CN104761464B - A kind of quinic acid derivatives, its processing procedure and application thereof - Google Patents
A kind of quinic acid derivatives, its processing procedure and application thereof Download PDFInfo
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Abstract
The present invention is on a kind of quinic acid derivatives, its processing procedure and application thereof, it has class chinic acid structure, and combined to block the signal path of T cell second that dependence CD28 molecules are participated in CD28 molecules using class chinic acid structure, and then suppress the activation of T cell, in addition, modified via by 1 carboxyl, 3 hydroxyls and 4 hydroxyls in chinic acid molecule, it is possible to decrease the toxicity of the quinic acid derivatives of generation；Its processing procedure is divided into two steps, and chinic acid and the first reagent reacting are generated into intermediate product under sour environment catalysis first, intermediate product and the second reagent reacting then are obtained into quinic acid derivatives；Its purposes then can pass through it and suppress the ability of T cell activation, and be used to treat autoimmune disease, allergy, graft rejection or other related immune disorders.
Description
Technical field
The invention relates to a kind of quinic acid derivatives, its processing procedure and application thereof, the Kui of its espespecially species cynarin
Buddhist nun acid derivative, can be combined with CD28 molecules and pass through suppression T cell activation and reach its pharmacological use person.
Background technology
T cell plays critical role during the starting and regulation of immune response caused by antigen, T cell
Activation has many positively or negatively regulation programs to turn to participate in machine, closely to control the activation degree of T cell, it is to avoid because immune
Overreact or immune response are not enough and cause pathological symptom.When T cell is by from extracellular specific antigen stimulation, need
Want the first signal path（signal 1 pathway）With the second signal path（signal 2 pathway）Common participation
Optimal T cell activation effect can be reached, the starting of the first signal path needs the φt cell receptor on T cell surface（T-cell
Receptor, TCR）With antigen presenting cells（Antigen-presenting cell, APC）Such as BMDC
（dendritic cell）The Major Histocompatibility compound showed Deng cell surface（major histocompatibility
Complex, MHC）Molecule and the antigen fragment presented through MHC molecule are be combined with each other, and the induction of the second signal path is then needed
Want the CD28 molecules on T cell surface and the co stimulatory molecule on APC surfaces（co-stimulatory molecule）Such as CD80 points
Son（Also known as B7-1 molecules）Or CD86 molecules（Also known as B7-2 molecules）It is combined with each other, to start co-stimulatory pathways（co-
stimulatory pathway）, lack the TCR association reactions under the second signal path（engagement）T cell will be caused to lose
Energy（anergy）So that T cell enters the state of low reaction ability.
When immune system meets with self-antigen or when anaphylactogen and need not trigger complete immune response, now T
If cell overactivity will cause autoimmune disease or allergic reaction, therefore, reduce the second signal path to cause T cell to be lost
It can be used as autoimmune disease or anaphylactoid therapeutic strategy.However, due to participating in the various signal transduction roads of cell interior
Footpath（signal transduction pathway）The factor have signal transduction path in suitable overlapping, interference cell very
Serious side effect may be caused（Do not have for example optionally while blocking the first signal path and the second signal path）, conversely
Ground, blocks signal transduction path to be mode that is relatively gentle and being more suitable for adjusting reaction signal intensity by outside
（It is for example optionally indivedual to block the first signal path or the second signal path）, for example, non-mitogenesis
（non-mitogenic）Anti-CD28 antibody can be used as blocking outside the T cell blocking agent of the second signal path, however,
Due to antibody more fragile and unstable property in itself, utilizing antibodies as medicine has many shortcomings, for example, antibody can be by
Acid and proteasome degradation into alimentary canal so that antibody is not suitable for offeing medicine with oral way, and the spatial configuration of antibody is difficult to tie up
Hold and it is related it is lost function, therefore be also not easy to preserve, along with antibody drug is a kind of for immune system in itself
Foreign protein antigen, it is also possible to induce immune response, these shortcomings can all cause during using antibody as medicine under effect
Drop.
