CN101817761A - Benzoate derivatives, preparation method and application - Google Patents

Benzoate derivatives, preparation method and application Download PDF

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CN101817761A
CN101817761A CN201010103089A CN201010103089A CN101817761A CN 101817761 A CN101817761 A CN 101817761A CN 201010103089 A CN201010103089 A CN 201010103089A CN 201010103089 A CN201010103089 A CN 201010103089A CN 101817761 A CN101817761 A CN 101817761A
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replacement
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CN101817761B (en
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戚建华
罗燕
向兰
高丽娟
孙恺悦
李金优
韩峰
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Hangzhou Ivy Leaf Medical Technology Co., Ltd.
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Zhejiang University ZJU
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Abstract

The invention provides benzoate derivatives. A series of benzoate derivatives are synthesized through a chemical method, comprising ester compounds, (sulfur) ether compounds and amide compounds, wherein most synthesized compounds have new chemical structures, and proved through in vitro cell activity experiments, the synthesized benzoate derivatives have obvious activities similar to nerve growth factors (NGF). Proved through an in vitro animal experiment, 2,3-dyhydroxy benzoic acid tetradecyl ester which is a new synthesized compound has the effect of enhancing the memory of senile mice, thus the benzoate derivative can be applied to preparing medicaments for preventing and treating senile dementia neurodegenerative diseases, particularly to preparing medicaments for treating the neurodegenerative diseases such as the Alzheimer's diseases (AD), and the like. The invention opens up a new medical application of the benzoate derivatives, has reasonable preparation method and simple and convenient operation and provides new treatment medicaments for preventing and treating the neurodegenerative diseases such as the senile dementia, and the like.

Description

Benzoate derivatives and preparation method and application
Technical field
The invention belongs to compounds process for production thereof and application, relate to the preparation method of benzoate derivatives, and the application of this compounds in nerve degenerative diseases such as prevention and treatment senile dementia.
Background technology
Senile dementia is broadly divided into the three major types type: the dementia of Alzheimer's disease (Alzheimer ' s disease, be called for short AD), vascular dementia and other types.Along with increasing of the aged, the morbidity of senile dementia obviously raises, and has become the 4th major cause that causes grownup's death, is only second to heart trouble, cancer, apoplexy.China senile dementia patient estimates to surpass 5,000,000, accounts for 1/4 of the total case load in the world; And along with the quickening of China's aging population process, this numeral will be more huge, bring great influence for social stability and development.According to statistics, the sickness rate over-65s of Chinese senile dementia is to be to be 30% more than 10%, 80 years old more than 5%, 70 years old, to more than 85 years old then up to 40%.After 20 years, middle-aged people of today will step into the elderly's ranks, and dementia patient's quantity will sharply increase, and the elderly's health also will be related to the stable and development of entire society.Therefore, research and develop effective prophylactic treatment senile dementia medicine and become the medical problem that the whole world presses for solution.
In senile dementia three macrotaxonomies, AD is that sickness rate is the highest, also is most important a kind of dementia form disease.AD is a kind of nerve degenerative diseases, is main clinical disease with memory and Cognitive function damage, can cause can't take care of oneself when serious.The definite pathomechanism of AD it be unclear that, and at present main academic viewpoint has following several: 1. beta-amyloyd polypeptide (A β) toxicity and deposition; 2. cholinergic lacks theory; 3. nerve retrograde affection (Neurodegeneration); 4. other multiple factor is as transgenation theory, oxidative stress theory.
A β deposition and toxicity are one of principal elements of A Shi dementia morbidity.The unusual adjusting of the app gene in the neurone causes the gathering of toxicity A β in neurocyte, causes the cascade reaction of pathological change, and then causes the degeneration of neurocyte.The focus of research concentrates on the generation that reduces A β both at home and abroad, thereby the configuration that suppresses A beta peptide aggregation, change A β reduces its neurotoxicity, has had several drugs to enter clinical trial at present.
The medicament categories of present stage treatment AD is a lot of, mainly contain cholinergic agent, acetylcholinesterase (Acetylcholinesterase wherein, AChE) inhibitor, the medicine of main listing has tacrine (tacrine), tartrate rivastigmine (rivastigmine), selagine (huperzine A), E2020 (donepezil) etc.; β, gamma secretase Depressant; The brain metabolism regulators is as vincamine, nimodipine, cinnarizine; Influence the medicine of Radical Metabolism, as vitamins C in conjunction with vitamin-E etc.But these AD medicines mainly are symptomatic treatments, can not delay the progress of the AD course of disease, and reduce gradually with the PD curative effect of medication, occur serious side effects simultaneously, and old friends turn to sight the research and development of new anti senile dementia drug.Searching becomes the focus and the difficult point of current research at the medicine and the method for the AD cause of disease.
