C-2 '), 121.8 (d, C-6 '), 123.5 (d, C-6), 127.9 (s, C-1), 130.9 (s, C-1 '), 145.0 (s, C-4 '), (146.9 s, C-3 '), 147.0 (d, C-7), 147.3 (s, C-3), 149.6 (s, C-4), 169.5 (s, C-9);
HRESIMS：m/z?325.06801[M+Na] +(calcd?for?C 16H 14NaO 6，325.06881)。
Embodiment eight
The preparation of 3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-dihydroxy phenyl) propyl ester
With 3,4-dihydroxy-benzene propionic acid and 3,4-Dihydroxy benzaldehyde are raw material, adopt the same procedure of embodiment two to prepare coffic acid 3,4-dihydroxy-benzene propyl ester, that is: and at first by 3,4-dihydroxy-benzene propionic acid prepares 3,4-dihydroxy-benzene methyl propionate; Secondly with 3,4-dihydroxy-benzene methyl propionate obtains 3,4-dihydroxy-benzene propyl alcohol through the reduction of tetrahydrochysene calorize lithium; With 3,4-dihydroxy-benzene propyl alcohol and Meldrum ' s acid-respons prepare propanedioic acid 3,4-dihydroxy-benzene propyl alcohol monoesters again; At last with propanedioic acid 3,4-dihydroxy-benzene propyl alcohol monoesters and 3,4-Dihydroxy benzaldehyde prepared in reaction obtains target compound (1.96 gram).
The molecular formula of this compound is C 18H 18O 6, the yellowish white powder is dissolved in methyl alcohol, ethyl acetate and the ethanol ferric chloride reaction positive.
1H-NMRMeOD-d 4，600MHz)：δ?1.96(2H，m，H-8′)，2.65(2H，t，J＝7.6Hz，H-7′)，4.16(2H，t，J＝6.7Hz，H-9′)，6.21(1H，d，J＝15.9Hz，H-8)，6.57(1H，dd，J＝2.0/8.0Hz，H-6′)，6.70(1H，d，J＝8.0Hz，H-5′)，6.73(1H，d，J＝2.0Hz，H-2′)，6.78(1H，d，J＝8.1Hz，H-5)，6.90(1H，dd，J＝2.0/8.1Hz，H-6)，7.02(1H，d，J＝2.0Hz，H-2)，7.51(1H，d，J＝15.9Hz，H-7)；
13C-NMR data (MeOH-d 4, 150MHz): δ 30.2 (t, C-8 '), 31.5 (t, C-7 '), 63.6 (t, C-9 '), 115.2 (d, C-2), 115.5 (d, C-8), 116.6 (d, C-5 '), 116.7 (d, C-5), 117.3 (d, C-2 '), 121.5 (d, C-6 '), 123.3 (d, C-6), 127.8 (s, C-1), 131.1 (s, C-1 '), (145.0 s, C-4 '), 146.6 (s, C-3 '), 147.1 (d, C-7), 147.4 (s, C-3), 149.5 (s, C-4), 169.3 (s, C-9);
HRESIMS：m/z?353.09926[M+Na] +(calcd?for?C 18H 18NaO 6，353.10011)。
Embodiment nine
The preparation of 3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) allyl ester
1) 3, the preparation of 4-dimethoxy-cinnamic acid methyl esters: with 3,4-dimethoxy-cinnamic acid (20.82 grams, 100mmol) be dissolved in the 200mL anhydrous methanol, (8.7mL 120mmol) and after stirring 15 minutes, at room temperature places and did not stop in 7-8 hour to stir to add thionyl chloride under the 00C condition gradually.Reactant gets residue behind concentrating under reduced pressure, its residue obtains 3 through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification, 4-dimethoxy-cinnamic acid methyl esters (19.9 grams, yield 89.4%).
2) 3, the preparation of 4-dimethoxy cinnamyl alcohol: with 3,4-dimethoxy-cinnamic acid methyl esters (17.78 grams, 80mmol) be dissolved in the 800mL anhydrous tetrahydro furan, branch add tetrahydrochysene calorize lithium (6.07 grams, 160mmol) after, at room temperature react and do not stop in 9-10 hour to stir.Reactant is used ethyl acetate extraction 3 times to going in the 400mL5% hydrochloric acid soln.Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration.Acetic acid ethyl ester extract obtains 3 through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification, 4-dimethoxy cinnamyl alcohol (13.8 grams, yield 88.8%).
3) propanedioic acid 3, the preparation of 4-dimethoxy cinnamyl alcohol monoesters: with Meldrum ' s acid (12.98 grams, 90mmol), 3,4-dimethoxy cinnamyl alcohol (11.65 grams, 60mmol) and the mixture of dioxane (180mL) naturally cooling after under the 95-110 ℃ of condition reflux 5-6 hour.The reactant decompression and solvent recovery, its residue gets propanedioic acid 3 through macroporous adsorbent resin column chromatography (using 35% ethanol elution) separation and purification, 4-dimethoxy cinnamyl alcohol monoesters (14.4 grams, yield 85.4%).
