CN104856983B - Synthesis and application of bornyl ferulate - Google Patents
Synthesis and application of bornyl ferulate Download PDFInfo
- Publication number
- CN104856983B CN104856983B CN201510243181.5A CN201510243181A CN104856983B CN 104856983 B CN104856983 B CN 104856983B CN 201510243181 A CN201510243181 A CN 201510243181A CN 104856983 B CN104856983 B CN 104856983B
- Authority
- CN
- China
- Prior art keywords
- forulic acid
- ester
- borneol
- dextrorotation
- ferulate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 C[C@@](CC1)(C[C@]1C1)[C@]1OC(C(C(OC)=C1)=C1O*)O Chemical compound C[C@@](CC1)(C[C@]1C1)[C@]1OC(C(C(OC)=C1)=C1O*)O 0.000 description 5
- CDWGCALUYHFAPH-SNAWJCMRSA-N C=[O]c1cc(/C=C/N)ccc1O Chemical compound C=[O]c1cc(/C=C/N)ccc1O CDWGCALUYHFAPH-SNAWJCMRSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N COc(cc(C=O)cc1)c1O Chemical compound COc(cc(C=O)cc1)c1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Emergency Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses bornyl ferulate, bornyl ferulate and a pharmaceutically acceptable prodrug thereof, which are applied to pharmacy, wherein the bornyl ferulate is applied to treating cerebrovascular diseases, the bornyl ferulate comprises two structures of dextroborneol ferulate and levoborneol ferulate, and the structural general formula of the dextroborneol ferulate is shown in the specificationThe structural general formula of the ferulic acid levo borneol ester isThe L-borneol ferulate is an enantiomer of the D-borneol ferulate. The synthesis process of the bornyl ferulate is short, the raw materials are economical and easy to obtain, and the synthesis process is easy to control; no harmful by-products are produced, the process is environment-friendly and economical, and can be widely applied to the production of medicaments for treating cerebrovascular diseases.
Description
Technical field
The invention belongs to chemical medicine, is specifically related to the synthesis and application of forulic acid right (left side) rotation norbornene ester.
Background technology
Forulic acid (Ferulic acid), initially found in the seed and leaf of plant, be a kind of presence
The phenolic acid extracted in the plants such as Radix Angelicae Sinensis, rhizome of chuanxiong, asafoetide, it has anti-inflammatory, anti-oxidant, antithrombotic and a variety of physiologically actives, extensively
Applied to fields such as health products, cosmetics, medicine, agricultural chemicals and food additives.
Find that forulic acid can suppress platelet aggregation and release by research, being capable of obvious Inhibition test thrombus shape
Into regulation immunity of organism, clear and suppression radical reaction, asafoetide acid molecule can be divided greatly vivo biodistribution by number of ways
The 26S Proteasome Structure and Function of son plays a protective role.
But forulic acid molecular hydrophylic is strong, fat-soluble difference, and its internal accretion rate is fast, brain distribution is few, it is more difficult to passes through
Blood-brain barrier plays a role, and it is restricted greatly in the application for the treatment of cranial vascular disease field, marketed drug sodium ferulate is injected
The application of liquid at present clinically mainly biases toward the treatment of angiocardiopathy.Therefore, modification preparation is carried out to asafoetide acid molecule
Derivative is a key solving forulic acid molecular defect to improve the fat-soluble research of molecule, forulic acid and alcohol react into Ah
Wei's acid esters is to improve its fat-soluble and using effect best approach.
Traditional Chinese medicine borneol has inducing resuscitation of having one's ideas straightened out, promotes medicine to have two-way tune through blood-brain barrier, Central nervous system
Section and protective effect and other effects, also have the effect of good for cerebral apoplexy disease treatment, and this is splendid the invention provides one
Research Thinking.
The occurrence cause more than one of many diseases of recent studies have shown that, corresponding treatment means can also have it is a variety of,
If suppressing multiple target spots of the generation of disease simultaneously, the effect of more preferable can be produced.Mutiple Targets medicine is based on raising curative effect
And (or) improve the overall goal of security and rationally design, may act on the multiple target spots related to some disease and produce
The drug molecule of more than one pharmacological activity.The combination of medicine is one of approach of more target drug designs.The application is according to more targets
The theory of point drug design, forulic acid and borneol are reacted to form forulic acid norbornene ester, looked for suffer from the patient of cranial vascular disease
To a preferable medicine.