Studies show that neurotrophic factor all has significant effects to the neurodevelopment and the neural lysis of growing up.In the neurodegeneration animal model, find that (nerve growthfactor NGF) can stop or reduce neuronic regression to nerve growth factor.NGF is human first neurotrophic factor of finding, also is most important neurotrophic factor; It is the biologically active polypeptides that there is the important regulating and controlling effect aspects such as a kind of growth to neurocyte, growth, differentiation and function maintenance; Treatment to sacred diseases such as neuratorphy, neurodegeneration, wound reparations has unusual effect.Discover that NGF to a certain degree can stop the AD progress, it promotes that nerve growth and neuroprotective are the long term studies focuses.Yet it is a polypeptide of being made up of more than 100 amino acid; Reasons such as big and polarity is strong owing to molecular weight, can not pass through hemato encephalic barrier (Blood Brain Barrier), and it is all multifactor to be difficult to mass preparation etc., has limited to its practical clinical, and NGF does not directly also find better methods of treatment the dispensing except that operation in the brain.Therefore, seek and to have similar NGF activity (NGF mimics) and maybe can strengthen its activity (NGFenhancer) and can just become the research focus naturally by the low molecular compound of hemato encephalic barrier.Because PC12 cell (Pheochromocytoma cells, the clone obtains from the rat adrenal pheochromocytoma) has the general feature of neurocyte and the characteristics that can go down to posterity, cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, the function PC12 cell at cellular and molecular level research NGF is a good model.At present, NGF mimics has been arranged in the phase iii clinical trial stage.
Recently, the separation and purification from the Chinese medicine rough gentian of this study group obtains a class 2,3-dyhydroxyl parabens new compound, and new discovery its have the good NGF mimics biological activity of anti-senile dementia.Up to now, Shang Weiyou research worker finds such material from natural product, does not more have this compounds to have the active relevant report of similar NGF of anti-senile dementia.Has only bibliographical information chemosynthesis and compound its structural similitude (aliphatic chain contains carbon number and is lower than 11), European patent (EP 1 930 002 A1) has been described the application of benzoate compounds (1) aspect treatment and prophylaxis of viral infections, the described benzoic acid derivative of Chinese patent (CN1411339A) is mainly used in antibacterial, as foodstuff additive etc.
Figure GSA00000017938200031
In the formula, R is C 1-11Alkyl; R 1, R 2, R 3, R 4And R 5Be independently hydroxyl or hydrogen, R 1, R 2, R 3, R 4And R 5One of them is a hydroxyl, and two or more are hydroxyl, but except the Whitfield's ointment; Optimum when carbonatoms is 1-3.
Acetylsalicylic acid (Aspirin has another name called acetylsalicylic acid) is with 2 of natural acquisition, the 3-dyhydroxyl parabens compound has similar parent nucleus, be classical small molecules NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), have stronger analgesic, analgesia, anti-inflammatory, anti rheumatism action.Aspirin has unique effects to anticoagulant, can stop thrombosis, prevents and treats cerebral apoplexy, coronary heart disease etc. with it, all can receive certain effect.In recent years, along with the research that deepens continuously to the NSAIDs pharmacological action, its novel clinical use is also constantly excavated.Epidemiological study shows that the old man who often takes acetylsalicylic acid suffers from the dangerous of AD and cognitive disorder and obviously reduces, and prompting NSAIDs has the potential using value of treatment AD.Research thinks that this possible mechanism is: acetylsalicylic acid can be prevented and treated the inflammatory process of AD and can directly regulate the metabolism of A β.
Aspirin is at the active testing of in-vitro screening model PC 12 cell systems, find that it does not have tangible similar NGF activity, separation and purification obtains from the Chinese medicine rough gentian natural 2, though the parent nucleus of 3-dyhydroxyl parabens compound is similar to the structure of Aspirin, but can cause a high proportion of PC12 cell generation nervous process elongation phenomenon, show naturally 2,3-resorcylic acid ester has good similar NGF activity, has the value of exploitation anti-senile dementia prophylactic treatment medicine.With 2,3-resorcylic acid ester cpds designs and synthesizes a series of benzoate derivatives as guide's thing, extensively carries out its external activity research, seeks the structure activity relationship of such material.Have more excellent activity of potential and/or more hypotoxic compound if can find, and can be used for nerve degenerative diseases such as prevention and treatment senile dementia, will have important practical significance.
Summary of the invention
The purpose of this invention is to provide benzoate derivatives, comprise ester compound, (sulphur) ether compound and amides, have following general structure:
In the formula:
R is the straight or branched alkyl, particularly C of carbonatoms from 1 to 30 12～C 22
R 1Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or the substituted-phenyl;
R 2Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
R 3Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or the substituted-phenyl;
R 4Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
R 5Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
X is O, N or CH 2In a kind of;
Y is O, S or CH 2In a kind of;
Another object of the present invention provides the preparation method of benzoate derivatives, realizes by following steps:
(1) preparation method of ester compound (formula I, II, IV, V, X=O), earlier with acid and alcohol or an amount of dissolution with solvents of phenol, coldly cause 0 ℃, stir and drip dewatering agent down, be raised to room temperature or reflux state reaction 1～2 day again, follow the tracks of reaction with thin-layer chromatography, reaction steams solvent after finishing, and gets ester compound through purification by silica gel column chromatography again.Used acid is the straight or branched lipid acid of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Used alcohol is the straight or branched Fatty Alcohol(C12-C14 and C12-C18) of carbonatoms from 1 to 30; Used phenol is (replacement) phenol or (replacement) naphthols; Dewatering agent is selected a kind of in the vitriol oil, DIC or the dicyclohexylcarbodiimide for use; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF) for use, or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile for use; Acid is 1: 1 to 1: 20 with the mol ratio of alcohol in the reaction, and acid is 1: 0.2 to 1: 3 with the mol ratio of dewatering agent.
