CN103102264A - Preparation method of salicylic acid compound - Google Patents
Preparation method of salicylic acid compound Download PDFInfo
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- CN103102264A CN103102264A CN2013100039986A CN201310003998A CN103102264A CN 103102264 A CN103102264 A CN 103102264A CN 2013100039986 A CN2013100039986 A CN 2013100039986A CN 201310003998 A CN201310003998 A CN 201310003998A CN 103102264 A CN103102264 A CN 103102264A
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Abstract
The invention discloses a preparation method of a salicylic acid compound (I). The method comprises the steps of: by taking acrylic ester compound and acetoacetic ester compound as initial materials; carrying out Michael addition and intramolecular Aldol condensation reaction under an alkaline condition to obtain a 1,3-cyclohexanedione compound; carrying out C-hydrocarbylation and O-hydrocarbylation reaction on the 1,3-cyclohexanedione compound and corresponding halogenated reagents under the alkaline condition after oxidative aromatization and single methylation, wherein the mixture of the obtained C-hydrocarbylation and O-hydrocarbylation product does not need to be processed by acid to break an ether bond; and purifying, and carrying out alkaline hydrolysis and acid neutralization to obtain the corresponding salicylic acid compound (I), wherein in the formula, R1 represents PhCH2CH2, PhHC=CH or CH3(CH2)3CH2, and R2 represents H, (CH3)2C=CHCH2 or H2C-CHCH2.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to a class chemical structure as
(I)The preparation method of shown salicylic acid compounds,
In formula: R
1Expression PhCH
2CH
2, PhHC=CH, CH
3(CH
2)
3CH
2R
2Expression H, (CH
3)
2C=CHCH
2, H
2C=CHCH
2
Background technology
Salicylic acid compounds of the present invention (
I) be from plant
Amorpha fruticosa,
Glycyrrhiza foetidaWith the tree beans (
Cajanus cajan(L.) an isolated class stilbene compound Millsp.), the bioactivity screening result shows, this compounds has extensive biological activity (as: resisting pathogenic microbes, anti-oxidant, antitumor, antiviral, anti-inflammatory, anti-diabetic, Weight-reducing and lipid-lowering, osteoporosis, anti-cerebral tissue ischemic etc.), and is used for the treatment of and/or prevents the nervus retrogression relative disease.For, toxicity and structure activity relationship, demanding party just prepares a large amount of samples rapidly for further this type of function of chemical compound mechanism of research, drug effect, medicine.At present, the method for this compounds of acquisition of bibliographical information mainly contains two kinds: (1) separation and purification from plant; (2) adopt simple chemical reagent to obtain through total synthesis method.When before utilizing, a kind of method prepares, exist plant resources limited, and because these effective constituents content in plant is low, separation and purification complex operation, a large amount of preparation difficulty, high in cost of production is not enough; Can effectively solve above-mentioned deficiency and adopt complete synthesis strategy to prepare this type of salicylic acid compounds, but present disclosed salicylic acid compounds (
I) total synthesis method [(1) Weidner, C.
Et. al.Proceedings of the National Academy of Sciences 2012,
109, 7257-7262; (2) Laclef,
Et. al.
Tetrahedron Letters 2012,
53, 225-227; (3) Ji Xing jumps etc. CN 102372627A] have that preparation process is many, severe reaction conditions, operation and the problem such as last handling process is loaded down with trivial details, environmental pollution is serious, yield is low, its a large amount of preparations are restricted.Therefore, to prepare in a large number this compounds significant for the total synthesis method of development simple and effective.
Summary of the invention
The objective of the invention is to be to avoid now methodical deficiency, provide that a kind of reaction conditions is gentle, aftertreatment is easy, reaction environment is friendly, yield is high, cost is low, can prepare in a large number salicylic acid compounds (
I) new synthetic method.
Preparation salicylic acid compounds proposed by the invention (
I) new synthetic method, be with acrylic ester compound (
1) and the acetylacetic ester compounds (
2) be starting raw material, under alkaline condition through the Michael addition reaction, get active intermediate (
3), proceed Aldol condensation reaction in molecule without separation, get the hydroresorcinol compounds (
4), the gained compound
4Through the oxidation aromizing get 2,4-dyhydroxyl parabens compound (
5), utilize methylating reagent with 4-position HM, get monomethylation key intermediate (
6), the gained compound
6Under alkaline condition with corresponding halogenating agent, C-hydrocarbonylation and O-alkylation reaction occur, get corresponding C-hydrocarbonylation and O-hydrocarbonylation product mixture (
7), (
8) and (
9), these compound polarity are very approaching, and the separation and purification difficulty needs repeatedly the column chromatography purification operation just can obtain corresponding sterling; We find in research process, can with the acid treatment of gained mixture, can with the C-O bond rupture of O-hydrocarbonylation product, obtain compound
6With required intermediate (
8), because these two compound polarity differences are large, adopt primary column chromatography can prepare the high purity intermediate (
8), and can reclaim compound
6Be used for next batch reaction recovery; The gained intermediate (
8) through further basic hydrolysis, can obtain corresponding salicylic acid compounds (
I), its synthetic route is as follows:
In above-mentioned reaction formula: R
1Expression PhCH
2CH
2, PhHC=CH, CH
3(CH
2)
3CH
2R
2And R
5Represent independently of one another H, (CH
3)
2C=CHCH
2, H
2C=CHCH
2R
3And R
4Represent independently of one another C
1-12Alkyl, benzyl.
