JPS6129962B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing carboxymethylethyl cellulose.

Conventionally, a method for obtaining cellulose ethers is known by treating cellulose with caustic alkali to obtain alkali cellulose, and then reacting with an etherifying agent such as an alkyl halide.
In this case, the product quality is greatly influenced by the uniformity of the distribution of substituted ether groups in the resulting cellulose ether. In other words, when the distribution of substituted ether groups is uniform, the cellulose ethers can be of high quality with excellent solubility in solvents and film-forming properties during film production, but when the distribution is uneven, It is known that it can only be of low quality, such as poor dissolution state and poor film forming properties when forming a film by coating. By the way, etherification agents such as alkyl halides not only react with celluloses but also cause side reactions with the coexisting water, so in order to increase their effective utilization rate, a high concentration is required to prepare the alkali cellulose used for etherification. Normally, a concentrated aqueous solution of caustic alkaline is used, but on the other hand, this reduces the uniform dispersion of alkali into cellulose and tends to produce cellulose ether with uneven distribution of ether groups. It has its drawbacks.
Furthermore, since the reaction system is carried out in a heterogeneous system consisting essentially of an aqueous layer, an organic layer, or a solid phase (cellulosic raw material), that is, it is a heterogeneous reaction, the distribution of ether groups is nonuniform. It has the fatal disadvantage of easily producing cellulose ether.

For this reason, as a method for producing cellulose ether with a uniform distribution of ether groups, for example,
A method of producing uniform alkali cellulose and using it as a raw material as described in Japanese Patent Publication No. 53-12954, Japanese Patent Publication No. 53-8751, and splitting solid alkali during the etherification reaction described in U.S. Patent No. 2254249. Although methods of adding such compounds have been reported, the reaction operations are complicated, and furthermore, the negative factors in heterogeneous reactions have not been fundamentally improved.

In recent years, attempts have been made to react in aprotic polar solvents such as dimethyl sulfoxide to compensate for the drawbacks of such heterogeneous reactions, but the solvents are expensive and it is difficult to recover the solvent after the reaction is completed. Since the dissolving power is low, there are problems such as the inability to increase the concentration of cellulose, and it is difficult to say that this method is industrially advantageous.

Therefore, if high-quality cellulose ether can be produced at low cost through simple reaction operations, it can be said to have extremely great industrial value.

The present inventors have conducted intensive studies on a method for producing high-grade cellulose ether that does not have the above-mentioned drawbacks, and have found that it can be easily achieved by using a quaternary salt as a phase transfer catalyst during the etherification reaction. The present invention has now been completed.

That is, the gist of the present invention is to prepare carboxymethylcellulose with the general formula 1 in the presence of a caustic alkali aqueous solution and an organic solvent that does not substantially dissolve water but dissolves the etherifying agent. (In the formula, M is nitrogen or phosphorus, R ₁ , R ₂ , R ₃ , R ₄ are alkyl or benzyl having 1 to 4 carbon atoms, and X ^- is an anion). This is a method for producing carboxymethylethyl cellulose, which is characterized by reacting an agent.

That is, by carrying out the present invention, one of the reaction substrates is solubilized in the other phase due to the effect of the phase transfer catalyst in the etherification reaction of carboxymethylcellulose, which is originally a heterogeneous system.In other words, the reaction field becomes more uniform, and the substituted ether High-quality carboxymethylethyl with a more uniform distribution of groups is obtained.

In addition, it not only solves the problem of poor reproducibility of conventional etherification reactions based on heterogeneous reactions, but also uses a caustic alkali aqueous solution with a concentration of 40% to less than 50% as the alkali used in the etherification reaction. It is sufficient to use it at the initial stage, and there is no need to add solid alkali during the reaction, which is extremely advantageous in terms of workability and process control. Of course, even if the alkali is present in an amount greater than the above concentration, the objective of uniformity of the reaction can be achieved.

Furthermore, as mentioned above, the reaction becomes more uniform, so
It becomes possible to reduce the amount of etherification agent required for the reaction and shorten the reaction time, making it possible to easily obtain high-grade carboxymethylethyl cellulose at a lower cost. Furthermore, when a water-soluble cellulose ether such as carboxymethyl cellulose is further reacted with an etherification agent such as an alkyl halide, conventionally the system often solidifies during the reaction, causing a decrease in heat conduction and resulting in local overheating. However, by carrying out the present invention, these drawbacks can be resolved, and coloring can be avoided, for example when manufacturing carboxymethylethyl cellulose used as a coating agent. The present invention is an extremely advantageous method when such problems arise.

