Method for producing azide compound, amine compound and edoxaban

Abstract

The purpose of the present invention is to provide a method for producing an azide compound and an amine compound, which suppress the generation of undesired diastereomers in an azidation reaction and have good diastereoselectivity. A method for producing an azide compound represented by formula (2), the method comprising azidation of an alcohol compound represented by formula (1).

Description

Technical Field

[0001] The present invention relates to a method for producing an azide compound and an amine compound useful as pharmaceutical intermediates, and a method for producing edoxaban. Background Art

[0002] As compounds that show an inhibitory effect on activated coagulation factor X and are useful as preventive and / or therapeutic drugs for thrombotic diseases, for example, N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-((5-methyl-4,5,6,7-tetrahydrothiazolidine[5,4-c]pyridine-2-carbonyl)amino)cyclohexyl)oxamide represented by the following formula (4), its salts, or solvates thereof (also known as edoxaban) are known.

[0003]

[0004] As a method for producing edoxaban, for example, there is known a method in which a compound represented by the following formula (11-2) is azidated to produce a compound represented by the following formula (12), the compound represented by the above formula (12) is reduced to produce a compound represented by the following formula (13), ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride is allowed to act on the compound represented by the above formula (13) to produce a compound represented by the following formula (14), the compound represented by the above formula (14) is deprotected, and then 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride is subjected to dehydration condensation (Patent Documents 1 to 3, etc.).

[0005]

[0006] (Wherein, Boc represents tert-butyloxycarbonyl.)

[0007] In addition, Patent Document 4 discloses the following method: a compound represented by the following formula (11-1) is reacted with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid to produce a compound represented by the following formula (1), phthalimide, phosphine, and an azo compound are reacted with the compound represented by the above formula (1) to produce a compound represented by the following formula (15), the compound represented by the above formula (15) is deprotected to obtain a compound represented by the following formula (3), and the compound represented by the above formula (3) is reacted with ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate.

[0008]

[0009] Prior art literature

[0010] Patent Literature

[0011] Patent Document 1: International Publication No. 2007 / 032498

[0012] Patent Document 2: Chinese Patent Application Publication No. 111606827

[0013] Patent Document 3: Chinese Patent Application Publication No. 113527124

[0014] Patent Document 4: Korean Patent Publication No. 10-2022-0087933 Summary of the Invention

[0015] Problems to be solved by the invention

[0016] However, in the conventional production methods disclosed in Patent Documents 1 to 3, which include a step of azidating the compound represented by the above formula (11-2) to produce the compound represented by the above formula (12), there is a case where the suppression of the diastereomer (trans isomer; see the following formula) produced as a by-product in the azidation reaction is insufficient.

[0017]

[0018] Furthermore, the present inventors conducted further experiments on the method disclosed in Patent Document 4 and found that even when the compound represented by formula (1) was reacted with phthalimide, the compound represented by formula (15) could not be obtained (see Comparative Example 4 in this specification).

[0019] The present invention has been developed in view of the above circumstances, and its object is to provide a method for producing azide compounds and amine compounds in which the formation of undesired diastereomers in an azidation reaction (nucleophilic substitution reaction of an azide group) is suppressed, i.e., with good diastereoselectivity. These azide compounds and amine compounds are useful as pharmaceutical intermediates, particularly as intermediates for the production of edoxaban.

[0020] Solutions to the Problem

[0021] To achieve the above object, the present inventors conducted intensive studies and found that azidation of the alcohol compound represented by the above formula (1) can produce a compound having a desired stereostructure with good diastereoselectivity, thereby completing the present invention.

[0022] The gist of the present invention is as follows.

[0023] [1] A method for producing an azide compound represented by the following formula (2), comprising azidating an alcohol compound represented by the following formula (1).

[0024]

[0025] [2] The manufacturing method according to [1], wherein

[0026] The azidation is carried out by allowing diphenylphosphoryl azide, a phosphine compound, and an azo compound to act on the alcohol compound represented by the formula (1).

[0027] [3] The manufacturing method according to [2], wherein

[0028] The phosphine compound is a triarylphosphine.

[0029] [4] The manufacturing method according to [3], wherein

[0030] The phosphine compound is triphenylphosphine.

[0031] [5] The manufacturing method according to any one of [2] to [4], wherein

[0032] The azo compound is azodicarboxylate.

[0033] [6] The manufacturing method according to [5], wherein

[0034] The azo compound is at least one selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-2-methoxyethyl azodicarboxylate.

[0035] [7] The manufacturing method according to [1], wherein

[0036] The azidation is carried out by allowing diphenylphosphoryl azide and a tertiary amine to act on the alcohol compound represented by the formula (1).

[0037] [8] The manufacturing method according to [7], wherein

[0038] The tertiary amine is at least one selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nonene-5, triethylamine, tributylamine, diisopropylethylamine, 1,1,3,3-tetramethylguanidine, 4-dimethylaminopyridine, triethylenediamine, benzyldimethylamine, triethanolamine, dimethylaminoethanol, and tris(dimethylaminomethyl)phenol.

[0039] [9] The manufacturing method according to [1], wherein

[0040] The azidation is carried out by the following method:

[0041] A sulfonylating agent and a base are allowed to act on the alcohol compound represented by the above formula (1) to obtain a sulfonate compound represented by the following formula (5), and a metal azide is allowed to act on the sulfonate compound represented by the above formula (5).

[0042]

[0043] (Where R 2 represents an alkyl group having 1 to 12 carbon atoms which may have a substituent, or an aryl group having 6 to 12 carbon atoms which may have a substituent.

[0044]

[10] The manufacturing method according to [9], wherein

[0045] The sulfonylating agent is at least one selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, chloromethanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and trifluoromethanesulfonic anhydride.

[0046]

[11] The manufacturing method according to [9] or

[10] , wherein

[0047] The base is a tertiary amine.

[0048]

[12] The manufacturing method according to [9] to

[11] , wherein

[0049] The metal azide is an alkali metal azide.

[0050]

[13] The manufacturing method according to [9] to

[12] , wherein

[0051] R in the formula (5) 2 It is at least one selected from an alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms.

[0052]

[14] The manufacturing method according to

[13] , wherein

[0053] R in the formula (5) 2 It is an alkyl group having 1 to 3 carbon atoms.

[0054]

[15] The manufacturing method according to [9] to

[14] , wherein

[0055] A phase transfer catalyst is allowed to act together with the metal azide.

[0056]

[16] The manufacturing method according to

[15] , wherein

[0057] The phase transfer catalyst is selected from quaternary ammonium salt and pyridine At least one of the compounds.

[0058]

[17] The manufacturing method according to

[16] , wherein

[0059] The phase transfer catalyst is tetrabutylammonium chloride or dodecylpyridinium chloride.

[0060]

[18] The manufacturing method according to [1] to

[17] , further comprising:

[0061] a step of subjecting 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid or a salt thereof to dehydration condensation with an amino alcohol compound represented by the following formula (11) or a salt thereof to obtain an alcohol compound represented by the above formula (1);

[0062]

[0063] (Where R 1 represents a hydrogen atom or a tert-butyloxycarbonyl group.)

[0064]

[19] The manufacturing method according to

[18] , wherein

[0065] R in the formula (11) 1 A hydrogen atom.

[0066]

[20] The manufacturing method according to

[18] or

[19] , wherein

[0067] A condensation agent is used in the dehydration condensation.

[0068]

[21] The manufacturing method according to

[20] , wherein

[0069] The condensing agent is a carbodiimide condensing agent.

[0070]

[22] A method for producing an amine compound represented by the following formula (3) or a salt thereof, the method comprising:

[0071] The azide compound represented by the formula (2) produced by the method of any one of [1] to

[21] is reduced,

[0072] .

[0073]

[23] The manufacturing method according to

[22] , wherein

[0074] The reduction is carried out by allowing phosphine and water to act on the azide compound represented by the above formula (2).

[0075]

[24] The manufacturing method according to

[23] , wherein

[0076] The phosphine is triphenylphosphine.

[0077]

[25] A method for producing N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino)cyclohexyl)oxamide represented by the following formula (4), a salt thereof, or a solvate thereof, the method comprising:

[0078] The amine compound represented by the above formula (3) produced by the method of any one of

[22] to

[24] is allowed to act with alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate or a salt thereof.

[0079]

[0080] Effects of the Invention

[0081] According to the present invention, there can be provided a method for producing an azide compound and an amine compound with excellent diastereoselectivity while suppressing the formation of undesired diastereomers. DETAILED DESCRIPTION

[0082] When describing the present invention, first, an outline of the synthesis routes of the compounds mentioned in this specification is shown below.

[0083]

[0084] (I) Method for producing azide compound (2)

[0085] The method for producing the azide compound represented by formula (2) of the present invention (hereinafter also referred to as azide compound (2)) comprises azidating an alcohol compound represented by formula (1) (hereinafter also referred to as alcohol compound (1)).

[0086]

[0087] According to the production method of the present invention, when an alcohol compound (1) is subjected to an azidation reaction (nucleophilic substitution reaction of an azide group), since the adjacent group at the position where the azide group is introduced has a bulky amide group represented by the following formula (21), the diastereoselectivity of the obtained azide compound (2) can be improved by suppressing the stereoconformation change caused by the bulkiness of the adjacent group (stereofactor). In addition, compared with the case where the adjacent group at the position where the azide group is introduced is a carbamate group as disclosed in Patent Documents 1 to 3, when the adjacent group is an amide group, the interference of the adjacent group (electronic factor) can be reduced, thereby further improving the diastereoselectivity of the obtained azide compound (2).

[0088]

[0089] (Where * represents the bonding site.)

[0090] When edoxaban is produced using the azide compound (2) as an intermediate, the group represented by the above formula (21) is a group possessed by the final target product. Therefore, the number of steps such as introduction and elimination reactions does not need to be increased, that is, the diastereoselectivity in the azidation reaction can be improved without reducing the production efficiency.

[0091] The mechanism of the azidation reaction of the alcohol compound (1) is not particularly limited, but is preferably at least one selected from the following azidation reactions 1 to 3.

[0092] <Azide Reaction 1>

[0093] The azidation of the alcohol compound (1) can be carried out, for example, by reacting diphenylphosphoryl azide, a phosphine compound, and an azo compound with the alcohol compound (1) (hereinafter also referred to as azidation reaction 1). In this reaction, the phosphine compound and the azo compound activate the hydroxyl group of the alcohol compound (1), and the azide ion generated by the diphenylphosphoryl azide replaces the activated hydroxyl group with a stereo inversion, thereby generating the target azide compound (2). Unlike general nucleophilic substitution reactions, the above reaction may use the formation of a stable double bond (P=O) as the driving force of the reaction. Therefore, the reaction can proceed under relatively mild conditions and can achieve both high diastereoselectivity and safety.

