JPH09309873A - New production method of camostat mesylate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method for producing camostat mesylate in an industrially good yield. SOLUTION: This method for producing camostat mesylate comprises performing an esterification reaction of 4-guanidinobenzoic acid or a reactive derivative thereof with 4-hydroxyphenylacetic acid N,N-dimethylcarbamoylmethyl ester in the presence of dicyclohexylcarbodiimide, treating with adding p- toluenesulfonic acid in an amount of or more than a theoretical amount by the chemical equivalence into the reaction system during the esterification reaction stage or at the completion of the esterification reaction, isolating the produced camostat as a p-toluene sulfonic acid salt, treating with an aqueous solution of sodium hydrogen carbonate for converting to camostat carbonate, performing a purification of the salt and then treating the salt with methanesulfonic acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for enhancing the activity of camostat mesilate [4- (4-guanidinobenzoyloxy) phenylacetic acid N, N-dimethylcarbamoylmethyl ester methanesulfonate] known as a therapeutic agent for pancreatitis. The present invention relates to a method for producing with high purity and industrially in high yield.

[0002]

2. Description of the Related Art As a method for producing camostat mesylate,
Several methods have been proposed so far. For example, Japanese Patent Publication No. 54-41583, Japanese Patent Publication No. 57-14670.
First, after synthesizing N, N-dimethyl-α-bromoacetic acid amide from bromoacetyl bromide and dimethylamine, 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl was prepared by ester reaction with 4-hydroxyphenylacetic acid. An ester was synthesized, and then 4-guanidinobenzoyl chloride hydrochloride obtained by heating 4-guanidinobenzoic acid with thionyl chloride was reacted with this ester compound in pyridine to induce camostat, followed by aqueous sodium hydrogen carbonate solution. (Hereinafter sometimes referred to simply as an aqueous solution of sodium bicarbonate), isolated and purified as a carbonate of camostat, then weakly acidified with methanesulfonic acid to produce the desired camostat mesylate. There is. However, in this production method, the yield is 3 as reported in the above patent publication.
It is as low as 3.6%.

Another manufacturing method is disclosed in Japanese Patent Laid-Open No. 54-5.
2052 includes 4- (4-nitrobenzoyloxy) phenylacetic acid N, N-dimethylcarbamoylmethyl ester reduced nitro group to give 4- (4-aminobenzoyloxy) phenylacetic acid N, N-dimethylcarbamoylmethyl ester. In addition, in the presence of an inorganic acid or an organic acid, for example, hydrochloric acid in the example of the publication, 4 times mol of highly toxic cyanamide is added and heated to obtain a hydrochloride salt of camostat, and then, in an aqueous solution of sodium bicarbonate. A method is disclosed in which conversion to a carbonate salt is carried out for purification, and then methanesulfonate is obtained. However, even with this method, the yield was only 47.5%. As described above, none of the conventionally proposed methods is satisfactory in terms of yield as an industrial production method, and there is a problem in the operation that a highly toxic substance is used. Therefore, there is a strong demand for the development of a method for producing camostat mesylate, which can be produced industrially in a high yield and easily.

[0004]

DISCLOSURE OF THE INVENTION As a result of various studies in view of the above situation, the present inventor obtained camostat by esterification of 4-guanidinobenzoic acid and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester. In the method, dicyclohexylcarbodiimide is used as the esterification catalyst, and this esterification step further comprises:
Alternatively, at the stage where the esterification is completed, p-toluenesulfonic acid in a stoichiometric amount or more is added to the reaction system for treatment, and chemically stable p-toluene of p-toluene is used in the middle.
It was newly found that camostat mesylate can be obtained with high purity and yield by passing through toluenesulfonate, and the present invention has been completed. Therefore, it is an object of the present invention to provide a method for industrially producing camostat mesylate, which has been poor in production yield up to now, with high purity and high yield.

[0005]

[Means for Solving the Problems]
In the present invention, 4-guanidinobenzoic acid or a reactive derivative thereof and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester are subjected to an esterification reaction in the presence of dicyclohexylcarbodiimide, and the esterification reaction step or ester At the stage of completion of the chemical reaction, p-toluenesulfonic acid in a stoichiometric amount or more of stoichiometric amount is added to the reaction system for treatment, and the resulting camostat is isolated as p-toluenesulfonic acid salt. Provided is a method for producing camostat mesilate, which comprises treating with an aqueous solution of sodium, converting it into a carbonate of camostat, purifying it, and then treating with methanesulfonic acid. If the manufacturing method of the present invention is represented by a chemical formula, it can be represented as follows.