4) 3-(3, the 4-dihydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) preparation of allyl ester: with propanedioic acid 3,4-dimethoxy cinnamyl alcohol monoesters (14.02 grams, 50mmol) with 3, (10.42 grams 75mmol) are dissolved in the pyridine (50mL) the 4-Dihydroxy benzaldehyde, add piperidines (5mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour.The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again.The reclaim under reduced pressure ethyl acetate, its residue through macroporous adsorbent resin column chromatography (using 70% ethanol elution) separate target compound (14.6 gram, yield 82.0%).
This compound molecule formula is C 20H 20O 6, colourless powder is dissolved in methyl alcohol, ethyl acetate, and in the ethanol, the ferric chloride reaction positive, apparent blue-fluorescence under the ultraviolet lamp.
1H-NMR data (MeOH-d 4, 600MHz) δ 3.78 (3H, s, OCH 3-4 '), 3.79 (3H, s, OCH 3-3 '), 4.85 (2H, d, J=6.3Hz, H-9 '), (6.23 1H, dt, J=6.3/15.9Hz, H-8 '), 6.33 (1H, d, J=15.8Hz, H-8), 6.63 (1H, d, J=15.9Hz, H-7 '), 6.70 (1H, dd, J=1.8/8.0Hz, H-6 '), 6.79 (1H, d, J=8.0Hz, H-5), (6.83 1H, d, J=8.0Hz, H-5 '), (6.88 1H, d, J=1.8Hz, H-2 '), 6.93 (1H, dd, J=1.8/8.0Hz, H-6), 7.06 (1H, d, J=1.8Hz, H-2), 7.58 (1H, d, J=15.8Hz, H-7);
13C-NMR(MeOH-d 4，150MHz)：δ?56.1(q，OCH 3-3′)，56.3(q，OCH 3-4′)，65.3(t，C-9′)，111.0(d，C-2′)，111.6(d，C-5′)，115.8(d，C-2)，115.9(d，C-8)，116.8(d，C-5)，122.0(d，C-6′)，123.5(d，C-6)，127.3(d，C-8′)，128.0(s，C-1)，129.2(d，C-7′)，133.2(s，C-1′)，146.9(d，C-7)，147.0(s，C-3)，149.3(s，C-3′)，150.0(s，C-4)，150.6(s，C-4′)，169.3(s，C-9)；
HRESIMS：m/z?379.11506[M+Na] +(calcd?for?C 20H 20NaO 6，379.11576)。
Embodiment ten
The preparation of 3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
1) preparation of 3-methyl-toluate: with 3-tolyl acid (13.62 grams, 100mmol) be dissolved in the 200mL anhydrous methanol, (8.7mL 120mmol) and after stirring 15 fens, at room temperature places and did not stop in 7-8 hour to stir to add thionyl chloride under the 00C condition gradually.Reactant behind concentrating under reduced pressure residue, its residue separates through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) and obtains 3-methyl-toluate (14.0 restrain, yield 93.1%).
2) preparation of 3-methylbenzyl alcohol: with the 3-methyl-toluate (9.1 grams 60mmol) are dissolved in the 600mL anhydrous tetrahydro furan, branch add tetrahydrochysene calorize lithium (4.55 grams, 120mmol) after, at room temperature react and do not stop in 9-10 hour to stir.Reactant is used ethyl acetate extraction 3 times to going in the 300mL5% hydrochloric acid soln.Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration.Acetic acid ethyl ester extract obtains 3-methylbenzyl alcohol (6.8 grams, yield 92.6%) through silica gel column chromatography (with hexanaphthene and ethyl acetate mixed solvent wash-out) separation and purification.
1H-NMR data (MeOH-d 4, 600MHz) δ 1.95 (3H, s, CH 3-3), 4.56 (2H, s, H-7), 7.04 (1H, d, J=7.5Hz, H-6), 7.13 (1H, d, J=7.5Hz, H-4), 7.16 (1H, brs, H-2), 7.19 (1H, t, J=7.5Hz, H-5);
13C-NMR(MeOH-d 4，150MHz)δ?21.7(q，CH 3-3)，65.3(t，C-7)，125.1(d，C-4)，128.7(d，C-2)，129.0(d，C-6)，129.3(d，C-5)，138.9(s，C-1)，142.4(s，C-3)。
3) preparation of propanedioic acid 3-methylbenzyl alcohol monoesters: with Meldrum ' s acid (8.64 grams, 60mmol), the 3-methylbenzyl alcohol (4.89 grams, 40mmol) and the mixture of dioxane (100mL) naturally cooling after under the 95-110 ℃ of condition reflux 5-6 hour.The reactant decompression and solvent recovery, its residue gets propanedioic acid 3-methylbenzyl alcohol monoesters (7.4 grams, yield 88.6%) through macroporous adsorbent resin column chromatography (using 35% ethanol elution) separation and purification.
