Process for the preparation of 1,3-benzodioxole derivatives

Abstract

An object of the present application is to provide an industrially useful and novel method for producing a 1,3-benzodioxole derivative with a high yield and few impurities, including a novel benzene ring chlorination reaction. In the novel method for producing a 1,3-benzodioxole derivative, it has been found that an industrially useful and novel benzene ring chlorination reaction is performed with a high yield and few impurities by using sulfuryl chloride. Based on this finding, the present application has been completed.

Description

Technical Field

[0001] The present invention relates to a novel method for preparing 1,3-benzodioxole derivatives, and particularly to a preparation method comprising a novel benzene ring chlorination reaction. Background Art

[0002] It is known that 1,3-benzodioxole derivatives can be used as drugs or raw materials for producing drugs, and can be used for treating tumors (Patent Document 1).

[0003] Patent Document 1 discloses various 1,3-benzodioxole derivatives and methods for their preparation. The preparation method disclosed in the document has the unique feature of introducing a chlorine atom into a benzene ring using N-chlorosuccinimide (Patent Document 1, Reference Example 2). In addition, methods for introducing a chlorine atom into a benzene ring using chlorine gas (Non-Patent Document 1) and reagents such as t-BuOCl (Non-Patent Document 2) are known. However, until now, a chlorination reaction using sulfuryl chloride to introduce a chlorine atom with high yield and minimal impurities has not been known.

[0004] Citation List

[0005] Patent Literature

[0006] Patent Document 1: WO2015141616

[0007] Non-patent literature

[0008] Non-patent literature 1: Watson, W.D. J. Org. Chem. 1985, 50, 2145;

[0009] Non-patent document 2: Lengyel, I.; Cesare, V.; Stephani, R. Synth. Commun. 1998, 28, 1891. Summary of the Invention

[0010] Technical issues

[0011] An object of the present invention is to provide an industrially useful and novel method for preparing 1,3-benzodioxole derivatives with high yield and minimal impurities, comprising a novel benzene ring chlorination reaction.

[0012] Solution to the problem

[0013] The present invention relates to the following (1) to (10).

[0014] (1) A preparation method comprising chlorinating a compound represented by formula (I) with sulfuryl chloride in a solvent:

[0015] [Formula 1]

[0016]

[0017] To obtain a compound represented by formula (II):

[0018] [Formula 2]

[0019]

[0020] In formula (I) and formula (II), R represents a C1-C6 alkyl group.

[0021] (2) The preparation method according to (1), wherein the solvent is a solvent comprising at least one selected from toluene, acetonitrile, methyl tert-butyl ether and cyclopentyl methyl ether, and water.

[0022] (3) The production method according to (1) or (2), wherein the solvent is a solvent containing toluene, acetonitrile and water.

[0023] (4) The production method according to (1), wherein the solvent is at least one solvent selected from the group consisting of acetonitrile, ethyl acetate, tetrahydrofuran, dimethylacetamide, and cyclopentyl methyl ether.

[0024] (5) The production method according to any one of (1) to (4), further comprising reacting the compound represented by formula (II) with tert-butyl (trans-4-ethynylcyclohexyl)carbamate using a ruthenium catalyst to obtain a compound represented by formula (III):

[0025] [Formula 3]

[0026]

[0027] Wherein, in formula (III), R is the same as defined in (1).

[0028] (6) The preparation method according to (5), wherein the ruthenium catalyst comprises Ru3(CO) 12 and P(o-Tol)3 catalysts.

[0029] (7) The production method according to any one of (1) to (6), wherein R is a methyl group.

[0030] (8) The production method according to any one of (5) to (7), further comprising the step of subjecting the compound represented by formula (III) to hydrolysis (i),

[0031] (ii) a step of performing optical resolution using an optically active amine, (iii) a step of removing the Boc group, and (iv) a step of performing dimethylation of the nitrogen atom to obtain a compound represented by formula (IV):

[0032] [Formula 4]

[0033]

[0034] or a pharmaceutically acceptable salt thereof.

[0035] (9) The production method according to (8), wherein the optically active amine is (1S)-1-phenylethylamine.

[0036] (10) The preparation method according to (8) or (9), further comprising condensing the compound represented by formula (IV) with 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one or a salt thereof to obtain a compound represented by formula (V):

[0037] [Formula 5]

[0038]

[0039] or a pharmaceutically acceptable salt thereof.

[0040] Advantageous Effects of the Invention

[0041] In a novel method for preparing 1,3-benzodioxole derivatives, it has been found that an industrially useful and novel benzene ring chlorination reaction can be carried out in high yield and with very few impurities by using sulfuryl chloride. Based on this finding, the present invention has been completed. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] [ Figure 1 ] Figure 1 Shown is a powder X-ray diffraction pattern of the crystals of the compound prepared in Example 7. The vertical axis of the figure represents diffraction intensity as relative X-ray intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

[0044] Description of the implementation plan

[0045] In the present invention, the "C1-C6 alkyl group" is a straight or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, and 4-methylpentyl.

[0046] In the present invention, "ruthenium catalyst" means a catalyst formed by a compound containing a ruthenium atom and a ligand. Examples of compounds containing a ruthenium atom include Ru3(CO) 12, [RuCl2(CO)3]2, Ru(acac)3, [RuCl2(benzene)], [RuCl2(mes)]2, [RuCl2(p-cym)]2 and RuCl2(1,5-cyclooctadiene). Preferably, Ru3(CO) 12 .

[0047] Examples of the ligand include P(o-Tol) 3 , P(tBu) 3 (HBF) and P(2-MeOPh) 3 . Preferably, P(o-Tol) 3 is used.

