Isoquinolinesulfonyl chloride acid addition salt and method for producing the same

Abstract

Provided are compounds useful as intermediates in the production of isoquinoline-6-sulfonamide compounds, and methods for producing the same. Isoquinoline-6-sulfonyl chloride acid addition salt.

Description

[Technical Field]

[0001] The present invention relates to an acid addition salt of isoquinoline-6-sulfonyl chloride, which is useful as a production intermediate for pharmaceuticals, and a method for producing the same. [Background technology]

[0002] Patent Documents 1 and 2 disclose that isoquinoline-6-sulfonamide compounds are useful as active ingredients in pharmaceuticals for preventing or treating glaucoma, ocular hypertension, cardiovascular disease, or diseases or disorders caused by neurodegeneration or nerve damage. They also disclose that isoquinoline-6-sulfonyl chloride (compound (1)) is used as a key intermediate to produce the sulfonamide compounds, and that they can be synthesized from the diazonium salt of 6-aminoisoquinoline (3) as shown in the following formula:

[0003] [ka]

[0004] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2010 / 146881 [Patent Document 2] International Publication No. 2012 / 086727 Summary of the Invention [Problem to be solved by the invention]

[0006] However, this method is undesirable as an industrial production method because it involves the use of unstable diazonium salts and sulfur dioxide gas. Furthermore, the above-mentioned patent documents disclose a method in which, taking into account the instability of compound (1), the compound is used in the next reaction in solution form without post-reaction purification. However, this procedure raises concerns about reduced reaction efficiency and quality of the final product due to impurities in the solution and the inability to calculate the appropriate equivalents of the reagents and raw materials used in the next step. Therefore, this is clearly disadvantageous from the perspective of strictly controlled pharmaceutical production. Furthermore, 6-aminoisoquinoline (3), which is used as a precursor, can be obtained by reacting 6-bromoisoquinoline (2) with aqueous ammonia under high temperature and pressure, but these extremely harsh conditions pose safety and operability challenges. In other words, no suitable production method or purification method for using compound (1) as a pharmaceutical production intermediate has been disclosed or made clear anywhere until now.

[0007] In general, the purity of pharmaceutical manufacturing intermediates has a significant impact on the quality of the final product, so there is a strong demand for simple and efficient manufacturing methods to obtain high-purity intermediates in each process. Therefore, the present invention aims to provide a novel industrially advantageous form of compound (1) and a method for producing the same, which is capable of producing high-quality compound (1) that is used as an intermediate to obtain high-quality isoquinoline-6-sulfonamide compounds useful as active ingredients of pharmaceuticals. [Means for solving the problem]

[0008] The present inventors first attempted to isolate and purify compound (1) from the extract solution obtained in the post-treatment of the above reaction. The extract solution containing compound (1) was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. However, the yield was found to be extremely low, at only 8%. This strongly suggests that, as pointed out in Patent Documents 1 and 2, the above isolation and purification procedure should be avoided. This result suggests that compound (1) is relatively stable in the organic solvent after extraction in the post-treatment of the reaction, but may decompose or denature during isolation and purification, resulting in a decrease in yield. In fact, in the experimental example described below, compound (1) was confirmed to denature or decompose even on a silica gel thin-layer chromatography (TLC) plate.

[0009] In view of this current situation, the present inventors considered that further investigation, including into the production method, of compound (1) is necessary in order to use it as a suitable intermediate for the production of pharmaceuticals.

[0010] In order to establish a simple and industrially feasible method for obtaining compound (1), the inventors attempted to obtain compound (1) by oxidative chlorination using the benzylthio compound (4), which can be obtained in one step from 6-bromoisoquinoline (2), as a precursor. This method confirmed that chlorosulfonylation proceeded efficiently. The crude product obtained in the post-treatment of this reaction was found to contain many impurities, necessitating further purification. However, as mentioned above, purification by silica gel column chromatography was not feasible because it would likely significantly reduce the yield of compound (1), and it was also impractical for industrial use. Purification by recrystallization was also an option, but heating was required, raising concerns about the stability of compound (1) and the potential for yield reduction due to the increased amount of solvent used to increase the purity. In any case, the use of aqueous sodium bicarbonate in the post-treatment of this reaction posed a risk of hydrolysis of compound (1).

[0011] Therefore, the present inventors conducted further studies and found that by converting compound (1) into an acid addition salt rather than isolating it as a free form, the purification efficiency is significantly improved and stable isolation is possible. They also found that the use of the acid addition salt of compound (1) allows the production of a highly pure isoquinoline-6-sulfonamide compound in high yield, thereby completing the present invention.