[0006]

Embedded image

In yet another embodiment of the present invention, 4-guanidinobenzoic acid p-toluene sulfonate is used.
Hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester is subjected to an esterification reaction in the presence of dicyclohexylcarbodiimide to obtain p-toluenesulfonate of camostat, which is treated with an aqueous sodium hydrogencarbonate solution to be converted to the carbonate of camostat. The present invention provides a method for producing camostat mesylate, which is characterized in that it is purified and then treated with methanesulfonic acid.

In particular, the present invention uses p-, which is sparingly soluble in water, as a camostat obtained by the esterification reaction of 4-guanidinobenzoic acid or its reactive derivative with 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester. It is characterized in that it is purified as a toluene sulfonate. To obtain this p-toluenesulfonate,
At the stage of esterification reaction or at the stage of completion of esterification reaction, p-toluenesulfonic acid in an amount equal to or more than the stoichiometric amount of stoichiometric amount is added into the reaction system, and the resulting camostat is added to p.
-Toluenesulfonic acid salt or 4-guanidinobenzoic acid is used as p-toluenesulfonic acid salt and the esterification reaction is carried out. The 4-guanidinobenzoic acid used as the starting material in this case can be used in the form of a salt in addition to the free compound, and examples of such a salt include hydrochloride, sulfate and bromide. Various salts such as inorganic acid salts such as hydrogen acid salts can be mentioned, and among them, hydrochloride is particularly preferable. Also, 4
-As the reactive derivative of guanidinobenzoic acid, acid halides are preferable, and among them, acid chlorides are particularly preferable.

[0009]

The manufacturing method of the present invention will be described in detail below by describing the results of the study conducted by the present inventor. In order to provide the above-mentioned method of the present invention, the inventor first obtained a low yield in the prior art method by the esterification reaction of 4-guanidinobenzoyl chloride and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester. In view of the fact that only the desired product can be obtained, a method capable of carrying out such an esterification step in good yield was investigated. As a result, at the stage of esterifying 4-guanidinobenzoic acid and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester, the ester is condensed with N, N′-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) to form an ester. It has been found that the method of formation has a high conversion to ester. This esterification reaction is preferably carried out in the presence of a suitable solvent, and as such a solvent, any solvent may be used so long as it does not directly affect the reaction, and among them, pyridine is used. Turned out to be good.

Regarding the esterification method using this DCC, as a prior art, for example, (1) a carboxylic acid component (for example, benzoic acid) and an alcohol component (for example, isopropyl alcohol) are esterified in a pyridine solvent. 0.02 per mole of ingredient
There is an example in which isopropyl benzoate is obtained in a yield as high as 98% by reacting in the presence of ˜0.10 mol, that is, a catalytic amount of a strong acid such as p-toluenesulfonic acid (Japanese Patent Publication No. 56- 9497). (2) Similarly, the hydrochloride of 4-guanidinobenzoic acid 0.0
46 mol and substituted phenol 0.14 to 0.21 mol,
Anhydrous p-toluenesulfonic acid 0.0046-0.01
80 mol (4.6 to 18.0 mmol) are dispersed in 30 ml of anhydrous pyridine at 0 ° C., and after 15 minutes, 0.14 to 0.2% of DCC in 30 ml of dry dimethylformamide.
A 21 mol solution is added and reacted for 2-3 days at room temperature to synthesize the ester. When methyl 4-hydroxybenzoate is used as the substituted phenol in this case,
The produced ester was said to be 81% even after recrystallization with ethanol-hexane (JM
Kaminski et al., Journal of Medicinal Chemistry, 2
9, 514-519 (1986)). (3) Further, Japanese Patent Publication No. 61-32310 describes that "when a guanidinobenzoic acid is directly reacted with hydroxypyridine, it is preferable to use a condensing agent such as DCC." Therefore, even from the above-mentioned prior art, the method of esterifying 4-guanidinobenzoic acid and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester in the presence of DCC to obtain camostat is particularly excellent. Prove.

