KR20220145941A - Method for manufacturing of guanidino-benzoate sulfonic acid compound - Google Patents

Abstract

The present invention provides a novel method for manufacturing a 6-amidino-2-naphthyl 4-guanidino-benzoate dimethanesulfonic acid salt, which is a useful compound as a serine protease inhibitor, wherein the method has a simple process, is capable of obtaining a product of high purity and high yield, and is economical. The method for manufacturing a guanidino-benzoate sulfonic acid compound according to the present invention comprises the steps of: (a) preparing a thioester compound by mixing a first guanidino-benzoic acid compound, a phosphine compound, and a disulfide compound; (b) preparing a second guanidino-benzoic acid compound by mixing the thioester compound with a first sulfonic acid compound; and (c) preparing a guanidino-benzoate sulfonic acid compound by mixing the second guanidino-benzoic acid compound with a second sulfonic acid compound.

Description

guanidino-benzoate sulfonic acid compound manufacturing method

The present invention relates to a novel method for preparing a guanidino-benzoate sulfonic acid compound, which is a compound useful as a serine protease inhibitor. A compound having a leaving group having good activity in the group (-COOH) is prepared, and the second guanidinobenzoic acid compound is prepared by continuously reacting it with the first sulfonic acid compound with or without isolation, and then the second It relates to a method for economically useful and efficient production of a guanidino-benzoate sulfonic acid compound by reacting with a sulfonic acid compound.

6-amidino-2-naphthyl-4-guanidino-benzoate has antitrypsin, antiplasmin, antikallikrein and antithrombin activity and It is a serine protease inhibitor with anticomplement activity.

The 6-amidino-2-naphthyl-4-guanidino-benzoate is effective in preventing perfusion blood clotting during extracorporeal circulation of blood in patients with pancreatic disease such as pancreatitis, disseminated intravascular blood clotting disease, and bleeding tendency. is a compound.

The dimethanesulfonic acid salt of the compound, that is, the compound represented by Formula 2 herein, is commercially available under the trade name 'Futhan ^® '.

With respect to the synthesis method of the compound, conventionally, 4-guanidinobenzoic acid hydrochloride was heated to reflux and activated to prepare 6-amidino-2-naphthyl-4-guanidino-benzoate.

In addition, 6-amidino-2-naphthyl-4-guanidino-benzoate was prepared using N,N'-dicyclohexylcarbodiimide (N,N'-dicyclohexylcarbodiimide, DCC).

and treating the 6-amidino-2-naphthyl-4-guanidino-benzoate with an aqueous sodium hydrogen carbonate solution to prepare 6-amidino-2-naphthyl 4-guanidino-benzoate carbonate, This was treated with a solution containing methanesulfonic acid to prepare 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt.

In this preparation process, thionyl chloride is used as an esterification reaction activator.

The thionyl chloride is corrosive and difficult to handle due to its high reactivity.

Sulfur dioxide (SO ₂ ) and hydrogen chloride (HCl), which are reaction by-products, must be very careful because they can cause environmental pollution and a fatal risk to the human body. In addition, there is a disadvantage in that a scavenger reagent is used or an expensive removal facility is required for post-reaction treatment. In addition, DCC has a high price and is difficult to store because it is very hygroscopic. In the presence of moisture, the reactivity is low and must be reacted under anhydrous conditions. In addition, in order to remove N,N'-dicyclohexylurea (N,N-Dicyclohexylurea, DCU), which is a by-product after the activation reaction using DCC, several steps of physical and chemical treatment are required. In addition, since the target compound and its intermediate have very poor water stability, the longer the time they are dissolved in water during the post-treatment process and the purification process, the more impurities are generated. For this reason, the reaction yield (47.6%) is low, which is uneconomical, and there is a difficulty in mass production.

Meanwhile, using N,N'-diisopropylcarbodiimide (N,N-Diisopropylcarbodi imide, DIC) as an activator and 4-dimethylaminopyridine (DMAP) as a reaction catalyst, the 6-amidino-2 -Naphthyl-4-guanidino-benzoate compound can be prepared.

6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt can be prepared using water (H ₂ O) and saturated sodium bicarbonate (NaHCO ₃ ), methanesulfonic acid.

However, since this manufacturing method uses DIC, which is an expensive activator similar to DCC, N,N'-dicyclohexylurea (N,N-Diisopropylurea, DCU), which is a by-product generated after the reaction, is generated. And there is a disadvantage that several steps of physical and chemical treatment is required to remove it.

