阅读说明：本技术 一种提高聚乙二醇类衍生物分子量分布的纯化方法 (Purification method for improving molecular weight distribution of polyethylene glycol derivatives ) 是由 薛文 佟圣宏 高明远 曾剑锋 张堃 于 2020-12-28 设计创作，主要内容包括：本发明公开了一种提高聚乙二醇类衍生物分子量分布的纯化方法,取待纯化的聚乙二醇衍生物溶于水,转移至物料平衡缸中,物料平衡缸通过供料泵与膜组件连接,开启供料泵,将物料转移至膜组件内,随着渗透液的不断流出,膜截留分子量大的聚乙二醇衍生物,分子量小的杂质及聚乙二醇衍生物分子随着水不断排出。本发明通过水溶解聚乙二醇衍生物,使其在一定尺寸膜组件内截留,小于该分子量的杂质及聚乙二醇衍生物分子不断被洗脱除去,达到富集所需分子量大小的目的。本发明操作简单,避免了柱层析及重结晶有机溶剂的使用,且只需介质水即可。因为聚乙二醇衍生物结构的含有乙二醇单元组成的长链,所以乙二醇衍生物表现出优良的水溶性。(The invention discloses a purification method for improving the molecular weight distribution of polyethylene glycol derivatives, which comprises the steps of dissolving polyethylene glycol derivatives to be purified in water, transferring the polyethylene glycol derivatives to a material balance cylinder, connecting the material balance cylinder with a membrane component through a feeding pump, starting the feeding pump, transferring the materials to the membrane component, and continuously discharging polyethylene glycol derivatives with high membrane cut-off molecular weight, impurities with low molecular weight and polyethylene glycol derivative molecules with water along with continuous outflow of penetrating fluid. The invention uses water to dissolve the polyethylene glycol derivative, and the polyethylene glycol derivative is intercepted in a membrane component with a certain size, and impurities with molecular weight less than the molecular weight and the polyethylene glycol derivative molecules are continuously eluted and removed, thereby achieving the purpose of enriching the needed molecular weight. The method is simple to operate, avoids the use of column chromatography and recrystallization organic solvents, and only needs medium water. The ethylene glycol derivative exhibits excellent water solubility because the polyethylene glycol derivative structure contains a long chain composed of ethylene glycol units.)

1. A purification method for improving the molecular weight distribution of polyethylene glycol derivatives is characterized in that polyethylene glycol derivatives to be purified are dissolved in water and transferred into a material balance cylinder, the material balance cylinder is connected with a membrane component through a feeding pump, the feeding pump is started, materials are transferred into the membrane component, the polyethylene glycol derivatives with high membrane cut-off molecular weight, impurities with low molecular weight and polyethylene glycol derivative molecules are continuously discharged along with water along with continuous outflow of penetrating fluid.

2. The purification method for improving the molecular weight distribution of the polyethylene glycol derivatives according to claim 1, wherein the membrane module is a 600D or 800D nanofiltration membrane, and the membrane module is made of polyethersulfone or polyvinylidene fluoride.

3. The purification method for improving the molecular weight distribution of polyethylene glycol derivatives according to claim 1, wherein the penetrating fluid is water.

4. The purification method for improving the molecular weight distribution of polyethylene glycol derivatives as claimed in claim 1, wherein the polyethylene glycol derivatives with high molecular weight retained by the membrane are refluxed to the material balance tank, and the cycle is repeated for 5-7 times.

5. The purification method for improving the molecular weight distribution of polyethylene glycol derivatives as claimed in claim 4, wherein the pipeline for returning the polyethylene glycol derivatives with high molecular weight retained by the membrane to the material balance cylinder is provided with a pressure regulating valve and a pressure gauge.

6. The purification method for improving the molecular weight distribution of polyethylene glycol derivatives as claimed in claim 1, wherein the power of the feeding pump is 200-350W.

Technical Field

The invention relates to a purification method for improving the molecular weight distribution of polyethylene glycol derivatives, belonging to the technical field of chemical synthesis.

