CN103626993B - Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof - Google Patents

Abstract

The invention discloses a kind of use phospholipid of natural soybean to prepare pharmaceutical carrier-Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative (MPEG-SPE) and preparation.Comprise the preparation of powdered soybean phospholipid, the preparation of poly glycol monomethyl ether carboxy derivatives and the preparation of MPEG-SPE, characterize the MPEG-SPE performance of preparation, it is about 100nm that result shows that it forms micella in water, and the micelle-forming concentration in its aqueous solution is 10 ^-6about mol/L, the emulsifying power in water-normal hexane system is better than powdered soybean phospholipid, is suitable for preparing target medicine carrier.Present invention incorporates the advantage of phospholipid of natural soybean, more unsaturated fatty acids is there is in the kephalin utilizing it to contain on the one hand, there is vessel softening, the function reducing cholesterol and reduce blood pressure, make it more be conducive to HUMAN HEALTH, utilize its raw material to be easy to get on the other hand, low price, reduce its production cost, there is larger economic benefit and social benefit.

Description

Polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative and its preparation

technical field

The invention relates to a polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative drug excipient and a preparation method thereof, belonging to the field of medicinal chemistry.

Background technique

Polyethylene glycol monomethyl ether (distearyl phosphatidylethanolamine (cephalin) derivative (MPEG-DSPE) is an amphiphilic polymer, which can form polymer micelles in water, which is a kind of Core-shell structure with a size of 100-200nm. It is usually used to coat hydrophobic drugs to increase the solubility of hydrophobic drugs in human blood to exert drug effects. Due to the formation of this small-sized polymer micelle It is a molecular chain segment of polyethylene glycol, which can form a dense conformational cloud covered by staggered on the outer surface of the micelles, forming a thicker steric hindrance layer, which hinders the attack of high-density lipoproteins in human blood and the phagocytosis of cells, thereby extending Increase the retention time of the drug in the body, so that it will not be consumed before reaching the lesion. At the same time, this kind of nano-micelle utilizes the permeability of the capillary in the damaged part of the tumor, inflammation or hypertensive blood vessel to be higher than that of the normal blood vessel, and at the same time The ability of lymphatic excretion is weakened, and biocompatible macromolecules, drug carriers and molecular aggregates are more likely to enter the tissue through the blood vessels of the pathological site and accumulate during the circulation in the body (EPR effect), so that they have a passive targeting effect. It has been widely used in anticancer targeted drugs.

At present, the price of anti-cancer targeted drugs is generally high, which has an important relationship with the source of raw materials and preparation methods of the drug itself. Therefore, it is more important to choose low-cost raw materials and simple preparation methods. The currently reported methods for preparing MPEG-DSPE are roughly divided into two categories, one is the direct use of polyethylene glycol or polyethylene glycol monomethyl ether and distearyl phosphatidylethanolamine (cephalin) in carbonyl diimidazole Condensation preparation under action (conversion rate 26%) (NoriyukiMaeda, YoshitoTakeuchi, MikiTakada, etal.Synthesisofangiogenesis-targetedpeptideandhydrophobizedpolyethyleneglycolconjugate.Bioorganic&MedicinalChemistryLetters,2004,14:1015-1017), another kind is polyethylene glycol or polyethylene glycol The hydroxyl group of ether is converted into carboxyl and then converted into the intermediate active ester with higher activity, then reacts with the amino group of distearoyl phosphatidylethanolamine to form an amide bond (Shih-KwangWu, Ting-GungChang, Chin-Lu, et al.SolidPhaseMethodForSynthesisPeptide -Spacer-Lipid Conjugates, Conjugates Synthesized Thereby And Targeted Liposomes Containing The Same [P]. US: 0229017A1, 2003-12-11). These preparation methods all use high-purity distearoyl phosphatidylethanolamine (cephalin) as a raw material. Distearoyl phosphatidylethanolamine (cephalin) has a relatively large molecular weight and a relatively complex structure. It usually adopts column chromatography and It is prepared by total synthesis method, with many reaction steps, difficult reaction and low yield, so the price of relatively pure distearoylphosphatidylethanolamine (cephalin) is very expensive (the latest quotation of Aladdin is 3000 yuan/25mg) .