On the other hand, a desired compound can be prepared using 4,5-dicyanoimidazole (DCI) as an activator, but there is a disadvantage of low economic feasibility because an expensive activator (DCI) is used.

Therefore, there is a need for a new method for preparing 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt that is more efficient, economical and highly pure.

An object of the present invention is to provide a novel method for preparing a guanidino-benzoate sulfonic acid compound that is economical due to a simple reaction process, short reaction time, and high reaction efficiency.

It is also an object of the present invention to provide a novel method for preparing a guanidino-benzoate sulfonic acid compound that can be obtained with high purity and high yield.

It is also an object of the present invention to provide a novel method for preparing a guanidino-benzoate sulfonic acid compound that can be mass-produced.

It is also an object of the present invention to provide a novel method for preparing an environmentally friendly guanidino-benzoate sulfonic acid compound that does not cause environmental pollution and is not harmful to the human body.

The present invention comprises the steps of (a) preparing a thioester compound by mixing a first guanidinobenzoic acid compound, a phosphine compound, and a disulfide compound; (b) preparing a second guanidinobenzoic acid compound by mixing the thioester compound with a first sulfonic acid compound; and (c) mixing the second guanidinobenzoic acid compound with a second sulfonic acid compound to prepare a guanidino-benzoate sulfonic acid compound; provides

The novel manufacturing method of the present invention has the effect of a simple reaction process, a short reaction time, and a high reaction efficiency.

In addition, the novel manufacturing method of the present invention uses a reaction activator that is much cheaper than a reaction activator used in the past, and thus has an economical advantage.

In addition, the novel preparation method of the present invention can prepare a guanidino-benzoate sulfonic acid compound with high purity and high yield.

In addition, the novel manufacturing method of the present invention has the advantage that mass production is possible.

In addition, the novel manufacturing method of the present invention does not cause environmental pollution, is not harmful to the human body, and is environmentally friendly.

The above-described objects, features and advantages will be described below in detail with reference to the accompanying drawings, and accordingly, those skilled in the art to which the present invention pertains will be able to easily implement the technical idea of the present invention. In describing the present invention, if it is determined that a detailed description of a known technology related to the present invention may unnecessarily obscure the gist of the present invention, the detailed description will be omitted. Hereinafter, preferred embodiments according to the present invention will be described in detail with reference to the accompanying drawings. In the drawings, the same reference numerals are used to indicate the same or similar components.

Also, when it is described that a component is “connected”, “coupled” or “connected” to another component, the components may be directly connected or connected to each other, but other components are “interposed” between each component. It is to be understood that “or, each component may be “connected”, “coupled” or “connected” through another component.

Hereinafter, a method for preparing a guanidino-benzoate sulfonic acid compound according to some embodiments of the present invention will be described.

The present invention is a guanidino-benzoate sulfonic acid compound, which is a useful compound as a serine protease inhibitor, wherein 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt is more efficiently and economically prepared. An object of the present invention is to provide a novel manufacturing method that can be manufactured with high purity and high yield.

In the present invention, a thioester compound having a leaving group having good activity in the carboxy group (-COOH) of the first guanidinobenzoic acid compound is prepared using a phosphine compound and a disulfide compound, and the thioester compound is isolated or not separated. A second guanidinobenzoic acid compound was prepared by successively reacting with the first sulfonic acid compound, and then reacted with the second sulfonic acid compound to prepare a guanidino-benzoate sulfonic acid compound with high purity and high yield.

The "compound" referred to in the present invention includes various forms of isomers depending on the type of substituent, including mixtures thereof, and derivatives and salts thereof. The salt is a pharmaceutically acceptable salt of the compound, and may form an acid addition salt or a salt with a base depending on the type of the substituent.

Specifically, the salt is an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, Acid addition salts with organic acids such as tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc. and salts with organic bases such as inorganic bases, methylamine, ethylamine, ethanolamine, lysine and ornithine, and salts and ammonium salts with various amino acids and amino acid derivatives such as acetylleucine.

In the present invention, as a guanidino-benzoate sulfonic acid compound, to prepare 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt, first, first guanidinobenzoic acid The compound, the phosphine compound and the disulfide compound are mixed to prepare an intermediate thioester compound.

