KR20150084165A - Method for preparing of nafamostat mesilate - Google Patents

Abstract

The present invention discloses a manufacturing method for nafamostat mesylate used as blood coagulation inhibitor where crystalline II type nafamostat mesylate is obtained with high purity and quality as well as regularity. According to the present invention, the manufacturing method for nafamostat mesylate comprises the following steps of: (a) initiating a chemical reaction between 4-guanidino benzoic acidic hydrochloride and 6-amidino-2-naphthol methanesulfonate with the existence of N,N′-Diisopropylcarbodiimide to manufacture the compound shown in Formula 1; (b) adding the manufactured compound in Formula 1 to solvent mixed with water H_2O and saturated sodium hydrogen carbonate NaHCO_3 to manufacture the compound shown in Formula 2; and (c) adding the compound in Formula 2 to solvent, and then adding methanesulfonate to manufacture the nafamostat mesylate compound shown in Formula 3.

Description

TECHNICAL FIELD The present invention relates to a method for preparing nafamostat mesylate,

More particularly, the present invention relates to a method for producing naphamostat mesylate which is used as a blood coagulation inhibitor in high purity, The present invention relates to a process for producing naphamostat mesylate capable of constantly producing a stat mesylate.

Nafamostat mesilate, or futhan, is one of the most commonly used anticoagulants or anticoagulants, and is known to be an antitumor agent, antitrypsin, anticoagulant, anti-carcranin, antithrombin Active and anticomplement, and can be represented by the following formula.

The preparation method of Napamos statem mesylate was firstly disclosed in 1981 by Torii Yakin Co., Ltd. of Japan, the first patentee (European Patent No. 0048433A3 (filed on September 1, 1981), Korean Patent Application No. 1981-0003427 (filed on September 1, 1981). 15 application, Japanese Patent Application Laid-Open No. 1983-0007527)). According to the process for preparing napamostat mesylate disclosed in Korean Patent Laid-Open Publication No. 1983-0007527, acid chloride produced by adding 4-guanidino benzoic acid hydrochloride (4-GDA.HCl) to a thionyl chloride solution and heating and stirring, 6-amidino-2-naphthol methanesulfonate (6-ANL.MsOH) was added to the filtrate obtained by filtering the by-products of the intermediate product, and sodium hydrogen carbonate was added and reacted to obtain 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate, which is suspended in methanol, followed by addition of methanesulfonic acid and ethyl ether, to give the precipitated white crystals of 6-amidino-2-naphthyl 4-guanidino Benzoate dimethanesulfonate (or naphamostat mesylate) can be prepared.

Korean Patent Laid-Open Publication No. 1983-0007527 also discloses a method for preparing naphamostat mesylate using N, N'-dicyclohexylcarbodiimide (DCC), wherein N, N ' -Dicyclohexylcarbodiimide is reacted with 4-guanidinobenzoic acid hydrochloride, and then 6-amidino-2-naphthol methanesulfonate is coupled thereto. Next, crystals produced and precipitated are filtered and washed, and then dissolved in water to remove and remove by-product N, N'-dicyclohexylurea (DCU). Then, Sodium is added and reacted to obtain 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate, which is suspended in methanol, followed by addition of methansulfuric acid and ethyl ether, Dino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate (or naphamostat mesylate) can be prepared. The reactants and the reaction intermediates when the naphamostat mesylate was prepared by the above two production methods were shown below according to the flow.

However, in the case of the first production method, the acid chloride is prepared using caustic thionyl chloride, and the starting materials (4-guanidinobenzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate) The acid chloride is not obtained purely due to the poor solubility, and the product contains a large amount of impurities and the purity of the final product is lowered. In the case of the production method using the second N, N'-dicyclohexylcarbodiimide (DCC), the filtration property of N, N'-dicyclohexylurea (DCU) is poor and it takes a long time for filtration. To remove the N, N'-dicyclohexylurea (DCU), a mixture of the intermediate and N, N'-dicyclohexylurea (DCU) was dissolved in water and again N, N '-Dicyclohexylurea (DCU), followed by a complicated step of treating the filtered aqueous layer with a saturated aqueous solution, the next product can be prepared. In addition, since the intermediate products containing the napamostat component are not very stable in water, the longer the time in which they are dissolved in water, the larger the amount of impurities is produced. In addition, since the method capable of purifying naphamostat mesylate by recrystallization is limited due to the solubility problem, the naphamostat mesylate can be produced with high purity only when the purity of the intermediate product is as high as possible . Thus, in order to produce a high purity naphamostat mesylate, purification at the time when the intermediate products are produced is very important. However, when N, N'-dicyclohexylcarbodiimide (DCC) is used, a large amount of impurities are contained in the products or intermediates in the production of the intermediate products, and ultimately the production of naphamostat mesylate . Therefore, currently, a method of easily producing a high-purity, high-quality product containing 0.1% or less of individual impurities (or a flexible substance) and 0.5% or less of total impurities is being sought.