However, when camostat is produced by the above-mentioned method, the conversion to camostat proceeds in a substantially quantitative yield, but the step of purifying and isolating the desired camostat mesylate from the reaction solution with high purity. So I was still not satisfied. For example, 4-guanidinobenzoic acid hydrochloride 0.1% in 71 ml of dry pyridine.
Using 1 mol and 0.1 mol of 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester, dry p
-After adding 0.1 mol of toluenesulfonic acid, stirring, dissolving and cooling, 0.11 mol of DCC was further added at about 10 ° C,
After stirring at the same temperature for 2 hours, the temperature was raised to room temperature and the mixture was stirred overnight to carry out an esterification reaction. Liquid chromatography (H
After confirming that the reaction is complete by PLC), a small amount of acetic acid is added to decompose excess DCC, and then N, N′-dicyclohexylurea (hereinafter, referred to as D
It is written as CU. ) Was filtered and washed with pyridine, the filtrates were combined and pyridine was lightly distilled off under reduced pressure. This was dispersed in a large amount of saturated sodium bicarbonate water to precipitate a pale red camostat carbonate. This was filtered and washed (the red component could not be removed even by washing with acetone or the like), dispersed in water, adjusted to pH 3 with a dilute aqueous solution of methanesulfonic acid, and dissolved. The insoluble material (mainly DCU) was filtered and then left in a refrigerator for several days, but the desired crystals of camostat mesylate were not precipitated. Therefore, when this solution was analyzed by HPLC,
In addition to the peak of camostat mesylate, a peak of decomposed products of about 7 to 8% was observed, and it was found that impurities produced in the manufacturing process were mixed in the solution.

Therefore, as a result of examining various production methods and purification methods, it was found that p-toluenesulfonate of camostat is a substance which is considerably insoluble in water, and that this product is wet or dry. It was found that the compound is chemically stable both thermally and thermally. Therefore,
The camostat obtained as a result of the above esterification reaction is once transformed into p-toluenesulfonate in the middle of the production process, and purified at this stage to improve the purity and to convert the desired mesylate salt. By carrying out, it became possible to obtain camostat mesylate with good purity and high yield.

The conversion of this camostat to p-toluenesulfonate is carried out by esterification reaction of 4-guanidinobenzoic acid or its reactive derivative with 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester as described above. The process can be carried out by adding p-toluenesulfonic acid in a stoichiometric amount or more, or by adding p-toluenesulfonic acid in a stoichiometric amount or more after the esterification reaction. In addition 4
It can also be obtained by reacting with p-toluenesulfonate of guanidinobenzoic acid. The following various methods can be mentioned for the synthesis of such p-toluenesulfonate, but the method is not limited to these methods.

First, the p-toluenesulfonic acid used in the present invention is preferably anhydrous, which can be easily obtained by dehydrating commercially available crystalline p-toluenesulfonic acid monohydrate. be able to. For example, a commercially available p-toluenesulfonic acid hydrate can be heated to 100 ° C. or higher to lose water, and a dark brown syrup of anhydrous p-toluenesulfonic acid having a melting point of 45 ° C. can be obtained. In addition, anhydrous p-toluenesulfonic acid can be obtained by heating under reduced pressure or by heating and refluxing with toluene using a Dean Stark trap to remove water.

In order to convert the 4-guanidinobenzoic acid hydrochloride used as a raw material in the present invention or the camostat hydrochloride obtained in the esterification step of the present invention as a reaction product into p-toluenesulfonate, For example, JP-A-55-8
9164, once the carbonate is once made with aqueous sodium hydrogen carbonate and then p-toluenesulfonic acid is added to obtain the corresponding p.
-It was found that the reaction can be easily performed with good yield by adding an excess of p-toluenesulfonic acid in a pyridine solution instead of using the toluenesulfonic acid salt. It has been found that the amount of p-toluenesulfonic acid used in this case should be at least the stoichiometric amount, preferably about twice the molar equivalent. The specific manufacturing method of the present invention is as follows, for example, but not limited thereto.