[0094] <<Diphenylphosphoryl azide>>

[0095] The amount of diphenylphosphoryl azide used as an azide source in the azidation reaction 1 is preferably 1.0 mol or more and 10 mol or less, more preferably 1.2 mol or more, even more preferably 1.5 mol or more, more preferably 8 mol or less, and even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of diphenylphosphoryl azide used is preferably 1.0 mol to 10 mol, more preferably 1.2 mol to 8 mol, and even more preferably 1.5 mol to 5 mol relative to 1 mol of the alcohol compound (1). By setting the amount of diphenylphosphoryl azide used within the above range relative to 1 mol of the alcohol compound (1), the target azide compound (2) can be obtained with high diastereoselectivity, preferably in good yield, and more safely.

[0096] <<Phosphine Compounds>>

[0097] The phosphine compound used in the azidation reaction 1 is considered to act together with the azo compound to activate the alcohol compound (1). The phosphine compound is not particularly limited, and for example, a tertiary phosphine is preferably used. As the tertiary phosphine, specifically, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tri(tert-butyl)phosphine, tricyclohexyl phosphine, triphenyl phosphine, tribenzyl phosphine, tri(o-tolyl)phosphine, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine, ethylenebis(diphenylphosphine), trimethylenebis(diphenylphosphine), 1,1'-ferrocenebis(diphenylphosphine), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, etc., preferably triphenylphosphine, tribenzylphosphine, tritolylphosphine, etc., more preferably triphenylphosphine. As the phosphine compound, only one kind may be used, or two or more kinds may be used in combination.

[0098] The amount of the phosphine compound used in the azidation reaction 1 is preferably 0.8 mol or more and 10 mol or less, more preferably 1.0 mol or more, further preferably 1.5 mol or more, further more preferably 8 mol or less, further more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the phosphine compound used is preferably 0.8 mol to 10 mol, more preferably 1.0 mol to 8 mol, further preferably 1.5 mol to 5 mol, relative to 1 mol of the alcohol compound (1). The amount of the phosphine compound used is preferably 0.5 mol or more and 1.5 mol or less, more preferably 0.7 mol or more, further preferably 0.9 mol or more, further more preferably 1.3 mol or less, further preferably 1.1 mol or less, relative to 1 mol of the azo compound. That is, the amount of the phosphine compound used is preferably 0.5 mol to 1.5 mol, more preferably 0.7 mol to 1.3 mol, further preferably 0.9 mol to 1.1 mol, relative to 1 mol of the azo compound.

[0099] <<Azo Compounds>>

[0100] The azo compound used in the azidation reaction 1 is not particularly limited. Examples thereof include azodicarboxylates such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and di-2-methoxyethyl azodicarboxylate (DMEAD); azodicarboxylates such as N,N,N',N'-tetraisopropyl azodicarboxylic acid amide (TIPA), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetramethyl azodicarboxylic acid amide (TMAD), and 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazolyzine-2,5-dione (DHTD). Azodicarboxylates are preferred, and DEAD, DIAD, and DMEAD are more preferred. The azo compound may be used alone or in combination of two or more.

[0101] The amount of the azo compound used in the azidation reaction 1 is preferably 0.8 mol or more and 10 mol or less, more preferably 1.0 mol or more, and even more preferably 1.5 mol or more, and more preferably 8 mol or less, and even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the azo compound used is preferably 0.8 mol to 10 mol, more preferably 1.0 mol to 8 mol, and even more preferably 1.5 mol to 5 mol relative to 1 mol of the alcohol compound (1).

[0102] Solvents

[0103] In the azidation reaction 1, a solvent may be used. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, butyl vinyl ether, ethylpropyl ether, cyclopentyl methyl ether, anisole, 2-methylanisole, 4-methylanisole, 2,3-dimethylanisole, 2,6-dimethylanisole, chloroanisole, anethole, phenethyl ether, 4-methylphenethyl ether, n-butylphenyl ether, pentyl ether, Benzyl ethyl ether, diphenyl ether, dibenzyl ether, veratrole, 1,2-dimethoxyethane, 1,1-diethoxyethane, 1,2-diethoxyethane, 1,2-dibutoxyethane, dimethanol acetal, tert-butyl methyl ether, tert-butyl ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, Ether solvents such as ethyl ether, diethylene glycol dibutyl ether, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 2,3-dihydrobenzofuran, tetrahydropyran, 4-methyltetrahydropyran, eucalyptol, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, 4-methyl-1,3-dioxane, and 4-phenyl-1,3-dioxane; ester solvents such as ethyl acetate and isopropyl acetate; hydrocarbon solvents such as benzene, toluene, xylene, and n-hexane; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile, propionitrile, and benzonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; urea solvents such as dimethylpropylene urea; hexamethylphosphonic acid triamide (hexamethylphosphonic acid triamide) These may be used alone or in combination of two or more.

[0104] As the solvent in the azidation reaction 1, from the viewpoint of improving diastereoselectivity and improving the yield of the azide compound (2), ether solvents, ester solvents, and hydrocarbon solvents are preferred, and ether solvents and hydrocarbon solvents are more preferred. In addition, as the solvent in the azidation reaction 1, from the viewpoint of improving diastereoselectivity, the dielectric constant at 25°C is preferably 6.0 or less. If the dielectric constant of the solvent is 6.0 or less, the formation of unstable conformations among the conformations of the 6-membered ring to which the group represented by formula (21) is bonded can be suppressed, and the target reaction is preferentially carried out from the stable conformation, which is expected to improve the diastereoselectivity. The dielectric constant of the solvent at 25°C is more preferably 5.5 or less, more preferably 5.2 or less, and even more preferably 5.0 or less. As the lower limit, it is preferably 2.00 or more, more preferably 2.20 or more, even more preferably 2.25 or more, and even more preferably 2.30 or more. That is, the dielectric constant of the solvent at 25°C is preferably 2.00 to 6.0, more preferably 2.20 to 5.5, even more preferably 2.25 to 5.2, and even more preferably 2.30 to 5.0. The solvent in the azidation reaction 1 is preferably an ether solvent or hydrocarbon solvent having a dielectric constant of 2.00 to 6.0 at 25°C. Specifically, the solvent in the azidation reaction 1 is preferably cyclopentyl methyl ether, anisole, t-butyl methyl ether, diethylene glycol dimethyl ether, ethyl acetate, toluene, 1,3-dioxane, and 1,4-dioxane, and more preferably cyclopentyl methyl ether, anisole, t-butyl methyl ether, and toluene.

[0105] Here, the dielectric constant (εr) is a value obtained by the following formula, and can be appropriately referred to in known literature such as Chemical Handbook (5th revised edition, edited by the Chemical Society of Japan, 2004, Basic Volume I, Table 14.26 on pages 620-622). Alternatively, it can be obtained using a dielectric constant measuring device.

[0106] εr=ε1 / ε0

[0107] (Here, ε0 represents the absolute permittivity in vacuum, and ε1 represents the absolute permittivity in solvent.)

[0108] The amount (volume) of the solvent used in the azidation reaction 1 is preferably 1 to 50 times (vol / w), more preferably 2 to 30 times (vol / w), and even more preferably 3 to 10 times (vol / w) the weight of the alcohol compound (1) from the viewpoint of further improving diastereoselectivity. Here, the unit of vol / w is ml / g.

[0109] <<Reaction Conditions of Azide Reaction 1>>

[0110] The method and order of adding the alcohol compound (1), diphenylphosphoryl azide, phosphine compound, azo compound, and, if necessary, solvent are not particularly limited. For example, the alcohol compound (1), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent may all be added to the reaction vessel simultaneously, or may be added sequentially. Alternatively, at least two selected from the group consisting of the alcohol compound (1), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent may be mixed first, and then the remaining components may be added. Furthermore, the alcohol compound (1), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent may be added all at once, or may be added in batches (e.g., 2 to 10 times).

[0111] Generally, the azidation reaction 1 is preferably carried out under an inert gas atmosphere such as nitrogen.

[0112] The reaction temperature in the azidation reaction 1 can be appropriately set depending on the types of the phosphine compound, the azo compound, and the solvent, and the amounts of the alcohol compound (1), diphenylphosphoryl azide, the phosphine compound, the azo compound, and the solvent used, and is preferably -20°C to 60°C, more preferably -5°C to 40°C, further preferably 0°C to 30°C, and even more preferably 15°C to 30°C. When the reaction temperature is within the above range, the target compound, the azide compound (2), can be obtained with high diastereoselectivity, safety, and preferably good yield.

[0113] The reaction time in the azidation reaction 1 can be appropriately set depending on the types of the phosphine compound, the azo compound, and the solvent, and the amounts of the alcohol compound (1), diphenylphosphoryl azide, the phosphine compound, the azo compound, and the solvent used, and is preferably 0.5 to 120 hours, more preferably 1 to 48 hours.

[0114] The diastereoselectivity (cis isomer:trans isomer) of the azide compound (2) obtained in the azidation reaction 1 is preferably in the range of 1:0.00 to 1:0.10, more preferably 1:0.00 to 1:0.06, and even more preferably 1:0.00 to 1:0.05.

[0115] The yield of the azide compound (2) obtained in the azidation reaction 1 is preferably 65 mol% or more, more preferably 70 mol% or more, further preferably 80 mol% or more, and even more preferably 85 mol% or more. There is no particular upper limit, and it may be 100 mol%.

[0116] <Azide Reaction 2>

[0117] The azidation of the alcohol compound (1) can be carried out, for example, by reacting diphenylphosphoryl azide and a tertiary amine with the alcohol compound (1) (hereinafter also referred to as azidation reaction 2). The desired azide compound (2) can be obtained by reacting diphenylphosphoryl azide with the alcohol compound (1) in the presence of a tertiary amine (this step is also referred to as azidation reaction 2-1), and then adding a base and heating (this step is also referred to as azidation reaction 2-2).