On the other hand, naphamostat mesylate has various kinds of crystals, and naphamostac mesylate having a different crystal form can be obtained by the production method or the like. Korean Patent Registration No. 10-0536786 classifies these crystal forms of naphamostat mesylate into three types of crystal types I, II and III. Crystalline types I and II are those having high solubility of naphamostat mesylate (H ₂ O), the yield is low, and naphamostat mesylate having a low purity is obtained because it is decomposed in water. The crystalline Form III is a crystalline form prepared by dispersing naphamostat mesylate dissolved in water in a large amount of acetone at a temperature of 20 ° C or lower and crystallizing in a mixed solvent state and is produced as a very fine powder and has poor filtration property, The byproducts generated upon dissolution are precipitated at the same time to deteriorate the quality and react sensitively to minute changes in the conditions under which the crystals are formed. Thus, it is difficult to reproduce the crystals. In the temperature range of 25 to 45 캜, There are disadvantages.

Even though these drawbacks exist, a method of manufacturing the crystalline Form III which can improve it has not been developed yet, and thus, it has been searched yet. In general, a compound having many crystal forms may have different properties depending on the crystal form, and the stability may also be different. Particularly, in a compound mainly used as a medicine such as napamostat mesylate used as an anti-blood coagulant, constant quality and high purity are required, so that a stable product must be constantly produced and provided.

It is an object of the present invention to provide a process for producing naphamostat mesylate which can be produced at a high purity by reducing impurities.

Another object of the present invention is to provide a method for producing crystalline naphthamostat mesylate which can improve reproducibility so that it can be stably and continuously produced.

In order to achieve the above object, the present invention relates to a process for the production of (a) reacting 4-guanidinobenzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate in the presence of N, N'-diisopropylcarbodiimide Lt; RTI ID = 0.0 > 1 < / RTI > (b) adding the compound of formula 1 to a solvent mixed with water (H ₂ O) and saturated aqueous sodium hydroxide (NaHCO ₃ ) to produce a compound of formula 2; And (c) adding the compound of Formula 2 to the solvent followed by addition of methanesulfonic acid to produce a naphamostat mesylate compound of Formula 3: < EMI ID = ≪ / RTI >

[Structural formula 1]

[Structural formula 2]

[Structural Formula 3]

The process for preparing naphamostat mesylate according to the present invention comprises introducing a step of purifying impurities using N, N'-diisopropylcarbodiimide (DIC, N'-diisopropylcarbodiimide) as a coupling reagent Accordingly, it is possible to reduce the impurities and thereby produce naphamostat mesylate of high purity and high quality. In addition, by using a solvent in which isopropyl alcohol (IPA) and water (H ₂ O) are mixed so as not to produce other crystalline naphamostat mesylate other than the naphamostat mesylate having the crystalline Form III, The reproducibility is improved and the crystalline type III naphamostat mesylate can be produced stably and continuously, and therefore, the mass production process is made more commercially available, thereby enabling economical operation.

Fig. 1 is an X-ray diffraction analysis of crystalline naphtho mastat mesylate prepared by the process for producing naphamostat mesylate of the present invention. Fig.

Hereinafter, the present invention will be described in detail.

In order to prepare naphamostat mesylate according to the present invention, as shown in the following reaction scheme 1, first, in the presence of N, N'-diisopropylcarbodiimide, 4- (4-guanidino benzoic acid hydrochloride, 4-GDA.HCl) and 6-amidino-2-naphthol methanesulfonate (6-ANL.MsOH) To prepare the compound of formula 1.

[Reaction Scheme 1]

The amount of the 4-guanidinobenzoic acid hydrochloride is 0.9 to 1.3 equivalents, preferably 1 to 1.2 equivalents, more preferably 1.2 equivalents, relative to 1 equivalent of the 6-amidino-2-naphthol methanesulfonate, If the amount of guanidinobenzoic acid hydrochloride is out of the above range, the reaction yield may be decreased or a large amount of starting material may remain in the reaction solution.