The step of preparing the thioester compound may be performed at 10 to 60° C. for 30 minutes to 36 hours, may be performed at 10 to 50° C., and preferably at 10 to 30° C. for 1 hour to 36 hours. and more preferably at 20-30° C. for 1 hour to 5 hours. By satisfying the above temperature range and time, mixing and stirring between the compounds can be sufficiently achieved, so that the compound to be synthesized can be obtained in high yield and high purity.

Conversely, when the temperature is out of the range and time, there is a problem in that the decomposition of the compound occurs.

The reaction may proceed by mixing an organic solvent with the compound in the step of preparing the thioester compound. The organic solvent may include an inert solvent such as a halogenated carbon compound or an aromatic carbon compound. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, benzene, toluene, xylene, and pyridine. Among them, at least one of dichloromethane and pyridine may be used in terms of easy removal of the organic solvent and increased reaction efficiency.

In the step of preparing the thioester compound, a total of 5 to 1000 g of the first guanidinobenzoic acid compound, the phosphine compound, and the disulfide compound may be mixed per 10 to 500 ml of the organic solvent, but is not limited thereto.

In the step of preparing the thioester compound, 1 to 2 moles of the phosphine compound and 1 to 2 moles of the disulfide compound may be mixed with respect to 1 mole of the first guanidinobenzoic acid compound. Preferably, 1 to 1.5 moles of the phosphine compound and 1 to 1.5 moles of the disulfide compound may be mixed.

By satisfying 1 to 2 moles of each of the phosphine compound and the disulfide compound, the reaction with the first guanidinobenzoic acid compound proceeds efficiently, and the synthesis of by-products can be minimized.

Conversely, when the amount of each of the phosphine compound and the disulfide compound is less than 1 mol, the reaction of the starting material does not proceed as much as the addition amount is insufficient, so that an amount of some starting material remains, and a process for removing them is required.

When each of the phosphine compound and the disulfide compound exceeds 2 moles, an excess of the compound remains and a process for removing it is required.

The first guanidinobenzoic acid compound may include 4-guanidinobenzoic acid hydrochloride (CAS42823-46-1) represented by Formula 1 below.

[Formula 1]

The 4-guanidinobenzoic acid hydrochloride is a starting material for the synthesis reaction, and is mixed with a phosphine compound and a disulfide compound to be described later.

The phosphine compound is a tri(4-tolyl)phosphine represented by the following Chemical Formula 2 in terms of reaction efficiency and economy, and a tri(2-furyl)phosphine (Tri(2) -furyl) phosphine) and triphenylphosphine (Tri-phenylphosphine) may include one or more.

[Formula 2]

wherein R ₁ =phenyl, 4-tolyl or 2-furyl.

The disulfide compound is diphenyl disulfide, 2,2'-dipyridyl disulfide, and 2,2'- represented by the following Chemical Formula 3 in terms of reaction efficiency and economy It may include at least one of dibenzothiazole disulfide (2,2'-Dibenzothiazyl disulfide).

[Formula 3]

wherein R ₂ =phenyl, 2-pyridyl or benzothiazole.

The thioester compound synthesized by mixing the first guanidinobenzoic acid compound, the phosphine compound, and the disulfide compound may include a compound represented by Formula 4 below.

[Formula 4]

wherein R ₂ =phenyl, 2-pyridyl or benzothiazole.

For example, the thioester compound may include benzothiazolyl-2-yl 4-guanidinobenzothioate represented by Formula A below.

[Formula A]

On the other hand, after synthesizing the thioester compound as an intermediate, isolation may be performed using an organic solvent. The organic solvent used for the separation is preferably a ketone solvent. For example, the organic solvent used for the separation may include at least one of acetone, methyl ethyl ketone, and methyl isopropyl ketone.

Then, the thioester compound is mixed with a first sulfonic acid compound to prepare a second guanidinobenzoic acid compound.

The step of preparing the second guanidinobenzoic acid compound may be performed at 10 to 70° C. for 30 minutes to 36 hours, and may be performed at 10 to 50° C., preferably at 10 to 30° C. for 12 hours to 36 hours. It may be carried out for a period of time, and more preferably, it may be carried out at 20 to 30° C. for 20 to 25 hours.

In this step, the reaction rate is proportional to the reaction temperature. For example, as the reaction temperature increases, the reaction rate tends to increase, and as the reaction temperature decreases, the reaction rate tends to decrease.

By satisfying the above temperature range and time, mixing and stirring between the compounds can be sufficiently achieved, so that the compound to be synthesized can be obtained in high yield and high purity.