Using simulating metabolite（metabolite）Organic molecule as medicine combining target acceptor to block spy
The shortcoming of afore mentioned antibodies medicine can be overcome by determining signal transduction path, in order to develop preferable T cell blocking agent, hair of the invention
A person of good sense establishes a kind of technology for screening medicine, referred to as immobilization recipient Motion capture（after flowing through
Immobilized receptor, AFTIR）And Taiwan patent announcement I355493 patent of invention is obtained, invent
People is using this triage techniques by Western herbs Echinacea（Echinacea purpurea）Isolated in extract to CD28 molecules
Target component with specific binding capacity, and confirm that this composition is cynarin（Cynarin, its chemical structural formula is referred to
Fig. 1）.There is higher cytotoxicity in itself yet with cynarin, more serious side effect will be caused, inventor transfers exploitation
The analog of cynarin, CD28 molecules can effectively be blocked and cytotoxicity is less than organic small point of cynarin by being desirably to obtain
Son, inventor carries out Molecular Dynamics through the threedimensional model of cynarin and CD28 molecules, finds arithoke acid molecular structures
In to combine CD28 molecules crucial blocking factor（Key blocking factor, KBF）It is a class chinic acid structure,
Inventor is the quinic acid derivatives for deriving a species cynarin by chinic acid, and enters modification to chinic acid skeleton, to reduce Kui
The cytotoxicity of Buddhist nun acid derivative.
Therefore, the present invention proposes the quinic acid derivatives of a species cynarin, the processing procedure of such a quinic acid derivatives of synthesis
And such a quinic acid derivatives participate in through dependence CD28 molecules are suppressed（CD28-dependent）T cell activation process and
The pharmacological use reached, through the implementation of the present invention, can improve known being used as immunomodulator using anti-CD28 antibody or cynarin
The shortcoming caused during thing, lifts the oral stability of medicine and reduces the toxicity of medicine.
The content of the invention
The main object of the present invention, is to provide a kind of quinic acid derivatives, and it can pass through had a class chinic acid
Structure is combined with CD28 molecules, and blocks the T cell activation reaction for relying on the participation of CD28 molecules.
The secondary objective of the present invention, is to provide a kind of processing procedure of quinic acid derivatives, and it is catalyzed in sour environment first
Lower generation lactone type intermediate product, then reacts lactone type intermediate product and amide reagent under microwave radiation environment, and gives birth to
Into quinic acid derivatives.
It is still a further object of the present invention is to provide a kind of purposes of quinic acid derivatives, it is through combination and blocks CD28
Molecule and the effect for suppressing T cell activation, and available for immune dysregulation diseases such as treatment autoimmune disease, allergy or graft rejections
Disease.
In order to reach above-mentioned censured each purpose and effect, present invention is disclosed a kind of quinic acid derivatives, its processing procedure
With and application thereof, quinic acid derivatives of the invention are a kind of analogs of cynarin, identical with arithoke acid molecule, and it has one
Class chinic acid structure, can be as the crucial blocking factor for combining and blocking CD28 molecules, to suppress the activation of T cell.
The quinic acid derivatives of the present invention, its chemical structural formula is：
Wherein, R1 is an organo-functional group, and R2 is then monohydroxy blocking group（hydroxyl-protecting
group）.
The combination that the quinic acid derivatives of the present invention have is with blocking the ability of CD28 molecules to be derived from a chinic acid skeleton
（That is such chinic acid structure）, as it was previously stated, being used for the specific binding sites with CD28 molecules in arithoke acid molecule
（specific binding site）It is such chinic acid structure with reference to person.Further, since 1- carboxyls in its chinic acid skeleton
With one second reagent（R1-NH2）In amido reaction generation one victory peptide bond, imply that and be connected to a carbon（C-1）- C (O) OH
Group is replaced by-C (O) NHR1 groups so that the toxicity of quinic acid derivatives of the invention declines.In addition, in order to reach more
Stable quinic acid derivatives, can further utilize one first reagent（R2=O）Monohydroxy blocking group is formed to protect chinic acid
3- hydroxyls or 4- hydroxyls in skeleton.It is in the same direction because 3- hydroxyls adjoin with 4- hydroxyls, and in the stereochemical structure of molecule
（cis）, 3- hydroxyls and 4- hydroxyls can be reacted with same molecule and the single hydroxyl of 3- hydroxyls and 4- hydroxyls can be protected simultaneously by being formed
Blocking group.