Background

The polyethylene glycol derivatives are produced in a wide molecular weight distribution due to different polymerization degrees, and the subsequent derivatization and purification are difficult. With the future higher requirements on the polyethylene glycol derivatives, higher requirements are necessarily put on the molecular weight distribution range of the polyethylene glycol derivatives.

The polyethylene glycol derivative is easy to adsorb and difficult to completely elute when purified by column chromatography due to the better hydrophilicity and polarity of the monomer ethylene glycol. In addition, the tailing is serious in the elution process, and the separation purpose cannot be completely achieved. Recrystallization is a relatively common purification method at present, but some impurity molecules with insignificant solubility differences are difficult to remove and cannot achieve the purpose of narrowing the molecular weight distribution.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a purification method for improving the molecular weight distribution of polyethylene glycol derivatives, which can not only achieve the aim of removing impurities, but also can narrow the molecular weight distribution of products.

In order to solve the technical problems, the invention provides a purification method for improving the molecular weight distribution of polyethylene glycol derivatives, which comprises the steps of dissolving polyethylene glycol derivatives to be purified in water, transferring the polyethylene glycol derivatives to a material balance cylinder, connecting the material balance cylinder with a membrane component through a feeding pump, starting the feeding pump, transferring the materials to the membrane component, and continuously discharging polyethylene glycol derivatives with high membrane cut-off molecular weight, impurities with low molecular weight and polyethylene glycol derivative molecules with water along with the continuous outflow of penetrating fluid.

Preferably, the membrane component is a 600D or 800D nanofiltration membrane, and the material of the membrane component is polyether sulfone or polyvinylidene fluoride.

Preferably, the permeate is water.

Preferably, the polyethylene glycol derivative with high molecular weight retained by the membrane flows back to the material balance cylinder, and the circulation is repeated for 5-7 times.

Preferably, a pressure regulating valve and a pressure gauge are arranged on a pipeline for refluxing the polyethylene glycol derivative with the large molecular weight intercepted by the membrane to the material balance cylinder.

Preferably, the power of the feeding pump is 200-350W.

The invention achieves the following beneficial effects: the polyethylene glycol derivative is a high polymer, the molecular weight of the polyethylene glycol derivative is distributed in a certain range, and the water-soluble membranes with different particle sizes are adopted to achieve purification and impurity removal, so that the concentration of the molecular weight is higher. The invention uses water to dissolve the polyethylene glycol derivative, and the polyethylene glycol derivative is intercepted in a membrane component with a certain size, and impurities with molecular weight less than the molecular weight and the polyethylene glycol derivative molecules are continuously eluted and removed, thereby achieving the purpose of enriching the needed molecular weight. The method is simple to operate, avoids the use of column chromatography and recrystallization organic solvents, and only needs medium water. The ethylene glycol derivative exhibits excellent water solubility because the polyethylene glycol derivative structure contains a long chain composed of ethylene glycol units.

Drawings

FIG. 1 is a flow diagram of a purification apparatus of the present invention;

FIG. 2 is a nuclear magnetic image of monomethoxypolyethylene glycol amine before purification in example 2 of the present invention;

FIG. 3 is a nuclear magnetic image of purified monomethoxypolyethylene glycol amine of example 2 of the present invention;

FIG. 4 is a high resolution mass spectrum of monomethoxy polyethylene glycol amine before purification in example 2 of the present invention;

FIG. 5 is a high resolution mass spectrum of the purified monomethoxy polyethylene glycol amine of example 2 of the present invention.

Detailed Description

The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.

As shown in figure 1, the invention provides a purification method for improving the molecular weight distribution of polyethylene glycol derivatives, which comprises the steps of dissolving polyethylene glycol derivatives to be purified in water, transferring the polyethylene glycol derivatives to a material balance cylinder 1, connecting the material balance cylinder 1 with a membrane module 3 through a feeding pump 2, starting the feeding pump 2, transferring the materials to the membrane module 3, and continuously discharging polyethylene glycol derivatives with large membrane cut-off molecular weight, impurities with small molecular weight and polyethylene glycol derivative molecules with water along with the continuous discharge of penetrating fluid.