The method of carrying out the present invention is to first prepare carboxymethylcellulose in an appropriate amount in a concentration range of 40% or more and less than 50% so that the amount of caustic alkali is 1 to 4 times the mole and the water content is 1 to 10 times the mole per hydroxyl group possessed by the carboxymethylcellulose. Treat with an alkaline aqueous solution. Furthermore, solid caustic alkali may be added. After mercerizing carboxymethylcellulose by immersing it in an excess aqueous alkaline solution, the aqueous alkali solution may be removed by means such as squeezing so that the above ratio is achieved, or alternatively, the mercerization step can be omitted and the mercerization step can be omitted. An alkaline aqueous solution may be added so as to achieve the above quantitative ratio range.

In the case of immersion mercerization of carboxymethylcellulose, conventional methods for mercerization of celluloses can be fully applied.

The etherification reaction of carboxymethylcellulose treated with an alkali under the above conditions is advantageously carried out using an etherification agent in an amount of 1.2 times the mole or more of the hydroxyl groups possessed by the cellulose and a quaternary salt represented by the general formula (1). Catalytic amount, i.e. 0.1 to
This is accomplished by adding 20 mol % (preferably 1 to 10 mol %) and heating to an appropriate temperature while stirring, without substantially dissolving the water.
An organic solvent that dissolves the etherification agent and is stable for the reaction, such as aliphatic hydrocarbons or aromatic hydrocarbons, is added in an amount 2 to 6 times (weight ratio) to the raw material carboxymethyl cellulose. It is preferable to do so.

In the present invention, the quaternary salt represented by general formula (1) is used as a phase transfer catalyst as described above.
The amount added is sufficient as a catalytic amount, and the purpose is completely different from the conventionally known reaction in an aqueous quaternary ammonium base solution in the etherification of cellulose with dialkyl sulfuric acid, etc., and is economical. It is easy to understand that there is no need to point out that it is much more advantageous from a general point of view.

The present invention will be explained in more detail.

The carboxymethyl cellulose referred to in the present invention also includes salt forms such as its sodium salt. Furthermore, it is not limited by the origin of cellulose or the method for producing carboxymethylcellulose.

The phase transfer catalyst used in the present invention is a quaternary ammonium salt or phosphonium salt represented by the general formula (1), such as tetraethylammonium chloride, tetraethylphosphonium chloride, benzyltriethylammonium chloride, etc. Quaternary salts in which an alkyl or aralkyl group is bonded as an organic group are preferred.

Note that the quaternary salt used as an etherification catalyst in the present invention includes those that are not quaternary salts at the time of addition, as long as they ultimately take the form of quaternary salts in the reaction system.

That is, general formula 2 (In the formula, M is nitrogen or phosphorus, R ₅ , R ₆ , R ₇ are hydrogen or alkyl having 1 to 4 carbon atoms, or benzyl) is added during the etherification reaction, and the etherification agent It is made to exist as a quaternary salt in the reaction system by reaction with

For example, in the case of quaternary ammonium salts, those that ultimately react with excess etherification agent to form quaternary ammonium salts, such as ammonia and various primary It is possible to use secondary and tertiary amines.

In general formula (1), X is preferably a halogen ion, particularly chlorine, and bromine, but when using an agent that generates halogen ions during the reaction, such as an alkyl halide, as an etherification agent, hydroxyl Even if it is a group, a sulfuric acid residue, etc., there is no problem because the halogen ions generated in large quantities during the reaction are exchanged.

As the etherification agent in the present invention, it is preferable to use an alkyl halide (provided that the halogen is chlorine or bromine) at a mole or more of 1.2 times or more based on the hydroxyl group possessed by carboxymethyl cellulose.