4) 3-(3-methoxyl group, the 4-hydroxy phenyl)-preparation of allyl acid (2-aminomethyl phenyl) methyl esters: with propanedioic acid 3-methylbenzyl alcohol monoesters (6.25 grams, 30mmol) with 4-hydroxy 3-methoxybenzene formaldehyde (6.09 grams, 40mmol) be dissolved in the pyridine (30mL), add piperidines (3mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour.The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again.The reclaim under reduced pressure ethyl acetate, its residue obtains target compound (7.7 grams, yield 86.3%) through macroporous adsorbent resin column chromatography (using 75% ethanol elution) separation.
The molecular formula of this compound is C 18H 18O 4, colourless powder is dissolved in methyl alcohol, and ethyl acetate is in the ethanol.
1H-NMR data (MeOH-d 4, 600MHz): δ 2.25 (3H, s, CH 3-3 '), 3.77 (3H, s, OCH 3-3), 5.10 (2H, s, H-7 '), 6.30 (1H, d, J=15.9Hz, H-8), 6.76 (1H, d, J=8.2Hz, H-5), 6.94 (1H, dd, J=1.9/8.2Hz, H-6), 7.04 (1H, d, J=1.9Hz, H-2), 7.05 (1H, d, J=7.5Hz, H-6 '), 7.11 (1H, d, J=7.5Hz, H-4 '), 7.13 (1H, brs, H-2 '), 7.16 (1H, t, J=7.5Hz, H-5 '), 7.56 (1H, d, J=15.9Hz, H-7);
13C-NMR data (MeOH-d 4, 150MHz) δ 21.6 (q, CH 3-3 '), 56.4 (q, OCH 3-3), 67.3 (t, C-7 '), 111.7 (d, C-2), 115.4 (d, C-8), 116.5 (d, C-5), 124.2 (d, C-6), 126.4 (d, C-4 '), 127.6 (s, C-1), 129.5 (d, C-5 '), 130.0 (d, C-2 '), 130.0 (d, C-6 '), 137.6 (s, C-1 '), (139.3 s, C-3 '), 147.0 (d, C-7), 149.1 (s, C-3), 150.3 (s, C-4), 169.0 (s, C-9).
HRESIMS：m/z?321.11006[M+Na] +(calcd?for?C 18H 18NaO 4，321.11028)。
Embodiment 11
The preparation of 3-(3-methoxyl group, 4-acetoxyl group phenyl)-allyl acid (2-aminomethyl phenyl) methyl esters
With 3-(3-methoxyl group, the 4-hydroxy phenyl)-allyl acid (2-aminomethyl phenyl) is (by embodiment ten preparation, 1.49 gram) be dissolved in the mixed solvent (80mL) of pyridine and aceticanhydride (2:1), room temperature adds a small amount of distilled water after placing and spending the night, question response thing naturally cooling gets residue behind concentrating under reduced pressure, its residue obtains target compound (1.59 gram) through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) separation and purification.
The molecular formula of this compound is C 20H 20O 5, colourless powder is dissolved in methyl alcohol, and ethyl acetate is in the chloroform.
1H-NMR data (MeOH-d 4, 600MHz): δ 2.23 (3H, OAc-4), 2.31 (3H, s, CH 3-3 '), 3.77 (3H, s, OCH 3-3), 5.16 (2H, s, H-7 '), 6.49 (1H, d, J=15.9Hz, H-8), 6.99 (1H, d, J=8.0Hz, H-5), 7.09 (1H, dd, J=1.8/8.0Hz, H-6), 7.12 (1H, d, J=7.5Hz, H-6 '), 7.16 (1H, d, J=7.5Hz, H-4 '), 7.20 (1H, brs, H-2 '), (7.21 1H, t, J=7.5Hz, H-5 '), 7.22 (1H, d, J=1.8Hz, H-2), 7.62 (1H, d, J=15.9Hz, H-7);
13C-NMR data (MeOH-d 4, 150MHz): δ 20.6 (q, OAc-4), 21.6 (q, CH 3-3 '), 56.6 (q, OCH 3-3), 67.6 (t, C-7 '), 112.9 (d, C-2), 119.2 (d, C-8), 122.4 (d, C-6), 124.4 (d, C-5), 126.5 (d, C-4 '), 129.6 (d, C-5 '), 130.1 (d, C-2 '), 130.1 (d, C-6 '), 134.8 (s, C-1), 137.6 (s, C-1 '), 139.5 (s, C-3 '), 143.1 (s, C-4), 145.9 (d, C-7), 153.0 (s, C-3), 168.4 (s, C-9), 170.6 (s, OAc-4).
HRESIMS?m/z?363.12013[M+Na] +(calcd?for?C 20H 20NaO 5，363.12084)。
Two, prepare benzene allyl acid benzene hydrocarbon base ester compound by chloride method
Embodiment 12
The preparation of 3-(3-hydroxyl, 4-p-methoxy-phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester: synthetic route is referring to accompanying drawing 2
1) 3, the preparation of 4-dimethoxy benzene alcoholic acid: with 3, (9.81 grams 50mmol) prepare 3 for raw material adopts embodiment two identical methods to the 4-dimethoxyphenylacetic acid, 4-dimethoxy phenylethyl alcohol (7.6 gram);
