KR102314436B1 - Process for Preparing Nafamostat Mesilate and Intermediate Thereof - Google Patents

Abstract

The present invention provides a method for efficiently manufacturing nafamostat mesylate through a simple process and a method for manufacturing 6-amidino-2-naphthol mesylate, which is an intermediate for the manufacture of nafamostat mesylate, in high yields under mild conditions.

Description

Method for preparing nafamostat mesilate and intermediates thereof {Process for Preparing Nafamostat Mesilate and Intermediate Thereof}

The present invention relates to a method for preparing nafamostat mesylate and an intermediate thereof, and more particularly, to a method for efficiently producing nafamostat mesylate through a simple process and 6-, which is an intermediate for preparing nafamostat mesylate. It relates to a method for preparing amidino-2-naphthol mesylate in high yield under mild conditions.

Napamostat mesylate is a generic name for 6'-amidino-2'-naphthyl 4-guanidinobenzoate 2 mesylic acid represented by the following formula (1), and is a pancreatitis symptom improving agent, anticoagulant, antiplatelet agent, and fibrinolytic agent. It is a drug used as

[Formula 1]

A method for preparing napamostat mesylate is disclosed in Korean Patent Publication No. 1986-0000254. Specifically, as shown in Scheme 1 below, 4-guanidinobenzoic acid hydrochloride (III) and 6-amidino-2-naphthol mesylate (II) are N,N'- as a coupling agent. The ester compound (IV) was obtained in the form of crystals by coupling reaction using dicyclohexylcarbodiimide (DCC), and then the resulting crystals were filtered and washed, and then dissolved in water to form N,N'- as a reaction by-product. A method for preparing nafamostat mesylate by removing dicyclohexylurea (DCU), adding sodium hydrogen carbonate to the filtrate to obtain carbonate (V), suspending the carbonate in methanol, and then adding methanesulfonic acid has been

[Scheme 1]

In addition, in Korean Patent No. 10-1595747, napamostat mesylate was prepared as shown in Scheme 1 using N,N'-diisopropylcarbodiimide (DIC) as a coupling agent. A method of making is disclosed.

However, in the conventional method for preparing napamostat mesylate, carbonate (V) must be passed through, and the carbonate (V) is face-like crystals, so it is difficult to filter and wash, and the filtration rate is 4.19 mL/π min (reduced pressure of 21). mmHg), so there is a problem in that productivity is significantly lowered.

Korean Patent Publication No. 1986-0000254 Republic of Korea Patent Registration No. 10-1595747

As a result of intensive research and review to solve the above problems in the preparation of nafamostat mesylate, the present inventors used 4-guanidinobenzoic acid mesylate instead of 4-guanidinobenzoic acid hydrochloride to pass through nafamostat carbonate. It was found that nafamostat mesylate can be mass-produced in a one-step process without doing so, and the present invention was completed.

Accordingly, it is an object of the present invention to provide a method for efficiently preparing nafamostat mesylate through a simple process.

Another object of the present invention is to provide a method for efficiently producing 6-amidino-2-naphthol mesylate, which is an intermediate for the production of nafamostat mesylate, under mild conditions.

One embodiment of the present invention is nafamostat mesyl of the following formula (1) comprising the step of reacting 6-amidino-2-naphthol mesylate of the following formula (2) with 4-guanidinobenzoic acid mesylate of the following formula (3) It relates to a method for preparing an acid salt.

[Formula 2]

[Formula 3]

[Formula 1]

Hereinafter, the method for preparing nafamostat mesylate of the present invention will be described in more detail with reference to Scheme 2 below. The method described in Scheme 2 below is merely an example of a typically used method, and the reaction reagent, reaction conditions, etc. may be changed according to the case.

[Scheme 2]

The coupling reaction may be performed in the presence of N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC) as a coupling agent.

The amount of 4-guanidinobenzoic acid mesylate used in the coupling reaction may be 1 to 1.2 equivalents, preferably 1 to 1.1 equivalents, based on 1 equivalent of 6-amidino-2-naphthol mesylate.

The amount of the coupling reagent may be 1 to 1.2 equivalents, preferably 1 to 1.1 equivalents, based on 1 equivalent of 6-amidino-2-naphthol mesylic acid.

The reaction solvent used in the coupling reaction is preferably pyridine, and the amount used is preferably about 5 to 20 times (ml/g) of 6-amidino-2-naphthol mesylate, and 8 to 12 times more preferred.

The reaction temperature of the binding reaction is 4 to 20 hours, preferably 6 to 18 hours under the conditions of room temperature (1 to 35 ° C), preferably 10 to 35 ° C, more preferably 15 to 30 ° C. .

The manufacturing method according to an embodiment of the present invention includes the steps of performing the above-described binding reaction, filtering the produced nafamostat mesylate in solid form, washing with pyridine and acetone, and purifying the washed nafamostat mesylate with purified water. And it may further comprise the step of crystallizing with acetone.

When the coupling reaction is performed in the presence of N,N'-dicyclohexylcarbodiimide (DCC), the washed napamo is used to remove N,N'-dicyclohexylurea (DCU), a reaction by-product. Start mesylate can be dissolved in purified water and filtered, and the filtered filtrate can be crystallized with acetone.