As the reaction solvent, as mentioned above, an organic solvent that does not substantially dissolve water, but which dissolves the etherifying agent and is stable for the reaction, such as aliphatic hydrocarbons, aromatic hydrocarbons, or ,
It is preferable to add halogenated hydrocarbons such as dichloromethane and trichloroethane that are stable under the reaction conditions in an amount of 2 to 6 times (weight ratio) to carboxymethylcellulose, but of course, instead of such organic solvents, etherification as described above can be used. Even if the agent is used in large excess, there is nothing contrary to the spirit of the present invention.

In the present invention, carboxymethyl ethyl cellulose produced by the reaction of carboxymethyl cellulose and ethyl halide has an ethoxyl group substitution degree (DS) of 1 to 2.4 carboxymethyl group substitution degree as described in Japanese Patent No. 649218.
Such compounds having a molecular weight of 0.3 to 1.2 are useful as enteric protective coatings for solid pharmaceuticals. When such carboxymethylethylcellulose is produced according to a conventionally known method, since the method is fundamentally a heterogeneous reaction, the reproducibility of the reaction is often poor, and the quality of the obtained product is poor, especially Although it has been recognized that it has poor solubility in coating solvents and that it is difficult to form a continuous film during coating, carboxymethylethylcellulose obtained by carrying out the present invention is a toluene-ethanol-based, dichloromethane-methanol-based, It has excellent solubility in common coating solvents such as ethyl cellosolve-acetone and ethyl cellosolve-acetone, and the resulting coating is strong and forms a completely continuous coating.

Next, the method of the present invention will be explained using examples, but the present invention is not limited to the following examples unless the gist thereof is exceeded.

Note that parts and % in the examples mean parts by weight and % by weight unless otherwise specified.

In addition, various test methods in the following examples are as follows.

(1) Solubility This is a visual observation of the behavior when 1 g of each sample was dissolved in 19 g of the solvent.

(2) Transmittance A 1% methanol solution of the sample was prepared and measured using a photoelectric colorimeter (using a 20 mm cuvette) using methanol as a blank.

(3) Film-forming property The solution obtained in (1) was applied onto a glass plate and dried at 80°C for 30 minutes to form a film with a thickness of approximately 50μ.

(4) Disintegration The dried glass plate coated with the sample in (3) was immersed in the first fluid (artificial gastric fluid) and second fluid (artificial intestinal fluid) in the Japanese Pharmacopoeia (9th revision) disintegration test at 37±1.
This is the result of observing the behavior with the naked eye after immersion at a temperature of °C.

Example 1 100 g of dissolving pulp, 67.5 g of 40% aqueous sodium hydroxide solution and (ethanol/toluene = 65/
35) Pour 200g of mixed solvent into a crushing kneader,
The pulp was soaked for 1 hour at 20-25°C and then ground while stirring for 1.5 hours while maintaining the temperature at 23-25°C.

Next, 30 g of monochloroacetic acid was added, and the mixture was stirred at a temperature of 23 to 25°C for 50 minutes, and then reacted with stirring at a temperature of 50 to 65°C for 2 hours. Next, most of the solvent was distilled and recovered, and the obtained carboxymethylcellulose was dried in a hot air dryer at 40 to 50°C until the water content reached 9.2%.

This carboxymethyl cellulose, 270 g of 48% sodium hydroxide aqueous solution, 400 g of toluene and 4.25 g of tetraethylammonium chloride were added to 1
While stirring vigorously in the autoclave, 255 g of ethyl chloride was added under reduced pressure. After the preparation was completed, the mixture was reacted at about 110°C for 20 hours with stirring.
After cooling, the granular carboxymethylethylcellulose sodium salt obtained by collecting most of the solvent by suction filtration was poured into 500g of water, and the pH was adjusted to about 2 with 12N sulfuric acid to obtain the granular carboxymethylethylcellulose. Obtained. 50-60
After thoroughly washing with warm water at 70°C, it was dried in a hot air dryer at 70°C until a constant weight was obtained, yielding 107 g of a purified product.

The purified product has a carboxymethyl group DS of 0.42 and an ethoxyl group DS of 2.18, and this product contains ethanol-water (80:20), toluene-ethanol (80:20), and methylene chloride-ethanol (50:50). The solution was completely dissolved in each of the above, and no insoluble matters were observed, resulting in a transparent homogeneous solution. The dried films obtained from these solutions were clear, colorless, smooth and strong.

