1,4-diazocane compound or its salt

Abstract

To provide a novel method for producing an isoquinoline-6-sulfonamide derivative useful as a medicinal drug, and an intermediate which is used in the method.SOLUTION: A method for producing an isoquinoline-6-sulfonamide derivative of formula (11) or a salt thereof is provided, the method comprising reacting a 1,4-diazocane compound or a salt thereof with a quinoline-6-sulfonyl halide of formula (9) or a salt thereof, and then performing the elimination reaction of an amino protecting group.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a 1,4-diazocane compound which is useful as a pharmaceutical synthesis intermediate, and use thereof. [Background technology]

[0002] Compounds in which a nitrogen-containing saturated heterocycle such as diazocane is bonded to the 6-position of an isoquinoline ring via a sulfonyl group are known to have a strong intraocular pressure reducing effect and are useful as therapeutic agents for ocular hypertension such as glaucoma (Patent Document 1). Among these isoquinoline-6-sulfonamide derivatives, those represented by the following formula (I)

[0003] [ka]

[0004] It is known that (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the formula (I) or a salt thereof has a particularly excellent intraocular pressure reducing effect and is useful as a therapeutic agent for glaucoma and ocular hypertension. Patent Document 1 describes that the compound can be produced according to the following reaction formula:

[0005] [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 4915010 Summary of the Invention [Problem to be solved by the invention]

[0007] However, the method for producing the compound of formula (I) according to Patent Document 1 has problems such as low yields in the reaction of isoquinoline-6-sulfonyl chloride with a diamine compound and the subsequent 1,4-diazocane formation reaction, high production costs, and the need for a purification step by column chromatography, and is therefore not satisfactory as an industrial method for producing pharmaceuticals. Therefore, an object of the present invention is to provide a new process for producing the compound represented by the above formula (I) via a new intermediate. [Means for solving the problem]

[0008] Therefore, the present inventors have conducted studies to develop a new method for producing the compound represented by the above formula (I), and as a result, have succeeded in synthesizing a novel 1,4-diazocane compound having an amino-protecting group, and have found that the compound represented by the above formula (I) can be produced in high yield by using this compound, thereby completing the present invention.

[0009] That is, the present invention provides the following [1] to [5].

[0010] [1] General formula (A)

[0011] [ka]

[0012] (In the formula, R 2a represents a hydrogen atom or an amino protecting group; R 4 indicates an amino protecting group) A 1,4-diazocane compound represented by the formula:

[0013] [2] General formula (B)

[0014] [ka]

[0015] (In the formula, R 2 represents an amino protecting group, R4 represents a hydrogen atom or an amino protecting group, and Z represents a number from 0 to 1. or a salt thereof, or a hydrate thereof.

[0016] [3] Formula (8)

[0017] [ka]

[0018] (In the formula, R 4 indicates an amino protecting group) or a salt thereof,

[0019] [ka]

[0020] (In the formula, X 2 indicates a halogen atom) or a salt thereof, and then carrying out a elimination reaction of the amino protecting group.

[0021] [ka]

[0022] A method for producing an isoquinoline-6-sulfonamide derivative represented by the formula:

[0023] [4] Formula (6)

[0024] [ka]

[0025] (In the formula, R 2 and R 4 each represents an amino protecting group) with an azodicarboxylate and triphenylphosphine, and then, if necessary, carrying out a elimination reaction of the amino-protecting group,

[0026] [ka]

[0027] (In the formula, R 2a represents a hydrogen atom or an amino protecting group; R 4 indicates an amino protecting group) A method for producing a 1,4-diazocane compound represented by the formula:

[0028] [5] Formula (3)

[0029] [ka]

[0030] (In the formula, R 2 represents an amino protecting group, R 3 represents a halogen atom or a substituted sulfonyloxy group. with 4-amino-1-butanol, and then optionally protecting the amino group,

[0031] [ka]

[0032] (In the formula, R 2 represents an amino protecting group, R 4 represents a hydrogen atom or an amino protecting group, and Z represents a number from 0 to 1. A method for producing a compound represented by the following formula (1): Effect of the Invention

[0033] According to the present invention, the compound represented by the general formula (A) or a salt thereof can be produced in high yield from inexpensive raw materials. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The 1,4-diazocane compound represented by the general formula (A) or a salt thereof is useful as a production intermediate for the isoquinoline-6-sulfonamide derivative represented by the formula (11) or a salt thereof.

