CN102229607A

CN102229607A - Berberine-phenylacetic acid derivative, its pharmaceutically acceptable salt and synthetic method

Info

Publication number: CN102229607A
Application number: CN2011101218486A
Authority: CN
Inventors: 周向东; 方波
Original assignee: Third Military Medical University TMMU
Current assignee: Third Military Medical University TMMU
Priority date: 2011-05-12
Filing date: 2011-05-12
Publication date: 2011-11-02

Abstract

The invention relates to a novel structural berberine-phenylacetic acid derivative and its pharmaceutically acceptable salt. The general structure formula is as shown in formula I: R is any one selected from the group consisting of methyl acetate group, ethyl acetate group, acetic acid group, potassium acetate group and sodium acetate group; X is halogen C1 or Br; and n=2-6. The invention also relates to a preparation method of the above derivative and salt, comprising the steps of: using hydroxyphenylacetic acid as a raw material, esterifying to obtain hydroxyphenylacetate, performing a selective substitution reaction with terminal dibromo alkane to obtain monobromo substituted alkyloxy phenylacetate; removing methyl from berberine under high temperature vacuum to obtain intermediate demethyl berberine, carrying out substitution, chlorination, hydrolyzation and acidification reactions on the monobromo substituted alkyloxy phenylacetate and the demethyl berberine to obtain the berberine-phenylacetic acid derivative. The method provided by the invention is simple, requires low cost and is applicable for industrial production; and the raw materials are easily available.

Description

Berberine-toluylic acid analog derivative reaches in pharmacy acceptable salt and synthetic method

Technical field

The present invention relates to berberine-toluylic acid analog derivative and synthetic method thereof, specifically, be a kind of be raw material with berberine and hydroxyl phenylacetic acid, by the synthetic method that alkane is puted together formation berberine-toluylic acid analog derivative and pharmacy acceptable salt thereof as connexon with berberine and toluylic acid, the invention still further relates to berberine-toluylic acid analog derivative and pharmacy acceptable salt thereof.

Background technology

Berberine (is a Berberine: Berberine) be a kind of quaternary ammonium morphinane alkaloid that extracts from plant roots and stems such as the coptis, golden cypress, Root of Chinese Barberry, Mahonia fortunei.Many clinically with its hydrochloride (Bererini Hydrochclorium: Berberine Hydrochloride), molecular formula: C ₂₀H ₁₈ClNO ₄2H ₂O.Molecular weight: 407.85.Its outward appearance is yellow needle-like crystal or powder, and odorless, flavor are extremely bitter.Decompose when being heated to 160～220 ℃, complete fusion in the time of 278～280 ℃ is soluble in hot water, is slightly soluble in cold water or ethanol, the atomic chloroform that is dissolved in, be insoluble to ether (Jiang Biao. from golden cypress, extract Bererini Hydrochclorium. guizhou chemical industry .2005,30,56-57.).The main production method of Bererini Hydrochclorium (extract product) has two kinds of acid extraction method and potass extraction methods, and this is mainly determined by which kind of raw material of employing.Better when generally making raw material with the acid extraction method with Root of Chinese Barberry, the coptis, Mahonia fortunei etc., better when making raw material with the potass extraction rule with golden cypress.

Traditional medicine thinks that berberine is inhibited to Gram-positive, negative bacterium, and clinical application mainly is confined to treatment of diseases such as intestinal tract infections that dysentery bacterium, intestinal bacteria, streptococcus aureus etc. cause, eye binding film inflammation.Along with deepening continuously of studying, find that the coptis have the enhancing myocardial contraction in recent years, reduce peripheral vascular resistance, obviously improve the effect of heart function.Berberine also has tangible antiarrhythmic effect, and does not have side effect such as tangible proarrhythmia, can make the accent fat effect that low density lipoprotein receptor raises and performance is different with Statins, and antiplatelet effects etc. is arranged.

This shows that berberine is widely used, have very big market.China's coptis resource is also very abundant, and all there is coptis planting base in Sichuan, Chongqing, Hubei, can provide a large amount of berberine directly as drug use or be used for the research and development of berberine related drugs.

The same with many natural extract medicines, also there are problems such as dissolving and absorption difficulty in berberine.Conventional formulation such as various tablets on the domestic and international market and capsule, can not overcome the first pass effect of its liver, because water-soluble and fat-soluble all little, cause defectives such as absorption difference and difficulty are transported in target site and the target cell effectively, and then cause its bioavailability low (being about 10%), patient's medication number of times is frequent, tolerance is poor, drug effect is poor, limit greatly its clinical application (Sun Hongwu, Ou Yangwuqing. development, quality and the safety evaluation of berberine oral administration nanometer breast. the journal .2007 of Shanghai Communications University, 25,60-65.).Berberine seldom is absorbed at enteron aisle, and Plasma Concentration is very low, and it is very short to hold time; And quiet notes produce the existing many cases of the report of untoward reaction, and therefore country just forbids the berberine drug administration by injection as far back as nineteen eighty-two.

Existing result of study shows, the berberine Symbiont also has multiple pharmacologically active, as palmatine (Palmatine), jateorhizine (Jatrorrhizine), coptisine (Coptisine), coralyne (Coralyne), xanthopuccine alkaloids such as (Canadine).Also there are some side effects in these medicines when alleviating illness for patient, eliminating a disease; And the common shortcoming of berberine class medicine is to dissolve and absorb the first pass effect of difficulty, liver etc.Though existing many studies show that modified the berberine structure and can be overcome some shortcoming, most compounds are when activity improves, and its toxicity also increases thereupon, and medicine that at last can be by the clinical trial listing seldom.

How to reduce the side effect of berberine, improve its activity, the derivative of seeking berberine is used to reduce the side effect of berberine, improves its activity, is the problem that numerous medical personnels are inquiring into always and expecting to solve.

Summary of the invention

The object of the present invention is to provide a kind of berberine-toluylic acid analog derivative and at pharmacy acceptable salt, its structure is new, and have the characteristics of efficient, low toxicity, wide spectrum, for berberine provides application prospect widely as the medicine of treatment disease.

Technical scheme of the present invention is:

Berberine-toluylic acid analog derivative and at pharmacy acceptable salt, shown in the following general formula I of its structure:

Wherein R is any one in 2-methyl acetate base, 3-methyl acetate base, 4-methyl acetate base, 2-ethyl acetate base, 3-ethyl acetate base, 4-ethyl acetate base, 2-acetoxyl, 3-acetoxyl, 4-acetoxyl, 2-potassium acetate or sodium base, 3-potassium acetate or sodium base, 4-potassium acetate or the sodium base; X is halogen Cl or Br; N=2～6.

Another object of the present invention has provided formula I compound and in the synthetic method of pharmacy acceptable salt.

Berberine-toluylic acid analog derivative that the present invention proposes and in the synthetic method of pharmacy acceptable salt is to be that raw material synthesizes berberine-toluylic acid analog derivative through series reaction and at pharmacy acceptable salt with berberine and hydroxyl phenylacetic acid.Concrete preparation method is as follows:

1), preparation hydroxyl phenylacetic acid ester compound (1)

In methyl alcohol or the ethanol organic solvent, an o-hydroxy phenylacetic acid or a hydroxyl phenylacetic acid or p-hydroxyphenylaceticacid and methyl alcohol or ethanol are converted into the hydroxyl phenylacetic acid ester compound the vitriol oil or concentrated hydrochloric acid catalysis and 50～80 ℃;

2), preparation single bromine substituted alkoxy phenylacetate compounds (2)

The hydroxyl phenylacetic acid ester of step 1) gained is at N, dinethylformamide, acetonitrile are or/and in any one or a few solvent in the chloroform, with salt of wormwood or yellow soda ash or potassium hydroxide or sodium hydroxide and phase transfer catalysis agent effect, under 60～100 ℃, carry out the selectivity substitution reaction with terminal two bromoalkanes, change into corresponding single bromine substituted alkoxy phenylacetate compounds;

3), preparation bromination berberine-phenylacetate compounds

N in dinethylformamide or the acetonitrile organic solvent, removes first berberine and single bromine substituted alkoxy phenylacetate, and reaction changes into bromination berberine-phenylacetate compounds under 60～110 ℃ and anhydrous condition;

4), preparation Berberine chloride-phenylacetate compounds

In the absolute methyl alcohol organic solvent, bromination berberine-phenylacetate compounds carries out halogen ion-exchange with the chlorination reagent reaction and is converted into Berberine chloride-phenylacetate compounds under room temperature and anhydrous condition;

5), Berberine chloride-toluylic acid potassium or sodium salt compounds

In the mixed solvent organic solvent of methyl alcohol or first alcohol and water, Berberine chloride-phenylacetate compounds, at room temperature, with potassium hydroxide or sodium hydroxide reaction, hydrolysis changes into Berberine chloride-toluylic acid potassium or sodium salt compounds;

6) Berberine chloride-toluylic acid compounds

In the mixed solvent organic solvent of methyl alcohol or first alcohol and water, Berberine chloride-toluylic acid potassium or sodium salt compound at room temperature, are converted into Berberine chloride-toluylic acid compounds with 5% aqueous hydrochloric acid acidifying.

In the described step 1), hydroxyl phenylacetic acid: acid: the mol ratio of alcohol is 1: 0.1～1.25: 10～12.

Described step 2) in, hydroxyl phenylacetic acid ester: alkali: the mol ratio of terminal two bromoalkanes is 1: 1.5: 1.5.

Described step 2) in, described phase transfer catalysis agent is Tetrabutyl amonium bromide, tetrabutylammonium iodide or bromo triethyl hexadecyldimethyl benzyl ammonium.

Described step 2) in, described terminal two bromoalkanes are glycol dibromides, 1,3-dibromopropane, 1,4-dibromobutane, pentamethylene bromide and 1,6-dibromo-hexane.

In the described step 3), remove the first berberine: the mol ratio of single bromine substituted alkoxy phenylacetate is 1: 2.5.

In the described step 4), bromination berberine-phenylacetate: the mol ratio of chlorination reagent is 1: 2～8; Described chlorination reagent is a silver chloride.

In the described step 5), Berberine chloride-phenylacetate: the mol ratio of alkali is 1: 10～500.

In the described step 6), the mol ratio of Berberine chloride-toluylic acid potassium or sodium salt and acid is 1: 5～50.

The present invention adopts said synthesis route and method, obtains target compound of the present invention---and berberine-phenylacetic acid derivatives and salt, structure is correct, the recovery rate height.Its synthetic method has easy, and raw material is easy to get, and cost is lower, is easy to the characteristics of suitability for industrialized production.

Embodiment

Technical scheme of the present invention is:

With hydroxyl phenylacetic acid cheap and easy to get and berberine is starting raw material, hydroxyl phenylacetic acid is transformed into the hydroxyl phenylacetic acid ester with the alcohol reaction under acid catalysis, gained hydroxyl phenylacetic acid ester carries out the selectivity substitution reaction with terminal two bromoalkanes and is transformed into corresponding single bromine substituted alkoxy phenylacetate under alkali and phase transfer catalysis agent effect.Gained list bromine substituted alkoxy phenylacetate removes first berberine reaction being transformed into berberine-toluylic acid analog derivative with Bererini Hydrochclorium through what vacuum high-temperature degraded obtained under the effect of alkali.

Method of the present invention is the preparation of berberine-toluylic acid analog derivative:

(1) hydroxyl phenylacetic acid (adjacent,, to) is dissolved in methyl alcohol or the ethanol, under the vitriol oil or concentrated hydrochloric acid catalysis, 50～80 ℃ down reaction be transformed into hydroxyl phenylacetic acid methyl esters or hydroxyl phenylacetic acid ethyl ester, yield 93.8%～94.6%.

(2), above-mentioned gained hydroxyl phenylacetic acid ester (adjacent,, to) is dissolved in N, dinethylformamide, acetonitrile or and chloroform in, under alkali salt of wormwood, yellow soda ash, potassium hydroxide or sodium hydroxide and phase transfer catalysis agent Tetrabutyl amonium bromide, tetrabutylammonium iodide or the effect of bromo triethyl hexadecyldimethyl benzyl ammonium, in 60～100 ℃ of following and terminal two bromoalkanes 1,2-ethylene dibromide, 1,3-dibromopropane, 1,4-dibromobutane, 1, pentamethylene bromide and 1,6-dibromo-hexane carry out the selectivity substitution reaction and are transformed into corresponding single bromine substituted alkoxy phenylacetate.Yield 20～90%.

