CN102702363A - Preparation method of hydroxypropyl methylcellulose acetate succinate in novel solvent system - Google Patents

Abstract

The invention discloses a preparation method of hydroxypropyl methylcellulose acetate succinate in a novel solvent system. The preparation method comprises the steps as follows: adding hydroxypropyl methylcellulose, inert solvents, esterifying agents and catalyzers into a reaction vessel, and heating and stirring for esterification; lowering the temperature to the room temperature after esterification, and adding precipitants for settling out products; washing the products, and distilling to separate the inert solvents, thereby obtaining hydroxypropyl methylcellulose acetate succinate. According to the invention, the preparation method has the advantages that the reaction condition is mild, the reaction rate is high, the solvents can be recovered, and the post processing for the products is simple.

Description

Preparation method of hydroxypropyl methylcellulose acetate succinate under novel solvent system

technical field

The invention belongs to the field of cellulose ether ester synthesis, in particular to a preparation method of hydroxypropyl methylcellulose succinate in a novel solvent system.

Background technique

Hydroxypropyl methylcellulose acetate succinate is white to pale yellow powder or granules, with a true density of 1.27-1.30g/cm ³ , easily soluble in acetone, methanol, ethanol-dichloroethane, and ethanol-water Mixed solvent, insoluble in ether and water.

Hydroxypropyl methylcellulose acetate succinate is a mixed diester of non-ionic cellulose ethers, which contains four groups of hydroxypropoxyl, methoxyl, acetyl, and succinyl, so its The properties show different solubility properties with different group content. Hydroxypropoxy is a hydrophilic group, and its presence makes the cellulose ether ester water-soluble; methoxy is a hydrophobic group, and its presence makes it soluble in certain organic solvents. It is beneficial to the preparation of the coating film; an appropriate amount of acetyl group increases the flexibility of the coating film, but reduces the solubility; while the presence of succinyl group can improve the solubility of the film, but the acid resistance and water resistance decrease.

Therefore, hydroxypropyl methylcellulose acetate succinate has a wide range of uses. Its most important use is as an enteric coating material. It has the characteristics of plasticity, good film-forming performance, and fast dissolution rate. A small amount of plasticizer can improve the strength of the coating film and improve the appearance of the drug. Therefore It also reduces the harm of plasticizers to the human body. Moreover, it can also prepare drug slow-control reagents and slow-control pellets, which play an important role in the targeted release of drugs. Due to its inherent group types, it has good solubility in the upper small intestine, increasing the Drugs are absorbed in the small intestine. In recent years, it has also been used in solid polymer carriers, slow and controlled release frameworks, etc., making it play an important role in excipients.

At present, the method for synthesizing hydroxypropyl methylcellulose acetate succinate both at home and abroad, no matter adopting a feeding method or a secondary feeding method reaction, mainly adopts a reaction system with acetic acid as a medium and sodium acetate as a catalyst. The operation of the one-time feeding method reaction is: firstly, the raw material hydroxypropyl methylcellulose, the solvent acetic acid, the esterification agent acetic anhydride and succinic anhydride, and the catalyst sodium acetate are simultaneously added to the reaction vessel, and the mixture is heated at 60-110°C. After reacting for 2-10 hours, add a large amount of water to completely precipitate the product, wash several times, and filter under normal pressure until the eluate is neutral, and then dry the product to obtain hydroxypropylmethylcellulose acetate succinate . When preparing cellulose ether ester by the secondary feeding method, the cellulose derivatives are reacted in the acetic acid solution for a period of time to dissolve or disperse the cellulose derivatives in the solution so as to activate the reactive groups on the cellulose, and then add the catalyst And esterification agent, maintain this temperature for reaction, after a period of time, use deionized water to complete the reaction, the product is precipitated, filtered, washed several times, and dried to obtain the target product.

However, in the process of industrialization, there are many disadvantages in using the original system, such as strong corrosion to equipment, non-recyclable solvent, and poor storage performance of products due to residual acetic acid. Moreover, the product is more cumbersome in the post-treatment stage, and it needs to be washed with a large amount of water to meet the requirements. At the same time, the product is embedded in acetic acid, which seriously affects the quality and performance of the product.