[0035] [ka]

[0036] In formula (A), R 2a R represents a hydrogen atom or an amino protecting group. 2a The amino protecting group of R 4 Any protecting group that can be removed under different conditions from the amino protecting group of R is acceptable, but from the viewpoint of forming a 1,4-diazocane ring by the Mitsunobu reaction of amino alcohol, a nitrobenzenesulfonyl group that also acts as an activating group for the amino group is preferred. Examples of the nitrobenzenesulfonyl group include the 2-nitrobenzenesulfonyl group (Ns), the 4-nitrobenzenesulfonyl group (Nos), and the 2,4-dinitrobenzenesulfonyl group (DNs). 2a is more preferably a hydrogen atom.

[0037] R 4 Examples of the amino-protecting group include carbamate-based protecting groups such as t-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethylcarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl (Troc), and allyloxycarbonyl group (Alloc), amide-based protecting groups such as trifluoroacetyl group, phthaloyl group, and p-toluenesulfonyl group. From the viewpoint of ease of deprotection, the carbamate-based protecting groups are preferred, and the t-butoxycarbonyl group (Boc) is more preferred.

[0038] Among the compounds of formula (A), the stereoisomer represented by the following formula (A1) is particularly preferred.

[0039] [ka]

[0040] (In the formula, R 2a and R 4 is the same as above) Here, R 2a is more preferably a hydrogen atom.

[0041] Furthermore, the compound represented by the general formula (B) or a salt thereof, or a hydrate of these is useful as a production intermediate for the compound represented by the above formula (A) or a salt thereof.

[0042] [ka]

[0043] In formula (B), R 2 R represents an amino protecting group. 2 The amino protecting group of R 4 Any protecting group that can be removed under different conditions from the amino protecting group of R is acceptable, but from the viewpoint of forming a 1,4-diazocane ring by the Mitsunobu reaction of amino alcohol, a nitrobenzenesulfonyl group that also acts as an activating group for the amino group is preferred. Examples of the nitrobenzenesulfonyl group include the 2-nitrobenzenesulfonyl group (Ns), the 4-nitrobenzenesulfonyl group (Nos), and the 2,4-dinitrobenzenesulfonyl group (DNs). 4 represents a hydrogen atom or an amino-protecting group, and is preferably the same as above. Z represents a number of 0 to 1.

[0044] Among the compounds of formula (B), the stereoisomer represented by the following formula (B1) is particularly preferred.

[0045] [ka]

[0046] (In the formula, R 2 , R 4 and Z is the same as above)

[0047] The production method of the present invention, starting from the starting materials, can be represented by the following reaction scheme.

[0048] [ka]

[0049] [ka]

[0050] (In the formula, R 1 and R 5 each independently represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group, a halogenoalkyl group, an alkenyl group, an alkoxy group, an alkylthio group, a hydroxy group, a mercapto group, a nitro group, an aryl group, an amino group, or an aminoalkylthio group; R 2 represents an amino protecting group, R 3 represents a substituted sulfonyloxy group or a halogen atom; L 1 represents a halogen atom, a hydroxyl group or a leaving group; Y 1 represents a halogen atom or a sulfinyl group, R 4 represents an amino protecting group, and Z represents a number from 0 to 1.

[0051] Each reaction step will be explained below.

[0052] (1) A process for producing compound (9) Compound (9) can be produced using commercially available 6-aminoisoquinoline (13) or 6-bromoisoquinoline (12). Compound (9) can be synthesized from compound (12) by a known method.

[0053] (2) A process for producing compound (2) from compound (1) It is preferable to use (R)-2-amino-1-propanol as compound (1). As a reagent used for protecting the amino acid of compound (1), as described above, it is preferable to use a nitrobenzenesulfonyl halide such as nitrobenzenesulfonyl chloride. This reaction is preferably carried out in the presence of an aromatic amine such as pyridine, or a tertiary amine such as triethylamine, dimethylaniline, or diisopropylethylamine. The amount of these amines used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, per mole of compound (1). As the reaction solvent, it is preferable to use an ether solvent such as tetrahydrofuran, diethyl ether, dioxane, or cyclopentyl methyl ether, a polar solvent such as acetonitrile, or an aromatic hydrocarbon solvent such as toluene. The reaction may be carried out at -10°C to 50°C for 1 to 12 hours.