[0012] That is, the present invention provides the following [1] to [6].

[0013] [1] Isoquinoline-6-sulfonyl chloride acid addition salt. [2] The acid addition salt according to [1], wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. [3] A method for producing isoquinoline-6-sulfonyl chloride or an acid addition salt thereof, which comprises subjecting 6-(benzylthio)isoquinoline to an oxidative chlorination reaction. [4] A method for producing an acid addition salt of isoquinoline-6-sulfonyl chloride, which comprises reacting 6-aminoisoquinoline with a nitrite or a nitrite ester, then reacting with thionyl chloride, and then reacting with an acid. [5] A method for producing an isoquinoline-6-sulfonamide compound, which comprises reacting an acid addition salt of isoquinoline-6-sulfonyl chloride with an amine compound. [6] 6-(benzylthio)isoquinoline. [Effects of the Invention]

[0014] The isoquinoline-6-sulfonyl chloride acid addition salt of the present invention can be easily and inexpensively obtained from known compounds and can be isolated as a highly pure salt. Furthermore, the use of the isoquinoline-6-sulfonyl chloride acid addition salt enables industrially advantageous production of highly pure isoquinoline-6-sulfonamide compounds useful as pharmaceuticals. [Brief explanation of the drawings]

[0015] [Figure 1]1H NMR chart of isoquinoline-6-sulfonyl chloride hydrochloride obtained in Example 2 is shown. [Figure 2] 1H NMR chart of isoquinoline-6-sulfonyl chloride hydrochloride obtained in Example 3 is shown. [Figure 3] 1H NMR chart of isoquinoline-6-sulfonyl chloride obtained in Reference Example 2 is shown below. [Figure 4] 1H NMR chart of isoquinoline-6-sulfonyl chloride obtained in Reference Example 3 is shown below. [Figure 5] The behavior of isoquinoline-6-sulfonyl chloride on a silica gel TLC plate is shown. [Figure 6] 1 shows an HPLC chart of a sulfonamide compound obtained using isoquinoline-6-sulfonyl chloride hydrochloride. DETAILED DESCRIPTION OF THE INVENTION

[0016] The isoquinoline-6-sulfonyl chloride acid addition salt of the present invention is represented by the following formula (5) (compound (5)).

[0017] [ka]

[0018] (wherein HX represents an acid)

[0019] Examples of the acid represented by HX include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, and organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. Of these, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are preferred, and hydrochloric acid is more preferred.

[0020] The process for producing isoquinoline-6-sulfonyl chloride acid addition salt (5) (compound (5)) of the present invention and the process for producing isoquinoline-6-sulfonamide compound (6) (compound (6)) using the same as an intermediate are shown in the following reaction schemes.

[0021] [ka]

[0022] (wherein Bn represents a benzyl group, HX represents an acid, and R 1 and R 2 represents a hydrogen atom or an organic group.

[0023] Compound (1) or compound (5) can be produced by subjecting 6-(benzylthio)isoquinoline (4) (compound (4)) to an oxidative chlorination reaction. Here, 6-(benzylthio)isoquinoline (4) can be obtained by reacting 6-bromoisoquinoline (2) with benzyl mercaptan in an organic solvent in the presence of a base. 6-(benzylthio)isoquinoline (4) is a novel compound. The reaction of compound (2) with benzyl mercaptan is preferably carried out in the presence of a base such as potassium tert-butoxide, potassium carbonate, or sodium hydride. The reaction can be carried out in a polar solvent such as dimethyl sulfoxide at room temperature to 150°C for 1 to 10 hours.

[0024] The oxidative chlorination reaction of compound (4) can be carried out by reacting compound (4) with an oxidative chlorinating agent such as 1,3-dichloro-5,5-dimethylhydantoin, sulfuryl chloride, N-chlorosuccinimide, chlorine gas, sodium hypochlorite, etc. The reaction is preferably carried out in a polar solvent such as acetic acid-acetonitrile-water, and the reaction may be carried out under mild conditions, for example, at room temperature or below, for 1 to 5 hours.