[0118] <<Diphenylphosphoryl azide>>

[0119] The amount of diphenylphosphoryl azide used as an azide source in the azidation reaction 2-1 is preferably 1.0 mol or more and 10 mol or less, more preferably 1.1 mol or more, even more preferably 1.2 mol or more, more preferably 8 mol or less, even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of diphenylphosphoryl azide used is preferably 1.0 mol to 10 mol, more preferably 1.1 mol to 8 mol, even more preferably 1.2 mol to 5 mol, relative to 1 mol of the alcohol compound (1).

[0120] <<Tertiary Amine>>

[0121] Examples of the tertiary amine used in the azidation reaction 2-1 include 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nonene-5-ol, triethylamine, tributylamine, diisopropylethylamine, 1,1,3,3-tetramethylguanidine, 4-dimethylaminopyridine, triethylenediamine, benzyldimethylamine, triethanolamine, dimethylaminoethanol, and tris(dimethylaminomethyl)phenol. 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, benzyldimethylamine, triethanolamine, dimethylaminoethanol, and tris(dimethylaminomethyl)phenol are preferred, and 1,8-diazabicyclo[5.4.0]undec-7-ene is particularly preferred.

[0122] The amount of the tertiary amine used in the azidation reaction 2-1 is preferably 1.0 mol or more and 10 mol or less, more preferably 1.1 mol or more, even more preferably 1.2 mol or more, more preferably 8 mol or less, even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the tertiary amine used is preferably 1.0 mol to 10 mol, more preferably 1.1 mol to 8 mol, even more preferably 1.2 mol to 5 mol, relative to 1 mol of the alcohol compound (1). The amount of the tertiary amine used is preferably 0.5 mol or more and 1.5 mol or less, more preferably 0.7 mol or more, even more preferably 0.9 mol or more, even more preferably 1.3 mol or less, even more preferably 1.1 mol or less, relative to 1 mol of diphenylphosphoryl azide. That is, the amount of the tertiary amine used is preferably 0.5 mol to 1.5 mol, more preferably 0.7 mol to 1.3 mol, even more preferably 0.9 mol to 1.1 mol, relative to 1 mol of diphenylphosphoryl azide.

[0123] Solvents

[0124] A solvent may be used in the azidation reaction 2-1. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents listed as solvents that can be used in the azidation reaction 1. The solvent may be used alone or in combination of two or more.

[0125] The solvent in the azidation reaction 2-1 is preferably a hydrocarbon solvent, and particularly preferably toluene.

[0126] The amount (volume) of the solvent used in the azidation reaction 2-1 is preferably 1 to 50 times (vol / w), more preferably 2 to 30 times (vol / w), and even more preferably 5 to 20 times (vol / w), relative to the weight of the alcohol compound (1). The unit of vol / w is ml / g.

[0127] <<Reaction Conditions of Azide Reaction 2-1>>

[0128] In the azidation reaction 2-1, the method and order of adding the alcohol compound (1), diphenylphosphoryl azide, tertiary amine, and the solvent used as needed are not particularly limited.

[0129] Generally, the azidation reaction 2-1 is preferably carried out under an inert gas atmosphere such as nitrogen.

[0130] The reaction temperature in the azidation reaction 2-1 is, for example, preferably 0°C to 90°C, more preferably 10°C to 80°C, and even more preferably 20°C to 70°C.

[0131] The reaction time in the azidation reaction 2-1 is, for example, preferably 0.1 to 10 hours, more preferably 0.5 to 5 hours.

[0132] <<Alkali>>

[0133] A base is added to the reaction solution of the alcohol compound (1) and diphenylphosphoryl azide to replace the phosphate group formed by the above reaction (azidation reaction 2-1) with an azide group (azidation reaction 2-2). The base may be an organic base or an inorganic base, preferably an inorganic base, and examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydrides such as sodium hydride, potassium hydride and calcium hydride; etc. The alkali metal hydroxide is preferably an alkali metal carbonate, more preferably an alkali metal carbonate.

[0134] The amount of the base used is preferably 1.0 mol or more and 15 mol or less, more preferably 1.1 mol or more, even more preferably 1.2 mol or more, more preferably 12 mol or less, and even more preferably 10 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the base used is preferably 1.0 mol to 15 mol, more preferably 1.1 mol to 12 mol, and even more preferably 1.2 mol to 10 mol relative to 1 mol of the alcohol compound (1).

[0135] <<Reaction Conditions of Azide Reaction 2-2>>

[0136] In the azidation reaction 2-2, the heat treatment temperature after the addition of the base is, for example, preferably 50° C. to 150° C., more preferably 70° C. to 130° C., and even more preferably 80° C. to 120° C. The heat treatment time is, for example, preferably 1 hour to 72 hours, and more preferably 5 hours to 36 hours.

[0137] The diastereoselectivity (cis isomer:trans isomer) of the azide compound (2) obtained in the azidation reaction 2 is preferably in the range of 1:0.00 to 1:0.16, more preferably 1:0.00 to 1:0.14.

[0138] The yield of the azide compound (2) obtained in the azidation reaction 2 is preferably 30 mol% or more, more preferably 35 mol% or more, further preferably 40 mol% or more, and even more preferably 45 mol% or more. There is no particular upper limit, and it may be 100 mol%.

[0139] <Azide Reaction 3>

[0140] The azidation of the alcohol compound (1) may be, for example, an azidation as follows: a sulfonylating agent and a base are allowed to act on the alcohol compound (1) to obtain a sulfonate compound represented by the following formula (5) (hereinafter also referred to as sulfonate compound (5)) (this step is also referred to as azidation reaction 3-1), and then a metal azide is allowed to act on the sulfonate compound (5) (this step is also referred to as azidation reaction 3-2).

[0141]

[0142] (Where R 2 represents an alkyl group having 1 to 12 carbon atoms which may have a substituent, or an aryl group having 6 to 12 carbon atoms which may have a substituent.

[0143] <<Sulfonylating Agent>>

[0144] Examples of the sulfonylating agent used in the azidation reaction 3-1 include: R 2 SO2X、(R 2 SO2)2O etc. (where R 2 As above, X represents a halogen atom such as a chlorine atom, preferably a chlorine atom. 2 SO2X, specifically, includes: methanesulfonyl chloride (also called methylsulfonyl chloride), p-toluenesulfonyl chloride, chloromethanesulfonyl chloride, as (R 2 SO2)2O, specifically, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc. As the sulfonylating agent, methanesulfonyl chloride and p-toluenesulfonyl chloride are preferred, and methanesulfonyl chloride is more preferred.

[0145] The amount of the sulfonylating agent used in the azidation reaction 3-1 is preferably 1.0 mol or more and 15 mol or less, more preferably 1.2 mol or more, and even more preferably 1.4 mol or more, and more preferably 10 mol or less, and even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the sulfonylating agent used is preferably 1.0 mol to 15 mol, more preferably 1.2 mol to 10 mol, and even more preferably 1.4 mol to 5 mol, relative to 1 mol of the alcohol compound (1).

[0146] <<Alkali>>

[0147] The base used in the azidation reaction 3-1 may be an organic base or an inorganic base, and examples thereof include: alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, ... Metal alkoxides such as potassium propoxide and potassium tert-butoxide; metal hydrides such as sodium hydride, potassium hydride, and calcium hydride; alkyl lithium reagents such as n-butyl lithium, methyl lithium, and lithium diisopropylamide; tertiary amines such as triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; heterocyclic compounds such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylpyrrolidine, and N-methylmorpholine; etc. The base is preferably an organic base, more preferably a tertiary amine, and particularly preferably triethylamine.

[0148] The amount of the base used in the azidation reaction 3-1 is preferably 0.1 mol or more and 15 mol or less, more preferably 0.5 mol or more, even more preferably 1.0 mol or more, more preferably 8 mol or less, and even more preferably 5 mol or less, relative to 1 mol of the alcohol compound (1). That is, the amount of the base used is preferably 0.1 mol to 15 mol, more preferably 0.5 mol to 8 mol, and even more preferably 1.0 mol to 5 mol relative to 1 mol of the alcohol compound (1).

[0149] In the azidation reaction 3-1, a quaternary ammonium salt such as tetrabutylammonium chloride or tetrabutylammonium bromide; a crown ether; or the like can be used together with a base as needed.

[0150] Solvents

[0151] In the reaction with the alcohol compound (1), the sulfonylating agent, and the base (azidation reaction 3-1), a solvent may be used. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples thereof include the solvents listed as usable solvents in the azidation reaction 1; and halogenated solvents such as dichloromethane (also known as methylene chloride), chloroform, and chlorobenzene. The solvent may be used alone or in combination of two or more.

[0152] The solvent in the azidation reaction 3-1 is preferably a halogen solvent, a ketone solvent, an ester solvent, or a hydrocarbon solvent, more preferably a halogen solvent, a ketone solvent, or an ester solvent, and even more preferably a halogen solvent.

[0153] The amount (volume) of the solvent used in the azidation reaction 3-1 is preferably 1 to 50 times (vol / w), more preferably 2 to 40 times (vol / w), and even more preferably 5 to 30 times (vol / w), relative to the weight of the alcohol compound (1). The unit of vol / w is ml / g.

[0154] <<Reaction Conditions of Azide Reaction 3-1>>

[0155] In the azidation reaction 3-1, the method and order of adding the alcohol compound (1), the sulfonylating agent, the base, and the solvent used as needed are not particularly limited.

[0156] Generally, the azidation reaction 3-1 is preferably carried out under an inert gas atmosphere such as nitrogen.

[0157] The reaction temperature in the azidation reaction 3-1 can be appropriately set depending on the types of the sulfonylating agent, base, and solvent, and the amounts of the alcohol compound (1), sulfonylating agent, base, and solvent used. For example, it is preferably -50°C to 60°C, more preferably -5°C to 40°C, and even more preferably 0°C to 30°C.

[0158] The reaction time in the azidation reaction 3-1 can be appropriately set depending on the types of the sulfonylating agent, base, and solvent, and the amounts of the alcohol compound (1), sulfonylating agent, base, and solvent used. For example, it is preferably 0.5 to 10 hours, more preferably 1 to 5 hours.

[0159] <<Sulfonic acid ester compound (5)>>

[0160] By reacting the alcohol compound (1) with the sulfonylating agent and a base in the azidation reaction 3-1, a sulfonic acid ester compound (5) is obtained.

[0161]

[0162] As R 2 The alkyl group represented by R may be linear or branched, and examples thereof include methyl, ethyl, propyl, and butyl. 2 The number of carbon atoms in the alkyl group represented is 1 to 12, preferably 1 to 6, and more preferably 1 to 3.