[0048] A preferred combination of a ruthenium atom-containing compound and a ligand is Ru3(CO) 12 and P(o-Tol)3 combination.

[0049] In the present invention, the reaction can be carried out using a very small amount of a ruthenium catalyst. The ruthenium catalyst to be used is 0.1 to 10 mol%, preferably 0.5 to 5 mol%, and more preferably 1 mol% relative to the equivalent amount of the compound represented by formula (II). The ruthenium atom is 0.3 to 30 mol%, preferably 1.5 to 15 mol%, and more preferably 3 mol% relative to the equivalent amount of the compound represented by formula (II).

[0050] The "optically active amine" that can be used in the present invention is not limited, as long as it can form diastereomeric salts with a racemic compound having an acidic group and can be optically resolved based on the difference in solubility of the diastereomeric salts in a solvent. Examples of optically active amines include (1S)-1-phenylethylamine and (2S)-2-amino-3-phenyl-1-propanol. Preferably, (1S)-1-phenylethylamine is used.

[0051] In the present invention, the "step of removing the Boc group" and the "step of performing dimethylation of the nitrogen atom" include not only a two-step reaction of removing the Boc group to isolate the intermediate and then performing dimethylation of the nitrogen atom, but also a one-pot reaction of removing the Boc group simultaneously with dimethylation of the nitrogen atom.

[0052] Examples of reagents that can be used to remove the Boc group include hydrochloric acid, p-toluenesulfonic acid, formic acid, and trifluoroacetic acid. Preferably, hydrochloric acid is used. Examples of reagents that can be used to dimethylate the nitrogen atom include formaldehyde and formic acid, or formaldehyde and sodium triacetoxyborohydride. Preferably, formaldehyde and formic acid are used.

[0053] The solvent that can be used in the present invention is not limited, as long as it is inert for each reaction. In the chlorination reaction using sulfuryl chloride, not only a single organic solvent can be used, but also a mixture of an organic solvent and water can be used. When an organic solvent is used alone, at least one solvent selected from acetonitrile, ethyl acetate, tetrahydrofuran, dimethylacetamide (DMAc) and cyclopentyl methyl ether (CPME) etc. can be used. Preferably, at least one solvent selected from acetonitrile, ethyl acetate, tetrahydrofuran and cyclopentyl methyl ether (CPME) is used. When a mixture of an organic solvent and water is used, for example, a mixture of at least one solvent selected from toluene, acetonitrile, methyl tert-butyl ether (MTBE) and cyclopentyl methyl ether and water can be used. Preferably, a mixture of toluene, acetonitrile and water is used. In the reaction using a ruthenium catalyst and (trans-4-ethynylcyclohexyl) tert-butyl carbamate, for example, toluene, α, α, α-trifluorotoluene, chlorobenzene, butyl acetate and / or methyl isobutyl ketone can be used. Preferably, toluene is used.

[0054] In the present invention, the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or a salt thereof, and the compound represented by formula (V) or a salt thereof include all isomers thereof (diastereomers, optical isomers, geometric isomers, rotational isomers).

[0055] In the present invention, "pharmaceutically acceptable salt" refers to a salt that does not have significant toxicity and can be used in a pharmaceutical composition. In the present invention, each of the compound represented by formula (IV) and the compound represented by formula (V) can be reacted with an acid to form a salt. Examples of salts include salts of hydrohalic acids such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides; inorganic salts such as nitrates, perchlorates, sulfates and phosphates; C1-C6 alkylsulfonates such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic salts such as acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and adipates; and amino acid salts such as glycinates, lysinates, argininates, ornithines, glutamates and aspartates.

[0056] In the present invention, when they are placed in the air or recrystallized, the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or its salt and the compound represented by formula (V) or its salt sometimes absorb water molecules to form hydrates. These hydrates are also included in the present invention.

[0057] In the present invention, when they are placed in a solvent or recrystallized, the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or a salt thereof, and the compound represented by formula (V) or a salt thereof sometimes absorb certain solvents to form solvates. These solvates are also included in the present invention.

[0058] Next, the present invention will be described. The reaction conditions of the present invention should not be construed as being limited to those described below. In the present invention, the functional groups of the compounds are sometimes protected with appropriate protecting groups. Examples of such functional groups include hydroxyl, carboxyl, and amino groups. For the types of protecting groups and the conditions for introducing or removing protecting groups, reference is made, for example, to Protective Groups in Organic Synthesis (TW Green and PGM Wuts, John Wiley & Sons, Inc., New York, 2006). Example

[0059] The present invention will be described in more detail by way of examples, but the scope of the present invention is not limited to these examples. The abbreviations used in the examples and their meanings are as follows:

[0060] mg: milligram, g: gram, kg: kilogram, mL: milliliter, L: liter, MHz: megahertz, rt: room temperature, ND: not detected.

[0061] In the following examples, tetramethylsilane was used as a reference to obtain nuclear magnetic resonance (hereinafter referred to as 1 HNMR (500 MHz) spectra were obtained, and chemical shift values ​​were expressed as δ values ​​(ppm). The splitting pattern was indicated by s for singlets, d for doublets, t for triplets, q for quartets, m for multiplets, and br for broad peaks (lines). In the Examples of the present invention, HPLC 10A (Shimadzu) or ACQUITY UPLC H-Class (Waters) was used as the "liquid chromatograph."

[0062] In the examples, the instrument and analysis conditions used for X-ray powder diffraction analysis are as follows.

[0063] Model: RigakuRintTTR-III

[0064] Sample: appropriate amount

[0065] X-ray generation conditions: 50kV, 300mA

[0066] Wavelength: 1.54 angstroms (Co-Kα rays)

[0067] Measurement temperature: room temperature

[0068] Scanning speed: 20° / min

[0069] Scanning range: 2 to 40°

[0070] Sampling width: 0.02°.