(3) single bromine substituted alkoxy phenylacetate is dissolved in N, in dinethylformamide or the acetonitrile, reacts with removing the first berberine down at 60～110 ℃, is transformed into bromination berberine-phenylacetate.Yield 45～90%.

(4) bromination berberine-phenylacetate is dissolved in the methyl alcohol, carries out halogen ion-exchange with the silver chloride reaction and be converted into Berberine chloride-phenylacetate compounds under room temperature.Yield 95～100%.

(5) Berberine chloride-the phenylacetate compounds is dissolved in methyl alcohol or/and water, and under room temperature, under potassium hydroxide or sodium hydroxide effect, hydrolysis gets Berberine chloride-toluylic acid sylvite or sodium salt.Yield 20～90%.

(6) Berberine chloride-toluylic acid sylvite or sodium salt is dissolved in methyl alcohol or/and water, under room temperature, the aqueous hydrochloric acid acidifying through 5% gets Berberine chloride-toluylic acid.Yield 95～100%.

Adopt method of the present invention can obtain 2-[2-(2-bromine oxethyl) phenyl of following structure] ethyl acetate, 2-[2-(3-bromine propoxy-) phenyl] ethyl acetate, 2-[2-(4-bromine butoxy) phenyl] ethyl acetate, 2-[2-(5-bromine pentyloxy) phenyl] ethyl acetate, 2-[2-(6-bromine hexyloxy) phenyl] ethyl acetate:

Adopt method of the present invention can obtain 2-[3-(2-bromine oxethyl) phenyl of following structure] ethyl acetate, 2-[3-(3-bromine propoxy-) phenyl] ethyl acetate, 2-[3-(4-bromine butoxy) phenyl] ethyl acetate, 2-[3-(5-bromine pentyloxy) phenyl] ethyl acetate, 2-[3-(6-bromine hexyloxy) phenyl] ethyl acetate:

Adopt method of the present invention can obtain the bromination 2-[2-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, bromination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, bromination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, bromination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, bromination 2-[2-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the bromination 2-[3-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, bromination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, bromination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, bromination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, bromination 2-[3-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the bromination 2-[4-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, bromination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, bromination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, bromination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, bromination 2-[4-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the chlorination 2-[2-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, chlorination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, chlorination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the chlorination 2-[3-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, chlorination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, chlorination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the chlorination 2-[4-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid ethyl ester, chlorination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester, chlorination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester, chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester, chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester:

Adopt method of the present invention can obtain the chlorination 2-[2-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid potassium or sodium, chlorination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium or sodium, chlorination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium or sodium, chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium or sodium, chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium or sodium

Adopt method of the present invention can obtain the chlorination 2-[3-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid potassium or sodium, chlorination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium or sodium, chlorination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium or sodium, chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium or sodium, chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium or sodium:

Adopt method of the present invention can obtain the chlorination 2-[4-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid potassium or sodium, chlorination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium or sodium, chlorination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium or sodium, chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium or sodium, chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium or sodium:

Adopt method of the present invention can obtain the chlorination 2-[2-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid, chlorination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid, chlorination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid, chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid, chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] phenylacetic acid:

Adopt method of the present invention can obtain the chlorination 2-[3-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid, chlorination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid, chlorination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid, chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid, chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] phenylacetic acid:

Adopt method of the present invention can obtain the chlorination 2-[4-[2-(9 '-berberine) of following structure] oxyethyl group] phenylacetic acid, chlorination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid, chlorination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid, chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid, chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] phenylacetic acid:

Below again foregoing of the present invention is described in further detail by embodiment the synthetic example of some particular compound.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Essence according to the present invention all belongs to protection scope of the present invention to the simple modifications that the present invention carries out.

Material therefor, reagent and instrument

Agents useful for same is chemical pure in the present embodiment;

Institute responds and all follows the tracks of with thin-layer chromatography, the efficient tlc silica gel plate (model C F-254) that uses the yellow affair silica gel of Yantai City's Zhifu development experiments factory to be produced, phospho-molybdic acid, ammonium molybdate, potassium permanganate or iodine colour developing.

The chromatographic silica gel (10-40 μ) that column chromatography is produced with the yellow affair silica gel of Yantai City's Zhifu development experiments factory, chromatography is 60～90 ℃ of AR with sherwood oil.

With the pre-treatment of sodium silk, the time spent all is back to blueness with sodium and benzophenone and steams stand-by under nitrogen protection with preceding for ether and tetrahydrofuran (THF).

Methylene dichloride with hydrolith reflux steam after a few hours stand-by.

Fusing point is measured with the WRR fusing point instrument that Shanghai Precision Scientific Apparatus Co., Ltd produces.

All compounds ¹HNMR and ¹³CNMR is measured by the Mercury Plus-400 nuclear magnetic resonance spectrometer that U.S. Varian company produces, and mark in TMS does without specified otherwise, is all used CDCl ₃Make solvent, δ value unit is ppm.Mass spectrum is measured by HP5989A type mass spectrograph, and IR is measured by Bruker Tensor 27 and FTIR spectrophotometer.

Embodiment 1: preparation 2-(2-hydroxy phenyl) ethyl acetate

In the 500mL round-bottomed flask, add 60.940g o-hydroxy phenylacetic acid (0.401mol), 280mL 95% ethanol (4.69mol) adds the vitriol oil of 30mL 98% gradually under the stirring at room, be warming up to back flow reaction.(EtoAc/pet, V/V after 1/3-1/5) monitoring reaction to raw material disappears, are chilled to room temperature to TLC, use solid Na ₂CO ₃Regulate pH to 7-8, ethyl acetate extraction, saturated common salt water washing, anhydrous Na ₂SO ₄Drying, removal of solvent under reduced pressure get pale red brown liquid 67.780g, yield 93.8%.

Embodiment 2: preparation 2-(3-hydroxy phenyl) ethyl acetate

Synthetic method is with embodiment 1, and reaction feeds intake and is hydroxyl phenylacetic acid between 61.430g (0.404mol), 280mL95% ethanol (4.69mol), the vitriol oil of 30mL98%.Aftertreatment gets reddish-brown liquid 68.870g, yield 94.6%.

Embodiment 3: preparation 2-(4-hydroxy phenyl) ethyl acetate

Synthetic method is with embodiment 1, and reaction feeds intake and is 61.455g p-hydroxyphenylaceticacid (0.404mol), 280mL 95% ethanol (4.69mol), the vitriol oil of 30mL 98%.Aftertreatment gets dark red brown liquid 68.650g, yield 94.3%.

