WO2014007326A1 - Process for producing nafamostat mesylate - Google Patents

Description

Method for producing nafamostat mesylate

The present invention relates to a method for producing nafamostat mesylate.

Nafamostat mesylate is an effective compound for preventing coagulation of perfused blood during extracorporeal circulation in patients with pancreatic diseases such as pancreatitis, generalized intravascular blood coagulation, hemorrhagic lesions or bleeding tendency.
Up to now, as a method for producing nafamostat mesylate, a sodium bicarbonate aqueous solution was added to a solution containing nafamostat to isolate nafamostat bicarbonate as a solid, and this nafamostat bicarbonate was mixed with methane. There is known a production method through a step of adding sulfonic acid to induce formation into nafamostat mesylate (Patent Documents 1 and 2).

Also, as another method, a method of converting to nafamostat mesylate by adding 10 equivalents of sodium methanesulfonate to nafamostat hydrochloride is also known (Non-patent Document 1).

Japanese Examined Patent Publication No. 61-1063 Japanese Patent Laid-Open No. 2004-284882

Chem. Pharm. Bull. 33 (4). 1470-1471 (1985)

However, as a result of the researches of the present inventors, in the methods disclosed in Patent Documents 1 and 2, since the crystals of nafamostat bicarbonate are fine, liquid drainage is poor and time is required for filtration. I found out there was a problem. In addition, in order to obtain nafamostat bicarbonate, it is necessary to expose nafamostat to basic conditions, but nafamostat, an ester compound, hydrolyzes quickly under neutral and basic conditions, and 4-guanidinobenzoic acid. Since degradation products such as acid and 6-amidino-2-naphthol are known to occur (Pharmaceutical Journal 105 (5), 512-516 (1985)), the problem of degradation of the purity of nafamostat due to degradation There was also.
On the other hand, the method disclosed in Non-Patent Document 1 has a problem that quality deteriorates because sodium methanesulfonate is mixed. Further, it is known that crystallization of nafamostat mesylate from water alone results in a gel-like lump, which makes it difficult to separate nafamostat mesylate by filtration (Japanese Patent No. 3796481, JP2012-87099). . Therefore, the method disclosed in Non-Patent Document 1 is not suitable for mass production.

The present invention has been made in view of the above-mentioned problems, and nafamostat mesylate without passing through nafamostat bicarbonate having poor filterability and stability and without being mixed with sodium mesylate. An object of the present invention is to provide a method of producing

In order to achieve the above-mentioned object, the present inventor has intensively studied a method for producing nafamostat mesylate, and as a result, nafamostat bicarbonate and nafamostat salt other than nafamostat mesylate are used as anion exchange resins. By contacting with an anion exchange resin whose anion is mesylate ion in the presence of a solvent, nafamostat mesylate without passing through nafamostat bicarbonate and without being mixed with sodium mesylate Has been found to be able to be produced, and the present invention has been completed.
That is, the present invention has the following configuration.
(1) preparing an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion;
(2) By contacting the anion exchange resin obtained in step (1) with a nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent, the nafamostat salt is converted to nafamostat salt. Salt exchange to mostat mesylate,
(3) a step of crystallizing the nafamostat mesylate obtained in step (2),
A process for producing nafamostat mesylate, comprising:

According to the present invention, nafamostat mesylate can be produced without going through nafamostat bicarbonate and without mixing sodium mesylate.
Therefore, a highly pure nafamostat mesylate can be produced in a shorter time than before. It is also suitable for mass production.
Moreover, when manufactured by a batch method, in addition to the above effects, the production amount of nafamostat mesilic acid per batch can be greatly increased, and therefore, it is more suitable for mass production. Moreover, since the amount of the solvent used in the anion exchange step and the amount of the solvent discarded after use can be greatly reduced, the influence on the environment can be kept low.

Nafamostat mesylate is the generic name for 6′-amidino-2′-naphthyl 4-guanidinobenzoate dimethanesulfonate, represented by the following formula:

The method for producing nafamostat mesylate of the present invention comprises (1) a step of preparing an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion, and (2) an anion obtained in step (1) A step of salt exchange of the nafamostat salt with nafamostat mesylate by contacting an ion exchange resin with nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent; (3 ) Crystallizing the nafamostat mesylate obtained in step (2).

