阅读说明：本技术 一种用于阿奇霉素生产用甲醇纯化的层析净化柱 (A chromatography purification column for azithromycin production is with methyl alcohol purification ) 是由 靳钊 曲皓童 刘欣然 孟祥伟 王辰龙 张田砚 曲文豪 张涵 于泽芳 张梦雪 于 2021-05-31 设计创作，主要内容包括：本发明公开了一种用于阿奇霉素生产用甲醇纯化的层析净化柱,涉及净化柱技术领域。本发明包括柱体,柱体为玻璃材质或不锈钢材质；柱体的直径为20cm～1m,高度为1m～2m；柱体的一端设有24mm的标口、另一端设有四氟节门；柱体的内部还设置有一砂芯滤板,还包括砂芯滤板内的球形填料,球形填料的粒径分布方差≤15％,平均粒径介于2mm～2cm之间；球形填料为官能团改性的多孔聚苯乙烯-二乙烯基苯微球；层析净化柱为一种或多种微球的组合。本发明通过采用更大体积的层析净化柱,可满足医药溶剂回收大通量处理要求；采用球形填料粒径更大、粒径分布更窄,大体积、高通量必然会带来柱前压力过大,选用球形填料,可降低柱前压力。(The invention discloses a chromatographic purification column for purifying methanol for azithromycin production, and relates to the technical field of purification columns. The invention comprises a cylinder body, wherein the cylinder body is made of glass materials or stainless steel materials; the diameter of the column body is 20 cm-1 m, and the height is 1 m-2 m; one end of the column body is provided with a 24mm mark port, and the other end is provided with a tetrafluoro gate; a sand core filter plate is arranged in the column body, and the sand core filter plate also comprises spherical fillers in the sand core filter plate, wherein the particle size distribution variance of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 2mm and 2 cm; the spherical filler is porous polystyrene-divinylbenzene microspheres modified by functional groups; the chromatographic purifying column is one or several microsphere combinations. The invention can meet the requirement of large-flux treatment for recovering medical solvent by adopting a chromatography purification column with larger volume; the adopted spherical filler has larger particle size and narrower particle size distribution, and the large volume and high flux inevitably bring overlarge pressure before the column.)

1. A chromatographic purification column for purifying methanol for producing azithromycin comprises:

the column body (1), the diameter of the column body (1) is 20 cm-1 m, and the height is 1 m-2 m;

one end of the column body (1) is provided with a 24mm mark opening (3), and the other end is provided with a tetrafluoro gate (4);

a sand core filter plate (2) is arranged in the column body (1);

the sand core filter plate also comprises spherical fillers in the sand core filter plate (2), wherein the particle size distribution variance of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 2mm and 2 cm;

the spherical filler is porous polystyrene-divinylbenzene microspheres modified by functional groups.

2. The chromatographic purification column for the methanol purification for azithromycin production according to claim 1, which is characterized in that the chromatographic purification columns are used in parallel or in series.

3. The chromatographic purification column for purifying azithromycin for production methanol, which is claimed in claim 1, is characterized in that the modified groups of the porous polystyrene-divinylbenzene microspheres comprise sulfonic acid groups, amino groups, pyrrolidone groups, carbamido groups and carboxyl groups, and the spherical filler is a combination of one or more functional group modified porous polystyrene-divinylbenzene microspheres.

4. The chromatographic purification column for the purification of the methanol for azithromycin production according to claim 1, which is used for the purification of the methanol for azithromycin production, and the method for purifying the methanol comprises the following steps:

step SS 01: the method comprises the following steps: when in use, the rectified methanol solvent flows through the chromatographic purification column from top to bottom, and the methanol purification solution flows out from the bottom end;

step SS 02: a washing step: when the total volume of the methanol solvent treated by the chromatographic purification column exceeds 1000 times of the volume of the chromatographic purification column, washing for 3-5 times by using an acetonitrile solvent-methanol solvent;

the washed chromatographic purification column can be reused.