Contents of the invention

The principle of the present invention is: soybean lecithin is mainly composed of phosphatidylcholine (lecithin) and phosphatidylethanolamine (cephalin), which is a by-product of processing soybean oil, which is cheap and easy to get, and the cephalin Fatty acids are mainly composed of oleic acid, linoleic acid, palmitic acid, stearic acid and linolenic acid, and there are more unsaturated fatty acids, which have the functions of softening blood vessels, lowering cholesterol and lowering blood pressure. The polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative (MPEG-SPE) prepared with it as a raw material is not only lower in cost than polyethylene glycol monomethyl ether (distearoylphosphatidylethanolamine (cephalin) derivative ( MPEG-DSPE) and more conducive to human cardiovascular health.

Therefore, the present invention aims at the rare and expensive characteristics of the cephalin raw materials used in the preparation of the existing MPEG-DSPE. The invention provides a method for preparing pharmaceutical auxiliary materials of polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivatives by using cheaper natural soybean lecithin.

Another object of the present invention is to provide a polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative.

The technical solution that realizes the object of the present invention is: a kind of polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative, its structure is as follows:

The technical solution that realizes another object of the present invention is: a kind of preparation of polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative, concrete steps are as follows:

Step 1: preparing soybean powder phospholipids with natural soybean phospholipids;

Step 2: preparing polyethylene glycol monomethyl ether carboxyl derivatives with polyethylene glycol monomethyl ether;

Step 3: preparing polyethylene glycol monomethyl ether acid chloride with polyethylene glycol monomethyl ether carboxyl derivatives;

Step 4: Using soybean powder phospholipids and polyethylene glycol monomethyl ether acid chloride as raw materials, using chloroform as a solvent, and triethylamine as a catalyst to prepare polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivatives, reaction conditions It is m (soybean powder phospholipid): m (polyethylene glycol monomethyl ether chloride) = 1: 1 ~ 10: 1; the reaction temperature is 10 ° C ~ 80 ° C; the reaction time is 0.5 h ~ 10 h;

Step 5: After the reaction, remove chloroform and unreacted triethylamine, add tetrahydrofuran to precipitate triethylamine hydrochloride, centrifuge, remove tetrahydrofuran from the upper liquid, and then add anhydrous ether to precipitate the reaction product.

The soybean powder phospholipid described in step 1 is prepared by an acetone extraction method.

The carboxyl derivative of polyethylene glycol monomethyl ether described in step 2 is prepared by using Jones reagent to oxidize polyethylene glycol monomethyl ether, wherein the molecular weight of polyethylene glycol monomethyl ether ranges from 1200 to 5000.

The polyethylene glycol monomethyl ether acid chloride described in step 3 is prepared by using thionyl chloride and polyethylene glycol monomethyl ether carboxyl derivatives.

The molar ratio of polyethylene glycol monomethyl ether chloride and triethylamine described in step 4 is: n (polyethylene glycol monomethyl ether chloride):n (triethylamine)=1:10～1: 40.

The ratio of the amount of polyethylene glycol monomethyl ether acid chloride to the volume of tetrahydrofuran described in step 5 is: n (polyethylene glycol monomethyl ether acid chloride (mmol)): v (tetrahydrofuran (ml))=1: 30 to 1:100, the ratio of the amount of polyethylene glycol monomethyl ether chloride to the volume of anhydrous ether is n (polyethylene glycol monomethyl ether chloride (mmol)): v (anhydrous ether ( ml))=1:30～1:100.

Compared with the existing MPEG-DSPE pharmaceutical excipients, the present invention combines the advantages of natural soybean phospholipids, on the one hand, it utilizes the cephalin contained in it to contain more unsaturated fatty acids, which has the functions of softening blood vessels, lowering cholesterol and lowering blood pressure , making it more beneficial to human health, on the other hand, the raw materials are easy to get and the price is cheap, which reduces the production cost and has great economic and social benefits. The technical effect of the MPEG-SPE prepared by the above method is: the size of the micelles formed by the MPEG-SPE in water was observed by TEM, and the results showed that the average particle size of the micelles formed in the aqueous solution was about 100nm. The critical aggregation concentration of MPEG-SPE was studied by fluorescent probe technology to characterize the thermodynamic stability of the product. The results showed that its critical micelle concentration in aqueous solution was about 10 ^-6 mol/L, and the thermodynamic stability of the formed micelles Superior to small molecule micelles. The kinetic stability of MPEG-SPE was characterized by emulsification force, and the results showed that its kinetic stability was better than that of soybean powder phospholipids, and it was suitable for the preparation of targeted drug carriers.