[0054] (3) A process for producing compound (3) from compound (2) R to be reacted with compound (2) 3 -Y 1 Examples of the substituted sulfonyl halides include substituted sulfonyl halides and thionyl halides. Examples of the substituted sulfonyl halides include alkanesulfonyl halides such as methanesulfonyl halide, and arylsulfonyl halides such as p-toluenesulfonyl halide. Examples of the thionyl halides include thionyl chloride and thionyl bromide. The reaction of compound (2) with a substituted sulfonyl halide is preferably carried out in the presence of an aromatic amine such as pyridine, or a tertiary amine such as triethylamine or dimethylaniline. The amount of these amines used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, per mole of compound (2). As the solvent for this reaction, it is preferable to use an ether solvent such as tetrahydrofuran, diethyl ether, or dioxane, a polar solvent such as acetonitrile, or an aromatic hydrocarbon solvent such as toluene. The reaction may be carried out at 0°C to 100°C for 1 hour to 12 hours. The reaction of compound (2) with a thionyl halide such as thionyl chloride is preferably carried out in the presence of an aromatic hydrocarbon solvent such as toluene or xylene, or an aromatic amine such as pyridine at 60 to 80° C. for 3 to 24 hours.

[0055] (4) A process for producing compound (5) from compound (3) Compound (5) can be produced by reacting compound (3) with 4-amino-1-butanol (4). This reaction is preferably carried out in the presence of a base. As the base, an alkali metal carbonate such as potassium carbonate or sodium carbonate, or an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide can be used. The amount of the base used is preferably 1 to 10 times by mole, more preferably 1 to 5 times by mole, per mole of compound (3). As the reaction solvent, a polar solvent such as acetonitrile is preferably used. The reaction may be carried out at 10°C to 150°C for 1 hour to 12 hours. Compound (5) can also be isolated in the form of a hydrate.

[0056] (5) A process for producing compound (6) from compound (5) Compound (6) can be obtained by protecting the amino group of compound (5). The compound used for protecting the amino group of compound (5) is the above-mentioned R 4 A compound corresponding to the amino protecting group of is used. For example, when protecting with a t-butoxycarbonyl group, di-t-butyl dicarbonate is used. These protecting group introduction reactions are preferably carried out in the presence of an aromatic amine such as pyridine, or a tertiary amine such as triethylamine or dimethylaniline. The amount of the amine used is preferably 1 to 10 times by mole, more preferably 1 to 3 times by mole, per mole of compound (5). As the reaction solvent, a halogenated hydrocarbon solvent such as dichloromethane, an alcohol solvent such as methanol, an ether solvent such as tetrahydrofuran or diethyl ether, a nitrile solvent such as acetonitrile, water, or the like, alone or mixed in an appropriate ratio, is used. The reaction may be carried out at 0°C to 150°C for 1 hour to 12 hours.

[0057] (6) A process for producing compound (7) from compound (6) The method of cyclizing compound (6) to produce compound (7) is preferably the Mitsunobu reaction, in which compound (7) is obtained by reacting compound (6) with an azodicarboxylate and triphenylphosphine. Examples of the azodicarboxylate include alkyl azodicarboxylates such as diisopropyl azodicarboxylate and diethyl azodicarboxylate. The amount of the azodicarboxylate used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, relative to 1 mole of compound (6). The amount of triphenylphosphine used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, relative to 1 mole of compound (6). The reaction may be carried out in an ether solvent such as tetrahydrofuran or an aromatic hydrocarbon solvent such as toluene at 0 to 100°C for 1 to 12 hours.