[0071] (Reference Example 1) Preparation of ethyl trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

[0072] [Formula 6]

[0073]

[0074] To a reaction vessel, under a nitrogen atmosphere, was added ethanol (624 L) and ethyl trans-4-aminocyclohexanecarboxylate monohydrochloride (138.7 kg, 667.8 mol). The reaction solution was cooled, and then triethylamine (151.2 kg, 1495.5 mol) and di-tert-butyl dicarbonate (160.9 kg, 737.2 mol) were each added dropwise while maintaining them at 20°C or lower. After the reaction mixture was stirred at 20-25°C for 4 hours, water (1526 kg) was added dropwise to the mixture at 25°C or lower, and the mixture was further stirred for 2 hours. The precipitated solid matter was obtained by filtration, washed with a mixture of ethanol:water = 1:4 (500 L), and dried at 40°C under reduced pressure to obtain the title compound (169.2 kg (yield 93.4%)).

[0075] 1 H NMR (500 MHz, CDC13): δ 4.37 (br, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.41 (br, 1H), 2.20 (tt, J = 4.8, 1.4 Hz, 1H), 2.07 (m, 2H), 2.00 (m, 2H), 1.52 (dq, J = 4.6, 1.4 Hz, 2H), 1.44 (s, 9H), 1.24 (t, J = 2.8 Hz, 3H), 1.11 (dq, J = 4.6, 1.4 Hz, 2H).

[0076] (Reference Example 2) Preparation of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate

[0077] [Formula 7]

[0078]

[0079] To a reaction vessel, tetrahydrofuran (968 kg), ethyl trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (110 kg, 405.4 mol), lithium chloride (27.5 kg, 648.6 mol), potassium borohydride (32.8 kg, 608.1 mol), and water (2.9 L, 162.2 mol) were added under a nitrogen atmosphere. The reaction solution was slowly warmed to 50°C, stirred for an additional 6 hours, and cooled to 0-5°C. Acetone (66 L) and a 9% by weight aqueous solution of ammonium chloride (1210 kg) were each added dropwise to the reaction solution while maintaining the temperature at 20°C or below. The solution was stirred at 20-25°C for one hour. Ethyl acetate (550 L) was further added to the solution. After discarding the aqueous layer, the organic layer was concentrated to 550 L. Ethyl acetate (1650 L) and a 9% by weight aqueous solution of ammonium chloride (605 kg) were added to the residue. After stirring the mixture, the aqueous layer was discarded and the organic layer was further washed with 9% by weight of ammonium chloride aqueous solution (605kg), 9% sodium chloride aqueous solution (605kg) and water (550L) successively. The organic layer was concentrated to 880L. Ethyl acetate (660L) was added to the residue. The mixture was concentrated to 880L while maintaining its internal temperature at 40-50°C. After the residue was cooled to 0-5°C and further stirred for one hour, petroleum ether (1760L) was added dropwise to the residue over a period of 30 minutes. The mixture was stirred at the same temperature for 2 hours. The solid matter precipitated was obtained by filtration, washed with a mixture (220L) of petroleum ether: ethyl acetate = 3:1 cooled to 0-5°C, and dried at 40°C under reduced pressure to obtain title compound (86.0kg (yield 92.3%)).

[0080] 1 HNMR (500MHz, CDCl3): δ4.37(br,1H),3.45(d,J=2.2Hz,2H),3.38(br,1H),2 .04(m,2H),1.84(m,2H),1.44(m,10H),1.28-1.31(m,1H),1.00-1.13(m,4H).

[0081] (Reference Example 3) Preparation of tert-butyl [trans-4-(2,2-dibromovinyl)cyclohexyl]carbamate

[0082] [Formula 8]

[0083]

[0084] (Step 1)

[0085] To a reaction vessel, ethyl acetate (50 L), tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (2.5 kg, 10.90 mol), potassium bromide (39.3 g, 0.33 mol), 2,2,6,6-tetramethylpiperidin-1-oxyl radical (51.1 g, 0.33 mol), and 4.8% sodium bicarbonate solution (26.25 kg) were added under a nitrogen atmosphere. The reaction solution was cooled to 0-5°C and 9.9% sodium hypochlorite (8.62 kg, 11.45 mol) was added to the reaction solution at 5°C or lower. The resulting reaction solution was further stirred at 0°C for 4 hours. Sodium sulfite (250 g) was added to the mixture. After stirring at 0-5°C for 30 minutes, the solution was warmed to 20-25°C. Thereafter, the aqueous layer was discarded, and the organic layer was washed with 20% aqueous sodium chloride solution (12.5 kg), dried over sodium sulfate, and concentrated to 7.5 L. To the residue was added ethyl acetate (12.5 L), and the mixture was concentrated again to 7.5 L to give a solution of tert-butyl (trans-4-formylcyclohexyl)carbamate, which was subjected to the subsequent reaction.