The N, N'-diisopropylcarbodiimide (DIC) is obtained by coupling the 4-guanidinobenzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate. The 4-guanidinobenzoic acid hydrochloride (H ₂ O) produced by the reaction of 6-amidino-2-naphthol methanesulfonate with one molecule of water per molecule of N, N'-diisopropylcarbodiimide, The N, N'-diisopropylcarbodiimide combined with water is N, N'-diisopropylurea (DIU). The amount of the N, N'-diisopropyl carbodiimide is 1: 1.2 equivalent, preferably 1: 1.1 equivalent, more preferably 1: 1 equivalent based on the amount of the 4-guanidinobenzoic acid hydrochloride used If the amount of the N, N'-diisopropylcarbodiimide is less than 1 equivalent based on the amount of the 4-guanidinobenzoic acid hydrochloride used, the reaction may not be terminated, and if the amount is more than 1.2 equivalents , There may not be any further improvement in the effect.

The solvent used in the reaction may be a compound used in the reaction and a solvent that does not modify the reaction product. Preferably, pyridine may be used. The amount of the solvent to be used is 5 to 10 times (w / v), preferably 6 to 9 times (w / v), more preferably 7 to 8 times (w / v) relative to the amount of the 4-guanidinobenzoic acid hydrochloride used (w / v), when the content of the solvent is less than 5 times (w / v) with respect to the amount of the 4-guanidinobenzoic acid hydrochloride used (that is, when 5 g of the solvent is added to 1 g of 4-guanidinobenzoic acid hydrochloride ), A solid may be generated during the reaction, which may result in difficulty in stirring, and if it exceeds 10 times (w / v), no further effect may be obtained. On the other hand, the solvent alone can form (or precipitate) only the compound of the structural formula 1 by dissolving N, N'-diisopropyl urea (DIU) produced as a by-product in the reaction.

In addition, the reaction is preferably carried out in the presence of 4-dimethylaminopyridine (DMAP). The 4-dimethylaminopyridine serves as a catalyst. The amount of the 4-dimethylaminopyridine to be used is 0 to 2 mol, preferably 0.5 to 1.5 mol, per 100 mol of the 6-amidino-2-naphthol methanesulfonate Preferably 0.8 to 1.2 moles. If the 4-dimethylaminopyridine is not used or is used in a trace amount, the reaction proceeds but the reaction time may become excessively long, and the amount of the 4-dimethylaminopyridine to 100 moles of the 6-amidino-2-naphthol methanesulfonate When the content exceeds 2 moles, there is no further improvement effect.

The reaction is carried out at room temperature (1 to 35 ° C), preferably 10 to 35 ° C, more preferably 15 to 35 ° C, for 8 to 15 hours, preferably 10 to 12 hours, When the reaction temperature is lower than room temperature, the reaction may be delayed. When the reaction temperature is higher than room temperature, there is a high possibility that a side reaction occurs without improving the effect.

If necessary, the compound of formula 1 may be washed with a washing solution to further improve the purity. The washing solution may be one which does not modify the compound of the structural formula 1 or can decompose the unreacted active material and may be selected from the group consisting of methanol (MeOH), pyridine, and mixtures thereof Can be used. The washing solution is used after the compound of the structural formula 1 is mixed with a solvent or after the compound of the structural formula 1 is filtered to decompose the unreacted active substance contained in the compound of the structural formula 1, And the purity of the compound of formula 1 is increased when the composition is changed. When the washing liquid is used, the content thereof is preferably 10 to 30% (v / v), preferably 15 to 30% (v / v) when the content of the washing liquid is added to the washing liquid, (V / v), there is a possibility that the effect of the washing solution may be reduced. When it is more than 30% (v / v) Only yield can be reduced without.

When the compound of the formula 1 mixed with the solvent is washed with the washing solution, the washing solution is added to the solvent containing the compound of the formula 1 for 30 to 90 minutes, preferably 40 to 80 minutes, , Which may be further washed with a homogeneous or heterogeneous washing solution, preferably pyridine and / or acetone, with the washing solution, and the purification process for washing is carried out once (Multiple times).