[0058] (7) A process for producing compound (8) from compound (7) The amino protecting group R of compound (7) 2 By removing the aryl group, compound (8) can be obtained. R 2 Depending on the type of amino-protecting group, a means for removing the group, such as a base or reduction, can be used. For example, 2 When is a nitrobenzenesulfonyl group, deprotection can be performed under mild conditions by reaction with a thiol such as thiophenol or dodecanethiol. Long-chain alkyl alkanethiol such as dodecanethiol is more preferable because it has a weak odor. The amount of thiol used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, relative to 1 mole of compound (7). The deprotection reaction is preferably performed in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide or a hydrate thereof. The amount of base used is preferably 1 to 20 times by mole, more preferably 1 to 10 times by mole, relative to 1 mole of compound (7). The reaction may be performed in a solvent such as a polar solvent such as acetonitrile or dimethylformamide, or an aromatic hydrocarbon solvent such as toluene, at room temperature to 100° C. for 30 minutes to 5 hours.

[0059] (8) A step of reacting compound (8) with compound (9) to produce compound (10). Compound (10) is obtained by reacting compound (8) with isoquinoline-6-sulfonyl halide or an acid addition salt thereof (9). This reaction is preferably carried out in the presence of an aromatic amine such as pyridine, or an amine such as triethylamine, dimethylaniline, or dimethylaminopyridine. The amount of these tertiary amines used is preferably 1 to 5 times by mole, more preferably 1 to 3 times by mole, per mole of compound (8). The reaction can be carried out in a polar solvent such as acetonitrile or dimethylformamide, or an aromatic hydrocarbon solvent such as toluene. The reaction can be carried out at 0°C to 100°C for 1 to 5 hours.

[0060] (9) A process for producing compound (11) from compound (10) The amino protecting group (R 4 ) is eliminated to give compound (11). 4 The deprotection reaction of R 4 Depending on the type of R, methods such as base, acid, reduction, etc. can be used. For example, R 4 When is a t-butoxycarbonyl group, deprotection may be performed under acidic conditions. To achieve acidic conditions, a mineral acid such as hydrochloric acid or sulfuric acid, or a strong acid such as trifluoroacetic acid may be used. To deprotect a benzyloxycarbonyl group, a hydrogenation reaction using a palladium catalyst, Birch reduction, or the like may be used. The deprotection reaction may be performed, for example, in an ether solvent such as dioxane, an aromatic hydrocarbon solvent such as toluene, or an ester solvent such as ethyl acetate at 0°C to 150°C for 1 hour to 20 hours.

[0061] Compound (11) is preferably isolated as an acid addition salt such as hydrochloride or sulfate, and is particularly preferably isolated as a hydrochloride from the viewpoint of use as a pharmaceutical. In order to isolate as an acid addition salt, it is preferable to add an acid such as hydrochloric acid in an organic solvent to obtain an acid addition salt. For example, compound (11) hydrochloride can be efficiently obtained by isolating compound (11) as a hydrochloride.

[0062] According to the process of the present invention, the compound (11) or an acid addition salt thereof which is useful as a medicine can be obtained industrially advantageously. EXAMPLES

[0063] The present invention will now be described in more detail with reference to examples.

[0064] Example 1

[0065] [ka]

[0066] (1) Steps 1 and 2

[0067] [ka]

[0068] (R)-2-amino-1-propanol (3.82 g) was dissolved in THF (150 mL), and triethylamine (7.08 mL) and 2-nitrobenzenesulfonyl chloride (11.2 g) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials by TLC, distilled water was added and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (R)-N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide as a white solid (13.4 g). THF (150 mL) was added to this, and after dissolving, triethylamine (7.08 mL) and methanesulfonyl chloride (3.93 mL) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials by TLC, distilled water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with n-hexane / ethyl acetate = 8 / 1 to obtain (R)-N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide as a white solid (14.9 g, yield 86%). 2; 11H NMR (500 MHz, CDCl3, δ ppm): 1.34 (d, J = 6.5 Hz, 3H), 2.64 (d, J = 7Hz, 1H), 3.49 - 3.52 (m, 1H), 3.57 - 3.64 (m, 2H), 7.72 - 7.77 (m, 2H), 7.86 - 7.89 (m, 1H), 8.16 - 8.19 (m, 1H). ESI-MS m / z : 261 [M+H] + , 283 [M+Na] + , 543 [2M+Na] + . 3; 1 1H NMR (500 MHz, CDCl3, δ ppm): 1.24 (d, J = 7.0 Hz, 3H), 2.99 (s, 3H), 3.87 - 3.91 (m, 1H), 4.11 - 4.18 (m, 2H), 5.52 (d, J = 8 Hz, 1H), 7.75 - 7.79 (m, 2H), 7.90 - 7.92 (m, 1H), 8.16 - 8.17 (m, 1H). ESI-MS m / z : 339 [M+H] + , 361 [M+Na] + , 699 [2M+Na] + .