(2) preparation method of (sulphur) ether compound (formula III, Y=O, S), earlier with phenol and an amount of dissolution with solvents of alkali, under agitation drip halides again, room temperature to 80 ℃ reaction 1～2 day is followed the tracks of reaction with thin-layer chromatography, after reaction finishes, system is poured in a large amount of distilled water, filtered, again water, 10% sodium hydroxide repeatedly washs, and aftertreatment gets (sulphur) ether compound.Used phenol is thiophenol, (replacement) phenol or (replacement) naphthols; Used halides is that the straight or branched alkyl chloride of carbonatoms from 1 to 30 is for thing, bromo-derivative or iodo thing; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF) for use, or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile for use; Used alkali is sodium hydroxide, potassium hydroxide, salt of wormwood or sodium hydride; The mol ratio of phenol and halides is 1: 1 to 1: 10 in the reaction, and the mol ratio of phenol and alkali is 1: 1 to 1: 5.
(3) (formula I, II, IV, V X=N), under protection of inert gas, are dissolved in an amount of exsiccant methylene dichloride with acid to the preparation method of amides, stir to drip exsiccant sulfur oxychloride or oxalyl chloride, room temperature reaction 1 day down.After reaction finished, underpressure distillation eliminated excessive sulfur oxychloride or oxalyl chloride, repeatedly washs with the exsiccant methylene dichloride and obtains acyl chlorides.Again acyl chlorides is dissolved with an amount of exsiccant methylene dichloride, stir the dichloromethane solution that drips amine and triethylamine down, room temperature reaction 2～5 hours.After reaction finished, with deionized water, 1 mole of every liter of sodium hydroxide solution, 1 mole of every liter of hydrochloric acid soln washing, anhydrous magnesium sulfate drying concentrated, at last with normal hexane wash amides; Used rare gas element is nitrogen or argon gas; Used acid is the lipid acid of the straight or branched of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Used amine is the aliphatic amide of the straight or branched of (replacement) aniline, (replacement) naphthylamines or carbonatoms from 1 to 30; Acid is 1: 2 to 1: 10 with the mol ratio of sulfur oxychloride or oxalyl chloride, and the mol ratio of acyl chlorides and amine is 1: 1 to 1: 5.
Another object of the present invention provides the benzoate derivatives formula (I～V) application in preparation prevention and treatment senile dementia nerve degenerative diseases medicine.It mainly is the application in preparation treatment Alzheimer's disease nerve degenerative diseases medicines such as (AD).
The present invention further also provides a kind of pharmaceutical composition that prevents nerve degenerative diseases such as senile dementia, and this pharmaceutical composition contains (benzoate compounds and derivative and the pharmaceutically acceptable carrier or the thinner shown in the I～V) of physiology significant quantity.
Pharmaceutically acceptable carrier described here is meant the pharmaceutical carrier of pharmaceutical field routine, and for example thinner, vehicle wait in this way, weighting agent such as starch, sucrose, Microcrystalline Cellulose etc.; Tackiness agent such as starch slurry, hydroxypropylcellulose, gelatin, polyoxyethylene glycol etc.; Wetting agent such as Magnesium Stearate, micropowder silica gel, polyethylene glycols etc.; Absorption enhancer gathers sorb fat, Yelkin TTS etc., and tensio-active agent poloxamer, smooth, the poly-sorb fat of lipid acid sorb or the like can also add other assistant agent such as flavouring agent, sweeting agent etc. in addition in composition.
Benzoate compounds of the present invention and derivative thereof can be with the unit dosage form administrations, and route of administration can be enteron aisle and non-enteron aisle, comprise oral, muscle, subcutaneous and nasal cavity.
Compound administration approach of the present invention can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy.
The various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are made into required formulation then.
Form of administration can be tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment, liniment or suppository.
Preparation method of the present invention is reasonable in design, easy and simple to handle, synthetic compound major part has new chemical structure, and confirm that by the cell in vitro activity experiment institute's synthetic benzoate derivatives has the activity of very significant similar nerve growth factor NGF, particularly interior animal experiment confirms synthetic new compound 2,3-resorcylic acid 14 fat have the effect that strengthens the Aged Mice memory, therefore benzoate derivatives can be used in preparation prevention and treatment senile dementia nerve degenerative diseases medicine, the especially application in preparation treatment Alzheimer's disease nerve degenerative diseases medicines such as (AD).The present invention has opened up the new pharmaceutical use of benzoate derivatives.For nerve degenerative diseases such as prevention and treatment senile dementia provide new medicine.
Description of drawings
Fig. 1 adds the considerable change of Compound I-6 PC 12 cellular neural projections after 48 hours.