If necessary, the washed and filtered compound of the structural formula 1 (in a state in which the impurities are not dried so as to minimize impurities) is added to the washing solution, stirred and filtered, and then the filtered compound of the formula 1 is treated with the same or different Further purification can be carried out by washing with different washings, preferably pyridine and / or acetone. On the other hand, the washing solution used before filtration is a mixture of two kinds of washing solutions (hereinafter referred to as first and second washing solutions), preferably methanol and pyridine, for example, 1 washing liquid for 5 to 20 minutes, preferably 5 to 15 minutes, more preferably 8 to 12 minutes, adding a second washing liquid such as pyridine thereto, and then stirring for 80 to 160 minutes, Preferably 100 to 140 minutes, more preferably 110 to 130 minutes, and then filtered.

Here, the content of the first washing liquid is 0.7 to 1.5 times (w / v) with respect to the content of the compound of the formula 1 (or the theoretical value of the compound represented by the formula 1 calculated to be produced by the reaction) (W / v), preferably 0.8 to 1.3 times (w / v), more preferably 0.9 to 1.1 times (w / v), and the content of the first washing liquid is 0.7 times ), There is a fear that the stirring may not be performed. If it is more than 1.5 times (w / v), the yield may decrease without any advantage. The content of the second washing liquid is 2 to 4 times (w / v), preferably 2.5 to 3.5 times (w / v), more preferably 2.8 to 3.2 times (w / v) ). When the content of the second washing liquid is less than 2 times (w / v) with respect to the content of the compound of the formula 1, the yield may decrease, and when the content of the second washing liquid is more than 4 times (w / v) , There is a concern that the purity may be lowered without further advantage. Accordingly, the content ratio of the compound of Formula 1, the first washing solution and the second washing solution is 1: 0.7 to 1.5 (w / v): 2 to 4 (w / v), preferably 1: 0.9 to 1.1 1 (w / v): 3 (w / v) in view of yield and purity, and more preferably 2.5 to 3.5 (w / v).

Next, as shown in the following Reaction Scheme 2, the compound of the structural formula 1 (a state in which the impurities are not dried so as to minimize impurities) is mixed with water (H ₂ O) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) ≪ / RTI > to give the compound of formula 2.

[Reaction Scheme 2]

When the compound of the formula 1 is added to the mixed solvent, it is preferable to slowly perform the reaction at a temperature of 20 to 30 ° C, preferably 23 to 27 ° C for 40 to 80 minutes, preferably 50 to 70 minutes , Stirring is carried out after or after the addition is started, and then the compound of formula 2 in the crystalline form can be filtered. On the other hand, if necessary, the filtrate may be washed with a washing solution to further improve the purity of the compound of the formula 2. The washing solution may be one that does not modify the compound of the structural formula 2, for example, may be selected from the group consisting of methanol, pyridine, acetone, water, and mixtures thereof. Preferably, water and acetone And can be carried out once or multiple times (multiple times).

Subsequently, as shown in the following Reaction Scheme 3, the compound of the structural formula 2 (in a state in which the impurities are not dried so as to minimize impurities) was added to the solvent, and methanesulfonic acid was added thereto, To prepare a mesostat mesylate compound.

[Reaction Scheme 3]

The compound of formula 2 is added to and dispersed in the solvent at room temperature, preferably at 10 to 35 占 폚, more preferably at 15 to 35 占 폚, and the solvent may be used without limitation Preferably a conventional organic solvent, more preferably methanol. After the addition of methanesulfonic acid, stirring is preferably carried out until no gas is generated. When stirring is completed, the mixture is cooled to 10 to 20 占 폚, preferably 12 to 18 占 폚, more preferably to 14 to 16 占 폚, followed by cooling for 5 to 15 minutes, preferably 7 to 13 minutes, Is stirred for 9 to 11 minutes at the same temperature as the cooling temperature, and then the compound of formula 3 (naphamostat mesylate) in crystalline form can be filtered.

On the other hand, if necessary, the filtrate may be washed with a washing solution to further improve the purity of the compound of the formula 3. The washing solution may be one which does not modify the compound of the structural formula 3. For example, the washing solution may be selected from the group consisting of methanol, acetone, and mixtures thereof. Preferably, the washing solution is prepared by sequentially using methanol and acetone And the compound of the formula 3 can be dried once or several times, and then the compound of the formula 3 can be dried to prepare a naphamostat mesylate having high purity by the simplified naphamostat mesylate production method can do.

