CN110590716A

CN110590716A - Preparation method of medicinal non-ionic surfactant

Info

Publication number: CN110590716A
Application number: CN201910921430.XA
Authority: CN
Inventors: 张阳洋; 肖舒文; 黄虎; 李盛; 曹金; 田佳; 吴琼; 冉文华; 李文文; 唐玉蛟; 冯文
Original assignee: HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPENTS CO Ltd
Current assignee: HUBEI GEDIAN HUMANWELL PHARMACEUTICAL EXCIPENTS CO Ltd
Priority date: 2019-09-27
Filing date: 2019-09-27
Publication date: 2019-12-20

Abstract

The invention discloses a preparation method of a medicinal non-ionic surfactant. The preparation method comprises the following steps: in the presence of alkali, carrying out etherification reaction on the compound I and ethylene oxide as follows to obtain a compound shown in a formula II; wherein the total water content of the alkali and the compound I is less than or equal to 0.01 percent, and the total water content is the mass percentage of the mass of water in the total mass of the alkali and the compound I; the water content of the ethylene oxide is less than or equal to 0.05 percent, and the water content is the mass percentage of water in the mass of the ethylene oxide. The pharmaceutical grade nonionic surfactant of the invention has low peroxide value, low moisture, low diethylene glycol content, low triethylene glycol content and no ethylene glycol and high molecular weight impurities.

Description

Preparation method of medicinal non-ionic surfactant

Technical Field

The invention relates to a preparation method of a medicinal non-ionic surfactant.

Background

Nonionic surfactants are those which do not ionize in aqueous solution and whose hydrophilic groups are composed predominantly of a certain number of oxygen-containing groups, typically ether and hydroxyl groups. Since the nonionic surfactant does not exist in an ionic state in the solution, it has high stability, is not easily affected by the presence of strong electrolytes, and is also not easily affected by acids and alkalis, and thus has various excellent properties such as washing, dispersing, emulsifying, foaming, wetting, solubilizing, antistatic, leveling, anti-corrosion, sterilizing, and protective colloids, and is widely used in various aspects such as textile, paper making, food, plastics, leather, fur, glass, petroleum, chemical fiber, medicine, pesticide, coating, dye, fertilizer, film, photography, metal processing, mineral separation, building materials, environmental protection, cosmetics, fire fighting, agriculture, and the like. Nonionic surfactants are classified by hydrophilic group and include both polyoxyethylene type and polyhydric alcohol type. Among them, polyoxyethylene sorbitol fatty acid ester is an important polyhydric alcohol type nonionic surfactant.

Polyoxyethylene sorbitol fatty acid ester is also called polysorbate, short for tween, is prepared by copolymerizing sorbitol and its dehydration product mono fatty acid ester with about 20 mol of ethylene oxide, is a non-ionic surfactant synthesized artificially, and is one of the common pharmaceutical adjuvants in pharmaceutical preparations. At present, two methods are used for synthesizing medical-grade polysorbate, one method is that sorbitol is esterified with fatty acid after dehydration and then polymerized with ethylene oxide to obtain the medical-grade polysorbate; the other is prepared by polymerizing ethylene oxide after the sorbitol loses water and esterifying with fatty acid.

Both of the above-mentioned preparation methods have the following disadvantages in common. The dehydration process of sorbitol produces a dark polymer of sugar alcohols which are difficult to remove and affect the color, saponification number and acid number of the final product. When ethylene oxide is polymerized, byproducts such as ethylene glycol, diethylene glycol and triethylene glycol are easily formed. For example, in the comparative examples of the present application, when the ethylene oxide and the content of water in the raw material were out of the ranges of the present application, the resultant products were higher in all of ethylene glycol, diethylene glycol, and triethylene glycol. Thirdly, the polymerization reaction of the ethylene oxide is exothermic, the reaction process is not well controlled, and the polymerization degree of the final product is unstable. Fourthly, after the preparation of the polysorbate, only basic operation procedures such as simple sedimentation, filtration and the like are usually required, and the large molecular weight substances generated by the reaction are difficult to remove. And fifthly, adding hydrogen peroxide for decoloring in the production process, so that the peroxide value of the product is larger and the water content is higher.

In order to overcome the defects of the preparation process of the medicinal polysorbate, a simple and effective method capable of improving the product quality and meeting the medicinal requirements needs to be developed.

Disclosure of Invention

The invention aims to overcome the defects that the product obtained by the preparation method of the medicinal nonionic surfactant in the prior art has high moisture and contains ethylene glycol, diethylene glycol, triethylene glycol and high-molecular-weight impurities, and provides the preparation method of the medicinal nonionic surfactant. The product prepared by the preparation method is colorless, low in peroxide value, low in moisture, low in diethylene glycol content and triethylene glycol content, and does not contain ethylene glycol and high-molecular-weight impurities.

The invention solves the technical problems through the following technical scheme.

The invention provides a preparation method of polyoxyethylene sorbitan fatty acid ester, which comprises the following steps: in the presence of alkali, carrying out etherification reaction on the compound I and ethylene oxide as follows to obtain a compound shown in a formula II;

wherein the total water content of the alkali and the compound I is less than or equal to 0.01 percent, and the total water content is the mass percentage of the mass of water in the total mass of the alkali and the compound I; the water content of the ethylene oxide is less than or equal to 0.05 percent, and the water content is the mass percentage of water in the mass of the ethylene oxide;

r is C₁₁H₂₃、C₁₅H₃₁、C₁₇H₃₅Or C₁₇H₃₃。

In the etherification reaction, the alkali may be an alkali metal hydroxide. The alkali metal in the alkali metal hydroxide can be lithium, sodium, potassium, rubidium or cesium. The alkali metal hydroxide may be potassium hydroxide and/or sodium hydroxide.

In the etherification reaction, the mass ratio of the alkali to the compound of formula I may be 0.002:1 to 0.01:1, or may be 0.002 to 0.003:1, such as 0.004:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, or 0.009: 1.