The processing procedure that utilization chinic acid proposed by the present invention prepares quinic acid derivatives includes two steps：First, utilize one
Strong acid or a strong acid and one first reagent（R2=O）Reacted with a chinic acid and generate an intermediate product, the chemistry of the intermediate product
Structural formula is：
Second, utilize one second reagent（R1-NH2）Reacted with the intermediate product, and generate the quinic acid derivatives.It incite somebody to action this
First or second step of processing procedure are placed under microwave radiation and are heated to 100 DEG C, can promote reaction rate, and cause each step
Reaction time reduce to only needing to complete within about five minutes.
The purposes of the quinic acid derivatives of the present invention is to pass through the T for combining CD28 molecules, blocking dependence CD28 molecules to participate in
The signal path of cell second, the pharmacology machine for finally achieving the regulation immune response for suppressing T cell activation effect turns, and can be as controlling
Treat the medicine of the immune disorder illnesss such as autoimmune disease, allergy or graft rejection.
Brief description of the drawings
Fig. 1：It is the chemical constitution of cynarin；
Fig. 2：It is the chemical constitution of the Series Molecules of the quinic acid derivatives of the present invention；
Fig. 3：It is the synthesis processing procedure of the Series Molecules of the quinic acid derivatives of the present invention；
Fig. 4：It is the yield of the Series Molecules of the quinic acid derivatives of the present invention；
Fig. 5：It is the cells ex vivo Toxic test results of the Series Molecules of the quinic acid derivatives of the present invention；
Fig. 6：It is the in vitro effect test result of the Series Molecules of the quinic acid derivatives of the present invention；
Fig. 7：It is the separating force test result of the preferable quinic acid derivatives of the present invention；
Fig. 8：It is the in vitro 503nhibiting concentration test result of the preferable quinic acid derivatives of the present invention；
Fig. 9：It is the in vivo immunosuppression ability test result of the preferable quinic acid derivatives of the present invention；
Figure 10：It is the live body Adverse event assessment result of the preferable quinic acid derivatives of the present invention；And
Figure 11：It is another live body Adverse event assessment result of the preferable quinic acid derivatives of the present invention.
【Figure number is to as directed】
KBF key blocking factors
Embodiment
In order that the architectural feature of the present invention and the effect reached have a better understanding and awareness, spy is with preferably
Embodiment and cooperation detailed description, are described as follows：
Referring to Fig. 2, its chemical constitution for the Series Molecules of the quinic acid derivatives of the present invention；As illustrated, this hair
The Series Molecules of bright quinic acid derivatives correspond to a numbering respectively, and have a molecular formula jointly：
Wherein, R1 is an organo-functional group, and R2 is then monohydroxy blocking group.As it was previously stated, 3- hydroxyls and 4- hydroxyls
Adjoin and be in the same direction in the stereochemical structure of molecule, therefore may be connected to same R2.As shown in FIG., the first reagent（R2=O）Respectively
It is bonded with the oxygen atom of 3- hydroxyls and the oxygen atom of 4- hydroxyls and disengages a hydrone, forms the hydroxy-protective group to protect 3-
Hydroxyl and 4- hydroxyls.The victory peptide bond can protect the quinic acid derivatives with the hydroxy-protective group, make its not facile hydrolysis, and avoid
Disengage the cytotoxic chinic acid of tool.
Refering to Fig. 3, it is the synthesis processing procedure of the Series Molecules of the quinic acid derivatives of the present invention；As illustrated, of the invention
Quinic acid derivatives Series Molecules synthesis program all include following two steps：
Step one：Reacted using an acid and one first reagent and a chinic acid, generate an intermediate product；And
Step 2：Reacted using one second reagent and the intermediate product, generate the quinic acid derivatives.