2) 3-(3-hydroxyl, the 4-p-methoxy-phenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) preparation of ethyl ester: (3.88 grams 20mmol) are dissolved in the 200mL dioxane, and the back adds thionyl chloride (4.4mL with 3-hydroxyl-4-methoxy cinnamic acid, 60mmol), mixture and argon add 3 in heating under the 96-100 ℃ of condition after 3 hours again, 4-dimethoxy phenylethyl alcohol (5.47 grams, 30mmol), its mixture continues heating 5-6 hour under 96-100 ℃ of condition.Behind the reactant decompression and solvent recovery residue, its residue separates through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) and obtains target compound (4.3 restrain, yield 60.0%).
This compound molecule formula is C 20H 22O 6
1H-NMR data (MeOH-d 4, 600MHz) δ 2.82 (2H, t, J=6.9Hz, H-7 '), 3.78,3.82,3.85 (each 3H, s, OCH 3-4,3 ', 4 '), 4.27 (2H, t, J=6.9Hz, H-8 '), 6.32 (1H, d, J=15.8Hz, H-8), 6.67 (1H, dd, J=1.8/8.0Hz, H-6 '), 6.86 (1H, d, J=8.0Hz, H-5 '), 6.87 (1H, d, J=1.8Hz, H-2 '), 6.91 (1H, dd, J=1.9/8.0Hz, H-6), 6.97 (1H, d, J=8.0Hz, H-5), 7.03 (1H, d, J=1.9Hz, H-2), 7.55 (1H, d, J=15.8Hz, H-7);
13C-NMR data (MeOH-d 4, 150MHz) δ 35.7 (t, C-7 '), 56.1,56.3,56.6 (each q, OCH 3-4,3 ', 4 '), 66.6 (t, C-8 '), 112.8 (d, C-5 '), 112.9 (d, C-5), 113.8 (d, C-2 '), 115.6 (d, C-2), 115.8 (d, C-8), 121.7 (d, C-6 '), 123.7 (d, C-6), 128.3 (s, C-1), 131.2 (s, C-1 '), 146.5 (s, C-4 '), 147.0 (d, C-7), 148.7 (s, C-3 '), 149.1 (s, C-3), 151.2 (s, C-4), 169.5 (s, C-9);
HRESIMS?m/z?381.13056[M+Na] +(calcd?for?C 20H 22NaO 6，381.13141)。
Embodiment 13
The preparation of 3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
With 3,4-dimethoxybenzoic acid and forulic acid are raw material, adopt the same procedure of embodiment 12 to prepare target compound (3.96 gram).
This compound molecule formula is C 19H 20O 6
1H-NMR(MeOH-d 4，600MHz)δ?3.78、3.80、3.87(each?3H，s，OCH 3-3，3′，4′)，5.11(2H，s，H-7′)，6.32(1H，d，J＝15.8Hz，H-8)，6.68(1H，dd，J＝1.9/8.0Hz，H-6′)，6.80(1H，d，J＝8.0Hz，H-5)，6.85(1H，d，J＝8.0Hz，H-5′)，6.88(1H，d，J＝1.9Hz，H-2′)，7.05(1H，dd，J＝1.9/8.0Hz，H-6)，7.17(1H，d，J＝1.9Hz，H-2)，7.54(1H，d，J＝15.8Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)：δ?56.2、56.4、56.6(each?q，OCH 3-3，3′，4′)，67.3(t，C-7′)，111.9(d，C-2)，113.1(d，C-5′)，113.6(d，C-2′)，115.7(d，C-8)，116.7(d，C-5)，121.8(d，C-6′)，123.9(d，C-6)，128.1(s，C-1)，131.3(s，C-1′)，146.0(s，C-4′)，147.0(d，C-7)，148.3(s，C-3′)，149.2(s，C-3)，150.2(s，C-4)，169.5(s，C-9)；
HRESIMS?m/z?367.11518[M+Na] +(calcd?for?C 19H 20NaO 6，367.11576)。
Embodiment 14
The preparation of 3-(3-methoxyl group, 4-hydroxy phenyl)-allyl acid 3-(3, the 4-Dimethoxyphenyl) propyl ester
With forulic acid and 3,4-dimethoxy phenylpropionic acid is a raw material, adopts the same procedure of embodiment 12 to prepare target compound (4.18 gram).
This compound molecule formula is C 21H 24O 6
1H-NMR(MeOH-d 4，600MHz)δ?1.95(2H，m，H-8′)，2.66(2H，t，J＝7.5Hz，H-7′)，3.79，3.81，3.86(each?3H，s，OCH 3-3，3′，4′)，4.15(2H，t，J＝6.7Hz，H-9′)，6.31(1H，d，J＝15.9Hz，H-8)，6.66(1H，dd，J＝1.9/8.0Hz，H-6′)，6.81(1H，d，J＝8.0Hz，H-5)，6.86(1H，d，J＝8.0Hz，H-5′)，6.88(1H，d，J＝1.9Hz，H-2′)，7.05(1H，dd，J＝1.9/8.0Hz，H-6)，7.16(1H，d，J＝1.9Hz，H-2)，7.53(1H，d，J＝15.9Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)δ?30.3(t，C-8′)，31.6(t，C-7′)，56.5、56.7、56.9(each?q，OCH 3-3，3′，4′)，63.8(t，C-9′)，111.8(d，C-2)，113.0(d，C-5′)，113.1(d，C-2′)，115.6(d，C-8)，116.6(d，C-5)，121.7(d，C-6′)，123.5(d，C-6)，127.9(s，C-1)，130.9(s，C-1′)，146.5(s，C-4′)，148.5(s，C-3′)，147.1(d，C-7)，149.2(s，C-3)，150.1(s，C-4)，169.6(s，C-9)；
HRESIMS?m/z?395.14687[M+Na] +(calcd?for?C 21H 24NaO 6，395.14706)。
Three, be equipped with benzene allyl acid benzene hydrocarbon base ester compound by CDI and DBU catalytic esterification legal system
Embodiment 15
The preparation of 3-(3, the 4-Dimethoxyphenyl)-allyl acid 2-(3, the 4-Dimethoxyphenyl) ethyl ester: synthetic line is referring to accompanying drawing 3