5. The chromatographic purification column for the methanol purification for azithromycin production according to claim 4, wherein the outflow rate of the methanol purification solution in the step SS01 is controlled to be 3mL/min to 50 mL/min.

6. The chromatographic purification column for purifying azithromycin for production methanol, which is used according to claim 1, is characterized in that the column body (1) is made of glass or stainless steel.

Technical Field

The invention belongs to the technical field of purification columns, and particularly relates to a chromatographic purification column for purifying methanol for azithromycin production.

Background

Methanol solvent is used in the production process of azithromycin, and only high-purity methanol is used in general production, but recovered methanol is not used, so that not only is the cost increased, but also the treatment capacity of waste methanol is increased, and the environmental pressure and the cost pressure are huge.

The reason why the recovered methanol is not used is that the recovered methanol still contains a small amount of impurities although being rectified, which affects the purity of the product medicine, and the impurity components are very complex and mainly comprise:

1. raw materials: erythromycin A, erythromycin B, erythromycin C, erythromycin D, erythromycin E, erythromycin F, azithromycin B, azithromycin C, azithromycin E and azithromycin F;

2. intermediate: erythromycin A oxime (Z), 6, 9-imino ether, azaerythromycin A, erythromycin A oxime (E), erythromycin C oxime (E), 9, 11-imino ether, erythromycin C6, 9-imino ether, erythromycin A lactam;

3. by-products: erythromycin-N-oxide, N-demethylerythromycin A, N-demethylazithromycin A, aminoazithromycin A, N-formyl-N-demethylazithromycin A, N-demethyl-N-benzenesulfonyl azithromycin, azithromycin N-oxide, 3 '-de (dimethylamino) -3', 4 '-dehydroazithromycin, O-tosyl erythromycin oxime, erythromycin Z oxime reefer, erythromycin Z-oxime-N, Azithromycin 11, 12-borate, N-dedimethyl N-formyl azithromycin A, propylazithromycin, 3' -N, N-dedimethyl amino-ketoazithromycin A, azithromycin 11, 12-borate;

4. degradation products: decladidine sugar azithromycin A, decladidine sugar azomycin, erythromycin 8, 9-anhydro-6, 9-hemiketal, erythromycin 6,9:9, 12-spiroketal;

the content of the impurities is extremely tiny, usually less than 1ppm, but the impurities have great influence on the quality of raw materials, the use of the recovered methanol in the synthesis of raw material medicaments is limited, and a chromatographic purification column for purifying the methanol for producing the azithromycin is provided for further purifying the methanol.

Disclosure of Invention

The invention aims to provide a chromatographic purification column for purifying methanol for azithromycin production, which adopts a column body with larger volume, spherical filler with larger particle size and narrower particle size distribution, wherein the spherical filler is porous polystyrene-divinylbenzene microspheres modified by functional groups, and the modified groups comprise sulfonic groups, amino groups, pyrrolidone, carbamido groups, carboxyl groups and the like; the chromatographic purification column is a combination of one or more porous polystyrene-divinylbenzene microspheres, and solves the problem that the existing chromatographic purification column for purifying the methanol for azithromycin production has poor purification effect on the methanol.

In order to solve the technical problems, the invention is realized by the following technical scheme:

the invention relates to a chromatographic purification column for purifying methanol for azithromycin production, which comprises a column body, wherein the column body is made of glass materials or stainless steel materials; the diameter of the column body is 20 cm-1 m, the height is 1 m-2 m, and the requirement of large-flux treatment for recycling medical solvents is met; one end of the column body is provided with a 24mm mark port, and the other end of the column body is provided with a tetrafluoro gate; a sand core filter plate is arranged in the column body; the spherical filler has larger grain diameter and narrower grain diameter distribution; the large volume and high flux inevitably bring overlarge pressure before the column, in order to reduce the pressure before the column, spherical fillers are required to be selected, and the spherical fillers also comprise spherical fillers in a sand core filter plate, wherein the particle size distribution variance of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 2mm and 2 cm; the spherical filler is porous polystyrene-divinylbenzene microspheres modified by functional groups.

Furthermore, the chromatographic purification columns are used in parallel or in series.