The mixing ratio of purified water to nafamostat mesylate in the crystallization step is 3.0 to 10.0 (v/w), preferably 4.0 to 8.0 (v/w), more preferably 5.0 (v/w), and the dissolution temperature may be 30 to 60 ℃, preferably 45 to 55 ℃, more preferably 50 to 55 ℃.

The mixing ratio of purified water and acetone constituting the crystallization solvent is 1: 6 to 15 (v/v), preferably 1: 9 to 12 (v/v), and the temperature when acetone is added is 0 to 30 ° C., preferably may be 0 to 15 °C, more preferably 0 to 5 °C.

According to the production method of the present invention, by performing the binding reaction using 4-guanidinobenzoic acid mesylate instead of 4-guanidinobenzoic acid hydrochloride, napamostat carbonate, which is difficult to filter and wash and inhibits production efficiency, is passed through Napamostat mesylate can be prepared in a one-step process without

One embodiment of the present invention relates to a method for preparing 6-amidino-2-naphthol mesylate of Formula 2, the method of the present invention comprising:

(i) reacting the compound of formula (4) with hydroxylamine sulfonic acid in the presence of acetic acid to obtain a compound of formula (5);

(ii) reacting the compound of Formula 5 with thionyl chloride or acetyl chloride and methanol to obtain a compound of Formula 6;

(iii) reacting the compound of Formula 6 with ammonium carbonate to obtain a compound of Formula 7; and

(iv) reacting the compound of formula 7 with sodium hydrogen carbonate and then reacting with methanesulfonic acid.

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

Hereinafter, the method for preparing 6-amidino-2-naphthol mesylate of the present invention will be described in more detail with reference to Scheme 3 below. The method described in Scheme 3 below is merely an example of a typically used method, and the reaction reagents, reaction conditions, etc. may be changed according to the case.

[Scheme 3]

Step 1: Synthesis of the compound of formula (5)

A compound of Formula 5 can be prepared by reacting a compound of Formula 4 with hydroxylamine sulfonic acid in the presence of acetic acid.

The molar ratio of the compound of Formula 4 and hydroxylamine sulfonic acid is preferably 1:1 to 1:2, and more preferably 1:1.1.

The molar ratio of the compound of formula (4) to acetic acid is preferably 1:1 to 1:2, and more preferably 1:1.

The reaction solvent is purified water or a mixed solvent of purified water and an organic solvent, and the organic solvent is preferably acetonitrile (CH ₃ CN), tetrahydrofuran (THF), acetone, or the like.

The reaction temperature is preferably 50 to 60° C., and the reaction time is preferably 5 to 7 hours.

Step 2: Synthesis of the compound of formula (6)

The compound of Formula 6 can be prepared by reacting the compound of Formula 5 with thionyl chloride or acetyl chloride and methanol.

The molar ratio of the compound of Formula 5 to thionyl chloride or acetyl chloride is preferably 1:1 to 1:2, and more preferably 1:1.2.

The reaction temperature is preferably 0 to 30° C., the reaction time is 5 to 12 hours, and the reaction solvent is methanol.

The compound of Formula 6 can be used in the next reaction without a separate separation process.

Step 3: Synthesis of the compound of Formula 7

The compound of Formula 7 may be prepared by reacting the compound of Formula 6 with ammonium carbonate.

The molar ratio of the compound of Formula 6 and ammonium carbonate is preferably 1:5 to 1:10, the reaction temperature is preferably 10 to 35°C, and the reaction time is preferably 5 to 12 hours.

The compound of Formula 7 can be used in the next reaction without a separate separation process.

Step 4: Synthesis of the compound of formula (2)

The compound of Formula 2 can be prepared by reacting the compound of Formula 7 with sodium hydrogen carbonate and then reacting it with methanesulfonic acid. Specifically, it can be prepared by adding sodium hydrogen carbonate to the compound of Formula 7 to prepare a compound of Formula 8, suspending the compound of Formula 8 in methanol, and then adding methanesulfonic acid.

According to the manufacturing method of the present invention, there is no toxicity risk by excluding the use of a reaction reagent such as copper cyanide (CuCN) and a toxic gas such as hydrochloric acid gas or ammonia gas, and 6-amidino-2-naphthol under very mild reaction conditions Mesylate can be prepared in high yield.

4-guanidinobenzoic acid mesylate of Formula 3 used in the method for preparing napamostat mesylate according to an embodiment of the present invention can be prepared by a method known in the art [European Journal of Medicinal Chemistry] , 1996, vol. 31, # 11, p. 895 - 899].

According to the manufacturing method of the present invention, nafamostat mesylate can be efficiently produced through a simple process, and 6-amidino-2-naphthol mesylate, which is an intermediate for the preparation of the nafamostat mesylate, is highly purified under mild conditions. It can be prepared in yield.