[0025] The oxidative chlorination reaction of compound (4) produces compound (1). Compound (1) can be precipitated by adding an acid to the reaction solution without isolating compound (1). Specifically, an ether solvent and a hydrocarbon solvent are added to the reaction solution, and then an excess amount of acid is directly added. The resulting precipitate is filtered to obtain a purified product of compound (5). The amount of acid added is preferably in the range of 1 to 10 equivalents, more preferably 1 to 3 equivalents. The amount of solvent added is preferably 1 to 10 times the volume of the reaction solution, more preferably 1 to 5 times. Examples of ether solvents include diethyl ether and methyl tert-butyl ether. Examples of hydrocarbon solvents include hexane. These reactions can be carried out at temperatures between 0°C and room temperature, more preferably 0°C.

[0026] Compound (5) can also be produced by reacting 6-aminoisoquinoline (3) (compound (3)) with a nitrite or a nitrite ester, then reacting with thionyl chloride, and then reacting with an acid. The reaction of compound (3) with a nitrite or a nitrite ester is a diazotization reaction. Nitrites to be used include metal nitrites such as sodium nitrite and potassium nitrite, and ammonium nitrite. Nitrites to be used include alkyl nitrites such as methyl nitrite. The reaction of compound (3) with a nitrite or a nitrite ester is carried out in an acidic aqueous solution and generally proceeds rapidly at a temperature between 0°C and room temperature.

[0027] The resulting diazonium compound is then reacted with thionyl chloride to obtain compound (1). This reaction is carried out by reacting a mixture of thionyl chloride and water in an acidic aqueous solution in the presence of copper chloride at 0°C to room temperature for 1 to 5 hours. This reaction is preferably carried out without isolating the diazonium compound.

[0028] Next, the resulting compound (1) can be converted into an acid addition salt without isolation. Compound (5) can be precipitated by adding an acid to the solution after the reaction or the solution neutralized after the reaction. Specifically, an excess amount of acid is added to the reaction solution, followed by addition of an ether solvent and a hydrocarbon solvent, and the resulting precipitate is filtered to obtain a purified product of compound (5). The amount of acid added is preferably in the range of 1 to 10 equivalents, more preferably 1 to 3 equivalents. The amount of solvent added is preferably 1 to 10 times the amount of the reaction solution, more preferably 1 to 5 times the amount. Examples of ether solvents include diethyl ether and methyl tert-butyl ether. Examples of hydrocarbon solvents include hexane. These reactions can be carried out at temperatures between 0°C and room temperature, more preferably 0°C.

[0029] As described above, compound (5) can be obtained in high purity by simply adding an acid to compound (1) in a reaction solution and then performing a simple filtration operation, and therefore does not require purification operations such as extraction, column chromatography, or recrystallization.

[0030] Compound (5) is added to an amine compound (R 1 (R 2 )NH) to produce isoquinoline-6-sulfonamide compound (6), which is useful as a medicine. 1 (R 2 Examples of the amine compound represented by NH include the compounds described in Patent Documents 1 and 2. 1 (R 2 Specific examples of )NH include primary amines, secondary amines, and tertiary amines (including cyclic amines) such as methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, butylamine, dibutylamine, pentylamine, dipentylamine, hexylamine, dihexylamine, benzylamine, dibenzylamine, aziridine, azetidine, pyrrolidine, piperidine, morpholine, 1-(tert-butoxycarbonyl)piperazine, hexahydro-1H-azepine, 1-(tert-butoxycarbonyl)homopiperazine, octahydroazocine, and octahydro-1H-azonine. [Example]

[0031] The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

[0032] Example 1 Synthesis of 6-(benzylthio)isoquinoline (4) Benzyl mercaptan (5.45 g) was dissolved in dimethyl sulfoxide (80 mL), and potassium tert-butoxide (4.92 g) was added portionwise at room temperature, followed by stirring for 20 minutes. Subsequently, 6-bromoisoquinoline (2) (6.1 g) was added, and the mixture was stirred at 100°C for 3 hours. The mixture was returned to room temperature, water (600 mL) was added, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, an appropriate amount of hexane was added to the resulting oily crude product, which was crystallized. The solid was washed with hexane and separated by filtration to obtain 6-(benzylthio)isoquinoline (6.29 g, 85% yield). 1 HNMR(500MHz,CDCl3,δ ppm):4.29(s,2H),7.26-7.33(m,3H),7.38-7.40(m,2H),7.46-7.49(m,2H),7 .59(s,1H),7.82(d,1H,J=8.5Hz),8.47(d,1H,J=6.0Hz),9.15(s,1H).Melting point: 80℃