[0069] (2) Steps 3, 4

[0070]

Chem.

[0071] 4-Amino-1-butanol (636 mg) and potassium carbonate (2.45 g) were suspended in acetonitrile (8 mL) and stirred at 70°C. (R)-N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide (2.00 g) dissolved in acetonitrile (30 mL) was added dropwise over 60 minutes. The reaction solution was stirred at the same temperature for another 2 hours, after which the disappearance of the raw material was confirmed by TLC and the solution was cooled to room temperature. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure to obtain (R)-N-[2-(4-hydroxy-butylamino)-1-methylethyl]-2-nitrobenzenesulfonamide as a crude product (2.14 g). Dichloromethane (40 mL) was added to the solution, and the solution was cooled to 0°C. Triethylamine (0.822 mL) and di-tert-butyl dicarbonate (1.28 g) were added thereto, and the mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials by TLC, 1N hydrochloric acid cooled at 0°C was added to wash the organic layer. The organic layer was then washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to obtain (R)-tert-butyl 4-hydroxybutyl-2-(2-nitrophenylsulfonamido)propylcarbamate (2.33 g, yield 91%). 4; 1 H NMR (500 MHz, CDCl3, δ ppm):1.11 (d, J = 7.0 Hz, 3H), 1.52-1.55 (m, 2H), 1.58-1.63 (m, 2H), 2.55-2.68 (m, 4H), 3.56-3.61 (m, 3H), 7.72-7.76 (m, 2H), 7.85-7.87 (m, 1H), 8.16-8.18 (m, 1H). ESI-MS m / z : 332 [M+H] + , 354 [M+Na] + , 685 [2M+Na] + . 5; 1H NMR (500 MHz, CDCl3, δ ppm):1.08 (brs, 3H), 1.42-1.57 (m, 13H), 3.05-3.42 (m, 4H), 3.63-3.64 (m, 2H), 3.83 (brs, 1H), 7.72 (brs, 2H), 7.84 (brs, 1H), 8.11 (d, J = 7.0 Hz, 1H). ESI-MS m / z : 332 [M-CO2C(CH3)3+H] + , 432 [M+H] + , 454 [M+Na] + , 885 [2M+Na] + .

[0072] (3) Step 5

[0073] [ka]

[0074] Under a nitrogen stream, (R)-tert-butyl 4-hydroxybutyl-2-(2-nitrophenylsulfonamido)propylcarbamate (2.33 g) and triphenylphosphine (2.12 g) were dissolved in tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (1.60 mL) was added dropwise at 0°C. The reaction solution was stirred at room temperature for 2 hours, and after confirming the disappearance of the raw material by TLC, it was concentrated under reduced pressure. The resulting residue was washed with hexane, and then ether was added. After removing the precipitate, the filtrate was concentrated to obtain orange oily (R)-tert-butyl 3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate as a crude product (4.3 g). 6; 1H NMR (500 MHz, CDCl3, δ ppm):0.92, 0.98 (d, J = 5.7 Hz, 3H), 1.48 (s, 9H), 1.67-1.77 (m, 2H), 1.85-1.95 (m, 2H), 3.07-3.12 (m, 1H), 3.32-3.50 (m, 4H), 3.69-3.71 (m, 1H), 4.16-4.20 (m, 1H), 7.57-7.59 (m, 1H), 7.64-7.69 (m, 2H), 7.97, 8.02 (d, J = 6.5 Hz, 1H). ESI-MS m / z: 414 [M+H] + , 436 [M+Na] + , 849 [2M+Na] + .