In step one, strong acid is added（Such as sulfuric acid）To be catalyzed the lactonization reaction or ketal reaction of chinic acid, in acidity
Under catalysis, the oxygen atom of the 5- hydroxyls of chinic acid carries out nucleophilicity to 1- carboxyls（nucleophilically）Attack, and generate
The lactone ring five membered of intermediate product（five membered lactone ring）Structure；When the first reagent（For a kind of ketone）Carbonyl
Base and acidic catalyst simultaneously in the presence of, the oxygen atom of 3- hydroxyls and the oxygen atom of 4- hydroxyls also can be to the carbon of the carbonyl of the first reagent
Atom carries out nucleophilic attack, and generates five yuan of ketal rings of the intermediate product with lactone structure（five membered
ketal ring）, this ketal structure can protect 3- hydroxyls and 4- hydroxyls.In addition, step one is placed in into high temperature（Such as 100 DEG C）Under
During progress, compare and carry out at room temperature, high temperature can make shortening the time required to reaction, furthermore, step one is placed in microwave radiation
During lower progress, the reaction rate of step one can be lifted further.For example, being reacted using acetone as the first reagent with chinic acid
When, if this reaction is placed at room temperature, it is necessary to just the yield of lactone intermediate product can be made to reach 85% by 12 hours, however, will
Same reaction is placed under microwave radiation and is heated to 100 DEG C, and 98% lactone intermediate product production was can reach within 5 minutes
Rate.
In step 2, lactone intermediate product and the reagent of amine second（With R1-NH2Molecular formula）React and generate Kui
Buddhist nun acid derivative, the carbonyl of the nitrogen-atoms of amido to lactone intermediate product（The lactone ring five membered structure formed for the moment positioned at step
It is interior）Nucleophilic attack is carried out, lactonic ring is opened and forms a victory peptide bond, and generates monamide product（I.e. the chinic acid derives
Thing）And disengage a hydrone.Step 2 is placed in when 100 DEG C are carried out and be heated under microwave radiation, reaction is only needed 5 minutes
Obtain the quinic acid derivatives of high yield.The yield of the Series Molecules of the quinic acid derivatives of the present invention is as shown in Figure 4.
For convenience of indicating, hereafter represented with each quinic acid derivatives in legend in the way of Cyn- is numbered.
Refering to Fig. 5, its for the quinic acid derivatives of the present invention Series Molecules in vitro（in vitro）Cytotoxicity
Test result；The longitudinal axis in figure is the survival rate of the T cell of in vitro culture, and as a percentage, transverse axis is to make an addition to T cell
Cynarin or the concentration of each quinic acid derivatives, unit is mcg/ml（μg/mL）, the survival rate of T cell tested with MTT, is tied
Fruit is as illustrated, addition Cyn-1315, Cyn-1316, Cyn-1317, Cyn-1318, Cyn-1319, Cyn-1320, Cyn-
1321st, the T cell of the quinic acid derivatives such as Cyn-1322, Cyn-1323 and Cyn-1324, its survival rate is higher than addition cynarin
T cell, conversely speaking, the cytotoxicity of those quinic acid derivatives be less than cynarin.
Refering to Fig. 6, it is the in vitro effect test result of the Series Molecules of the quinic acid derivatives of the present invention；In figure
The longitudinal axis represents IL-2 performance amount, is represented with the multiple relative to PBS, and the transverse axis in figure represents each quinic acid derivatives and arithoke
Acid, and different concentration are distinguished with coloring in for bar graph, when the activation of T cell is disturbed, IL-2 performance amount is by under
Drop, as a result as illustrated, Cyn-1316, Cyn-1319, Cyn-1320, Cyn-1321, Cyn-1323, Cyn-1324, Cyn-
The quinic acid derivatives such as 1325 and Cyn-1326 show equivalent or higher than cynarin suppression to the priming reaction of T cell and imitated
Really.