In the etherification reaction, the base may be mixed with the compound of formula I in the form of an aqueous solution. The concentration of the alkali can be 10-50%, and the concentration is the mass percentage of the mass of the alkali to the total mass of the solution, such as 20%, 30% and 40%.

When the base is mixed with the compound of formula I in the form of an aqueous solution, the base and the compound of formula I are preferably subjected to water removal treatment, more preferably high temperature vacuum water removal treatment. The vacuum degree of the water removal can be more than 0.099 MPa. The time for the high-temperature vacuum dehydration can be 1-3 h, such as 1.5h, 2.0h and 2.5 h. The temperature of the high-temperature vacuum dehydration can be 95-125 ℃, such as 100 ℃,105 ℃ and 110 ℃.

In the etherification reaction, the compound shown in the formula I can be sorbitan laurate, sorbitan palmitate, sorbitan stearate or sorbitan oleate.

In the etherification reaction, the mass ratio of the ethylene oxide to the compound of the formula I may be 1.9:1 to 4.8:1, for example, 2.0:1, 3.0:1, 3.5:1, 4.5: 1.

In the etherification reaction, the water content of the ethylene oxide can be 0.01-0.05%, and can also be 0.03-0.05%, wherein the water content is the mass percentage of water in the ethylene oxide.

In the etherification reaction, the ethylene oxide may be subjected to water removal treatment, preferably high temperature water removal. The temperature of the high-temperature water removal can be 100-125 ℃, such as 110 ℃, 115 ℃, 120 ℃ and 125 ℃. The time for high-temperature water removal can be 1-4 h, such as 1.5h, 2.0h, 3.0h and 4.0 h.

The temperature of the etherification reaction can be 100-125 ℃.

The process of the etherification reaction can be monitored by the pressure in the reaction kettle, and the pressure in the reaction kettle is lower than-0.06 Mpa as the end point of the reaction. The time of the etherification reaction may not be particularly limited.

In a preferred technical scheme of the invention, step 1, mixing the alkali and the compound of formula I in water to obtain a mixture A;

step 2, removing water from the mixture A obtained in the step 1 to obtain a mixture B; wherein the water content of the mixture B is less than or equal to 0.01 percent, and the water content is the mass percentage of water in the total mass of the mixture B;

and 3, carrying out etherification reaction on the mixture B obtained in the step 2 and the ethylene oxide to obtain a compound shown in the formula II.

In a preferable technical scheme of the invention, the mass ratio of the alkali to the compound of the formula I is 0.002-0.003: 1; the compound of the formula I is sorbitan palmitate or sorbitan oleate; the total water content of the alkali and the compound of the formula I is 0.01 percent, and the total water content is the mass percent of the mass of water in the total mass of the mixture B;

the water content of the ethylene oxide is 0.03-0.05%, and the water content is the mass percentage of water in the ethylene oxide.

The post-treatment of the preparation method can comprise the following steps: and (3) after the etherification reaction is finished, mixing the compound of the formula II prepared in the step (3) with an adsorbent, filtering and concentrating.

In the post-treatment step, the mass ratio of the adsorbent to the adsorbent may be 0.0001:1 to 0.05:1, for example, 0.0002:1, 0.001:1, 0.002:1, 0.005:1, 0.008:1, 0.01:1, 0.03:1, or 0.02: 1.

In the post-treatment step, the adsorbent preferably comprises the following raw materials in parts by weight: 30-100 parts of adsorbent 1, 0-70 parts of adsorbent 2 and 0-10 parts of adsorbent 3;

the adsorbent 1 is one or more of activated carbon, activated clay, attapulgite and diatomite; the adsorbent 2 is one or more of zeolite, molecular sieve, silica gel, iron aluminosilicate, hydrotalcite, crospovidone, croscarmellose sodium and macroporous resin; the adsorbent 3 is one or more of zinc powder, iron powder, alumina, magnesium oxide, barium oxide, zirconium oxide, hydrotalcite, calcium carbonate and magnesium carbonate;

more preferably, the feed additive comprises the following raw materials in parts by weight: 40-100 parts of adsorbent 1, 0-52 parts of adsorbent 2 and 0-10 parts of adsorbent 3; the adsorbent 1 is one or more of activated carbon, activated clay, attapulgite and diatomite; the adsorbent 2 is one or more of zeolite, molecular sieve, silica gel, iron aluminosilicate, hydrotalcite, crospovidone, croscarmellose sodium and macroporous resin; the adsorbent 3 is one or more of zinc powder, iron powder, alumina, magnesium oxide, barium oxide, zirconium oxide, hydrotalcite, calcium carbonate and magnesium carbonate;

further preferred are "70 parts of diatomaceous earth, 29 parts of iron aluminosilicate and 1 part of magnesium carbonate", "30 parts of attapulgite and 70 parts of zeolite", "92 parts of activated clay, 5 parts of crospovidone and 3 parts of zirconia", "activated carbon", "75 parts of activated clay, 23 parts of silica gel and 2 parts of alumina", "90 parts of activated carbon and 10 parts of zinc powder", "60 parts of activated clay, 34 parts of iron aluminosilicate and 6 parts of magnesium oxide", "80 parts of activated carbon, 15 parts of molecular sieve and 5 parts of barium oxide", "40 parts of attapulgite, 52 parts of hydrotalcite and 8 parts of calcium carbonate", "30 parts of diatomaceous earth, 60 parts of macroporous resin and 10 parts of magnesium aluminate", or "56 parts of attapulgite, 40 parts of hydrotalcite, 4 parts of calcium carbonate";

still more preferably, "activated carbon", "90 parts of activated carbon and 10 parts of zinc powder", "40 parts of attapulgite, 52 parts of hydrotalcite and 8 parts of calcium carbonate", or "56 parts of attapulgite, 40 parts of hydrotalcite, 4 parts of calcium carbonate".