[0163] As R 2 Examples of the aryl group represented by include phenyl, tolyl, xylyl, and naphthyl. 2 The number of carbon atoms in the aryl group represented may be 6 to 12, preferably 6 to 10, and particularly preferably 6 to 8.

[0164] As R 2Examples of the substituents that the alkyl group represented by the above-mentioned group may have and the substituents that the aryl group may have include: halogen atoms such as fluorine, chlorine, bromine, and iodine; alkoxy groups such as methoxy, ethoxy, phenoxy, and benzyloxy (preferably having 1 to 10 carbon atoms); cyano; nitro; and carbamoyl.

[0165] As R 2 , preferably an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aryl group having 6 to 10 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms, further preferably an alkyl group having 1 to 3 carbon atoms, or an aryl group having 6 carbon atoms, further preferably an alkyl group having 1 to 3 carbon atoms, and particularly preferably a methyl group.

[0166] The sulfonate compound (5) can be purified and isolated by known methods as needed. After purification and / or isolation, it can be reacted with a metal azide (azidation reaction 3-2), or the reaction mixture can be reacted with a metal azide as it is (azidation reaction 3-2). As a method for purification and / or isolation, for example, extraction, concentration, crystallization, column chromatography, etc. can be appropriately combined. From the viewpoint of the yield of the azide compound (2), it is preferred to purify and / or isolate the sulfonate compound (5) before reacting it with a metal azide.

[0167] <<Metal Azides>>

[0168] Examples of the metal azide used in the azidation reaction 3-2 include: alkali metal azides such as lithium azide, sodium azide, and potassium azide; alkaline earth metal azides such as magnesium azide, calcium azide, and strontium azide; lead azide, iron azide, copper azide, and zinc azide, among which alkali metal azides are preferred, and sodium azide is particularly preferred.

[0169] The amount of the metal azide used as the azide source in the azidation reaction 3-2 is preferably 0.1 mol or more and 15 mol or less, more preferably 0.5 mol or more, even more preferably 1.0 mol or more, more preferably 10 mol or less, even more preferably 5 mol or less, relative to 1 mol of the sulfonic acid ester compound (5). That is, the amount of the metal azide used is preferably 0.1 mol to 15 mol, more preferably 0.5 mol to 10 mol, even more preferably 1.0 mol to 5 mol relative to 1 mol of the sulfonic acid ester compound (5).

[0170] <<Phase Transfer Catalyst>>

[0171] In the azidation reaction 3-2, a phase transfer catalyst may be used together with the metal azide as needed. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium sulfate, and trioctylmethylammonium chloride; quaternary phosphonium salts such as tetrabutylphosphonium chloride; pyridine salts such as dodecylpyridinium chloride; Compounds; crown ethers; etc. As phase transfer catalysts, quaternary ammonium salts, pyridine The compound is more preferably tetrabutylammonium chloride or dodecylpyridinium chloride, and even more preferably dodecylpyridinium chloride.

[0172] When a phase transfer catalyst is used, the amount of the phase transfer catalyst used in the azidation reaction 3-2 is preferably 0.05 mol or more and 5 mol or less, more preferably 0.08 mol or more, even more preferably 0.1 mol or more, more preferably 3 mol or less, even more preferably 1.0 mol or less, relative to 1 mol of the sulfonic acid ester compound (5). That is, the amount of the phase transfer catalyst used is preferably 0.05 mol to 5 mol, more preferably 0.08 mol to 3 mol, even more preferably 0.1 mol to 1.0 mol relative to 1 mol of the sulfonic acid ester compound (5).

[0173] Solvents

[0174] In the reaction of the sulfonic acid ester compound (5) and the metal azide (azidation reaction 3-2), a solvent may be used. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents listed as solvents that can be used in the azidation reaction 1. The solvent may be used alone or in combination of two or more.

[0175] The solvent in the azidation reaction 3-2 is preferably a hydrocarbon solvent, an amide solvent, a urea solvent, a sulfoxide solvent, or an ester solvent, more preferably a hydrocarbon solvent or an amide solvent, further preferably a hydrocarbon solvent, and even more preferably toluene.

[0176] The amount (volume) of the solvent used in the azidation reaction 3-2 is preferably 1 to 50 times (vol / w), more preferably 2 to 40 times (vol / w), and even more preferably 5 to 30 times (vol / w) the weight of the sulfonic acid ester compound (5). The unit of vol / w is ml / g.

[0177] <<Reaction Conditions of Azide Reaction 3-2>>

[0178] In the azidation reaction 3-2, the method and order of adding the sulfonic acid ester compound (5), the metal azide, and the phase transfer catalyst used as needed, and the solvent are not particularly limited.

[0179] The reaction temperature in the azidation reaction 3-2 can be appropriately set depending on the types of the metal azide, the phase transfer catalyst, and the solvent, and the amounts of the sulfonate compound (5), the metal azide, the phase transfer catalyst, and the solvent used. For example, it is preferably -50°C to 120°C, more preferably 0°C to 100°C, and even more preferably 50°C to 90°C.

[0180] The reaction time in the azidation reaction 3-2 can be appropriately set depending on the types of the metal azide, the phase transfer catalyst, and the solvent, and the amounts of the sulfonate compound (5), the metal azide, the phase transfer catalyst, and the solvent used. For example, it is preferably 1 to 96 hours, more preferably 5 to 72 hours, and even more preferably 8 to 48 hours.

[0181] The diastereoselectivity (cis isomer:trans isomer) of the azide compound (2) obtained in the azidation reaction 3 is preferably in the range of 1:0.00 to 1:0.42, more preferably 1:0.00 to 1:0.40, and even more preferably 1:0.00 to 1:0.35.

[0182] The yield of the azide compound (2) obtained in the azidation reaction 3 is preferably 30 mol% or more, more preferably 35 mol% or more, further preferably 40 mol% or more, and even more preferably 45 mol% or more, based on the alcohol compound (1). There is no particular upper limit, and it may be 100 mol%.

[0183] The azide compound (2) obtained by the azidation reaction (particularly preferably any of the above-mentioned azidation reactions 1 to 3) can be purified and isolated by known methods as needed. From the viewpoint of safety, the azide compound (2) preferably does not require purification and isolation, and is preferably used as a raw material for further reactions as the reaction mixture itself.

[0184] (II) Method for producing alcohol compound (1)

[0185] The alcohol compound (1) to be subjected to azidation can be produced, for example, by subjecting 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid or a salt thereof to dehydration condensation with an amino alcohol compound represented by the following formula (11) (hereinafter also referred to as amino alcohol compound (11)) or a salt thereof.

[0186]

[0187] (Where R 1represents a hydrogen atom or a tert-butyloxycarbonyl group (hereinafter, sometimes referred to as a Boc group).

[0188] The salt of the amino alcohol compound (11) is not particularly limited as long as it is a salt acceptable in pharmaceuticals. It should be noted that the salt acceptable in pharmaceuticals refers to a salt that does not cause allergic reactions such as gastrointestinal disorders and dizziness when administered to humans and is commonly used by those having ordinary knowledge in the field in the manufacture of pharmaceutical preparations. Examples of the salt of the amino alcohol compound (11) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium, sodium, potassium, cesium, and rubidium; alkaline earth metal salts such as magnesium and calcium; ammonium salts such as ammonium, alkylammonium, dialkylammonium, trialkylammonium, and tetraalkylammonium; and complex salts thereof. The formation reaction of the salt of the amino alcohol compound (11) can be carried out by a known method.

[0189] The salt of the amino alcohol compound (11) is preferably an organic acid salt such as a carboxylate or a sulfonate, or an inorganic acid salt.

[0190] Next, let R in formula (11) 1 The compound in which R is a hydrogen atom is called amino alcohol compound (11-1), and R 1 The compound containing tert-butyloxycarbonyl is called amino alcohol compound (11-2).

[0191]

[0192] It should be noted that the Boc group is removed from the Boc-protected amino alcohol compound (11-2) or its salt (deprotection reaction) to form the amino alcohol compound (11-1) or its salt, which is then subjected to dehydration condensation with 5-methyl-4,5,6,7-tetrahydrothiazolidine[5,4-c]pyridine-2-carboxylic acid or its salt.

[0193] The deprotection reaction can be carried out by a known method, for example, by treatment with an acid such as methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid at -20°C to 70°C (preferably 0°C to 40°C) for 0.1 to 8 hours (preferably 0.1 to 5 hours).

[0194] As the amino alcohol compound (11), the amino alcohol compound (11-1) (ie, R 1=Hydrogen atom). Since the amino alcohol compound (11-2) is often produced by protecting the amino group in the alcohol compound (11-1) with Boc, the Boc group needs to be deprotected as described above in order to produce the alcohol compound (1), so the process is cumbersome. In contrast, the amino alcohol compound (11-1) can avoid the introduction and deprotection of the Boc group, and can simplify the reaction route.

[0195] Alcohol compound (1) can be obtained by subjecting 5-methyl-4,5,6,7-tetrahydrothiazolyl[5,4-c]pyridine-2-carboxylic acid or a salt thereof to dehydration condensation with amino alcohol compound (11-1) or a salt thereof. 5-methyl-4,5,6,7-tetrahydrothiazolyl[5,4-c]pyridine-2-carboxylic acid or a salt thereof may be a derivative derived from a mixed acid anhydride, an acid halide, an active ester, or the like, as required. Such a derivative may be formed by a known method.

[0196] The dehydration condensation reaction is preferably carried out in the presence of a base. Examples of the base include those listed as bases that can be used in the azidation reaction 3. A single base may be used, or a combination of two or more may be used. The base is preferably an organic base, more preferably a tertiary amine, and particularly preferably triethylamine.

[0197] The amount of the base used in the dehydration condensation reaction is preferably 0.5 mol or more and 20 mol or less, more preferably 1.0 mol or more, even more preferably 1.5 mol or more, more preferably 15 mol or less, even more preferably 10 mol or less, relative to 1 mol of the amino alcohol compound (11-1) or its salt. That is, the amount of the base used is preferably 0.5 mol to 20 mol, more preferably 1.0 mol to 15 mol, even more preferably 1.5 mol to 10 mol, relative to 1 mol of the amino alcohol compound (11-1) or its salt.

[0198] The dehydration condensation reaction is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include the solvents listed as solvents that can be used in the azidation reaction 3-1, and water. As the solvent, only one type may be used, or two or more types may be used in combination.