For said synthesis route, its each step specifically describes as follows:
A)With acrylic ester compound (
1) and the acetylacetic ester compounds (
2) be starting raw material, solvent-free or have under solvent condition and the alkali effect, through the Michael addition reaction, get active intermediate (
3), gained
3Proceed Aldol condensation reaction in molecule without separation, get the hydroresorcinol compounds (
4); Wherein, the reaction solvent for use is: C
1-6Fatty Alcohol(C12-C14 and C12-C18),
N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), C
5~ C
8Alkane, orthodichlorobenzene or aromatic hydrocarbon, preferred solvent is: methyl alcohol, ethanol, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), benzene or toluene; Reacting alkali used is: C
1~ C
8An alkali metal salt, basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline earth metal hydride, the butyllithium, 1 of alcohol, 8-diazabicyclo [5,4,0] combination of 11 carbon-7-alkene or above-mentioned various alkali; Preferred bases is: sodium methylate, sodium ethylate, trimethyl carbinol lithium, potassium hydride KH, sodium hydride; Acrylic ester compound (
1): the acetylacetic ester compounds (
2): the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0, and preferred molar feed ratio is 1.0:1.0 ~ 10.0:1.0 ~ 10.0; Temperature of reaction is 0 ~ 150 ℃, and preferable reaction temperature is room temperature ~ 100 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
By step
A)The hydroresorcinol compounds that obtains (
4) in solvent through the further oxidation aromizing of dehydrogenating agent get 2,4-dyhydroxyl parabens compound (
5); Wherein, the reaction solvent for use is: C
1-6Lipid acid, C
1-6Fatty Alcohol(C12-C14 and C12-C18),
N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), acetonitrile, C
5~ C
8Alkane, orthodichlorobenzene or aromatic hydrocarbon, preferred solvent is: acetic acid, acetonitrile,
N,N-dimethyl formamide, methylene dichloride, toluene or dimethylbenzene; Reacting dehydrogenating agent used is: Br
2, I
2, BrCCl
3, dihalide copper, dihalide copper and alkali metal halide or alkaline earth metal halide mixture, C
1-6Lipid acid mercury, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or palladium content are 1% ~ 30% Pd-C, and preferred dehydrogenating agent is: Br
2, CuBr
2, CuCl
2, CuCl
2With MgCl
2Mixture, CuCl
2With LiCl mixture, DDQ or mercuric acetate; Compound (
4): the molar feed ratio of dehydrogenating agent is 1.0:0.05 ~ 10.0, and preferred molar feed ratio is 1.0:0.2 ~ 6.0; The molar feed ratio of dihalide copper and alkali metal halide or alkaline earth metal halide is 1.0:0.1 ~ 2.0, and preferred molar feed ratio is 1.0:0.2 ~ 1.2; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
By step
B)Obtain 2, the 4-dyhydroxyl parabens compound (
5) under solvent and alkaline condition with the methylating reagent effect, get the monomethylation product (
6); Wherein, the reaction solvent for use is: ether, tetrahydrofuran (THF),
N,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C
3~ C
8Aliphatic ketone, benzene, toluene, acetonitrile or C
5~ C
8Alkane, preferred solvent is:
N,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF) or toluene; Reacting alkali used is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, C
1~ C
8An alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol (as: triethylamine, Tributylamine, trioctylamine, pyridine,
N-methylmorpholine,
N-methyl piperidine, triethylene diamine, TBAH), preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Methylating reagent used is methyl-sulfate or methyl iodide; Compound (
5): methylating reagent: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0, and preferred molar feed ratio is 1.0:1.0 ~ 3.0:1.0 ~ 5.0; Temperature of reaction is 0 ~ 120 ℃, and preferable reaction temperature is room temperature ~ 80 ℃; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 18 hour.
By step
C)The monomethylation product that obtains (
6) under solvent and alkaline condition with corresponding halogenating agent, C-hydrocarbonylation and O-alkylation reaction occur, get corresponding C-hydrocarbonylation and O-hydrocarbonylation product mixture (
7), (
8) and (
9); Wherein, the reaction solvent for use is: C
1-6Fatty Alcohol(C12-C14 and C12-C18),
N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), C
5~ C
8Alkane, acetonitrile, orthodichlorobenzene or aromatic hydrocarbon, preferred solvent is: methyl alcohol, ethanol, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), acetonitrile, benzene or toluene; Reacting alkali used is: C
1~ C
8An alkali metal salt, basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline earth metal hydride, the butyllithium of alcohol; Preferred bases is: sodium methylate, sodium ethylate, trimethyl carbinol lithium, potassium hydride KH, sodium hydride or butyllithium; Halogenating agent used is: (CH
3)
2C=CHCH
2X or H
2C=CHCH
2X, above-mentioned X represents I, Br or Cl; Compound (
6): halogenating agent: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0, and preferred molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is 0 ~ 120 ℃, and preferable reaction temperature is room temperature ~ 90 ℃; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 2 ~ 18 hours.