Fig. 2 adds the variation of the nervous process differentiation rate of Compound I-6 PC 12 cells after 48 hours with the dosage increase.
Fig. 3 adds the variation of the nervous process differentiation rate of Compound I-8, I-12, I-14, I-15, I-16 and I-18 PC 12 cells after 48 hours with the dosage increase.
Fig. 4 adds the variation of the nervous process differentiation rate of Compound I I-1, III-1, IV-2 and V-1 PC 12 cells after 48 hours with the dosage increase.
Fig. 5 injects Compound I-6 back mouse and always advances arm number and the alternately variation of action rate.
Embodiment
Below again foregoing of the present invention is described in further detail by embodiment and the accompanying drawing that such some particular compound is prepared example, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Compound I-1:2, the 3-dihydric ethyl benzoate
Will (154mg, 1mmol) 2,3-resorcylic acid, 10ml ethanol place the 25ml round-bottomed flask, are chilled to 0 ℃, drip 2～3 vitriol oils, reflux and stir 24h.With thin-layer chromatography (developping agent: n-hexane/ethyl acetate, 5/1, V/V) follow the tracks of reaction, after reaction stops, steam ethanol, get thick product 390mg, silica gel column chromatography (developping agent: n-hexane/ethyl acetate, 5/1, V/V), get white solid 180mg, yield: 99%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.12(dd，1H，J＝1.0，7.5Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.66(s，1H，benzene?3-OH)，4.41(q，2H，J＝7.0Hz)，1.42(t，3H，J＝7.0Hz)；MS(m/z)：182[M] +.
Compound I-2:2,3-resorcylic acid pentyl ester
Synthetic method is with compound I-1, reaction feed intake into: (154mg, 1mmol) 2,3-resorcylic acid, 10ml amylalcohol obtain white solid 170mg, yield: 76%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.12(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene?3-OH)，4.41(t，2H，J＝7.0Hz)，1.78(m，2H)，1.33～1.38(m，4H)，0.90(t，3H，J＝7.0Hz)；MS(m/z)：224[M] +.
Compound I-3:2,3-resorcylic acid monooctyl ester
Synthetic method is with compound I-1, reaction feed intake into: (154mg, 1mmol) 2,3-resorcylic acid, 10ml octanol obtain white solid 128mg, yield: 48%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.64(s，1H，benzene?3-OH)，4.35(t，2H，J＝7.0Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.38(m，8H)，0.89(t，3H，J＝7.0Hz)；MS(m/z)：266[M] +.
Compound I-4:2,3-resorcylic acid ester in the last of the ten Heavenly stems
Will (154mg, 1mmol) 2, the 3-resorcylic acid, (316mg, 2mmol) nonylcarbinol, 10ml tetrahydrofuran (THF) place the 25ml round-bottomed flask, are chilled to 0 ℃, add (145mg, 0.7mmol) dicyclohexylcarbodiimide, stirring at room 24h.With thin-layer chromatography (developping agent: n-hexane/ethyl acetate, 2/1, V/V) tracking reaction.After reaction stops, steaming solvent, the resistates acetic acid ethyl dissolution, filter, filtrate is filtered through anhydrous sodium sulfate drying with 5% citric acid solution, saturated sodium bicarbonate solution, washing, ester layer, revolve inspissation contract head product 440mg, silica gel column chromatography (developping agent: n-hexane/ethyl acetate, 2/1, V/V), get white solid 41mg, yield: 14%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.09(dd，1H，J＝1.5，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene3-OH)，4.35(t，2H，J＝7.0Hz)，1.78(m，2H)，1.44(m，2H)，1.27～1.35(m，12H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：294[M] +.
Compound I-5:2,3-resorcylic acid dodecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (372mg, 2mmol) dodecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 180mg, yield: 56%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.64(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，16H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：322[M] +.
Compound I-6:2,3-resorcylic acid tetradecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 150mg, yield: 43%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.5Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：350[M] +.
Compound I-7:2,3-resorcylic acid n-Hexadecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (484mg, 2mmol) cetyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 178mg, yield: 47%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.25～1.35(m，24H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：378[M] +.
Compound I-8:2,3-resorcylic acid octadecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (540mg, 2mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 170mg, yield: 42%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.25～1.35(m，28H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：406[M] +.
Compound I-9:2,3-resorcylic acid eicosane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (896mg, 3mmol) eicosanol, (206mg, 1mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 104mg, yield: 24%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝0.5，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.78(m，2H)，1.43(m，2H)，1.25～1.35(m，32H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-10:2,3-resorcylic acid docosane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (653mg, 2mmol) V-1326, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 102mg, yield: 22%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.78(m，2H)，1.43(m，2H)，1.25～1.35(m，36H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：462[M] +.
Compound I-11:2,3-resorcylic acid triacontane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,3-resorcylic acid, (1.32g, 3mmol) triacontanol price quote, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 20ml tetrahydrofuran (THF) obtains white solid 75mg, yield: 13%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.5Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.77(m，2H)，1.45(m，2H)，1.25～1.35(m，52H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：575[M] +.