[0075] (4) Step 6

[0076] [ka]

[0077] (R)-tert-butyl 3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate (4.3 g) was dissolved in acetonitrile (20 mL), and potassium carbonate (4.0 g) was added. Thiophenol (1.2 mL) was added to the mixture at room temperature, and the mixture was stirred at 50° C. for 1 hour. After confirming the disappearance of the raw materials by TLC, the insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. 2N hydrochloric acid was added to the residue to adjust the pH to 3. The mixture was washed with ethyl acetate, and the aqueous layer was adjusted to about pH 9 with potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure to obtain (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate as a yellow oil (758 mg, 61% yield for two steps). 7; 1H NMR (500 MHz, CDCl3, δ ppm):1.04 (d, J = 6.0 Hz, 3H), 1.46 (s, 9H), 1.53-1.77 (m, 4H), 2.53-2.70 (m, 2H), 2.99-3.17 (m, 3H), 3.58-3.92 (m, 2H). ESI-MS m / z : 229 [M+H] + .

[0078] (5) Step 7

[0079] [ka]

[0080] (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate (1.09 g) and triethylamine (1.32 mL) were dissolved in acetonitrile (20 mL), and 6-chlorosulfonylisoquinoline hydrochloride (1.26 g) was added under ice-water cooling, and the mixture was stirred for 2 hours under ice-water cooling. After confirming the disappearance of the raw materials by TLC, the mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain (R)-tert-butyl 4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate as a yellow oil (2.08 g). 8; 1H NMR (500 MHz, CDCl3, δ ppm):0.82, 0.90 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H), 1.73-2.02 (m, 4H), 2.98-3.08 (m, 1H), 3.31-3.51 (m, 4H), 3.60-3.63 (m, 1H), 4.22-4.26 (m, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 9.35 (s, 1H). ESI-MS m / z: 420 [M+H] + , 839 [2M+H] + , 861 [2M+Na] + .

[0081] (7) Step 8

[0082] [ka]

[0083] (R)-tert-Butyl 4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (2.08 g) was dissolved in ethyl acetate (8 mL) and 4M hydrochloric acid / 1,4-dioxane solution (12 mL) was added at room temperature. After stirring at room temperature for 16 hours, ethyl acetate was added and the solid was washed. The solvent was removed with a pipette and the remaining solid was dissolved by adding water. This aqueous layer was washed once with ethyl acetate and then made basic by adding sodium hydroxide. It was then extracted with dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain (R)-6-(2-methyl-1,4-diazocane-1-ylsulfonyl)isoquinoline as a yellow oil (1.17 g, 77% yield for two steps). 9; 1H NMR (500 MHz, CDCl3, δ ppm):0.8 (d, J = 6.5 Hz, 3H), 1.50-1.65 (m, 2H), 1.89-1.94 (m, 1H), 2.01-2.04 (m, 1H), 2.67-2.71 (m, 1H), 2.77-2.82 (m, 1H), 2.95-3.00 (m, 2H), 3.48-3.59 (m, 2H), 3.97-4.00 (m, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.7Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.66 (d, J = 6.0 Hz, 1H), 9.34 (s, 1H). ESI-MS m / z : 320 [M+H] + , 639 [2M+H] + .

[0084] (8) Step 9

[0085] [ka]

[0086] (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline (0.69 g) was dissolved in ethyl acetate (5 mL), and 1M hydrochloric acid / diethyl ether (2.0 mL) was added at room temperature and stirred for 20 hours. The precipitate was washed with ethyl acetate and filtered to obtain (R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline hydrochloride as a white solid (0.7 g, yield 91%). 10; 1H NMR (400 MHz, D2O, δ ppm):0.73 (d, J = 6.8 Hz, 3H), 1.82-2.20 (m, 4H), 3.18-3.40 (m, 4H), 3.50-3.60 (m, 1H), 3.72-3.80 (m, 1H), 4.40-4.52 (m, 1H), 7.95 (d, J = 6.0 Hz, 1H), 8.0 (dd, J = 1.8, 8.7Hz, 1H,), 8.28 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 8.57 (d, J = 6.0 z, 1H), 9.31 (s, 1H). ESI-MS m / z: 320 [M+H] + , 639 [2M+H] + .Anal.calcd for C 16 H 22 ClN3O2S: C, 54.00%; H, 6.23%; N, 11.81%. Found: C, 53.90%; H, 6.23%; N, 11.60%.