[0199] The solvent used in the dehydration condensation reaction is preferably a halogen solvent, an ether solvent, a hydrocarbon solvent (especially an aromatic hydrocarbon solvent such as toluene and benzene), an amide solvent, a sulfoxide solvent, a ketone solvent, or an aqueous solvent; more preferably a halogen solvent, an ether solvent, an aromatic hydrocarbon solvent, an amide solvent, or an aqueous solvent; further preferably a halogen solvent or an aqueous solvent.

[0200] The amount (volume) of the solvent used in the dehydration condensation reaction is preferably 1 to 50 times (vol / w), more preferably 2 to 40 times (vol / w), and even more preferably 5 to 30 times (vol / w), relative to the weight of the amino alcohol compound (11-1) or its salt. The unit of vol / w is ml / g.

[0201] A condensing agent is preferably used in the dehydration condensation reaction. Examples of the condensing agent include: carbodiimide-based condensing agents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, and N,N'-diisopropylcarbodiimide; imidazole-based condensing agents such as N,N'-carbonyldiimidazole and 1,1'-carbonylbis(1,2,4-triazole); and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine. Chloride, triazine-based condensing agents such as (4,6-dimethoxy-1,3,5-triazin-2-yl)-(2-octyloxy-2-oxoethyl)dimethylammonium trifluoromethanesulfonate; phosphonium-based condensing agents such as 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, (7-azabenzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate, chlorotripyrrolidinylphosphonium hexafluorophosphate, fluorotris(dimethylamino)phosphonium hexafluorophosphate, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one; and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea. Hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate, O-(N-succinimidyl)-N,N,N',N'-tetramethylurea Tetrafluoroborate, O-(N-succinimidyl)-N,N,N',N'-tetramethylurea Hexafluorophosphate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethylurea Tetrafluoroborate, S-(1-oxo-2-pyridyl)-N,N,N',N'-tetramethylurea Tetrafluoroborate, O-[2-oxo-1(2H)-pyridinyl]-N,N,N',N'-tetramethylurea Tetrafluoroborate, urea such as {{[(1-cyano-2-ethoxy-2-oxyethylidene)amino]oxy}-4-morpholinylmethylene}dimethylammonium hexafluorophosphate Condensation agent; 2-chloro-1,3-dimethylimidazole Hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidine Hexafluorophosphate, 2-fluoro-1,3-dimethylimidazole Hexafluorophosphate, fluoro-N,N,N',N'-tetramethylformamide hexafluorophosphate and other haloureas As the condensing agent, only one type may be used, or two or more types may be used in combination.

[0202] As the condensing agent in the dehydration condensation reaction, a carbodiimide-based condensing agent is preferred.

[0203] When a condensing agent is used in the dehydration condensation reaction, the amount used is preferably 0.1 mol or more and 20 mol or less, more preferably 0.5 mol or more, even more preferably 1.0 mol or more, more preferably 10 mol or less, and even more preferably 5 mol or less, relative to 1 mol of the amino alcohol compound (11-1) or its salt. That is, the amount of the condensing agent used is preferably 0.1 mol to 20 mol, more preferably 0.5 mol to 10 mol, and even more preferably 1.0 mol to 5 mol relative to 1 mol of the amino alcohol compound (11-1) or its salt.

[0204] When a condensing agent is used in the dehydration condensation reaction, it is preferably used in combination with a condensation additive. Examples of the condensation additive include 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, and N,N'-disuccinimidyl carbonate. 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole are preferred, and 1-hydroxy-7-azabenzotriazole is more preferred.

[0205] When a condensing agent and a condensation additive are used in the dehydration condensation reaction, the amount of the condensation additive used is preferably 0.5 mol or more and 5 mol or less, more preferably 0.7 mol or more, even more preferably 0.8 mol or more, more preferably 3 mol or less, even more preferably 2 mol or less, per 1 mol of the condensing agent. In other words, the amount of the condensation additive used is preferably 0.5 mol to 5 mol, more preferably 0.7 mol to 3 mol, even more preferably 0.8 mol to 2 mol per 1 mol of the condensing agent.

[0206] When no condensing agent is used, the reaction temperature in the dehydration condensation reaction is, for example, preferably 50°C to 156°C, more preferably 80°C to 150°C. When a condensing agent is used, the reaction temperature is, for example, preferably -20°C to 100°C or lower, more preferably 0°C to 60°C.

[0207] The reaction time in the dehydration condensation reaction is, for example, preferably 10 minutes to 36 hours, more preferably 0.1 hour to 30 hours, and even more preferably 0.5 hour to 24 hours.

[0208] Examples of the salt of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt; and complex salts thereof are also possible. The salt of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid is preferably an inorganic acid salt or an alkali metal salt, more preferably a hydrochloride or a lithium salt, and still more preferably a hydrochloride.

[0209] The alcohol compound (1) obtained by the above reaction can be purified and isolated by known methods as needed, and can be used for the azidation reaction after purification and / or isolation, or can be used for the azidation reaction as the reaction mixture itself. As a method for purification and / or isolation, for example, extraction, concentration, crystallization, column chromatography, etc. can be appropriately combined. From the viewpoint of the yield of the azide compound (2), it is preferred to purify and / or isolate the alcohol compound (1) before using it for the azidation reaction.

[0210] (III) Method for producing amine compound (3)

[0211] By reducing the azide group of the azide compound (2) obtained by azidating the alcohol compound (1), an amine compound represented by the following formula (3) (hereinafter also referred to as amine compound (3)) or a salt thereof can be produced.

[0212]

[0213] The reduction reaction is carried out without affecting the stereochemistry of the amino group. Since the azide compound (2) obtained by the above-mentioned azidation reaction can be obtained with high diastereoselectivity, the amine compound (3) obtained by the production method using the azide compound (2) as a starting material also has high diastereomeric purity.

[0214] Examples of methods for reducing an azide group include a method involving the reaction of a transition metal catalyst and a hydrogen source (reduction reaction 1), a method involving the reaction of a phosphine and water (reduction reaction 2), and a method involving the reaction of a metal hydride (reduction reaction 3). From the perspective of reduction selectivity, reduction reaction 1 (a method involving the reaction of a transition metal catalyst and a hydrogen source) and reduction reaction 2 (a method involving the reaction of a phosphine and water) are preferred, with reduction reaction 2 being more preferred.

[0215] <Reduction Reaction 1>

[0216] Reduction reaction 1 is a reaction in which a transition metal catalyst and a hydrogen source are allowed to act on the azide group of the azide compound (2) to cause hydrogenation and decomposition, thereby reducing the azide group.

[0217] As the above-mentioned transition metal catalyst, there can be mentioned: for example, metals such as platinum, rhodium, palladium, nickel, cobalt, ruthenium, iridium, rhenium, alloys, or chlorides thereof. As the transition metal catalyst, it can be a catalyst dispersed in a powder carrier. As the above-mentioned powder carrier, there can be mentioned: for example, carbon, aluminum oxide, silica aluminum oxide, silicon dioxide, barium carbonate, barium sulfate, calcium carbonate, titanium oxide, zirconium oxide, zeolite, etc. As the transition metal catalyst, preferably Pd / C, Raney nickel, Raney cobalt, platinum, more preferably Pd / C, Raney nickel, platinum, and even more preferably Pd / C. As the transition metal catalyst, only one type can be used, or two or more types can be used in combination.

[0218] A large amount of the transition metal catalyst is not preferred in terms of cost, and therefore, the amount is preferably 10 times or less by mass, more preferably 5 times or less by mass, further preferably 2 times or less by mass, and further preferably 1 time or less by mass relative to the mass of the azide compound (2). Furthermore, as a lower limit, the amount is preferably 0.0001 times or more by mass, more preferably 0.001 times or more by mass, and further preferably 0.01 times or more by mass relative to the mass of the azide compound (2). That is, the amount of the transition metal catalyst used is preferably 0.0001 times by mass to 10 times by mass, more preferably 0.001 times by mass to 5 times by mass, further preferably 0.01 times by mass to 2 times by mass, and further preferably 0.01 times by mass to 1 time by mass relative to the mass of the azide compound (2).

[0219] As the above-mentioned hydrogen source, there can be mentioned: for example, hydrogen gas, hydrogen donors. As hydrogen donors, there can be mentioned: for example, hydrazines such as hydrazine, methylhydrazine, allylhydrazine, phenylhydrazine; formic acids such as formic acid, sodium formate, ammonium formate; etc. As hydrogen sources, formic acids are preferred. When formic acids are used as hydrogen sources, the amount used is preferably 1 mol or more and 30 mol or less, more preferably 2 mol or more, further preferably 5 mol or more, more preferably 20 mol or less, further preferably 10 mol or less, relative to 1 mol of the azide compound (2). That is, the amount of formic acid used is preferably 1 mol to 30 mol, more preferably 2 mol to 20 mol, further preferably 5 mol to 10 mol relative to 1 mol of the azide compound (2).

[0220] Reduction Reaction 1 can be carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples include the solvents listed as solvents that can be used in the azidation reaction 1; alcoholic solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, and tert-butanol; and the like. The solvent may be used alone or in combination of two or more.

[0221] The solvent in the reduction reaction 1 is preferably an alcohol solvent, more preferably an alcohol solvent having 1 to 5 carbon atoms.

[0222] The amount (volume) of the solvent used in the reduction reaction 1 is preferably 0.1 to 100 times (vol / w), more preferably 0.5 to 50 times (vol / w), and even more preferably 1 to 20 times (vol / w) the weight of the azide compound (2). The unit of vol / w is ml / g.

[0223] The method and order of adding the azide compound (2), the transition metal catalyst, the hydrogen source, and the solvent used as needed in the reduction reaction 1 are not particularly limited.

[0224] The reaction temperature in the reduction reaction 1 is not particularly limited and can be appropriately set. From the viewpoint of suppressing the formation of by-products, it is preferably -20°C to 100°C, more preferably 0°C to 70°C, and even more preferably 20°C to 50°C.

[0225] The reaction time in the reduction reaction 1 is not particularly limited and can be appropriately set. For example, it is preferably 0.1 to 48 hours, and more preferably 0.5 to 24 hours.

[0226] <Reduction Reaction 2>

[0227] Reduction reaction 2 is a method in which phosphine and water are allowed to act on the azide group of the azide compound (2). More specifically, phosphine is first allowed to act on the azide compound (2) to form an iminophosphane having a nitrogen-phosphorus double bond, and then water is allowed to act on the iminophosphane to hydrolyze it, thereby reducing the azide group.