Embodiment 4: preparation 2-[2-(2-bromine oxethyl) phenyl] ethyl acetate

In the 150mL round-bottomed flask, add 7.646g K ₂CO ₃(55.3mmol), 7.069g 2-(2-hydroxy phenyl) ethyl acetate (39.2mmol), 18.870g 1, the TEBA of 2-ethylene dibromide (100.4mmol), catalytic amount and 10mL acetonitrile, device is connected to the condensing reflux pipe of drying tube, stirs and be warming up to gradually back flow reaction.TLC (1/3-1/10) monitoring reaction to reaction is finished, and is chilled to room temperature for EtoAc/pet, V/V, suction filtration, and ethyl acetate washing leaching cake three times, filtrate is revolved to steam and is removed most of solvent, ethyl acetate extraction, saturated common salt water washing, anhydrous Na ₂SO ₄Drying concentrates, and (V/V 1/100-3/100) gets pink liquid 3.919g, yield 25.9% to column chromatography for pet, EtoAc/pet.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.27-7.19 (m, 2H, Ph4,6-H), 6.98-6.94 (m, 1H, Ph 5-H), 6.86-6.83 (m, 1H, Ph 3-H), 4.30 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 4.19-4.14 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.66 (s, 2H, Ph-CH ₂), 3.62 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 1.26 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 5: preparation 2-[2-(3-bromine propoxy-) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.932g K ₂CO ₃(57.4mmol), 6.406g 2-(2-hydroxy phenyl) ethyl acetate (35.5mmol), 19.302g 1, the TEBA of 3-dibromopropane (95.6mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 4.518g, yield 42.2%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.27-7.18 (m, 2H, Ph4,6-H), 6.95-6.91 (m, 1H, Ph 5-H), 6.88-6.86 (m, 1H, Ph 3-H), 4.17-4.12 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.11 (t, 2H, J=5.6Hz, OCH ₂(CH ₂) ₂Br), 3.63-3.60 (m, 4H, Ph-CH ₂, O (CH ₂) ₂CH ₂Br), 2.34-2.28 (m, 2H, OCH ₂CH ₂CH ₂Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 6: preparation 2-[2-(4-bromine butoxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.651g K ₂CO ₃(55.4mmol), 6.376g 2-(2-hydroxy phenyl) ethyl acetate (35.4mmol), 19.952g 1, the TEBA of 4-dibromobutane (92.4mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 5.010g, yield 44.9%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.26-7.18 (m, 2H, Ph4,6-H), 6.94-6.90 (m, 1H, Ph 5-H), 6.85-6.83 (m, 1H, Ph 3-H), 4.18-4.13 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.00 (t, 2H, J=6.0Hz, OCH ₂(CH ₂) ₃Br), 3.61 (s, 2H, Ph-CH ₂), 3.48 (t, 2H, J=6.4Hz, O (CH ₂) ₃CH ₂Br), 2.10-1.90 (m, 4H, OCH ₂(CH ₂) ₂CH ₂Br), 1.26 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 7: preparation 2-[2-(5-bromine pentyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.708g K ₂CO ₃(55.8mmol), 6.380g 2-(2-hydroxy phenyl) ethyl acetate (35.4mmol), 21.586g pentamethylene bromide (93.9mmol), the TEBA of catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 5.595g, yield 48.0%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.26-7.17 (m, 2H, Ph4,6-H), 6.93-6.89 (m, 1H, Ph 5-H), 6.85-6.83 (m, 1H, Ph 3-H), 4.18-4.12 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.97 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₄Br), 3.62 (s, 2H, Ph-CH ₂), 3.44 (t, 2H, J=6.8Hz, O (CH ₂) ₄CH ₂Br), 1.96-1.77 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂Br), 1.66-1.60 (m, 2H, O (CH ₂) ₂CH ₂(CH ₂) ₂Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 8: preparation 2-[2-(6-bromine hexyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.578g K ₂CO ₃(54.8mmol), 6.369g 2-(2-hydroxy phenyl) ethyl acetate (35.3mmol), 22.666g 1, the TEBA of 6-dibromo-hexane (92.9mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 6.580g, yield 54.2%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.26-7.17 (m, 2H, Ph4,6-H), 6.92-6.90 (m, 1H, Ph 5-H), 6.85-6.83 (m, 1H, Ph 3-H), 4.17-4.12 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.96 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₅Br), 3.61 (s, 2H, Ph-CH ₂), 3.43 (t, 2H, J=6.8Hz, O (CH ₂) ₅CH ₂Br), 1.91-1.76 (m, 4H, OCH ₂CH ₂(CH ₂) ₂CH ₂CH ₂Br), 1.52-1.49 (m, 4H, O (CH ₂) ₂(CH ₂) ₂(CH ₂) ₂Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 9: preparation 2-[3-(2-bromine oxethyl) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 8.246g K ₂CO ₃(60.0mmol), 6.358g 2-(3-hydroxy phenyl) ethyl acetate (35.3mmol), 16.770g glycol dibromide (89.3mmol), the TEBA of catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 5.491g, yield 54.2%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.23 (d, 1H, Ph 5-H), and 6.91-6.80 (Ph 2,4 for m, 3H, 6-H), and 4.29 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 4.18-4.12 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.63 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 3.58 (s, 2H, Ph-CH ₂), 1.26 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 10: preparation 2-[3-(3-bromine propoxy-) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.807g K ₂CO ₃(56.5mmol), 6.355g 2-(3-hydroxy phenyl) ethyl acetate (35.3mmol), 20.123g 1, the TEBA of 3-dibromopropane (99.7mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 6.707g, yield 63.1%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.30-7.27 (m, 1H, Ph5-H), 6.92-6.84 (Ph 2,4 for m, 3H, 6-H), and 4.19-4.14 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.12 (t, 2H, J=6.0Hz, OCH ₂(CH ₂) ₂Br), 3.62 (t, 2H, J=6.0Hz, O (CH ₂) ₂CH ₂Br), 3.61 (s, 2H, Ph-CH ₂), 2.35-2.29 (m, 2H, OCH ₂CH ₂CH ₂Br), 1.28 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 11: preparation 2-[3-(4-bromine butoxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 15.083g K ₂CO ₃(109.1mmol), 12.710g 2-(3-hydroxy phenyl) ethyl acetate (70.5mmol), 39.187g 1, the TEBA of 4-dibromobutane (181.5mmol), catalytic amount, 20mL acetonitrile.Aftertreatment gets weak yellow liquid 17.369g, yield 78.2%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.28-7.24 (m, 1H, Ph5-H), 6.90-6.81 (Ph 2,4 for m, 3H, 6-H), and 4.21-4.16 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.10 (t, 2H, J=6.0Hz, OCH ₂(CH ₂) ₃Br), 3.61 (s, 2H, Ph-CH ₂), 3.52 (t, 2H, J=6.4Hz, O (CH ₂) ₃CH ₂Br), 2.12-1.95 (m, 4H, OCH ₂(CH ₂) ₂CH ₂Br), 1.29 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 12: preparation 2-[3-(5-bromine pentyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 15.071g K ₂CO ₃(109.0mmol), 12.707g 2-(3-hydroxy phenyl) ethyl acetate (70.5mmol), 41.541g pentamethylene bromide (180.7mmol), the TEBA of catalytic amount, 20mL acetonitrile.Aftertreatment gets weak yellow liquid 18.429g, yield 79.4%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.30-7.24 (m, 1H, Ph5-H), 6.90-6.82 (Ph 2,4 for m, 3H, 6-H), and 4.22-4.16 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.00 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₄Br), 3.61 (s, 2H, Ph-CH ₂), 3.48 (t, 2H, J=6.8Hz, O (CH ₂) ₄CH ₂Br), 2.01-1.62 (m, 6H, OCH ₂(CH ₂) ₃CH ₂Br), 1.29 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 13: preparation 2-[3-(6-bromine hexyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 15.892g K ₂CO ₃(115.0mmol), 12.605g 2-(3-hydroxy phenyl) ethyl acetate (70.0mmol), 44.110g 1, the TEBA of 6-dibromo-hexane (180.8mmol), catalytic amount, 20mL acetonitrile.Aftertreatment gets weak yellow liquid 20.592g, yield 85.7%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.32-7.24 (m, 1H, Ph5-H), 6.92-6.83 (Ph 2,4 for m, 3H, 6-H), and 4.22-4.16 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.99 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₅Br), 3.62 (s, 2H, Ph-CH ₂), 3.46 (t, 2H, J=6.8Hz, O (CH ₂) ₅CH ₂Br), 1.95-1.82 (m, 4H, OCH ₂CH ₂(CH ₂) ₂CH ₂CH ₂Br), 1.56-1.55 (m, 4H, O (CH ₂) ₂(CH ₂) ₂(CH ₂) ₂Br), 1.30 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 14: preparation 2-[4-(2-bromine oxethyl) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.896g K ₂CO ₃(57.1mmol), 6.352g 2-(4-hydroxy phenyl) ethyl acetate (35.2mmol), 17.209g glycol dibromide (91.6mmol), the TEBA of catalytic amount, 10mL acetonitrile.Aftertreatment gets white solid 5.420g.Mp.178.2-181.5 ℃; . yield 53.6%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.23-7.19 (m, 2H, Ph2,6-H), 6.89-6.85 (Ph 3 for m, 2H, 5-H), and 4.28 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 4.17-4.11 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.63 (t, 2H, J=6.4Hz, OCH ₂CH ₂Br), 3.55 (s, 2H, Ph-CH ₂), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 15: preparation 2-[4-(3-bromine propoxy-) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.539g K ₂CO ₃(54.5mmol), 6.401g 2-(4-hydroxy phenyl) ethyl acetate (35.5mmol), 18.404g 1, the TEBA of 3-dibromopropane (91.2mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 6.046g, yield 56.5%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.21-7.18 (m, 2H, Ph2,6-H), 6.88-6.84 (Ph 3 for m, 2H, 5-H), and 4.17-4.11 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.09 (t, 2H, J=6.0Hz, OCH ₂(CH ₂) ₂Br), 3.60 (t, 2H, J=6.0Hz, O (CH ₂) ₂CH ₂Br), 3.55 (s, 2H, Ph-CH ₂), 2.34-2.28 (m, 2H, OCH ₂CH ₂CH ₂Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 16: preparation 2-[4-(4-bromine butoxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.615g K ₂CO ₃(55.1mmol), 6.393g 2-(4-hydroxy phenyl) ethyl acetate (35.5mmol), 19.717g 1, the TEBA of 4-dibromobutane (91.3mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 7.472g, yield 66.8%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.21-7.17 (m, 2H, Ph2,6-H), 6.86-6.82 (Ph 3 for m, 2H, 5-H), and 4.16-4.11 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.98 (t, 2H, J=6.0Hz, OCH ₂(CH ₂) ₃Br), 3.54 (s, 2H, Ph-CH ₂), 3.49 (t, 2H, J=6.0Hz, O (CH ₂) ₃CH ₂Br), 2.10-2.03 (m, 2H, OCH ₂CH ₂(CH ₂) ₂Br), 1.97-1.92 (m, 2H, O (CH ₂) ₂CH ₂CH ₂Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 17: preparation 2-[4-(5-bromine pentyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 7.835g K ₂CO ₃(56.7mmol), 6.388g 2-(4-hydroxy phenyl) ethyl acetate (35.4mmol), 21.060g pentamethylene bromide (91.6mmol), the TEBA of catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 7.874g, yield 67.5%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.22-7.18 (m, 2H, Ph2,6-H), 6.89-6.85 (Ph 3 for m, 2H, 5-H), and 4.18-4.12 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.55 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₅Br), 3.52 (s, 2H, Ph-CH ₂), 3.40 (t, 2H, J=6.4Hz, O (CH ₂) ₄CH ₂Br), 1.98-1.82 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂Br), 1.64-1.53 (m, 2H, O (CH ₂) ₂CH ₂(CH ₂) ₂Br), 1.26 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 18: preparation 2-[4-(6-bromine hexyloxy) phenyl] ethyl acetate

Synthetic method is with embodiment 4, and reaction feeds intake and is 8.070g K ₂CO ₃(58.4mmol), 6.318g 2-(4-hydroxy phenyl) ethyl acetate (35.1mmol), 22.073g 1, the TEBA of 6-dibromo-hexane (90.5mmol), catalytic amount, 10mL acetonitrile.Aftertreatment gets weak yellow liquid 10.073g, yield 83.6%.

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (400MHz, CDCl ₃) δ ppm:7.21-7.17 (m, 2H, Ph2,6-H), 6.87-6.82 (Ph 3 for m, 2H, 5-H), and 4.17-4.11 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.52 (t, 2H, J=6.4Hz, OCH ₂(CH ₂) ₅Br), 3.54 (s, 2H, Ph-CH ₂), 3.42 (t, 2H, J=6.4Hz, O (CH ₂) ₅CH ₂Br), 1.91-1.77 (m, 4H, OCH ₂CH ₂(CH ₂) ₂CH ₂CH ₂Br), 1.52-1.49 (m, 4H, O (CH ₂) ₂(CH ₂) ₂(CH ₂) 2Br), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 19: preparation bromination 2-[2-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

In the single neck eggplant-shape bottle of 50mL, 722mg removes first berberine (2.02mmol), 1.452g 2-(2-(2-bromotrifluoromethane oxygen base) phenyl) ethyl acetate (5.06mmol), 5.0mL dry DMF.Device is connected to the condensing reflux pipe of drying tube, stirs to be warming up to 100 ℃ of reactions down gradually.TLC monitoring reaction to raw material disappears.System is dissolved in the 250mL chloroform, and the saturated aqueous common salt of 2 times of volumes is given a baby a bath on the third day after its birth inferior, the chloroform layer anhydrous Na ₂SO ₄Drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/100～4/100) yellow solid powder 796mg, yield 64.9%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 528[M-Br] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2982,2909,2849 (CH ₂, CH ₃), 1729 (C=O), 1622,1602,1568,1506 (aryl skeleton, C=C), 1481,1454,1391,1364,1340,1273,1254,1225,1158,1102,1058,1033,931,869,832,754;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.08 (s, 1H, 8-H), 8.82 (s, 1H, 13-H), 8.15 (d, 1H, J=9.2Hz, 11-H), 7.89 (d, 1H, J=9.2Hz, 12-H), 7.52 (s, 1H, 1-H), 7.25～7.23 (m, 1H, Ph 4-H), 7.18～7.15 (m, 1H, Ph 3-H), 7.02～7.00 (m, 1H, Ph 6-H), 6.94～6.90 (m, 1H, Ph 5-H), 6.74 (s, 1H, 4-H), 6.06 (s, 2H, O CH ₂O), 4.84 (t, 2H, J=6.4Hz, 6-H), 4.80～4.78 (m, 2H, OCH ₂CH ₂OPh), 4.52～4.49 (m, 2H, OCH ₂CH ₂OPh), 4.09～4.03 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.08 (s, 3H, O CH ₃), 3.55 (s, 2H, Ph-CH ₂), 3.08 (t, 2H, J=6.4Hz, 5-H), 1.20 (t, 3H, J=7.2Hz, O CH ₂CH ₃).

Embodiment 20: preparation bromination 2-[2-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.719mg removes first berberine (2.01mmol), 1.522g 2-(2-(3-bromopropyl oxygen base) phenyl) ethyl acetate (5.05mmol).Synthetic yellow solid powder 1.083g, yield 86.6%.

After testing, the products therefrom fusing point is: mp.168.3～170.5 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 542[M-Br] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2922,2851 (CH ₂, CH ₃), 1733 (C=O), 1635,1602,1567,1506 (aryl skeleton, C=C), 1477,1456,1400,1386,1367,1337,1273,1253,1230,1157,1101,1036,936,874,833,753;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 9.91 (s, 1H, 8-H), 8.48 (s, 1H, 13-H), 8.04 (d, 1H, J=9.2Hz, 11-H), 7.78 (d, 1H, J=9.2Hz, 12-H), 7.43 (s, 1H, 1-H), 7.36～7.31 (m, 1H, Ph 4-H), 7.16～7.12 (Ph 3 for m, 2H, 6-H), 6.96～6.92 (m, 1H, Ph 5-H), 6.72 (s, 1H, 4-H), 6.03 (s, 2H, OCH ₂O), 4.69 (t, 2H, J=6.0Hz, 6-H), 4.53 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 4.43 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 3.94 (s, 3H, OCH ₃), 3.76～3.70 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.56 (s, 2H, Ph-CH ₂), 3.05 (t, 2H, J=6.0Hz, 5-H), 2.52～2.46 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.04 (t, 3H, J=7.2Hz, O CH ₂CH ₃).

Embodiment 21: preparation bromination 2-[2-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.718mg removes first berberine (2.01mmol), 1.584g 2-(2-(4-brombutyl oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 792mg, yield 61.7%.

After testing, the products therefrom fusing point is: mp.189.8～192.3 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 556[M-Br] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3032 (Ar-H), 2983,2958,2915 (CH2, CH ₃), 1733 (C=O), 1635,1620,1602,1569,1507 (aryl skeleton, C=C), 1480,1455,1402,1367,1337,1275,1235,1211,1169,1111,1060,1140,962,938,873,838,752; ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.37 (s, 1H, 8-H), 8.34 (s, 1H, 13-H), 7.89 (d, 1H, J=9.2Hz, 11-H), 7.79 (d, 1H, J=9.2Hz, 12-H), 7.39 (s, 1H, 1-H), 7.26～7.22 (m, 1H, Ph 4-H), 7.18～7.15 (m, 1H, Ph 3-H), 6.93～6.87 (Ph 5 for m, 2H, 6-H), and 6.80 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.23 (t, 2H, J=6.0Hz, 6-H), 4.57 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.17～4.09 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.02 (s, 3H, OCH ₃), 3.62 (s, 2H, Ph-CH ₂), 3.26 (t, 2H, J=6.0Hz, 5-H), 2.25～2.20 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.14～2.08 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.23 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 22: preparation bromination 2-[2-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.718mg removes first berberine (2.01mmol), 1.652g 2-(2-(5-bromine amyl group oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 801mg, yield 61.2%.