Due in the Series Molecules of above-mentioned quinic acid derivatives, Cyn-1324 shows minimum cytotoxicity and to T
The high of cytoactive suppresses effect, and inventor is then as progress subsequent experimental is represented, further to test its effect.Cyn-
1324 chemical structural formula is as follows：
And according to IUPAC（International Union of Pure and
Applied Chemistry, IUPAC）The standard nomenclature of formulation is (3a is suitable, and 5 is suitable, and 7 is suitable, and 7a is inverse) -5,7- dihydroxies-N-
(2- first propyl group) six hydroxyl spiral shells [1,3- benzos two dislike cyclopentadienyl -2,1'- hexamethylenes] -5- carboxylic amine（(3aR,5R,7R,7aS)-5,7-
dihydroxy-N-(2-methylpropyl)hexahydrospiro[1,3-be nzodioxole-2,1'-
cyclohexane]-5-carboxamide）.
Refering to Fig. 7, it is the quinic acid derivatives Cyn-1324 of present invention separating force test result；Longitudinal axis table in figure
Show the intermolecular combination probability of the CD80 of CD28 molecules and B cell of T cell（binding probability）, transverse axis represents
Separating force（unbinding force）Size, unit be skin newton（pN）, sign (A) field references do not add Cyn-
1324 separating force test result, the field references of sign (B) add Cyn-1324 separating force test result, as illustrated,
When not adding Cyn-1324, the average separating force about 41.9pN measured is added after Cyn-1324, and average separating force declines
To about 29.1pN, this result, which provides physical proof, confirms that Cyn-1324 makes CD28 molecules decline with the intermolecular combinations of CD80,
And the second signal path for acting on and inducing between CD28 molecules and costimulatory molecules such as CD80 or CD86 can be blocked.
Refering to Fig. 8, it is the quinic acid derivatives Cyn-1324 of the present invention in vitro 503nhibiting concentration test result；Figure
In the longitudinal axis represent the inhibitions of the IL-2 performance amounts that Cyn-1324 is induced costimulation, as a percentage, transverse axis is represented
Cyn-1324 concentration is taken the logarithm value, 503nhibiting concentration（IC50）Expression can be up to the second signal path of suppression and make T cell
The dosage that IL-2 performance amounts halve, as shown in FIG., Cyn-1324 reaches the 503nhibiting concentration of blocking t cell immune response about
For 20 μ g/mL.
Refering to Fig. 9, its be the quinic acid derivatives Cyn-1324 of the present invention in vivo（in vivo）Immunosuppression ability
Test result, method of testing is by four groups of BALB/c mouses respectively with phosphate buffer（phosphate-buffered
Saline, PBS）, ovalbumin（Ovalbulmin, OVA）, OVA and Cyn-1324, OVA and Cyclosporine A（cyclosporin
A, CSA）Processing, PBS is used as negative control（negative control）Control group, OVA is produce BALB/c mouse
Immune response, CSA is then recently clinically to suppress the new drug of immune response, can be used as positive control（positive
control）And the control group of drug effect reference, serum was collected with mouse again by 14 days after processing, and with elisa assay
Immunoglobulin in Serum G（IgG）Immunoglobulin E（IgE）Content.The longitudinal axis in figure represents the concentration of immunoglobulin,
Unit is μ g/mL, and transverse axis represents four groups of mouse, and sign A left column is the content of IgG in mice serum, and sign B right column is small
IgE content in mouse serum, as illustrated, compared to the mouse only handled with OVA, being handled in the lump with OVA and Cyn-1324
IgG content reduces about 30% in its serum of mouse and IgE contents reduce about 23%, in addition, the mouse handled in the lump with OVA and CSA its
IgG content reduces about 45% in serum and IgE contents reduce about 12%, and display Cyn-1324 can effectively suppress immune response.
Refering to Figure 10, it is the quinic acid derivatives Cyn-1324 of present invention live body Adverse event assessment result；Test side
Method is by four groups of mouse one of which with PBS processing, and it is all handled to trigger immune response, and in OVA sensitization in three groups with OVA
Afterwards respectively with PBS, Cyn-1324 and CSA processing, and the body weight of four groups of mouse is kept track, as a result as illustrated, in figure
The longitudinal axis is mouse weight, as a percentage, and transverse axis is Mouse Age, and unit is all, is evident that what is handled with CSA in figure
Mouse gradually mitigates in 12 week old to body weight between 20 week old, is flown up again to during 22 week old, and the mouse of remaining group its body
Weight all increasess slowly rising with the age, therefore Cyn-1324 side effect may be gentle compared with CSA.