<< (1) Preparation Process of Anion Exchange Resin >>
In the present invention, an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion is used to salt-exchange nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate to nafamostat mesylate. Used for.
Although there is no restriction | limiting in particular in the kind of anion exchange resin, The thing which substituted the basic anion of basic anion exchange resin with mesylic acid (methanesulfonic acid) is used preferably.

Examples of basic ion exchange resins include strong basic anion exchange resins having quaternary ammonium groups and weak basic anion exchange resins having primary to tertiary amino groups as functional groups. Among these, a strongly basic anion exchange resin is particularly preferable, and a reaction product of chloromethylated product and trimethylamine of copolymerization of styrenedivinylbenzene is more preferable.

There is no particular limitation on the method of replacing the basic anion of the basic anion exchange resin with mesylic acid (methanesulfonic acid), and the replacement may be performed by a conventionally used method. For example, it can be substituted by a method such as adding methanesulfonic acid to a strong ionic exchange resin substituted with hydroxide ions.

<< (2) Salt exchange process >>
Next, an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion (hereinafter sometimes referred to as a mesylated anion exchange resin), nafamostat bicarbonate and nafamostat mesylate The nafamostat salt other than the salt is contacted in the presence of a solvent to exchange the nafamostat salt with nafamostat mesylate.
This salt exchange to nafamostat mesylate may be carried out by any method that can be assumed by those skilled in the art, for example, nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate, and mesylated anion. Use a batch method in which an ion exchange resin is mixed in a reaction vessel in the presence of a solvent, or a column method in which a solution containing nafamostat salt is passed through a column / resin tower packed with an anion exchange resin substituted with mesylate ions. Salt exchange.

<Batch method>
In the batch method, salt exchange is performed by mixing a mesylated anion exchange resin and a nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent.
The batch method is not particularly limited as long as a mesyl-oxidized anion exchange resin is used.For example, a methanesulfonate-oxidized anion exchange resin and a nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate, Salt exchange can be performed by mixing using a solvent such as 50 vol% acetone aqueous solution.

(Nafamostat salt concentration)
The molecular weight of nafamostat is 347.37, the molecular weight of nafamostat hydrochloride is 420.29, and the molecular weight of nafamostat mesylate is 539.58. Even though the amount of nafamostat molecule itself is the same, The mass (concentration) of nafamostat salt contained in the solution changes. Therefore, the Nafamostat salt concentration is defined as follows as a unified index.
Nafamostat equivalent concentration of nafamostat salt:
When all the nafamostat salt dissolved in the solution containing the nafamostat salt and the solvent (the solution containing the nafamostat salt) is replaced with nafamostat (molecular weight: 347.37), the solution is dissolved in the solution. The ratio (% by mass) of the nafamostat.

The concentration of the nafamostat salt in the solution containing the nafamostat salt is preferably 3% by mass to 10% by mass, more preferably 4% by mass to 9% by mass, and further preferably 5% by mass to 8% by mass. .
Usually, nafamostat salts other than nafamostat mesylate have low solubility in water and solvents such as N, N-dimethylformamide (at most about 0.1 to 2% by mass), and the nafamostat salt is dissolved in the solvent. This requires a large amount of solvent. Surprisingly, however, the inventors' research has shown that mesyl-oxidized ion exchange resins and nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate in a reaction vessel in the presence of a solvent. In the case of mixing, the solubility of nafamostat salt in the solution containing nafamostat salt is greatly improved. Therefore, by using the batch method, a higher concentration of nafamostat salt-containing solution can be prepared than before, and the production amount of nafamostat mesylic acid per batch can be greatly increased. Further, by using the batch method, the amount of the solvent used in the anion exchange step and the amount of the solvent discarded after use can be greatly reduced.

(temperature)
The salt exchange by the batch method is preferably performed with stirring under a temperature condition within a range of −10 ° C. to 45 ° C., more preferably 0 ° C. to 40 ° C., and even more preferably 10 ° C. to 35 ° C. By salt exchange under temperature conditions within the above range, it becomes easy to prevent decomposition and to obtain highly pure nafamostat mesylate.