By step
D)The mixture of the C-hydrocarbonylation that obtains and O-hydrocarbonylation product (
7), (
8) and (
9) do not need separation and purification, solvent-free or have under solvent condition and acid-respons, obtain compound (
6) and intermediate (
8); Wherein, the reaction solvent for use is: water, C
1-6Lipid acid, C
1-6Fatty Alcohol(C12-C14 and C12-C18),
N,N-dimethyl formamide, tetrahydrofuran (THF), C
3~ C
8Aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO), preferred solvent is: water, acetic acid, methyl alcohol, ethanol, Isosorbide-5-Nitrae-dioxane or acetone; Acid used is: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C
1-6Alkylsulphonic acid, Phenylsulfonic acid or tosic acid, preferred acid is: hydrochloric acid, phosphoric acid, methanesulfonic; The volume ratio of acid in reaction system is 0.1%-100%, and preferred volume ratio is 1.0%-30%, and temperature of reaction is 0 ~ 120 ℃, and preferable reaction temperature is room temperature ~ 90 ℃; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 8 hour.
By step
E)The intermediate that obtains (
8) method reported according to document again is through basic hydrolysis, can obtain corresponding salicylic acid compounds (
I).
Embodiment
Can conduct further description the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 12, the preparation of 4-dioxy-6-(2-styroyl)-heptanaphthenic acid methyl esters (4a)
Add successively 5-phenyl-2-amylene-4 acid methyl ester (0.12 mol), methyl acetoacetate (0.15 mol) and sodium methylate (0.36 mol) in reaction flask, 60-65 ℃ of insulation reaction 8 h, after reaction finishes, add deionized water 100 ml, to acid, water layer extracts with methylene dichloride 100 ml, merges organic layer with aqueous hydrochloric acid neutralization solution pH, use the saturated common salt water washing, organic layer is through anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, namely gets 2,4-dioxy-6-(2-styroyl)-heptanaphthenic acid methyl esters crude product, yield approximately 95%.This crude product need not purifying can be directly used in the next step.
Embodiment 22, the preparation of 4-dioxy-6-(2-styroyl)-heptanaphthenic acid ethyl ester (4b)
Add 5-phenyl-2-pentenoic acid ethyl ester (0.12 mol), methyl aceto acetate (0.15 mol), toluene 60 ml and sodium hydride (0.30 mol) in reaction flask, room temperature insulation reaction 18 h, after reaction finishes, extremely acid with aqueous hydrochloric acid neutralization solution pH, organic layer is used deionized water 50 ml successively, saturated aqueous common salt 50 ml washings, organic layer is through anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, namely gets 2,4-dioxy-6-(2-styroyl)-heptanaphthenic acid ethyl ester crude product, yield approximately 90%.This crude product need not purifying can be directly used in the next step.
Embodiment 32, the preparation of 4-dioxy-6-(2-styryl)-heptanaphthenic acid ethyl ester (4c)
The same embodiment of operating process
2, just with 5-phenyl-2-pentenoic acid ethyl ester with 5-phenyl-2,4-pentadienoic acid ethyl ester substitutes, sodium hydride substitutes with trimethyl carbinol lithium, gets 2,4-dioxy-6-(2-styryl)-heptanaphthenic acid ethyl ester crude product, yield approximately 88%.This crude product need not purifying can be directly used in the next step.
Embodiment 42, the preparation of 4-dioxy-6-amyl group-heptanaphthenic acid ethyl ester (4d)
The same embodiment of operating process
2, just 5-phenyl-2-pentenoic acid ethyl ester being substituted with 2-octylenic acid ethyl ester, sodium hydride substitutes with potassium hydride KH, gets 2,4-dioxy-6-amyl group-heptanaphthenic acid ethyl ester crude product, yield approximately 95.5%.This crude product need not purifying can be directly used in the next step.
Embodiment 52, the preparation of 4-dioxy-6-(2-styroyl)-heptanaphthenic acid benzyl ester (4e)
The same embodiment of operating process
2, just methyl aceto acetate is substituted with benzyl acetoacetate, get 2,4-dioxy-6-(2-styroyl)-heptanaphthenic acid benzyl ester crude product, yield approximately 89.0%.This crude product need not purifying can be directly used in the next step.
Embodiment 62, the preparation of 4-dioxy-6-amyl group-heptanaphthenic acid benzyl ester (4f)
The same embodiment of operating process
2, just 5-phenyl-2-pentenoic acid ethyl ester being substituted with 2-octylenic acid ethyl ester, methyl aceto acetate substitutes with benzyl acetoacetate, gets 2,4-dioxy-6-amyl group-heptanaphthenic acid benzyl ester crude product, yield approximately 85.0%.This crude product need not purifying can be directly used in the next step.
Embodiment 72, the preparation of 4-dihydroxyl-6-(2-styroyl)-methyl benzoate (5a)
add 2 in reaction flask, 4-dioxy-6-(2-styroyl)-heptanaphthenic acid methyl esters (0.1 mol), acetonitrile 80 ml, cupric chloride (0.2 mol) and lithium chloride (0.05 mol), temperature rising reflux stirring reaction 8 h, after reaction finishes, remove solvent under reduced pressure, resistates is dissolved in methylene dichloride 120ml, use successively 10% aqueous hydrochloric acid, saturated NaCl solution washing, organic layer is through anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, the gained crude product is through column chromatography purification (elutriant: petroleum ether-ethyl acetate=2:1 v/v), get colorless oil 2, 4-dihydroxyl-6-(2-styroyl)-methyl benzoate, yield 72.0%.