[0228] Preferred examples of the phosphine include tertiary phosphines such as triphenylphosphine, diphenylmethylphosphine, dimethylphenylphosphine, trimethylphosphine, triethylphosphine, and tripropylphosphine, with triphenylphosphine being more preferred. The phosphine may be used alone or in combination of two or more.

[0229] The amount of the phosphine used is preferably 0.8 mol or more and 35 mol or less, more preferably 1.0 mol or more, even more preferably 1.5 mol or more, more preferably 20 mol or less, even more preferably 10 mol or less, relative to 1 mol of the azide compound (2). That is, the amount of the phosphine used is preferably 0.8 mol to 35 mol, more preferably 1.0 mol to 20 mol, even more preferably 1.5 mol to 10 mol relative to 1 mol of the azide compound (2).

[0230] The amount of water used for hydrolysis in the reduction reaction 2 is preferably 1 mol or more and 50 mol or less, more preferably 5 mol or more, further preferably 10 mol or more, more preferably 40 mol or less, further preferably 35 mol or less, relative to 1 mol of the azide compound (2). That is, the amount of water used is preferably 1 mol to 50 mol, more preferably 5 mol to 40 mol, further preferably 10 mol to 35 mol, relative to 1 mol of the azide compound (2).

[0231] When the amounts of phosphine and water used are within the above ranges, the amine compound (3) can be produced from the azide compound (2) with good production efficiency and high yield.

[0232] Reduction Reaction 2 can be carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents listed as those usable in Reduction Reaction 1.

[0233] The solvent in the reduction reaction 2 is preferably an ether solvent, an ester solvent, or a hydrocarbon solvent, more preferably tetrahydrofuran, tert-butyl methyl ether, diethylene glycol dimethyl ether, ethyl acetate, or toluene, further preferably tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, or toluene, and still more preferably tetrahydrofuran, tert-butyl methyl ether, or toluene.

[0234] The amount (volume) of the solvent used in the reduction reaction 2 is preferably 1 to 80 times (vol / w), more preferably 5 to 50 times (vol / w), based on the weight of the azide compound (2). The unit of vol / w is ml / g.

[0235] The reaction temperature in the reduction reaction 2 is not particularly limited and can be appropriately set. From the viewpoint of suppressing the formation of by-products and from the viewpoint of safety, it is preferably 0°C to 60°C, more preferably 10°C to 58°C, and even more preferably 30°C to 55°C.

[0236] The reaction time in the reduction reaction 2 is not particularly limited and can be appropriately set. For example, it is preferably 0.1 to 48 hours, and more preferably 1 to 36 hours.

[0237] <Reduction Reaction 3>

[0238] Reduction reaction 3 is a hydrogenation reduction reaction in which a metal hydride as a hydrogen donor acts on the azide group of the azide compound (2).

[0239] Examples of the metal hydride include sodium borohydride, lithium borohydride, and lithium aluminum hydride, with sodium borohydride being preferred. The metal hydride may be used alone or in combination of two or more.

[0240] The amount of the metal hydride used is preferably 0.9 mol or more and 10 mol or less, more preferably 1.0 mol or more, more preferably 5 mol or less, and even more preferably 3 mol or less, relative to 1 mol of the azide compound (2). That is, the amount of the metal hydride used is preferably 0.9 mol to 10 mol, more preferably 1.0 mol to 5 mol, and even more preferably 1.0 mol to 3 mol relative to 1 mol of the azide compound (2).

[0241] Reduction reaction 3 can be carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents listed as solvents that can be used in reduction reaction 1, and water. As the solvent, only one type may be used, or two or more types may be used in combination.

[0242] The solvent in the reduction reaction 3 is preferably an ether solvent, an ester solvent, a hydrocarbon solvent, an alcohol solvent, or an aqueous solvent, more preferably an alcohol solvent or an aqueous solvent, and even more preferably an alcohol solvent having 1 to 5 carbon atoms or an aqueous solvent.

[0243] The amount (volume) of the solvent used in the reduction reaction 3 is preferably 0.1 to 100 times (vol / w), more preferably 0.5 to 50 times (vol / w), and even more preferably 1 to 20 times (vol / w) the weight of the azide compound (2). The unit of vol / w is ml / g.

[0244] The method and order of adding the azide compound (2), the metal hydride, and the solvent used as needed in the reduction reaction 3 are not particularly limited.

[0245] The reaction temperature in the reduction reaction 3 is not particularly limited and can be appropriately set. From the viewpoint of reaction efficiency, it is preferably 0°C to 120°C, more preferably 10°C to 80°C, and even more preferably 20°C to 50°C.

[0246] The reaction time in the reduction reaction 3 is not particularly limited and can be appropriately set. For example, it is preferably 10 minutes to 24 hours, and more preferably 0.5 hours to 10 hours.

[0247] In the above-mentioned azidation reaction and reduction reaction, different solvents or the same solvent may be used. When the same solvent is used, it is preferred to continue using the solvent used in the azidation reaction in the reduction reaction from the viewpoint of production efficiency. Even when the solvent used in the azidation reaction is continued to be used, a new solvent may be added in the reduction reaction.

[0248] The yield of the amine compound (3) obtained by the reduction reaction (based on the azide compound (1)) is preferably 50 mol% or more, more preferably 60 mol% or more, further preferably 65 mol% or more, and there is no particular upper limit, and it may be 100 mol%.

[0249] The amine compound (3) obtained by the reduction reaction can be isolated and / or purified as needed. For this purpose, conventional separation methods such as extraction, concentration, crystallization, column chromatography, etc. can be appropriately combined. The amine compound (3) can be further used as a raw material for the reaction, for example, as a synthetic intermediate for edoxaban, an anticoagulant described later.

[0250] The salt of the amine compound (3) is not particularly limited as long as it is a salt acceptable in pharmaceuticals. Examples of the salt of the amine compound (3) include, for example, the salts listed as salts of the amino alcohol compound (11). The formation reaction of the salt of the amine compound (3) can be carried out by a known method.

[0251] As the salt of the amine compound (3), organic acid salts such as carboxylates and sulfonates, and inorganic acid salts are preferred.

[0252] (IV) Method for producing the compound represented by formula (4)

[0253] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino)cyclohexyl)oxamide, a salt thereof, or a solvate thereof (edoxaban) represented by the following formula (4) can be produced by allowing 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic acid alkyl ester or a salt thereof to act on an amine compound (3) or a salt thereof (hereinafter referred to as condensation reaction A). Hereinafter, the compound represented by formula (4) is also referred to as compound (4).

[0254]

[0255] Since the condensation reaction A proceeds without affecting the stereochemistry of the amino group, the target compound can be obtained with high diastereomeric purity by using the amine compound (3) with high diastereomeric purity as a starting material.

[0256] The alkyl group of alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate may be linear or branched, and examples thereof include methyl, ethyl, propyl, and butyl. The alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a linear alkyl group having 1 to 5 carbon atoms, further preferably a methyl group or an ethyl group, and even more preferably an ethyl group.

[0257] If necessary, alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate or its salt may be a derivative derived from a mixed acid anhydride, an acid halide, an active ester, etc. Such a derivative can be formed by a known method.

[0258] Examples of the salt of alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate include the salts listed above as the salts of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid, preferably inorganic acid salts, alkali metal salts, and alkaline earth metal salts, more preferably inorganic acid salts, and even more preferably hydrochloride.

[0259] Condensation Reaction A is preferably carried out in the presence of a base. Examples of the base include those listed as bases that can be used in the azidation reaction 3. A single base may be used alone, or two or more may be used in combination. The base is preferably an organic base, more preferably a tertiary amine, and particularly preferably 4-dimethylaminopyridine.

[0260] The amount of the base used in the condensation reaction A is preferably 0.5 mol or more and 15 mol or less, more preferably 0.8 mol or more, even more preferably 1.0 mol or more, more preferably 10 mol or less, even more preferably 5 mol or less, relative to 1 mol of the amine compound (3). That is, the amount of the base used is preferably 0.5 mol to 15 mol, more preferably 0.8 mol to 10 mol, even more preferably 1.0 mol to 5 mol relative to 1 mol of the amine compound (3).

[0261] Condensation reaction A is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents listed as solvents that can be used in azidation reaction 3-1. As the solvent, only one type may be used, or two or more types may be used in combination.

[0262] The solvent in the condensation reaction A is preferably a halogen solvent, an ether solvent, a hydrocarbon solvent (especially an aromatic hydrocarbon solvent such as toluene and benzene), an amide solvent, or a nitrile solvent, more preferably a halogen solvent, an ether solvent, an aromatic hydrocarbon solvent, or a nitrile solvent, and still more preferably a nitrile solvent.

[0263] The amount (volume) of the solvent used in the condensation reaction A is preferably 1 to 50 times (vol / w), more preferably 2 to 40 times (vol / w), and even more preferably 5 to 30 times (vol / w), relative to the weight of the amine compound (3). The unit of vol / w is ml / g.

[0264] The reaction temperature in the condensation reaction A is, for example, preferably -50°C to 150°C, more preferably 0°C to 100°C.

[0265] The reaction time in the condensation reaction A is, for example, preferably 0.5 to 72 hours, more preferably 1 to 60 hours, and even more preferably 2 to 48 hours.

[0266] The yield of compound (4) obtained by condensation reaction A (based on amine compound (3)) is preferably 50 mol% or more, more preferably 60 mol% or more, and even more preferably 65 mol% or more. There is no particular upper limit, and it may be 100 mol%.

[0267] The compound (4) obtained by the condensation reaction A can be isolated and / or purified as needed. For this purpose, conventional separation methods such as extraction, concentration, crystallization, column chromatography, etc. can be appropriately combined.

[0268] The salt of compound (4) is not particularly limited as long as it is a salt acceptable in pharmaceuticals. Examples of the salt of compound (4) include, for example, the salts listed as salts of amine compound (3). The formation reaction of the salt of compound (4) can be carried out by a known method.

[0269] The salt of compound (4) is preferably an organic acid salt such as a carboxylate or a sulfonate, or an inorganic acid salt, more preferably an organic acid salt, and still more preferably a sulfonate.

[0270] Compound (4) or its salt may be a solvate. A solvate refers to a substance formed by stabilization by forming a covalent bond, hydrogen bond, ionic bond, van der Waals force, complex, inclusion, or the like between compound (4) or its salt and a solvent. The above-mentioned solvent is not limited, and examples thereof include: water, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, and the like. As a solvate, there is no particular limitation as long as it is permitted in pharmaceuticals, but preferably it is a hydrate or an ethanolate, and more preferably a hydrate.