The content of the invention
In order to solve the above technical problems, the present invention provides the synthetic method of forulic acid norbornene ester, the asafoetide that the present invention obtains
Sour norbornene ester is fat-soluble good, can effectively improve the brain blood circulation disorder illness of cerebral apoplexy patient, to the brain god of patient
Through playing a good protection.
To reach above-mentioned purpose, technical scheme is as follows：
The application of a kind of forulic acid norbornene ester and its pharmaceutically acceptable salt and prodrug pharmaceutically, Ah
Wei's acid norbornene ester is applied in cranial vascular disease is treated, and is particularly applicable in treatment cerebral apoplexy disease, and it includes the forulic acid right side
Two kinds of structures of norbornene ester and forulic acid L-Borneol ester are revolved, the general structure of the forulic acid dextrorotation norbornene ester isThe general structure of the forulic acid L-Borneol ester isThe forulic acid L-Borneol ester is the enantiomerism of the forulic acid dextrorotation norbornene ester
Body.
In the preferred embodiment of the present invention, further comprise, the synthetic line of the forulic acid dextrorotation norbornene ester
For：
Wherein, 1a is dextrorotation borneol, and 2 be the forulic acids of phenolic hydroxyl group protection, and R is protection group, the forulic acid of phenolic hydroxyl group protection
The forulic acid dextrorotation norbornene ester 3a of phenolic hydroxyl group protection is condensed to yield with dextrorotation borneol under condensing agent catalysis, then is obtained through deprotection
Forulic acid dextrorotation norbornene ester；
The synthetic line of the forulic acid L-Borneol ester also includes：
Wherein, 1b is L-Borneol, and the forulic acid of phenolic hydroxyl group protection is condensed to yield under condensing agent catalysis with L-Borneol
The forulic acid L-Borneol ester 3b of phenolic hydroxyl group protection, then obtain forulic acid L-Borneol ester through deprotection.
The present invention a preferred embodiment in, further comprise, the protection group include it is following in any one：
Methyl, the tert-butyl group, trityl group, methoxy, trimethyl silicon substrate, t-Butyldimethylsilyl, benzyl, oxinane
Base；The condensing agent includes following one or more：Dicyclohexylcarbodiimide, DIC, 1- (3- diformazan ammonia
Base propyl group) -3- ethyl carbodiimides, DMAP, I-hydroxybenzotriazole and 4- pyrollidinopyridines.
In the preferred embodiment of the present invention, further comprise, the synthetic line of the forulic acid dextrorotation norbornene ester
Also include：
Haloacetyl dextrorotation norbornene ester 4a reacts to obtain wittig phosphorus reagent 5a with organophosphorus reagent, and then wittig phosphorus tries
Agent 5a carries out wittig with the hydroxy benzaldehyde 6 of 3- methoxyl groups -4 again in the presence of alkali and reacts to obtain forulic acid dextrorotation norbornene ester；
The synthetic line of the forulic acid L-Borneol ester also includes：
Haloacetyl L-Borneol ester 4b reacts to obtain wittig phosphorus reagent 5b with organophosphorus reagent, and then wittig phosphorus tries
Agent 5b carries out wittig with the hydroxy benzaldehyde 6 of 3- methoxyl groups -4 again in the presence of alkali and reacts to obtain forulic acid L-Borneol ester；
Wherein X is Cl, Br or I, R PPh3X、P(O)Ph2Or P (O) (OEt)2。
The present invention a preferred embodiment in, further comprise, the organophosphorus reagent include it is following in it is any
It is a kind of：In triphenyl phosphorus, ethoxy diphenyl base phosphorus and triethyl phosphite；The alkali includes following one or more：Tetrahydrochysene aluminium
Lithium, sodium methoxide, caustic alcohol, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
In the preferred embodiment of the present invention, further comprise, pharmaceutical composition, it is included in any of the above one
Described forulic acid norbornene ester, described pharmaceutical composition includes the forulic acid norbornene ester of therapeutically effective amount or its is pharmaceutically acceptable
Salt, solvate or prodrug.
The beneficial effects of the invention are as follows:
One, the synthesis technique of forulic acid norbornene ester of the present invention are brief, and raw material economics is easy to get, and synthesis process is easy
Control.
Secondly, generation of the synthetic route without harmful side product of forulic acid norbornene ester of the present invention, be environmental protection and economy type technique,
It can be widely applicable in the production for the treatment of cerebrovascular disease medicament.
