CN101302159B - Method for synthesizing monobenzoyl quinate compound - Google Patents
Method for synthesizing monobenzoyl quinate compound Download PDFInfo
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- CN101302159B CN101302159B CN2008100617330A CN200810061733A CN101302159B CN 101302159 B CN101302159 B CN 101302159B CN 2008100617330 A CN2008100617330 A CN 2008100617330A CN 200810061733 A CN200810061733 A CN 200810061733A CN 101302159 B CN101302159 B CN 101302159B
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Abstract
The invention provides a method for synthesizing a mono-substituted benzoyl quinic acid compound, which has the following structural formula, wherein, X is one or a plurality of electron donating and/or electron withdrawing substitutional groups; R1 is hydrogen, alkyl containing 1 to 8 carbons, phenmethyl, alkali metal or alkaline-earth metal. The synthetic method is as follows: firstly, a benzoic acid compound reacts with a bis-oxo protective quinic acid compound through the condensation reaction to generate a compound (IV); and the compound (IV) is hydrolyzed to generate a target compound (I). The method has reasonable design; compared with the prior acyl chloride method preparation, the method has simple operation, short steps, and simple post treatment, can directly take substituted benzoic acid as raw material, save the steps of preparing acyl chloride; reaction conditions are moderate, and the reaction can be carried out under room temperature; and the method has better yield.
Description
Technical field
The present invention relates to organic chemistry filed, in particular to a kind of method of synthetic single-substituted formyl quinic acid compounds.
Background technology
Single-substituted formyl quinic acid compounds be a class be widespread in nature have an active quinic acid derivative of important biomolecule, they have multiple biological activitys such as antiviral, antitumor, anti-oxidant, wherein represent the report of Nutgalls acyl quinic acid maximum about its typical case.Nineteen ninety-five, Taiwan's scholars is reported the antiviral Mechanism Study of Nutgalls acyl, caffetannic acid compounds, discovers, this two compounds all has stronger restraining effect [Chang, C.W. to hiv reverse transcriptase; Lin, M.T.; Lee, S.S.; Liu, K.C.S.C.; Hsu, F.L.; Lin, J.Y. (1995) Antiviral Research, 27,367～374].1992, people such as Yoshiki reported the anti-tumor activity [Yoshiki, Kashiwada (1992) Journal of Natural Products, 55 (8), 1033～1043] of Nutgalls acyl quinic acid compounds.Still mainly concentrate at present in the research of pharmacologically active and plant chemical ingredient about the research of this compounds, then seldom the report of its synthetic method.Up to now, also mainly extract by in the plant in the source of single-substituted formyl quinic acid compounds, and its content in plant is lower.The chemical synthesis process of the single-substituted formyl quinic acid compounds of report is also arranged in addition, and what see is chloride method more, but this method synthetic yield is lower.Simultaneously, the single-substituted formyl quinic acid compounds kind that occurring in nature exists is fewer, except the derivative of common gallic acid and quinic acid condensation, the quinate compounds that other benzoyl replaces is then comparatively rare, the derivative for preparing this compounds for convenience, seek the relation between structure and the activity, the method for seeking the single-substituted formyl quinic acid compounds of easy, eco-friendly preparation is very necessary.
Summary of the invention
The purpose of this invention is to provide a kind of method of synthetic single-substituted formyl radical quinic acid compounds, described single-substituted formyl quinic acid compounds (I) has following general structure:
Wherein X is that one or more give electronics and/or electron-withdrawing substituent; R
1Be hydrogen, contain the alkyl of 1～8 carbon, benzyl, basic metal or alkaline-earth metal.
Novel synthetic single-substituted formyl quinic acid compounds (I) provided by the invention is realized by following steps:
Reaction formula:
Wherein X is that one or more give electronics and/or electron-withdrawing substituent; R
1Be hydrogen, contain the alkyl of 1～8 carbon, benzyl, basic metal or alkaline-earth metal; R
1' and R
2' can be identical or different, be selected from hydrogen, contain the alkyl of 1～8 carbon, the aryl that contains 6～10 carbon or R
1' and R
2' represent the saturated or unsaturated ring that contains 3～7 carbon atoms with adjacent carbon atom.