This film did not show any change even when immersed for 2 hours in the artificial gastric fluid described in the Japanese Pharmacopoeia, and it quickly dissolved in the artificial intestinal fluid.

Example 2 Carboxymethylation and ethylation reactions were carried out under exactly the same conditions as in Example 1, except that 11 g of tetraethylammonium bromide was used as a phase transfer catalyst in the ethylation reaction of carboxymethyl cellulose.

The obtained carboxymethylethylcellulose was treated in the same manner as in Example 1 to obtain 105 g of purified carboxymethylethylcellulose.

The DS of the carboxymethyl group in this product is 0.42,
The DS of the ethoxyl group was 2.35, and the results of solubility, film-forming and disintegration tests were as good as in Example 1.

Example 3 400 g of dissolving pulp, 270 g of 40% aqueous sodium hydroxide solution and ethanol-toluene (35:
65) 800g of mixed solvent and 120g of monochloroacetic acid
Carboxymethylcellulose was obtained by reacting under the same conditions as in Example 1. This material was washed with a mixed solvent of methanol and water (80:20) at 70°C until the pH of the washing solution reached approximately 7, and then dried at 70°C until the water content was 5.5%. Obtained.

80 g of this purified carboxymethylcellulose (purity equivalent) was immersed in 400 g of a 48% sodium hydroxide aqueous solution, kept at 25°C for 20 hours, and then mercerized. The weight ratio of CMC was compressed to 3.7, and the amount of sodium hydroxide and water content were adjusted.

This mercerized carboxymethyl cellulose,
400g of benzene, and 3.21g of triethylamine
was charged into an autoclave, and 170.5 g of ethyl chloride was added under reduced pressure while stirring vigorously. After the preparation was completed, the mixture was reacted at 105 to 120°C for 20 hours while stirring. After cooling, most of the solvent was distilled and recovered, 240 g of pure water was added, and the mixture was stirred at room temperature for 2 hours. Next, the pH of the system was adjusted to about 2 with 12N sulfuric acid to obtain granular carboxymethylethylcellulose. This product was treated in the same manner as in Example 1 to obtain 86 g of purified carboxymethylethyl cellulose.

The DS of the carboxymethyl group of this product was 0.42, and the DS of the ethoxyl group was 2.05, and the results of the solubility, film forming and disintegration tests were as good as in Example 1.

Example 4 80 g of the same purified carboxymethyl cellulose used in Example 3 (purity equivalent) and 216 g of a 48% aqueous sodium hydroxide solution were placed in a grinding kneader and stirred at 30°C to 46°C for 45 minutes to mercerize the carboxymethylcellulose. It became.

Using this mercerized carboxymethylcellulose as a raw material, the reaction temperature was 105-115℃ and the reaction time was 18℃.
The reaction and post-treatment were carried out under the same conditions as in Example 3, except for the time difference, to obtain 90.4 g of purified carboxymethylethyl cellulose.

The DS of the carboxymethyl group in this product is 0.42,
The DS of the ethoxyl group was 2.10, and the results of solubility, film-forming and disintegration tests were as good as in Example 1.

Example 5 The reaction and post-treatment were carried out under the same conditions as in Example 4, except that 6.2 g of a 30% trimethylamine aqueous solution was used instead of triethylamine and 320 g of toluene was used as the reaction solvent, and 90 g of purified carboxymethylethyl cellulose was obtained.

The DS of the carboxymethyl group in this product is 0.42,
The DS of the ethoxyl group was 2.08, and the results of solubility, film-forming and disintegration tests were as good as in Example 1.

Example 6 Benzylamine 5.6 instead of trimethylamine
g, and the reaction temperature was increased to 96-114℃, the reaction time was increased to 20.5℃.
All under the same conditions as Example 5 except for the time,
After reaction and work-up, 75.2 g of purified carboxymethylethylcellulose was obtained.

The DS of the carboxymethyl group of this product is 0.422,
The DS of the ethoxyl group was 1.91, and the results of the solubility film-forming and disintegration tests were good.

Example 7 Cellulose was prepared under the same conditions as in Example 1, except that 200 g of dissolving pulp, 174.4 g of 40% aqueous sodium hydroxide solution, 70 g of monochloroacetic acid, and 800 g of ethanol-toluene (65:35) mixed solvent were used. After carboxymethylation, purified carboxymethyl cellulose having a water content of 5.0% was obtained in the same manner as in Example 3.