Hereinafter, the present invention will be described in more detail by way of Examples. It is apparent to those skilled in the art that these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1: Preparation of 6-cyano-2-naphthol (5)

5000 g of purified water, 600 g of acetic acid, 1130.9 g of hydroxylamine sulfonic acid and 1721.8 g of 6-hydroxy-2-naphthylaldehyde were added, and the mixture was heated at 50-55° C. for 5 hours, and then cooled to room temperature. A 10% aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated and then concentrated. Ethanol and purified water were added to the concentrated residue in a ratio of (1w: 3w) for crystallization, followed by vacuum drying at 50-55° C. for 12 hours to obtain 1.45 kg of the title compound (yield: 85.7%).

Example 2: Preparation of 6-amidino-2-naphthol mesylate (2)

1.45 kg of 6-cyano-2-naphthol obtained in Example 1 and 3 kg of methanol were added and cooled to 0-5 °C. 1.22 kg of thionyl chloride was slowly added, stirred at 0-30° C. for 12 hours, and then concentrated in vacuo. 5.0 kg of methanol and 4.12 kg of ammonium carbonate were added to the concentrated residue, stirred at room temperature for 5 hours, filtered, and the filtered filtrate was concentrated in vacuo. After adding 10% aqueous sodium hydrogen carbonate solution to the concentrate and stirring for 30 minutes to neutralize, the resulting solid was filtered and washed with purified water. Methanol was added to the filtrate in a wet state, and methanesulfonic acid was slowly added until bubbles were not generated, stirred at room temperature for 2 hours, filtered, washed with acetone, and vacuum dried at 55 to 60° C. for 12 hours. Thus, 1.45 kg of the title compound was obtained (yield: 60%).

Example 3: Preparation of nafamostat mesylate (1)

1.0 kg of 6-amidino-2-naphthol mesylate (2) obtained in Example 2, 10.0 kg of pyridine, 1.02 kg of 4-guanidinobenzoic acid mesylate (3) and N,N'-dicyclohexylcarbodiimide (DCC) 0.8 kg was added and stirred at room temperature for 12 hours. The resulting solid was filtered and washed with pyridine and acetone to obtain nafamostat mesylate in a wet state. Napamostat mesylate in a wet state and 7.6 kg of purified water were added, and N,N'-dicyclohexylurea (DCU), an insoluble reaction by-product, was removed by filtration by heating to 50-55°C. The filtered filtrate was cooled to 0-5° C., 91.8 kg of acetone was added, and the resulting solid was filtered to obtain 12.07 kg of nafamostat mesylate (yield 63.2%). The filtration rate of the title compound at this time was 54.5 mL/π min.

Example 4: Preparation of Napamostat Mesylate (1)

1 kg of 6-amidino-2-naphthol mesylate (2) obtained in Example 2, 10 kg of pyridine, 1.24 kg of 4-guanidinobenzoic acid mesylate (3) and N,N'-diisopropylcarbodiimide (DIC) 0.5 kg was added and stirred at room temperature for 18 hours. The resulting solid was filtered and washed with pyridine and acetone to obtain nafamostat mesylate in a wet state. Napamostat mesylate in a wet state and 7.6 kg of purified water are added, dissolved by heating to 50~55℃, cooled to 0~5℃, 91.8kg of acetone is added, the resulting solid is filtered, and napamostat mesyl is 1.18 kg of acid salt was obtained (yield 62.1%). The filtration rate of the title compound at this time was 53.9 mL/π min.

Claims (7)

(i) reacting a compound of Formula 4 with hydroxylamine sulfonic acid in the presence of acetic acid to obtain a compound of Formula 5, wherein the molar ratio of the compound of Formula 4 to acetic acid is 1:1 to 1:2, the temperature is 50 to 60 °C;
(ii) reacting the compound of Formula 5 with thionyl chloride or acetyl chloride and methanol to obtain a compound of Formula 6;
(iii) reacting the compound of Formula 6 with ammonium carbonate to obtain a compound of Formula 7;
(iv) reacting a compound of Formula 7 with sodium hydrogen carbonate and then reacting with methanesulfonic acid to obtain 6-amidino-2-naphthol mesylate of Formula 2; and
(v) a method for preparing nafamostat mesylate of the following formula (1), comprising the step of reacting 6-amidino-2-naphthol mesylate of the following formula (2) with 4-guanidinobenzoic acid mesylate of the following formula (3) :
[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 2]

[Formula 3]

[Formula 1]

. The preparation according to claim 1, wherein the binding reaction in step (v) is carried out in the presence of N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC) Way. The method of claim 1, wherein after the binding reaction in step (v), the solid form of nafamostat mesylate is filtered, washed with pyridine and acetone, and the washed nafamostat mesylate is purified with purified water and acetone. A manufacturing method further comprising the step of crystallizing. delete delete The method according to claim 1, wherein the molar ratio of the compound of Formula 5 and thionyl chloride or acetyl chloride in step (ii) is 1:1 to 1:2, and the reaction temperature is 0 to 30°C. The method according to claim 1, wherein in step (iii), the molar ratio of the compound of Formula 6 and ammonium carbonate is 1:5 to 1:10, and the reaction temperature is 10 to 35°C.