Thirdly, the present invention forulic acid norbornene ester it is fat-soluble good, be applicable to antithrombotic, reducing blood lipid and treatment cerebral apoplexy
Medicine in, and have no apparent side effect.
Brief description of the drawings
Technical scheme in technology in order to illustrate the embodiments of the present invention more clearly, in being described below to embodiment technology
The required accompanying drawing used is briefly described, it should be apparent that, drawings in the following description are only some realities of the present invention
Example is applied, for those of ordinary skill in the art, on the premise of not paying creative work, can also be according to these accompanying drawings
Obtain other accompanying drawings.
Fig. 1 is the nuclear-magnetism figure of the forulic acid dextrorotation norbornene ester of the present invention.
Fig. 2 is the mass spectrogram of the forulic acid dextrorotation norbornene ester of the present invention.
Fig. 3 is the nuclear-magnetism figure of the forulic acid L-Borneol ester of the present invention.
Fig. 4 is that the forulic acid right (left side) of the present invention revolves the effect experiment blank group brain section figure of norbornene ester.
Fig. 5 is that the forulic acid right (left side) of the present invention revolves the effect experiment sodium ferulate group brain section figure of norbornene ester.
Fig. 6 is that the forulic acid right (left side) of the present invention revolves the effect experiment Nimodipine group brain section figure of norbornene ester.
Fig. 7 is that the forulic acid right (left side) of the present invention revolves the effect experiment L-Borneol ester group brain section figure of norbornene ester.
Fig. 8 is that the forulic acid right (left side) of the present invention revolves the effect experiment dextrorotation norbornene ester group brain section figure of norbornene ester.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, rather than whole embodiments.It is based on
Embodiment in the present invention, those of ordinary skill in the art are obtained every other under the premise of creative work is not made
Embodiment, belong to the scope of protection of the invention.
Embodiment 1
A kind of synthetic route of forulic acid dextrorotation norbornene ester and specific synthetic method are disclosed in the present embodiment, wherein closing
It is into route：
Wherein, 1a is dextrorotation borneol, and 2 be the forulic acids of phenolic hydroxyl group protection, and R is protection group, the forulic acid of phenolic hydroxyl group protection
The forulic acid dextrorotation norbornene ester 3a of phenolic hydroxyl group protection is condensed to yield with dextrorotation borneol under condensing agent catalysis, then is obtained through deprotection
Forulic acid dextrorotation norbornene ester；Above-mentioned protection group include it is following in any one：Methyl, the tert-butyl group, trityl group, methoxy
Ylmethyl, trimethyl silicon substrate, t-Butyldimethylsilyl, benzyl and THP trtrahydropyranyl；Above-mentioned condensing agent includes：Dicyclohexyl carbon
Diimine, DIC, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides, DMAP, 1- hydroxyls
Base BTA and 4- pyrollidinopyridines.
The synthetic method of the forulic acid dextrorotation norbornene ester includes the following steps：
A. 4- benzyls forulic acid (7.5g, 0.026mol) is put into dichloromethane (50ml), ice salt bath is cooled to 0 DEG C
Afterwards, dicyclohexylcarbodiimide (5.43g, 0.026mol) and DMAP (0.96g, 0.008mol) are added, is added
Drying tube, react 1h；Dextrorotation borneol (4.065g, 0.026mol) is dissolved in dichloromethane in (25ml), is added drop-wise to reaction
In liquid；After being added dropwise, ice salt bath is removed, is heated up naturally, reaction is overnight；After reaction terminates, filter solid is crossed, filter cake is with appropriate two
Chloromethanes washs, and filtrate is evaporated, and residue obtains compound 3a (9.8g) through column chromatography.
B. compound 3a (9g, 0.021mol) is put into tetrahydrofuran (90ml), stirred, add ammonium formate
(6.84g, 0.105mol), palladium charcoal (1.8g, 0.147mol) is being added, is reacting 3h.After reaction terminates, palladium is filtered with diatomite
Charcoal, and washed with appropriate tetrahydrofuran, filtrate is evaporated.Residue petroleum ether or recrystallisation from isopropanol, obtain compound Ah
Wei's acid dextrorotation norbornene ester.