[0086] (Step 2)

[0087] To the reaction vessel, tetrahydrofuran (30 L) and triphenylphosphine (5.72 kg, 21.8 mol) were added under a nitrogen atmosphere. The reaction solution was warmed to 40°C and stirred for 5 minutes. Carbon tetrabromide (3.61 kg, 10.9 mol) was added to the reaction solution over a period of 30 minutes. The reaction mixture was further stirred at 40-45°C for 30 minutes. To the reaction mixture, a mixture of tert-butyl (trans-4-formylcyclohexyl)carbamate solution and triethylamine (2.54 kg, 25.1 mol) was added over a period of 20 minutes at a temperature less than 45°C. The resulting reaction mixture was further stirred at 40°C for 15 hours and cooled to 0°C. Thereafter, water (0.2 L) was added to the mixture at 10°C or lower, and additional water (25 L) was added. After the reaction solution was warmed to 20-25°C, the aqueous layer was discarded. Ethyl acetate (4.5 kg) and 10% aqueous sodium chloride solution (25 kg) were added to the organic layer. Under reduced pressure, 40 ℃ of filtration, 10 ℃ of dryings, 1 hour filtration, 1 hour filtration.After stirring, discard water layer again.The organic layer obtained is concentrated to 15L, and 2-propyl alcohol (19.65kg) is added thereto.The mixture is concentrated to 17.5L.In residue, 2-propyl alcohol (11.78kg) and 5mol / L hydrochloric acid (151.6g) are added.The mixture is stirred 2.5 hours at 25-35 ℃.In the mixture obtained, water (16.8L) is added dropwise.The mixture is stirred 30 minutes at 20-25 ℃, then stirred 2 hours at 0 ℃.The solid matter of precipitation is obtained by filtration, washed with a mixture (11kg) of acetonitrile: water=60:40 cooled to 0-5 ℃, and dried at 40 ℃ under reduced pressure to obtain title compound (3.05kg (yield 73.0%)).

[0088] 1 HNMR (500MHz, CDCl3): δ6.20(d,J=3.6Hz,1H),4.37(br,1H),3.38(br,1H),2.21(dtt,J=3.6,4.6,1.4Hz,1H),2.05 -2.00(m,2H),1.80-1.83(m,2H),1.44(s,9H),1.23(ddd,J=9.9,5.3,1.2Hz,2H),1.13(ddt,J=4.6,1.4,5.2Hz,2H).

[0089] (Reference Example 4) Preparation of tert-butyl (trans-4-ethynylcyclohexyl)carbamate

[0090] [Formula 9]

[0091]

[0092] Toluene (1436 kg), tert-butyl [trans-4-(2,2-dibromovinyl)cyclohexyl]carbamate (110 kg, 287.1 mol), and N,N,N',N'-tetramethylethane-1,2-diamine (106.7 kg, 918.8 mol) were added to a reaction vessel under a nitrogen atmosphere. The reaction solution was cooled to -10°C. Isopropylmagnesium chloride-tetrahydrofuran solution (2.0 mol / L, 418 kg, 863 mol) was added dropwise to the reaction solution at -5°C or below. The reaction solution was stirred at -10°C for 30 minutes. After the reaction was completed, 5 mol / L hydrochloric acid (465 kg) was added to the reaction solution at 5°C or below. The reaction solution was warmed to 20-25°C and the pH of the solution was adjusted to 5.0-6.0 with 5 mol / L hydrochloric acid (41.8 kg). After the water layer is discarded, the organic layer is washed twice with water (550L) and concentrated to 550L. 2-propanol (1296kg) is added to the concentrate. The mixture is concentrated to 550L again. 2-propanol (1296kg) is further added to the residue. The mixture is concentrated to 550L, then, water (770L) is divided into 4 parts, which are added dropwise to the mixture respectively. Each time water is added, the mixture is stirred for 30 minutes. After the addition is completed, the mixture is stirred for one hour, and further stirred at 0°C for one hour. The precipitated solid matter is obtained by filtration, washed with a mixture (550L) of 2-propanol: water = 5:7 cooled to 0-5°C, and dried at 40°C under reduced pressure to obtain the title compound (57.8kg (yield 90.2%)).

[0093] 1HNMR (500MHz, CDCl3): δ4.36(br,1H),3.43(br,1H),2.18-2.23(m,1H),1.97-2.04(m,5H),1.44-1.56(m,11H),1.06-1.14(m,2H).

[0094] (Reference Example 5) Preparation of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0095] [Equation 10]

[0096]

[0097] To a reaction vessel, water (300 L), 2-cyanoacetamide (20 kg, 238 mol), 1-pentane-2-4-dione (26.2 kg, 262 mol), and potassium carbonate (3.29 kg, 23.8 mol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 hours or longer. After the reaction was completed, the precipitated solid material was obtained by filtration, washed with water (60 L), then washed with a mixture of methanol (40 L) and water (40 L), and dried under reduced pressure at 40° C. to obtain the title compound (34.3 kg (yield 97.3%)).

[0098] 1 HNMR (500MHz, DMSO-d6): δ2.22(s,3H),2.30(s,3H),6.16(s,1H),12.3(brs,1H).

[0099] (Reference Example 6) Preparation of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one monohydrochloride

[0100] [Equation 11]

[0101]

[0102] To a reaction vessel, water (171 L), methanol (171 L), 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.1 kg, 116 mol), concentrated hydrochloric acid (15.8 kg, 152 mol), and 5% palladium on carbon (55% water-wetted) (3.82 kg) were added under a nitrogen atmosphere. Thereafter, the gas in the reaction vessel was replaced with hydrogen. The hydrogen pressure was then increased, and the reaction mixture was stirred at 30°C overnight. After the reaction was completed, the gas in the reaction vessel was replaced with nitrogen. The palladium on carbon was filtered out and washed with a 70% aqueous 2-propanol solution (51 L). Activated carbon (0.86 kg) was added to the filtrate, and the resulting mixture was stirred for 30 minutes. The activated carbon was filtered out and washed with a 70% aqueous 2-propanol solution (51 L). The filtrate was concentrated under reduced pressure to a volume of 103 L, and 2-propanol (171 L) was then added to the concentrate. The obtained solution was concentrated to a volume of 103 L under reduced pressure again. After this, 2-propanol (171 L) was added to the solution and stirred for one hour or longer. After confirming the precipitation of the solid material, the mixture was concentrated to a volume of 103 L. Further, 2-propanol (51 L) was added to the concentrate, and then the mixture was concentrated to a volume of 103 L under reduced pressure again and stirred at 50 ° C for 30 minutes. While maintaining the internal temperature of the mixture at 40 ° C or higher, acetone (171 L) was added to the mixture over one hour. The mixture was stirred at 40 to 45 ° C for 30 minutes, cooled to 25 ° C, and stirred for 2 hours or longer. The precipitated solid material was obtained by filtration, washed with acetone (86 L) and dried at 40 ° C under reduced pressure to obtain the title compound (19.7 kg (yield 90.4%)).