In the adsorbent, the weight fractions of the adsorbent 2 and the adsorbent 3 may be both not 0.

In the adsorbent, the activated carbon may be activated carbon conventional in the art. The activated carbon is preferably medicinal activated carbon, and can also be activated carbon with 200 meshes. The activated carbon may be activated carbon produced by Shanghai activated carbon Co.

In the adsorbent, the activated clay can be activated clay which is conventional in the field. The activated clay is preferably food-grade activated clay, and may be preferably 100-mesh activated clay. The activated clay can also be the activated clay produced by Zhejiang Hongyu New materials GmbH.

In the adsorbent, the attapulgite can be attapulgite which is conventional in the field. The attapulgite is preferably food-grade attapulgite, and can also be preferably 100-mesh attapulgite. The attapulgite can also be produced by materials for Xuyi county Huafeng oil field drilling fluid.

In the adsorbent, the diatomite can be diatomite which is conventional in the field. The diatomite is preferably medicinal diatomite and can also be 200-mesh diatomite. The diatomite can be diatomite produced by chemical reagents of national drug group, Inc.

In the adsorbent, the zeolite may be a zeolite conventional in the art. The zeolite is preferably reagent grade zeolite, can also be preferably powdery zeolite powder, and can also be preferably 200-mesh zeolite. The zeolite can be the zeolite produced by national drug group chemical agent company Limited.

In the adsorbent, the molecular sieve may be a molecular sieve conventional in the art, preferably a 4A type molecular sieve. The molecular sieve can be a molecular sieve produced by Zibomia new material technology Co.

In the adsorbent, the silica gel can be silica gel which is conventional in the field, and 200-mesh silica gel is preferred. The silica gel can be produced by Qingdao ocean chemical industry Co.

In the adsorbent, the iron aluminosilicate can be conventional in the field. The iron aluminosilicate is preferably industrial-grade iron aluminosilicate, and can also be 100-mesh iron aluminosilicate. The iron aluminosilicate can be iron aluminosilicate produced by win-win water purification materials Limited company in the Gunay city.

In the adsorbent, the hydrotalcite may be one conventional in the art. The hydrotalcite is preferably medicinal grade hydrotalcite, and can also be 200-mesh hydrotalcite. The hydrotalcite may be hydrotalcite produced by Nordic lake pharmaceuticals, Inc.

In the adsorbent, the crospovidone may be one conventional in the art. The crospovidone is preferably medicinal grade crospovidone, and also can be 100-mesh crospovidone. The crospovidone can be produced by Hubei Pueraria Hubei Koufuye pharmaceutical adjuvant (LLC) company.

In the adsorbent, the croscarmellose sodium can be croscarmellose sodium which is conventional in the field. The croscarmellose sodium is preferably pharmaceutical-grade croscarmellose sodium, and also can be croscarmellose sodium with 200 meshes. The croscarmellose sodium can be produced by Hubei Pueraria Hubei pharmaceutical adjuvant Limited liability company.

In the adsorbent, the macroporous resin can be a macroporous resin which is conventional in the field. The macroporous resin is preferably a cationic exchange resin, and is more preferably a D001X 7 type cationic exchange resin. The macroporous resin can be macroporous resin produced by Tianjin Passion resin science and technology limited.

In the adsorbent, the zinc powder can be conventional in the art. The zinc powder is preferably reagent grade zinc powder, and can also be 200-mesh zinc powder. The zinc powder can be produced by national medicine group chemical reagent limited company.

In the adsorbent, the iron powder can be iron powder which is conventional in the field. The iron powder is preferably reagent-grade iron powder, and can also be 200-mesh iron powder. The iron powder can be iron powder produced by national drug group chemical reagent limited company.

In the adsorbent, the specifications of alumina, magnesia, barium oxide, zirconia, aluminum magnesium carbonate, calcium carbonate and magnesium carbonate are all reagent grade specifications, and the mesh number is 100 meshes. The alumina, the magnesia, the barium oxide, the zirconia, the aluminum magnesium carbonate, the calcium carbonate and the magnesium carbonate can be all produced by chemical reagents of national medicine group, Inc.

In the post-treatment step, the adsorbent may be subjected to an activation treatment. The temperature for activation may be a temperature that is conventional in the art, and is preferably 60 to 200 ℃, for example, 70 ℃,95 ℃,110 ℃, 120 ℃, 130 ℃, 140 ℃, 190 ℃. The activating time can be the time conventional in the art, and is preferably 1-12 h, such as 2h, 3h, 3.5h, 4h, 6h, 8h, 9h, 9.5h, and 10 h.

In the post-treatment step, the compound of formula II may be dissolved in a solvent and adsorbed by the adsorbent. The solvent can be one or more of water, alcohol solvents, ketone solvents, nitrile solvents and ester solvents. The alcohol solvent can be one or more of methanol, ethanol, propanol and isopropanol. The ketone solvent can be acetone and/or butanone. The nitrile solvent may be acetonitrile. The ester solvent can be ethyl acetate and/or butyl acetate. The amount of the solvent added can be 0 to 100 times of the amount of the compound of the formula II. The adsorption method can be a direct adsorption method or an indirect adsorption method. The heating temperature in the direct adsorption method can be 40-90 ℃. The adsorption time in the direct adsorption method is 2-10 h.

In the post-treatment step, the filtration may be plate-and-frame filtration, for example, a 0.22um filter membrane is used as a medium for filtration. The filtering device can be a funnel, a filter cylinder, a glass column or a stainless steel column. The concentration temperature can be 50-100 ℃. The vacuum degree of the concentration can be more than 0.09 MPa. The solvent residue in the concentrated compound of formula II may not exceed 0.1%, where the solvent residue is the mass percentage of the mass of the solvent in the compound of formula II to the mass of the solvent in the compound of formula II and the compound of formula II.