Contents of the invention

The purpose of the present invention is to overcome the above-mentioned shortcoming that uses acetic acid system to exist in the prior art, and the preparation method of hydroxypropyl methylcellulose acetate succinate under a kind of feasible novel solvent system is provided for industrialized production. The invention selects a new organic reaction solvent system, that is, adopts acetone as a medium and 4-dimethylaminopyridine as a catalyst to carry out the reaction, and after the end, the post-treatment of the product is simple. The method of the present invention is simpler and cheaper than the conventional method. Through the new reaction system, the amount of acetic acid remaining in the product is reduced, the organic solvent can be recovered, and the cost is saved. At the same time, it also has the advantages of less catalyst consumption, mild reaction conditions, and easy reaction. The time is short, the yield is high, and the advantages of less side reactions.

To achieve the above object, the present invention provides multiple technical solutions as follows.

The preparation method of hydroxypropyl methylcellulose acetate succinate under novel solvent system comprises the following steps:

(1) Esterification: Add hydroxypropyl methylcellulose, inert solvent, esterification agent, and catalyst into the reaction vessel, heat and stir for esterification;

(2) Product extraction: After the esterification reaction is completed and the temperature is lowered to normal temperature, a precipitant is added to precipitate the product, the product is washed, and the inert solvent is separated by distillation to obtain hydroxypropylmethylcellulose acetate succinate.

Preferably, the inert solvent described in step (1) is more than one of the hydrophilic organic solvent acetone, 1,4-dioxane, and dimethylformamide, and the inert solvent and hydroxypropyl methyl The dosage ratio of base cellulose is 4-50 mL/g.

Preferably, the esterifying agent described in step (1) is acetic anhydride and succinic anhydride, the ratio of the amount of acetic anhydride to hydroxypropyl methylcellulose is 0.3-30 in mL/g, the acetic anhydride and The weight ratio of hydroxypropyl methylcellulose is 0.3-30.

Preferably, the acetic anhydride and succinic anhydride in step (1) are added simultaneously or one of them is added first to participate in the reaction, and then the other is added.

，其中R₁和R₂为C_nH_2n+1，n=为正整数，用量为羟丙基甲基纤维素质量的0.01~5倍。 Preferably, the catalyst described in step (1) is

, wherein R ₁ and R ₂ are C _n H _2n+1 , n= is a positive integer, and the dosage is 0.01 to 5 times the mass of hydroxypropyl methylcellulose.

Preferably, the n=1, that is, the catalyst is 4-dimethylaminopyridine.

Preferably, the temperature of the esterification reaction in step (1) is 50-130° C., the reaction time is 2-24 hours, and the pressure is 1-10 bar.

Preferably, the reaction vessel in step (1) is a high-pressure reactor or a three-necked flask.

Preferably, the precipitating agent described in step (2) is deionized water, dilute hydrochloric acid or dilute sulfuric acid, and the amount ratio of the precipitating agent to the esterification product is 20-1000 mL/g.

Preferably, deionized water or boiling water is used for the washing in step (2).

Preferably, the solvent used in the washing described in step (2) is deionized water, and the temperature of the washing water is 85-100°C.

Compared with the prior art, the present invention has the following beneficial effects: the present invention adopts novel solvent systems such as acetone, and 4-dimethylaminopyridine is the method for catalyst preparation of hydroxypropyl methylcellulose succinate, which can reduce reaction The required temperature and shorter reaction time; stable esterification reaction, less side reactions, less catalyst consumption; low reaction temperature, short reaction time, simple post-treatment of reaction products, less residual acetic acid content; in the production process, energy consumption Low, the solvent can be recycled, the corrosion to equipment is reduced, the overall cost is low, and it is in line with the direction of energy saving and emission reduction.

Description of drawings

Figure 1 is the infrared spectrum of hydroxypropylmethylcellulose acetate succinate (8.2% acetyl content, 12.5% succinyl content).

Detailed ways

The present invention will be described in further detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto.