Synthesis step:
(1) condensation reaction: be with reacting shown in benzoic acid compounds shown in the compound (II) and the compound (III), generate compound (IV) together with dioxy fork protection quinic acid compounds.
Substituent X in the benzoic acid compounds of the present invention is meant that electron-donating group is hydroxyl, alkyl, alkoxyl group or amido; Electron-withdrawing group is fluorine, chlorine, bromine, iodine, cyano group, aldehyde radical, trifluoromethyl or the carboxyl that directly links to each other with aromatic ring.
Be reflected in the organic solvent and carry out under the stirring, under the catalysis of condensing agent and analogue and organic bases, 0～100 ℃ of temperature of reaction, 1～72 hour reaction times.Wherein compound (III) is 1: 1 to 1: 10 with the mol ratio of compound (II); Compound (II) is 1: 1 to 1: 50 with the mol ratio of dicyclohexylcarbodiimide and analogue thereof; The mole dosage of organic bases is 1%～50% of dicyclohexylcarbodiimide and an analogue thereof.
Wherein used condensing agent is dicyclohexylcarbodiimide (DCC) and analogue thereof, and described analogue is methyl-isobutyl carbodiimide, DIC or cyclohexyl isobutyl-carbodiimide.
Used organic bases is selected from pyridine, sodium alkoxide, triethylamine, aniline, 4-Dimethylamino pyridine, 1, one or more in 8-diazabicyclo [5,4,0] 11 alkane-7-alkene, 4-pyrrolidyl pyridine, the N-crassitude.
Used organic solvent is selected from pyridine, triethylamine, dimethyl formamide, methylene dichloride, trichloromethane, benzene, toluene, tetrahydrofuran (THF) or acetonitrile.
(2) step hydrolysis reaction: the compound (IV) of gained in the step (1) is hydrolyzed obtains purpose compound (I).Compound (IV) can be hydrolyzed 0～100 ℃ of temperature of reaction, 1～96 hour reaction times in the presence of the acid solution that dilutes such as formic acid, acetate, hydrochloric acid, nitric acid or sulfuric acid.
The present invention has following advantage:
1, compare with traditional chloride method preparation, the present invention is simple to operate, and step is short, can be raw material by substituted benzoic acid directly, saves the step of preparation acyl chlorides.
2, the present invention is compared with using expensive N, and the two imidazoles (CDI) of N '-carbonyl are the direct condensation method of condensing agent, and its cost descends greatly, is beneficial to suitability for industrialized production.
3, aftertreatment is simple, and reaction is activated by condensing agent such as dicyclohexylcarbodiimide, can generate urea in reaction, but direct filtration is removed after the reaction.
4, reaction conditions gentleness at room temperature can be reacted.
5, productive rate is better.
Embodiment
Further specify the present invention below by embodiment.Embodiment has provided representative compounds (1), promptly has 5-oxygen-Nutgalls acyl quinic acid synthetic of structure shown in the formula (1).Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: compound (1) synthetic
In reaction flask, add 1.2 mmoles 3,4,5-triacetyl aminobenzoic acid, 2 mmole dicyclohexylcarbodiimide, 20 milliliters of anhydrous methylene chlorides, at room temperature stirred 20 minutes, white casse appears and after, add 1 mmole 3,4-two-oxygen-acetonylidene quinic acid, 0.2 mmole 4-Dimethylamino pyridine (DMAP), whole solution at room temperature reacted 12 hours, suction filtration is removed insolubles, Dropwise 5 milliliter 1N hydrochloric acid again, at room temperature reacted 3 days, and detected product and raw material ratio no longer changes by thin layer chromatography TLC, it is saturated to add salt in reaction system, with chloroform extraction (20 milliliters * 4), combined chloroform layer massive laundering, saturated common salt water washing, anhydrous sodium sulfate drying.Use reversed-phase column RP-C
18(60% methanol-water) separation obtains white solid compound (1), and productive rate is 58.7%.R
f(chloroform/methanol/formic acid=50: 2: 1): 0.10; Proton nmr spectra
1H NMR (400MHz, deuterated methanol): δ 2.16～2.36 (4H, multiplet, H-2,6), 3.78 (1H, ddd is triple bimodal, H-3), 4.06 (1H, double doublet, H-4), 4.98 (1H, ddd is triple bimodal, H-5), 6.87 (1H, bimodal, H-2 '), 6.89 (1H, bimodal, H-6 ').