[0103] 1 H NMR (500 MHz, methanol-d4): δ 2.27 (s, 3H), 2.30 (s, 3H), 4.02 (s, 2H), 6.16 (s, 1H).

[0104] (Example 1-1) Preparation of 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester

[0105] [Equation 12]

[0106]

[0107] Into a reaction vessel, water (420 L), toluene (420 L), acetonitrile (420 L) and methyl 3,4-dihydroxy-2-methylbenzoate (1) (60 kg, 329 mol) were added under a nitrogen atmosphere. After cooling, sulfuryl chloride (133.4 kg, 988 mol) was added dropwise to the reaction solution while maintaining its temperature at 20°C or lower. After the reaction was completed, the reaction solution was separated into an organic layer 1 and an aqueous layer. Acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer. After stirring the mixture, the aqueous layer was discarded to obtain an organic layer 2. Water (420 L) and acetonitrile (210 L) were added to the organic layer 1. After cooling, sulfuryl chloride (88.9 kg, 659 mol) was added dropwise to the mixture at 20°C or lower, and additional sulfuryl chloride (53.2 kg, 394 mol) was divided into several portions and added separately. After the reaction is completed, the mixture is separated into an organic layer 3 and an aqueous layer. Organic layer 2 is added to the aqueous layer. After the mixture is stirred, the aqueous layer is discarded. The obtained organic layer is combined with organic layer 3. Water (420L) and acetonitrile (210L) are added to the combined organic layer. Thereto, sulfuryl chloride (44.5kg, 329mol) is added dropwise at 20°C or lower, and additional sulfuryl chloride (106.4kg, 788mol) is divided into several portions and added. After the reaction is completed, the mixture is separated into an organic layer 4 and an aqueous layer. Acetonitrile (60L) and toluene (120L) are added to the aqueous layer. After the mixture is stirred, the aqueous layer is discarded and the organic layer is combined with organic layer 4. The combined organic layer is washed three times with a 20% by weight sodium chloride aqueous solution (300L) and concentrated to 600L under reduced pressure. Toluene (300L) is added to the concentrate and the mixture is concentrated to 600L again under reduced pressure. This operation was repeated twice, and then the mixture was heated at 60° C. for one hour with stirring. After the mixture was cooled to room temperature, the precipitated solid material was obtained by filtration, washed with toluene (120 L), and dried under reduced pressure at 40° C. to obtain a crude product of the title compound (2) (52.1 kg (yield 73.0%)).

[0108] Toluene (782 L) and the crude product of the title compound (52.1 kg, 241 mol) were added to the reaction vessel under a nitrogen atmosphere. The reaction mixture was warmed to 80°C. After confirming that the crystals were completely dissolved, the mixture was filtered and washed with heated toluene (261 L). The filtrate was cooled to 60°C for crystallization and then stirred for 0.5 hours. After the mixture was cooled to 10°C, the precipitated solid material was obtained by filtration, washed with toluene (156 L) and dried under reduced pressure at 40°C to obtain the title compound (2) (47.9 kg (yield 91.9%)).

[0109] 1H NMR (500 MHz, methanol-d4): δ 2.41 (s, 3H), 3.82 (s, 3H), 7.41 (s, 1H).

[0110] (Example 1-2) Study on chlorination conditions 1

[0111] Since it is difficult to remove the compound (1) as a raw material and the compound (4) (which is a reaction by-product) even in the subsequent steps, it is necessary to control the amount of the unreacted compound (1) and the amount of the compound (4) to be produced. Therefore, chlorination was carried out in the same manner as in Example 1-1 using the compound (1) as a raw material. The results are shown in Table 1.

[0112] [Equation 13]

[0113]

[0114] [Table 1]

[0115]

[0116] NCS: N-chlorosuccinimide, DCH: 1,3-dichloro-5,5-dimethylhydantoin,

[0117] Na-diCl: sodium dichloroisocyanurate, TriCl: trichloroisocyanuric acid

[0118] a) Quantification by HPLC: 33.5%.

[0119] HPLC conditions

[0120] Detection: 220nm

[0121] Column: ACQUITYUPLC BEH C18 (2.1mm ID×50mm, 1.7μm, Waters)

[0122] Column temperature: 40°C

[0123] Mobile phase: A: 0.1% trifluoroacetic acid in water, B: acetonitrile

[0124] Gradient conditions:

[0125] [Table 2]

[0126] Time (min) 0 3 4 4.01 6 Concentration of solution B 10 70 90 10 10

[0127] Flow rate: 1.0 mL / min

[0128] Injection volume: 1 μL

[0129] Solution for dissolving samples: acetonitrile / water (1:1)

[0130] Washing solution: acetonitrile / water (1:1)

[0131] Purification solution: acetonitrile / water (1:1)

[0132] Seal washing solution: acetonitrile / water (1:1)

[0133] Sample-cooler temperature: Unspecified

[0134] Measurement time: 5 minutes

[0135] Time for measuring area: about 0.5 minutes to 4.0 minutes

[0136] Compound 1: 1.11 min, Compound 2: 1.55 min,

[0137] Compound 3: 1.44 min, Compound 4: 1.70 min.