Example 1

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 80mL of solvent acetone, 8g of esterification agent succinic anhydride and 40mL of acetic anhydride, and 0.5g of catalyst 4-dimethylaminopyridine into the autoclave. The mixed system was reacted for 2 hours under the conditions of a pressure of 2 bar and a temperature of 85° C., and then the reaction was stopped.

(2) Product extraction: After the esterification reaction is completed, lower it to normal temperature, add an appropriate amount of water to the product, precipitate the product, wash it with boiling water for 3 times until it is odorless, dry it at 60°C, and distill and separate acetone to obtain the product After testing, the content of acetyl group is 8.2% (mass fraction, the same below), and the content of succinyl group is 12.5% (mass fraction, the same below).

Example 2

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 80mL of solvent acetone, 9g of succinic anhydride, and 1g of catalyst 4-dimethylaminopyridine into the autoclave. React at 85°C for 30 minutes, then add 40 mL of acetic anhydride into the autoclave, keep the original reaction temperature constant, continue the reaction for 2 hours, and then stop the reaction.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of dilute hydrochloric acid to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 8.9% and the succinyl content was 13.2%.

Example 3

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 500mL of solvent acetone, 8g of succinic anhydride, 1g of catalyst 4-dimethylaminopyridine, and 60mL of acetic anhydride into the autoclave. It was reacted for 4 hours under the conditions of 5 bar and 95° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 9.4% and the succinyl content was 11.9%.

Example 4

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 40mL of solvent acetone, 8g of succinic anhydride, 5g of catalyst 4-dimethylaminopyridine, and 60mL of acetic anhydride into the autoclave. It was reacted for 7 hours under the conditions of 2 bar and 105° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 11.4% and the succinyl content was 14.5%.

Example 5

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 80mL of solvent acetone, 6g of succinic anhydride, and 0.1g of catalyst 4-dimethylaminopyridine into the autoclave. The pressure of the mixed system is 7bar, The reaction was carried out at 85° C. for 1 h, and then 50 mL of acetic anhydride was added into the autoclave to keep the original reaction temperature constant. After continuing the reaction for 7 h, the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of dilute hydrochloric acid to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 7.5% and the succinyl content was 10.7%.

Example 6

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 200mL, succinic anhydride 15g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 50 g, 100 mL of acetic anhydride, the mixed system was reacted for 5 h under the conditions of pressure of 6 bar and temperature of 100 ° C, and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 12.6% and the succinyl content was 14.5%.

Example 7

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 90mL, succinic anhydride 11g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 2 g, 60 mL of acetic anhydride, and the mixed system was reacted for 24 h at a pressure of 10 bar and a temperature of 85° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 10.9% and the succinyl content was 13.3%.

Example 8

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 80mL, succinic anhydride 9g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 0.5g, the mixed system was reacted at a pressure of 4bar and a temperature of 50°C for 2h, and then 30mL of acetic anhydride was added to the autoclave to keep the original reaction temperature constant, and the reaction was continued for 10h before stopping the reaction.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of dilute hydrochloric acid to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 9.0% and the succinyl content was 12.3%.

Example 9

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 40mL, succinic anhydride 8g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 2 g, 60 mL of acetic anhydride, and the mixed system was reacted for 5 h at a pressure of 2 bar and a temperature of 130° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 10.3% and the succinyl content was 13.6%.

Example 10

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 120mL of solvent acetone, 3g of succinic anhydride, 2g of catalyst 4-dimethylaminopyridine, and 70mL of acetic anhydride into the autoclave. It was reacted for 9 hours under the conditions of 4 bar and 85° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , distilled and separated acetone to obtain the target product, the acetyl content was 9.3% and the succinyl content was 8.9%.

Example 11

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 250mL, succinic anhydride 30g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 4 g, 100 mL of acetic anhydride, the mixed system was reacted for 9 h under the conditions of pressure of 3 bar and temperature of 75 ° C, and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 10.2% and the succinyl content was 15.1%.

Example 13

(1) Esterification reaction: Add raw material hydroxypropyl methylcellulose 10g, solvent acetone 150mL, succinic anhydride 10g, catalyst 4-dimethylaminopyridine into a high-pressure reactor (US PARR Pressure Stirred Reactor-4500 series) 4 g, 10 mL of acetic anhydride, and the mixed system was reacted for 5 h at a pressure of 2 bar and a temperature of 115° C., and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 7.7% and the succinyl content was 9.4%.