Further, the modified groups of the porous polystyrene-divinylbenzene microspheres include sulfonic acid groups, amino groups, pyrrolidone groups, urea groups, and carboxyl groups, and the spherical filler is a combination of one or more functional group-modified porous polystyrene-divinylbenzene microspheres.

Further, the chromatographic purification column is used for a purification method of the methanol for producing the azithromycin, and the method comprises the following steps:

step SS 01: the method comprises the following steps: when in use, the rectified methanol solvent flows through the chromatographic purification column from top to bottom, and the methanol purification solution flows out from the bottom end;

step SS 02: a washing step: when the total volume of the methanol solvent treated by the chromatographic purification column exceeds 1000 times of the volume of the chromatographic purification column, washing for 3-5 times by using an acetonitrile solvent-methanol solvent;

the washed chromatographic purification column can be reused.

Further, the outflow rate of the methanol purification solution in the step SS01 is controlled to be 3mL/min to 50 mL/min.

The invention has the following beneficial effects:

1. the invention can meet the requirement of large-flux treatment for recovering medical solvent by adopting a chromatography purification column with larger volume;

2. the spherical filler adopted by the invention has larger particle size and narrower particle size distribution, the large volume and high flux inevitably bring overlarge pressure before the column, and the spherical filler is selected, so that the pressure before the column can be reduced.

Of course, it is not necessary for any product in which the invention is practiced to achieve all of the above-described advantages at the same time.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a schematic structural diagram of a chromatographic purification column for purifying azithromycin production methanol according to the invention;

in the drawings, the components represented by the respective reference numerals are listed below:

1-cylinder, 2-sand core filter plate, 3-mark port and 4-tetrafluoro gate.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the description of the present invention, it is to be understood that the terms "upper", "lower", "thickness", "top", "length", "inner", "end", "bottom", and the like, indicate orientations or positional relationships for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referenced components or elements must have a particular orientation, be constructed and operated in a particular orientation, and thus, should not be construed as limiting the present invention.

The first embodiment is as follows:

a chromatography purification column for purifying methanol for azithromycin production is shown in figure 1 and comprises a column body 1, wherein the column body 1 is made of glass; in order to meet the requirement of large-flux treatment for recovering medical solvents, the diameter of the column body 1 is 50cm, and the height is 2 m; one end of the column body 1 is provided with a 24mm mark opening 3, and the other end is provided with a tetrafluoro gate 4; a sand core filter plate 2 is also arranged in the column body 1; the large volume and high flux inevitably bring overlarge pressure before the column, and in order to reduce the pressure before the column, spherical fillers are needed to be selected, so that the sand core filter plate 2 is filled with the spherical fillers, the variance of the particle size distribution of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 2mm and 1 cm; the spherical filler has larger grain diameter and narrower grain diameter distribution; the spherical filler is a functional group modified porous polystyrene-divinylbenzene microsphere, the modified group of the porous polystyrene-divinylbenzene microsphere comprises sulfonic acid group, amino group, pyrrolidone, carbamido group and carboxyl group, and the spherical filler is a combination of one or more functional group modified porous polystyrene-divinylbenzene microspheres.

As one embodiment provided by the present invention, preferably, the chromatographic purification column is used in a purification method of methanol for azithromycin production, which comprises the following steps:

step SS 01: the method comprises the following steps: when the device is used, the rectified methanol solvent flows through the chromatographic purification column from top to bottom, and the methanol purification solution flows out from the bottom end, wherein 8 chromatographic purification columns are used in series in the embodiment; controlling the outflow rate of the methanol purification solution at 50 mL/min;

step SS 02: a washing step: when the total volume of the methanol solvent treated by the chromatographic purification column exceeds 1000 times of the volume of the chromatographic purification column, washing for 5 times by using an acetonitrile solvent-methanol solvent; the washed chromatographic purification column can be reused. The purity of azithromycin produced by adopting the methanol solvent prepared by the method is 96.11%.