The preparation method of the sorbitol fatty acid ester can further comprise the following steps: in the presence of a catalyst, carrying out esterification reaction of sorbitol and fatty acid as shown in the following formula to obtain a compound shown in the formula I;

wherein R is C₁₁H₂₃、C₁₅H₃₁、C₁₇H₃₅Or C₁₇H₃₃。

The operation of the esterification reaction may be conventional in the art, and the following operations and conditions are particularly preferred in the present invention:

in the esterification reaction, the catalyst can be a base a and an acid a, the base a can be one or more of an alkali metal base (such as potassium hydroxide and sodium hydroxide), an alkali metal carbonate (such as sodium carbonate) and an alkali metal bicarbonate (such as sodium bicarbonate), and the acid a can be phosphoric acid and/or phosphorous acid.

Wherein the mass ratio of the alkali A to the sorbitol can be 0.002: 1-0.01: 1, such as 0.005:1 and 0.007: 1.

The concentration of the alkali A can be 10-40% of the aqueous solution, and the concentration is the mass percentage of the mass of the alkali A to the total mass of the solution, such as 20% and 30%.

Wherein the mass ratio of the acid A to the sorbitol can be 0.002: 1-0.01: 1, such as 0.003:1 and 0.005: 1.

The concentration of the acid A can be 10-40% of aqueous solution, and the concentration is the mass percentage of the mass of the acid A to the total mass of the solution, such as 20% and 30%.

In the esterification reaction, the sorbitol can be sorbitol powder and/or 70% sorbitol aqueous solution. The content of reducing sugar in the sorbitol can be less than 0.05 percent, and the total sugar content can be more than 0.3 percent.

In the esterification reaction, the fatty acid can be lauric acid, palmitic acid, stearic acid or oleic acid. The oleic acid can be common oleic acid with the content higher than 58 percent, and can also be high-purity oleic acid with the content higher than 98 percent.

In the esterification reaction, the mass ratio of the fatty acid to the sorbitol can be 1.0-2.5, such as 1.5 and 2.0.

In the esterification reaction, the esterification reaction can be carried out under the vacuum degree of more than 0.09 MPa.

In the esterification reaction, the temperature of the esterification reaction refers to the temperature in the stage heating process and the heat preservation reaction process, the stage heating process can be 80-180 ℃, and the heat preservation process can be 195-205 ℃.

In the esterification reaction, the time of the esterification reaction refers to the time in the stage heating process and the heat preservation reaction process, the time in the stage heating process can be more than or equal to 2 hours, and the time in the heat preservation process can be more than or equal to 6 hours.

In the esterification reaction, the compound of the formula I can be directly prepared into the compound of the formula II without post-treatment.

In the invention, the term "pharmaceutical grade" means meeting the national pharmaceutical standard specification.

In the present invention, "food grade" means meeting the national food standard or food industry standard.

In the present invention, "reagent grade" refers to conventional chemical reagents.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the sorbitol fatty acid ester has the advantages of low product color, less than 20ppm of diethylene glycol and triethylene glycol, and no ethylene glycol and high molecular weight impurities.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Specific information on the adsorbents used in the following examples is as follows:

the active carbon is in a medicinal grade specification, the mesh number is 200 meshes, and the manufacturer is Shanghai active carbon Co.

The activated clay is of food grade specification, the mesh number is 100 meshes, and the producer is Zhejiang Hongyu New Material Co.

The attapulgite is of a food-grade specification, the mesh number is 100 meshes, and the manufacturer is a Xuyi county Huafeng material for oil field drilling fluid.

The diatomite is of a pharmaceutical grade specification, the mesh number is 200 meshes, and a manufacturer is chemical reagent limited company of national drug group.

The zeolite is zeolite powder, is in a reagent grade specification, has a mesh number of 200 meshes, and is produced by a manufacturer of national drug group chemical reagent limited company.

The molecular sieve is a 4A type molecular sieve, and the manufacturer is Zibomia new material technology Co.

The silica gel is column chromatography silica gel with 200 meshes, and the manufacturer is Qingdao ocean chemical industry Co.

The iron aluminosilicate is in an industrial grade specification, the mesh number is 100 meshes, and a producer is a win-win water purification material company Limited in the consolidated market.

The hydrotalcite is of medicinal grade specification, the mesh number is 200 meshes, and the producer is Hubei Europe and Europe pharmaceutical Co.

The crospovidone is of a pharmaceutical grade specification, the mesh number is 100 meshes, and the manufacturer is Hubei Pueraria shop Fujian pharmaceutic adjuvant Limited liability company.

The croscarmellose sodium is in a pharmaceutical grade specification, the mesh number is 200 meshes, and a manufacturer is Hubei Pueraria shop Fujian pharmaceutic adjuvant Limited liability company.

The macroporous resin is D001 multiplied by 7 type cation exchange resin, and the producer is Tianjin Basff resin science and technology limited company.

The zinc powder is in a reagent grade specification, and the mesh number is 200 meshes. The iron powder is in a reagent grade specification, and the mesh number is 200 meshes. Alumina, magnesia, barium oxide, zirconia, aluminum magnesium carbonate, calcium carbonate and magnesium carbonate which are all in reagent grade specification, and the mesh number is 100 meshes. The above reagent manufacturers are all chemical reagents of national drug group, ltd.

EXAMPLE 1 Synthesis of Compounds of formula I

Example 1.1

70g of sodium hydroxide is prepared into 50 percent of aqueous solution by mass fraction, and 60g of phosphoric acid is prepared into 40 percent of aqueous solution by mass fraction for standby. 10kg of sorbitol solid and 20kg of lauric acid were added to a reaction vessel, and then the prepared aqueous sodium hydroxide solution and phosphoric acid solution were added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 3h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 6h at 195-205 ℃.

Example 1.2

80g of sodium bicarbonate is prepared into a 10% mass fraction aqueous solution, and 100g of phosphorous acid is prepared into a 20% mass fraction aqueous solution for standby. 10kg of sorbitol aqueous solution and 10kg of palmitic acid were added to a reaction kettle, and then the prepared sodium bicarbonate aqueous solution and phosphorous acid aqueous solution were added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 2.5h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 7.5h at 195-205 ℃.