The structure of the forulic acid dextrorotation norbornene ester obtained in the present embodiment is confirmed with magnetic nuclear resonance method, its collection of illustrative plates
As shown in fig. 1, the architectural feature of the forulic acid dextrorotation norbornene ester is：1H-NMR(CDCl3, 500MHz) and 0.88,0.90,
0.94 (each 3H, s, H-8,9,10), 1.05 (1H, dd, J=13.3,3.3Hz, H-3b), 1.29 (1H, m, H-5b), 1.31 (1H,
M, H-6b), 1.71 (1H, m, H-4), 1.78 (1H, m, H-5a), 2.06 (1H, m, H-6a), 2.41 (1H, dddd, J=13.8,
10.0,4.0,3.5Hz, H-3a), 3.94 (3H, s, OMe), 5.01 (1H, ddd, J=10.0,3.3,1.8Hz, H-2), 6.31
(1H, d, J=15.9Hz, H-8 '), 6.92 (1H, d, J=8.5Hz, H-5 '), 7.04 (1H, dd, J=8.5,2.0Hz, H-6 '),
7.06 (1H, d, J=2.0Hz, H-2 '), 7.59 (1H, d, J=15.9Hz, H-7 ').Authenticating compound is forulic acid dextrorotation borneol
Ester.
The structural information of the forulic acid dextrorotation norbornene ester obtained in the present embodiment is confirmed by mass spectrography, such as Fig. 2 institutes
Show, [the M of EI-MS M/Z 331.6+], 329.6 [M-]。
Embodiment 2
Present embodiment discloses a kind of synthetic route of forulic acid L-Borneol ester, route are as follows：
Wherein, 1b is L-Borneol, and the forulic acid of phenolic hydroxyl group protection is condensed to yield under condensing agent catalysis with L-Borneol
The forulic acid L-Borneol ester 3b of phenolic hydroxyl group protection, then obtain forulic acid L-Borneol ester through deprotection.
Above-mentioned protection group include it is following in any one：Methyl, the tert-butyl group, trityl group, methoxy, three
Methylsilyl, t-Butyldimethylsilyl, benzyl and THP trtrahydropyranyl；Phenolic hydroxyl group protection forulic acid condensing agent catalysis under with
L-Borneol is condensed to yield the forulic acid L-Borneol ester of phenolic hydroxyl group protection, then obtains forulic acid L-Borneol ester through deprotection.
Specific synthetic method：
A. 4- benzyls forulic acid (7.5g, 0.026mol) is put into dichloromethane (50ml), ice salt bath is cooled to 0 DEG C
Afterwards, DIC (5.43g, 0.026mol) and I-hydroxybenzotriazole and 4- pyrollidinopyridines are added
(0.96g, 0.008mol), plus drying tube, react 1h；L-Borneol (4.065g, 0.026mol) is dissolved in dichloromethane
In in (25ml), be added drop-wise in reaction solution；After being added dropwise, ice salt bath is removed, is heated up naturally, reaction is overnight；After reaction terminates,
Filter solid is crossed, filter cake is washed with q. s. methylene chloride, and filtrate is evaporated, and residue obtains compound 3b (10.5g) through column chromatography.
B. compound 3b (9g, 0.021mol) is put into tetrahydrofuran (90ml), stirred, add ammonium formate
(6.84g, 0.105mol), palladium charcoal (1.8g, 0.147mol) is being added, is reacting 3h.After reaction terminates, palladium is filtered with diatomite
Charcoal, and washed with appropriate tetrahydrofuran, filtrate is evaporated.Residue petroleum ether or recrystallisation from isopropanol, obtain compound Ah
Wei's acid L-Borneol ester.
The forulic acid L-Borneol ester of above-mentioned acquisition is confirmed using nuclear-magnetism method to its structure, as shown in figure 3, obtaining
Result be：1H-NMR(CDCl3, 500MHz) and 0.88,0.90,0.95 (each 3H, s, H-8,9,10), 1.05 (1H, dd, J=
13.9,3.4Hz,H-3b),1.29(1H,m,H-5b),1.31(1H,m,H-6b),1.71(1H,m,H-4),1.78(1H,m,H-
5a), 2.06 (1H, m, H-6a), 2.41 (1H, dddd, J=13.3,9.7,3.8,3.4Hz, H-3a), 3.94 (3H, s, OMe),
5.07 (1H, dd, J=9.7,3.0, H-2), 6.31 (1H, d, J=15.9Hz, H-8 '), 6.92 (1H, d, J=8.5Hz, H-
5 '), 7.04 (1H, dd, J=8.5,2.0Hz, H-6 '), 7.06 (1H, d, J=2.0Hz, H-2 '), 7.59 (1H, d, J=
15.9Hz, H-7 ').Authenticating compound is forulic acid dextrorotation norbornene ester.