After testing, the products therefrom fusing point is: mp.175.3～177.6 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 570[M-Br] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2981,2938,2907 (CH ₂, CH ₃), 1730 (C=O), 1635,1602,1568,1507 (aryl skeleton, C=C), 1479,1453,1402,1385,1366,1336,1294,1273,1234,1164,1102,1060,1037,972,941,876,835,752;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.21 (s, 1H, 8-H), 8.37 (s, 1H, 13-H), 7.92 (d, 1H, J=8.8Hz, 11-H), 7.74 (d, 1H, J=8.8Hz, 12-H), 7.37 (s, 1H, 1-H), 7.25～7.21 (m, 1H, Ph 4-H), 7.16～7.14 (m, 1H, Ph 3-H), 6.91～6.86 (Ph 5 for m, 2H, 6-H), and 6.76 (s, 1H, 4-H), 6.05 (s, 2H, OCH ₂O), 5.18 (t, 2H, J=6.0Hz, 6-H), 4.50 (t, 2H, J=6.8Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.12～4.03 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.00 (s, 3H, OCH ₃), 3.60 (s, 2H, Ph-CH ₂), 3.25 (t, 2H, J=6.0Hz, 5-H), 2.14～2.06 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.96～1.89 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.77～1.71 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.20 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 23: preparation bromination 2-[2-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.725mg removes first berberine (2.03mmol), 1.723g 2-(2-(6-bromine hexyl oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 666mg, yield 49.3%.

After testing, the products therefrom fusing point is: mp.188.2～191.0 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 584[M-Br] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3035,3009 (Ar-H), 2979,2934,2858 (CH ₂, CH ₃), 1736 (C=O), 1634,1602,1568,1543,1508 (aryl skeleton, C=C), 1478,1454,1403,1385,1367,1339,1275,1236,1208,1169,1156,1103,1059,1038,988,961,938,890,870,838,754;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.22 (s, 1H, 8-H), 8.31 (s, 1H, 13-H), 7.87 (d, 1H, J=8.8Hz, 11-H), 7.77 (d, 1H, J=8.8Hz, 12-H), 7.36 (s, 1H, 1-H), 7.25～7.20 (m, 1H, Ph 4-H), 7.17～7.15 (m, 1H, Ph 3-H), 6.90～6.86 (Ph 5 for m, 2H, 6-H), and 6.79 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.22 (t, 2H, J=6.0Hz, 6-H), 4.53 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.03 (s, 3H, OCH ₃), 3.99 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.61 (s, 2H, Ph-CH ₂), 3.30 (t, 2H, J=6.0Hz, 5-H), 2.10～2.04 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.88～1.81 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.68～1.58 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 24: preparation bromination 2-[3-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.726mg removes first berberine (2.03mmol), 1.457g 2-(3-(2-bromotrifluoromethane oxygen base) phenyl) ethyl acetate (5.07mmol).Synthetic yellow solid powder 801mg, yield 65.0%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2980,2935,2848 (CH ₂, CH ₃), 1727 (C=O), 1635,1602,1567,1507 (aryl skeleton, C=C), 1482,1445,1394,1363,1337,1273,1233,1152,1102,1064,1037,980,962,872,837,782,714,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.34 (s, 1H, 8-H), 8.41 (s, 1H, 13-H), 7.97 (d, 1H, J=9.2Hz, 11-H), 7.79 (d, 1H, J=9.2Hz, 12-H), 7.40 (s, 1H, 1-H), 7.22～7.18 (m, 1H, Ph 5-H), 6.84～6.78 (m, 3H, Ph 2,4,6-H), 6.76 (s, 1H, 4-H), 6.05 (s, 2H, OCH ₂O), 5.09 (t, 2H, J=6.4Hz, 6-H), 4.85～4.83 (m, 2H, OCH ₂CH ₂OPh), 4.61～4.59 (m, 2H, OCH ₂CH ₂OPh), 4.14～4.08 (q, 2H, J=7.2Hz, O CH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 3.55 (s, 2H, Ph-CH ₂), 3.20 (t, 2H, J=6.4Hz, 5-H), 1.20 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 25: preparation bromination 2-[3-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.726mg removes first berberine (2.03mmol), 1.512g 2-(3-(3-bromopropyl oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 682mg, yield 54.2%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3034 (Ar-H), 2977,2936 (CH ₂, CH ₃), 1732 (C=O), 1635,1601,1569,1542,1508 (aryl skeleton, C=C), 1480,1447,1403,1368,1340,1276,1234,1172,1148,1132,1102,1059,1038,1003,958,939,872,840,777,753,724,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.34 (s, 1H, 8-H), 8.29 (s, 1H, 13-H), 7.86 (d, 1H, J=9.2Hz, 11-H), 7.76 (d, 1H, J=9.2Hz, 12-H), 7.36 (s, 1H, 1-H), (7.23 d, 1H, J=8.0Hz, Ph 5-H), 6.90～6.84 (m, 3H, Ph 2,4,6-H), 6.78 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.12 (t, 2H, J=6.0Hz, 6-H), 4.69 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 4.38 (t, 2H, J=5.6Hz, O CH ₂CH ₂CH ₂OPh), 4.15～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.93 (s, 3H, OCH ₃), 3.59 (s, 2H, Ph-CH ₂), 3.23 (t, 2H, J=6.0Hz, 5-H), 2.28～2.10 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 26: preparation bromination 2-[3-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.726mg removes first berberine (2.03mmol), 1.584g 2-(3-(4-brombutyl oxygen base) phenyl) ethyl acetate (5.28mmol).Synthetic yellow solid powder 920mg, yield 61.7%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3106,3014 (Ar-H), 2980,2955,2937,2912,2844 (CH ₂, CH ₃), 1725 (C=O), 1636,1607,1585,1541,1509 (aryl skeleton, C=C), 1481,1451,1402,1385,1368,1341,1302,1273,1235,1192,1161,1101,1055,1035,944,870,838,767,729,688;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.34 (s, 1H, 8-H), 8.25 (s, 1H, 13-H), 7.83 (d, 1H, J=9.2Hz, 11-H), 7.78 (d, 1H, J=9.2Hz, 12-H), 7.34 (s, 1H, 1-H), 7.21 (t, 1H, J=8.0Hz, Ph 5-H), 6.84～6.80 (m, 4H, 4-H, Ph 2,4,6-H), 6.08 (s, 2H, OCH ₂O), 5.28 (t, 2H, J=6.4Hz, 6-H), 4.60 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.20～4.11 (m, 4H, O CH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.02 (s, 3H, OCH ₃), 3.57 (s, 2H, Ph-CH ₂), 3.31 (t, 2H, J=6.4Hz, 5-H), 2.28～2.10 (m, 4H, OCH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 27: preparation bromination 2-[3-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.90mg removes first berberine (0.25mmol), 167mg 2-(3-(5-bromine amyl group oxygen base) phenyl) ethyl acetate (0.51mmol).Synthetic yellow solid powder 95mg, yield 58.3%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: I R (KBr) cm ^-1: 3105,3035 (Ar-H), 2982,2930,2872,2852 (CH ₂, CH ₃), 1730 (C=O), 1635,1600,1569,1508 (aryl skeleton, C=C), 1479,1446,1404,1386,1367,1340,1293,1189,1167,1140,1101,1060,1035,966,930,894,872,839,806,782,729,712,693;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.28 (s, 1H, 8-H), 8.28 (s, 1H, 13-H), 7.85 (d, 1H, J=9.2Hz, 11-H), 7.76 (d, 1H, J=9.2Hz, 12-H), 7.35 (s, 1H, 1-H), 7.21 (t, 1H, J=8.0Hz, Ph 5-H), 6.84～6.80 (m, 4H, 4-H, Ph 2,4,6-H), 6.07 (s, 2H, OCH ₂O), 5.26 (t, 2H, J=6.0Hz, 6-H), 4.55 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.11 (q, 2H, J=7.2, OCH ₂CH ₃), 4.04～4.02 (m, 5H, OCH ₃, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.57 (s, 2H, Ph-CH ₂), 3.31 (t, 2H, J=6.0Hz, 5-H), 2.17～2.12 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.96～1.92 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.80～1.74 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2, Hz, OCH ₂CH ₃).

Embodiment 28: preparation bromination 2-[3-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.720mg removes first berberine (2.01mmol), 1.730g 2-(3-(6-bromine hexyl oxygen base) phenyl) ethyl acetate (5.04mmol).Synthetic yellow solid powder 916mg, yield 68.7%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3107 (Ar-H), 2970,2938,2904,2868,2783 (CH ₂, CH ₃), 1736 (C=O), 1636,1600,1569,1508 (aryl skeleton, C=C), 1476,1444,1400,1384,1368,1340,1266,1234,1165,1135,1101,1058,1037,1008,976,961,929,869,841,780,733,712.690;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400M Hz) and δ _Ppm: 10.37 (s, 1H, 8-H), 8.29 (s, 1H, 13-H), 7.86 (d, 1H, J=9.2Hz, 11-H), 7.77 (d, 1H, J=9.2Hz, 12-H), 7.35 (s, 1H, 1-H), 7.23～7.19 (m, 1H, Ph 5-H), 6.84～6.78 (m, 4H, 4-H, Ph 2,4,6-H), 6.07 (s, 2H, OCH ₂O), 5.32 (t, 2H, J=6.4Hz, 6-H), 4.52 (t, 2H, J=6.8Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.11 (q, 2H, J=7.2, OCH ₂CH ₃), 4.03 (s, 3H, OCH ₃), 3.97 (t, 2H, J=6.8Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.57 (s, 2H, Ph-CH ₂), 3.31 (t, 2H, J=6.4Hz, 5-H), 2.12～2.05 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.88～1.81 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.64～1.58 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2, Hz, OCH ₂CH ₃).