Embodiment 82, the preparation of 4-dihydroxyl-6-(2-styroyl)-ethyl benzoate (5b)
add 2 in reaction flask, 4-dioxy-6-(2-styroyl)-heptanaphthenic acid ethyl ester (0.1 mol), acetic acid 80 ml, mercuric acetate (0.3 mol) and sodium acetate (0.3 mol), temperature rising reflux stirring reaction 3 h, after reaction finishes, be cooled to room temperature, add 10% aqueous hydrochloric acid 50 ml, filter, add methylene dichloride 120ml in filtrate, use successively 10% aqueous hydrochloric acid 50 ml, deionized water 50 ml and the 50 ml washings of the saturated NaCl aqueous solution, organic layer is through anhydrous sodium sulfate drying, filter, the filtrate decompression desolventizing, the gained crude product is through column chromatography purification (elutriant: petroleum ether-ethyl acetate=2:1 v/v), get colorless oil 2, 4-dihydroxyl-6-(2-styroyl)-ethyl benzoate, yield 60.0%.
Embodiment 92, the preparation of 4-dihydroxyl-6-(2-styryl)-ethyl benzoate (5c)
Add 2 in reaction flask, 4-dioxy-6-(2-styryl)-heptanaphthenic acid ethyl ester (0.01 mol), toluene 80 ml and 2,3-two chloro-5,6-dicyano-1,4-benzoquinones (0.015 mol), temperature rising reflux stirring reaction 12 h, after reaction finishes, be cooled to room temperature, filter the filtrate decompression desolventizing, the gained crude product is through column chromatography purification (elutriant: petroleum ether-ethyl acetate=2:1 v/v), get colorless oil 2,4-dihydroxyl-6-(2-styryl)-ethyl benzoate, yield 42.0%.
Embodiment 10 2, the preparation of 4-dihydroxyl-6-amyl group-ethyl benzoate (5d)
add 2 in reaction flask, 4-dioxy-6-amyl group-heptanaphthenic acid ethyl ester (0.01 mol), acetonitrile 40 ml, cupric chloride (0.02 mol) and magnesium chloride (0.01 mol), temperature rising reflux stirring reaction 8 h, after reaction finishes, remove solvent under reduced pressure, resistates is dissolved in methylene dichloride 50ml, use successively 10% aqueous hydrochloric acid, saturated NaCl solution washing, organic layer is through anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, the gained crude product is through column chromatography purification (elutriant: petroleum ether-ethyl acetate=2:1 v/v), get colorless oil 2, 4-dihydroxyl-6-amyl group-ethyl benzoate, yield 76.0%.
Embodiment 11 2, the preparation of 4-dihydroxyl-6-(2-styroyl)-peruscabin (5e)
The same embodiment of operating process
8, just 2,4-dioxy-6-(2-styroyl)-heptanaphthenic acid ethyl ester is substituted with 2,4-dioxy-6-(2-styroyl)-heptanaphthenic acid benzyl ester, get colorless oil 2,4-dihydroxyl-6-(2-styroyl)-peruscabin, yield 52.7%.
Embodiment 12 2, the preparation of 4-dihydroxyl-6-amyl group-peruscabin (5f)
The same embodiment of operating process
9, just 2,4-dioxy-6-(2-styryl)-heptanaphthenic acid ethyl ester is substituted with 2,4-dioxy-6-amyl group-heptanaphthenic acid benzyl ester, get colorless oil 2,4-dihydroxyl-6-amyl group-peruscabin, yield 58.5%.
The preparation of embodiment 13 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate (6a)
Add 2 in reaction flask, 4-dihydroxyl-6-(2-styroyl)-methyl benzoate (0.01 mol), acetone 30 ml, Anhydrous potassium carbonate (0.015 mol) and methyl-sulfate (0.012 mol), 40-50 ℃ of insulated and stirred reaction 3 h, after reaction finishes, filter, filtrate decompression is steamed and is desolventized, and gets colorless oil 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate, yield 96.0%.
The preparation of embodiment 14 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-ethyl benzoates (6b)
The same embodiment of operating process
13, just 2,4-dihydroxyl-6-(2-styroyl)-methyl benzoate is substituted with 2,4-dihydroxyl-6-(2-styroyl)-ethyl benzoate, get colorless oil 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, yield 93.5%.
The preparation of embodiment 15 2-hydroxyl-4-methoxyl group-6-(2-styryl)-ethyl benzoates (6c)
Operate same embodiment
13Just 2,4-dihydroxyl-6-(2-styroyl)-methyl benzoate is substituted with 2,4-dihydroxyl-6-(2-styryl)-ethyl benzoate, get colorless oil 2-hydroxyl-4-methoxyl group-6-(2-styryl)-ethyl benzoate, yield 90.8%.
The preparation of embodiment 16 2-hydroxyls-4-methoxyl group-6-amyl group-ethyl benzoate (6d)
Operate same embodiment
13, be with 2 with 2,4-dihydroxyl-6-(2-styroyl)-methyl benzoate, 4-dihydroxyl-6-amyl group-ethyl benzoate substitutes, methyl-sulfate substitutes with methyl iodide, gets colorless oil 2-hydroxyl-4-methoxyl group-6-amyl group-ethyl benzoate, yield 82.0 %.