[0271] This application claims the benefit of priority based on Japanese Patent Application No. 2023-036824, filed on March 9, 2023. The entire contents of the specification of Japanese Patent Application No. 2023-036824, filed on March 9, 2023, are incorporated herein by reference.

[0272] Example

[0273] Hereinafter, the present invention will be described in more detail with reference to the following embodiments. The present invention is not limited to the following embodiments and can, of course, be appropriately modified within the scope of the above and / or the following purports, all of which are included in the technical scope of the present invention.

[0274] In the Examples and Comparative Examples, each compound was analyzed by high performance liquid chromatography (HPLC), and the yield and diastereoselectivity were calculated. The HPLC conditions are as follows.

[0275] Chromatographic column: COSMOSIL 5C18-AR-II (4.6 × 250 mm) (manufactured by Nacalai Tesque Co., Ltd.)

[0276] Column temperature: 40°C

[0277] Detection wavelength: 210nm

[0278] Mobile phase A: acetonitrile

[0279] Mobile phase B: 0.1wt% phosphoric acid aqueous solution

[0280] Gradient conditions:

[0281] Time (min) Mobile phase A (%) Mobile phase B (%) 0 5 95 32.5 80 20 39.49 80 20 39.5 5 95 44.5 5 95

[0287] Flow rate: 0.8ml / min

[0288] Injection volume: 10 μl

[0289] Retention time: alcohol compound (1); 8.2 minutes, azide compound (2); 12.7 minutes, diastereomer (trans isomer) of azide compound (2); 13.5 minutes, azide compound (2A); 20.0 minutes, diastereomer (trans isomer) of azide compound (2A); 20.7 minutes, amine compound (2B); 6.3 minutes, diastereomer (trans isomer) of amine compound (2B); 7.1 minutes, sulfonate compound (5-1); 10.5 minutes, CPOE; 27.2 minutes, compound (4); 18.3 minutes

[0290] The yield and diastereoselectivity were calculated as follows.

[0291] Yield (mol %) = (amount of product) / (amount of raw material) × 100

[0292] Diastereoselectivity (cis isomer: trans isomer) = 1: (mass of the diastereomer of the target compound / mass of the target compound)

[0293] (Example 1: Production of Alcohol Compound (1) 1)

[0294]

[0295] Under a nitrogen atmosphere, methanesulfonic acid (8.46 g, 88.0 mmol) was added to a solution of the amino alcohol compound represented by formula (11-2) (5.04 g, 17.6 mmol) and dichloromethane (50.0 mL) at 0°C. The mixture was warmed to room temperature (approximately 20-25°C) and stirred for 30 minutes. The mixture was then cooled to 0°C and triethylamine (13.0 g, 128 mmol), 1-hydroxy-7-azabenzotriazole (1.08 g, 7.92 mmol), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (TPCM) hydrochloride (4.54 g, 19.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) hydrochloride (5.06 g, 26.4 mmol) were added. The mixture was then warmed to 40°C and stirred for 17 hours. The reaction solution was cooled to room temperature and 100 mL of saturated sodium bicarbonate aqueous solution was added. After the organic layer was separated from the aqueous layer, the aqueous layer was further extracted 4 times with 50 mL of dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate. After filtration and separation, it was concentrated under reduced pressure to form a reddish-brown oil. 40 mL of acetonitrile was added thereto, stirred at 0°C for 5 hours, and the orange slurry solution was filtered. The obtained solid was vacuum-dried for 18 hours to obtain an alcohol compound (1) (4.51 g, 12.3 mmol, purity 97.6 area%, yield 70.0%) as a white solid.

[0296] 1 H-NMR(CDCl3)δ: 7.19(d,J=7.5Hz,1H),4.43-4.38(m,1H),3.71-3.68(m,3H),3.21(brs,1H),3.04(s,3H),2.95-2.91(m,5H),2. 83(t,J=6.0Hz,2H),2.52(s,3H),2.32-2.27(m,1H),1.99-1.94(m,1H),1.90-1.86(m,2H),1.69-1.64(m,1H),1.62-1.57(m,1H)

[0297] (Example 2-1: Production 2 of Alcohol Compound (1))

[0298]

[0299] Under a nitrogen atmosphere, triethylamine (2.21 g, 21.8 mmol), 1-hydroxybenzotriazole (1.59 g, 11.7 mmol), TPCM hydrochloride (2.16 g, 9.22 mmol), EDCI hydrochloride (2.41 g, 12.6 mmol) were added to a solution of an amino alcohol compound (1.56 g, 8.38 mmol) represented by formula (11-1) and dichloromethane (15.6 mL) at 0°C, the temperature was raised to 40°C, and the mixture was stirred for 2 hours. The reaction solution was cooled to room temperature and 30 mL of a saturated aqueous sodium bicarbonate solution was added. After separation of the organic layer from the aqueous layer, the aqueous layer was further extracted 4 times with 15 mL of dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate. After filtration and separation, it was concentrated under reduced pressure to form a reddish-brown oil. 23 mL of acetonitrile was added thereto at 0°C and stirred for 5 hours, and the orange slurry solution was filtered. The obtained solid was vacuum-dried for 17 hours to obtain alcohol compound (1) (2.01 g, 5.48 mmol, purity 93.7 area%, yield 65.4%) as a white solid.

[0300] (Example 2-2: Production 2 of Alcohol Compound (1))

[0301] Water was used instead of dichloromethane as the solvent for the amino alcohol compound represented by formula (11-1), the temperature was raised to 40°C, and stirring was carried out at room temperature for 19 hours instead of 2 hours. The same reaction as in Example 2-1 was carried out to obtain the target compound with a purity of 94.4 area% and a yield of 44.2%.

[0302] (Example 3-1: Production of Azide Compound (2) 1-1)

[0303]

[0304] Under a nitrogen atmosphere, methyl tert-butyl ether (dielectric constant: 4.50) (3.0 mL) was cooled to 0°C. After cooling, diisopropyl azodicarboxylate (0.455 mL, 2.32 mmol) and diphenylphosphoryl azide (0.747 mL, 3.48 mmol) were added and stirred for 5 minutes. Triphenylphosphine (0.608 g, 2.32 mmol) was added and stirred for 1 hour. After stirring, alcohol compound (1) (0.500 g, content 85.0 wt%, 1.16 mmol) was added and the temperature was raised to 25°C. After heating, the mixture was stirred at 25°C for 21 hours. The reaction solution was analyzed by HPLC, and the yield of azide compound (2) was 91.0%, and the diastereoselectivity was 1:0.04.

[0305] 1H-NMR(CDCl3)δ: 7.25(d,J=7.5Hz,1H),4.59-4.56(m,1H),3.93-3.89(m,1H),3.75(d,J=15.2Hz,1H),3.69(d,J=15.2Hz,1H),3.00(s,3H),2.95( ddd,J=6.0,6.0,1.4Hz,2H),2.93(s,3H).2.89-2.78(m,3H),2.52(s,3H) ,2.22(ddd,J=13.2,6.4,3.0Hz,1H),2.18-213(m,1H),1.88-1.74(m,4H)

[0306] (Example 3-2: Production of Azide Compound (2) 1-1)

[0307] Azide compound (2) was produced by the same operation as in Example 3-1 except that methyl tert-butyl ether was replaced with cyclopentyl methyl ether (dielectric constant (25°C): 4.76). The yield of azide compound (2) was 91.3% and the diastereoselectivity was 1:0.04.

[0308] (Example 3-3: Production of Azide Compound (2) 1-1)

[0309] Azide compound (2) was produced by the same operation as in Example 3-1 except that methyl tert-butyl ether was replaced with anisole (dielectric constant (25°C): 4.33). The yield of azide compound (2) was 88.8%, and the diastereoselectivity was 1:0.02.

[0310] (Example 3-4: Production of Azide Compound (2) 1-1)

[0311] Azide compound (2) was produced by the same operation as in Example 3-1 except that methyl tert-butyl ether was replaced with toluene (dielectric constant (25°C): 2.38). The yield of azide compound (2) was 91.6% and the diastereoselectivity was 1:0.02.

[0312] (Comparative Example 1: Production of Azide Compound (2A) and Amine Compound (2B) 1-2)

[0313]

[0314] Under a nitrogen atmosphere, the amino alcohol compound represented by Formula (11-2) (500.0 mg, 1.746 mmol) was suspended in tert-butyl methyl ether (6 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (706.1 mg, 3.492 mmol) and diphenylphosphoryl azide (1441.5 mg, 5.238 mmol) were added to the suspension in that order at the same temperature, and the mixture was stirred for 5 minutes. Triphenylphosphine (915.9 mg, 3.492 mmol) was then added at 0°C, and the mixture was then warmed to room temperature. After 3 hours, HPLC analysis of the reaction solution revealed a yield of 67.1% for the azide compound represented by Formula (2A) (also referred to as azide compound (2A)). Triphenylphosphine (1831.8 mg, 6.984 mmol) was added to the reaction solution, and the mixture was heated to 50°C. One hour later, water (1 mL) was added at the same temperature, and hydrolysis was carried out for 18 hours. Analysis of the reaction solution by HPLC revealed that the diastereoselectivity of the amine compound represented by formula (2B) (also referred to as amine compound (2B)) was 1:0.07, and the yield (based on the amino alcohol compound represented by formula (11-2)) was 47.8%. Since the reduction reaction proceeds without affecting the steric structure of the amino group, the diastereoselectivity of amine compound (2B) was 1:0.07, and it was estimated that the diastereoselectivity of azide compound (2A) was also 1:0.07.

[0315] Examples 3-1 to 3-4 and Comparative Example 1 are examples of azidation of a hydroxyl group using diphenylphosphoryl azide, a phosphine compound, and an azo compound. Compared to Comparative Example 1, Examples 3-1 to 3-4, in which an alcohol compound (1) having a bulky amide group (specifically, a group represented by the above formula (21)) is azidated as an adjacent group to the hydroxyl group, can improve the diastereoselectivity of the resulting azide compound.