[0033] <Example 2> Synthesis of isoquinoline-6-sulfonyl chloride hydrochloride (5a) from 6-(benzylthio)isoquinoline (4) 6-(Benzylthio)isoquinoline (5 g) was dissolved in acetic acid (7.5 mL), water (5 mL), and acetonitrile (200 mL). 1,3-Dichloro-5,5-dimethylhydantoin (7.9 g) was added slowly in portions at 0°C. After stirring for 2 hours at or below 5°C, methyl tert-butyl ether (200 mL) was added. Subsequently, 4 M hydrochloric acid / 1,4-dioxane solution (5 mL) was added and stirred for 30 minutes. The precipitated solid was isolated by filtration and washed with an appropriate amount of methyl tert-butyl ether to give isoquinoline-6-sulfonyl chloride hydrochloride as a white solid (4.50 g, 85% yield). 1 HNMR(500MHz,DMSO-d6,δ ppm):8.16(d,1H,J=8.5Hz),8.50-8.53(m,2H),8.61(d,1H,J=6.5Hz),8.67(d,1H,J=6.5Hz),9.88(s,1H).Melting point: 102℃ (decomposition) Figure 1 shows the actual 1 The HNMR chart is shown in Figure 1. As is clear from Figure 1, no peaks of impurities other than the target product were observed.

[0034] Example 3 Synthesis of isoquinoline-6-sulfonyl chloride hydrochloride (5a) from 6-aminoisoquinoline (3) 6-Aminoisoquinoline (500 mg) was dissolved in concentrated hydrochloric acid (10 mL) at 0°C, and sodium nitrite (260 mg) dissolved in water (1 mL) was slowly added. The mixture was stirred at 0°C for 15 minutes. This solution was then slowly added to a solution prepared by adding thionyl chloride (1.1 mL) to a mixture of acetic acid (4 mL) and water (2 mL) at 0°C, followed by copper chloride (35 mg) at 0°C. The mixture was stirred for 1 hour. An appropriate amount of dichloromethane was added, and the mixture was neutralized by alternately adding sodium bicarbonate (13 g) and water. Insoluble components were removed by filtration through Celite, and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was filtered. To the resulting solution, 2M hydrochloric acid / diethyl ether solution (6 mL) was added at 0°C, followed by the addition of an appropriate amount of diethyl ether. The precipitated solid was isolated by filtration and washed with a suitable amount of diethyl ether to obtain isoquinoline-6-sulfonyl chloride hydrochloride as a pale yellow solid (484 mg, yield 52%). 1 The HNMR peak and melting point values ​​were consistent with those obtained in Example 2. 1 The HNMR chart is shown in Figure 2. As is clear from Figure 2, no peaks of impurities other than the target product were observed.

[0035] Example 4 Synthesis of isoquinoline-6-sulfonyl chloride hydrobromide (5b) from 6-(benzylthio)isoquinoline (4) Using 6-(benzylthio)isoquinoline (4) (1 g), a reaction was carried out under the same conditions as in Example 2, with hydrobromic acid added instead of hydrochloric acid, to give isoquinoline-6-sulfonyl chloride hydrobromide (1.04 g, yield 84%). 1 1 HNMR data indicated that the reaction gave the desired product as a single compound.

[0036] <Example 5> Synthesis of isoquinoline-6-sulfonyl chloride sulfate (5c) from 6-(benzylthio)isoquinoline (4) Using 6-(benzylthio)isoquinoline (4) (1 g), a reaction was carried out under the same conditions as in Example 2, with sulfuric acid added instead of hydrochloric acid, to obtain isoquinoline-6-sulfonyl chloride sulfate (944 mg, yield 72%). 1 1 HNMR data indicated that the reaction gave the desired product as a single compound.

[0037] Example 6 Synthesis of isoquinoline-6-sulfonyl chloride phosphate (5d) from 6-(benzylthio)isoquinoline (4) Using 6-(benzylthio)isoquinoline (4) (1 g), a reaction was carried out under the same conditions as in Example 2, with phosphoric acid added instead of hydrochloric acid, to obtain isoquinoline-6-sulfonyl chloride phosphate (872 mg, yield 67%). 1 1 HNMR data indicated that the reaction gave the desired product as a single compound.

[0038] <Reference example 1> Synthesis of isoquinoline-6-sulfonyl chloride (1) from 6-aminoisoquinoline (3) Using 6-aminoisoquinoline (280 mg), the reaction was carried out under the conditions described in Patent Document 1. After completion of the reaction, extraction, concentration under reduced pressure, and purification by silica gel column chromatography were carried out to obtain isoquinoline-6-sulfonyl chloride (35 mg, yield 8%). 1 HNMR(500MHz,CDCl3,?ppm):8.01(d,1H,J=5.0Hz),8.23(d,1H,J=10Hz),8.38(d,1H,J=10Hz),8.66(s,1H),8.79(d,1H,J=5.0Hz),9.59(s,1H).