The preparation of embodiment 17 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-peruscabins (6e)
Operate same embodiment
13, just 2,4-dihydroxyl-6-(2-styroyl)-methyl benzoate is substituted with 2,4-dihydroxyl-6-(2-styroyl)-peruscabin, get colorless oil 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-peruscabin, yield 88.3%.
The preparation of embodiment 18 2-hydroxyls-4-methoxyl group-6-amyl group-peruscabin (6f)
Operate same embodiment
13, just 2,4-dihydroxyl-6-(2-styroyl)-methyl benzoate is substituted with 2,4-dihydroxyl-6-amyl group-peruscabin, get colorless oil 2-hydroxyl-4-methoxyl group-6-amyl group-peruscabin, yield 97.0%.
Embodiment 19 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (7A
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (8A
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (9A
1
) preparation
Add 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate (0.01 mol), toluene 100 ml, sodium hydride (0.02 mol) and isopentene group chlorine (0.015 mol) in reaction flask, 70-75 ℃ of insulated and stirred reaction 5 h, after reaction finishes, be cooled to room temperature, organic layer is successively with 10% aqueous hydrochloric acid 50 ml, deionized water 50 ml and the 50 ml washings of the saturated NaCl aqueous solution, organic layer is through anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, the gained crude product need not purifying can be directly used in the next step.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=20:1 v/v), can obtain simultaneously 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-methyl benzoate, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 20 2-allyloxy-4-methoxyl group-6-(2-styroyl)-methyl benzoate (7A
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate (8A
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate (9A
3
) preparation
The same embodiment of operating process
19Just isopentene group chlorine is substituted with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-(2-styroyl)-methyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-(2-styroyl)-methyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 21 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (7B
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (8B
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (9B
1
) preparation
The same embodiment of operating process
19just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, isopentene group chlorine substitutes with isoprenyl bromide, can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, the mixture of 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate,
1H-NMR (400 MHz, CDCl
3): δ: 7.31-7.27 (m, 2H), 7.22-7.18 (m, 3H), 6.34 (d,
J=2.0 Hz, 1H), 6.25 (d,
J=2.0 Hz, 1H), 5.46-5.42 (m, 1H), 4.52 (d,
J=6.4 Hz, 2H), 4.38 (q,
J=7.2 Hz, 2H), 3.75 (s, 3H), 2.91-2.85 (m, 4H), 1.77 (s, 3H), 1.72 (s, 3H), 1.37 (t,
J=7.2 Hz, 3H); HR-ESI-MS:Calcd. for C
23H
28O
4[M+K]
+: 407.1625, found:407.1624; 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate,
1H-NMR (400 MHz, CDCl
3): δ: 11.83 (s, 1H), 7.31-7.27 (m, 2H), 7.22-7.17 (m, 3H), 6.16 (s, 1H), 5.20 (t,
J=7.2 Hz, 1H), 4.44 (q,
J=7.2 Hz, 2H), 3.77 (s, 3H), 3.34 (d,
J=7.2 Hz, 2H), 3.22 (t,
J=7.6 Hz, 2H), 2.88 (t,
J=7.6 Hz, 2H), 1.78 (s, 3H), 1.70 (s, 3H), 1.39 (t,
J=7.2 Hz, 3H); HR-ESI-MS:Calcd. for C
23H
28O
4[M+K]
+: 407.1625, found:407.1628; 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate,
1H-NMR (400 MHz, CDCl
3): δ: 7.31-7.28 (m, 2H), 7.22-7.17 (m, 3H), 6.39 (s, 1H), 5.50 (t,
J=6.8 Hz, 1H), 5.15 (t,
J=6.4 Hz, 1H), 4.38 (d,
J=6.4 Hz, 2H), 4.36 (q,
J=6.8 Hz, 2H), 3.78 (s, 3H), 3.33 (d,
J=6.4 Hz, 2H), 2.91-2.86 (m, 4H), 1.77 (s, 3H), 1.74 (s, 3H), 1.67 (s, 6H), 1.37 (t,
J=7.2 Hz, 3H);
13C-NMR (100 MHz, CDCl
3): δ: 168.7,159.1,155.2,141.6,138.5,137.3,131.4,128.4,128.3,125.9,122.9,121.8,121.5,120.5,107.5,72.3,61.1,55.6,37.8,36.1,25.8,25.7,23.0,18.0,17.9,14.3; HR-ESI-MS:Calcd. for C
28H
36O
4[M+K]
+: 475.2251, found:475.2257.