Embodiment 3
A kind of synthetic route of forulic acid dextrorotation norbornene ester is disclosed in the present embodiment：
Haloacetyl dextrorotation norbornene ester 4a reacts to obtain wittig phosphorus reagent 5a with organophosphorus reagent, and then wittig phosphorus tries
Agent 5a carries out wittig with the hydroxy benzaldehyde 6 of 3- methoxyl groups -4 again in the presence of alkali and reacts to obtain forulic acid dextrorotation norbornene ester.
Wherein, X Cl, Br or I, R PPh3X、P(O)Ph2Or P (O) (OEt)2。
Organophosphorus reagent includes：In triphenyl phosphorus, ethoxy diphenyl base phosphorus and triethyl phosphite；The alkali includes：Four
Hydrogen aluminium lithium, sodium methoxide, caustic alcohol, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
The specific method step of said synthesis route is：
Step 1：By chloracetyl dextrorotation norbornene ester 4a (21.5g, 93.2mmol), triphenylphosphine (48.9g, 186mmol),
Toluene (215ml) is added in reaction bulb, is warming up to backflow, reacts 12h, evaporated under reduced pressure, residue dichloromethane/petroleum ether
Recrystallization, obtains compound 5a (34.2g).
Step 2：Under nitrogen protection, compound 5a (34.2g, 69.4mmol) is added to anhydrous tetrahydro furan
In (342ml), -78 DEG C are cooled to, n-BuLi (11.0g, 173mmol) is added dropwise, 0.5h is reacted after dripping, 3- methoxies are added dropwise
Tetrahydrofuran (70ml) solution of base -4- hydroxy benzaldehydes 6 (13.3g, 87.5mmol), -78 DEG C of reaction 3h are kept after adding.Instead
Room temperature is warmed naturally to after having answered, saturated sodium bicarbonate solution (200ml), ethyl acetate (150ml × 3) are added dropwise into reaction solution
Extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying 4h, filter, filtrate is concentrated to dryness, residue stone
Oily ether or recrystallisation from isopropanol, obtain compound forulic acid dextrorotation norbornene ester.
Embodiment 4
The synthetic line of forulic acid L-Borneol ester is disclosed in the present embodiment, it is as follows：
Haloacetyl L-Borneol ester 4b reacts to obtain wittig phosphorus reagent 5b with organophosphorus reagent, and then wittig phosphorus tries
Agent 5b carries out wittig in the presence of alkali with the hydroxy benzaldehyde of 3- methoxyl groups -4 and reacts to obtain forulic acid L-Borneol ester again；
Wherein X is Cl, Br or I, R PPh3X、P(O)Ph2Or P (O) (OEt)2.Organophosphorus reagent includes：Triphenyl phosphorus,
In ethoxy diphenyl base phosphorus and triethyl phosphite；Above-mentioned alkali includes：Lithium Aluminium Hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide, hydrogen
Change sodium, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
The specific method step of said synthesis route is：
Step 1：By 2- chloracetyl L-Borneol ester 4b (21.5g, 93.2mmol), triphenylphosphine (48.9g,
186mmol), toluene (215ml) is added in reaction bulb, is warming up to backflow, reacts 12h, evaporated under reduced pressure, residue dichloromethane
Alkane/petroleum ether recrystallization, obtains compound 5b (35.8g).
Step 2：Under nitrogen protection, compound 5b (35.8g, 72.6mmol) is added to anhydrous tetrahydro furan
In (358ml), -78 DEG C are cooled to, n-BuLi (11.6g, 182mmol) is added dropwise, 0.5h is reacted after dripping, 3- methoxies are added dropwise
Tetrahydrofuran (70ml) solution of base -4- hydroxy benzaldehydes 6 (13.9g, 91.4mmol), -78 DEG C of reaction 3h are kept after adding.Instead
Room temperature is warmed naturally to after having answered, saturated sodium bicarbonate solution (200ml), ethyl acetate (150ml × 3) are added dropwise into reaction solution
Extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying 4h, filter, filtrate is concentrated to dryness, residue stone
Oily ether or recrystallisation from isopropanol, obtain compound forulic acid L-Borneol ester.