Compound I-12:2,6-resorcylic acid tetradecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,6-resorcylic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 66mg, yield: 19%. 1H?NMR(500MHz，CDCl 3)δ：9.79(s，2H)，7.32(t，1H，J＝8.5Hz)，6.48(d，2H，J＝8.5Hz)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：350[M] +.
Compound I-13:2,6-resorcylic acid eicosane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (154mg, 1mmol) 2,6-resorcylic acid, (597mg, 2mmol) eicosanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 104mg, yield: 24%. 1H?NMR(500MHz，CDCl 3)δ：9.79(s，2H)，7.31(t，1H，J＝8.5Hz)，6.48(d，2H，J＝8.5Hz)，4.50(t，2H，J＝6.5Hz)，1.83(m，2H)，1.43(m，2H)，1.25～1.35(m，32H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-14:2-hydroxy-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feed intake into: (138mg, 1mmol) 2 hydroxybenzoic acid, ((the 15ml tetrahydrofuran (THF) obtains white solid 164mg, yield: 49% for 250mg, 1.2mmol) dicyclohexylcarbodiimide for 428mg, 2mmol) tetradecanol. 1H?NMR(500MHz，CDCl 3)δ：10.88(s，1H)，7.37(m，1H)，7.10(m，1H)，6.91(m，1H)，6.80(t，1H，J＝8.0Hz)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：334[M] +.
Compound I-15:3-hydroxy-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feed intake into: (138mg, 1mmol) the 3-hydroxy-benzoic acid, ((the 15ml tetrahydrofuran (THF) obtains white solid 174mg, yield: 52% for 250mg, 1.2mmol) dicyclohexylcarbodiimide for 428mg, 2mmol) tetradecanol. 1H?NMR(500MHz，CDCl 3)δ：9.76(s，1H)，7.57(m，1H)，7.37(m，1H)，7.25(m，1H)，7.01(m，1H)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：334[M] +.
Compound I-16:2,3-dimethoxybenzoic acid tetradecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (182mg, 1mmol) 2,3-dimethoxybenzoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 162mg, yield: 43%. 1H?NMR(500MHz，CDCl 3)δ：7.08(t，1H，J＝7.5Hz)，6.95(dd，1H，J＝1.5，8.0Hz)，6.79(dd，1H，J＝1.0，7.0Hz)，4.35(t，2H，J＝6.5Hz)，3.92(s，3H)，3.88(s，3H)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：378[M] +.
Compound I-17:2,3-dimethoxybenzoic acid octadecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (182mg, 1mmol) 2,3-dimethoxybenzoic acid, (540mg, 2mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 170mg, yield: 39%. 1H?NMR(500MHz，CDCl 3)δ：7.06(t，1H，J＝8.0Hz)，6.93(dd，1H，J＝1.5，8.0Hz)，6.77(dd，1H，J＝1.5，8.0Hz)，4.35(t，2H，J＝6.5Hz)，3.92(s，3H)，3.88(s，3H)，1.78(m，2H)，1.44(m，2H)，1.25～1.35(m，28H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-18:2,3-dimethoxy-N-tetradecyl benzamide
Will (1.1g, 6mmol) 2, the 3-dimethoxybenzoic acid, (7ml, 0.09mol) sulfur oxychloride places the 25ml round-bottomed flask, stirring at room 24h under the nitrogen protection.After reaction stopped, underpressure distillation eliminated excessive sulfur oxychloride, repeatedly washs with the exsiccant methylene dichloride, obtains acyl chlorides.Under nitrogen protection, will (0.5g, 2.5mmol) acyl chlorides dissolves with a small amount of exsiccant methylene dichloride, again ((0.9ml, 9mmol) triethylamine is dissolved in 10ml exsiccant methylene dichloride respectively and splashes into successively for 640mg, 3mmol) tetradecylamine.Stirring at room 2h after reaction stops, washing with deionized water, 1 mole of every liter of sodium hydroxide solution, deionized water, 1 mole of every liter of hydrochloric acid soln, deionization.Anhydrous magnesium sulfate drying concentrates, and the normal hexane washing obtains white solid 219mg, yield: 58%. 1H?NMR(500MHz，CDCl 3)δ：7.94(bt，1H)，7.57(dd，1H，J＝1.5，8.0Hz)，7.09(dd，1H，J＝1.5，8.0Hz)，6.85(t，1H，J＝8.0Hz)，3.82(bs，6H)，3.37(q，2H，J＝5.8Hz)，1.58(m，2H)，1.17～1.35(m，22H)，0.86(t，3H，J＝7.0Hz)；MS(m/z)：377[M] +.
Compound I-19:2,3-dihydroxyl-N-tetradecyl benzamide
Under nitrogen protection, (188mg 0.5mmol) is dissolved in 30ml exsiccant methylene dichloride, drips (2ml) boron tribromide, absorbs the hydrogen bromide that generates, stirring at room three days with 1 mole every liter sodium hydroxide solution with Compound I-19.Reaction slowly drips the frozen water cancellation after finishing, and steams solvent, repeatedly washs with methyl alcohol again, gets gray solid 140mg, yield: 40%. 1H?NMR(500MHz，DMSO-d 6)δ：12.71(s，1H)，8.58(s，1H)，8.05(bt，1H)，7.35(dd，1H，J＝1.5，8.5Hz)，6.98(dd，1H，J＝1.0，8.0Hz)，6.75(t，1H，J＝8.0Hz)，3.25～3.38(m，2H)，1.71(m，2H)，1.18～1.35(m，22H)，0.86(t，3H，J＝7.0Hz)；MS(m/z)：349[M] +.