Conversely, if the temperature is out of the range and time, mixing and stirring between the compounds may not be sufficiently performed, and thus the yield of the compound to be synthesized may be lowered. In particular, when the reaction temperature exceeds 70 °C, impurities are generated.

In the step of preparing the second guanidinobenzoic acid compound, the reaction may proceed by mixing the compound and an organic solvent. The organic solvent may include an inert solvent such as a halogenated carbon compound or an aromatic carbon compound. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, benzene, toluene, xylene, and pyridine. Among them, at least one of dichloromethane and pyridine may be used in terms of easy removal of the organic solvent and increased reaction efficiency.

Oxide phosphine compounds, sulfide compounds, etc., which are by-products generated in this step or already generated in this step, are easy to remove because they are easily dissolved in the inert solvent, and the main product is easily separated (isolated) because it shows poor solubility in the inert solvent. ) is characteristic.

In the step of preparing the second guanidinobenzoic acid compound, a total of 5 to 1000g of the second guanidinobenzoic acid compound and the first sulfonic acid compound may be mixed per 10 to 500ml of the organic solvent, but is not limited thereto.

In the step of preparing the second guanidinobenzoic acid compound, the addition standard of the first sulfonic acid compound may vary depending on whether the thioester compound is separated. When the synthesized compound is separated, impurities and by-products are removed to secure higher purity and higher yield.

After isolating the thioester compound, 0.5 to 2 moles of the first sulfonic acid compound may be mixed with respect to 1 mole of the separated thioester compound. Preferably, 0.7 to 1.5 moles of the first sulfonic acid compound may be mixed.

Alternatively, 0.5 to 2 moles of the first sulfonic acid compound may be mixed with respect to 1 mole of the first guanidinobenzoic acid compound without separating the thioester compound. Preferably, 0.7 to 1.2 moles of the first sulfonic acid compound may be mixed, and more preferably 0.88 to 1.1 moles.

When the first sulfonic acid compound satisfies 0.5 to 2 moles, the reaction with the thioester compound proceeds efficiently, and the synthesis of by-products can be minimized.

Conversely, when the amount of the first sulfonic acid compound is less than 0.5 mol, the reaction rate is not affected, but the thioester compound remains and a process of removing it is required.

When the amount of the first sulfonic acid compound exceeds 2 moles, an excess of the first sulfonic acid compound remains and a process for removing the first sulfonic acid compound is required, which may affect the yield.

The first sulfonic acid compound may include 6-amidino-2-naphthol methanesulfonate represented by Formula 5 below.

[Formula 5]

The second guanidinobenzoic acid compound synthesized by mixing the thioester compound and the first sulfonic acid compound is 6-amidino-2-naphthyl-4-guanidino- benzoate.

[Formula 6]

Finally, the second guanidinobenzoic acid compound is mixed with the second sulfonic acid compound to prepare a guanidino-benzoate sulfonic acid compound.

Since the second guanidinobenzoic acid compound reacts with the second sulfonic acid compound, it is advantageous for mass production and industrially more useful.

The step of preparing the guanidino-benzoate sulfonic acid compound may be carried out at 10-50 ° C. for 30 minutes to 36 hours, preferably at 10-30 ° C. for 12 hours to 36 hours, more Preferably, it may be carried out at 20 to 30° C. for 20 to 25 hours.

By satisfying the above temperature range and time, mixing and stirring between the compounds can be sufficiently achieved, so that the compound to be synthesized can be obtained in high yield and high purity.

In the step of preparing the guanidino-benzoate sulfonic acid compound, the reaction may proceed by mixing an organic solvent with the second guanidinobenzoic acid compound and the second sulfonic acid compound. The organic solvent may include a C1-C4 alkyl alcohol solvent. Preferably, it may include at least one of ethanol, methanol, and isopropyl alcohol, and more preferably, it may include methanol.

In the step of preparing the guanidino-benzoate sulfonic acid compound, a total of 5 to 1000 g of the second guanidinobenzoic acid compound and the second sulfonic acid compound per 10 to 500 ml of the organic solvent may be mixed, but is not limited thereto.

In the step of preparing the guanidino-benzoate sulfonic acid compound, 1 to 2.5 moles of the second sulfonic acid compound may be mixed with respect to 1 mole of the second guanidinobenzoic acid compound. Preferably, 1.8 to 2.2 moles of the second sulfonic acid compound may be mixed.