(Agitation time)
The stirring time in the batch method is not particularly limited as long as salt exchange is performed, and may be appropriately determined, but is preferably 1 minute to 1 week, more preferably 10 minutes to 1 day, and further preferably 30 minutes to 1 hour 30 minutes. It is. When the stirring time is within the above range, ion exchange is facilitated.

<Column method>
The salt exchange step using an anion exchange resin may be performed using a column method in addition to the batch method. In the column method, salt exchange is carried out by passing a solution containing mesilnafamostat salt other than nafamostat bicarbonate and nafamostat mesylate through a column / resin tower packed with mesylated anion exchange resin.
The column method is not particularly limited as long as a column filled with mesyl-oxidized anion exchange resin is used. For example, a glass column is filled with mesyl-oxidized strong basic ion-exchange resin and washed with a solvent such as 50 vol% acetone aqueous solution. And it can carry out by letting the solution which melt | dissolved the said nafamostat salt in the solvent pass the said column.

<Number of salt exchanges>
The salt exchange using the anion exchange resin may be performed only once, but is preferably repeated twice or more, more preferably three or more times. As an example, salt exchange can be repeated 1 to 10 times, preferably 2 to 8 times, more preferably 3 to 6 times. By repeating the salt exchange, the ratio (mass%) of nafamostat mesylic acid in the total nafamostat salt contained after the salt exchange can be increased.

When the salt exchange is repeated twice or more, either the batch method or the column method may be used, or a combination of these may be used.
Preferably, at least the first salt exchange is performed by a batch method. More preferably, all salt exchange is performed by a batch method.
By performing at least the first salt exchange by a batch method, a large amount of nafamostat salt can be dissolved in the solution, so that nafamostat mesylate can be obtained efficiently. In addition, the amount of solvent used during salt exchange and the amount of solvent discarded after use can be reduced.

<Nafamostat salt>
The form of the salt of nafamostat other than nafamostat bicarbonate and nafamostat mesylate used in the production method of the present invention is preferably a chemically acceptable salt of a strong acid or weak acid, more preferably a strong acid salt. is there. Examples of strong acid salts include hydrochloride, bromate, iodate, paratoluenesulfonate, and benzenesulfonate. Among these, hydrochloride (dihydrochloride) is preferable. Each of the above nafamostat salts may be a commercially available salt or may be produced by synthesis. In the case of synthesis, it may be produced by any known method, and is described in, for example, Non-Patent Document 1 (Chem. Pharm. Bull. 33 (4). 1470-1471 (1985)). You can see how it is.
The concentration of nafamostat salt in the nafamostat salt-containing solution is preferably 0.5% by mass to 10% by mass. When the batch method is used, as described above, it is preferably 3% by mass to 10% by mass, more preferably 4% by mass to 9% by mass, and still more preferably 5% by mass to 8% by mass.

<PH>
The pH of the solution containing nafamostat bicarbonate other than nafamostat bicarbonate and nafamostat mesylate used in the salt exchange step is preferably in the range of 1 to 5, more preferably 1 to 3. Even more preferred is 5-2.5. Most preferably it is about pH2. By setting the pH within the above range, it is possible to improve the stability (inhibition of decomposition) of the nafamostat. The pH can be adjusted by adding an acid or a base to the solution. Preferably the pH is adjusted by adding acid, more preferably mesylic acid (methanesulfonic acid) to the solution.

<Solvent>
The solvent used in the salt exchange step is preferably water or a mixed solvent of a water-soluble solvent and water. More preferred is a mixed solvent of a water-soluble solvent and water.
Examples of the water-soluble solvent include acetone, tetrahydrofuran (THF), 2-propanol, acetonitrile, and 2-butanol. Among these, acetone and THF are preferable. That is, the mixed solvent of the water-soluble solvent and water is preferably a mixed solvent of acetone and water or a mixed solvent of THF and water.
When a mixed solvent of a water-soluble solvent and water is used, the mixing ratio of the water-soluble solvent and water is preferably 1: 9 to 9: 1, more preferably 3: 7 to 7: 3, still more preferably Is 4: 6 to 6: 4 (volume ratio). If it is in the said range, the amount of solvent required for melt | dissolution can be decreased.