Embodiment 5
The forulic acid dextrorotation norbornene ester obtained in above-described embodiment and forulic acid L-Borneol ester are carried out in the present embodiment
Effect experiment, it is evaluated in brain by influence of the forulic acid norbornene ester therapeutic administratp to rat permanent cerebral ischemia induced brain injury
Drug effect in palsy disease treatment.
Above-mentioned experimental program is：
1st, cleaning grade male SD rat 100 (being 50% into mould rate), body weight 250-300g, using internal carotid line are prepared
Bolt method prepares inaccessible (MCAO) model of intraluminal middle cerebral artery occlusion in rats：Rat is injected intraperitoneally with 3% chloral hydrate (300mg/kg)
(ip) anaesthetize, on supine surgical platform, neck median incision, exposure right carotid, outwards draw digastric muscle and chest lock mastoid process
Flesh, dissociated successively by arteria carotis communis crotch head-end, ligature and cut the branch of external carotid artery：Artery and thyroid gland under occipital bone
Upper artery.Ligatured in external carotid artery distal end, it is standby that cut-out external carotid artery makes its trunk dissociate.Then internal carotid is separated, with silk
Line is made a call to one in external carotid artery root and released, and folder closes arteria carotis communis and internal carotid.By fishing line (long 40mm, diameter 0.26mm) through neck
Outer artery trunk otch, slowly enter cranium direction to internal carotid and promote, unclamped after fishing line enters internal carotid on internal carotid
Artery clamp.Using arteria carotis communis crotch as mark, resistance is felt when promoting 18mm or so, that is, moved before having reached thinner brain
In arteries and veins, MCA all blood supply sources are blocked, external carotid artery root has been tightened and releases.Skin suture, completing MCAO causes permanently
Cerebral ischemic model.
2nd, after rats in sham-operated group anesthesia, aortic bifurcation inside and outside neck, not inaccessible MCA are only exposed.The 2h tails after the completion of model
Intravenously administrable, it is divided into 5 groups, every group 20, is respectively：Sodium ferulate group, forulic acid dextrorotation norbornene ester group, forulic acid L-Borneol
Ester, positive control Nimodipine group and blank group (physiological saline for giving isometric(al))；Daily intravenously administrable once, successive administration
3 days, administration volume was 0.2ml/100g body weight.
3rd, neurological deficit standards of grading：Classification is carried out by Bederson method to the neurological deficit of animal to comment
Point, standard is as follows：
0 point：Not it was observed that nervous symptoms.
1 point：Carry tail it is hanging when, the operation offside forelimb of animal shows as wrist elbow flexing, shoulder inward turning, elbow abduction, is close to chest
Wall.
2 points：Animal is placed in smooth flat, pushing hands art side shoulder to offside move when, resistance reduce.
3 points：Side ring is turned or turn-taked to operation when animal freely walks.
4 points；Collapse from physical exhaustion, limbs are without spontaneous activity.
Experiment carries out preliminary pharmacodynamic results statistics, neurological deficit score and cerebral infarction volume statistics to above-mentioned four groups of experiments after terminating
As a result it is as shown in table 1：
The pharmacodynamic experiment result statistical form of table 1
| Group | n | Neurological deficit score | Cerebral infarction volume (mm2) |
| Blank control group | 10 | 2.50±0.53 | 35.2±4.38 |
| Sodium ferulate group | 10 | 2.30±0.54 | 33.8±4.85 |
| Nimodipine group | 10 | 1.40±0.52* | 20.0±5.13* |
| Forulic acid L-Borneol ester group | 9 | 1.60±0.55* | 21.8±4.78* |
| Forulic acid dextrorotation norbornene ester group | 10 | 1.40±0.50* | 18.1±5.43* |
* P ＜ 0.05, compared with blank group.
Counted from the neurological deficit score in Fig. 4-8 and table 1 and cerebral infarction volume, marketed drug sodium ferulate is for brain soldier
Middle disease there's almost no therapeutic effect, and forulic acid L-Borneol ester and forulic acid dextrorotation norbornene ester show good medicine
Effect, wherein forulic acid L-Borneol ester is suitable with positive control drug Nimodipine, and forulic acid dextrorotation norbornene ester is right better than positive
According to medicine Nimodipine.
By that can be obtained in the above embodiment of the present invention, the synthesis technique of forulic acid norbornene ester of the present invention is brief, former
Expect it is economical and easily available, it is nontoxic, and synthesis process is easy to control；Generation without harmful side product, it is environmental protection and economy type work
Skill, it can be widely applicable in the production for the treatment of cerebrovascular disease medicament.