As a first method, 2 equivalents of anhydrous p-toluenesulfonic acid is added to pyridine to prepare a pyridine salt solution of p-toluenesulfonic acid, and then 4-guanidinobenzoic acid hydrochloride is further added. 1 equivalent and 4- equivalents of 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester are added, and 1 equivalent or more of DCC is added to this solution under cooling, preferably at about 15 ° C. or lower,
After heating to room temperature for about 2 hours, preferably for 2 hours, the reaction is carried out by stirring overnight at the same temperature. After completion of the reaction, DCU produced as a by-product was removed by filtration, washed with pyridine, and the filtrate and the washing solution were combined and concentrated under reduced pressure to form a syrup-like substance. A precipitate of p-toluenesulfonate of camostat comes out. This is collected by filtration, washed with a large amount of water, and then dried in a vacuum to obtain white crystals of p-toluenesulfonate of camostat almost quantitatively. Although a very small amount of DCU was dissolved in pyridine and mixed in as it was in this crystal, such a small amount of DCU can be easily removed in the final step of forming a mesylate salt.

As a second method, first, 1 equivalent of 4-guanidinobenzoic acid hydrochloride and 1 equivalent of 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester are esterified in a pyridine solution in the presence of DCC. A chemical reaction is performed, 2 equivalents of anhydrous p-toluenesulfonic acid is added to the solution after the reaction, and the mixture is stirred at room temperature. After that, the same process as the first method, that is, the D generated by
After the CU was filtered off, the mixture was concentrated under reduced pressure, water was added to the residue and the mixture was stirred to precipitate the p-toluenesulfonate of camostat, which is sparingly soluble in water, and is filtered, washed, and then vacuum-dried to obtain a substantially constant amount. As a result, white crystals of p-toluenesulfonate of camostat can be obtained.

The third method is to add to the solution obtained after the completion of the esterification reaction of 4-guanidinobenzoic acid hydrochloride and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester in the above-mentioned second method. In place of the anhydrous p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate was added to the reaction solution in an amount of about 2 equivalents, and the mixture was stirred overnight at room temperature. Thereafter, the same treatment is carried out to obtain the desired p-toluenesulfonate of camostat as white crystals. In a fourth method, the hydrochloride of 4-guanidinobenzoic acid as a starting material used in the first to third methods is heated together with thionyl chloride to give an acid chloride which is a reactive derivative of 4-guanidinobenzoic acid. And anhydrous p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate was excessively added to a pyridine reaction solution of 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester to obtain p-toluenesulfonic acid. Use salt. After that, the first
The target p-toluenesulfonic acid salt of camostat can be obtained by performing the same treatment as the above method.

Further, as a fifth method, a p-toluenesulfonic acid salt of 4-guanidinobenzoic acid is used in place of the hydrochloride salt of 4-guanidinobenzoic acid to carry out an esterification reaction. That is, p of 4-guanidinobenzoic acid
-Toluenesulfonate 1 equivalent and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester 1 equivalent in a pyridine solution were added DCC 1 equivalent or more to carry out an esterification reaction to give p.
-Toluene sulfonate is produced. After the completion of the ester reaction, the same post-treatment as in the first method is performed to quantitatively obtain the desired p-toluenesulfonate of camostat. As described above, the present invention uses camostat obtained as a result of the esterification reaction of 4-guanidinobenzoic acid or its reactive derivative and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester as an intermediate compound. Since it is characterized in that it is purified as a toluene sulfonate, it is preferable to appropriately select and carry out the above-mentioned first to fifth production methods according to the purpose.

The thus-produced p-toluenesulfonate of camostat is efficiently converted into carbonate by the following method, purified, and then induced to camostat mesylate. That is, the conversion of p-toluenesulfonate of camostat to carbonate can be easily converted to the carbonate of camostat by, for example, stirring the p-toluenesulfonate in an aqueous sodium bicarbonate solution. . Specifically, for example, dried p-toluenesulfonate of camostat is dissolved in a solvent such as dimethylformamide or dimethylsulfoxide. In this case, it solidifies immediately after being dissolved, but to this solidified product, saturated aqueous sodium hydrogen carbonate solution is added little by little and kneaded, and then a large excess of saturated aqueous sodium hydrogen carbonate solution is added to form a slurry, preferably for 2 hours or more at room temperature. Stir evenly to complete conversion to carbonate. The purified carbonate is then filtered off and HP
While checking by LC, filter with a large amount of dilute sodium bicarbonate aqueous solution (for example, 0.1% to 2%, preferably about 1% sodium bicarbonate aqueous solution) until the carbonate is completely free of p-toluenesulfonic acid. The carbonate taken is washed. As another method, the wet body of p-toluenesulfonate of camostat before drying is mixed with a saturated aqueous solution of sodium bicarbonate, and further mechanically and vigorously mixed with a device such as a homogenizer to obtain p-toluenesulfone. The acid can also be removed as the soluble sodium salt. After that, the same filtration and washing with a large amount of diluted sodium bicarbonate aqueous solution can be performed to obtain camostat carbonate.