(Equivalent ratio of anion exchange resin and nafamostat salt)
The amount of mesylated anion exchange resin used in the batch process is preferably 2 to 20 equivalents, more preferably 2.3 to nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate. Equivalent to 16 equivalents, more preferably 2.3 to 13 equivalents. By setting the amount of the anion exchange resin in the above range, ion exchange of nafamostat salt to mesylate ion is facilitated.

<< (3) Crystallization process >>
In the method for producing nafamostat mesylate according to the present invention, nafamostat mesylate is crystallized from a solution containing nafamostat mesylate obtained through the salt exchange step. The crystallization step may be performed using the solution containing nafamostat mesylate obtained in the salt exchange step as it is, or may be performed after concentrating the solution under reduced pressure.

There is no particular limitation on the crystallization method of nafamostat mesylate, and it is possible to crystallize nafamostat mesylate using a generally known crystallization apparatus and method.
For example, a water-soluble solvent or a mixed solution of water and a water-soluble solvent is added to a solution containing nafamostat mesylate, and the crystals are precipitated by adding nafamostat mesylate as a seed crystal and stirring. By separating and drying the crystals thus obtained, a highly pure nafamostat mesylate can be obtained.
Examples of the water-soluble solvent used in this case include THF, acetone, acetonitrile, 2-butanol, and 2-propanol. Among these, THF is preferably used. The content ratio after adding a mixture of water and a water-soluble solvent to a solution containing nafamostat mesylate is preferably 1: 1 to 1:50, and preferably 1: 3 to 1:15. More preferably, it is more preferably 1: 8 (water: water-soluble solvent (volume ratio)).
In addition to the above-described method, the crude nafamostat mesylate can be crystallized by dissolving in water at high temperature and cooling (see, for example, Non-Patent Document 1, JP-A 2012-87099, etc.). be able to.).

[Example 1]
<Column method>
A glass column (inner diameter 0.8-0.9 cm, height 6 cm) was packed with 29.26 g of strong ionic exchange resin substituted with hydroxide ions (2.3 equivalents relative to the following Nafamostat hydrochloride). After washing with water, the solution was methanesulfonated through a solution obtained by diluting 18.5 ml of methanesulfonic acid with 288 ml of water, and washed with 160 ml of 50 vol% acetone aqueous solution.
Separately, 200 ml of water and 200 ml of acetone were added to 10.3 g of nafamostat hydrochloride (net amount 8.0 g, HPLC purity: 99.8%) to prepare a solution having a concentration of 1.8% in terms of nafamostat. The pH was adjusted to 2.0 by adding 3.8 ml of 0 mol / L methanesulfonic acid aqueous solution.
The nafamostat solution was passed through the column and washed with 160 ml of 50 vol% acetone aqueous solution. Only the fraction containing nafamostat was combined (341 g), and 736 ml of acetone was added to this solution while stirring at 8 ° C., and nafamostat mesylate was added as a seed crystal. Further, 1288 ml of acetone and 16 ml of water were added. The precipitated crystals were filtered and dried with a Kiriyama funnel having an inner diameter of 60 mm over 20 minutes to obtain 8.81 g of nafamostat mesylate (HPLC purity: 99.9%, residual chloride ion: 0.007%).