Compound I-20:2-chloro-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feed intake into: (156mg, 1mmol) the 2-chloro-benzoic acid, ((the 15ml tetrahydrofuran (THF) obtains white solid 150mg, yield: 43% for 250mg, 1.2mmol) dicyclohexylcarbodiimide for 428mg, 2mmol) tetradecanol. 1H?NMR(500MHz，CDCl 3)δ：7.65(m，1H)，7.30(m，2H)，7.08(m，1H)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：352[M] +.
Embodiment 2
Compound I I-1:1,2-phenylene 20 acid esters
Synthetic method is with compound I-4, reaction feed intake into: (110mg, 1mmol) o-phenol, ((the 15ml tetrahydrofuran (THF) obtains white solid 391mg, yield: 56% for 250mg, 1.2mmol) dicyclohexylcarbodiimide for 310mg, 1mmol) arachic acid. 1H?NMR(500MHz，CDCl 3)δ：7.13～7.16(t，1H，J＝7.5Hz)，7.09～7.11(d，1H，J＝7.5Hz)，7.02～7.04(d，1H，J＝7.5Hz)，6.92～6.95(t，1H，J＝7.5Hz)，2.63(t，2H，J＝6.5Hz)，2.42(t，2H，J＝6.5Hz)，1.96～1.99(m，12H)，1.17～1.42(m，60H)，0.89(bs，6H)；MS(m/z)：699[M] +.
Embodiment 3
Compound III-1:1, two (tetradecyloxyaniline) benzene of 4-
Under nitrogen protection, will (110mg, 1mmol) Resorcinol, (280mg, 5mmol) potassium hydroxide, 10ml N, dinethylformamide place the 25ml round-bottomed flask, drip (830mg, 3mmol) bromotetradecane.Stirred overnight at room temperature after reaction stops, being poured system in a large amount of distilled water into, and yellow solid is separated out on the upper strata, filter, water, 10% sodium hydroxide wash product 111mg, yield: 22%. 1H?NMR(500MHz，CDCl 3)δ：6.76(bs，4H)，3.75～3.80(t，4H，J＝6.5Hz)，1.82(m，4H)，1.25～1.33(m，44H)，0.85(t，6H，J＝7.0Hz)；MS(m/z)：502[M] +.
Embodiment 4
Compound IV-1:1-hydroxyl-2-naphthoic acid tetradecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (188mg, 1mmol) 1-hydroxyl-2-naphthoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 184mg, yield: 48%. 1H?NMR(500MHz，CDCl 3)δ：12.09(s，1H)，8.41(d，1H，J＝8.5Hz)，7.76～7.79(m，2H)，7.59～7.62(m，1H)，7.51～7.54(m，1H)，7.28(d，1H，J＝9.0Hz)，4.39(t，2H，J＝6.5Hz)，1.82(m，2H)，1.47(m，2H)，1.25～1.38(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：384[M] +.
Compound IV-2:1-hydroxyl-2-naphthoic acid octadecane ester
Synthetic method is with compound I-4, and reaction feeds intake and is (188mg, 1mmol) 1-hydroxyl-2-naphthoic acid, (270mg, 1mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, the 15ml tetrahydrofuran (THF) obtains white solid 198mg, yield: 45%. 1H?NMR(500MHz，CDCl 3)δ：12.09(s，1H)，8.41(d，1H，J＝8.5Hz)，7.75～7.79(m，2H)，7.59～7.63(m，1H)，7.51～7.54(m，1H)，7.28(d，1H，J＝9.0Hz)，4.39(t，2H，J＝6.5Hz)，1.82(m，2H)，1.47(m，2H)，1.25～1.38(m，28H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：440[M] +.
Embodiment 5
Compound V-1:1-naphthyl myristinate
Synthetic method is with compound I-4, reaction feed intake into: (144mg, 1mmol) naphthols, ((the 15ml tetrahydrofuran (THF) obtains white solid 258mg, yield: 70% for 250mg, 1.2mmol) dicyclohexylcarbodiimide for 228mg, 1mmol) tetradecanoic acid. 1H?NMR(500MHz，CDCl 3)δ：8.39(d，1H，J＝8.5Hz)，7.77～7.82(m，2H)，7.59～7.62(m，2H)，7.49～7.51(m，1H)，7.28(m，1H)，2.32(t，2H，J＝6.5Hz)，1.76～1.88(m，6H)，1.14～1.32(m，18H)，0.88(s，3H)；MS(m/z)：368[M] +.