Since camostat carbonate is stable and hardly soluble in water and organic solvents in the prior art, it is purified at this stage by washing with water, washing with acetone, etc.
Surprisingly, the inventors of the present invention have found that this compound is easily hydrolyzed, and that washing with water according to the prior art results in a hydrolysis product, if any. From this point of view, in order to meet the specifications of the hydrolyzate of the final product, it is not preferable to hydrolyze at this stage, and in order to avoid the production of this hydrolyzate, it is preferable that the hydrolyzate should be prepared in the same manner as in the present invention. It has been found that washing with a 1% to 2%, preferably about 1%, diluted sodium bicarbonate aqueous solution is preferable.

In order to induce the camostat carbonate obtained as described above into camostat mesylate, which is the object of the present invention, it can be specifically carried out by the following method. That is, the carbonate is dispersed and stirred in a small amount of water, and the pH is adjusted to 2.5 to 3.5, preferably about 3 by adding mesylic acid dropwise, and the carbonate becomes a mesylate and becomes water. It will dissolve. At this stage, an insoluble matter is sometimes produced. This is because the DCU produced at the stage of the esterification reaction using DCC was dissolved in pyridine and was mixed in the carbonate of camostat and was not removed. Since this substance is extremely insoluble in water, it can be completely removed at this stage by means such as filtration. When the aqueous solution obtained by filtering the insoluble matter is stirred for a while under ice-cooling, the target substance, camostat mesylate, will precipitate as crystals. This is collected by filtration, washed with a small amount of ice water, and dried under vacuum to obtain the desired camostat mesylate as primary crystals in a yield of 73.0%.

Since camostat mesilate remains in the filtrate and the washing solution, both solutions are combined, and saturated sodium bicarbonate aqueous solution is excessively added to the solution, so that free camostat mesilate dissolved in the solution is temporarily added. Precipitate as carbonate. The precipitate was collected by filtration, washed with a dilute aqueous solution of sodium hydrogen carbonate, the obtained carbonate was dispersed in a small amount of water, and mesylic acid was added dropwise to p.
It is dissolved by adjusting to about H3, and ice-precipitated to precipitate crystals. The crystals were collected by filtration, washed and dried to obtain camostat mesylate as secondary crystals in a yield of 4.0%. Then, when the primary crystals and the secondary crystals are added together, the desired camostat mesylate can be obtained with a high yield of 77.0%, which is a yield of 33% in the preceding production method. This is equivalent to 2.3 times as much as 0.6%, which proves the usefulness of the present invention.

[0024]

EXAMPLES The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.

Example 1: A 500 ml four-necked flask was equipped with a Dean Stark trap equipped with a stirrer, a thermometer and a reflux condenser, and 38 g (0.2 g) of p-toluenesulfonic acid monohydrate was added. Charge 80 ml of toluene and heat with stirring. Water azeotroping with toluene was introduced into a Dean Stark trap and removed from the flask, and toluene was further refluxed to completely remove water. Toluene was removed by distillation under reduced pressure to obtain a dark brown hot syrupy anhydrous p-toluenesulfonic acid. Then, with stirring and cooling, anhydrous pyridine 15
7 ml was added dropwise to p-toluenesulfonic acid, and the whole amount was added to obtain a suspension. At room temperature, 21.6 g (0.1 mol) of 4-guanidinobenzoic acid hydrochloride was added and stirred for a while to dissolve the suspension. Then, Japanese Examined Japanese Patent Publication Sho 54-4158
4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester 23.7 synthesized by the method described in No. 3
g (0.1 mol) was added and dissolved. After cooling to about 10 ° C., 24.8 g (0.12 mol) of DCC was added. After attaching the desiccant trap and maintaining the same temperature for 2 hours, the temperature was raised to room temperature and the mixture was stirred overnight.