Example two:

a chromatographic purification column for purifying methanol for producing azithromycin comprises a column body 1, wherein the column body 1 is made of glass or stainless steel; in order to meet the requirement of large-flux treatment for recovering medical solvents, the diameter of the column body 1 is 1m, and the height is 2 m; one end of the column body 1 is provided with a 24mm mark opening 3, and the other end is provided with a tetrafluoro gate 4; a sand core filter plate 2 is also arranged in the column body 1; the large volume and high flux inevitably bring overlarge pressure before the column, and in order to reduce the pressure before the column, spherical fillers are needed to be selected and placed in the sand core filter plate 2, the particle size distribution variance of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 2mm and 10 mm; the spherical filler has larger grain diameter and narrower grain diameter distribution; the spherical filler is a functional group modified porous polystyrene-divinylbenzene microsphere, the modified group of the porous polystyrene-divinylbenzene microsphere comprises sulfonic acid group, amino group, pyrrolidone, carbamido group and carboxyl group, and the spherical filler is a combination of one or more functional group modified porous polystyrene-divinylbenzene microspheres.

The chromatographic purification column is used for purifying the methanol for producing the azithromycin, and the method comprises the following steps:

step SS 01: the method comprises the following steps: when in use, 5 chromatographic purification columns are connected in parallel and then connected in series with 3 chromatographic purification columns, the rectified methanol solvent flows through the 5 chromatographic purification columns connected in parallel from top to bottom and then flows into the 3 chromatographic purification columns connected in series, and the methanol purification solution flows out from the bottom end; controlling the outflow rate of the methanol purification solution at 15 mL/min;

step SS 02: a washing step: when the total volume of the methanol solvent treated by the chromatographic purification column exceeds 1000 times of the volume of the chromatographic purification column, washing for 5 times by using an acetonitrile solvent-methanol solvent; the washed chromatographic purification column can be reused. The purity of azithromycin produced by adopting the methanol solvent prepared by the method is 95.63 percent.

Example three:

a chromatographic purification column for purifying methanol for producing azithromycin comprises a column body 1, wherein the column body 1 is made of glass or stainless steel; in order to meet the requirement of large-flux treatment for recovering medicinal solvent, the diameter of the column body 1 is 1.5, and the height is 2 m; one end of the column body 1 is provided with a 24mm mark opening 3, and the other end is provided with a tetrafluoro gate 4; a sand core filter plate 2 is also arranged in the column body 1; the large volume and high flux inevitably bring overlarge pressure before the column, and in order to reduce the pressure before the column, spherical fillers are needed to be selected and placed in the sand core filter plate 2, the particle size distribution variance of the spherical fillers is less than or equal to 15 percent, and the average particle size is between 5mm and 50 mm; the spherical filler has larger particle size and narrower particle size distribution, and is the combination of pyrrolidone, carbamido and porous polystyrene-divinylbenzene microspheres modified by carboxyl functional groups.

The chromatographic purification column is used for purifying the methanol for producing the azithromycin, and the method comprises the following steps:

step SS 01: the method comprises the following steps: when in use, 10 chromatographic purification columns are connected in parallel for use, and after the rectified methanol solvent flows through the 10 chromatographic purification columns from top to bottom, the methanol purification solution flows out from the bottom end; controlling the outflow rate of the methanol purification solution at 10 mL/min;

step SS 02: a washing step: when the total volume of the methanol solvent treated by the chromatographic purification column exceeds 1000 times of the volume of the chromatographic purification column, washing for 5 times by using an acetonitrile solvent-methanol solvent; the washed chromatographic purification column can be reused. The purity of azithromycin produced by adopting the methanol solvent prepared by the method is 95.58 percent.

A chromatographic purification column for purifying methanol for azithromycin production can meet the requirement of large-flux treatment for medical solvent recovery by adopting a chromatographic purification column with larger volume; the adopted spherical filler has larger particle size and narrower particle size distribution, the large volume and high flux inevitably bring overlarge pressure before the column, and the spherical filler can reduce the pressure before the column.

In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best utilize the invention. The invention is limited only by the claims and their full scope and equivalents.