Embodiment 29: preparation bromination 2-[4-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.718mg removes first berberine (2.01mmol), 1.449g 2-(4-(2-bromotrifluoromethane oxygen base) phenyl) ethyl acetate (5.05mmol).Synthetic yellow solid powder 682mg, yield 63.7%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1): 3033 (Ar-H), 2980,2905,2846 (CH ₂, CH ₃), 1731 (C=O), 1635,1603,1568,1509 (aryl skeleton, C=C), 1480,1445,1393,1364,1340,1302,1274,1229,1173,1147,1102,1063,1036,960,929,873,831,783,754,735,710;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.43 (s, 1H, 8-H), 8.35 (s, 1H, 13-H), 7.93 (d, 1H, J=9.2Hz, 11-H), 7.79 (d, 1H, J=9.2Hz, 12-H), 7.38 (s, 1H, 1-H), 7.15～7.13 (Ph 2,6-H) for m, 2H, 6.86～6.84 (Ph 3 for m, 2H, 5-H), and 6.78 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.12 (t, 2H, J=6.4Hz, 6-H), 4.86～4.84 (m, 2H, OCH ₂CH ₂OPh), 4.64～4.62 (m, 2H, OCH ₂CH ₂O Ph), 4.14～4.09 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 3.51 (s, 2H, Ph-CH ₂), 3.20 (t, 2H, J=6.4Hz, 5-H), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 30: preparation bromination 2-[4-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.724mg removes first berberine (2.01mmol), 1.515g 2-(4-(3-bromopropyl oxygen base) phenyl) ethyl acetate (5.03mmol).Synthetic yellow solid powder 791mg, yield 62.9%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3033 (Ar-H), 2981,2929,2847 (CH ₂, CH ₃), 1731 (C=O), 1635,1604,1568,1541,1510 (aryl skeleton, C=C), 1479,1403,1367,1339,1299,1275,1232,1173,1150,1102,1060,1039,977,939,874,833,810,734,710,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.54 (s, 1H, 8-H), 8.25 (s, 1H, 13-H), 7.82 (d, 1H, J=8.8Hz, 11-H), 7.77 (d, 1H, J=8.8Hz, 12-H), 7.35 (s, 1H, 1-H), 7.20～7.18 (Ph 2,6-H) for m, 2H, 6.95～6.93 (Ph 3 for m, 2H, 5-H), and 6.80 (s, 1H, 4-H), 6.08 (s, 2H, OCH ₂O), 5.22 (t, 2H, J=6.0Hz, 6-H), 4.70 (t, 2H, J=7.2Hz, OCH ₂CH ₂CH ₂OPh), 4.38 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂O Ph), 4.16～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.93 (s, 3H, OCH ₃), 3.54 (s, 2H, Ph-CH ₂), 3.24 (t, 2H, J=6.0Hz, 5-H), 2.62～2.56 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 31: preparation bromination 2-[4-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.730mg removes first berberine (2.04mmol), 1.586g 2-(4-(4-brombutyl oxygen base) phenyl) ethyl acetate (5.03mmol).Synthetic yellow solid powder 658mg, yield 50.5%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3105,3031 (Ar-H), 2919,2868 (CH ₂, CH ₃), 1729 (C=O), 1634,1602,1567,1509 (aryl skeleton, C=C), 1479,1443,1397,1382,1365,1336,1299,1273,1235,1173,1156,1101,1059,1039,1004,955,940,927,874,833,796,733;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.32 (s, 1H, 8-H), 8.29 (s, 1H, 13-H), 7.87 (d, 1H, J=8.8Hz, 11-H), 7.75 (d, 1H, J=8.8Hz, 12-H), 7.35 (s, 1H, 1-H), 7.17 (d, 2H, J=8.8Hz, Ph 2,6-H), 6.87 (d, 2H, J=8.8Hz, Ph 3,5-H), 6.79 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.27 (t, 2H, J=6.0Hz, 6-H), 4.59 (t, 2H, J=7.2Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.00 (s, 3H, OCH ₃), 3.53 (s, 2H, Ph-CH ₂), 3.31 (t, 2H, J=6.0Hz, 5-H), 2.26～2.22 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.13～2.09 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 32: preparation bromination 2-[4-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.Remove first berberine 722mg2.02mmol), 1.654g 2-(4-(5-bromine amyl group oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 806mg, yield 61.4%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3108,3034 (Ar-H), 2981,2938,2906 (CH ₂, CH ₃), 1724 (C=O), 1636,1604,1569,1510 (aryl skeleton, C=C), 1479,1449,1404,1384,1368,1340,1299,1274,1237,1173,1144,1101,1059,1038,978,960,935,873,835,810,753,709;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.41 (s, 1H, 8-H), 8.27 (s, 1H, 13-H), 7.84 (d, 1H, J=9.2Hz, 11-H), 7.77 (d, 1H, J=9.2Hz, 12-H), 7.35 (s, 1H, 1-H), 7.18～7.16 (Ph 2,6-H) for m, 2H, 6.86～6.84 (Ph 3 for m, 2H, 5-H), and 6.80 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.32 (t, 2H, J=6.4Hz, 6-H), 4.54 (t, 2H, J=7.2Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 4.02 (t, 2H, J=7.2Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.53 (s, 2H, Ph-CH ₂), 3.30 (t, 2H, J=6.4Hz, 5-H), 2.18～2.10 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.97～1.90 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.80～1.72 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 33: preparation bromination 2-[4-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 19.Remove first berberine 726mg (2.01mmol), 1.728g 2-(4-(6-bromine hexyl oxygen base) phenyl) ethyl acetate (5.02mmol).Synthetic yellow solid powder 734mg, yield 54.2%.

After testing, the products therefrom fusing point is: mp.178.2～181.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3033 (Ar-H), 2939,2863 (CH ₂, CH ₃), 1724 (C=O), 1634,1603,1567,1509 (aryl skeleton, C=C), 1478,1424,1402,1386,1366,1338,1230,1273,1236,1173,1145,1102,1061,1037,999,960,929,872,832,733;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.25 (s, 1H, 8-H), 8.29 (s, 1H, 13-H), 7.87 (d, 1H, J=8.8Hz, 11-H), 7.75 (d, 1H, J=8.8Hz, 12-H), 7.35 (s, 1H, 1-H), 7.17 (dd, 1H, J=8.8Hz, Ph 2,6-H), 6.84 (dd, 1H, J=8.8Hz, Ph 3,5-H), 6.79 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.26 (t, 2H, J=6.0Hz, 6-H), 4.52 (t, 2H, J=7.2Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 3.97 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.53 (s, 2H, Ph-CH ₂), 3.32 (t, 2H, J=6.0Hz, 5-H), 2.12～2.04 (m 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.88～1.81 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 34: preparation chlorination 2-[2-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

In the single neck eggplant-shape bottle of 50mL, 306mg bromination 2-(2-(2-berberine oxygen ethyl oxygen base) phenyl) ethyl acetate (0.50mmol), 289mg AgCl (2.02mmol), 20.0mL anhydrous methanol.Stirring reaction under the room temperature.TLC monitoring reaction progress, question response is finished, suction filtration, anhydrous methanol washing filter residue, filtrate is spin-dried for and promptly gets yellow solid powder 283mg, yield 99.8%.

After testing, the products therefrom fusing point is: mp.175.1～176.8 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 528[M-Cl] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2982,2920,2850 (CH ₂, CH ₃), 1731 (C=O), 1634,1621,1603,1566,1541,1506 (aryl skeleton, C=C), 1455,1392,1364,1340,1297,1272,1256,1230,1157,1103,1060,1035,959,932,870,832,754,711;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.12 (s, 1H, 8-H), 8.59 (s, 1H, 13-H), 8.13 (d, 1H, J=9.2Hz, 11-H), 7.90 (d, 1H, J=9.2Hz, 12-H), 7.52 (s, 1H, 1-H), 7.26～7.23 (m, 1H, Ph 4-H), 7.18～7.16 (m, 1H, Ph 3-H), 7.03～7.01 (m, 1H, Ph 6-H), 6.94～6.90 (m, 1H, Ph 5-H), 6.76 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 4.85 (t, 2H, J=6.4Hz, 6-H), 4.81～4.79 (m, 2H, OCH ₂CH ₂OPh), 4.53～4.51 (m, 2H, OCH ₂CH ₂OPh), 4.10～4.04 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.09 (s, 3H, OCH ₃), 3.56 (s, 2H, Ph-CH ₂), 3.08 (t, 2H, J=6.4Hz, 5-H), 1.20 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 35: preparation chlorination 2-[2-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.560mg bromination 2-(2-(3-berberine oxygen propyl group oxygen base) phenyl) ethyl acetate (0.90mmol), 518mg AgCl (3.61mmol).Synthetic yellow solid powder 501mg, yield 97.8%.

After testing, the products therefrom fusing point is: mp.163.1～164.9 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 542[M-Cl] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3033 (Ar-H), 2979,2915 (CH ₂, CH ₃), 1732 (C=O), 1634,1621,1602,1567,1541,1505 (aryl skeleton, C=C), 1478,1456,1399,1366,1337,1293,1272,1252,1224,1170,1103,1063,1040,1002,974,933,887,854,821,754;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.05 (s, 1H, 8-H), 8.44 (s, 1H, 13-H), 8.01 (d, 1H, J=8.8Hz, 11-H), 7.82 (d, 1H, J=8.8Hz, 12-H), 7.44 (s, 1H, 1-H), 7.35～7.30 (m, 1H, Ph 4-H), 7.18～7.15 (m, 1H, Ph 3-H), 7.12～7.10 (m, 1H, Ph 6-H), 6.96～6.92 (m, 1H, Ph 5-H), 6.75 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 4.77 (t, 2H, J=6.0Hz, 6-H), 4.57 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 4.43 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 3.96 (s, 3H, OCH ₃), 3.82～3.76 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.58 (s, 2H, Ph-CH ₂), 3.08 (t, 2H, J=6.0Hz, 5-H), 2.55～2.49 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.07 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 36: preparation chlorination 2-[2-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.410mg bromination 2-(2-(4-berberine oxygen-butyl oxygen base) phenyl) ethyl acetate (0.64mmol), 369mg AgCl (2.57mmol).Synthetic yellow solid powder 375mg, yield 98.4%.

After testing, the products therefrom fusing point is: mp.188.7～190.2 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 556[M-Cl] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3036 (Ar-H), 2984,2935 (CH ₂, CH ₃), 1733 (C=O), 1634,1602,1567,1541,1507 (aryl skeleton, C=C), 1482,1456,1402,1384,1365,1335,1294,1272,1235,1159,1106,1062,1037,965,923,886,837,754;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.37 (s, 1H, 8-H), 8.33 (s, 1H, 13-H), 7.89 (d, 1H, J=9.2Hz, 11-H), 7.80 (d, 1H, J=9.2Hz, 12-H), 7.39 (s, 1H, 1-H), 7.26～7.21 (m, 1H, Ph 4-H), 7.18～7.16 (m, 1H, Ph 3-H), 6.93～6.87 (Ph 5 for m, 2H, 6-H), and 6.80 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.23 (t, 2H, J=6.4Hz, 6-H), 4.57 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.17～4.10 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.02 (s, 3H, OCH ₃), 3.62 (s, 2H, Ph-CH ₂), 3.25 (t, 2H, J=6.0Hz, 5-H), 2.25～2.20 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.14～2.09 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 1.22 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 37: preparation chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.362mg bromination 2-(2-(5-berberine oxygen amyl group oxygen base) phenyl) ethyl acetate (0.56mmol), 322mg AgCl (2.25mmol).Synthetic yellow solid powder 336mg, yield 98.2%.

After testing, the products therefrom fusing point is: mp.168.1～169.6 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 570[M-Cl] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2972,2938,2845 (CH ₂, CH ₃), 1735 (C=O), 1635,1603,1569,1507 (aryl skeleton, C=C), 1477,1455,1402,1385,1367,1340,1273,1248,1235,1164,1102,1060,1037,977,961,931,872,842,787,756;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.31 (s, 1H, 8-H), 8.31 (s, 1H, 13-H), 7.87 (d, 1H, J=8.8Hz, 11-H), 7.79 (d, 1H, J=8.8Hz, 12-H), 7.38 (s, 1H, 1-H), 7.24～7.22 (m, 1H, Ph 4-H), 7.17～7.14 (m, 1H, Ph 3-H), 6.91～6.87 (Ph 5 for m, 2H, 6-H), and 6.79 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.22 (bs, 2H, 6-H), 4.51 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.12～4.03 (m, 7H, OCH ₂CH ₃, O CH ₂CH ₂CH ₂CH ₂CH ₂OPh, OCH ₃), 3.61 (s, 2H, Ph-CH ₂), 3.25 (bs, 2H, 5-H), 2.14～2.06 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.94～1.91 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.77～1.72 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.21 (t, 3H, J=7.2Hz, O CH ₂CH ₃).

Embodiment 38: preparation chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.203mg bromination 2-(2-(6-berberine oxygen hexyl oxygen base) phenyl) ethyl acetate (0.31mmol), 178mg AgCl (1.24mmol).Synthetic yellow solid powder 182mg, yield 96.7%.

After testing, the products therefrom fusing point is: mp.174.2～175.7 ℃;

Products therefrom is through mass spectrometric detection, and data are as follows: MS (ESI, m/z): 584[M-Cl] ⁺

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3006 (Ar-H), 2939 (CH ₂, CH ₃), 1729 (C=O), 1635,1603,1569,1508 (aryl skeleton, C=C), 1478,1458,1403,1385,1367,1339,1274,1255,1236,1189,1172,1102,1061,1040,1005,978,960,931,873,839,785,757;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.35 (s, 1H, 8-H), 8.29 (s, 1H, 13-H), 7.86 (d, 1H, J=8.8Hz, 11-H), 7.79 (d, 1H, J=8.8Hz, 12-H), 7.37 (s, 1H, 1-H), 7.24～7.20 (m, 1H, Ph 4-H), 7.17～7.14 (m, 1H, Ph 3-H), 6.90～6.85 (Ph 5 for m, 2H, 6-H), and 6.80 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 5.28 (bs, 2H, 6-H), 4.51 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.03 (s, 3H, OCH ₃), 3.99 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.61 (s, 2H, Ph-CH ₂), 3.29 (bs, 2H, 5-H), 2.08 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.88～1.81 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.61 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 39: preparation chlorination 2-[3-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.500mg bromination 2-(3-(2-berberine oxygen ethyl oxygen base) phenyl) ethyl acetate (0.82mmol), 476mg AgCl (3.32mmol).Synthetic yellow solid powder 442mg, yield 95.4%.