Example 1.3

90g of sodium carbonate is prepared into a 40% mass fraction aqueous solution, and 20g of phosphoric acid is prepared into a 50% mass fraction aqueous solution for standby. 10kg of sorbitol solid and 35kg of stearic acid were added to a reaction kettle, and then the prepared sodium carbonate aqueous solution and phosphoric acid aqueous solution were added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 2h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 6.5h at 195-205 ℃.

Example 1.4

200g of potassium hydroxide is prepared into 20 mass percent aqueous solution, and 250g of phosphoric acid is prepared into 10 mass percent aqueous solution for standby. 50kg of sorbitol aqueous solution and 75kg of common oleic acid are added into a reaction kettle, and then the prepared potassium hydroxide aqueous solution and phosphoric acid aqueous solution are added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 4h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 7h at 195-205 ℃.

Example 1.5

800g of sodium hydroxide is prepared into 30 percent aqueous solution by mass fraction, and 400g of phosphorous acid is prepared into 30 percent aqueous solution by mass fraction for standby. 100kg of sorbitol aqueous solution and 200kg of high-purity oleic acid are added into a reaction kettle, and then prepared sodium hydroxide aqueous solution and phosphorous acid aqueous solution are added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 3h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 8.5h at 195-205 ℃.

Example 1.6

1kg of sodium bicarbonate is prepared into 10 percent aqueous solution by mass fraction, and 300g of phosphoric acid is prepared into 20 percent aqueous solution by mass fraction for standby. 100kg of sorbitol aqueous solution and 350kg of lauric acid are added into a reaction kettle, and then the prepared sodium bicarbonate aqueous solution and phosphoric acid aqueous solution are added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 2h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 9h at 195-205 ℃.

Example 1.7

400g of sodium hydroxide is prepared into a 40% mass fraction aqueous solution, and 1.4kg of phosphorous acid is prepared into a 40% mass fraction aqueous solution for standby. 200kg of sorbitol solid and 500kg of palmitic acid were added to a reaction vessel, and then the prepared aqueous sodium hydroxide solution and aqueous phosphorous acid solution were added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 3h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 8h at 195-205 ℃.

Example 1.8

600g of sodium carbonate is prepared into 20 percent aqueous solution by mass fraction, and 1.6kg of phosphorous acid is prepared into 10 percent aqueous solution by mass fraction for standby. 200kg of sorbitol aqueous solution and 700kg of stearic acid are added into a reaction kettle, and then the prepared sodium carbonate aqueous solution and phosphorous acid aqueous solution are added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 5h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 6.5h at 195-205 ℃.

Example 1.9

3kg of sodium carbonate is prepared into 50 percent of aqueous solution by mass fraction, and 4.5kg of phosphorous acid is prepared into 30 percent of aqueous solution by mass fraction for standby. 500kg of sorbitol solid and 1000kg of ordinary oleic acid were added to a reaction kettle, and then the prepared sodium carbonate aqueous solution and phosphorous acid aqueous solution were added. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 2.5h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 7h at 195-205 ℃.

Example 1.10

2.5kg of potassium hydroxide is prepared into 30 percent aqueous solution by mass fraction, and 3kg of phosphoric acid is prepared into 50 percent aqueous solution by mass fraction for standby. 500kg of sorbitol solids and 1250kg of high-purity oleic acid (98%) were added to the reaction vessel, followed by addition of the prepared aqueous potassium hydroxide solution and aqueous phosphoric acid solution. And vacuumizing the reaction kettle to ensure that the vacuum degree is more than 0.09 MPa. Starting heating, slowly heating to 180 ℃ within 3.5h after heating to 80 ℃, then heating, and carrying out heat preservation reaction for 7.5h at 195-205 ℃.

EXAMPLE 2 Synthesis of Compound of formula II

Example 2.1

100g of sodium hydroxide was prepared as a 20% aqueous solution for future use. 100kg of the compound of the formula I (example 1.1) and aqueous sodium hydroxide are mixed in a reaction vessel to give a mixture, the reaction vessel is evacuated to a vacuum of more than 0.099MPa and the temperature is maintained at 100 ℃ for 1.5 h. The water content of the detected mixture is 0.01 percent through detection. 190kg of ethylene oxide is heated to 100 ℃ in a gasification kettle, and heat preservation is carried out for 2h for removing water. The water content of the ethylene oxide was found to be 0.02%. And then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 100 ℃ until the pressure in the reaction kettle is lower than-0.08 MPa.

Example 2.2

200g of potassium hydroxide was made into a 10% aqueous solution for future use. 100kg of the compound of formula I (example 1.7) and aqueous potassium hydroxide solution were added to a reaction vessel and mixed to obtain a mixture, the reaction vessel was evacuated to a vacuum degree of more than 0.099MPa, the temperature was maintained at 105 ℃ for 2 hours, and the water content of the mixture was determined to be 0.01%. 200kg of ethylene oxide is heated to 115 ℃ in a gasification kettle, heat preservation is carried out for 3 hours to remove water, and the water content of the ethylene oxide is detected to be 0.03 percent. And then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 115 ℃ until the pressure in the reaction kettle is lower than-0.06 MPa.

Example 2.3

600g of sodium hydroxide are made up into a 30% aqueous solution for future use. 200kg of the compound of formula I (example 1.8) and aqueous sodium hydroxide solution were added to a reaction vessel and mixed to obtain a mixture, the reaction vessel was evacuated to a vacuum degree of more than 0.099MPa, the temperature was maintained at 95 ℃ for 3 hours, and the water content of the mixture was determined to be 0.01%. 600kg of ethylene oxide is heated to 120 ℃ in a gasification kettle, the temperature is kept for 1.5h for removing water, and the water content of the ethylene oxide is detected to be 0.03%. And then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 120 ℃ until the pressure in the reaction kettle is lower than-0.07 MPa.