Embodiment 6
Biological activity is identified: in the neurodegeneration animal model, discover that NGF can stop or reduce neuronic regression, to a certain degree can stop the AD progress, have the nerve growth of promotion and neuroprotective.Because the PC12 cell has the general feature of neurocyte, the PC12 cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, can cause the PC12 cell transformation to become the compound of neuron cell to have the using value of nerve degenerative diseases such as prevention and treatment senile dementia.
Experimental technique:
1) cultivation of PC 12 cells: connect 20 * 10 4Individual PC 12 cells contain 10ml DMEM substratum (wherein containing 10% horse serum, 5% foetal calf serum) in the culture dish of 100mm, change a subculture two days later, after three days subcultures.Earlier cell is washed twice, add 10ml PBS again in culture dish with PBS, at 37 ℃, 5%CO 2Incubator in cultivated 10 minutes, purge is transferred to the disposable centrifuge tube of 15ml, counts on the blood counting chamber of centrifugal back.The every hole of 24 porocyte culture plates adds the DMEM substratum that 1ml contains serum earlier, and after the cell counting, every hole connects 2 * 10 4Individual cell, CO 2Incubator is cultivated application of sample after 24 hours.
2) active testing: with the negative contrast of DMSO, the positive contrast of NGF 40ng is configured to Compound I-6 the DMSO solution of different concns.The DMEM solution (not containing serum) that contains 1%DMSO and sample with 1ml is put into 37 ℃, 5%CO after the former substratum in every hole of 24 porocyte plates is replaced 2Incubator in cultivate.Under the inverted microscope every 24 hours, continuous 6 days observation of cell metamorphosis, record cytodifferentiation rate NA (nervous process is longer than the ratio of total cell number under the cell number of one times of cell space diameter and the visual field), about 100 cells under each visual field, picked at random 3 places, and statistics mapping.
Fig. 1: add the considerable change of Compound I-6 nervous process of PC 12 cells after 48 hours, the negative contrast of A:1%DMSO; B:NGF 40ng/ml, positive contrast; C: Compound I-6, concentration, 1 μ M; )
Fig. 2: add of the variation of the nervous process differentiation rate of Compound I-6 PC 12 cells after 48 hours, C: negative control 1%DMSO, the concentration unit of I-6: μ M with the dosage increase;
Fig. 3: add of the variation of the nervous process differentiation rate of Compound I-8, I-12, I-14, I-15, I-16 and I-18 PC12 cell after 48 hours, C: negative control 1%DMSO, compound concentrations unit: μ M with the dosage increase;
Fig. 4: add of the variation of the nervous process differentiation rate of Compound I I-1, III-1, IV-2 and V-1 PC 12 cells after 48 hours, C: negative control 1%DMSO, compound concentrations unit: μ M) with the dosage increase.
3) experimental result: found that under the concentration of 0.03-10 μ M, the 48 as a child back compounds of being tested all demonstrate the NGF-mimics activity.Compound I-6 is under the condition of optimal concentration 1 μ M, and the nervous process that this compound induces PC 12 cells to produce can surpass NGF inductive projection.
Embodiment 7
Experimentation on animals: Compound I-6 (2,3-resorcylic acid tetradecane ester) is improved the investigation of effect to aged mouse short-term memory
1) acute poisoning test: with 4 age in week 20 of ICR male mices be divided into control group at random, the 100mg/kg treatment group.The Compound I-6 that will be dissolved in 1%Tween-80 according to dosage disposable celiac is injected in the animal body, observes a week continuously, observes the mental status of animal every day, measures body weight and food ration.The compound input after 10 minutes the mouse limbs occur crispaturaing, amount of exercise reduces.After 1 hour, full recovery is normal.Mouse does not have death condition in one week, and food ration does not have considerable change, but body weight change obviously reduces.The heart, liver, spleen, kidney and white adipose tissue weight and observe there was no significant difference.
2) test of pesticide effectiveness: 18 of the ICR male mices at 12 monthly ages are divided into control group at random, 1mg/kg treatment group and 10mg/kg treatment group.Do control group with the young ICR mouse in 4 ages in week simultaneously, inject the Compound I-6 that corresponding dosage is dissolved in Tween-80 every day.Offerd medicine 11 days, and measured the variation of food ration and body weight every day, utilized the improvement situation of Y labyrinth test compounds in 12 days the short-term memory effect.Test-results shows 1mg/kg treatment group mouse body weight change and food ration and aged mouse control group relatively, all no significant difference.Always advance arm number and alternately action rate increase (Fig. 5, injection Compound I-6 back mouse always enters arm number and the alternately variation of action rate, P＜0.05).10mg/kg treatment group food ration is always advanced the arm number and is replaced the action rate and do not have considerable change, and body weight obviously reduces.This result shows that this compound has the effect of improvement to the short-term memory of aged mouse.There is certain side effect in 10mg/kg dosage.

Claims (4)

1. a benzoate derivatives comprises ester compound, (sulphur) ether compound and amides, it is characterized in that, has following general structure:
Figure FSA00000017938100011
In the formula:
R is the straight or branched alkyl, particularly C of carbonatoms from 1 to 30 12～C 22
R 1Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or the substituted-phenyl;
R 2Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
R 3Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or the substituted-phenyl;
R 4Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
R 5Be a kind of in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or the alkoxyl group;
X is O, N or CH 2In a kind of;
Y is O, S or CH 2In a kind of.