The DCU formed was filtered and washed with pyridine. The filtrate and the washing solution were combined and pyridine was distilled off under reduced pressure to obtain a yellow syrup. When 251 ml of water was added and stirred vigorously, the syrup crystallized and became a white suspension. After stirring for a while, the cake was obtained by filtration and washed with a large amount of water. The washed cake was heated overnight and dried under vacuum to obtain 56 g of camostat p-toluenesulfonate as white crystals. HP
By LC, almost only two peaks of camostat and p-toluenesulfonic acid were confirmed. The apparent yield was 98.1%. 50 g of the p-toluenesulfonate of camostat obtained as described above was added to N, N
-Although it is dissolved in 149 ml of dimethylformamide with stirring and then solidified, saturated aqueous sodium hydrogen carbonate solution is added little by little and kneaded, and further aqueous sodium hydrogen carbonate solution is added to bring the total amount to 1050.
ml was added to make a suspension of camostat carbonate. Two
After stirring vigorously for an hour, it is filtered and the cake is washed with a large amount of a 1% aqueous sodium bicarbonate solution, and partly sampled,
Check by HPLC and wash until p-toluenesulfonic acid is gone.

Next, the obtained wet body of the carbonate salt of camostat was dispersed in 175 ml of pure water, and while checking with a pH meter, a methanesulfonic acid aqueous solution (1: 2) was added dropwise to adjust the pH to 3. Although carbonate was dissolved in this vicinity, insoluble DCU and others were removed by filtration together with a small amount of activated carbon. The obtained aqueous solution was ice-cooled with stirring, seed crystals were inoculated, and stirring was continued for about 1 hour, whereby white crystals of methanesulfonate of camostat (camostat mesylate) were precipitated. After further stirring for 2 hours at the same temperature, it was filtered, washed with a small amount of ice water, and dried in vacuum. 32.2 g (yield 73.0%: yield from hydrochloride of 4-guanidinobenzoic acid) of white camostat mesylate was obtained. Melting point 195 [deg.] C.
The filtrate and the washing solution were combined, and a saturated aqueous solution of sodium bicarbonate was added thereto to restore the carbonate of camostat, which was collected by filtration and washed with an aqueous solution of 1% sodium bicarbonate to obtain a carbonate of camostat. This was similarly adjusted to pH 3 with an aqueous solution of methanesulfonic acid, cooled and crystallized to give camostat mesylate as a secondary crystal of 1.8.
g (yield: 4.0%) was obtained.

Example 2: A 100 ml four-necked flask was equipped with a stirrer, a thermometer and a dry trap, in which 4.31 g (0.30g) of 4-guanidinobenzoic acid hydrochloride was added.
02 mol) and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester 4.75 g (0.0
2 mol) and 20 ml of dry pyridine are added and dissolved by stirring,
It was then cooled to 10 ° C. DCC 5g (0.02
4 mol) was added and the mixture was stirred at the same temperature for 2 hours, warmed to room temperature and stirred overnight. Since the reaction was incomplete, further DCC
Added 3 g. Pyridine (10 ml) was added, p-toluenesulfonic acid monohydrate (7.6 g, 0.04 mol) was added little by little, and the mixture was stirred at room temperature for one day. Filter the reaction,
DCU on the filter paper was washed with pyridine, and the filtrate and the washing solution were combined and concentrated under reduced pressure. 100m of water in the obtained syrup
1 was added and vigorously stirred to crystallize. It was collected by filtration, washed with a large amount of water, and dried under vacuum to obtain 9.1 g (apparent yield: 8
0.3%) of camostat p-toluenesulfonate was obtained as white crystals. By HPLC, almost two peaks of camostat and p-toluenesulfonic acid were confirmed. This product was converted to camostat mesylate by the same treatment as in Example 1.

Example 3: 4-Guanidinobenzoic acid hydrochloride was dissolved in water and neutralized with a dilute aqueous solution of sodium hydroxide, whereby a precipitate was deposited. After filtering, washing with water and drying, 4-
Light brown crystals of the free form of guanidinobenzoic acid were obtained.
A 100 ml four-necked flask was equipped with a stirrer, a thermometer and a dry trap, into which dry pyridine was added,
While stirring, 3.79 g (0.022 mol) of anhydrous solid (melting point: about 45 ° C.) p-toluenesulfonic acid was added little by little. Then 3.58 g of free 4-guanidinobenzoic acid
(0.02 mol) was added, and 4.75 g (0.02 mol) of 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester was further added. After cooling to 10 ° C., 5.2 g (0.0252 mol) of DCC was added, and 2
After stirring for an hour, the mixture was warmed to room temperature and stirred overnight. It was checked by HPLC and unreacted matter still remained, so 2 g and 1 g of DCC were further added and stirred. After completion of the reaction, the precipitated DCU was filtered, washed with pyridine, and the filtrate and the washing solution were combined and concentrated under reduced pressure to obtain a syrup. 100 ml of water
Was added and vigorously stirred to crystallize. The obtained crystals were collected by filtration, washed with a large amount of water, and dried under vacuum to obtain 9.12 g.
White crystals of p-toluenesulfonate of camostat (apparent yield: 80.0%) were obtained. By HPLC, almost two peaks of camostat and p-toluenesulfonic acid were confirmed. This product was also treated in the same manner as in Example 1 and converted into camostat mesylate.