Embodiment 2: compound (1) synthetic
In reaction flask, add 1.2 mmoles 3,4,5-triacetyl aminobenzoic acid, 2 mmole methyl-isobutyl carbodiimides, 20 milliliters of anhydrous methylene chlorides, at room temperature stirred 20 minutes, white casse appears and after, add 1 mmole 3,4-two-oxygen-acetonylidene quinic acid, 0.2 mmole 4-Dimethylamino pyridine (DMAP), whole solution at room temperature reacted 24 hours, suction filtration is removed insolubles, Dropwise 5 milliliter 1N hydrochloric acid again, at room temperature reacted 62 hours, and detected product and raw material ratio no longer changes by thin layer chromatography TLC, it is saturated to add salt in reaction system, with chloroform extraction (20 milliliters * 4), combined chloroform layer massive laundering, saturated common salt water washing, anhydrous sodium sulfate drying.Use reversed-phase column RP-C
18(60% methanol-water) separation obtains white solid compound (1), and productive rate is 43.6%.R
f(chloroform/methanol/formic acid=50: 2: 1): 0.10; Proton nmr spectra
1H NMR (400MHz, deuterated methanol): data are with compound (1) among the embodiment 1
1H NMR data.
Embodiment 3: compound (1) synthetic
In reaction flask, add 1.2 mmoles 3,4,5-triacetyl aminobenzoic acid, 2 mmole dicyclohexylcarbodiimide, 20 milliliters of anhydrous methylene chlorides, at room temperature stirred 20 minutes, white casse appears and after, add 1 mmole 3,4-two-oxygen-acetonylidene quinic acid, 0.2 mmole 4-pyrrolidyl pyridine (PPY), whole solution at room temperature reacted 18 hours, suction filtration is removed insolubles, Dropwise 5 milliliter 1N hydrochloric acid again, at room temperature reacted 3 days, and detected product and raw material ratio no longer changes by thin layer chromatography TLC, it is saturated to add salt in reaction system, with chloroform extraction (20 milliliters * 4), combined chloroform layer massive laundering, saturated common salt water washing, anhydrous sodium sulfate drying.Use reversed-phase column RP-C
18(60% methanol-water) separation obtains white solid compound (1), and productive rate is 53.6%.R
f(chloroform/methanol/formic acid=50: 2: 1): 0.10; Proton nmr spectra
1HNMR (400MHz, deuterated methanol): data are with compound (1) among the embodiment 1
1The HNMR data.
Embodiment 4: compound (1) synthetic
In reaction flask, add 1.2 mmoles 3,4,5-triacetyl aminobenzoic acid, 2 mmole dicyclohexylcarbodiimide, 20 milliliters of anhydrous tetrahydro furans, at room temperature stirred 20 minutes, white casse appears and after, add 1 mmole 3,4-two-oxygen-acetonylidene quinic acid, 0.2 mmole 4-pyrrolidyl pyridine (PPY), whole solution at room temperature reacted 22 hours, suction filtration is removed insolubles, Dropwise 5 milliliter 1N hydrochloric acid again, at room temperature reacted 3 days, and detected product and raw material ratio no longer changes by TLC, it is saturated to add salt in reaction system, with chloroform extraction (20 milliliters * 4), combined chloroform layer massive laundering, saturated common salt water washing, anhydrous sodium sulfate drying.Use reversed-phase column RP-C
18(60% methanol-water) separation obtains white solid compound (1), and productive rate is 48.3%.R
f(chloroform/methanol/formic acid=50: 2: 1): 0.10; Proton nmr spectra
1H NMR (400MHz, deuterated methanol): data are with compound (1) among the embodiment 1
1H NMR data.