Since the target compound of the second sulfonic acid compound is a methanesulfonic acid salt, it is preferable to always use 2 moles or more of the second sulfonic acid compound.

By satisfying 1 to 2.5 moles of the second sulfonic acid compound, the reaction with the second guanidinobenzoic acid compound proceeds efficiently, and the synthesis of by-products can be minimized.

Conversely, when the amount of the second sulfonic acid compound exceeds 2.5 moles, discoloration occurs during drying.

The second sulfonic acid compound may include methanesulfonic acid.

The guanidino-benzoate sulfonic acid compound synthesized by mixing the second guanidinobenzoic acid compound with the second sulfonic acid compound is 6-amidino-2-naphthyl-4-guanidino represented by the following Chemical Formula 7 -benzoate dimethanesulfonic acid salt.

[Formula 7]

As such, in the present invention, 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt represented by Chemical Formula 7 is prepared through a novel preparation method with a simple reaction process and high reaction efficiency. It can be prepared with high purity and high yield.

The 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt is also called 6-amidino-2-naphthyl-4-guanidino-benzoate dimesylate, serine It can be used as a protease inhibitor.

As described above, specific examples of the method for preparing the guanidino-benzoate sulfonic acid compound are as follows.

[Example 1]

1) Preparation of benzothiazolyl-2-yl 4-guanidinobenzothioate (Benzothiazol-2-yl 4-Guanidinobenzothioate).

To a solution of 6.13 g of triphenylphosphine in 100 ml of dichloromethane was added 7.77 g of 2,2'-dibenzothiazole disulfide, stirred for 30 minutes, and 5.04 g of 4-guanidinobenzoic acid hydrochloride and 3.26 triethylamine ml was added.

After stirring at 25°C for 2 hours and confirming the completion of the reaction, the solvent was evaporated under reduced pressure at 25°C to obtain a pale yellow solid. After adding 70 ml of acetone to the solid, the mixture was stirred at 25° C. for 2 hours, and the resulting solid was filtered and 5.75 g of pale yellow benzothiazolyl-2-yl 4-guanidinobenzothioate (90%, HPLC purity 99.7%). ) was obtained.

m.p : 278 ~ 284℃

¹ H NMR (400MHz, DMSO): δ 7.07 ~ 8.10(m, 12H)

IR (cm ^-1 ): 3374, 1590, 1514, 1336, 1230

2) Preparation of 6-amidino-2-naphthyl-4-guanidinobenzoate dimethanesulfonic acid salt.

To a solution of 5.0 g of benzothiazolyl-2-yl 4-guanidinobenzothioate in 50 ml of pyridine, 3.64 g of 6-amidino-2-naphthol methanesulfonic acid salt was added and stirred at 25° C. for 24 hours. After confirming the completion of the reaction, the resulting solid was filtered, and the filtrate was washed with pyridine and acetone. The solid was suspended in 15 ml of methanol and stirred at 10° C. for 10 minutes, and then 1.67 ml (2eq) of methanesulfonic acid was added dropwise so as not to exceed 30° C. After stirring at 25° C. for 1 hour, the solid was filtered, the filtrate was washed with methanol and acetone, and dried under reduced pressure at 50° C. for 8 hours. 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfur 15.77 g (75%, HPLC purity 99.6%) of the phonic acid salt were obtained.

¹ H NMR (400 MHz, DMSO) δ 2.41 (s, 6H, -SO ₂ CH ₃ ), 7.46 (d, 2H, Ar H ), 7.65 (dd, 1H, Ar H ), 7.87 to 7.89 (m, 5H , Ar H , NH ₂ ), 8.02 (s, 1H, ArH), 8.17 to 8.27 (m, 4H, ArH), 8.57 (s, 1H, Ar H ), 9.19 (s, 2H, Ar H ,), 9.47 (s, 2H, Ar H ), 10.24 (s, 1H, NH)

[Example 2]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt.

To a solution of 12.26 g of triphenylphosphine in 100 ml of pyridine, 15.55 g of 2,2'-dibenzothiazole disulfide was added, and after stirring for 30 minutes, 10.08 g of 4-guanidinobenzoic acid hydrochloride was added. After stirring at 25° C. for 1 hour, 11 g of 6-amidino-2-naphthol methanesulfonate was added, followed by stirring for 24 hours. After confirming the completion of the reaction, the resulting solid was filtered, and the filtrate was washed with pyridine and acetone.