Embodiment 22 2-allyloxy-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (7B
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (8B
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (9B
3
) preparation
The same embodiment of operating process
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, isopentene group chlorine is substituted with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-ethyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 23 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styryl)-ethyl benzoate (7C
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate (8C
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate (9C
1
) preparation
The same embodiment of operating process
19just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styryl)-ethyl benzoate, isopentene group chlorine substitutes with isoprenyl bromide, can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styryl)-ethyl benzoate, the mixture of 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styryl)-ethyl benzoate, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 24 2-allyloxy-4-methoxyl group-6-(2-styryl)-ethyl benzoate (7C
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate (8C
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate (9C
3
) preparation
Operate same embodiment
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styryl)-ethyl benzoate, isopentene group chlorine substitutes with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-(2-styryl)-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-(2-styryl)-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 25 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-ethyl benzoate (7D
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate (8D
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate (9D
1
) preparation
The same embodiment of operating process
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-amyl group-ethyl benzoate, isopentene group chlorine substitutes with isoprenyl bromide, can obtain the mixture of 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-ethyl benzoate, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-ethyl benzoate, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 26 2-allyloxys-4-methoxyl group-6-amyl group-ethyl benzoate (7D
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate (8D
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate (9D
3
) preparation
Operate same embodiment
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-amyl group-ethyl benzoate, isopentene group chlorine substitutes with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-amyl group-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-amyl group-ethyl benzoate, 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 27 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-peruscabin (7E
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin (8E
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin (9E
1
) preparation
Operate same embodiment
19just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-peruscabin, isopentene group chlorine substitutes with isoprenyl bromide, can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-peruscabin, the mixture of 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-peruscabin, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-peruscabin, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 28 2-allyloxy-4-methoxyl group-6-(2-styroyl)-peruscabin (7E
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin (8E
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin (9E
3
) preparation
Operate same embodiment
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-peruscabin, isopentene group chlorine substitutes with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-(2-styroyl)-peruscabin, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-(2-styroyl)-peruscabin, 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin and 2-allyloxy-3-allyl group-4-methoxyl group-6-(2-styroyl)-peruscabin, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 29 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-peruscabin (7F
1
), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin (8F
1
) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin (9F
1
) preparation
Operate same embodiment
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-amyl group-peruscabin, isopentene group chlorine substitutes with isoprenyl bromide, can obtain the mixture of 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-peruscabin, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-amyl group-peruscabin, 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-peruscabin, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 30 2-allyloxys-4-methoxyl group-6-amyl group-peruscabin (7F
3
), 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-peruscabin (8F
3
) and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-peruscabin (9F
3
) preparation
Operate same embodiment
19Just 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate is substituted with 2-hydroxyl-4-methoxyl group-6-amyl group-peruscabin, isopentene group chlorine is substituted with allyl bromide 98, can obtain the mixture of 2-allyloxy-4-methoxyl group-6-amyl group-peruscabin, 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-peruscabin and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-peruscabin.Take a morsel crude product through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can obtain simultaneously 2-allyloxy-4-methoxyl group-6-amyl group-peruscabin, 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-peruscabin and 2-allyloxy-3-allyl group-4-methoxyl group-6-amyl group-peruscabin, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 31 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (8A
1
) preparation
Will be according to embodiment
19Preparation-obtained 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
7A 1 ), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
9A 1 ) mixture and ethanol 20 ml add in reaction flask, add 10% aqueous hydrochloric acid 20 ml, 40-45 ℃ of insulated and stirred reaction 3 h, after reaction finishes, removal of solvent under reduced pressure, resistates through column chromatography purification (elutriant: petroleum ether-ethyl acetate=15:1 v/v), can be respectively 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ), yield 41.5%; And 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
6a), yield 43.0%.
Embodiment 32 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (8B
1
) preparation
Operate same embodiment
31, just incite somebody to action (
7A 1 ), (
8A 1 ) and (
9A 1 ) mixture embodiment
21Preparation-obtained 2-(3-methyl but-2-ene oxygen base)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (
7B 1 ), 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (
8B 1 ) and 2-(3-methyl but-2-ene oxygen base)-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (
9B 1 ) mixture replacing, 10% hydrochloric acid substitutes with 10% phosphoric acid, can be respectively 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (
8B 1 ), yield 46.0%; And 2-hydroxyl-4-methoxyl group-6-(2-styroyl)-ethyl benzoate (
6b), yield 40.5%.
The preparation of embodiment 33 other compounds (8)
Adopt embodiment
31With
32Similar approach, just with reaction raw materials (
7A 1 ), (
8A 1 ) and (
9A 1 ) use embodiment
20-30The respective mixtures of gained substitutes, can prepare corresponding compound (
8), and reclaim corresponding compound (
6).
Embodiment 34 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-phenylformic acid (IA
1
) preparation
With 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) (0.01 mol), ethanol 30 ml, deionized water 30 ml and sodium hydroxide (0.1 mol) adds in reaction flask, temperature rising reflux stirring reaction 5 h, after reaction finishes, be cooled to room temperature, remove ethanol under reduced pressure, residual water solution is neutralized to acidity with 10% aqueous hydrochloric acid, water layer extracts with ether 100 ml, merge organic layer, use the saturated common salt water washing, organic layer is through anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, resistates gets white crystals 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-phenylformic acid, yield 91.5% through ethyl acetate-normal hexane (1:1 v/v) recrystallization, m.p. 136-138 ℃
1H-NMR (400 MHz, acetone-
d 6 ): δ: 7.30-7.27 (m, 4H), 7.20-7.18 (m, 1H), 6.50 (s, 1H), 5.19 (t,
J=1.2 Hz, 1H), 3.85 (s, 3H), 3.31-3.27 (m, 4H), 2.93 (t,
J=8.0 Hz, 2H), 1.76 (s, 3H), 1.63 (s, 3H);
13C-NMR (100 MHz, acetone-
d 6 ): δ: 174.4,163.4,162.1,145.9,143.1,131.2,129.2,129.0,126.5,123.5,115.2,106.7,105.4,55.9,39.9,39.1,25.8,22.5,17.8. HR-ESI-MS:Calcd. for C
21H
24O
4[M+Na]
+: 363.1572, found:363.1573.