Earlier with 3, the 4-dimethoxyphenylacetic acid is a raw material, prepare 3 with embodiment two identical methods, 4-dimethoxy phenylethyl alcohol (3.06 gram), then with 3,4-dimethoxy-cinnamic acid (2.09 grams, 10mmol) be dissolved in the 100mL tetrahydrofuran (THF), (2.3 restrain, 14.4mmol) to add CDI, its mixture and argon are after 40-45 ℃ of stirring reaction 15-20 minute, add again and contain 3,4-dimethoxy phenylethyl alcohol (2.01 grams, 11mmol) and DBU (1.68 restrain, tetrahydrofuran solution 11mmol) (100mL), its mixture continue reaction 20-24 hour under 40-45 ℃ of condition.Behind the reactant decompression and solvent recovery residue, its residue separates through silica gel column chromatography (with the mixed solvent wash-out of hexanaphthene and ethyl acetate) and obtains target compound (2.1 restrain, yield 56.5%).
This compound molecule formula is C 21H 24O 6
1H-NMR(MeOH-d 4，600MHz)δ?2.81(2H，t，J＝6.8Hz，H-7′)，3.78、3.82、3.85、3.86(each?3H，s，OCH 3-3，4，3′，4′)，4.28(2H，t，J＝6.8Hz，H-8′)，6.33(1H，d，J＝15.8Hz，H-8)，6.68(1H，dd，J＝1.8/8.0Hz，H-6′)，6.85(1H，d，J＝8.0Hz，H-5′)，6.86(1H，d，J＝1.8Hz，H-2′)，6.93(1H，dd，J＝1.9/8.0Hz，H-6)，6.97(1H，d，J＝8.0Hz，H-5)，7.16(1H，d，J＝1.9Hz，H-2)，7.56(1H，d，J＝15.8Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)δ?35.6(t，C-7′)，55.5、56.6、56.7、56.9(each?q，OCH 3-3，4，3′，4′)，66.5(t，C-8′)，111.9(d，C-2)，112.7(d，C-5′)，112.8(d，C-5)，113.6(d，C-2′)，115.6(d，C-8)，121.8(d，C-6′)，123.9(d，C-6)，128.1(s，C-1)，131.1(s，C-1′)，146.6(s，C-4′)，147.1(d，C-7)，148.3(s，C-3′)，150.1(s，C-3)，151.2(s，C-4)，169.6(s，C-9)；
HRESIMS?m/z?395.14668[M+Na] +(calcd?for?C 21H 24NaO 6，395.14706)。
Embodiment 16
The preparation of 3-(3, the 4-Dimethoxyphenyl)-allyl acid (3, the 4-Dimethoxyphenyl) methyl esters
With 3, the 4-dimethoxybenzoic acid is a raw material, makes 3 with embodiment two identical methods earlier, the 4-3,5-dimethoxybenzoic alcohol, again with 3,4-dimethoxy-cinnamic acid and 3, the 4-3,5-dimethoxybenzoic alcohol is a raw material, adopts embodiment 15 same procedure to make target compound (2.36 gram).
This compound molecule formula is C 20H 22O 6
1H-NMR(MeOH-d 4，600MHz)δ?3.79、3.81、3.82、3.85(each?3H，s，OCH 3-3，4，3′，4′)，5.13(2H，s，H-7′)，6.31(1H，d，J＝15.9Hz，H-8)，6.67(1H，dd，J＝1.8/8.0Hz，H-6′)，6.86(1H，d，J＝8.0Hz，H-5′)，6.87(1H，d，J＝1.8Hz，H-2′)，6.95(1H，dd，J＝1.9/8.0Hz，H-6)，6.98(1H，d，J＝8.0Hz，H-5)，7.15(1H，d，J＝1.9Hz，H-2)，7.53(1H，d，J＝15.9Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)δ?55.6、56.7、56.8、56.9(each?q，OCH 3-3，4，3′，4′)，67.5(t，C-8′)，111.8(d，C-2)，112.6(d，C-5′)，112.8(d，C-5)，113.5(d，C-2′)，115.5(d，C-8)，121.9(d，C-6′)，123.8(d，C-6)，128.0(s，C-1)，131.0(s，C-1′)，146.5(s，C-4′)，147.1(d，C-7)，148.5(s，C-3′)，150.0(s，C-3)，151.3(s，C-4)，169.6(s，C-9)；
HRESIMS?m/z?381.13100[M+Na] +(calcd?for?C 20H 22NaO 6，381.13141)。
Embodiment 17
The preparation of 3-(3, the 4-Dimethoxyphenyl)-allyl acid 3-(3-methoxyl group, 4-hydroxy phenyl) propyl ester
Be raw material with 4-hydroxyl 3-anisole propionic acid earlier, make 4-hydroxyl 3-anisole propyl alcohol with embodiment two identical methods, with 3,4-dimethoxy-cinnamic acid and 4-hydroxy 3-methoxybenzene propyl alcohol are raw material again, adopt embodiment 15 same procedure to make target compound (2.66 gram).
This compound molecule formula is C 21H 24O 6
1H-NMR(MeOH-d 4，600MHz)δ?1.95(2H，m，H-8′)，2.66(2H，t，J＝7.5Hz，H-7′)，4.17(2H，t，J＝6.6Hz，H-9′)，3.78、3.84、3.86(each?3H，s，OCH 3-3，4，3′)，6.32(1H，d，J＝15.8Hz，H-8)，6.68(1H，dd，J＝1.9/8.0Hz，H-6′)，6.71(1H，d，J＝8.0Hz，H-5′)，6.85(1H，d，J＝1.9Hz，H-2′)，6.93(1H，dd，J＝1.9/8.0Hz，H-6)，6.97(1H，d，J＝8.0Hz，H-5)，7.16(1H，d，J＝1.9Hz，H-2)，7.54(1H，d，J＝15.8Hz，H-7)；
13C-NMR(MeOH-d 4，150MHz)δ?30.1(t，C-8′)，31.5(t，C-7′)，55.5、56.6、56.9(each?q，OCH 3-3，4，3′)，63.8(t，C-9′)，111.9(d，C-2)，112.7(d，C-5)，113.4(d，C-2′)，115.6(d，C-5′)，115.7(d，C-8)，121.8(d，C-6′)，123.7(d，C-6)，128.1(s，C-1)，131.1(s，C-1′)，144.6(s，C-4′)，147.0(d，C-7)，148.1(s，C-3′)，150.1(s，C-3)，151.2(s，C-4)，169.5(s，C-9)；
HRESIMS?m/z?395.14675[M+Na] +(calcd?for?C 21H 24NaO 6，395.14706)。