The forulic acid norbornene ester good water solubility of the present invention, it is applicable to antithrombotic, reducing blood lipid and treatment cranial vascular disease
Medicine in, and have no apparent side effect.
The foregoing description of the disclosed embodiments, professional and technical personnel in the field are enable to realize or using the present invention.
A variety of modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, it is of the invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope caused.
Claims (2)
1. a kind of synthetic method of forulic acid norbornene ester, the forulic acid norbornene ester includes forulic acid dextrorotation norbornene ester and forulic acid
Two kinds of structures of L-Borneol ester, the general structure of the forulic acid dextrorotation norbornene ester areInstitute
The general structure for stating forulic acid L-Borneol ester isThe forulic acid L-Borneol ester is
The enantiomter of the forulic acid dextrorotation norbornene ester；
Characterized in that, wherein, the synthetic line of the forulic acid dextrorotation norbornene ester includes：
Haloacetyl dextrorotation norbornene ester 4a reacts to obtain wittig phosphorus reagent 5a with organophosphorus reagent, then wittig phosphorus reagent 5a
Wittig is carried out in the presence of alkali with the hydroxy benzaldehyde 6 of 3- methoxyl groups -4 again to react to obtain forulic acid dextrorotation norbornene ester；
The synthetic line of the forulic acid L-Borneol ester also includes：
Haloacetyl L-Borneol ester 4b reacts to obtain wittig phosphorus reagent 5b with organophosphorus reagent, then wittig phosphorus reagent 5b
Wittig is carried out in the presence of alkali with the hydroxy benzaldehyde 6 of 3- methoxyl groups -4 again to react to obtain forulic acid L-Borneol ester；
Wherein X is Cl, Br or I, R PPh3X、P(O)Ph2Or P (O) (OEt)2。
2. the synthetic method of forulic acid norbornene ester according to claim 1, it is characterised in that the organophosphorus reagent is selected from
Any one in below：Triphenyl phosphorus, ethoxy diphenyl base phosphorus and triethyl phosphite；The alkali is selected from following a kind of or several
Kind：Lithium Aluminium Hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510243181.5A CN104856983B (en) | 2015-05-13 | 2015-05-13 | Synthesis and application of bornyl ferulate |
| PCT/CN2015/089396 WO2016179932A1 (en) | 2015-05-13 | 2015-09-10 | Synthesis and application of bornyl ferulate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510243181.5A CN104856983B (en) | 2015-05-13 | 2015-05-13 | Synthesis and application of bornyl ferulate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104856983A CN104856983A (en) | 2015-08-26 |
| CN104856983B true CN104856983B (en) | 2017-12-26 |
Family
ID=53903458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510243181.5A Active CN104856983B (en) | 2015-05-13 | 2015-05-13 | Synthesis and application of bornyl ferulate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104856983B (en) |
| WO (1) | WO2016179932A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910018B (en) * | 2015-05-13 | 2017-02-22 | 苏州沪云肿瘤研究中心股份有限公司 | Ferulic acid D-borneol ester crystal form |
| CN104856983B (en) * | 2015-05-13 | 2017-12-26 | 苏州沪云肿瘤研究中心股份有限公司 | Synthesis and application of bornyl ferulate |
| CN104856944A (en) * | 2015-05-13 | 2015-08-26 | 苏州沪云肿瘤研究中心股份有限公司 | Bornyl ferulate injection |
| CN107619376A (en) * | 2017-11-09 | 2018-01-23 | 宁波职业技术学院 | A kind of valine norbornene ester and its preparation method and application |
| CN108047048B (en) * | 2017-12-30 | 2021-01-12 | 苏州沪云肿瘤研究中心股份有限公司 | Phenylpropanoate compound and preparation method and application thereof |
| CN108084030B (en) * | 2017-12-30 | 2021-08-31 | 苏州沪云新药研发股份有限公司 | Phenylpropanoid ester compound and preparation method and application thereof |
| CN112426433B (en) * | 2020-12-23 | 2022-08-05 | 湖南中医药大学 | Borneol angelica polysaccharide liposome for resisting cerebral ischemia inflammatory reaction and preparation method thereof |