Embodiment 35 2-hydroxyls-3-allyl group-4-methoxyl group-6-(2-styroyl)-phenylformic acid (IA
3
) preparation
Adopt embodiment
34Similar approach, just with 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) use 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 3 ) substitute, get final product to get 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styroyl)-phenylformic acid, yield 95.0%, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 36 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-phenylformic acid (IC
1
) preparation
Adopt embodiment
34Similar approach, just with 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) use 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-ethyl benzoate (
8C 1 ) substitute, get final product to get 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styryl)-phenylformic acid, yield 91.0%, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 37 2-hydroxyls-3-allyl group-4-methoxyl group-6-(2-styryl)-phenylformic acid (IC
3
) preparation
Adopt embodiment
34Similar approach, just with 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) use 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styryl)-ethyl benzoate (
8C 3 ) substitute, get final product to get 2-hydroxyl-3-allyl group-4-methoxyl group-6-(2-styryl)-phenylformic acid, yield 91.6%, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 38 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-phenylformic acid (ID
1
) preparation
Adopt embodiment
34Similar approach, just with 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) use 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-ethyl benzoate (
8D 1 ) substitute, get final product to get 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-amyl group-phenylformic acid, yield 88.0%, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Embodiment 39 2-hydroxyls-3-allyl group-4-methoxyl group-6-amyl group-phenylformic acid (ID
3
) preparation
Adopt embodiment
34Similar approach, just with 2-hydroxyl-3-(3-methyl but-2-ene-1-yl)-4-methoxyl group-6-(2-styroyl)-methyl benzoate (
8A 1 ) use 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-ethyl benzoate (
8D 3 ) substitute, get final product to get 2-hydroxyl-3-allyl group-4-methoxyl group-6-amyl group-phenylformic acid, yield 92.1%, its chemical structure warp
1H NMR,
13C NMR and HR-ESIMS conclusive evidence.
Claims (8)
- One class chemical structure as (I)The preparation method of shown salicylic acid compounds,In formula: R 1Expression PhCH 2CH 2, PhHC=CH, CH 3(CH 2) 3CH 2R 2Expression H, (CH 3) 2C=CHCH 2, H 2C=CHCH 2It is characterized in that comprising the steps:A)With acrylic ester compound ( 1) and the acetylacetic ester compounds ( 2) be starting raw material, solvent-free or have under solvent condition and the alkali effect, through the Michael addition reaction, get active intermediate ( 3), gained 3Proceed Aldol condensation reaction in molecule without separation, get the hydroresorcinol compounds ( 4);
In above-mentioned formula: R 1Expression PhCH 2CH 2, PhHC=CH, CH 3(CH 2) 3CH 2R 2Expression H, (CH 3) 2C=CHCH 2, H 2C=CHCH 2R 3And R 4Represent independently of one another C 1-12Alkyl, benzyl;B)By step A)Gained hydroresorcinol compounds ( 4) in solvent through the further oxidation aromizing of dehydrogenating agent get 2,4-dyhydroxyl parabens compound ( 5);
In above-mentioned formula: R 1Expression PhCH 2CH 2, PhHC=CH, CH 3(CH 2) 3CH 2R 4Expression C 1-12Alkyl, benzyl;C)By step B)Obtain 2, the 4-dyhydroxyl parabens compound ( 5) under solvent and alkaline condition with the methylating reagent effect, get the monomethylation product ( 6);D)By step C)The monomethylation product that obtains ( 6) under solvent and alkaline condition with corresponding halogenating agent, C-hydrocarbonylation and O-alkylation reaction occur, get corresponding C-hydrocarbonylation and O-hydrocarbonylation product mixture ( 7), ( 8) and ( 9);In above-mentioned formula: R 1Expression PhCH 2CH 2, PhHC=CH, CH 3(CH 2) 3CH 2R 2And R 5Represent independently of one another H, (CH 3) 2C=CHCH 2, H 2C=CHCH 2R 4Expression C 1-12Alkyl, benzyl;E)By step D)The mixture of the C-hydrocarbonylation that obtains and O-hydrocarbonylation product ( 7), ( 8) and ( 9) do not need separation and purification, solvent-free or have under solvent condition and acid-respons, obtain compound ( 6) and ( 8);F)By step E)The intermediate that obtains ( 8) method reported according to document again is through basic hydrolysis, can obtain corresponding salicylic acid compounds ( I). - Salicylic acid compounds as claimed in claim 1 ( I) the preparation method, it is characterized in that described step A)In, the reaction solvent for use is: C 1-6Fatty Alcohol(C12-C14 and C12-C18), N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C 1-6Lipid acid and C 1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), C 5~ C 8Alkane, orthodichlorobenzene or aromatic hydrocarbon; Reacting alkali used is: C 1~ C 8An alkali metal salt, basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline earth metal hydride, the butyllithium, 1 of alcohol, 8-diazabicyclo [5,4,0] combination of 11 carbon-7-alkene or above-mentioned various alkali; Acrylic ester compound ( 1): the acetylacetic ester compounds ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0; Temperature of reaction is 0 ~ 150 ℃; Reaction times is 1 ~ 72 hour.