The membrane module 3 is a 600D or 800D nanofiltration membrane, the product loss is large when the membrane module is larger than the size, the impurity residue is more when the membrane module is smaller than the size, and the membrane module 3 is made of polyether sulfone (PES) or polyvinylidene fluoride (PVDF). The permeate is water. And refluxing the polyethylene glycol derivative with the large molecular weight intercepted by the membrane to the material balance cylinder 1, and repeatedly circulating for 5-7 times. And a pressure regulating valve 4 and a pressure gauge 5 are arranged on a pipeline through which the polyethylene glycol derivative with large molecular weight intercepted by the membrane flows back to the material balance cylinder 1. The power of the feeding pump 2 is 200-350W.

Example 1:

US5606038A1,1997 discloses a preparation method of monomethoxy polyethylene glycol methanesulfonate (intermediate A) (the synthetic route is shown below). The invention synthesizes the intermediate A according to the patent method.

50.0g monomethoxypolyethylene glycol (molecular weight 2000) was weighed as a raw material, added to 300mL Dichloromethane (DCM) and stirred to dissolve it, followed by addition of 9.0g methanesulfonyl chloride (MsCl), and after the above mixed solution was clarified, 14mL triethylamine (EtN) was slowly added dropwise₃) Stirring at room temperature, and gradually deepening the color of the reaction system from nearly colorless to yellow or even brown. The reaction was stopped without monomethoxy polyethylene glycol by HPLC. After 4 hours of reaction, the reaction is completed, the reaction is concentrated under reduced pressure to obtain yellow oily matter, 1L of purified water is added to dissolve the yellow oily matter, the yellow oily matter is added to a material balance cylinder, a feeding pump is started to continuously pass through a membrane assembly (the 600D membrane is loaded at the moment) for circulation once, 200mL of purified water is added to the volume of 1L, the operation is repeated for 5 times, then concentrated solution is discharged, and the concentrated solution is concentrated to obtain an intermediate A.

¹H-NMR (intermediate A, 400M): delta 3.52-3.90(m,202H),3.38(s,3H),3.15(s,3H)。 MS(EI):m/e＝2026.1

Detecting by nuclear magnetic hydrogen spectrum that has no micromolecule substrate impurity methanesulfonyl chloride (MsCl) and triethylamine (EtN)₃) And the like, and other impurities are not seen.

Example 2:

other derivatives such as monomethoxypolyethylene glycol amine (MW 2000) (CAS:80506-64-5) were also purchased directly from the invention, and membrane separation and purification were also used to validate the invention.

Weighing 50.0g of monomethoxy polyethylene glycol amine (marked as A1) and dissolving in 1L of water, adding into a material balance cylinder, starting a feed pump to continuously pass through a membrane module (loaded with an 800D membrane at the moment) for one circulation, adding 200mL of purified water to 1L of volume, repeating the operation for 7 times, discharging a concentrated solution, and concentrating the concentrated solution to obtain the monomethoxy polyethylene glycol amine (marked as A2).

The invention respectively makes nuclear magnetism for A1 and A2¹H-NMR,D₂O) and high resolution mass spectrometry (MOLDI-TOF), as shown in fig. 2 to 5.

From the nuclear magnetism, the purchased A1 contains not only aromatic impurities but also partial homologue impurities, but the impurities are removed after membrane purification, and the purity is obviously improved.

From the molecular weight distributions of a1 and a2, the overall average molecular weight increases, indicating that the membrane washes away the polymer with the lower degree of polymerization, and the product molecular weight becomes more concentrated, showing a tendency and effect of narrowing the molecular weight.

The invention overcomes the defects of the existing purification method, combines the properties of polyethylene glycol, not only can achieve the purpose of impurity removal, but also can narrow the molecular weight distribution of the product.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.