[0138] (Example 1-3) Study 2 of chlorination conditions

[0139] Using compound (1) as a starting material and sulfuryl chloride as a chlorination agent, chlorination in various solvents was investigated. The results are shown in Table 3.

[0140] [Table 3]

[0141]

[0142] a) Isolation yield: 73.0%

[0143] *When toluene alone was used as a solvent, the reaction hardly proceeded.

[0144] (Example 2) Preparation of methyl (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate

[0145] [Equation 14]

[0146]

[0147] To a reaction vessel, toluene (9.0 L), tert-butyl (trans-4-ethynylcyclohexyl)carbamate (2.23 kg, 9.99 mol), methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (1.80 kg, 8.31 mol), tri(o-tolyl)phosphine (76.0 g, 250 mmol), and triruthenium dodecacarbonyl (53.0 g, 82.9 mmol) were added under a nitrogen atmosphere. The reaction solution was heated at 80-90° C. for 7 hours with stirring while supplying oxygen-containing nitrogen. The reaction solution was cooled to room temperature to obtain a toluene solution of the title compound.

[0148] (Example 3) Preparation of (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid

[0149] [Equation 15]

[0150]

[0151] To a toluene solution (13 L, 7.83 mol equivalent) of methyl (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate obtained in Example 2, methanol (9.0 L), 1,2-dimethoxyethane (3.6 L), and a 5 mol / L aqueous sodium hydroxide solution (2.50 L, 12.5 mol) were added. The reaction solution was stirred at 55-65°C for 3 hours. After adding water (5.4 L), the reaction solution was separated into an organic layer and an aqueous layer. After the aqueous layer was cooled to room temperature, 1,2-dimethoxyethane (16.2 L) was added to the aqueous layer, and the pH was adjusted to 4.0 to 4.5 with 3 mol / L hydrochloric acid. Then, toluene (5.4 L) was added. After heating to 50-60°C, the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with 20 wt% sodium chloride aqueous solution (7.2 L). 1,2-dimethoxyethane (21.6 L) was then added to the organic layer. The mixture was concentrated to 9 L under reduced pressure, and thereafter, 1,2-dimethoxyethane (21.6 L) was added to the mixture. Thereafter, the mixture was heated to 50-60 ° C and filtered to remove inorganic matter. Subsequently, the filtrate was washed with 1,2-dimethoxyethane (1.8 L) and concentrated to 21.6 L under reduced pressure to obtain a 1,2-dimethoxyethane solution of the title compound (quantitative value 89.6% (total yield from Examples 2 to 3), 7.45 mol equivalent).

[0152] (Example 4) Preparation of (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (1S)-1-phenylethylamine

[0153] [Equation 16]

[0154]

[0155] A dimethoxyethane solution of (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid obtained in Example 3 (21.6 L, 7.45 mol equivalent) was warmed to 75-80°C. Subsequently, (1S)-1-phenylethylamine (1.02 kg, 8.42 mmol) was added to the solution, and the mixture was stirred for 4 hours. A mixture of 1,2-dimethoxyethane (9.2 L) and water (3.4 L) heated to 50-60°C was added to the resulting solution. After stirring, the mixture was cooled to room temperature. The precipitated solid matter was obtained by filtration and washed with 1,2-dimethoxyethane (9 L) to give a crude product of the title compound (1.75 kg (on a dry basis), yield 38.5% (total yield from Example 2), optical purity 93.8% ee).

[0156] To a reaction vessel, a 1,2-dimethoxyethane aqueous solution (13.6 L) and the crude product of (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (1S)-1-phenylethylamine obtained in step 1 (equivalent to 1.70 kg, 3.11 mol) were added under a nitrogen atmosphere. Then, 5 mol / L hydrochloric acid (0.56 L, 2.8 mol) was added dropwise. After the reaction solution was stirred at room temperature for 10 minutes or longer and heated to 75° C. or higher, a solution prepared by dissolving (1S)-1-phenylethylamine (360 g, 2.97 mmol) in 1,2-dimethoxyethane (2.6 L) was added dropwise over one hour or longer. Thereafter, the reaction mixture was washed with 1,2-dimethoxyethane (0.9 L), stirred for 2 hours, and cooled to 0-5° C. The precipitated solid matter was obtained by filtration and washed with 1,2-dimethoxyethane (5.1 L) cooled to 0-5° C. to obtain the title compound (1.56 kg on a dry basis, 91.9% yield, 99.5% ee optical purity).

[0157] 1 HNMR (500MHz, methanol-d4): δ1.15-1.23(m,2H),1.28-1.35(m,2H),1.42(s,9H),1.59(s,3H),1.60-1.61(d,3H,J=7.0Hz,3H),1.80-1.86(d t,J=12.0,3.0Hz,1H),1.95-1.96(m,4H),2.27(s,3H),3.24-3.28(m,1H),4.39-4.43(q,J=7.0Hz,1H),7.07(s,1H),7.37-7.45(m,5H).