Description of drawings

Fig. 1 is the flow chart of the preparation process of MPEG-SPE of the present invention.

Fig. 2 is a graph showing the influence of MPEG2000-SPE concentration on the I384/I373 ratio in Example 1 of the present invention.

detailed description

Example 1

In Figure 1, in the first step, weigh 12g of soybean lecithin and add it to 100ml of acetone, stir until solids appear, filter under reduced pressure, add the filter cake to two 20ml centrifuge tubes, add 10ml of acetone respectively, Centrifuge at a rotational speed for 2 minutes, pour out the liquid, and repeat the above process several times until the liquid in the centrifuge tube is colorless, take out the solid in the centrifuge tube, and put it in a vacuum drying oven to dry at room temperature for 24 hours.

In the second step, weigh 5g of mPEG2000 into a 500mL flask filled with 100mL of acetone solution, and stir magnetically at 25°C until mPEG is completely dissolved. Then add 4.25mL Jones reagent and react for 24h. After the reaction is over, add isopropanol to quench, filter with suction, add 50mL distilled water to the filtrate, remove acetone in the system by rotary evaporation (remove as much as possible), and add a certain amount of potassium bicarbonate to the remaining solution until no bubbles are generated in the system , evaporate the water in the system to dryness, fully extract the residue with chloroform, filter with suction, remove the chloroform by rotary evaporation of the filtrate, then add 10% hydrochloric acid solution to the residue until the pH of the system is 1, evaporate Water and hydrogen chloride gas were discharged, and sodium chloride was precipitated in the residue. At this time, it was extracted with chloroform, filtered with suction, and the filtrate was rotary evaporated to remove chloroform to obtain the product. After cooling, a white solid product was obtained. Yield: 4.90 g (98%). Acid value: actual value, 0.497mmol carboxyl group/g; theoretical value, 0.500mmol carboxyl group/g. IR: 1735cm ^-1 (characteristic peak of carbonyl), 3480cm ^-1 (stretching vibration peak of -OH), 1100cm ^-1 (stretching vibration peak of C—O—C). ¹ HNMR (DMSOd ₆ ): δ _H 3.24 (-O-CH ₃ ), 4.01 (methine of -O-CH ₂ -COOH), 3.31-3.58 (repeating unit -CH ₂ -CH ₂ -O-), 12.55 (—COOH).

In the third step, weigh 2g of CmPEG2000 and add it into 10ml of dichloromethane, then add 20ml of thionyl chloride into the reaction system, and react under reflux for 6h. Distill under reduced pressure, add anhydrous diethyl ether to precipitate, and filter with suction to obtain a white solid.

The fourth step is to weigh 6.0g of soybean powder lecithin and dissolve it in 30ml of chloroform, transfer it into a 150ml three-neck flask, add 25mmol of triethylamine, stir it magnetically, heat up to 45, and dissolve 2g of polyethylene glycol monomethyl Ether 2000 acid chloride was dissolved in 20ml of chloroform, and added dropwise into a three-necked flask using a dropping funnel. Reaction 4h.

In the fifth step, after the reaction is finished, chloroform and unreacted triethylamine are removed by rotary evaporation. Then add 30ml of tetrahydrofuran to precipitate the hydrochloride of triethylamine, centrifuge, remove tetrahydrofuran from the upper liquid, add 20ml of anhydrous ether to precipitate unreacted polyethylene glycol monomethyl ether 2000 acid chloride and reaction product, respectively use 10ml of anhydrous Washed three times with ether, dried and weighed. IR: 1650cm-1 (carbonyl stretching vibration peak of —C(O) NH—), 1533cm-1 (bending vibration peak of amino group in-plane of —C(O) NH—), 1100cm-1 (C—O—C stretching vibration peak vibration peak).

Example 2

first step, ditto

In the second step, weigh 6g of mPEG1200 and add it into a 500mL flask containing 100mL of acetone solution, and stir magnetically at 25°C until mPEG is completely dissolved. Then add 8.5mL Jones reagent and react for 24h. The post-processing method is the same as above. Yield: 5.61 g (93.5%). Acid value: actual value, 0.830 mmol carboxyl group/g; theoretical value, 0.833 mmol carboxyl group/g. IR: 1744cm ^-1 (carbonyl characteristic peak), 3486cm ^-1 (stretching vibration peak of -OH), 1088cm ^-1 (stretching vibration peak of C—O—C). ¹ HNMR (DMSOd ₆ ): δ _H 3.23 (-O-CH ₃ ), 4.01 (methine of -O-CH ₂ -COOH), 3.33-3.50 (repeating unit -CH ₂ -CH ₂ -O-), 12.54 (—COOH).