2. the preparation method of benzoate derivatives according to claim 1 is characterized in that, realizes by following steps:
(1) preparation method of ester compound: earlier with acid and alcohol or phenol dissolution with solvents, be chilled to 0 ℃, stir and drip dewatering agent down, be raised to room temperature or reflux state reaction 1～2 day again, follow the tracks of reaction, after reaction finishes with thin-layer chromatography, steam solvent, get ester compound through purification by silica gel column chromatography again; Used acid is the straight or branched lipid acid of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Used alcohol is the straight or branched Fatty Alcohol(C12-C14 and C12-C18) of carbonatoms from 1 to 30; Used phenol is (replacement) phenol or (replacement) naphthols; Dewatering agent is selected a kind of in the vitriol oil, DIC or the dicyclohexylcarbodiimide for use; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF) for use, or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile for use; Acid is 1: 1 to 1: 20 with the mol ratio of alcohol in the reaction, and acid is 1: 0.2 to 1: 3 with the mol ratio of dewatering agent.
(2) preparation method of (sulphur) ether compound, earlier with phenol and an amount of dissolution with solvents of alkali, under agitation drip halides again, room temperature to 80 ℃ reaction 1～2 day is followed the tracks of reaction with thin-layer chromatography, after reaction finishes, system is poured in a large amount of distilled water, filter, water, 10% sodium hydroxide repeatedly wash again, and aftertreatment gets (sulphur) ether compound.Used phenol is thiophenol, (replacement) phenol or (replacement) naphthols; Used halides is that the straight or branched alkyl chloride of carbonatoms from 1 to 30 is for thing, bromo-derivative or iodo thing; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF) for use, or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile for use; Used alkali is sodium hydroxide, potassium hydroxide, salt of wormwood or sodium hydride; The mol ratio of phenol and halides is 1: 1 to 1: 10 in the reaction, and the mol ratio of phenol and alkali is 1: 1 to 1: 5.
(3) preparation method of amides, under protection of inert gas, acid is dissolved in the exsiccant methylene dichloride, stir and drip exsiccant sulfur oxychloride or oxalyl chloride down, room temperature reaction 1 day, after reaction finished, underpressure distillation eliminated excessive sulfur oxychloride or oxalyl chloride, repeatedly washs with the exsiccant methylene dichloride and obtains acyl chlorides, again acyl chlorides is dissolved with the exsiccant methylene dichloride, stir the dichloromethane solution that drips amine and triethylamine down, room temperature reaction 2～5 hours is after reaction finishes, use deionized water, 1 mole of every liter of sodium hydroxide solution, 1 mole of every liter of hydrochloric acid soln washing, anhydrous magnesium sulfate drying concentrates, at last with normal hexane wash amides; Used rare gas element is nitrogen or argon gas; Acid is the lipid acid of the straight or branched of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Used amine is the aliphatic amide of the straight or branched of (replacement) aniline, (replacement) naphthylamines or carbonatoms from 1 to 30; Acid is 1: 2 to 1: 10 with the mol ratio of sulfur oxychloride or oxalyl chloride, and the mol ratio of acyl chlorides and amine is 1: 1 to 1: 5.
3. the application of benzoate derivatives according to claim 1 in the nerve degenerative diseases medicine of preparation prevention and treatment senile dementia etc.
4. application according to claim 3 is characterized in that, the application in the nerve degenerative diseases medicine of preparation treatment Alzheimer's disease.
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WO2011091692A1 (en) * 2010-01-29 2011-08-04 浙江大学 Uses of benzoate and its derivatives
CN103118677A (en) * 2010-01-29 2013-05-22 浙江大学 Uses of benzoate and its derivatives
CN103340880A (en) * 2013-05-13 2013-10-09 杭州耐奇睿生物医药科技有限公司 Application of 2,3-dihydroxy benzoic acid ester compound in preparation of foods and medicines for treating diabetes
CN103340880B (en) * 2013-05-13 2014-12-24 杭州耐奇睿生物医药科技有限公司 Application of 2,3-dihydroxy benzoic acid ester compound in preparation of foods and medicines for treating diabetes
CN105085348A (en) * 2014-05-20 2015-11-25 浙江大学 Thiobenzoate compound and use thereof
CN106608824A (en) * 2015-10-21 2017-05-03 复旦大学 Aromatic acid ester compound and preparation method and application thereof
CN106608824B (en) * 2015-10-21 2019-12-20 复旦大学 Aromatic acid ester compound and preparation method and application thereof
CN108553456A (en) * 2016-12-29 2018-09-21 天津中医药大学 The new application of benzoic acid and its derivative
CN109422858A (en) * 2017-08-19 2019-03-05 中国铁道科学研究院铁道建筑研究所 A kind of polyalcohol being grafted UV absorption agent molecule
CN114292192A (en) * 2022-01-17 2022-04-08 山东泓瑞医药科技股份公司 Synthesis method of 3, 4-dimethoxybenzoic acid methyl ester
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