Example 14

(1) Esterification reaction: Add 10g of raw material hydroxypropyl methylcellulose, 80mL of solvent acetone, 12g of succinic anhydride, and catalyst 4-dimethylaminopyridine into a high-pressure reactor (PARR pressure stirred reactor-4500 series in the United States) 6 g, 270 mL of acetic anhydride, the mixed system was reacted for 5 h under the conditions of pressure of 4 bar and temperature of 100 ° C, and the reaction was stopped.

(2) Product purification: After the esterification reaction, cool down to room temperature, add an appropriate amount of water to the container to precipitate the product, filter under normal pressure, wash the product with boiling water for 3 times until it is odorless, and then dry it in an oven at 60°C , acetone was separated by distillation to obtain the target product, and the acetyl content was 13.3% and the succinyl content was 11.8%.

The infrared spectrogram of above-mentioned example (as example 1) product is as shown in Figure 1, as can ^be seen from Figure 1, product has strong absorption peak at wavenumber 1750cm ^-1 place, and this is the absorption peak of carbonyl; The absorption peak at 1454cm ^-1 is the stretching vibration peak of -CH ₃ ; the absorption peak at 2941cm ^-1 is the stretching vibration peak of -CH ₃ ; the absorption peak at 3473cm ^-1 is the absorption of -OH peak. From this, it was confirmed that the target product was synthesized.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, and combinations made without departing from the spirit and principle of the present invention , simplification, all should be equivalent replacement methods, and are all included in the protection scope of the present invention.

Claims (10)

1. the preparation method of hydroxypropyl methylcellulose acetate succinate under novel solvent system, its feature comprises following operation steps: (1) Esterification: Add hydroxypropyl methylcellulose, inert solvent, esterification agent, and catalyst into the reaction vessel, heat and stir for esterification; (2) Product extraction: After the esterification reaction is completed and the temperature is lowered to normal temperature, a precipitant is added to precipitate the product, the product is washed, and the inert solvent is separated by distillation to obtain hydroxypropylmethylcellulose acetate succinate. 2. The preparation method according to claim 1, characterized in that, the inert solvent described in step (1) is a hydrophilic organic solvent acetone, 1,4-dioxane, dimethylformamide More than one, the amount ratio of the inert solvent to hydroxypropyl methylcellulose is 4-50 mL/g. 3. The preparation method according to claim 1, characterized in that, the esterification agent described in step (1) is acetic anhydride and succinic anhydride, and the dosage ratio of acetic anhydride to hydroxypropyl methylcellulose is 0.3 The unit of -30 is mL/g, and the weight ratio of acetic anhydride to hydroxypropyl methylcellulose is 0.3-30. 4. The preparation method according to claim 3, characterized in that, the acetic anhydride and succinic anhydride in step (1) are added at the same time or one of them is added first to participate in the reaction, and then the other is added. 5. The preparation method according to claim 1, characterized in that, the catalyst described in step (1) is

, wherein R ₁ and R ₂ are C _n H _2n+1 , n= is a positive integer, and the dosage is 0.01 to 5 times the mass of hydroxypropyl methylcellulose. 6. The preparation method according to claim 5, characterized in that said n=1, that is, said catalyst is 4-dimethylaminopyridine. 7 . The preparation method according to claim 1 , wherein the temperature of the esterification reaction in step (1) is 50-130° C., the reaction time is 2-24 hours, and the pressure is 1-10 bar. 8. The preparation method according to claim 1, wherein the reaction vessel in step (1) is a high-pressure reactor or a three-necked flask. 9. The preparation method according to claim 1, characterized in that, the precipitant in step (2) is deionized water, dilute hydrochloric acid or dilute sulfuric acid, and the dosage ratio of the precipitant to the esterification product is 20- 1000 mL/g. 10. The preparation method according to any one of claims 1-9, characterized in that deionized water or boiling water is used for the washing in step (2).

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