In the third step, weigh 2g of CmPEG1200 and add it into 10ml of dichloromethane, then add 30ml of thionyl chloride into the reaction system, and react under reflux for 6h. The product was obtained by distillation under reduced pressure.

The fourth step is to weigh 12.0g of soybean powder lecithin and dissolve it in 30ml of chloroform, transfer it into a 150ml three-neck flask, add 10mmol of triethylamine, stir it magnetically, heat up to 10°C and dissolve 1.2g of polyethylene glycol Dimethyl ether 1200 acid chloride was dissolved in 20ml of chloroform, and added dropwise into a three-neck flask using a dropping funnel. Reaction 0.5h.

In the fifth step, after the reaction is finished, chloroform and unreacted triethylamine are removed by rotary evaporation. Then add 30ml of tetrahydrofuran to precipitate triethylamine hydrochloride, centrifuge, remove tetrahydrofuran from the upper liquid, cool to below 10°C, add 15ml of anhydrous ether to precipitate unreacted polyethylene glycol monomethyl ether 1200 acid chloride and react The products were washed three times with 5 ml of anhydrous ether, dried and weighed. IR: 1653cm-1 (carbonyl stretching vibration peak of -C(O)NH-), 1537cm-1 (in-plane bending vibration peak of amino group of -C(O)NH-), 1090cm-1 (C—O—C stretching vibration peak vibration peak).

Example 3

first step, ditto

In the second step, weigh 5g of mPEG5000 and add it into a 500mL flask filled with 100mL of acetone solution, and stir magnetically at 25°C until mPEG is completely dissolved. Then add 1.7mL Jones reagent and react for 24h. The post-processing method is the same as above. Yield: 4.91 g (98.2%). Acid value: actual value, 0.196 mmol carboxyl group/g; theoretical value, 0.200 mmol carboxyl group/g. IR: 1732cm ^-1 (carbonyl characteristic peak), 3480cm ^-1 (stretching vibration peak of -OH), 1106cm ^-1 (stretching vibration peak of C—O—C). ¹ HNMR (DMSOd ₆ ): δ _H 3.22 (-O-CH ₃ ), 4.01 (methine of —O—CH ₂ —COOH), 3.33-3.51 (repeating unit—CH ₂ —CH ₂ —O—)n , 12.54 (—COOH).

In the third step, 5g of CmPEG5000 was weighed and added to 10ml of dichloromethane, and then 30ml of thionyl chloride was added to the reaction system, and the reaction was refluxed for 6h. Distill under reduced pressure, add anhydrous diethyl ether to precipitate, and filter with suction to obtain a white solid.

Step 4: Dissolve 5g of soybean powder phospholipids into 30ml of chloroform, transfer to a 150ml three-necked flask, add 40mmol of triethylamine, stir magnetically, heat up to 80, ℃ and dissolve 5g of polyethylene glycol monomethyl ether 5000 g of acid chloride was dissolved in 20 ml of chloroform, and added dropwise into a three-necked flask using a dropping funnel. Reaction 10h.

In the fifth step, after the reaction is finished, chloroform and unreacted triethylamine are removed by rotary evaporation. Then add 100ml of tetrahydrofuran to precipitate the hydrochloride of triethylamine, centrifuge, remove the tetrahydrofuran by rotary evaporation of the upper layer liquid, then add 70ml of anhydrous ether to precipitate unreacted polyethylene glycol monomethyl ether 5000 acid chloride and the reaction product, respectively use 10ml Washed three times with anhydrous ether. Weigh dry. IR: 1655cm-1 (carbonyl stretching vibration peak of -C(O)NH-), 1533cm-1 (in-plane bending vibration peak of amino group of -C(O)NH-), 1106cm-1 (C—O—C stretching vibration peak vibration peak).

The performance characterization of the polyethylene glycol monomethyl ether soybean phosphatidylethanolamine derivative prepared in Example 1 is carried out, and the results are as follows:

1. The micellar particle size of MPEG2000-SPE:

MPEG2000-SPE is a polymer surfactant. When its concentration in water is greater than the critical micelle concentration, it can form nano-micelles with hydrophobic chain ends as the core and hydrophilic chain ends as the core. It can be used to transport drugs. It has targeting properties when it reaches a certain nanometer size. In this part, transmission electron microscopy is used to measure the micelle particle size of MPEG2000-SPE. The method is as follows: Weigh a certain amount of MPEG2000-SPE and dissolve it in water, and place it at room temperature for 3 hours, so that MPEG2000-SPE forms stable micelles in water and sticks to copper. On the grid, the size of the micelles was observed on a TEM after the copper grid was dried at room temperature. The experimental results show that the micelles of MPEG2000-SPE are spherical, the average particle diameter is about 100nm, and the particles are relatively uniform.

2. Thermodynamic stability research of MPEG2000-SPE:

MPEG2000-SPE can form micelles in aqueous solution. The thermodynamic stability of micelles refers to the concentration of polymer micelles when they depolymerize to monomers, that is, the critical micelle concentration (CMC) is also the critical aggregation concentration (CAC). In this part, the fluorescent probe technology with high sensitivity is used to measure the CAC of MPEG2000-SPE. The method is as follows: first prepare 1×10 ^-7 , 2×10 ^-7 , 3×10 ^-7 , 5×10 ^-7 , 7×10 ^-7 , 1×10 ^-6 , 2×10 ^-6 , 3×10 ^-6 , 5×10 ^-6 , 1×10 ^-5 , 2×10 ^-5 , 3×10 ^-5 , 5×10 ^-5 , 7×10 ^-5 , 10×10 ^-5 , 15×10 ^-5 mol/L concentration of MPEG-SPE solution, and then configure 2×10 ^-4 mol/L pyrene in acetone solution, then take 0.1ml of pyrene in acetone solution and add it to a 10ml volumetric flask. Pipette 10ml of the above-mentioned MPEG2000-SPE solution into the volumetric flask, and then sonicate for 30min after shaking several times. Then measure the fluorescence intensity of a series of MPEG-SPE solutions with different concentrations at 373nm and 384nm at 335nm, take the logarithm of the MPEG2000-SPE concentration as the X-axis, and the value of I384/I373 as the Y-axis plot, find out from the figure As shown in Figure 2, when x=-5.69, the value of I384/I373 changes abruptly, indicating that the CAC has been reached at this time, and the critical micelle concentration is 2×10 ^-6 mol/L, far from Much smaller than the critical micelle concentration of small molecules (10 ^-3 mol/L), the thermodynamic stability of MPEG-SPE is better than that of small molecule micelles.

3. MPEG2000-SPE study on the kinetic stability of micelles:

The stability of polymer micelles is usually evaluated by thermodynamic stability and kinetic stability. Kinetic stability refers to the speed at which micelles decompose into monomers. We design an emulsion system formed by n-hexane and water. According to the emulsion Liquid separation of a certain volume of liquid to characterize the speed at which micelles decompose into monomers, compared with soybean powder phospholipids under the same conditions. The operation is as follows: dissolve 0.05g sample with 50ml of distilled water, place it in a 100ml stoppered measuring cylinder, measure 50ml of n-hexane, put on the lid and vibrate violently until it is fully emulsified, then measure the water-oil phase separation of 10ml by time immediately time. The experimental results are shown in Table 1: the time taken by MPEG2000-SPE to separate 10ml is 183s, which is far longer than the time taken by soybean powder phospholipids of 6s, and when the MPEG-SPE emulsion is separated into a volume of 41ml, the oil-water will no longer separate, and the upper part of the measuring cylinder will appear stable gel state. Therefore, the kinetic stability of MPEG-SPE is better than soybean powder phospholipids.

Table 1 The relationship between the volume of oil-water two-phase separation of different substances and the time (s) used

Claims (10)

1. a Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative, is characterized in that structure is as follows:

Wherein R ₁, R ₂represent the group after any one dehydrogenation in oleic acid, linolenic acid, linolic acid, stearic acid or palmitinic acid, and R ₁, R ₂it is asynchronously the group after oleic acid, stearic acid or palmitinic acid dehydrogenation.

2. Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 1, is characterized in that described derivative is prepared by following concrete steps:

Step 1, prepares powdered soybean phospholipid with phospholipid of natural soybean;

Step 2, prepares poly glycol monomethyl ether carboxy derivatives with poly glycol monomethyl ether;

Step 3, prepares poly glycol monomethyl ether acyl chlorides with poly glycol monomethyl ether carboxy derivatives;

Step 4, with powdered soybean phospholipid and poly glycol monomethyl ether acyl chlorides for raw material, take trichloromethane as solvent, take triethylamine as catalyzer, preparation Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative, wherein by quality ratio, powdered soybean phospholipid: poly glycol monomethyl ether acyl chlorides=1:1 ~ 10:1; Temperature of reaction is 10 DEG C ~ 80 DEG C; Reaction times is 0.5h ~ 10h;

Step 5, after reaction terminates, removing trichloromethane and unreacted triethylamine, add the hydrochloride that tetrahydrofuran (THF) is settled out triethylamine, centrifugation, and supernatant liquid removing tetrahydrofuran (THF) adds anhydrous diethyl ether again and is settled out reaction product.

3. Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 2, is characterized in that the powdered soybean phospholipid described in step 1 adopts extraction by propanone preparation; Poly glycol monomethyl ether carboxy derivatives described in step 2 adopts Jones reagent oxidation poly glycol monomethyl ether legal system standby, and wherein the molecular weight ranges of poly glycol monomethyl ether is 1200 ~ 5000.

4. Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 2, is characterized in that the poly glycol monomethyl ether acyl chlorides described in step 3 adopts thionyl chloride and the preparation of poly glycol monomethyl ether carboxy derivatives.

5. Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 2, is characterized in that in amount of substance ratio in step 4, poly glycol monomethyl ether acyl chlorides: triethylamine=1:10 ~ 1:40.

6. Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 2, it is characterized in that, the amount of substance of the poly glycol monomethyl ether acyl chlorides described in step 4 and the volume ratio=1:30 ~ 1:100mmol/ml of the tetrahydrofuran (THF) described in step 5, the amount of substance of poly glycol monomethyl ether acyl chlorides and the volume ratio=1:30 ~ 1:100mmol/ml of anhydrous diethyl ether.

7. a preparation for Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative, is characterized in that concrete steps are as follows:

Step 1, prepare powdered soybean phospholipid with phospholipid of natural soybean;

Step 2, prepare poly glycol monomethyl ether carboxy derivatives with poly glycol monomethyl ether;

Step 3, prepare poly glycol monomethyl ether acyl chlorides with poly glycol monomethyl ether carboxy derivatives;

Step 4, with powdered soybean phospholipid and poly glycol monomethyl ether acyl chlorides for raw material, take trichloromethane as solvent, take triethylamine as catalyzer, preparation Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative, wherein by quality ratio, powdered soybean phospholipid: poly glycol monomethyl ether acyl chlorides=1:1 ~ 10:1; Temperature of reaction is 10 DEG C ~ 80 DEG C; Reaction times is 0.5h ~ 10h;

After step 5, reaction terminate, removing trichloromethane and unreacted triethylamine, add the hydrochloride that tetrahydrofuran (THF) is settled out triethylamine, centrifugation, and supernatant liquid removing tetrahydrofuran (THF) adds anhydrous diethyl ether again and is settled out reaction product.

8. the preparation of Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 7, is characterized in that the powdered soybean phospholipid described in step 1 adopts extraction by propanone preparation; Poly glycol monomethyl ether carboxy derivatives described in step 2 adopts Jones reagent oxidation poly glycol monomethyl ether legal system standby, and wherein the molecular weight ranges of poly glycol monomethyl ether is 1200 ~ 5000; Poly glycol monomethyl ether acyl chlorides described in step 3 adopts thionyl chloride and the preparation of poly glycol monomethyl ether carboxy derivatives.

9. the preparation of Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 7, is characterized in that in amount of substance ratio in step 4, poly glycol monomethyl ether acyl chlorides: triethylamine=1:10 ~ 1:40.

10. the preparation of Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative according to claim 7, it is characterized in that, the amount of substance of the poly glycol monomethyl ether acyl chlorides described in step 4 and the volume ratio=1:30 ~ 1:100mmol/ml of the tetrahydrofuran (THF) described in step 5, the amount of substance of poly glycol monomethyl ether acyl chlorides and the volume ratio=1:30 ~ 1:100mmol/ml of anhydrous diethyl ether.