[0087] Example 2

[0088] [ka]

[0089] (1) Step 1

[0090] [ka]

[0091] (R)-2-amino-1-propanol (20.0 g) was dissolved in tetrahydrofuran (800 mL), triethylamine (26.9 g) was added, and the mixture was cooled to 0° C. 2-nitrobenzenesulfonyl chloride (59.0 g) was added, and the mixture was stirred at 25° C. for 3 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and concentrated to give (R)-N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide (72.1 g). The NMR spectrum data was the same as in Example 1.

[0092] (2) Step 2

[0093] [ka]

[0094] (R)-N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide (17.3 g) was dissolved in tetrahydrofuran (40 mL), thionyl chloride (27.7 g) was added, and the mixture was stirred at 60° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, toluene was added, and the mixture was concentrated. Toluene was added to the residue, and the precipitate was filtered to obtain (R)-N-(2-chloro-1-methylethyl)-2-nitrobenzenesulfonamide (10.4 g). 11; 1 H NMR (300 MHz, CDCl3, δ ppm):1.26 (d, J = 6.6 Hz, 3H), 3.55 (d, J = 4.4 Hz, 2H), 3.84-3.96 (m, 1H), 5.61 (d, J = 7.7 Hz, 1H), 7.74-7.80 (m, 2H), 7.89-7.93 (m, 1H), 8.14-8.18 (m, 1H). MS m / z ::229 [M+H] + Melting point: 90℃ IR:3304, 3281, 1540, 1426, 1357, 1339, 1163, 748, 601, 562(cm -1 )

[0095] (3) Step 3

[0096] [ka]

[0097] 4-Amino-1-butanol (5.1 g) was dissolved in acetonitrile (40 mL), potassium carbonate (14.9 g) was added, and the mixture was heated to 70° C. A solution of (R)-N-(2-chloro-1-methylethyl)-2-nitrobenzenesulfonamide (10.0 g) in acetonitrile (70 mL) was added dropwise. After the addition, the mixture was stirred at 70° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted with acetonitrile. The organic layer was concentrated, ethyl acetate was added to the residue, and the precipitated yellow solid was collected by filtration to obtain (R)-N-[2-(4-hydroxy-butylamino)-1-methylethyl]-2-nitrobenzenesulfonamide monohydrate (7.8 g). 12; 1 H NMR (300 MHz, CDCl3, δ ppm):1.10 (d, J = 7.0 Hz, 3H), 1.50-1.65 (m, 4H), 2.55-2.70 (m, 4H), 3.55-3.64 (m, 3H), 7.72-7.79 (m, 2H), 7.83-7.88 (m, 1H), 8.16-8.20 (m, 1H). MS m / z: 332 [M+H] + Melting point: 58℃ (decomposition) IR:3331, 1533, 1371, 1172, 1156, 908, 855, 655(cm -1 )

[0098] (4) Steps 4 to 9

[0099] [ka]

[0100] Step 4

[0101] (R)-N-[2-(4-hydroxybutylamino)-1-methylethyl]-2-nitrobenzenesulfonamide monohydrate (100 g) was dissolved in methanol (570 mL), and a solution of triethylamine (41.5 g) and di-tert-butyl dicarbonate (89.6 g) in methanol (75 mL) was added dropwise thereto, followed by stirring at 15° C. for 1 hour. After the reaction was completed, the mixture was concentrated, water was added, and the mixture was extracted with toluene. The organic layer was washed with 10% saline and concentrated. The obtained toluene solution (372 g) of (R)-tert-butyl 4-hydroxybutyl-2-(2-nitrophenylsulfonamido)propylcarbamate was used in the next reaction. The NMR spectrum data was the same as in Example 1.