[0316] (Example 4: Production of Azide Compound (2) 2-1)

[0317]

[0318] Under a nitrogen atmosphere, triethylamine (524 mg, 5.18 mmol) and methanesulfonyl chloride (534 mg, 4.66 mmol) were added to a dichloromethane (10 mL) solution of alcohol compound (1) (949 mg, 2.59 mmol) at 0 ° C. After stirring at room temperature for 2 hours, methanol (1 mL) was added at room temperature. Dichloromethane (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the above reaction solution and separated. After separation, the organic layer was dried over sodium sulfate (1.0 g), filtered and concentrated. The crude product obtained was purified by silica gel column chromatography to obtain a light yellow solid. The light yellow solid obtained was dissolved in dichloromethane (3 mL), added n-hexane (6 mL) and stirred at room temperature for 1 hour to wash, and the white slurry solution was filtered. The resulting solid was dried for 4 hours to obtain the sulfonate compound represented by formula (5-1) (also referred to as sulfonate compound (5-1)) (893 mg, 2.01 mmol, purity 99.47 area%, yield 77.6%) as a white solid. The obtained sulfonate compound (5-1) (400 mg, 0.90 mmol) was suspended in toluene (210 mL), and dodecylpyridinium chloride (0.13 g, 0.45 mmol) and sodium azide (130 mg, 1.80 mmol) were added, followed by heating and stirring at 70°C for 20 hours. Analysis of the reaction solution by HPLC revealed a yield of 47.2% for the azide compound (2) and a diastereoselectivity of 1:0.12.

[0319] (Comparative Example 2: Production of Azide Compound (2A) 2-2)

[0320] Methanesulfonyl chloride (12.79 g, 111.7 mmol) was added to a solution of 4-methyl-2-pentanone (550 mL) of an amino alcohol compound (20.00 g, 69.84 mmol) represented by formula (11-2) at room temperature. Triethylamine (13.43 g, 132.7 mmol) was added to the reaction solution at room temperature and stirred at the original temperature for 2 hours. Methanol (86 mL) and water (126 mL) were added to the reaction solution and stirred for 15 minutes, and then the organic layer was separated. After washing the organic layer with 5% aqueous sodium bicarbonate solution (100 mL), the solvent was concentrated under reduced pressure. The obtained slurry solution was aged at 0°C for 3 hours and then filtered to obtain a methanesulfonyl oxide compound (21.06 g, yield 91.5%). At room temperature, sodium azide (1.784 g, 27.44 mmol) and dodecylpyridinium chloride (1.947 g, 6.860 mmol) were added to a toluene (25 mL) solution of the obtained methanesulfonyl oxide compound (5.000 g, 13.72 mmol). After stirring at 70°C for 27 hours, the reaction solution was analyzed by HPLC. The yield of the azide compound (2A) was 66%, and the diastereoselectivity was 1:0.18.

[0321] Example 4 and Comparative Example 2 are both examples of azidation of a hydroxyl group using diphenylphosphoryl azide and a tertiary amine. Compared to Comparative Example 2, Example 4, in which an alcohol compound (1) having a bulky amide group (specifically, a group represented by the above formula (21)) is azidated as an adjacent group to the hydroxyl group, can improve the diastereoselectivity of the obtained azide compound.

[0322] (Example 5: Production of Azide Compound (2) 3-1)

[0323]

[0324] Under a nitrogen atmosphere, diphenylphosphoryl azide (427 mg, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (237 mg, 1.55 mmol) were added to a toluene (4.5 mL) solution of the alcohol compound (1) (475 mg, 1.30 mmol), and the mixture was stirred at 50°C for 1 hour. Potassium carbonate (0.29 g, 2.07 mmol) was then added, and the mixture was heated at 100°C for 20 hours. The reaction mixture was analyzed by HPLC, revealing a yield of 44.9% for the azide compound (2) and a diastereoselectivity of 1:0.33.

[0325] (Comparative Example 3: Production of Azide Compound (2A) 3-2)

[0326] The amino alcohol compound represented by formula (11-2) (500.0 mg, 1.746 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (350.2 mg, 2.300 mmol), and diphenylphosphoryl azide (624.7 mg, 2.270 mmol) were added to toluene (2.9 mL) and the temperature was raised to 50°C. After 4 hours, anhydrous potassium carbonate (417.4 mg, 3.020 mmol) was added, and the mixture was stirred at 100°C for 18 hours. The reaction solution was analyzed by HPLC, revealing a yield of 38% for the azide compound (2A) and a diastereoselectivity of 1:0.48.

[0327] Both Example 5 and Comparative Example 3 are examples of azidating a hydroxyl group by forming a sulfonate compound using a sulfonylating agent and a base, and then reacting the sulfonate compound with a metal azide. Compared to Comparative Example 3, Example 5, in which an alcohol compound (1) having a bulky amide group (specifically, a group represented by the above formula (21)) as an adjacent group to the hydroxyl group is azidated, can improve the diastereoselectivity of the resulting azide compound.

[0328] (Comparative Example 4: Production of a Compound Represented by Formula (15))

[0329]

[0330] Under a nitrogen atmosphere, to a solution of the alcohol compound (1) (1.00 g, 2.72 mmol) in tetrahydrofuran (4.0 mL) were added phthalimide (0.48 g, 3.24 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) in this order at room temperature, and the mixture was cooled to 0° C. A solution of diethylazodicarboxylate (0.72 g, 4.11 mmol) in toluene (1.79 g) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hours and then at 45° C. for 17 hours. The reaction solution was analyzed by HPLC, but no compound represented by formula (15) was observed.

[0331] (Example 6: Production of amine compound (3))

[0332]

[0333] Triphenylphosphine (0.4057 g, 1.55 mmol) was added to a solution of azide compound (2) (0.3626 g, content 83.49 wt%, 0.773 mmol) and tetrahydrofuran (3.63 mL) at room temperature and stirred at 50°C for 2 hours. The light yellow solution after the reaction was cooled to room temperature, and water (0.2786 g, 15.5 mmol) was added, followed by stirring at 50°C for 19 hours. After the reaction, the solution was cooled to room temperature, ethyl acetate (5 mL) was added, and then dried over anhydrous sodium sulfate (1.200 g). After filtration and separation, the solution was concentrated under reduced pressure at 30°C to obtain a yellow oil (0.8871 g). The obtained yellow oil was purified by column chromatography (Rf=0.17, 0.36, Ethyl acetate / MeOH=40 / 1, universal L (amino), gradient) to obtain the amine compound (3) (0.2194 g, yield 77.7%) as a pale yellow amorphous substance.

[0334] 1 H-NMR(CDCl3)δ: 7.51(d,J=6.3Hz,1H),4.23-4.21(m,1H),3.72(d,J=15.5Hz,1H),3.67(d,J=15.5Hz,1H) ,3.13(ddd,J=12.0,4.0,4.0Hz,1H),2.98(s,3H),2.94(dd,J=5.7,5.7Hz,2H),2.90(s,3H),2.82(ddd,J= 12.8,5.7,5.7Hz,1H),2.79(ddd,J=12.8,5.7,5.7Hz,1H),2.71(dddd,J=11.7,11.7,3.4,3.4Hz,1H),2.5 0(s,3H),2.37-2.33(m,1H),1.83-1.67(m,4H),1.47(brs,2H),1.46(dddd,J=12.0,12.0,12.0,4.0Hz,1H)

[0335] (Example 7: Production of Compound (4))

[0336]

[0337] 4-Dimethylaminopyridine (86.8 mg, 0.710 mmol) and ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (CPOE) (0.1624 g, 0.710 mmol) were added to a solution of amine compound (3) (0.1997 g, 0.546 mmol) and acetonitrile (1.14 mL) at room temperature, and the mixture was stirred at 70°C for 6 hours. After the reaction, acetonitrile (0.166 mL) was added at room temperature, and the temperature was lowered to 10°C. After stirring for 16 hours, the resulting solid was filtered to obtain compound (4) (0.2291 g, content 99.70 wt%, purity 96.67 area%, yield 76.3%) as a white solid.

[0338] 1 H-NMR(CDCl3)δ: 9.74(brs,1H),8.31-8.30(m,1H),8.17(ddd,J=8.8,0.7,0.7Hz,1H),8.06(d,J=7.7Hz,1H), 7.69(ddd,J=8.8,0.7,0.7Hz,1H),7.42(d,J=8.6Hz,1H),4.70-4.67(m,1H),4.14-4.09(m,1H),3.75(dd,J=15 .4,1.0Hz,1H),3.69(dd,J=15.4,1.0Hz,1H),3.06(s,3H),2.95(s,3H),2.94(brs,2H),2.87-2.79(m,3H),2.5 2(s,3H),2.13-2.03(m,2H),1.99-1.87(m,2H),1.88-1.78(m,1H),1.67(dddd,J=12.9,12.9,12.9,3.7Hz,1H)

Claims

1. A method for producing an azide compound represented by the following formula (2), the method comprising: The alcohol compound represented by the following formula (1) is azidated. 。 2. The manufacturing method according to claim 1, wherein The azidation is carried out by allowing diphenylphosphoryl azide, a phosphine compound, and an azo compound to act on the alcohol compound represented by the formula (1).

3. The manufacturing method according to claim 1, wherein The azidation is carried out by allowing diphenylphosphoryl azide and a tertiary amine to act on the alcohol compound represented by the formula (1).

4. The manufacturing method according to claim 1, wherein The azidation is carried out by the following method: The alcohol compound represented by the formula (1) is reacted with a sulfonylating agent and a base to obtain a sulfonate compound represented by the following formula (5), and the sulfonate compound represented by the formula (5) is reacted with a metal azide. Where R 2 It represents an alkyl group having 1 to 12 carbon atoms which may have a substituent, or an aryl group having 6 to 12 carbon atoms which may have a substituent.

5. The production method according to any one of claims 1 to 4, further comprising: a step of subjecting 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid or a salt thereof to dehydration condensation with an amino alcohol compound represented by the following formula (11) or a salt thereof to obtain an alcohol compound represented by the above formula (1); Where R 1 represents a hydrogen atom or a tert-butyloxycarbonyl group.

6. The manufacturing method according to claim 5, wherein: R in the formula (11) 1 A hydrogen atom.

7. A method for producing an amine compound represented by the following formula (3) or a salt thereof, the method comprising: The azide compound represented by formula (2) produced by the method according to any one of claims 1 to 4 is reduced, 。 8. The manufacturing method according to claim 7, wherein: The reduction is performed by allowing phosphine and water to act on the azide compound represented by the formula (2).

9. A method for producing N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino)cyclohexyl)oxamide represented by the following formula (4), a salt thereof, or a solvate thereof, the method comprising: Allowing 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetic acid alkyl ester or a salt thereof to act on the amine compound represented by formula (3) produced by the method according to claim 7, 。

Images