100g of this purified carboxymethyl cellulose
(purity equivalent) and 48% sodium hydroxide aqueous solution
Carboxymethyl cellulose was mercerized by charging 270 g into a crushing kneader under the same conditions as in Example 4.

This mercerized cellulose, 350g of toluene,
and 6.75 g of 30% trimethylamine aqueous solution 1
Place in autoclave and add ethyl chloride
220g was added under reduced pressure.

Next, the mixture was reacted at 105 to 115° C. for 18 hours with stirring, and was further post-treated in the same manner as in Example 3 to obtain 98 g of purified carboxymethylethyl cellulose.

The DS of the carboxymethyl group in this product is 0.60,
The DS of the ethoxyl group was 1.95, and the results of solubility, film-forming and disintegration tests were as good as in Example 1.

Comparative Example 1 Example 3 except that 80 g of purified carboxymethylcellulose (purity equivalent) used in Example 3 was used, and no triethylamine was added.
Mercerized carboxymethyl cellulose and ethyl chloride were reacted under the same conditions. After cooling, the reaction solution was filtered to obtain a sodium salt of carboxymethylethylcellulose solidified into a gum. This product was treated in the same manner as in Example 1, and the carboxymethyl group had a DS of 0.42 and the ethoxyl group had a DS of 0.42.
75.2 g of purified carboxymethylethylcellulose with a DS of 1.95 was obtained.

This is ethanol-water (80:20), toluene-ethanol (80:20), methylene chloride-
When dissolved in ethanol (50:50), a considerable amount of insoluble matter was observed in each, and the solution was also colored yellow-orange.

The dried films obtained from these solutions did not form completely continuous films, but were discontinuous films with scales or cracks.

Examples 1 to 7 of films obtained from this product
In order to obtain a continuous film equivalent to that of , it was necessary to add 10% or more of triacetin as a plasticizer to carboxymethylethylcellulose.

Comparative Example 2 A sodium salt of carboxymethylethyl cellulose obtained under the same conditions as in Example 1 except that no tetraethylammonium chloride was added was solidified into a gum-like form as in Comparative Example 1. This product was treated in the same manner as in Example 1 to obtain 95 g of purified carboxymethylethyl cellulose.

The DS of the carboxymethyl group in this product is 0.42,
The DS of ethoxyl group is 2.05, and ethanol-
Water (80:20), toluene-ethanol (80:20)
When dissolved in methylene chloride-ethanol (50:50), a considerable amount of insoluble matter was observed, and the solution was colored yellow-orange.

The dry films obtained from these solutions are also relatively 1
The results were as unsatisfactory as shown in .

In addition, the films obtained from this product were used in Examples 1-
In order to obtain a continuous film equivalent to that of Example 7, it was necessary to add 10% or more of triacetin as a plasticizer to carboxymethylethylcellulose.

Example 8 Treated under the same conditions as Example 3, resulting in a moisture content of 6.0%.
Purified carboxymethyl cellulose was obtained.

80g of this purified carboxymethyl cellulose (purity equivalent) and 216g of 42% sodium hydroxide aqueous solution
was charged into a grinding kneader and stirred at 30 to 46°C for 45 minutes to mercerize carboxymethylcellulose.

This mercerized cellulose, 400 g of toluene, and 5.8 g of a 30% trimethylamine aqueous solution were placed in one autoclave, and 170.5 g of ethyl chloride was added under reduced pressure while stirring vigorously.

After the preparation was completed, the mixture was reacted at 100 to 113°C for 18 hours while stirring. This product was treated in the same manner as in Example 3 to obtain purified carboxymethylethylcellulose 84.0%
I got g.

The DS of the carboxymethyl group in this product is 0.42,
The DS of the ethoxyl group was 2.10, and the results of solubility, film-forming and disintegration tests were also good as in Example 1.

Example 9 The same purified carboxymethyl cellulose used in Example 8 was treated in the same manner as in Example 8 except that 208 g of a 45% aqueous sodium hydroxide solution was used to mercerize the carboxymethyl cellulose.