Claims (10)

1, the preparation method of the benzene allyl of structural formula (1) acid benzene hydrocarbon base ester compound,
Figure A200910115002C00021
Wherein, m is 0,1,2,3,4 or 5,
Each R 1Represent hydroxyl, methyl, methoxyl group or acetoxyl group independently of one another,
L represents C 1-C 3Alkyl,
T is 0,1,2,3 or 4,
Each R 2Represent hydroxyl, methyl, methoxyl group or acetoxyl group independently of one another,
Comprise following reactions steps:
With the acid compounds esterification of structural formula (2),
Figure A200910115002C00022
Wherein X represents C 0-C 2Alkyl, the esterification thing of generating structure formula (3),
Figure A200910115002C00023
Be reduced into the alcohol compound of structural formula (4) then,
Figure A200910115002C00024
Then
(a) with the alcohol compound of structural formula (4) and the Meldrum ' s acid-respons of structural formula (5),
Figure A200910115002C00025
The malonic acid monoester compound of generating structure formula (6),
Figure A200910115002C00031
Aldehyde compound last and structural formula (7) reacts;
Figure A200910115002C00032
Or
(b) alcohol compound of structural formula (4) and the acid compounds of structural formula (8) are reacted.
2, according to the preparation method of the described benzene allyl of claim 1 acid benzene hydrocarbyl carbonate, it is characterized in that, the acid compounds of structural formula (2) is dissolved in the anhydrous methanol, adding the thionyl chloride stirring under the zero degree condition gradually after 10-15 minute, at room temperature place and do not stop in 7-8 hour to stir, reactant promptly gets the esterification thing of structural formula (3) through column chromatographic isolation and purification; The amount ratio of described structural formula (2) acid compounds, thionyl chloride and methyl alcohol is 1.0 (mmol): 1.2-1.3 (mmol): 2-4 (mL).
3, according to the preparation method of the described benzene allyl of claim 1 acid benzene hydrocarbyl carbonate, it is characterized in that, the esterification thing of structural formula (3) is dissolved in the anhydrous tetrahydro furan, progressively add tetrahydrochysene calorize lithium, room temperature is placed and was not stopped in 9-10 hour to stir, and reactant promptly gets the alcohol compound of structural formula (4) through column chromatographic isolation and purification; The amount ratio of the methyl compound of described structural formula (3), tetrahydrochysene calorize lithium and tetrahydrofuran (THF) is 1.0 (mmol): 2.0-3.0 (mmol): 10-12 (mL).
4, according to the preparation method of the described benzene allyl of claim 1 acid benzene hydrocarbyl carbonate, it is characterized in that, in the described method (a), Meldrum ' s the acid of the alcohol compound of structural formula (4) and structural formula (5) is dissolved in dioxane, 95-110 ℃ was reacted 5-6 hour, and was cooled to room temperature afterreaction thing promptly gets structural formula (6) through column chromatographic isolation and purification malonic acid monoester compound; Meldrum ' s the acid of the alcohol compound of described structural formula (4), structural formula (5) and the amount ratio of dioxane are 1.4-2.0 (mmol): 1.0 (mmol): 2-4 (mL).
5, according to the preparation method of the described benzene allyl of claim 1 acid benzene hydrocarbyl carbonate, it is characterized in that: in the described method (a), the aldehyde compound of the malonic acid monoester compound of structural formula (6) and structural formula (7) is dissolved in the pyridine, add piperidines again, stir under the room temperature after 36-48 hour, reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; The amount ratio of aldehyde compound, pyridine and the piperidines of the malonic acid monoester compound of described structural formula (6), structural formula (7) is 1.0 (mmol): 1.3-1.6 (mmol): 1.0-1.2 (mL): 0.1-0.12 (mL).
According to the preparation method of the described benzene allyl acid of claim 1 benzene hydrocarbyl carbonate, it is characterized in that 6, in the described method (b), the alcohol compound of structural formula (4) reacts by the acid compounds of following reactions steps and structural formula (8):
(i) with the acid compounds carboxyl chloride of structural formula (8), the chloride compounds of generating structure formula (9),
Figure A200910115002C00041
(ii) the chloride compounds of described structural formula (9) and the alcohol compound of structural formula (4) are reacted.
7, according to the preparation method of the described benzene allyl of claim 6 acid benzene hydrocarbyl carbonate, it is characterized in that, the acid compounds of structural formula (8) is dissolved in dioxane, feed argon gas, add thionyl chloride, 96-100 ℃ was reacted 3 hours down, adds the alcohol compound of structural formula (4) again, 96-100 ℃ is continued reaction 5-6 hour down, and reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; The amount ratio of alcohol compound, thionyl chloride and the dioxane of the acid compounds of described structural formula (8), structural formula (4) is 1.0 (mmol): 1.5-2.0 (mmol): 3.0-4.0 (mmol): 10-13 (mL).