After testing, the products therefrom fusing point is: mp.179.0～180.2 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3041 (Ar-H), 2978,2937,2846 (CH ₂, CH ₃), 1729 (C=O), 1603,1584,1565,1508 (aryl skeleton, C=C), 1486,1446,1394,1363,1338,1301,1272,1233,1142,1102,1062,1035,977,961,925,881,833,815,770,731,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.38 (s, 1H, 8-H), 8.41 (s, 1H, 13-H), 7.97 (d, 1H, J=9.2Hz, 11-H), 7.80 (d, 1H, J=9.2Hz, 12-H), 7.41 (s, 1H, 1-H), 7.21～7.17 (m, 1H, Ph 5-H), 6.83～6.79 (m, 3H, Ph 2,4,6-H), 6.76 (s, 1H, 4-H), 6.05 (s, 2H, OCH ₂O), 5.10 (t, 2H, J=6.4Hz, 6-H), 4.83～4.81 (m, 2H, OCH ₂CH ₂OPh), 4.60～4.58 (m, 2H, OCH ₂CH ₂O Ph), 4.14～4.08 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 3.54 (s, 2H, Ph-CH ₂), 3.19 (t, 2H, J=6.4Hz, 5-H), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 40: preparation chlorination 2-[3-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.340mg bromination 2-(3-(3-berberine oxygen propyl group oxygen base) phenyl) ethyl acetate (0.55mmol), 318mg AgCl (2.22mmol).Synthetic yellow solid powder 306mg, yield 96.4%.

After testing, the products therefrom fusing point is: mp.177.6～178.9 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3036 (Ar-H), 2978,2935,2846 (CH ₂, CH ₃), 1733 (C=O), 1636,1602,1569,1508 (aryl skeleton, C=C), 1482,1447,1403,1368,1343,1317,1297,1277,1234,1174,1131,1102,1059,1039,1004,958,939,873,845,777,722,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.51 (s, 1H, 8-H), 8.30 (s, 1H, 13-H), 7.86 (d, 1H, J=8.8Hz, 11-H), 7.76 (d, 1H, J=8.8Hz, 12-H), 7.36 (s, 1H, 1-H), 7.26～7.21 (m, 1H, Ph 5-H), 6.90～6.88 (Ph 2 for m, 2H, 4-H), 6.85～6.83 (m, 1H, Ph 6-H), 6.79 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.21 (t, 2H, J=6.4Hz, 6-H), 4.66 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.36 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.15～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.92 (s, 3H, OCH ₃), 3.58 (s, 2H, Ph-CH ₂), 3.22 (t, 2H, J=6.4Hz, 5-H), 2.60～2.54 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 41: preparation chlorination 2-[3-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.410mg bromination 2-(3-(4-berberine oxygen-butyl oxygen base) phenyl) ethyl acetate (0.64mmol), 372mg AgCl (2.60mmol).Synthetic yellow solid powder 376mg, yield 98.6%.

After testing, the products therefrom fusing point is: mp.172.3～173.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3014 (Ar-H), 2980,2956,2936,2913,2845 (CH ₂, CH ₃), 1725 (C=O), 1636,1608,1585,1509 (aryl skeleton, C=C), 1451,1401,1385,1368,1342,1302,1273,1236,1192,1161,1102,1056,1036,944,871,840,767,729,688;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.46 (s, 1H, 8-H), 8.28 (s, 1H, 13-H), 7.85 (d, 1H, J=9.2Hz, 11-H), 7.78 (d, 1H, J=9.2Hz, 12-H), 7.36 (s, 1H, 1-H), 7.22～7.18 (t, 1H, J=8.0Hz, Ph 5-H), 6.84～6.80 (m, 4H, 4-H, Ph 2,4,6-H), 6.07 (s, 2H, OCH ₂O), 5.33 (t, 2H, J=6.0Hz, 6-H), 4.57 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.10 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.01 (s, 3H, OCH ₃), 3.57 (s, 2H, Ph-CH ₂), 3.29 (t, 2H, J=6.4Hz, 5-H), 2.26～2.21 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.14～2.09 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2, Hz, OCH ₂CH ₃).

Embodiment 42: preparation chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.225mg bromination 2-(3-(5-berberine oxygen amyl group oxygen base) phenyl) ethyl acetate (0.35mmol), 205mg AgCl (1.43mmol).Synthetic yellow solid powder 204mg, yield 96.3%.

After testing, the products therefrom fusing point is: mp.168.3～170.1 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2984,2947,2912,2873,2850 (CH ₂, CH ₃), 1729 (C=O), 1635,1601,1570,1542,1508 (aryl skeleton, C=C), 1479,1447,1403,1385,1367,1340,1293,1262,1234,1188,1168,1140,1102,1061,1036,968,936,896,873,841,807,784,730,712,694;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.46 (s, 1H, 8-H), 8.27 (s, 1H, 13-H), 7.84 (d, 1H, J=9.2Hz, 11-H), 7.79 (d, 1H, J=9.2Hz, 12-H), 7.35 (s, 1H, 1-H), 7.21 (t, 1H, J=8.0Hz, Ph 5-H), 6.84～6.79 (m, 4H, 4-H, Ph 2,4,6-H), 6.07 (s, 2H, OCH ₂O), 5.34 (t, 2H, J=6.0Hz, 6-H), 4.53 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.11 (q, 2H, J=7.2, OCH ₂CH ₃), 4.04～4.00 (m, 5H, OCH ₃, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.57 (s, 2H, Ph-CH ₂), 3.29 (t, 2H, J=6.0Hz, 5-H), 2.18～2.10 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.97～1.90 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.80～1.76 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=7.2, Hz, OCH ₂CH ₃).

Embodiment 43: preparation chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.351mg bromination 2-(3-(6-berberine oxygen hexyl oxygen base) phenyl) ethyl acetate (0.53mmol), 305mg AgCl (2.13mmol).Synthetic yellow solid powder 321mg, yield 97.7%.

After testing, the products therefrom fusing point is: mp.165.8～167.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 2971,2938,2904,2868,2782 (CH ₂, CH ₃), 1737 (C=O), 1636,1601,1569,1509 (aryl skeleton, C=C), 1476,1445,1400,1385,1368,1340,1301,1266,1234,1163,1135,1101,1059,1038,1008,977,961,930,870,843,781,733,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.40 (s, 1H, 8-H), 8.28 (s, 1H, 13-H), 7.85 (d, 1H, J=9.2Hz, 11-H), 7.78 (d, 1H, J=9.2Hz, 12-H), 7.36 (s, 1H, 1-H), 7.20 (t, 1H, J=8.0Hz, Ph 5-H), 6.84～6.78 (m, 4H, 4-H, Ph 2,4,6-H), 6.07 (s, 2H, OCH ₂O), 5.33 (t, 2H, J=6.0Hz, 6-H), 4.50 (t, 2H, J=6.8Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.16～4.11 (q, 2H, J=7.2, OCH ₂CH ₃), 4.03 (s, 3H, OCH ₃), 3.97 (t, 2H, J=6.8Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.56 (s, 2H, Ph-CH ₂), 3.30 (t, 2H, J=6.0Hz, 5-H), 2.10～2.05 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.87～1.81 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.68～1.58 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.25 (t, 3H, J=72, Hz, OCH ₂CH ₃).

Embodiment 44: preparation chlorination 2-[4-[2-(9 '-berberine)] oxyethyl group] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.405mg bromination 2-(4-(2-berberine oxygen ethyl oxygen base) phenyl) ethyl acetate (0.67mmol), 318mg AgCl (2.70mmol).Synthetic yellow solid powder 368mg, yield 97.0%.

After testing, the products therefrom fusing point is: mp.170.8～172.5 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3071 (Ar-H), 2982,2924,2850 (CH ₂, CH ₃), 1734 (C=O), 1604,1565,1542,1509 (aryl skeleton, C=C), 1481,1445,1424,1393,1367,1335,1300,1271,1255,1233,1176,1142,1103,1065,1035,1004,983,960,928,871,820,754,733;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.42 (s, 1H, 8-H), 8.36 (s, 1H, 13-H), 7.94 (d, 1H, J=9.2Hz, 11-H), 7.79 (d, 1H, J=9.2Hz, 12-H), 7.39 (s, 1H, 1-H), 7.15～7.12 (Ph 2,6-H) for m, 2H, 6.85～6.81 (Ph 3 for m, 2H, 5-H), and 6.77 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.11 (t, 2H, J=6.0Hz, 6-H), 4.83～4.81 (m, 2H, OCH ₂CH ₂OPh), 4.62～4.60 (m, 2H, OCH ₂CH ₂OPh), 4.14～4.08 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.02 (s, 3H, OCH ₃), 3.50 (s, 2H, Ph-CH ₂), 3.18 (t, 2H, J=6.0Hz, 5-H), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 45: preparation chlorination 2-[4-[3-(9 '-berberine)] propoxy-] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.377mg bromination 2-(4-(3-berberine oxygen propyl group oxygen base) phenyl) ethyl acetate (0.61mmol), 350mg AgCl (2.44mmol).Synthetic yellow solid powder 346mg, yield 98.2%.

After testing, the products therefrom fusing point is: mp.180.7～182.3 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3034 (Ar-H), 2980,2925,2845 (CH ₂, CH ₃), 1738 (C=O), 1635,1603,1568,1510 (aryl skeleton, C=C), 1480,1463,1445,1405,1368,1340,1299,1276,1231,1173,1118,1101,1060,1037,978,937,874,830,807,770,751,736,710,690;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.41 (s, 1H, 8-H), 8.30 (s, 1H, 13-H), 7.87 (d, 1H, J=8.8Hz, 11-H), 7.75 (d, 1H, J=8.8Hz, 12-H), 7.34 (s, 1H, 1-H), 7.18 (d, 2H, J=8.4Hz, Ph 2,6-H), 6.93 (m, 2H, J=8.4Hz, Ph 3,5-H), 6.77 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.14 (t, 2H, J=5.2Hz, 6-H), 4.65 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂O Ph), 4.36 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.15～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 3.91 (s, 3H, OCH ₃), 3.54 (s, 2H, Ph-CH ₂), 3.21 (t, 2H, J=5.2Hz, 5-H), 2.57～2.52 (m, 2H, OCH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 46: preparation chlorination 2-[4-[4-(9 '-berberine)] butoxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.350mg bromination 2-(4-(4-berberine oxygen-butyl oxygen base) phenyl) ethyl acetate (0.55mmol), 316mg AgCl (2.20mmol).Synthetic yellow solid powder 323mg, yield 99.2%.

After testing, the products therefrom fusing point is: mp.182.8～185.1 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3052 (Ar-H), 2981,2924,2850 (CH ₂, CH ₃), 1733 (C=O), 1602,1566,1509 (aryl skeleton, C=C), 1481,1444,1425,1400,1364,1333,1298,1271,1232,1170,1103,1063,1035,960,924,881,824,795,723,691;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.40 (s, 1H, 8-H), 8.28 (s, 1H, 13-H), 7.85 (d, 1H, J=8.8Hz, 11-H), 7.78 (d, 1H, J=8.8Hz, 12-H), 7.36 (s, 1H, 1-H), 7.16 (d, 2H, J=8.4Hz, Ph 2,6-H), 6.86 (d, 2H, J=8.4Hz, Ph 3,5-H), 6.80 (s, 1H, 4-H), 6.06 (s, 2H, OCH ₂O), 5.30 (t, 2H, J=5.2Hz, 6-H), 4.56 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.15～4.09 (m, 4H, OCH ₂CH ₃, OCH ₂CH ₂CH ₂CH ₂OPh), 4.01 (s, 3H, OCH ₃), 3.52 (s, 2H, Ph-CH ₂), 3.28 (t, 2H, J=5.2Hz, 5-H), 2.24～2.19 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.13～2.08 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 47: preparation chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.380mg bromination 2-(4-(5-berberine oxygen amyl group oxygen base) phenyl) ethyl acetate (0.58mmol), 335mg AgCl (2.34mmol).Synthetic yellow solid powder 349mg, yield 98.6%.