Next, the same procedure as in Example 8 was carried out except that the reaction temperature was 105 to 120° C. and the reaction time was 17 hours, to obtain 85.0 g of purified carboxymethylethyl cellulose.

The DS of the carboxymethyl group in this product is 0.42,
The DS of the ethoxyl group was 2.18, and the results of solubility, film-forming and disintegration tests were also good as in Example 1.

Example 10 200 g of dissolving pulp, 162 g of 40% aqueous sodium hydroxide solution, and 800 g of ethanol/toluene (65:35) mixed solvent were charged into a grinding type kneader, and 20 to 25
℃ for 1 hour, and then pulverized with stirring for 1.5 hours while maintaining the temperature at 23-25°C. Next, 61 g of monochloroacetic acid was added and stirred at a temperature of 23 to 25°C for 50 minutes, and then reacted with stirring at 50 to 65°C for 2 hours. The reaction product was washed with a methanol/water (80:20) mixture at 70°C until the pH of the washing solution was approximately 7, and then further heated at 70°C.
It was dried at ℃ until the moisture content became 5.5% to obtain purified carboxymethyl cellulose.

100g of this purified carboxymethyl cellulose
(purity equivalent) and 48% sodium hydroxide aqueous solution
Pour 200g into a grinding kneader and heat to 45℃ at 30℃ to 48℃.
The mixture was stirred for a minute to mercerize the carboxymethyl cellulose.

To this mercerized carboxymethyl cellulose, 350 g of toluene and 7.3 g of 30% triethylamine aqueous solution.
g and 36 g of granular sodium hydroxide were charged, and 212 g of ethyl chloride was added under reduced pressure while stirring vigorously. After the preparation is complete, heat at 102 to 115℃ for 18 hours while stirring.
Allowed time to react.

After cooling this material, most of the solvent was distilled and recovered.
300 g of pure water was added and stirred at room temperature for 2 hours. then
Granular carboxymethylethyl cellulose was obtained by adjusting the pH of the system to about 2 with 12N sulfuric acid.
After thoroughly washing this with warm water at 50 to 60°C and drying it at 70°C, purified carboxymethylethyl cellulose is produced.
Obtained 115g. The carboxymethyl group of this
DS is 0.50, DS of ethoxyl group is 2.20, and the results of solubility, film forming and disintegration tests are as in Example 1.
It was as good as in the case of .

The carboxymethylethyl cellulose obtained in Example 1 and Comparative Example 2 was mixed with methylene chloride/
A 5% solution was prepared by dissolving in ethanol (50:50). Apply this material on a glass plate and heat it for 30 minutes at 70℃.
A film with a thickness of about 50 μm was obtained by drying for 1 minute.

This film was examined using a scanning electron microscope (JSM) manufactured by JEOL Ltd.
Electron micrographs (x2000) taken using the -U3 type in a conventional manner are shown in Figs. 1 and 2, respectively.

As is clear from both figures, the uniformity of the film obtained by carrying out the present invention is extremely good, but the film obtained in the comparative example has a nearly laminated structure with poor uniformity.

[Brief explanation of the drawing]

FIG. 1 is an electron micrograph of a film made using carboxymethylethyl cellulose obtained in Example 1 and FIG. 2 in Comparative Example 2.

Claims (1)

[Claims] 1. Carboxymethylcellulose is prepared by formula 1 in the presence of an aqueous caustic solution and an organic solvent that does not substantially dissolve water and dissolves the etherifying agent. (In the formula, M is nitrogen or phosphorus, R ₁ , R ₂ , R ₃ , R ₄ are alkyl or benzyl having 1 to 4 carbon atoms, and X ^- is an anion). A method for producing carboxymethyl cellulose, which comprises reacting it with ethyl chloride. 2 General formula 2 (In the formula, M is nitrogen or phosphorus, R ₅ , R ₆ , R ₇ are hydrogen or alkyl having 1 to 4 carbon atoms, or benzyl) is added during the etherification reaction to form an ethyl halide. 2. The method for producing carboxymethylethylcellulose according to claim 1, wherein the carboxymethylethyl cellulose is present as a quaternary salt in the reaction system. 3. The method for producing carboxymethylethyl cellulose according to claim 1 or 2, wherein the aqueous caustic alkali solution is an aqueous sodium hydroxide solution with a concentration of 40% or more and less than 50%.