Next, in order to stably and continuously prepare the naphamostat mesylate, water (H ₂ O) and water (H ₂ O) were added to the naphamostat mesylate of the above-prepared structural formula 3 (in a state that the impurities were not dried to minimize impurities) And a solvent for dissolution and dispersion containing isopropyl alcohol (IPA) are successively mixed to prepare a crystalline type III naphamostat mesylate.

In order to prepare naphamostat mesylate in the crystalline form III, it is necessary to mix and disperse the naphamostac mesylate and the solvent, and to dissolve and disperse the crystals to precipitate the crystals. The conventionally used acetone is a very nonpolar organic solvent, Is dispersed in acetone, it is difficult to obtain pure crystalline III-form naphamostat mesylate by precipitating as solid from the initial stage of dropwise addition. Therefore, in the present invention, isopropyl alcohol (IPA) is used as a solvent which is more polar than acetone. First, in a solvent for dissolving non-cooled ordinary water and isopropyl alcohol, It is preferable to add a small amount of water to isopropyl alcohol and then add a cooling solvent for dispersion in order to slightly increase the polarity and slow the precipitation time of crystals after adding statam mesylate.

The mixing ratio of the naphamostat mesylate and the solvent for dissolving is preferably 2.8 to 3.2 (w / v), 1: 1.8 to 2.2 (w / v) of Napamostat mesylate: water: isopropyl alcohol (W / v): 1.9 to 2.1 (w / v): 2.9 to 3.1 (w / v), more preferably 1: 2 Is dissolved at a temperature of 45 to 55 占 폚, more preferably 45 to 50 占 폚.

The mixing ratio of water and isopropyl alcohol constituting the dispersion solvent is 1: 26 to 28 (v / v), preferably 1 (v / v): 26.5 to 27.5 (v / v) , More preferably 1 (v / v): 27 (v / v), and after mixing, should be cooled to 3 to 12 캜, preferably 4 to 11 캜, more preferably 5 to 10 캜.

After the dispersion solvent is added to the mixture of the naphamostat mesylate and the dissolution solvent, it is preferable to cool and stir for 15 to 25 minutes, preferably 17 to 22 minutes, and more preferably 19 to 21 minutes , And the resulting crystals are filtered and dried to prepare naphamostat mesylate in crystalline form III.

On the other hand, it is preferable to filter the insoluble matter contained in the mixed solution before adding the dispersing solvent to the mixed solution of the naphamostat mesylate and the dissolution solvent. On the other hand, if necessary, it may be washed with a washing solution in order to further improve the purity of the filtered crystalline Form III napamostamp mesylate. The washing solution may be one which does not modify the crystalline type III naphamostat mesylate. For example, it may be selected from the group consisting of isopropyl alcohol, acetone, and mixtures thereof, preferably acetone, This process can be carried out once or several times (multiple times).

On the other hand, the ratio of water constituting the dissolution solvent to isopropyl alcohol may be 3 (v / v): 0 to 3 (v / v) considering the solubility of the naphamostat mesylate in water , The mixing ratio of water and isopropyl alcohol in the solvent finally obtained is from 2.8 to 3.2 (v / v): 28 to 32 (v / v), preferably from 2.9 to 3.1 (v / v) (v / v): 30 (v / v), because water and isopropyl alcohol constituting the dispersion solvent should be 0 (v / v) v). Therefore, the ratio of the water constituting the dissolution solvent to isopropyl alcohol (IPA) is 1.8-2.2 (w / v): 2.8-3.2 (w / v) by the fine crystallization condition, The crystalline form I or II form can be obtained in addition to the crystalline form III, except that the ratio of the constituent water and isopropyl alcohol (IPA) is 1 (v / v): 26 to 28 (v / v) , The reproducibility of achieving the same production is lowered, so that the possibility of stably producing crystalline napharmostat mesylate in crystalline form III is lowered. Fig. 1 is an X-ray diffraction pattern of crystalline naphtho mastat mesylate prepared by the process for producing naphamostat mesylate of the present invention, which shows a peak unique to crystalline naphthol mastat mesylate Able to know.

On the other hand, when the amount of the finally obtained solvent is larger than the amount of the solvent for dissolution and dispersion used, there is a possibility that the yield is lowered, and the amount of the solvent for dissolution depending on the solubility of the naphamostat mesylate The amount of the finally obtained solvent is smaller than the amount of the solvent for dissolution and dispersion used as long as the ratio of water contained in the finally obtained solvent and isopropyl alcohol (IPA) is maintained Quality concerns are low.