After testing, the products therefrom fusing point is: mp.176.2～178.6 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3033 (Ar-H), 2919,2853,2778 (CH ₂, CH ₃), 1724 (C=O), 1636,1603,1569,1510 (aryl skeleton, C=C), 1479,1449,1403,1384,1368,1340,1299,1274,1237,1172,1144,1101,1059,1037,978,935,873,832,810,753,710;

¹HNMR(CDCl ₃，400MHz)δ _ppm：10.27(s，1H，8-H)，8.33(s，1H，13-H)，7.88(d，1H，J＝9.2Hz，11-H)，7.75(d，1H，J＝9.2Hz，12-H)，7.36(s，1H，1-H)，7.16(d，2H，J＝8.4Hz，Ph?2，6-H)，6.84(d，2H，J＝8.4Hz，Ph?3，5-H)，6.78(s，1H，4-H)，6.05(s，2H，OCH ₂O)，5.26(t，2H，J＝5.6Hz，6-H)，4.49(t，2H，J＝6.4Hz，OCH ₂CH ₂CH ₂CH ₂CH ₂OPh)，4.15～4.10(q，2H，J＝7.2Hz，OCH ₂CH ₃)，4.02～3.99(m，5H，OCH ₃，OCH ₂CH ₂CH ₂CH ₂CH ₂OPh)，3.52(s，2H，Ph-CH ₂)，3.28(t，2H，J＝5.6Hz，5-H)，2.13～2.06(m，2H，O?CH ₂CH ₂CH ₂CH ₂CH ₂OPh)，1.94～1.86(m，2H，OCH ₂CH ₂CH ₂CH ₂CH ₂OPh)，1.77～1.70(m，2H，OCH ₂CH ₂CH ₂CH ₂CH ₂OPh)，1.24(t，3H，J＝7.2Hz，OCH ₂CH ₃)。

Embodiment 48: preparation chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] the phenylacetic acid ethyl ester

Press the synthetic method of embodiment 34.354mg bromination 2-(4-(6-berberine oxygen hexyl oxygen base) phenyl) ethyl acetate (0.53mmol), 306mgAgCl (2.14mmol).Synthetic yellow solid powder 318mg, yield 96.8%.

After testing, the products therefrom fusing point is: mp.171.4～173.3 ℃;

Products therefrom is through infrared detection, and data are as follows: IR (KBr) cm ^-1: 3037 (Ar-H), 2978,2939,2852 (CH ₂, CH ₃), 1735 (C=O), 1632,1603,1565,1509 (aryl skeleton, C=C), 1480,1425,1402,1386,1365,1332,1300,1271,1236,1173,1140,1102,1062,1034,996,961,927,890,873,817,795,755,735;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CDCl ₃, 400MHz) δ _Ppm: 10.26 (s, 1H, 8-H), 8.33 (s, 1H, 13-H), 7.88 (d, 1H, J=9.2Hz, 11-H), 7.76 (d, 1H, J=9.2Hz, 12-H), 7.36 (s, 1H, 1-H), 7.16 (d, 1H, J=8.4Hz, Ph 2,6-H), 6.83 (dd, 1H, J=8.4Hz, Ph 3,5-H), 6.78 (s, 1H, 4-H), 6.05 (s, 2H, OCH ₂O), 5.27 (t, 2H, J=5.6Hz, 6-H), 4.46 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂O Ph), 4.15～4.10 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 4.01 (s, 3H, OCH ₃), 3.96 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.52 (s, 2H, Ph-CH ₂), 3.29 (t, 2H, J=5.6Hz, 5-H), 2.06～2.01 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.84～1.81 (m, 2H, O CH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.60 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.24 (t, 3H, J=7.2Hz, OCH ₂CH ₃).

Embodiment 49: preparation chlorination 2-[2-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 60mg chlorination 2-[2-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid ethyl ester (0.106mmol) is dissolved in the 8mL methanol solution.Add the 1.873g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 38mg, yield 62.3%.

After testing, the products therefrom fusing point is: mp.146.8～149.2 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.68 (s, 1H, 8-H), 8.60 (s, 1H, 13-H), 8.08 (d, 1H, J=9.2Hz, 11-H), 7.96 (d, 1H, J=9.2Hz, 12-H), 7.59 (s, 1H, 1-H), 7.21～7.19 (m, 1H, Ph 4-H), 7.12～7.08 (m, 1H, Ph 3-H), 6.88～6.83 (m, 3H, 4-H, Ph 5,6-H), and 6.07 (s, 2H, OCH ₂O), 4.80～4.78 (m, 2H, OCH ₂CH ₂OPh), 4.68 (t, 2H, J=6.4Hz, 6-H), 4.32～4.30 (m, 2H, OCH ₂CH ₂OPh), 4.10 (s, 3H, OCH ₃), 3.43 (s, 2H, Ph-CH ₂), 3.05 (t, 2H, J=6.4Hz, 5-H).

Embodiment 50: preparation chlorination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 120mg chlorination 2-[2-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester (0.208mmol) is dissolved in the 10mL methanol solution.Add the 2.058g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 25mg, yield 20.7%.

After testing, the products therefrom fusing point is: mp.186.4～188.6 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.26 (s, 1H, 8-H), 8.58 (s, 1H, 13-H), 8.05 (d, 1H, J=9.2Hz, 11-H), 7.95 (d, 1H, J=9.2Hz, 12-H), 7.58 (s, 1H, 1-H), 7.27～7.21 (m, 2H, Ph 3,4-H), 7.06 (d, 1H, J=8.0Hz, Ph 6-H), 6.94 (t, 1H, J=7.6Hz, Ph 5-H), 6.87 (s, 1H, 4-H), 6.07 (s, 2H, OCH ₂O), 4.57 (t, 2H, J=6.4Hz, 6-H), 4.36 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.14 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, O CH ₃), 3.45 (s, 2H, Ph-CH ₂), 2.98 (t, 2H, J=6.4Hz, 5-H), 2.42～2.36 (m, 2H, OCH ₂CH ₂CH ₂OPh).

Embodiment 51: preparation chlorination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 50mg chlorination 2-[2-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester (0.084mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 28mg, yield 56.0%.

After testing, the products therefrom fusing point is: mp.143.6～146.1 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.77 (s, 1H, 8-H), 8.61 (s, 1H, 13-H), 8.06 (d, 1H, J=9.2Hz, 11-H), 7.92 (d, 1H, J=9.2Hz, 12-H), 7.61 (s, 1H, 1-H), 7.17～7.08 (Ph 3,4-H) for m, 2H, 6.92 (s, 1H, 4-H), 6.87～6.80 (m, 2H, Ph 5,6-H), and 6.08 (s, 2H, OCH ₂O), 4.84 (t, 2H, J=6.4Hz, 6-H), 4.48 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.10 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 3.48 (s, 2H, Ph-CH ₂), 3.16 (t, 2H, J=6.4Hz, 5-H), 2.19～2.14 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh), 2.05～2.00 (m, 2H, OCH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 52: preparation chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 52mg chlorination 2-[2-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester (0.086mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 34mg, yield 64.0%.

After testing, the products therefrom fusing point is: mp.173.2～174.9 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.72 (s, 1H, 8-H), 8.62 (s, 1H, 13-H), 8.06 (d, 1H, J=9.2Hz, 11-H), 7.93 (d, 1H, J=9.2Hz, 12-H), 7.61 (s, 1H, 1-H), 7.17～7.09 (Ph 3,4-H) for m, 2H, 6.92 (s, 1H, 4-H), 6.87～6.80 (m, 2H, Ph 5,6-H), and 6.08 (s, 2H, OCH ₂O), 4.86 (t, 2H, J=6.4Hz, 6-H), 4.43 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 4.03 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.47 (s, 2H, Ph-CH ₂), 3.17 (t, 2H, J=6.4Hz, 5-H), 2.03～1.78 (m, 6H, OCH ₂CH ₂CH ₂CH ₂CH ₂O Ph).

Embodiment 53: preparation chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 51mg chlorination 2-[2-[6-(9 '-berberine)] hexyloxy] phenylacetic acid ethyl ester (0.082mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 31mg, yield 59.8%.

After testing, the products therefrom fusing point is: mp.168.3～170.1 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.69 (s, 1H, 8-H), 8.64 (s, 1H, 13-H), 8.07 (d, 1H, J=9.2Hz, 11-H), 7.94 (d, 1H, J=9.2Hz, 12-H), 7.62 (s, 1H, 1-H), 7.15～7.13 (m, 1H, Ph 3-H), 7.10～7.06 (m, 1H, Ph 4-H), 6.93 (s, 1H, 4-H), 6.83～6.77 (m, 2H, Ph 5,6-H), and 6.09 (s, 2H, OCH ₂O), 4.86 (t, 2H, J=6.4Hz, 6-H), 4.43 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 3.97 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.45 (s, 2H, Ph-CH ₂), 3.18 (t, 2H, J=6.4Hz, 5-H), 2.00～1.93 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.85～1.81 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.66～1.60 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 54: preparation chlorination 2-[3-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 220mg chlorination 2-[3-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid ethyl ester (0.390mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 68mg, yield 33.3%.

After testing, the products therefrom fusing point is: mp.169.8～171.6 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.49 (s, 1H, 8-H), 8.54 (s, 1H, 13-H), 8.04 (d, 1H, J=8.8Hz, 11-H), 7.93 (d, 1H, J=8.8Hz, 12-H), 7.51 (s, 1H, 1-H), (7.07 t, 1H, J=8.0Hz, Ph 5-H), 6.85～6.82 (m, 3H, Ph 2,4-H, 4-H), 6.52～6.49 (m, 1H, Ph 6-H), 6.05 (s, 2H, OCH ₂O), 4.68 (bs, 2H, OCH ₂CH ₂OPh), 4.50 (t, 2H, J=5.6Hz, 6-H), 4.30 (bs, 2H, OCH ₂CH ₂OPh), 4.06 (s, 3H, OCH ₃), 3.40 (s, 2H, Ph-CH ₂), 3.02 (t, 2H, J=5.6Hz, 5-H).

Embodiment 55: preparation chlorination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 56mg chlorination 2-[3-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester (0.097mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 30mg, yield 52.6%.

After testing, the products therefrom fusing point is: mp.176.7～178..3 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.35 (s, 1H, 8-H), 8.64 (s, 1H, 13-H), 8.09 (d, 1H, J=8.8Hz, 11-H), 7.98 (d, 1H, J=8.8Hz, 12-H), 7.60 (s, 1H, 1-H), 7.16 (t, 1H, J=8.0Hz, Ph 5-H), 7.03～6.02 (m, 1H, Ph 4-H), 6.93～6.90 (m, 2H, 4-H, Ph 2-H), 6.74～6.72 (m, 1H, Ph 6-H), 6.08 (s, 2H, OCH ₂O), 4.57 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂O Ph), 4.37 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.30 (t, 2H, J=6.4Hz, 6-H), 4.06 (s, 3H, OCH ₃), 3.44 (s, 2H, Ph-CH ₂), 3.03 (t, 2H, J=6.0Hz, 5-H), 2.38～2.32 (m, 2H, O CH ₂CH ₂CH ₂OPh).

Embodiment 56: preparation chlorination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 56mg chlorination 2-[3-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester (0.095mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 36mg, yield 63.2%.

After testing, the products therefrom fusing point is: mp.143.9～145.6 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.62 (s, 1H, 8-H), 8.66 (s, 1H, 13-H), 8.09 (d, 1H, J=9.2Hz, 11-H), 7.96 (d, 1H, J=9.2Hz, 12-H), 7.64 (s, 1H, 1-H), 7.09 (t, 1H, J=8.0Hz, Ph 5-H), 6.94 (s, 1H, 4-H), 6.87～6.82 (Ph 2 for m, 2H, 4-H), and 6.67～6.64 (m, 1H, Ph 6-H), 6.09 (s, 2H, OCH ₂O), 4.78 (t, 2H, J=6.4Hz, 6-H), 4.52 (t, 2H, J=6.0Hz, O CH ₂CH ₂CH ₂CH ₂OPh), 4.11 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 3.39 (s, 2H, Ph-CH ₂), 3.18 (t, 2H, J=6.4Hz, 5-H), 2.11～2.02 (m, 4H, OCH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 57: preparation chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 58mg chlorination 2-[3-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester (0.096mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 28mg, yield 46.9%.