The filtered solid was suspended in 39 ml of methanol, stirred at 10° C. for 20 minutes, and 5.06 ml (2eq) of methanesulfonic acid was added dropwise so as not to exceed 30° C. After stirring at 25° C. for 1 hour and filtering the solid, the filtrate was washed with methanol and acetone. The filtrate was dried under reduced pressure at 50° C. for 8 hours to obtain 15.35 g (73%, HPLC purity 99.5%) of 6-amidino-2-naphthyl-4-guanidinobenzoate dimethanesulfonic acid salt.

[Example 3]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt.

In the same manner as in Example 2, using 14.23 g of tri-(4-tolyl) phosphine and 15.55 g of 2,2'-dibenzothiazole disulfide, 6-amidino-2- 14.30 g (64%, HPLC purity 99.5%) of naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt was obtained.

[Example 4]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt.

6-amidino-2-naphthyl 4-guanidinobenzoate disulfide using 10.86 g of tri(2-furyl)phosphine and 15.55 g of 2,2'-dibenzothiazole disulfide in the same manner as in Example 2 14.82 g (70.5%, HPLC purity 99.3%) of methanesulfonic acid salt were obtained.

[Example 5]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt.

In the same manner as in Example 2, using 12.26 g of triphenylphosphine and 10.21 g of diphenyl disulfide, 15.14 g of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt (72%, HPLC) purity of 99.3%) was obtained.

[Example 6]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt.

In the same manner as in Example 2, using 12.26 g of triphenylphosphine and 10.30 g of 2,2'-dipyridyl disulfide, 15.77 g of 6-amidino-2-naphthyl 4-guanidinobenzoate dimesylate ( 75%, HPLC purity 99.4%) was obtained.

[Comparative example]

Preparation of 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonic acid salt [Formula 2] according to Example 15 described in Korean Patent No. 10-0021328, [Example 15] (Compound number 27)

Synthesis of 6-amidino-2-naphthyl 4-guanidinobenzoate:

<Method A>

To 100 ml of thionyl chloride was added 21.6 g of 4-guanidinobenzoic acid hydrochloride. The mixture is refluxed for one hour and heated with stirring. When n-hexane is added to the reaction mixture, pale yellow crystals of 4-guanidinobenzoyl chloride hydrochloride are obtained. In 200 ml of pyridine, 28.2 g of 6-amidino-2-naphthol ditansulfonate is dissolved. To the resulting solution, 4-guanidinobenzoyl chloride hydrochloride obtained above is added under ice-cooling. The mixture is ice-cooled and stirred for 1 hour, then stirred overnight at room temperature. After the reaction is completed, the reaction mixture is mixed with about 300 ml of ethyl ether. The separated oil is dissolved in about 300 ml of water, and the insoluble matter is filtered off.

When a saturated aqueous solution of sodium bicarbonate is added to the filtrate, pale yellow crystals are collected. The crystals were collected by filtration and washed with water and acetone to obtain 30 g (yield 63.7%) of 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate. The carbonate is suspended in 100 ml of methanol. When 17 g of methanesulfonic acid is added to the suspension, the clear solution formed produces effgrvescence. About 200 ml of ethyl ether was added to the solution, and the precipitated white crystals were collected by filtration to obtain 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate. 6-amidino-2-naphthyl 4-guanidinobenate di-p-toluenesulfonate is obtained in a similar manner. 6-amidino-2-naphthyl 4-guanidino benzoate dihydrochloride is obtained by adding a mixture of DMF-HCl to the obtained carbonate.

<Method B>

To 100 ml pyridine are added 8.6 g of 4-guanidinobenzoic acid hydrochloride and 9.0 g of DCC. The mixture is stirred under ice cooling for 1 hour (reaction mixture A). To 100 ml of pyridine is added 113 g of 6-amidino-2-naphthol methanesulfonate. To the mixture, ice-cooled and stirred, and a portion A of the reaction mixture was added over 1 hour. After all the addition, the resulting mixture was cooled on ice, stirred for an additional hour, and then stirred overnight at room temperature. The precipitated crystals are collected by filtration and washed with pyridine and acetone. Then, the crystals are dissolved in about 200 ml of water, and the insoluble DCU is filtered off.

When a saturated aqueous solution of sodium bicarbonate is added to the filtrate, pale yellow crystals are precipitated. Washing the crystals with water and acetone gives 15 g (79.8% yield) of 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate. From this carbonate, other acid addition salts can be obtained by the procedure described in Method A.