Claims (5)
1. the method for a synthetic single-substituted formyl radical quinic acid compounds, described single-substituted formyl quinic acid compounds (I) has following general structure
Wherein X is that one or more give electronics and/or electron-withdrawing substituent, and electron-donating group is a hydroxyl, and electron-withdrawing group is fluorine, chlorine, bromine, iodine, cyano group, aldehyde radical, trifluoromethyl or the carboxyl that directly links to each other with aromatic ring, R
1Be hydrogen, contain the alkyl of 1～8 carbon, benzyl or basic metal; It is characterized in that realizing by following steps:
Reaction formula
R wherein
1' and R
2' identical or different, be selected from hydrogen, contain the alkyl of 1～8 carbon, the aryl that contains 6～10 carbon or R
1' and R
2' represent the saturated or unsaturated ring that contains 3～7 carbon atoms with adjacent carbon atom;
(1) condensation reaction: be with reacting shown in benzoic acid compounds shown in the compound (II) and the compound (III) together with dioxy fork protection quinic acid compounds, generate compound (IV), be reflected at and stir in the organic solvent down, under the catalysis of condensing agent and organic bases, carry out;
(2) hydrolysis reaction: the compound (IV) of gained in the step (1) is hydrolyzed obtains purpose compound (I), and compound (IV) is hydrolyzed 0～100 ℃ of temperature of reaction, 1～96 hour reaction times in the presence of the acid solution of dilution;
Used condensing agent is selected dicyclohexylcarbodiimide and analogue thereof for use in the step (1), and described analogue is selected a kind of in methyl-isobutyl carbodiimide, DIC or the cyclohexyl isobutyl-carbodiimide for use.
2. the method for a kind of synthetic single-substituted formyl radical quinic acid compounds according to claim 1, it is characterized in that: step (1) is under stirring in organic solvent, carries out under the catalysis of condensing agent and organic bases, 0～100 ℃ of temperature of reaction, 1～72 hour reaction times; Wherein compound (III) is 1: 1 to 1: 10 with the mol ratio of compound (II); Compound (II) is 1: 1 to 1: 50 with the mol ratio of dicyclohexylcarbodiimide and analogue thereof; The mole dosage of organic bases is 1%～50% of dicyclohexylcarbodiimide and an analogue thereof.
3. the method for a kind of synthetic single-substituted formyl radical quinic acid compounds according to claim 1; it is characterized in that: the used organic bases of step (1) is selected from pyridine, sodium alkoxide, triethylamine, aniline, 4-Dimethylamino pyridine, 1; 8-diazabicyclo [5; 4,0] one or more in 11 alkane-7-alkene, 4-pyrrolidyl pyridine, the N-crassitude.
4. the method for a kind of synthetic single-substituted formyl radical quinic acid compounds according to claim 1, it is characterized in that: the used organic solvent of step (1) is selected from pyridine, triethylamine, dimethyl formamide, methylene dichloride, trichloromethane, benzene, toluene, tetrahydrofuran (THF) or acetonitrile.
5. the method for a kind of synthetic single-substituted formyl radical quinic acid compounds according to claim 1 is characterized in that: the used acid solution of step (2) is selected a kind of in formic acid, acetate, hydrochloric acid, nitric acid or the sulfuric acid for use.
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| CN101302159B true CN101302159B (en) | 2011-09-21 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270955A (en) * | 1999-04-16 | 2000-10-25 | 中国人民解放军军事医学科学院放射医学研究所 | Preparation of 1,5-di-o-coffeic acyl quininic acid derivative |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270955A (en) * | 1999-04-16 | 2000-10-25 | 中国人民解放军军事医学科学院放射医学研究所 | Preparation of 1,5-di-o-coffeic acyl quininic acid derivative |
Non-Patent Citations (1)
| Title |
|---|
| Tadao Kondo,et al..Essential structure of co-pigment for blue sepal-colour development of hydrangea..Tetrahedron Letters.46.2005,466646页Table 1,Scheme 2.. * |
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