[0102] Step 5

[0103] A solution of triphenylphosphine (179 g) dissolved in toluene was added to a toluene solution (372 g) of (R)-tert-butyl 4-hydroxybutyl-2-(2-nitrophenylsulfonamido)propylcarbamate. This solution was added dropwise to a toluene solution (550 mL) of diisopropyl azodicarboxylate (84.4 g). After the dropwise addition, the mixture was stirred at 0°C for 15 hours, and the precipitate was filtered. The filtrate was concentrated. The obtained toluene solution (1235 g) of (R)-tert-butyl 3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate was used in the next reaction. The NMR spectrum data was the same as in Example 1.

[0104] Step 6

[0105] Dodecanethiol (83.9 g) was dissolved in N,N-dimethylformamide (800 mL) and lithium hydroxide monohydrate (47.9 g) was added. A toluene solution (1235 g) of (R)-tert-butyl 3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate was added dropwise thereto. After the dropwise addition, the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was washed with water. 1N hydrochloric acid was added to the organic layer, which was then extracted with water. Potassium carbonate was added to the aqueous layer, which was then extracted with toluene, and the organic layer was concentrated. The resulting toluene solution (195 g) of (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate was used in the next reaction. The NMR spectrum data was the same as in Example 1.

[0106] Step 7

[0107] Triethylamine (31.7 g), 4-dimethylaminopyridine (0.2 g), toluene (510 mL), and N,N-dimethylformamide (350 mL) were added to a toluene solution (174 g) of (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate, and the mixture was cooled to 0° C. 6-Chlorosulfonylisoquinoline hydrochloride (41.3 g) was added, and the mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the reaction mixture was washed with water, and the resulting toluene solution (827 g) of (R)-tert-butyl 4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate was used in the next reaction. The NMR spectrum data was the same as in Example 1.

[0108] Step 8

[0109] To a toluene solution (825 g) of (R)-tert-butyl 4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate, 10% sulfuric acid (600 g) was added, and the mixture was stirred at 20° C. for 15 hours. After the reaction was completed, the mixture was separated, 10% aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution (824 g) of (R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline was used in the next reaction. The NMR spectrum data was the same as in Example 1.

[0110] Step 9

[0111] Methanol (360 mL) was added to an ethyl acetate solution (812 g) of (R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline, and the mixture was cooled to 5° C. A solution of 35% hydrochloric acid (9.3 g) in methanol (30 mL) was added dropwise thereto, and the mixture was stirred at 2° C. for 20 hours. The precipitated yellowish white solid was collected by filtration to obtain (R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline hydrochloride (26.7 g). The NMR spectrum data was the same as in Example 1.

[0112] Example 3

[0113] [ka]

[0114] (R)-tert-butyl 4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (0.100 g) was dissolved in ethyl acetate (1.5 mL) and methanol (3.0 mL), and 4M hydrochloric acid / ethyl acetate solution (0.6 mL) was added at room temperature. After stirring at room temperature for 3 days, ethyl acetate was added to precipitate a solid. The precipitate was filtered while washing with ethyl acetate, and (R)-6-((2-methyl-1,4-diazocane-1-yl)sulfonyl)isoquinoline dihydrochloride was obtained as a white solid (0.092 g, 99% yield). 13; 1H NMR (400 MHz, D2O, δ ppm):0.74 (d, J = 6.6 Hz, 3H), 1.82-2.18 (m, 4H), 3.20-3.39 (m, 4H), 3.48-3.58 (m, 1H), 3.72-3.81 (m, 1H), 4.42-4.56 (m, 1H), 8.24 (dd, J = 1.8,8.8 Hz,1H), 8.34 (d, J = 6.2Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 6.2 Hz, 1H), 8.75 (s, 1H), 9.61 (s, 1H). ESI-MS m / z : 320 [M+H] + , 639 [2M+H] + .

Claims

[Claim 1] Formula (8) 【Chemistry 1】 (In the formula, R 4 represents a t-butoxycarbonyl group). or a salt thereof, in the presence of a tertiary amine, 【Chemistry 2】 (In the formula, X 2 indicates a halogen atom) and then carrying out a tert-butoxycarbonyl group elimination reaction under acidic conditions using hydrochloric acid, sulfuric acid or trifluoroacetic acid, 【Chemistry 3】 The present invention relates to a method for producing an isoquinoline-6-sulfonamide derivative represented by the formula:

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