As described above, the coupling reagent of 4-guanidinobenzoic acid hydrochloride (4-GDA.HCl) and 6-amidino-2-naphthol methanesulfonate (6-ANL.MsOH) (N, N'-diisopropylurea, DIU) produced as a by-product after the reaction is reacted with an organic solvent used in the reaction The compound of the structural formula 1 can be filtered and precipitated singly. Therefore, when N, N'-dicyclohexylcarbodiimide (DCC) was used as a coupling reagent for 4-guanidino benzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate, N, N'-dicyclohexylurea (DCU) was not dissolved in the organic solvent, and the filtration was improved as compared with the case where the N, N'-dicyclohexylurea (DCU) was filtered at the same time as the precipitate. In addition, since only the compound of the structural formula 1 is filtered out, it is possible to perform an additional purification process which was not possible in the production of the existing naphamostat mesylate, thereby increasing the purity of the compound. The naphamostat mesylate, which is an end product, as well as the compound of the structural formula 2 can be easily obtained with high purity. Further, since the compound of formula 2 is prepared in the state where the impurities are removed, there is also an advantage that the time existing in water can be minimized. Further, by using the naphamostat mesylate together with isopropyl alcohol (IPA) which is more polar than the organic solvent used in the past, the reproducibility is improved, and the crystalline naphthamate can be stably and continuously produced .

Hereinafter, the present invention will be described in more detail with reference to specific examples. The following examples illustrate the present invention and are not intended to limit the scope of the present invention.

[Example 1] Preparation of naphamostat mesylate using N, N'-diisopropylcarbodiimide (DIC)

25.94 g of 4-guanidino benzoic acid hydrochloride (4-GDA.HCl) was added to 207.5 ml of pyridine solvent at room temperature, and 18.6 ml of N, N'-diisopropylcarbodiimide (DIC) . Next, 28.3 g of 6-amidino-2-naphthol methanesulfonate (6-ANL.MsOH) and 122 mg of 4-dimethylaminopyridine (DMAP) were added to the reaction solution containing the above reaction, And stirred overnight at the same temperature as the reaction. Subsequently, 69.3 ml of methanol (MeOH) was added to the stirred reaction mixture, which was stirred for 1 hour, filtered, and then washed sequentially with an appropriate amount of pyridine and acetone to prepare a compound represented by the above formula (1). Next, the compound of formula (1) was suspended in 48 ml of methanol for 10 minutes without drying, 144 ml of pyridine was added thereto, stirred for 2 hours, filtered, Further purification was carried out by sequentially washing again. Subsequently, the compound of formula (1), which had been purified by further purification to 99% purity, was treated with 233.28 ml of water (H ₂ O) and 92.73 ml of saturation (Purity: 50% by mass) was obtained by gradually adding sodium hydroxide (NaHCO ₃ ) to a mixed solution (solvent) and stirring to precipitate crystals. The crystals were collected by filtration and then sequentially washed with water and acetone, 98.9%). Next, the compound of Formula 2 was dispersed in 72.87 ml of methanol without being dried at room temperature, 9.3 ml of methanesulfonic acid (MsOH) was gradually added, Was continuously stirred until no reaction occurred. The resulting solid was filtered, washed successively with methanol and acetone, and dried in hot air at a temperature of 50 ° C. to obtain a naphtha according to the formula 3 30.97 g of moscat mesylate was obtained (purity: 99.1%, yield: 62.78%).

[Example 2] Preparation of crystal form III napamostat mesylate

After adding 50.1 g of Napamosstat mesylate to a solvent for dissolving 133.6 ml of water and 150.3 ml of isopropyl alcohol (IPA), the mixture was heated to 45 ° C to dissolve and react. Then, 10.02 g of Activated carbon was added and stirred for 10 minutes at the same temperature as the above-mentioned reaction, followed by filtration. Then, 16.7 ml of water and 1,352.7 ml of isopropyl alcohol (IPA) were mixed, and the filtrate by filtration was added to the dispersion solvent which had been previously cooled to 5 to 10 占 폚 over 5 minutes, The crystals formed by cooling and stirring were filtered, washed with acetone, and then dried with hot air at 50 ° C to obtain 42.89 g of crystalline naphthamostat mesylate (purity: 99.7%, yield: 85.6%).