- Salicylic acid compounds as claimed in claim 1 ( I) the preparation method, it is characterized in that described step B)In, the reaction solvent for use is: C 1-6Lipid acid, C 1-6Fatty Alcohol(C12-C14 and C12-C18), N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C 1-6Lipid acid and C 1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), acetonitrile, C 5~ C 8Alkane, orthodichlorobenzene or aromatic hydrocarbon; Reacting dehydrogenating agent used is: Br 2, I 2, BrCCl 3, dihalide copper, dihalide copper and alkali metal halide or alkaline earth metal halide mixture, C 1-6Lipid acid mercury, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone or palladium content are 1% ~ 30% Pd-C; Compound ( 4): the molar feed ratio of dehydrogenating agent is 1.0:0.05 ~ 10.0; The molar feed ratio of dihalide copper and alkali metal halide or alkaline earth metal halide is 1.0:0.1 ~ 2.0; Temperature of reaction is room temperature ~ 150 ℃; Reaction times is 1 ~ 72 hour.
- Salicylic acid compounds as claimed in claim 1 ( I) the preparation method, it is characterized in that described step C)In, the reaction solvent for use is: ether, tetrahydrofuran (THF), N,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3~ C 8Aliphatic ketone, benzene, toluene, acetonitrile or C 5~ C 8Alkane; Reacting alkali used is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, C 1~ C 8An alkali metal salt, triethylamine, Tributylamine, trioctylamine, pyridine of alcohol, N-methylmorpholine, N-methyl piperidine, triethylene diamine, TBAH; Methylating reagent used is methyl-sulfate or methyl iodide; Compound ( 5): methylating reagent: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0; Temperature of reaction is 0 ~ 120 ℃; Reaction times is 30 minutes ~ 24 hours.
- Salicylic acid compounds as claimed in claim 1 ( I) the preparation method, it is characterized in that described step D)In, the reaction solvent for use is: C 1-6Fatty Alcohol(C12-C14 and C12-C18), N,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C 1-6Lipid acid and C 1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), C 5~ C 8Alkane, acetonitrile, orthodichlorobenzene or aromatic hydrocarbon; Reacting alkali used is: C 1~ C 8An alkali metal salt, basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline earth metal hydride, the butyllithium of alcohol; Halogenating agent used is: (CH 3) 2C=CHCH 2X or H 2C=CHCH 2X, above-mentioned X represents I, Br or Cl; Compound ( 6): halogenating agent: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0; Temperature of reaction is 0 ~ 120 ℃; Reaction times is 30 minutes ~ 24 hours.
- Salicylic acid compounds as claimed in claim 1 ( I) the preparation method, it is characterized in that described step E)In, the reaction solvent for use is: water, C 1-6Lipid acid, C 1-6Fatty Alcohol(C12-C14 and C12-C18), N,N-dimethyl formamide, tetrahydrofuran (THF), C 3~ C 8Aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO); Acid used is: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C 1-6Alkylsulphonic acid, Phenylsulfonic acid or tosic acid; The volume ratio of acid in reaction system is 0.1%-100%, and temperature of reaction is 0 ~ 120 ℃; Reaction times is 30 minutes ~ 24 hours.
- 7. a class salicylic acid compounds, is characterized in that it is the compound with following chemical structure of general formula,
In above-mentioned formula: R 1Expression PhCH 2CH 2, PhHC=CH, CH 3(CH 2) 3CH 2R 2Expression (CH 3) 2C=CHCH 2, H 2C=CHCH 2R 2=R 5And all be not equal to H; R 4Expression C 1-12Alkyl, benzyl. - As claimed in claim 7 compound the preparation salicylic acid compounds claimed in claim 1 ( I) in application.
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| CN103483187A (en) * | 2013-08-30 | 2014-01-01 | 香港科技大学 | 4-oxethyl-2-hydroxyl-6-methyl benzoic acid as well as medicinal composition and application thereof |
| CN111116371A (en) * | 2019-12-23 | 2020-05-08 | 华宝香精股份有限公司 | Novel moss fen-flavor compound 4-methoxy ethyl olivetolate, preparation method and application thereof |
| CN113603568A (en) * | 2021-07-19 | 2021-11-05 | 厦门朝阳生物工程有限公司 | Preparation method of cannabidiol |
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| CN102372627A (en) * | 2010-08-18 | 2012-03-14 | 中国医学科学院医药生物技术研究所 | Preparation method of cajanin and substance with similar structure |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483187A (en) * | 2013-08-30 | 2014-01-01 | 香港科技大学 | 4-oxethyl-2-hydroxyl-6-methyl benzoic acid as well as medicinal composition and application thereof |
| WO2015027669A3 (en) * | 2013-08-30 | 2015-04-23 | 香港科技大学 | Phenyl-substituted compound, pharmaceutical composition and uses thereof |
| CN103483187B (en) * | 2013-08-30 | 2016-08-24 | 香港科技大学 | 4-ethyoxyl-2-hydroxyl-6-methyl benzoic acid and Pharmaceutical composition thereof and application |
| CN111116371A (en) * | 2019-12-23 | 2020-05-08 | 华宝香精股份有限公司 | Novel moss fen-flavor compound 4-methoxy ethyl olivetolate, preparation method and application thereof |
| CN111116371B (en) * | 2019-12-23 | 2022-02-01 | 华宝香精股份有限公司 | Novel moss fen-flavor compound 4-methoxy ethyl olivetolate, preparation method and application thereof |
| CN113603568A (en) * | 2021-07-19 | 2021-11-05 | 厦门朝阳生物工程有限公司 | Preparation method of cannabidiol |
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