Example 2.4

200g of potassium hydroxide was made into a 10% aqueous solution for future use. 200kg of the compound of formula I (example 1.4) and an aqueous solution of potassium hydroxide are added into a reaction kettle and mixed to obtain a mixture, the reaction kettle is vacuumized to ensure that the vacuum degree is more than 0.099Mpa, the temperature is kept at 110 ℃ for 1h, and the water content of the mixture is detected to be 0.01%. 700kg of ethylene oxide is heated to 125 ℃ in a gasification kettle, heat preservation is carried out for 4h to remove water, and the water content of the ethylene oxide is detected to be 0.03%. And then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 125 ℃ until the pressure in the reaction kettle is lower than-0.06 MPa.

Example 2.5

1kg of sodium hydroxide was made into a 30% aqueous solution for future use. 500kg of the compound of the formula I (example 1.5) and aqueous sodium hydroxide are added to a reaction vessel and mixed to obtain a mixture, the reaction vessel is evacuated to a vacuum degree of more than 0.099MPa, the temperature is maintained at 105 ℃ for 3 hours, and the water content of the mixture is detected to be 0.01%. 2250kg of ethylene oxide was heated to 105 ℃ in a gasification kettle and kept at the temperature for 2h to remove water, as detected, the water content of ethylene oxide was 0.05%. Then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 105 ℃ until the pressure in the reaction kettle is lower than-0.07 MPa.

Example 2.6

1.5kg of potassium hydroxide was made into a 25% aqueous solution for future use. 500kg of the compound of formula I (example 1.10) and aqueous potassium hydroxide solution were added to a reaction vessel and mixed to obtain a mixture, the reaction vessel was evacuated to a vacuum degree of more than 0.099MPa, and the temperature was maintained at 100 ℃ for 2.5 hours, and the water content of the mixture was determined to be 0.01%. 2400kg of ethylene oxide is heated to 110 ℃ in a gasification kettle, heat preservation is carried out for 1 hour to remove water, and the water content of the ethylene oxide is detected to be 0.04%. And then pressing the dehydrated ethylene oxide into a reaction kettle, and reacting at 110 ℃ until the pressure in the reaction kettle is lower than-0.06 MPa.

Example 3

Mixing diatomite, ferric aluminosilicate and magnesium carbonate according to the mass ratio of 70:29:1, and heating and activating at 150 ℃ for 3.5h for later use.

10kg of the compound of the formula II (example 2.1) are dissolved in 300kg of propanol. 10g of activated adsorbent was loaded into the funnel. And (3) leaching the adsorbent by using the compound solution shown in the formula II, and collecting the leaching solution. Distilling the solvent under reduced pressure at 90 deg.C with the vacuum degree of 0.09 MPa. When the residual solvent content is less than 0.1%, the distillation under reduced pressure is stopped.

Example 4

Mixing attapulgite and zeolite according to a mass ratio of 30:70, and heating and activating at 120 ℃ for 6 hours for later use.

10kg of the compound of the formula II (example 2.2) are dissolved in 1000kg of ethanol. 80g of activated adsorbent was loaded onto a stainless steel column. And (3) leaching the adsorbent by using the compound solution shown in the formula II, and collecting the leaching solution. Distilling the solvent under reduced pressure at 60 deg.C, and keeping vacuum degree greater than 0.09 MPa. When the residual solvent content is less than 0.1%, the distillation under reduced pressure is stopped.

Example 5

Mixing activated clay, crospovidone and zirconia according to the mass ratio of 92:5:3, and heating and activating at 95 ℃ for 9.5 hours for later use.

50kg of the compound of the formula II (example 2.3) are taken and dissolved in 2500kg of water. Adding 100g of activated adsorbent, adsorbing at 90 deg.C for 10 hr, and filtering to remove adsorbent. The filtrate was collected. And distilling the solvent under reduced pressure at the temperature of 80 ℃ of the filtrate, and keeping the vacuum degree to be more than 0.09 MPa. When the residual water content is less than 0.1%, the vacuum distillation is stopped.

Example 6

The activated carbon is heated and activated for 12 hours at 100 ℃ to be used. 50kg of the compound of the formula II (example 2.4) are dissolved in 4000kg of isopropanol.

500g of activated sorbent was loaded into the cartridge. And (3) leaching the adsorbent by using the compound solution shown in the formula II, and collecting the leaching solution. Distilling the solvent under reduced pressure at 100 deg.C, and keeping vacuum degree greater than 0.09 MPa. When the residual solvent content is less than 0.1%, the distillation under reduced pressure is stopped.

Example 7

Mixing activated clay, silica gel and alumina according to the mass ratio of 75:23:2, and heating and activating at 190 ℃ for 10 hours for later use.

2.5kg of activated adsorbent was loaded into a glass column. 50kg of the compound of the formula II (example 2.5) were rinsed directly with the adsorbent and the rinse was collected.

Example 8

Mixing activated carbon and zinc powder according to a mass ratio of 90:10, and heating and activating at 70 ℃ for 2h for later use.

100kg of the compound of the formula II (example 2.6) are dissolved in 200kg of acetone. Adding 3kg of activated adsorbent, adsorbing at 30 deg.C for 4 hr, and filtering to remove adsorbent. The filtrate was collected. And distilling the solvent under reduced pressure at the temperature of 50 ℃ of the filtrate, and keeping the vacuum degree to be more than 0.09 MPa. When the residual water content is less than 0.1%, the vacuum distillation is stopped.

Example 9

Mixing activated clay, iron aluminosilicate and magnesium oxide according to the mass ratio of 60:34:6, and heating and activating at 200 ℃ for 8h for standby.