[Example 2]
<Batch method>
(Methanesulfonated resin preparation)
After adding 220 ml of water to 133.14 g of strong basic ion exchange resin substituted with hydroxide ions (12 equivalents to the following nafamostat hydrochloride), 14.3 ml of methanesulfonic acid was added dropwise at 20 ° C. And stirred at 20 ° C. for 1 hour and 10 minutes. This resin was separated and washed, then suspended in 213 ml of 50 vol% acetone aqueous solution and stirred at 20 ° C. for 20 minutes. This resin was separated and washed to obtain 124.50 g of methanesulfonated resin.
(Ion exchange)
After 41.49 g of this methane sulfonated resin was added to 105 ml of 50 vol% acetone aqueous solution, 8.31 g of nafamostat hydrochloride (net amount 7.00 g) was added. After adjusting the pH to 2 by adding 0.18 g of methanesulfonic acid, the mixture was stirred at 21 ° C. for 1 hour and 11 minutes (the concentration of nafamostat hydrochloride in the solution was 6.8% (concentration of nafamostat 5.6%)). The ion exchange resin was separated by filtration, and the resin was washed with 35 ml of 50 vol% acetone aqueous solution. 41.49 g of methane sulfonated resin was added to the obtained filtrate. After this suspension was stirred at 21 ° C. for 1 hour, the ion exchange resin was separated, and the resin was washed with 35 ml of a 50 vol% acetone aqueous solution. This process was repeated once more, and 178.69 g of the filtrate obtained was concentrated under reduced pressure to 49.79 g. After the completion of concentration, 8.6 ml of water and 99 ml of THF were added and cooled to 8 ° C. After adding 124 ml of THF to the concentrated liquid after cooling, 0.04 g of nafamostat mesylate was added as a seed crystal and stirred for 3 hours. 173 ml of THF was added dropwise over 1 hour and 6 minutes, and the mixture was further stirred for 16 hours. The precipitated crystals were filtered with a Kiriyama funnel having an inner diameter of 95 mm for 7 minutes and dried to obtain 8.46 g of nafamostat mesylate (HPLC purity: 99.9%, residual chloride ion: 0.012%).

[Example 3]
<Batch method>
(Methanesulfonated resin preparation)
After adding 157 ml of water to 94.36 g of strongly basic ion exchange resin substituted with hydroxide ions (12 equivalents to the following nafamostat hydrochloride), 15.09 g of methanesulfonic acid was added dropwise at 25 ° C. , And stirred at 25 ° C. for 1 hour or longer. This resin was separated and washed, then suspended in 151 ml of 50 vol% THF aqueous solution and stirred at 25 ° C. for 10 minutes. This resin was separated and washed to obtain 87.38 g of methanesulfonated resin.
(Ion exchange)
After adding 30.17 g of this methanesulfonated resin to 50 ml of 50 vol% THF aqueous solution, 5.07 g of nafamostat hydrochloride (net amount: 5.00 g, HPLC purity: 99.5%) was added, followed by stirring for 5 minutes. A few drops of 10% aqueous methanesulfonic acid was added to adjust the pH to 2 (the concentration of nafamostat hydrochloride in the solution was 9.6% (concentration of nafamostat 7.9%)). After this suspension was stirred at 25 ° C. for 1 hour or longer, the ion exchange resin was separated by filtration, and the resin was washed with 40 ml of 50 vol% THF aqueous solution. To the obtained filtrate, 30.19 g of methane sulfonated resin was added. After this suspension was stirred at 25 ° C. for 1 hour or longer, the ion exchange resin was separated, and the resin was washed with 40 ml of 50 vol% THF aqueous solution. This process was repeated once more, and 140.27 g of the obtained filtrate was concentrated under reduced pressure to 23.3 g. After the completion of concentration, 3 ml of water and 20 ml of THF were added and cooled to 8 ° C. After adding 0.05 g of nafamostat mesylate as a seed crystal to the cooled solution, the solution was stirred for 30 minutes, and further 200 ml of THF was added over 2.5 hours. After stirring for 3 hours, the precipitated crystals were filtered and dried with a Kiriyama funnel having an inner diameter of 40 mm over 30 minutes to obtain 6.03 g of nafamostat mesylate (HPLC purity: 99.9%, residual chloride ion: 0 .018%).

[Comparative Example 1]
(Production method according to Patent Document 1)
Nafamostat hydrochloride 9.89 g (net amount 7.00 g, HPLC purity: 99.7%) was added to 700 ml of water and dissolved at 25 ° C. (concentration of nafamostat 0.8%). To this solution, 48.20 g of an 8.7% aqueous sodium hydrogen carbonate solution was added and stirred for 19 hours and 40 minutes. The precipitated crystals were filtered with a Kiriyama funnel having an inner diameter of 95 mm over 50 minutes and dried at room temperature to obtain 7.51 g of nafamostat bicarbonate.
7.51 g of this nafamostat bicarbonate was suspended in 25 ml of methanol, and 4.26 g of methanesulfonic acid was added. After addition of 50 ml of diethyl ether and stirring for 3 hours and 20 minutes, the precipitated crystals were filtered and dried to obtain 8.73 g of nafamostat mesylate (HPLC purity: 98.3%).