After testing, the products therefrom fusing point is: mp.146.5～148.3 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.63 (s, 1H, 8-H), 8.65 (s, 1H, 13-H), 8.08 (d, 1H, J=9.2Hz, 11-H), 7.96 (d, 1H, J=9.2Hz, 12-H), 7.62 (s, 1H, 1-H), 7.08 (t, 1H, J=8.0Hz, Ph 5-H), 6.93 (s, 1H, 4-H), 6.85～6.82 (Ph 2 for m, 2H, 4-H), and 6.66～6.63 (m, 1H, Ph 6-H), 6.09 (s, 2H, OCH ₂O), 4.81 (t, 2H, J=6.4Hz, 6-H), 445 (t, 2H, J=6.4Hz, O CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 3.99 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.40 (s, 2H, Ph-CH ₂), 3.17 (t, 2H, J=6.4Hz, 5-H), 2.01～1.72 (m, 6H, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 58: preparation chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 132mg chlorination 2-[3-[6-(9 '-berberine)] hexyloxy] phenylacetic acid ethyl ester (0.213mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 79mg, yield 57.7%.

After testing, the products therefrom fusing point is: mp.140.1～141.8 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.64 (s, 1H, 8-H), 8.66 (s, 1H, 13-H), 8.09 (d, 1H, J=9.2Hz, 11-H), 7.96 (d, 1H, J=9.2Hz, 12-H), 7.63 (s, 1H, 1-H), 7.07 (t, 1H, J=8.0Hz, Ph 5-H), 6.94 (s, 1H, 4-H), 6.85～6.80 (Ph 2 for m, 2H, 4-H), and 6.65～6.63 (m, 1H, Ph 6-H), 6.10 (s, 2H, OCH ₂O), 4.84 (t, 2H, J=6.4Hz, 6-H), 4.44 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.08 (s, 3H, OCH ₃), 3.96 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.40 (s, 2H, Ph-CH ₂), 3.18 (t, 2H, J=6.4Hz, 5-H), 1.96～1.92 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.82～1.79 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.64～1.59 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh)..

Embodiment 59: preparation chlorination 2-[4-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 55mg chlorination 2-[4-[2-(9 '-berberine)] oxyethyl group] phenylacetic acid ethyl ester (0.098mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 31mg, yield 55.1%.

After testing, the products therefrom fusing point is: mp.223.8～225.2 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.61 (s, 1H, 8-H), 8.68 (s, 1H, 13-H), 8.13 (d, 1H, J=8.8Hz, 11-H), 8.03 (d, 1H, J=8.8Hz, 12-H), 7.63 (s, 1H, 1-H), 7.16 (d, 2H, J=8.4Hz, Ph 2,6-H), 6.91 (s, 1H, 4-H), 6.73 (d, 2H, J=8.4Hz, Ph 3,5-H), and 6.09 (s, 2H, OCH ₂O), 4.75～4.73 (m, 2H, OCH ₂CH ₂OPh), 4.59 (t, 2H, J=6.4Hz, 6-H), 4.37～4.35 (m, 2H, OCH ₂CH ₂OPh), 4.11 (s, 3H, OCH ₃), 3.45 (s, 2H, Ph-CH ₂), 3.07 (t, 2H, J=6.4Hz, 5-H).

Embodiment 60: preparation chlorination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 56mg chlorination 2-[4-[3-(9 '-berberine)] propoxy-] phenylacetic acid ethyl ester (0.097mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 46mg, yield 80.4%.

After testing, the products therefrom fusing point is: mp.158.3～161.1 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.38 (s, 1H, 8-H), 8.66 (s, 1H, 13-H), 8.09 (d, 1H, J=9.2Hz, 11-H), 7.98 (d, 1H, J=9.2Hz, 12-H), 7.61 (s, 1H, 1-H), 7.25～7.22 (Ph 2,6-H) for m, 2H, 6.91 (s, 1H, 4-H), 6.90～6.88 (m, 2H, Ph 3,5-H), and 6.08 (s, 2H, OCH ₂O), 4.57 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂OPh), 4.37 (t, 2H, J=6.4Hz, 6-H), 4.33 (t, 2H, J=5.6Hz, OCH ₂CH ₂CH ₂OPh), 4.05 (s, 3H, OCH ₃), 3.45 (s, 2H, Ph-CH ₂), 3.08 (t, 2H, J=6.4Hz, 5-H), 2.39～2.33 (m, 2H, OCH ₂CH ₂CH ₂OPh).

Embodiment 61: preparation chlorination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 48mg chlorination 2-[4-[4-(9 '-berberine)] butoxy] phenylacetic acid ethyl ester (0.081mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 22mg, yield 45.7%.

After testing, the products therefrom fusing point is: mp.152.3～156.4 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.64 (s, 1H, 8-H), 8.66 (s, 1H, 13-H), 8.08 (d, 1H, J=8.8Hz, 11-H), 7.96 (d, 1H, J=8.8Hz, 12-H), 7.63 (s, 1H, 1-H), 7.16 (d, 2H, J=8.0Hz, Ph 2,6-H), 6.94 (s, 1H, 4-H), 6.78 (d, 2H, J=8.0Hz, Ph 3,5-H), and 6.09 (s, 2H, OCH ₂O), 4.85 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂OPh), 4.48 (t, 2H, J=6.0Hz, 6-H), 4.09～4.06 (m, 5H, OCH ₂CH ₂CH ₂CH ₂Oph, OCH ₃), 3.40 (s, 2H, Ph-CH ₂), 3.20 (t, 2H, J=6.0Hz, 5-H), 2.09～2.01 (m, 4H, OCH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 62: preparation chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 106mg chlorination 2-[4-[5-(9 '-berberine)] pentyloxy] phenylacetic acid ethyl ester (0.175mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 47mg, yield 43.4%.

After testing, the products therefrom fusing point is: mp.168.3～170.1 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.62 (s, 1H, 8-H), 8.66 (s, 1H, 13-H), 8.07 (d, 1H, J=9.2Hz, 11-H), 7.95 (d, 1H, J=9.2Hz, 12-H), 7.64 (s, 1H, 1-H), 7.16～7.12 (Ph 2,6-H) for m, 2H, 6.95 (s, 1H, 4-H), 6.73～6.70 (m, 2H, Ph 3,5-H), and 6.10 (s, 2H, OCH ₂O), 4.81 (t, 2H, J=6.4Hz, 6-H), 4.46 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.06 (s, 3H, OCH ₃), 3.97 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.35 (s, 2H, Ph-CH ₂), 3.17 (t, 2H, J=6.4Hz, 5-H), 2.00～1.71 (m, 6H, OCH ₂CH ₂CH ₂CH ₂CH ₂O Ph).

Embodiment 63: preparation chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] phenylacetic acid potassium

In the single neck eggplant-shape bottle of 50mL, 88mg chlorination 2-[4-[6-(9 '-berberine)] hexyloxy] phenylacetic acid ethyl ester (0.142mmol) is dissolved in the 6mL methanol solution.Add the 1.236g solid KOH under the stirring at room in system, the TLC monitoring is finished to reaction, and chloroform, distilled water go to separating funnel with system, extract three times, and the combined chloroform layer, anhydrous sodium sulfate drying concentrates column chromatography (CH ₃OH/CHCl ₃, V/V, 1/20～1/3) yellow solid powder 52mg, yield 58.5%.

After testing, the products therefrom fusing point is: mp.148.7～150.2 ℃;

Products therefrom is through magnetic resonance detection, and data are as follows: ¹HNMR (CD ₃OD, 400MHz) δ _Ppm: 9.63 (s, 1H, 8-H), 8.67 (s, 1H, 13-H), 8.09 (d, 1H, J=9.2Hz, 11-H), 7.96 (d, 1H, J=9.2Hz, 12-H), 7.64 (s, 1H, 1-H), 7.16～7.13 (Ph 2,6-H) for m, 2H, 6.95 (s, 1H, 4-H), 6.74～6.70 (m, 2H, Ph 3,5-H), and 6.10 (s, 2H, OCH ₂O), 4.85 (t, 2H, J=6.4Hz, 6-H), 4.44 (t, 2H, J=6.4Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 4.07 (s, 3H, OCH ₃), 3.94 (t, 2H, J=6.0Hz, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 3.35 (s, 2H, Ph-CH ₂), 3.19 (t, 2H, J=6.4Hz, 5-H), 1.96～1.93 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.81～1.78 (m, 2H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh), 1.64～1.58 (m, 4H, OCH ₂CH ₂CH ₂CH ₂CH ₂CH ₂OPh).

Embodiment 64: preparation 9-removes the first berberine

In the 100ml eggplant-shape bottle, add the 17.017g berberine, the oil bath heating, temperature is controlled at 190 ℃.Become redness gradually by yellow, become garnet again.TLC monitors to raw material reaction complete.Vacuum-drying obtains 9-at last and removes first berberine 14.467g, yield 78.6%.

Conclusion: at present, do not see about berberine-toluylic acid analog derivative and at pharmacy acceptable salt and preparation method's report.Adopt the berberine-toluylic acid analog derivative of the inventive method preparation to reach at pharmacy acceptable salt, structure is correct, the recovery rate height.And have the preparation method easy, raw material is easy to get, the characteristics that cost is lower, be easy to suitability for industrialized production.

Should be realized that,, can under the situation that does not break away from principle of the present invention and scope, carry out various improvement although narrated specific embodiment of the present invention at this for illustrative purposes.Therefore.The present invention is unrestricted except appended claim.

Claims

1. berberine-toluylic acid analog derivative and at pharmacy acceptable salt is characterized in that: shown in the following general formula I of its structure:

2. the described berberine of claim 1-toluylic acid analog derivative and in the preparation method of pharmacy acceptable salt, it is characterized in that with berberine and hydroxyl phenylacetic acid being that raw material synthesizes berberine-toluylic acid analog derivative and at pharmacy acceptable salt, following steps arranged through series reaction:

1), preparation hydroxyl phenylacetic acid ester compound (1)

2), preparation single bromine substituted alkoxy phenylacetate compounds (2)

3), preparation bromination berberine-phenylacetate compounds

4), preparation Berberine chloride-phenylacetate compounds

5), Berberine chloride-toluylic acid potassium or sodium salt compounds

6) Berberine chloride-toluylic acid compounds

3. method according to claim 2 is characterized in that in the described step 1) hydroxyl phenylacetic acid: acid: the mol ratio of alcohol is 1: 0.1～1.25: 10～12.

4. method according to claim 2 is characterized in that described step 2) in, hydroxyl phenylacetic acid ester: alkali: the mol ratio of terminal two bromoalkanes is 1: 1.5: 1.5.

5. method according to claim 2 is characterized in that described step 2) in, described phase transfer catalysis agent is Tetrabutyl amonium bromide, tetrabutylammonium iodide or bromo triethyl hexadecyldimethyl benzyl ammonium.

6. method according to claim 2 is characterized in that described step 2) in, described terminal two bromoalkanes are glycol dibromides, 1,3-dibromopropane, 1,4-dibromobutane, pentamethylene bromide and 1,6-dibromo-hexane.

7. method according to claim 2, it is characterized in that removing the first berberine in the described step 3): the mol ratio of single bromine substituted alkoxy phenylacetate is 1: 2.5.

8. method according to claim 2 is characterized in that in the described step 4) bromination berberine-phenylacetate: the mol ratio of chlorination reagent is 1: 2～8; Described chlorination reagent is a silver chloride.

9. method according to claim 2 is characterized in that in the described step 5) Berberine chloride-phenylacetate: the mol ratio of alkali is 1: 10～500.

10. method according to claim 2 is characterized in that in the described step 6), and the mol ratio of Berberine chloride-toluylic acid potassium or sodium salt and acid is 1: 5～50.