Refering to Figure 10, it is the quinic acid derivatives Cyn-1324 of the present invention another live body Adverse event assessment result；Figure
The picture of middle sign (A) is that the picture of sign (B) in the back photo of mouse, figure is the belly photo of mouse, and two pictures are left
Side is all the mouse to be handled after OVA sensitization through Cyn-1324, and right side is all the mouse to be handled after OVA sensitization through CSA, is such as schemed
It is shown, there is the side effect of body swelling with the CSA mouse handled, and there is not identical in the mouse handled with Cyn-1324
Side effect.In addition, single dose toxicity test（single dose toxicity test）Result, mouse is to Cyn-1324
Maximal allowance dose（Maximum tolerance dose, MTD）For 400 milligrams of per kilogram of body weight.
In summary, the present invention proposes a kind of quinic acid derivatives, its can pass through class chinic acid structure that it has with
CD28 molecules are combined, and the signal path of T cell second that CD28 molecules are participated in is relied on to block, so suppress the activation of T cell with
Immune response, and have in vitro with intravital experimental data as evidence, in addition, its processing procedure of the quinic acid derivatives of the present invention
It is divided into two steps, chinic acid and the first reagent reacting is generated into intermediate product under sour environment catalysis first, make the first examination
Agent generation can protect the monohydroxy blocking group of 3- hydroxyls and 4- hydroxyls in chinic acid molecule simultaneously, then by intermediate product with
Second reagent reacting and obtain quinic acid derivatives, after the 1- carboxyl reactions in the amido in the second reagent and chinic acid molecule into
For relatively stable acid amides, it is possible to decrease the toxicity of quinic acid derivatives, in addition, suppressing T because the quinic acid derivatives of the present invention have
The ability of cell activation, available for treatment autoimmune disease, allergy, graft rejection or other related immune disorders.
Above is only presently preferred embodiments of the present invention, not for limiting the scope that the present invention is implemented, Fan Yibenfa
The equivalent changes and modifications carried out by shape, construction, feature and spirit described in bright right, all should be included in the present invention
Right in.
Claims (15)
1. a kind of quinic acid derivatives, it is characterised in that it includes a class chinic acid structure, and such chinic acid structure is to combine
To a CD28 molecules, the chemical structural formula of the wherein chinic acid structure is:
Wherein, R1 is an organo-functional group, and R1 is selected from-CH2CH2Ph、-CH2CH2CH(CH3)2、-CH2(CH2)2OCH3, positive fourth
Base ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-CH2(CH2)2Ph or。
2. quinic acid derivatives as claimed in claim 1, it is characterised in that wherein the quinic acid derivatives are used to treat one certainly
Body immunological diseases, an allergic reaction, a graft-rejection or other immune disorder illnesss.
3. a kind of quinic acid derivatives, it is characterised in that it includes a class chinic acid structure, and such chinic acid structure is to combine
To a CD28 molecules, the chemical structural formula of the wherein quinic acid derivatives is：
Wherein, R1 is an organo-functional group, and R1 is selected from-CH2CH2Ph、-CH2CH2CH(CH3)2、 -CH2(CH2)2OCH3, positive fourth
Base ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-CH2(CH2)2Ph orAnd R2 is monohydroxy blocking group.
4. quinic acid derivatives as claimed in claim 3, it is characterised in that wherein R2 is selected from
5. a kind of processing procedure of quinic acid derivatives, it is characterised in that its step is included：
Reacted using an acid and one first reagent and a chinic acid, generate an intermediate product, the chemical structural formula of the intermediate product
For：
And
Reacted using one second reagent and the intermediate product, generate the quinic acid derivatives；
Wherein, the step of generating the intermediate product with chinic acid reaction using the acid and first reagent second is tried using this
The step of agent generates the quinic acid derivatives with intermediate product reaction is in progress under microwave radiation；First reagent has a carbonyl
Base, second reagent has a chemical formula R1-NH2, and R1 is an organo-functional group, and selected from-CH2CH2Ph、-CH2CH2CH
(CH3)2、 -CH2(CH2)2OCH3, normal-butyl ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-CH2(CH2)2Ph orR2 is monohydroxy
Blocking group.