As described above, the present invention has been described with reference to the illustrated drawings, but the present invention is not limited by the embodiments and drawings disclosed in the present specification. It is obvious that variations can be made. In addition, although the effects according to the configuration of the present invention are not explicitly described and described while describing the embodiments of the present invention, it is natural that the effects predictable by the configuration should also be recognized.

Claims (13)

(a) preparing a thioester compound by mixing a first guanidinobenzoic acid compound, a phosphine compound, and a disulfide compound;
(b) preparing a second guanidinobenzoic acid compound by mixing the thioester compound with a first sulfonic acid compound; and
(c) preparing a guanidino-benzoate sulfonic acid compound by mixing the second guanidinobenzoic acid compound with a second sulfonic acid compound; guanidino-benzoate sulfonic acid compound manufacturing method comprising a.
According to claim 1,
The first guanidinobenzoic acid compound is a method for producing a guanidino-benzoate sulfonic acid compound comprising 4-guanidinobenzoic acid hydrochloride represented by the following formula (1).
[Formula 1]

According to claim 1,
The phosphine compound is tri (4-tolyl) phosphine (Tri- (4-tolyl) phosphine), tri (2-furyl) phosphine (Tri (2-furyl) phosphine) and triphenyl represented by Formula 2 A method for preparing a guanidino-benzoate sulfonic acid compound comprising at least one of phosphine (Tri-phenylphosphine).
[Formula 2]

wherein R ₁ =phenyl, 4-tolyl or 2-furyl.
According to claim 1,
The disulfide compound is diphenyl disulfide, 2,2'-dipyridyl disulfide (2,2'-Dipyridyl disulfide) and 2,2'-dibenzothiazole disulfide (2, 2'-Dibenzothiazyl disulfide) of guanidino-benzoate sulfonic acid compound comprising at least one method for producing a compound.
[Formula 3]

wherein R ₂ =phenyl, 2-pyridyl or benzothiazole.
According to claim 1,
The thioester compound is a method for producing a guanidino-benzoate sulfonic acid compound comprising a compound represented by the following formula (4).
[Formula 4]

According to claim 1,
The first sulfonic acid compound includes 6-amidino-2-naphthol methanesulfonate represented by the following formula (5),
The second sulfonic acid compound is a guanidino-benzoate sulfonic acid compound comprising methanesulfonic acid.
[Formula 5]

According to claim 1,
The second guanidinobenzoic acid compound is a method for producing a guanidino-benzoate sulfonic acid compound comprising 6-amidino-2-naphthyl-4-guanidino-benzoate represented by the following Chemical Formula 6.
[Formula 6]

According to claim 1,
The guanidino-benzoate sulfonic acid compound is a guanidino-benzoate sulfonic acid salt including 6-amidino-2-naphthyl-4-guanidino-benzoate dimethanesulfonic acid salt represented by the following Chemical Formula 7 A method for producing a phonic acid compound.
[Formula 7]

According to claim 1,
Each of steps (a) to (c) is
A method for preparing a guanidino-benzoate sulfonic acid compound carried out at 10 to 50° C. for 30 minutes to 36 hours.
According to claim 1,
In each of steps (a) and (b),
A method for producing a guanidino-benzoate sulfonic acid compound, wherein the reaction is performed by adding an organic solvent containing at least one of carbon tetrachloride, chloroform, dichloromethane, benzene, toluene, xylene and pyridine.
According to claim 1,
In step (a), with respect to 1 mole of the first guanidinobenzoic acid compound, 1 to 2 moles of the phosphine compound and 1 to 2 moles of the disulfide compound are mixed. A method of preparing a guanidino-benzoate sulfonic acid compound.
According to claim 1,
After isolating the thioester compound of step (a), 0.5 to 2 moles of the first sulfonic acid compound are mixed with 1 mole of the thioester compound separated in step (b), or
Without separating the thioester compound of step (a), 0.5 to 2 moles of the first sulfonic acid compound are mixed with respect to 1 mole of the first guanidinobenzoic acid compound in step (b). A method for producing a phonic acid compound.
According to claim 1,
In the step (c), with respect to 1 mole of the second guanidinobenzoic acid compound, 1 to 2.5 moles of the second sulfonic acid compound are mixed. A method of preparing a guanidino-benzoate sulfonic acid compound.