[Comparative Example] Preparation of naphamostat mesylate using N, N'-dicyclohexylcarbodiimide (DCC)

A mixture prepared by adding 8.6 g of 4-guanidino benzoic acid hydrochloride and 9 g of N, N'-dicyclohexylcarbodiimide (DCC) to 100 ml of pyridine was added to ice- Lt; / RTI > for 1 hour (mixture A). Further, 113 g of 6-amidino-2-naphthol methanesulfonate was added to 100 ml of pyridine to prepare a mixture (mixture B). Next, the mixture B was added to the mixture A for 1 hour under an ice-cooling temperature and stirred, and then the mixture in which the mixture A and B were completely mixed was stirred for 1 hour at an ice-cooling temperature, . The precipitated crystals were filtered and washed with pyridine and acetone to prepare the compound according to the formula (1) (purity: 92.3%). Subsequently, the compound of Formula 1 was dissolved in about 200 ml of water, and the insoluble material N, N'-dicyclohexylurea (DCU) was filtered. To the remaining solution, hydrogen carbonate A saturated aqueous solution of sodium was added to precipitate pale yellow crystals and the crystals were washed with water and acetone to give the compound according to Formula 2 (purity: 93.5%). Next, the compound of Chemical Formula 2 was added to 100 ml of methanol and suspended. 17 g of methanesulfonic acid was added thereto to prepare a clear solution which was foamed. To this, about 200 ml of ethyl ether was added The white precipitated crystals were collected by filtration and collected to obtain naphamostat mesylate (purity: 94.2%) using N, N'-dicyclohexylcarbodiimide (DCC).

Claims (7)

(a) reacting 4-guanidinobenzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate in the presence of N, N'-diisopropylcarbodiimide to prepare a compound of formula 1;
(b) adding the compound of formula 1 to a solvent mixed with water (H ₂ O) and saturated aqueous sodium hydroxide (NaHCO ₃ ) to produce a compound of formula 2; And
(c) a step of preparing a naphamostac mesylate compound represented by the following structural formula 3 by adding the above-prepared compound of the structural formula 2 to a solvent and then adding methanesulfonic acid thereto .
[Structural formula 1]

[Structural formula 2]

[Structural Formula 3]

The process according to claim 1, wherein the naphamostat mesylate compound of formula 3 is prepared by mixing water and a solvent for dissolution and dispersion containing isopropyl alcohol in order to prepare naphamostat mesylate of crystalline form III ≪ / RTI > 3. The method of claim 2, wherein the mixing ratio of water and isopropyl alcohol constituting the dissolution solvent is 1: 1.8-2.2 (w / v): 2.8-3.2 (w / v) Wherein the mixing ratio of water and isopropyl alcohol constituting the solvent is 1 (v / v): 26 to 28 (v / v), and the dispersing solvent should be cooled to 3 to 12 캜. ≪ / RTI > The method of claim 1, wherein the amount of 4-guanidinobenzoic acid hydrochloride used in step (a) is 0.9 to 1.3 equivalents based on 1 equivalent of the 6-amidino-2-naphthol methanesulfonate, The amount of diisopropylcarbodiimide is 1: 1.2 equivalent based on the amount of the 4-guanidinobenzoic acid hydrochloride used. The solvent used in the reaction is pyridine, the amount of which is used in the amount of 4-guanidinobenzoic acid hydrochloride Dimethylaminopyridine catalyst used in the reaction is used in an amount of 0 to 2 moles relative to 100 moles of the 6-amidino-2-naphthol methanesulfonate used ≪ / RTI > The method of claim 1, wherein the reaction of step (a) is carried out at room temperature for 8 to 15 hours. The method according to claim 1, wherein the compound prepared in step (a) is washed with a washing solution selected from the group consisting of methanol, pyridine and a mixture thereof, and the compound prepared in step (b) is methanol, pyridine, And a mixture thereof, and the compound prepared in the step (c) is washed with a washing solution selected from the group consisting of methanol, acetone and a mixture thereof, and in the step (a) Lt; RTI ID = 0.0 > 1, < / RTI > wherein the compound of formula 1 is capable of further purification. The process according to claim 1, wherein each compound produced in steps (a), (b) and (c) is not dried but proceeds to the next step.

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