100kg of the compound of the formula II (example 2.1) are dissolved in 1000kg of butyl acetate. Adding 0.5kg of activated adsorbent, adsorbing at 70 deg.C for 6 hr, and filtering to remove adsorbent. The filtrate was collected. And distilling the solvent under reduced pressure at the temperature of 80 ℃ of the filtrate, and keeping the vacuum degree to be more than 0.09 MPa. When the residual water content is less than 0.1%, the vacuum distillation is stopped.

Example 10

Mixing activated carbon, a molecular sieve and barium oxide according to a mass ratio of 80:15:5, and heating and activating at 140 ℃ for 4h for later use.

200kg of the compound of the formula II (example 2.2) are dissolved in 200kg of methanol. Adding 4kg of activated adsorbent, adsorbing at 50 deg.C for 8 hr, and filtering to remove adsorbent. The filtrate was collected. And distilling the solvent under reduced pressure at the temperature of 50 ℃ of the filtrate, and keeping the vacuum degree to be more than 0.09 MPa. When the residual water content is less than 0.1%, the vacuum distillation is stopped.

Example 11

Mixing attapulgite, hydrotalcite and calcium carbonate according to the mass ratio of 40:52:8, and heating and activating at 130 ℃ for 9 hours for later use.

500kg of the compound of the formula II (example 2.3) are dissolved in 3750kg of ethyl acetate. 100g of activated sorbent was loaded into the cartridge. And (3) leaching the adsorbent by using the compound solution shown in the formula II, and collecting the leaching solution. Distilling the solvent under reduced pressure at 60 deg.C, and keeping vacuum degree greater than 0.09 MPa. When the residual solvent content is less than 0.1%, the distillation under reduced pressure is stopped.

Example 12

Mixing diatomite, macroporous resin and hydrotalcite according to the mass ratio of 30:60:10, and heating and activating at 110 ℃ for 3h for later use.

500kg of the compound of the formula II (example 2.4) are dissolved in 4000kg of acetonitrile. Adding 250g of activated adsorbent, adsorbing at 80 deg.C for 2 hr, and filtering to remove adsorbent. The filtrate was collected. And distilling the solvent under reduced pressure at 70 ℃ of the filtrate, and keeping the vacuum degree to be more than 0.09 MPa. When the residual water content is less than 0.1%, the vacuum distillation is stopped.

Example 13

Mixing attapulgite, hydrotalcite and calcium carbonate according to the mass ratio of 56:40:4, and heating and activating at 60 ℃ for 1h for later use.

500kg of the compound of the formula II (example 2.6) are dissolved in 2000kg of butanone. 50g of activated sorbent was loaded into the cartridge. And (3) leaching the adsorbent by using the compound solution shown in the formula II, and collecting the leaching solution. Distilling the solvent under reduced pressure at 90 deg.C with the vacuum degree of 0.09 MPa. When the residual solvent content is less than 0.1%, the distillation under reduced pressure is stopped.

Comparative examples 1 to 3

Referring to the synthesis of example 2.6, the mixture and ethylene oxide were reacted under the water content conditions in the table below.

	Comparative example 1	Comparative example 2	Comparative example 3
				Water content of the mixture	0.1％	0.85％	0.01％
Water content of ethylene oxide	1.5％	0.01％	1.50％

Comparative examples 4 to 6

Referring to the synthesis of example 2.6, the mixture was reacted with ethylene oxide at the water content conditions in the table below. Purification of the compound of formula II was carried out as in example 3, synthesis of the compound of formula I was carried out as in example 1.1,

detection method and apparatus

The method of water content measurement refers to the general rule of the chinese pharmacopoeia 2015 edition (0832 first method).

The acid value, saponification value and peroxide value are measured according to the general rule (0713) of the Chinese pharmacopoeia 2015 edition.

The chroma is measured by a chroma meter, and is calibrated by a platinum-cobalt chroma standard solution, and the color of < 2.0' is lighter than that of standard yellow No. 2 liquid.

Ethylene glycol, diethylene glycol and triethylene glycol are detected by gas chromatography, and the method refers to the method of 'ethylene glycol, diethylene glycol and triethylene glycol' under the fourth polysorbate 80 (for injection) variety in the 2015 edition of Chinese pharmacopoeia. The lower limit of detection by gas chromatography was 0.1 ppm.

Impurities having a molecular weight of 2000 or more were determined by ESI-MS (electrospray mass spectrometry).

The residue on ignition is measured according to the general rules of the Chinese pharmacopoeia 2015 edition (0841).

The water content was measured according to the first method of the general rules of the Chinese pharmacopoeia 2015 edition (0832).

The residual solvent is determined according to the general rules of the Chinese pharmacopoeia 2015 edition (0861).

TABLE 1 acid number and saponification number of the compounds of the formula I

	Acid value	Saponification number
			Example 1.1	5	164
Example 1.2	4	145
			Example 1.3	4	152
Example 1.4	3	153
			Example 1.5	2	150
Example 1.6	7	162
			Example 1.7	6	141
Example 1.8	9	150
			Example 1.9	2	152
Example 1.10	4	146

TABLE 2 physicochemical parameters of the Compounds of formula II

Remarking: the lower limit of detection of "not detected" in Table 2 was 0.1 ppm.

TABLE 3 physicochemical values of the products obtained after treatment with the treating agent

Remarking: the lower limit of detection of "not detected" in Table 3 was 0.1 ppm; in the table, "- -" indicates that no test was performed.