(Production method according to Non-Patent Document 1)
[Comparative Example 2]
19.67 g of sodium methanesulfonate was dissolved in 206 ml of water to adjust the pH to 4.4. To this solution was added 9.89 g of nafamostat hydrochloride (net amount 7.00 g, HPLC purity: 99.7%), and the mixture was stirred at 25 ° C. for 19 hours and 20 minutes. The precipitated solid was filtered with a Kiriyama funnel having an inner diameter of 95 mm over 24 hours and 5 minutes, and dried at 60 ° C. 35 ml of water was added to the obtained solid and stirred at 70 ° C. for 30 minutes to dissolve. The solution was cooled and stirred at 25 ° C. for 13 hours and 40 minutes. The precipitated solid was filtered through a Kiriyama funnel with an inner diameter of 95 mm for 1 hour and 10 minutes and still contained water, but dried in this state to obtain 9.68 g of nafamostat mesylate (HPLC purity: 99 .6%, sodium methanesulfonate content 18.6%).

<Result>
Compared to Example 2 using the same size Kiriyama funnel, it was found that the method of Comparative Example 1 took time to filter the precipitated nafamostat bicarbonate, and was not suitable for mass production. Moreover, the purity of the obtained nafamostat mesylate was also low.
Similarly, in the method of Comparative Example 2, it was found that it took a very long time to filter the precipitated nafamostat mesylate, and it was not suitable for mass production. Furthermore, contamination with sodium methanesulfonate was also observed.
On the other hand, in the method of the present invention, compared with the methods of Comparative Examples 1 and 2, the filtration time was short, and the purity of the obtained nafamostat mesylate was very high (Examples 1 to 3). Furthermore, when the batch method was used, the amount of solvent required to dissolve the nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate could be greatly reduced (Example 2). ~ 3).
Therefore, the method for producing nafamostat mesylate of the present invention is superior to the conventional method, and is suitable for mass production of nafamostat.

Claims (10)

(1) preparing an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion;
(2) By contacting the anion exchange resin obtained in step (1) with a nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent, the nafamostat salt is converted to nafamostat salt. Salt exchange to mostat mesylate,
(3) a step of crystallizing the nafamostat mesylate obtained in step (2),
A process for producing nafamostat mesylate, comprising: 2. The nafamostat mesyl according to claim 1, wherein the salt exchange in the step (2) is performed by mixing the anion exchange resin obtained in the step (1) and the nafamostat salt in the presence of a solvent. Method for producing acid salt. The method for producing nafamostat mesylate according to claim 2, wherein in the step (2), the concentration of nafamostat in the mixed solution containing the nafamostat salt and the solvent is 3 to 10% by mass. . The method for producing nafamostat mesylate according to claim 3, wherein the concentration of nafamostat salt in terms of nafamostat is 4 to 9% by mass. 2. The nafa according to claim 1, wherein the salt exchange in the step (2) is performed by passing a solution containing the nafamostat salt and a solvent through a column packed with the anion exchange resin obtained in the step (1). A method for producing mostat mesylate. The method for producing nafamostat mesylate according to any one of claims 1 to 5, wherein the nafamostat salt is a nafamostat strong acid salt. The method for producing nafamostat mesylate according to claim 6, wherein the nafamostat strong acid salt is nafamostat hydrochloride. The method for producing nafamostat mesylate according to any one of claims 1 to 7, wherein in the step (2), the pH of the solution containing the nafamostat salt and the solvent is adjusted within a range of 1 to 5. . 9. The solvent according to claim 1, wherein the solvent is a mixed solvent of water and at least one water-soluble solvent selected from the group consisting of acetone, tetrahydrofuran, 2-propanol, 2-butanol, and acetonitrile. The manufacturing method of the nafamostat mesylate described in 1. The method for producing nafamostat mesylate according to any one of claims 1 to 9, wherein the amount of the ion exchange resin is 2 to 20 equivalents relative to the nafamostat salt.