Example 4 10.8 g (0.05 mol) of 4-guanidinobenzoic acid hydrochloride was dissolved in 150 ml of water and neutralized with 50 ml of a 1N aqueous sodium hydroxide solution to precipitate. After filtering, washing well with water, and drying, 4-
8.55 g of light brown crystals of the free form of guanidinobenzoic acid
(Yield: 95.4%) was obtained. Of this, 5 g (0.
(0279 mol) was dispersed in a solution of 5.8 g of p-toluenesulfonic acid monohydrate and 50 ml of water, stirred overnight at room temperature, filtered, washed with water and dried to give p-toluenesulfonic acid of 4-guanidinobenzoic acid. 8.7 g (yield: 88.4%) of salt crystals were obtained. The melting point was 234 ° C.

A 100 ml four-necked flask was equipped with a stirrer, a thermometer and a dry trap, in which p-toluenesulfonate of 4-guanidinobenzoic acid 7.03 was added.
g (0.02 mol) and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester 4.75
g (0.02 mol) and 50 ml of dry pyridine were added,
It was dissolved with stirring. After cooling to 10 ° C, DCC 5g (0.02
(4 mol) was added and the mixture was stirred for 2 hours, warmed to room temperature and stirred overnight. After checking the completion of the reaction by checking by HPLC, the precipitated DCU was filtered, washed with pyridine, and the filtrate and the washing solution were combined and concentrated under reduced pressure to obtain a yellow syrup. Water 10
0 ml was added and vigorously stirred to precipitate crystals. The precipitated crystals were collected by filtration, washed with a large amount of water, and dried under vacuum to obtain 9.78 g (apparent yield: 85.8%) of p-toluenesulfonate of camostat as white crystals. HPL
In C, almost two peaks of camostat and p-toluenesulfonic acid were confirmed. This one,
It was treated in the same manner as in Example 1 and converted into camostat mesylate.

[0032]

As described above, the present invention provides a camostat obtained by the esterification reaction of 4-guanidinobenzoic acid or its reactive derivative with 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester.
The present invention is completely novel in that camostat mesylate can be obtained in good purity and in good yield by purifying it as a water-insoluble p-toluenesulfonic acid salt. It is a specific method for industrially producing camostat mesylate, which was not very good, with high purity and high yield.

Claims (3)

[Claims] 1. An esterification reaction of 4-guanidinobenzoic acid or a reactive derivative thereof and 4-hydroxyphenylacetic acid N, N-dimethylcarbamoylmethyl ester in the presence of dicyclohexylcarbodiimide to carry out an esterification reaction step or After completion of the esterification reaction, a stoichiometric amount of p-toluenesulfonic acid in a stoichiometric amount or more is added to the reaction system for treatment, and the resulting camostat is isolated as p-toluenesulfonate,
A process for producing camostat mesilate, which comprises treating with an aqueous solution of sodium hydrogen carbonate to convert it into a carbonate of camostat for purification, and then treating with methanesulfonic acid. 2. The method for producing camostat mesilate according to claim 1, wherein the reactive derivative of 4-guanidinobenzoic acid is a salt or acid halide of 4-guanidinobenzoic acid. 3. A p-toluenesulfonic acid salt of 4-guanidinobenzoic acid and 4-hydroxyphenylacetic acid N, N-
Dimethylcarbamoyl methyl ester is esterified in the presence of dicyclohexylcarbodiimide,
A method for producing camostat mesylate, which comprises obtaining p-toluenesulfonate of camostat, treating it with an aqueous sodium hydrogencarbonate solution, converting it into carbonate of camostat for purification, and then treating with methanesulfonic acid.