6. the processing procedure of quinic acid derivatives as claimed in claim 5, it is characterised in that wherein R2 is selected from
7. the processing procedure of quinic acid derivatives as claimed in claim 5, it is characterised in that wherein first reagent is selected from
8. a kind of processing procedure of quinic acid derivatives, it is characterised in that its step is included：
Reacted using an acid and one first reagent and a chinic acid, generate an intermediate product, the chemical structural formula of the intermediate product
For：
And
Reacted using one second reagent and the intermediate product, generate the quinic acid derivatives；
Wherein, first reagent has a carbonyl, and second reagent has a chemical formula R1-NH2, and R1 is an organic functional base
Group, and selected from-CH2CH2Ph、-CH2CH2CH(CH3)2、 -CH2(CH2)2OCH3, normal-butyl ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-
CH2(CH2)2Ph orR2 is monohydroxy blocking group.
9. the processing procedure of quinic acid derivatives as claimed in claim 8, it is characterised in that wherein R2 is selected from
10. the processing procedure of quinic acid derivatives as claimed in claim 8, it is characterised in that wherein first reagent is selected from
11. the processing procedure of quinic acid derivatives as claimed in claim 8, it is characterised in that wherein using the acid and first examination
The step of agent generates the intermediate product with chinic acid reaction generates the Kui using second reagent and intermediate product reaction
The step of Buddhist nun acid derivative at 100 DEG C carry out and the reaction time be less than or equal to 5 minutes.
12. a kind of processing procedure of quinic acid derivatives, it is characterised in that its step is included：
Reacted using an acid and a chinic acid, generate an intermediate product, the chemical structural formula of the intermediate product is：
And
Reacted using one second reagent and the intermediate product, generate the quinic acid derivatives；
Wherein, second reagent has a chemical formula R1-NH2, and R1 be an organo-functional group, wherein R1 be selected from-
CH2CH2Ph、-CH2CH2CH(CH3)2、-CH2(CH2)2OCH3, normal-butyl ,-CH2CH(CH3)2、-
CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-CH2(CH2)2Ph or
13. a kind of quinic acid derivatives, it is characterised in that its molecular structural formula is：
Wherein, R1 is an organo-functional group, and wherein R1 is selected from-CH2CH2Ph、-CH2CH2CH(CH3)2、-CH2(CH2)2OCH3, just
Butyl ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,Positive penta
Base,-CH2(CH2)2Ph or
14. a kind of quinic acid derivatives, it is characterised in that its molecular structural formula is：
Wherein, R1 is an organo-functional group, and R2 is monohydroxy blocking group, and wherein R1 is selected from-CH2CH2Ph、-CH2CH2CH
(CH3)2、-CH2(CH2)2OCH3, normal-butyl ,-CH2CH(CH3)2、-CH2CH2CH(Ph)2, cyclopenta,N-pentyl,-CH2(CH2)2Ph or
15. quinic acid derivatives as claimed in claim 14, it is characterised in that wherein R2 is selected from
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| CN201410007374.6A Active CN104761464B (en) | 2014-01-03 | 2014-01-03 | A kind of quinic acid derivatives, its processing procedure and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1230946A (en) * | 1996-08-23 | 1999-10-06 | 吉里德科学公司 | Preparation of cyclohexene carboxylate derivatives |
| CN101284799A (en) * | 2007-03-23 | 2008-10-15 | 浙江医药股份有限公司新昌制药厂 | Nitrogen-contained derivates of caffeoylquinic acid, method for preparing same, pharmaceutical compositions thereof and uses |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1230946A (en) * | 1996-08-23 | 1999-10-06 | 吉里德科学公司 | Preparation of cyclohexene carboxylate derivatives |
| CN101284799A (en) * | 2007-03-23 | 2008-10-15 | 浙江医药股份有限公司新昌制药厂 | Nitrogen-contained derivates of caffeoylquinic acid, method for preparing same, pharmaceutical compositions thereof and uses |
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| CN104761464A (en) | 2015-07-08 |
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