Claims

1. The preparation method of the polyoxyethylene sorbitan fatty acid ester is characterized by comprising the following steps: in the presence of alkali, carrying out etherification reaction on the compound I and ethylene oxide as follows to obtain a compound shown in a formula II;

wherein the total water content of the alkali and the compound I is less than or equal to 0.01 percent, and the total water content is the mass percentage of water in the total mass of the alkali and the compound I; the water content of the ethylene oxide is less than or equal to 0.05 percent, and the water content is the mass percentage of water in the mass of the ethylene oxide;

r is C₁₁H₂₃、C₁₅H₃₁、C₁₇H₃₅Or C₁₇H₃₃。

2. The process according to claim 1, wherein in the etherification, the base is an alkali metal hydroxide;

and/or in the etherification reaction, the mass ratio of the alkali to the compound of the formula I is 0.002: 1-0.01: 1;

and/or, in the etherification reaction, the alkali is mixed with the compound of the formula I in the form of aqueous solution;

and/or, in the etherification reaction, the compound of the formula I is sorbitan laurate, sorbitan palmitate, sorbitan stearate or sorbitan oleate;

and/or in the etherification reaction, the mass ratio of the ethylene oxide to the compound of the formula I is 1.9: 1-4.8: 1;

and/or in the etherification reaction, the water content of the ethylene oxide is 0.01-0.05%, and the water content is the mass percentage of water in the ethylene oxide;

and/or, in the etherification reaction, the ethylene oxide is subjected to high-temperature water removal;

and/or, in the etherification reaction, the temperature of the etherification reaction is 100-125 ℃.

3. The process according to claim 2, wherein in the etherification reaction, when the alkali is an alkali metal hydroxide, the alkali metal hydroxide is potassium hydroxide and/or sodium hydroxide;

and/or in the etherification reaction, the mass ratio of the alkali to the compound of the formula I is 0.002: 1-0.003: 1;

and/or in the etherification reaction, when the alkali is mixed with the compound shown in the formula I in the form of an aqueous solution, the concentration of the alkali is 10-50%, and the concentration is the mass percentage of the mass of the alkali to the total mass of the solution;

and/or, in the etherification reaction, when the alkali is mixed with the compound of the formula I in the form of aqueous solution, the alkali and the compound of the formula I are subjected to high-temperature vacuum water removal;

and/or in the etherification reaction, the water content of the ethylene oxide is 0.03-0.05%, and the water content is the mass percentage of water in the ethylene oxide;

and/or in the etherification reaction, when the ethylene oxide is subjected to high-temperature dehydration, the temperature of the high-temperature dehydration is 100-125 ℃;

and/or in the etherification reaction, when the ethylene oxide is subjected to high-temperature water removal, the high-temperature water removal time is 1-4 h.

4. The process according to claim 3, wherein in the etherification reaction,

in the etherification reaction, when the alkali and the compound shown in the formula I are subjected to high-temperature vacuum water removal; the vacuum degree of the high-temperature vacuum dewatering is more than 0.099 Mpa;

and/or in the etherification reaction, when the alkali and the compound of the formula I are subjected to high-temperature vacuum water removal, the high-temperature vacuum water removal time is 1-3 h;

and/or in the etherification reaction, when the alkali and the compound of the formula I are subjected to high-temperature vacuum water removal, the temperature of the high-temperature vacuum water removal is 95-125 ℃.

5. The method of claim 1, wherein step 1, mixing the base and the compound of formula I in water to provide mixture a; step 2, removing water from the mixture A obtained in the step 1 to obtain a mixture B; wherein the water content of the mixture B is less than or equal to 0.01 percent, and the water content is the mass percentage of water in the total mass of the mixture B; step 3, carrying out etherification reaction on the mixture B obtained in the step 2 and the ethylene oxide to obtain a compound shown in a formula II;

or the mass ratio of the alkali to the compound of the formula I is 0.002-0.003: 1; the compound of the formula I is sorbitan palmitate or sorbitan oleate; the total water content of the alkali and the compound of the formula I is 0.01 percent, and the water content is the mass percentage of water in the total mass of the mixture B; the water content of the ethylene oxide is 0.03-0.05%, and the water content is the mass percentage of water in the ethylene oxide.

6. The preparation method according to any one of claims 1 to 5, wherein the post-treatment of the preparation method comprises the following steps: and (3) after the etherification reaction is finished, mixing the compound of the formula II prepared in the step (3) with an adsorbent, filtering and concentrating.

7. The preparation method of claim 6, wherein the adsorbent comprises the following raw materials in parts by weight: 30-100 parts of adsorbent 1, 0-70 parts of adsorbent 2 and 0-10 parts of adsorbent 3; the adsorbent 1 is one or more of activated carbon, activated clay, attapulgite and diatomite; the adsorbent 2 is one or more of zeolite, molecular sieve, silica gel, iron aluminosilicate, hydrotalcite, crospovidone, croscarmellose sodium and macroporous resin; the adsorbent 3 is one or more of zinc powder, iron powder, alumina, magnesium oxide, barium oxide, zirconium oxide, hydrotalcite, calcium carbonate and magnesium carbonate;

8. The preparation method according to claim 6, wherein the mass ratio of the adsorbent to the compound of formula II is 0.0001:1 to 0.05: 1;

and/or, when the treating agent is an adsorbent, the adsorbent is subjected to activation treatment; preferably, the activation temperature is 60-200 ℃; the activation time is 1-12 h;

and/or, when the treating agent is an adsorbent, the compound of the formula II is dissolved in a solvent and then adsorbed by the adsorbent;

and/or, the filtration is plate-frame filtration;

and/or the concentration temperature is 50-100 ℃;

and/or the vacuum degree of the concentration is more than 0.09 MPa.

9. The method of claim 1, further comprising the steps of: in the presence of a catalyst, carrying out esterification reaction of sorbitol and fatty acid as shown in the following formula to obtain a compound shown in the formula I;

10. the preparation method of claim 9, wherein in the esterification reaction, the catalyst is a base A and an acid A, the base A is one or more of an alkali metal base, an alkali metal carbonate and an alkali metal bicarbonate, and the acid A is phosphoric acid and/or phosphorous acid;

and/or, in the esterification reaction, the fatty acid is lauric acid, palmitic acid, stearic acid or oleic acid;

and/or in the esterification reaction, the mass ratio of the fatty acid to the sorbitol is 1.0-2.5;

and/or in the esterification reaction, the esterification reaction is carried out under the vacuum degree of more than 0.09 MPa.