[0158] (Example 5) Preparation of (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride A

[0159] [Equation 17]

[0160]

[0161] (Step 1)

[0162] To a reaction vessel, 1,2-dimethoxyethane (200 L), (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (1S)-1-phenylethylamine (equivalent to 87.64 kg, 160 mol), and 35% hydrochloric acid (16.7 kg, 160 mol) were added under a nitrogen atmosphere. The reaction solution was heated to 45-55°C, and 35% hydrochloric acid (36.7 kg, 352 mol) was added dropwise in seven portions. The mixture was stirred for 3 hours, cooled to room temperature, and added to a mixture of water (982 L) and 5 mol / L sodium hydroxide solution (166.34 kg, 702 mol). To the resulting solution, 3 mol / L hydrochloric acid (22.4 kg) was added dropwise at 30°C. After confirming the precipitation of crystals, the mixture was stirred for 30 minutes or longer, cooled to 10°C, and further stirred for 2 hours. Thereafter, 3 mol / L hydrochloric acid (95.1 kg) was further added dropwise to the mixture at 10°C to adjust the pH to 7.0. The precipitated solid material was obtained by filtration and washed with water (293 L) cooled to 10°C to obtain (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid trihydrate (57.63 kg (on a dry basis), a yield of 94.7%).

[0163] 1 H NMR (500MHz, methanol-d4+D2O): 1.32-1.44(m,4H), 1.61(s,3H), 1.89-1.94(m,1H), 2.01-2.13(m,4H), 2.27(s,3H), 2.99-3.07(m,1H), 7.06(s,3H).

[0164] (Step 2)

[0165] To a reaction vessel, 1,2-dimethoxyethane (115 L), (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid trihydrate (equivalent to 57.63 kg, 152 mmol), formic acid (34.92 kg, 759 mol), and 37% formaldehyde aqueous solution (93.59 kg, 1153 mol) were added under a nitrogen atmosphere. The reaction solution was stirred at 55-65°C for 2 hours and cooled to room temperature. 2-Propanol (864 L) was added to the reaction solution. The solution was concentrated to 576 L under reduced pressure. 2-Propanol (231 L) was added to the solution, and the solution was again concentrated to 576 L under reduced pressure. 2-Propanol (231 L) was further added to the solution, and the solution was concentrated to 576 L under reduced pressure. After that, 35% hydrochloric acid (20.40 kg, 196 mol) was added dropwise to the solution over a period of 2 hours. The mixture was stirred at room temperature for 30 minutes. Ethyl acetate (576 L) was added to the resulting slurry over a period of 30 minutes. The mixture was concentrated to 692 L. After ethyl acetate (461 L) was added to the mixture, the mixture was further concentrated to 519 L. Ethyl acetate (634 L) was added to the residue and the resulting residue was stirred at room temperature for 2 hours. The precipitated solid was filtered, washed with ethyl acetate (491 L) and dried under reduced pressure at 40 ° C to obtain the title compound (51.56 kg, 87.1% yield).

[0166] 1 HNMR (500 MHz, methanol-d4): δ 1.38-1.47 (m, 2H), 1.53-1.61 (m, 2H), 1.67 (s, 3H), 1.99-2.05 (m, 1H), 2.13-2.18 (m, 4H), 2.38 (s, 3H), 2.84 (s, 6H), 3.19-3.25 (dt, J = 12.5, 3.5 Hz, 1H), 7.53 (s, 1H).

[0167] (Example 6) Preparation of (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride B

[0168] [Equation 18]

[0169]

[0170] To a reaction vessel, formic acid (20 mL), 37% aqueous formaldehyde solution (15 mL), dimethoxyethane (10 mL), and (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (1S)-1-phenylethylamine (10 g, 18.3 mmol) were added under a nitrogen atmosphere. The reaction solution was stirred at 80°C for 10 hours and cooled to room temperature. After insoluble matter was filtered off, 2-propanol (100 mL) was added to the filtrate, which was then concentrated under reduced pressure to a volume of 30 mL. While the filtrate was stirred at room temperature, ethyl acetate (120 mL) and concentrated hydrochloric acid (6.1 mL) were added to the filtrate to obtain a slurry. The slurry was concentrated under reduced pressure to 30 mL, and ethyl acetate (120 mL) was added thereto. The slurry was then concentrated again under reduced pressure to 30 mL. After adding ethyl acetate (120 mL), the precipitated solid matter was obtained by filtration, washed with ethyl acetate (50 mL) and dried under reduced pressure at 40°C to give the title compound (6.56 g (yield 92.0%)).

[0171] (Example 7) Preparation of (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate

[0172] [Equation 19]

[0173]

[0174] To a reaction vessel, acetone (6.5 L), purified water (1.3 L), (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride (650.4 g, 1.67 mol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one monohydrochloride (330.1 g, 1.75 mol), and triethylamine (337 g, 3.33 mol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Thereafter, 1-hydroxybenzotriazole monohydrate (255 g, 1.67 mol) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (383 g, 2.00 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After the pH of the reaction solution was adjusted to 11 with a 5mol / L sodium hydroxide solution, toluene (9.8L) was added thereto. The reaction solution was stirred and then separated into an organic layer 1 and an aqueous layer. Toluene (3.3L) was added to the aqueous layer. The mixture was stirred and the aqueous layer was discarded. The organic layer thus obtained was merged with the previously obtained organic layer 1. The combined organic layer was concentrated to 9.75L under reduced pressure and toluene (6.5L) was added thereto. The obtained mixture was washed twice with purified water (3.25L). The obtained organic layer was concentrated to 4.875L under reduced pressure and 2-propanol (1.625L) was added thereto. A solution was prepared by dissolving p-toluenesulfonic acid monohydrate (0.12kg, 0.631mol) in 4-methyl-2-pentanone (1.14L), and added dropwise to the organic layer heated to 68°C over 1.5 hours. The mixture was stirred at 68°C for 30 minutes. Further, a solution prepared by dissolving p-toluenesulfonic acid monohydrate (0.215 kg, 1.13 mol) in 4-methyl-2-pentanone (2.11 L) was added dropwise over 3.5 hours. The resulting mixture was stirred at 68 ° C for 30 minutes. Thereafter, 4-methyl-2-pentanone (6.5 L) was added dropwise over one hour. The mixture was cooled to room temperature and filtered to obtain a precipitated solid, which was washed with 4-methyl-2-pentanone (3.25 L) and dried under reduced pressure at 40 ° C to obtain a crude product of the title compound (1.035 kg (yield 94.2%)).