[0039] <Reference example 2> Synthesis of isoquinoline-6-sulfonyl chloride (1) from 6-(benzylthio)isoquinoline (4) Using 6-(benzylthio)isoquinoline (1 g), the reaction was carried out under the same conditions as in Example 2. After the reaction was completed, the solvent was concentrated under reduced pressure. Dichloromethane was added, and then a 5% aqueous solution of sodium bicarbonate was added at 0°C. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, a crude product of isoquinoline-6-sulfonyl chloride (1.39 g) was obtained. Figure 3 shows the actual product. 1 The HNMR chart is shown below. As is clear from the chart, peaks for the target compound (1) were observed, as well as peaks for impurities.

[0040] <Reference example 3> Synthesis of isoquinoline-6-sulfonyl chloride (1) from 6-aminoisoquinoline (3) The reaction was carried out under the same conditions as in Example 3 using 6-aminoisoquinoline (500 mg). After the reaction was completed, the solution obtained after extraction and drying was concentrated to obtain a crude product of isoquinoline-6-sulfonyl chloride (1) (367 mg). Figure 4 shows the actual product. 1 The HNMR chart is shown below. As is clear from the chart, peaks for the target compound (1) were observed, as well as peaks for impurities.

[0041] <Test Example 1> Behavior of compound (1) on silica gel TLC plates A teaspoonful of the highly pure white solid isoquinoline-6-sulfonyl chloride hydrochloride (5a) obtained in Example 2 or 3 was placed in a microtube and suspended in an appropriate amount of ethyl acetate. Saturated aqueous sodium bicarbonate solution was then added to prepare a clear two-layer solution, with free isoquinoline-6-sulfonyl chloride dissolved in the upper organic layer. A 2 cm portion of solvent was drawn up from the organic layer using a glass capillary, and the compound (1) solution was spotted near one corner of a 5 cm square TLC plate. The plate was then placed in a developing chamber containing an appropriate amount of methyl tert-butyl ether and allowed to develop until the solvent reached near the top of the TLC plate. After development, the plate was dried, and the location of the compound (1) spot was confirmed by UV irradiation (Figure 5, left). After leaving the plate for 10 minutes, the TLC plate was rotated 90 degrees and the compound (1) spot was again developed. After development, the plate was dried, and the location of the compound (1) spot was confirmed by UV irradiation (Figure 5, right). As can be seen from Figure 5, the spot after development of compound (1) immediately after spotting generally gave a single spot mainly consisting of compound (1), whereas the TLC plate developed a second time after standing for 10 minutes showed a large spot different from compound (1) near the origin, and the amount of compound (1) was also observed to have decreased, suggesting that compound (1) had decomposed or denatured on the silica gel. This result was consistent with the result in Reference Example 1, in which the yield of compound (1) was drastically reduced by purifying it by silica gel column chromatography.

[0042] <Test Example 2> Elemental analysis of isoquinoline-6-sulfonyl chloride hydrochloride (5a), the compound of the present invention obtained in Examples 2 and 3, gave the following results. Note that the values ​​in parentheses indicate theoretical values. Isoquinoline-6-sulfonyl chloride hydrochloride (5a) C:41.0%(40.93%),H:2.87%(2.67%),N:5.38%(5.30%)

[0043] <Test Example 3> The present compound, isoquinoline-6-sulfonyl chloride hydrochloride (5a), was reacted with an amine compound. The crude product was analyzed by HPLC to examine the reaction selectivity and impurity content of the present compound (5a). Specifically, an appropriate amount of the present compound (5a) and an appropriate amount of n-butylamine were mixed in 1 mL of dichloromethane in the presence of an appropriate amount of triethylamine and reacted. After several minutes, a portion of the reaction solution was analyzed by HPLC (Figure 6). The product was a single sulfonamide compound. The content of by-products and impurities was also found to be extremely low. The above results indicate that the isoquinoline-6-sulfonyl chloride hydrochloride (5a), a compound of the present invention, is highly pure and has sufficient quality for use in reactions with amine compounds.

Claims

1. A process for producing an acid addition salt of isoquinoline-6-sulfonyl chloride, which comprises subjecting 6-(benzylthio)isoquinoline to an oxidative chlorination reaction and then reacting with an acid.

2. 6-(benzylthio)isoquinoline.

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