8, according to the preparation method of the described benzene allyl of claim 1 acid benzene hydrocarbyl carbonate, it is characterized in that: in the described method (b), at N, N-carbonyl dimidazoles and 1,8-diazabicylo (5,4,0) under hendecene-7 catalysis, the acid compounds generation esterification of the alcohol compound of structural formula (4) and structural formula (8).
9, according to the preparation method of the described benzene allyl of claim 8 acid benzene hydrocarbyl carbonate, it is characterized in that: the acid compounds of structural formula (8) is dissolved in the tetrahydrofuran (THF), add N, the N-carbonyl dimidazoles, feed argon gas, 40-45 ℃ after stirring reaction 15-20 minute, the alcohol compound and 1 that adds structural formula (4) again, 8-diazabicylo (5,4,0) tetrahydrofuran solution of hendecene-7, mixture continue to react 20-24 hour down at 40-45 ℃, and reactant promptly gets the benzene allyl acid benzene hydrocarbyl carbonate of structural formula (1) through column chromatographic isolation and purification; Alcohol compound, the N of the acid compounds of described structural formula (8), structural formula (4), N-carbonyl dimidazoles, 1,8-diazabicylo (5,4,0) amount ratio of hendecene-7 and tetrahydrofuran (THF) is 1.0 (mmol): 1.1-1.2 (mmol): 1.4-1.6 (mmol): 1.1-1.3 (mmol): 10-12 (mL).
According to the preparation method of the described benzene allyl acid of claim 1 benzene hydrocarbon base ester compound, it is characterized in that 10, described benzene allyl acid benzene hydrocarbon base ester compound is the coffic acid 3 of structural formula (10), 4-dihydroxy-benzene ethyl ester,
Figure A200910115002C00042
Prepare through following reactions steps:
The preparation of (1) 3,4-dihydroxyphenyl acetic acid methyl esters: with 3, the 4-dihydroxyphenyl acetic acid is dissolved in the anhydrous methanol, after adding thionyl chloride under the 00C condition gradually and stirring 15 minutes, at room temperature places and does not stop in 7-8 hour to stir; Reactant will contain 3 through the mixed solvent wash-out of silica gel column chromatography with hexanaphthene and ethyl acetate (4:1), and the elutriant of 4-dihydroxyphenyl acetic acid methyl esters merges back recovery solvent and obtains 3,4-dihydroxyphenyl acetic acid methyl esters; Described 3, the amount ratio of 4-dihydroxyphenyl acetic acid, thionyl chloride and methyl alcohol is 1.0 (mmol): 1.2-1.3 (mmol): 2-4 (mL);
The preparation of (2) 3,4-dihydroxyphenyl ethanols: with described step (1) make 3,4-dihydroxyphenyl acetic acid methyl esters is dissolved in the anhydrous tetrahydro furan, progressively add tetrahydrochysene calorize lithium after, at room temperature react and do not stop in 9-10 hour to stir; Reactant is poured in 5% hydrochloric acid soln, uses ethyl acetate extraction 3 times; Acetic acid ethyl acetate extract after the merging reclaims solvent and gets acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration; Acetic acid ethyl ester extract is through silica gel column chromatography, and the mixed solvent wash-out with hexanaphthene and ethyl acetate (2:1) will contain 3, and the elutriant of 4-dihydroxyphenyl ethanol merges back recovery solvent and obtains 3, the 4-dihydroxyphenyl ethanol; Described 3, the amount ratio of 4-dihydroxyphenyl acetic acid methyl esters, tetrahydrochysene calorize lithium and tetrahydrofuran (THF) is 1.0 (mmol): 2.0-3.0 (mmol): 10-12 (mL);
(3) propanedioic acid 3, the preparation of 4-dihydroxyphenyl ethanol monoesters: with Meldrum ' s acid, described step (2) make 3, the mixture of 4-dihydroxyphenyl ethanol and dioxane under 95-110 ℃ of condition 56 hours postcooling of reflux to room temperature; Decompression and solvent recovery, residue are used 30% ethanol elution through macroporous adsorbent resin column chromatography, must fall propanedioic acid 3,4-dihydroxyphenyl ethanol monoesters; Described 3, the amount ratio of 4-dihydroxyphenyl ethanol, Meldrum ' s acid and dioxane is 1.4-2.0 (mmol): 1.0 (mmol): 2-4 (mL);
(4) coffic acid 3, the preparation of 4-dihydroxy-benzene ethyl ester: with the propanedioic acid 3 that described step (3) makes, 4-dihydroxyphenyl ethanol monoesters and 3, the 4-Dihydroxy benzaldehyde is dissolved in the pyridine, add piperidines (20mL) again, its mixture did not at room temperature stop stirring reaction 36-48 hour; The reactant decompression and solvent recovery, its residue is dissolved in the ethyl acetate, uses 5% hydrochloric acid and distilled water wash respectively, spends the night with anhydrous magnesium sulfate drying again; The reclaim under reduced pressure ethyl acetate gets coffic acid 3,4-dihydroxy-benzene ethyl ester crude product, and this crude product is used 65% ethanol elution through macroporous adsorbent resin column chromatography, obtains coffic acid 3, the pure product of 4-dihydroxy-benzene ethyl ester.
CN2009101150024A 2009-03-05 2009-03-05 Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound Expired - Fee Related CN101497567B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2009101150024A CN101497567B (en) 2009-03-05 2009-03-05 Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2009101150024A CN101497567B (en) 2009-03-05 2009-03-05 Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound

Publications (2)

Publication Number Publication Date
CN101497567A true CN101497567A (en) 2009-08-05
CN101497567B CN101497567B (en) 2012-07-25

Family

ID=40944862

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2009101150024A Expired - Fee Related CN101497567B (en) 2009-03-05 2009-03-05 Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound

Country Status (1)

Country Link
CN (1) CN101497567B (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774918A (en) * 2009-12-31 2010-07-14 华侨大学 Preparation method of cinnamate derivates
CN101993376A (en) * 2010-10-29 2011-03-30 西南大学 Caffeic acid p-nitrophenyl ethyl ester as well as preparation method and application of caffeic acid p-nitrophenyl ethyl ester
CN102503826A (en) * 2011-10-06 2012-06-20 中国科学院昆明植物研究所 Compound Blapsins A and B, pharmaceutical composition containing the same, and preparation method and application thereof
CN102949384A (en) * 2012-10-29 2013-03-06 浙江大学 Application of coffee acid 3, 4-dihydroxy benzene ethyl ester to preparation of antitumor drug
CN104592025A (en) * 2015-02-04 2015-05-06 杨安民 Ferulate compound and preparation method thereof
JP2016074606A (en) * 2014-10-02 2016-05-12 富士フイルム株式会社 Method for producing 3,4,5-tricaffeoylquinic acid
CN108164398A (en) * 2018-01-26 2018-06-15 山东省药学科学院 A kind of improved method of hydroxytyrosol synthesis technology
CN108752212A (en) * 2015-03-06 2018-11-06 北京大学 9- decarboxylation Rosmarinic acid analogs and its synthetic method and application
CN109456183A (en) * 2018-11-21 2019-03-12 浙江科技学院 A kind of preparation method of coffee acid benzyl ester
CN109942429A (en) * 2019-03-01 2019-06-28 陕西科技大学 Novel hydroxyl tyrosol shikimate compound and its preparing the application in cardiovascular medicament
CN111807958A (en) * 2020-08-14 2020-10-23 蔚源生物科技(平顶山)有限公司 Synthesis method of caffeic acid phenethyl ester

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5364700A (en) * 2000-01-13 2001-07-19 Medicam Chemical & Pharmaceutical Co., Ltd. One pot processes for preparation of caffeic acid ester derivatives
CN1332929C (en) * 2005-07-21 2007-08-22 浙江工业大学 One-pot-method for preparing caffeic acid ester derivants

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774918A (en) * 2009-12-31 2010-07-14 华侨大学 Preparation method of cinnamate derivates
CN101993376A (en) * 2010-10-29 2011-03-30 西南大学 Caffeic acid p-nitrophenyl ethyl ester as well as preparation method and application of caffeic acid p-nitrophenyl ethyl ester
CN101993376B (en) * 2010-10-29 2013-06-12 西南大学 Caffeic acid p-nitrophenyl ethyl ester as well as preparation method and application of caffeic acid p-nitrophenyl ethyl ester
CN102503826A (en) * 2011-10-06 2012-06-20 中国科学院昆明植物研究所 Compound Blapsins A and B, pharmaceutical composition containing the same, and preparation method and application thereof
CN102503826B (en) * 2011-10-06 2014-10-01 中国科学院昆明植物研究所 Compound Blapsins A and B, pharmaceutical composition containing the same, and preparation method and application thereof
CN102949384A (en) * 2012-10-29 2013-03-06 浙江大学 Application of coffee acid 3, 4-dihydroxy benzene ethyl ester to preparation of antitumor drug
JP2016074606A (en) * 2014-10-02 2016-05-12 富士フイルム株式会社 Method for producing 3,4,5-tricaffeoylquinic acid
CN104592025A (en) * 2015-02-04 2015-05-06 杨安民 Ferulate compound and preparation method thereof
CN104592025B (en) * 2015-02-04 2017-05-17 杨安民 Ferulate compound and preparation method thereof
CN108752212A (en) * 2015-03-06 2018-11-06 北京大学 9- decarboxylation Rosmarinic acid analogs and its synthetic method and application
CN108752212B (en) * 2015-03-06 2024-03-12 北京大学 9-decarboxylated rosmarinic acid analogue and synthetic method and application thereof
CN108164398A (en) * 2018-01-26 2018-06-15 山东省药学科学院 A kind of improved method of hydroxytyrosol synthesis technology
CN109456183A (en) * 2018-11-21 2019-03-12 浙江科技学院 A kind of preparation method of coffee acid benzyl ester
CN109942429A (en) * 2019-03-01 2019-06-28 陕西科技大学 Novel hydroxyl tyrosol shikimate compound and its preparing the application in cardiovascular medicament
CN111807958A (en) * 2020-08-14 2020-10-23 蔚源生物科技(平顶山)有限公司 Synthesis method of caffeic acid phenethyl ester

Also Published As

Publication number Publication date
CN101497567B (en) 2012-07-25

Similar Documents

Publication Publication Date Title
CN101497567B (en) Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound
CN102002031B (en) Full chemical synthesis method for mangiferin aglycones
CN103374050B (en) One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid
CN103374049B (en) One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid
CN115073406B (en) Eucalyptus type sesquiterpene lactone TBA derivative and application thereof
CN101665418B (en) Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof
CN101245067B (en) Process for producing entecavir and midbody
CN114315933A (en) Preparation method of potential anti-new coronavirus medicine monatipivir
RU2709493C1 (en) Method of producing roxadustat
CN105732547A (en) Preparation method of dehydrated andrographolide diacid half ester basic salt
CN101792451A (en) Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A
CN101805380B (en) Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
CN110713483A (en) Elaprepilin intermediate and preparation method of elaprilin
CN101830872A (en) Synthetic method of 3-hydroxyl benzofuran derivatives
CN112574033B (en) Synthesis method of 1-hydroxy-2,5,8-trimethyl-9-fluorenone
CN114213483B (en) Preparation method of marine flavone glycoside
CN111662260B (en) Synthetic method of natural product saffloneoside
CN114133421B (en) Preparation method of beta-mouse cholic acid
CN113979851B (en) 2' -halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof
Lu et al. Total synthesis of wikstrol A and wikstrol B
CN111662155B (en) Method for extracting phenolic compounds from Lepidium europaeum and extracted phenolic compounds
US11434217B2 (en) Method for synthesis of lobaric acid and analog thereof
CN108383723B (en) Preparation method of beta-methyl glutarate monomethyl ester with high purity and high yield
Kuo et al. An efficient synthesis of a potent anti-inflammatory agent, viscolin, and its inducible nitric oxide synthase inhibitory activity
CN117534613A (en) Preparation method of 3-aminopyridine-2-carboxylic acid methyl ester

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20120725

Termination date: 20190305

CF01 Termination of patent right due to non-payment of annual fee