[0175] To the reaction vessel, 2-propanol (6.65 L) and the crude product of the title compound obtained above (950 g) were added under a nitrogen atmosphere. The mixture was stirred and purified water (0.23 L) was added thereto. After the solid matter was completely dissolved in the solution at 68° C., the solution was filtered and washed with hot 2-propanol (0.95 L). After confirming that the solid matter was completely dissolved at an internal temperature of 68° C., the solution was cooled to 50° C. Thereafter, seed crystals were added. *(9.5 g, 0.01 wt) and the resulting slurry was stirred at 50 °C overnight. The separated tert-butyl methyl ether (11.4 L) was added dropwise in four portions, each over 30 minutes. The mixture was stirred for 30 minutes after each addition. After the resulting mixture was cooled to room temperature, the precipitated solid material was obtained by filtration, washed with a mixture of 2-propanol (0.38 L) and tert-butyl methyl ether (3.42 L), followed by tert-butyl methyl ether (4.75 L), and dried under reduced pressure at 40 °C to obtain the title compound (915.6 g, yield 96.4%).

[0176] 1 HNMR (500 MHz, Methanol-d4): δ 1.35-1.43 (m, 2H), 1.49-1.57 (m, 2H), 1.62 (s, 3H), 1.94-2.00 (dt, J = 12.5, 3.0 Hz, 1H), 2.09-2.13 (m, 4H), 2.17 (s, 3H), 2.24 (s, 3H), 2.35 (s, 3H), 2.36 (s, 3H), 2.82 (s, 6H), 3.16-3.22 (dt, J = 12.0, 3.5 Hz, 1H), 4.42 (s, 2H), 6.10 (s, 1H), 6.89 (s, 1H), 7.22-7.24 (d, J = 8.0 Hz, 2H), 7.69-7.71 (dt, J = 8.0, 1.5 Hz, 2H)

[0177] *Seed formation To a reaction vessel, under a nitrogen atmosphere, 2-propanol (79.0 L) and the crude product of the title compound (7.90 kg) were added. The reaction mixture was stirred and to it, purified water (7.9 L) was added to completely dissolve the solid material. Further, activated carbon (0.40 kg) was added, stirred, filtered and washed with 2-propanol (79.0 L). The filtrate was concentrated to 58 L. To the residue, 2-propanol (5 L) was added and the mixture was warmed to 64 °C. To the mixture, tert-butyl methyl ether (19.8 L) was added. After confirming the precipitation of crystals, further tert-butyl methyl ether (75.1 L) was added in three portions. The mixture was stirred for 30 minutes after each addition. After the resulting mixture was cooled to room temperature, the precipitated solid material was obtained by filtration, washed with a mixture of 2-propanol (7.9 L) and tert-butyl methyl ether (15.8 L) and dried under reduced pressure at 40 °C to obtain the title compound (7.08 kg, yield 89.6%) which served as seeds.

[0178] Crystals of (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate obtained in Example 7 were analyzed by powder X-ray diffraction. The diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction pattern are listed in Table 4.

[0179] [Table 4]

[0180]

Claims

1. A preparation method comprising using a ruthenium catalyst to react a compound represented by formula (II) Reaction with tert-butyl (trans-4-ethynylcyclohexyl)carbamate to obtain a compound represented by formula (III): in, R represents a C1-C6 alkyl group; The ruthenium catalyst comprises Ru3(CO) 12 and P(o-Tol)3 catalysts. The preparation method according to claim 1 , wherein R is a methyl group.

3. The preparation method according to claim 1, further comprising subjecting the compound represented by formula (III) to: (i) performing a hydrolysis step; (ii) a step of performing optical resolution using an optically active amine; (iii) a step of removing the Boc group; and (iv) a step of dimethylating the nitrogen atom, To obtain a compound represented by formula (IV): or a pharmaceutically acceptable salt thereof. The preparation method according to claim 3 , wherein the optically active amine is (1S)-1-phenylethylamine.

5. The preparation method according to claim 3, further comprising condensing the compound represented by formula (IV) with 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one or a salt thereof to obtain a compound represented by formula (V): or a pharmaceutically acceptable salt thereof.

6. The preparation method according to any one of the preceding claims, further comprising chlorinating the compound represented by formula (I) with sulfuryl chloride in a solvent. To obtain a compound represented by formula (II); wherein the solvent is: i) a solvent comprising at least one selected from the group consisting of toluene, acetonitrile, methyl tert-butyl ether and cyclopentyl methyl ether, and water; or ii) a solvent selected from at least one of the group consisting of acetonitrile, ethyl acetate, tetrahydrofuran, dimethylacetamide and cyclopentyl methyl ether.

7. The preparation method according to claim 6, wherein the solvent is a solvent comprising at least one selected from toluene, acetonitrile, methyl tert-butyl ether and cyclopentyl methyl ether and water.

8. The preparation method according to claim 6, wherein the solvent is a solvent comprising toluene, acetonitrile and water.

9. The preparation method according to claim 6, wherein the solvent is at least one solvent selected from the group consisting of acetonitrile, ethyl acetate, tetrahydrofuran, dimethylacetamide and cyclopentyl methyl ether.

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