| CN114106298B (en) * | 2021-10-18 | 2023-05-30 | 哈尔滨工业大学（深圳） | Ferulic acid lignin micro-nano particles capable of treating colonitis and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232347A (en) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | A brain targeting prodrug for CNS (central nervous system) drugs and a preparation method thereof, and applications of borneol in the brain targeting prodrug for CNS drugs |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007051114A (en) * | 2005-08-19 | 2007-03-01 | Nippon Menaade Keshohin Kk | Glutathione reductase activity promoter |
| CN100574752C (en) * | 2007-11-29 | 2009-12-30 | 中山大学 | A kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular and preparation method thereof |
| CN104856983B (en) * | 2015-05-13 | 2017-12-26 | 苏州沪云肿瘤研究中心股份有限公司 | Synthesis and application of bornyl ferulate |
| CN104856944A (en) * | 2015-05-13 | 2015-08-26 | 苏州沪云肿瘤研究中心股份有限公司 | Bornyl ferulate injection |
-
2015
- 2015-05-13 CN CN201510243181.5A patent/CN104856983B/en active Active
- 2015-09-10 WO PCT/CN2015/089396 patent/WO2016179932A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232347A (en) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | A brain targeting prodrug for CNS (central nervous system) drugs and a preparation method thereof, and applications of borneol in the brain targeting prodrug for CNS drugs |
Non-Patent Citations (1)
| Title |
|---|
| "7_羟基异黄酮阿魏酸酯衍生物的合成及相关活性研究";周北斗;《中国优秀硕士学位论文全文数据库》;20120315;中文摘要 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016179932A1 (en) | 2016-11-17 |
| CN104856983A (en) | 2015-08-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104856983B (en) | Synthesis and application of bornyl ferulate | |
| TW450953B (en) | Glycoprotein IIb/IIIa antagonists | |
| CN101781226B (en) | Agomelatine and medicine composition thereof | |
| WO2003086407A1 (en) | Use of stimulators of soluble guanylate cyclase for treating glaucoma | |
| EP3563873B1 (en) | Application of combination of polyethylene glycol and local anesthetic in non-narcotic analgesia | |
| EP3111940A1 (en) | Silicon phthalocyanine complex, preparation method and medicinal application thereof | |
| CN101195597A (en) | 1-substituted-4,4-2 substituted thiosemicarbazide compounds, production method and uses of the same | |
| CN104341450B (en) | A kind of synthesis of phosphocreatine derivative and pharmaceutical applications | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN111217749A (en) | Deuterated pentazocine, preparation method, medical composition and application | |
| CN107955059B (en) | Arenobufagin derivative and the preparation method and application thereof | |
| CN109721579A (en) | The plain derivative of 7,8- dehydrogenation grapevine penta, its preparation method and pharmaceutical composition and purposes | |
| CN101591226B (en) | 1,3-diarylpropane derivatives and application thereof | |
| JP5903166B2 (en) | Derivatives of butylphthalide and methods for producing and using the same | |
| CN108864082B (en) | Indolizine compound with anticancer activity and derivative thereof | |
| CN109485674B (en) | Compound with creatine phosphate and bilobalide B composite structure, preparation and medical application thereof | |
| JP4015853B2 (en) | N-substituted benzyl or phenyl aromatic sulfonamide compounds and uses thereof | |
| CN109942665A (en) | Triptolide alcohol derivative and its preparation method and application | |
| CN110981865B (en) | Medicine for treating brain glioma and preparation method thereof | |
| CN100422133C (en) | Novel 2-(alpha-hydroxyl amyl) and its preparing method and use | |
| CN114072381A (en) | Use of aminothiol compounds as neurocerebroprotective or cardioprotective agents | |
| JPS61500437A (en) | Ether of n-propanolamine derivative | |
| CN101463045A (en) | Thiophosphate nucleotide compound | |
| CN113549046B (en) | Bisbecklonin S derivative and preparation method and application thereof | |
| JPS59204167A (en) | Hydroquinone derivative and production thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 215123 floor 5, building 5, Zone C, Dongfang Industrial Park, No. 1, Huayun Road, Suzhou Industrial Park, Jiangsu Province Patentee after: SUZHOU PHARMAVAN CANCER RESEARCH CENTER Co.,Ltd. Address before: 215123 floor 5, building 5, Zone C, Dongfang Industrial Park, No. 1, Huayun Road, Suzhou Industrial Park, Jiangsu Province Patentee before: SUZHOU PHARMAVAN CANCER RESEARCH CENTER Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |