Methods for producing triazine compounds

Abstract

The present invention provides a method for producing compound IV or a salt thereof by a reaction represented by the following scheme; wherein the symbols are the same as those described in the specification; a method for producing 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine by a reaction represented by the following scheme; and a method for producing 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine by a reaction represented by the following scheme: wherein the symbols are the same as those described in the specification.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 669,645, filed July 10, 2024, and Japanese Application No. 2023-150472, filed September 15, 2023, the contents of each of which are hereby incorporated by reference.

[0002] Throughout this application, various disclosures, including those cited in parentheses, are referenced. The disclosures of all such disclosures mentioned herein are hereby incorporated in their entirety to provide further description of features in the field to which this invention pertains and in fields that may be used in conjunction with this invention. Background Technology

[0003] PCT International Patent Application Publication No. WO 2015 / 163427 discloses the following method for producing 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine (hereinafter also referred to as "triazine compound A").

[0004]

[0005] PCT International Patent Application Publication No. WO 2022 / 059700 discloses the following method for generating the triazine compound A.

[0006] Summary of the Invention

[0007] This invention relates to a method for producing a triazine compound or an intermediate thereof, said triazine compound or intermediate thereof having an inhibitory effect on aldosterone synthase and being usable as a medicine, particularly as a preventive or therapeutic medicine for primary aldosteronism, etc. More specifically, this invention relates to a method for producing 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine or an intermediate thereof having excellent properties as an active pharmaceutical ingredient.

[0008] The problem to be solved by this invention The object of this invention is to provide a method for producing triazine compound A or its intermediates, which is superior to conventional methods in one or more aspects such as yield, production cost, number of production steps, and ease of purification, and is more suitable for industrial-scale operation.

[0009] Another object of the present invention is to provide a method for crystallizing the monohydrobromide of triazine compound A, the method maximizing the yield while allowing control over the particle size.

[0010] Problem Solving Methods The inventors have diligently studied ways to solve the aforementioned problems. Therefore, the inventors have discovered a production route from inexpensive starting materials via the generation of intermediates without protection and deprotection reactions, and have successfully developed a method for generating triazine compound A or its generation intermediates using inexpensive reagents in short steps and high yields. Furthermore, the inventors have also successfully developed a production method in which the generation intermediate is not isolated in a specific step, but is directly used in the next step, thus completing the present invention.

[0011] That is, the present invention provides the following: Method for producing compounds represented by formula IV (1) A method for producing a compound represented by formula IV or a salt thereof:

[0012] Formula IV Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:

[0013] Where R 2 and R 3 Each of the hydrogen atom, acetyl group, or amino protecting group is independently represented; and the wavy line indicates the connection point with the rest of the molecule; the method comprises: (a) Reacting a compound of formula I or a salt thereof, an activator, and a compound of formula III or a salt thereof to produce the compound of formula IV or a salt thereof:

[0014] Formula I

[0015] Formula III Where R 1 This indicates that it is the same as defined above;

[0016] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group.

[0017] (2) The method according to (1), wherein reacting the compound represented by formula I or a salt thereof, the activator, and the compound represented by formula III or a salt thereof to produce the compound represented by formula IV or a salt thereof is carried out without separating the compound represented by formula II or a salt thereof:

[0018] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; and Where R 2 and R 3 Each can independently represent a hydrogen atom or an amino protecting group.

[0019] (3) The method according to (1), wherein reacting the compound represented by formula I or a salt thereof, the activator, and the compound represented by formula III or a salt thereof to produce the compound represented by formula IV or a salt thereof comprises separating the compound represented by formula II or a salt thereof:

[0020] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group.

[0021] Method for producing compounds represented by formula IV' (4) The method according to any one of (1) to (3), wherein R 1 Representing hydrogen atoms, the method is used to produce compounds of formula IV':

[0022] Formula IV'.

[0023] Method for producing compounds represented by formula V (5) A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0024] Formula V The method includes: (a) To produce a compound represented by formula IV' or a salt thereof by any one of the methods according to (1) to (4):

[0025] Formula IV'; as well as (b) Reacting the compound represented by formula IV' or a salt thereof with a compound represented by formula VI or a salt thereof to produce the compound represented by formula V or a pharmacologically acceptable salt thereof:

[0026] Style VI Where X 1 It represents a chlorine atom, a bromine atom, or a leaving group.

[0027] Method for producing a compound or a salt thereof represented by formula VI (6) The method according to (5) further comprises reacting a compound represented by formula VII or a salt thereof, a base, and a compound represented by formula VIII or a salt thereof in a solvent to produce the compound represented by formula VI or a salt thereof:

[0028] Equation VII

[0029] Formula VIII Where X 1 This indicates that it is the same as defined above; and X 2 It represents a chlorine atom, a bromine atom, or a leaving group.

[0030] Method for producing compounds represented by formula VII (7) The method according to (6) further comprises subjecting the compound represented by formula IX or a salt thereof to a reduction reaction to produce the compound represented by formula VII or a salt thereof:

[0031] Formula IX.

[0032] Method for producing compounds represented by formula VII (8) The method according to (6) further comprises subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce the compound represented by formula VII or a salt thereof:

[0033] Formula X.

[0034] Method for producing compounds represented by formula VII (9) A method for producing a compound represented by formula VII, the method comprising subjecting a compound represented by formula X to a reduction reaction:

[0035] Equation VII

[0036] Formula X.

[0037] Methods for producing compounds represented by formula V or their pharmacologically acceptable salts. (10) A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0038] Formula V The method includes: (a) Reacting a compound represented by formula I or a salt thereof with an activator to produce and isolate a compound represented by formula II or a salt thereof:

[0039] Formula I

[0040] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; (b) Reacting the compound represented by Formula II or a salt thereof with the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof:

[0041] Formula III Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:

[0042] Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule.

[0043] Formula IV Where R 1 This indicates that it is the same as defined above; and (c) subjecting a compound represented by formula IX or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof:

[0044] Formula IX

[0045] Formula VII.

[0046] Methods for producing compounds represented by formula V or their pharmacologically acceptable salts. (11) A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0047] Formula V The method includes: (a) Reacting a compound represented by formula I or a salt thereof with an activator to produce and isolate a compound represented by formula II or a salt thereof:

[0048] Formula I

[0049] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; (b) Reacting the compound represented by Formula II or a salt thereof with the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof:

[0050] Formula III Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:

[0051] Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule.

[0052] Formula IV Where R 1 This indicates that it is the same as defined above; and (c) subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof:

[0053] Formula X

[0054] Formula VII.

[0055] Method for producing compounds represented by formula V (12) The method according to (10) or (11) further comprises: (a) Reacting the compound represented by formula VII or a salt thereof, a base, and the compound represented by formula VIII or a salt thereof in a solvent to produce the compound represented by formula VI or a salt thereof:

[0056] Formula VIII Where X 1 and X 2 Each can independently represent a chlorine atom, a bromine atom, or a leaving group;

[0057] Style VI Where X 1 This indicates that it is the same as defined above; and (b) Reacting the compound represented by formula IV or a salt thereof with the compound represented by formula VI or a salt thereof to produce the compound represented by formula V or a pharmacologically acceptable salt thereof.

[0058] (13) The method according to any one of (7) to (12), wherein the reduction reaction is carried out by reacting with a metal catalyst and hydrogen in a polar solvent.

[0059] (14) The method according to (13), wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile or dimethylacetamide.

[0060] (15) The method according to (13) or (14) wherein the metal catalyst is ruthenium-alumina (Ru / Al2O3), ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon or nickel-diatomite, nickel-alumina or Raney nickel.

[0061] (16) The method according to (8) or (9), wherein the reduction reaction is carried out by reacting the compound represented by formula X, the metal catalyst and hydrogen in a polar solvent.

[0062] (17) The method according to (16), wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile or dimethylacetamide, preferably methanol or tetrahydrofuran, more preferably a mixture of methanol and tetrahydrofuran.

[0063] (18) The method according to (16) or (17), wherein the metal catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, nickel-diatomite, nickel-alumina or Raney nickel, preferably Raney nickel.

[0064] (19) The method according to any one of (16) to (18), wherein the metal catalyst is washed with a polar aprotic solvent, preferably tetrahydrofuran (THF), before being combined with a solution of the compound represented by formula X or its salt and a polar solvent, wherein the polar solvent is preferably methanol.

[0065] (20) The method according to any one of (16) to (19), wherein the reduction reaction comprises stirring the compound represented by formula X or a salt thereof and the metal catalyst in the polar solvent in the presence of hydrogen, preferably at 40-50°C and under 0.35-0.50 MPa of hydrogen, preferably for 2-6 hours.

[0066] (21) The method according to any one of (16) to (20), wherein the solid containing the compound represented by formula VII is formed by said reduction reaction:

[0067] Formula VII.

[0068] (22) According to the method of (21), the ratio of the peak area of ​​the compound represented by formula X to that of the compound represented by formula VII produced by the solid is less than or equal to 1% as measured by high-performance liquid chromatography (“HPLC”).

[0069] (23) The method according to (22) further comprises preferably separating the solid containing the compound represented by formula VII by a concentration, filtration and washing step, preferably wherein the filtration is carried out with diatomaceous earth, preferably wherein the washing is carried out with a polar aprotic solvent, more preferably THF, and still more preferably wherein the separation comprises a final concentration step, followed by washing with an organic solvent, preferably ethyl acetate, and then drying.

[0070] (24) The method according to any one of (16) to (23), wherein the reaction produces the compound represented by formula VII with a purity greater than 94%, more preferably 95-97%, preferably wherein the reaction produces less than 5% of the cis isomer of the compound represented by formula VII, more preferably 1-3% of the cis isomer of compound VII.

[0071] Method for producing compounds represented by formula V (25) A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0072] Formula V; The method comprises reacting a compound represented by formula II or a salt thereof with a compound represented by formula XIII or a salt thereof:

[0073] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group, preferably chlorine;

[0074] Formula XIII.

[0075] (26) According to the method of (25), wherein the compound represented by formula XIII or a salt thereof is produced by subjecting the compound represented by formula XII or a salt thereof to a deprotection reaction, preferably wherein the deprotection reaction is a reduction reaction:

[0076] Formula XII R1 represents a protecting group, preferably an amino protecting group, and more preferably a benzyloxycarbonyl group.

[0077] (27) According to the method of (26), wherein the compound represented by formula XII is produced by reacting a compound represented by formula VII or a salt thereof, a base, and a compound represented by formula XI or a salt thereof in a solvent in the presence of a condensing agent:

[0078] Formula XI Wherein R1 represents an amino protecting group, preferably a benzyloxycarbonyl group;

[0079] Formula VII.

[0080] (28) According to the method of (27), wherein the compound represented by formula VII or a salt thereof is produced by subjecting a compound represented by formula X or a salt thereof to a reduction reaction:

[0081] Formula X.

[0082] (29) The method according to any one of (25) to (28), wherein the compound represented by formula II or a salt thereof is produced by reacting a compound represented by formula I or a salt thereof with an activator:

[0083] Formula I.

[0084] Method for crystallizing the monohydrobromide of compound V (30) The method according to any one of (5) to (8) and (10) to (29), wherein a free base of the compound represented by formula V is produced, the method further comprising a method for crystallizing the monohydrobromide salt of the compound represented by formula V, the method comprising: (a) A solution is produced that contains: (1) a free base of the compound represented by formula V; (2) a solvent, such as ethanol or methanol; (3) water; and (4) hydrobromic acid; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; and (c) Collect the obtained crystals.

[0085] (31) A method for crystallizing the monohydrobromide of a compound represented by formula V:

[0086] Formula V; The method includes: (a) A solution is produced that contains: (1) a free base of the compound represented by formula V; (2) a solvent, such as ethanol or methanol; (3) water; and (4) hydrobromic acid; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; and (c) Collect the obtained crystals.

[0087] (32) The method according to (30) or (31) includes the following steps: (a) The free base of the compound represented by formula V is mixed with ethanol, water and hydrobromic acid; (b) Add the resulting solution to acetone, preferably dropwise; (c) Wash the resulting mixture with a mixture of ethanol and water; (d) Cool and stir the resulting mixture; (e) Collect the obtained crystals; and (f) Optionally wash the collected crystals with acetone; (g) Optionally, dry the washed crystals.

[0088] (33) The method according to (32) includes one or more or all of the following features: (a) In step (a), the weight ratio of the compound represented by formula V: ethanol: water: hydrobromic acid is about 15:14.22:11.91:2.69; (b) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; (c) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, over 1 hour; (d) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; (e) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; (f) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2-24 hours, preferably about 18 hours; (g) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and (h) The yield of the method is at least 90%, preferably at least 93%, and more preferably 93% to 97%.

[0089] (34) The method according to (30) or (31) includes the following steps: (a) The free base of the compound represented by formula V is suspended in a solution of methanol and water to form a suspension of the compound represented by formula V; (b) Adding an aqueous HBr solution to the suspension of the compound represented by formula V to obtain a first mixture; (c) Heating the first mixture to obtain a first solution; (d) Filter the first solution; (e) Acetone and seed crystals are added to the first solution to obtain a second mixture; (f) Add additional acetone to the second mixture to obtain a third mixture; (g) Maintain and cool the third mixture; (h) Filter the third mixture to obtain a filter cake; (i) Wash the filter cake to obtain crystals of the monohydrobromide of the compound represented by formula V.

[0090] (35) The method according to (34), wherein the method comprises one or more or all of the following features: (i) Step a) comprises suspending the free base of the compound represented by formula V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, of about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water; (ii) Step b) comprises adding about 1.00 to 1.025 molar equivalents, preferably about 1.01 molar equivalents, of an aqueous HBr solution to the suspension of the compound represented by formula V to obtain the first mixture; (iii) Step c) comprises heating the first mixture to about 45°C to 60°C, preferably about 50°C, to obtain the first solution; (iv) Step d) includes filtering the first solution through a fine filter; (v) Step e) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; (vi) Step f) comprises loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, to obtain the third mixture; (vii) Step g) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, followed by cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; (viii) Step h) comprises filtering the third mixture to form a filter cake; (ix) Step i) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and (x) The yield of the method is approximately 85%.

[0091] Method for recrystallizing the monohydrobromide of the compound represented by formula V (36) The method according to any one of (30) to (35), further comprising recrystallizing the monohydrobromide of the compound represented by formula V, the method comprising: (a) Dissolving crystals of the monohydrobromide salt of the compound represented by formula V in (1) a solvent, such as ethanol or methanol and (2) water; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; and (c) Collect the obtained crystals.

[0092] (37) A method for recrystallizing the monohydrobromide of a compound represented by formula V:

[0093] Formula V; The method includes: (a) Dissolving crystals of the monohydrobromide salt of the compound represented by formula V in (1) a solvent, such as ethanol or methanol and (2) water; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; and (c) Collect the obtained crystals.

[0094] (38) The method according to (36) or (37) includes the following steps: (a) Mixing the crystals of the monohydrobromide of the compound represented by formula V with ethanol and water; (b) Add the resulting solution to acetone, preferably dropwise; (c) Wash the resulting mixture with a mixture of ethanol and water; (d) Cool and stir the resulting mixture; (e) Collect the obtained crystals; and (f) Optionally wash the collected crystals with acetone; (g) Optionally, dry the washed crystals.

[0095] (39) The method according to (38) includes one or more or all of the following features: (i) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; (ii) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, over 1 hour; (iii) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; (iv) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; (v) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2-24 hours, preferably about 18 hours; (vi) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and (vii) The yield of the method is at least 90%, preferably at least 93%, and more preferably 93% to 97%.

[0096] (40) The method according to claim (36) or (37), comprising the following steps: (a) Dissolving crystals of the monohydrobromide salt of the compound represented by formula V in a solution of methanol and water to obtain a first solution; (b) Filter the first solution; (c) Acetone and seed crystals are added to the first solution to obtain a second mixture; (d) Add additional acetone to the second mixture to obtain a third mixture; (e) Maintain and cool the third mixture; (f) Filter the third mixture to obtain a filter cake; (g) Wash the filter cake to obtain crystals of the monohydrobromide of the compound represented by formula V.

[0097] (41) The method according to (40), wherein the method comprises one or more or all of the following features: (i) Step a) comprises suspending crystals of the monohydrobromide of the compound represented by formula V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, of about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water; (ii) Step a) involves heating to about 45°C to 60°C, preferably about 50°C; (iii) Step b) includes filtering the first solution through a fine filter; (iv) Step c) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; (v) Step d) includes loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, to obtain the third mixture; (vi) Step e) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, followed by cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; (vii) Step f) comprises filtering the third mixture to form a filter cake; (viii) Step g) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and (ix) The yield of the method described is approximately 85%.

[0098] The method according to any of the aspects described herein (42) A method which is substantially as described in any of the aspects described herein.

[0099] Compounds and compositions produced according to the method of the present invention (43) A compound or composition produced according to any one of (1) to (42).

[0100] Effects of the present invention Compared with conventional methods, the method of the present invention for producing triazine compound A is superior in one or more aspects such as yield, production cost, number of production steps, and ease of purification, and is more suitable for industrial-scale operation, and therefore can be used as an industrial method for producing active pharmaceutical ingredients.

[0101] The crystallization method of the present invention allows for the true crystallization of the monohydrobromide of triazine compound A, whereas previous crystallization methods for triazine compound A involved a slurry-to-slurry conversion. Furthermore, the crystallization method of the present invention maximizes the yield of the product, particularly relative to dihydrobromide, while allowing for control of particle size. Detailed Implementation

[0102] definition Unless otherwise stated, the definitions of each group in this specific embodiment may be optionally combined with each other.

[0103] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates. While similar or equivalent methods and materials may be used to practice or test embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including its definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0104] In this discussion, unless otherwise stated, adjectives such as “substantially” and “about” that modify one or more features of embodiments of the invention are understood to mean that the condition or feature is limited to an operationally acceptable tolerance range for the intended application of the embodiment. In embodiments, “about” means within the standard deviation of measurements generally acceptable in the art. In embodiments, “about” means extending to + / - 10% of a specified value. In embodiments, “about” includes the specified value. Unless otherwise stated, the word “or” in the specification and claims is considered inclusive rather than exclusive and indicates at least one or any combination of the items combined therewith.

[0105] It should be understood that, as used above and elsewhere herein, the terms “a” and “an” refer to “one or more of the listed components.” Those skilled in the art will appreciate that, unless otherwise specified, the singular usage includes the plural. Therefore, the terms “a,” “an,” or “at least one” are used interchangeably in this application.

[0106] To better understand this teaching, and in no way to limit its scope, all figures and other numerical values ​​used in this specification and claims to express quantities, percentages, or proportions should be understood to be modified by the term "about" in all cases, unless otherwise stated. Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may be varied depending on the desired properties sought. At a minimum, each numerical parameter should be interpreted based on the number of significant figures reported and by applying conventional rounding techniques.

[0107] In the description and claims of this application, the verbs “comprising,” “including,” and “having,” and each of their cognates, used to indicate one or more objects of a verb, are not necessarily a complete list of components, elements, or parts of one or more subjects of the verb. Other terms as used herein are intended to be defined by their meanings known in the art.

[0108] In this specific embodiment, alkyl refers to an alkyl group having 1 to 6 carbon atoms (C6H ... 1-6 Straight-chain or branched saturated hydrocarbon groups, and particularly preferably having 1 to 4 carbon atoms (C4H4H4H4H4H4H4H4H4H4H4H4H4H5 ... 1-4 ) is a group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isopentyl, n-pentyl, and n-hexyl, with preferred examples including methyl, ethyl, isopropyl, and tert-butyl.

[0109] In this specific embodiment, alkoxy refers to a monovalent group in which the above-mentioned alkyl group is bonded to an oxygen atom, and preferably has 1 to 6 carbon atoms (C). 1-6 The group has a group having 1 to 4 carbon atoms (C). 1-4 ) groups. Specific examples include methoxy, ethoxy, n-propoxy, hexylpropoxy, n-butoxy, tert-butoxy, isopentoxy, n-pentoxy, and n-hexyloxy, and preferred examples include methoxy, ethoxy, isopyroxoxy, and tert-butoxy.

[0110] In this specific embodiment, alkoxycarbonyl refers to a group in which the alkoxy group is bonded to a carbonyl group. Examples include groups having 2 to 7 carbon atoms (C...). 2-7 The linear or branched alkoxy carbonyl group, and preferred examples include those having 1 to 4 carbon atoms (C 1-4 (or in some cases has 2 to 5 carbon atoms) 2-5 ) is an alkoxycarbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, and tert-butoxycarbonyl.

[0111] In this specific embodiment, aryl refers to a 6- to 10-membered aromatic cyclic hydrocarbon group, and preferably a monocyclic or bicyclic aryl. Specific examples include phenyl and naphthyl, and particularly preferred examples include phenyl.

[0112] In this specific embodiment, the sulfonate group refers to a group represented by the following formula:

[0113] Where R 4This indicates an optionally substituted alkyl or optionally substituted aryl group. Examples of substituents in an optionally substituted alkyl group include one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, cyano groups, and alkoxy groups, with preferred examples including one or more halogen atoms. Examples of substituents in an optionally substituted aryl group include alkyl and nitro groups, with preferred examples including methyl and nitro groups. Preferred examples of aryl groups in an optionally substituted aryl group include phenyl groups.

[0114] In this specific embodiment, "ester group" refers to a group represented by the following formula:

[0115] Where R 5 The term indicates an optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted amino group, preferably an optionally substituted alkyl or optionally substituted amino group, wherein the optionally substituted alkyl group preferably does not contain a hydroxyl substituent. Examples of substituents for optionally substituted alkyl and optionally substituted alkoxy groups include one or more substituents selected from the group consisting of halogen atoms, hydroxyl, cyano, and alkoxy, and preferred examples include one or more halogen atoms. Examples of substituents for optionally substituted amino groups include alkyl groups.

[0116] In this specific embodiment, the phosphate ester group refers to a group represented by the following formula:

[0117] Where R 6 and R 7 Each independently represents an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkoxy group, or -(OPO(R) 8 )) n -OH (where R) 8 The alkyl group represents an alkyl group, and n represents any integer from 1 to 6, along with an optionally substituted amino group. Examples of the substituted alkyl and substituted alkoxy groups include one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, cyano groups, and alkoxy groups. Examples of the substituted amino groups include alkyl groups.

[0118] In this specific embodiment, preferred examples of "activators" include condensing agents, and specific examples include chlorinating agents, brominating agents, PyBrop (registered trademark) (bromo-tri-pyrrolyl-phospho-hexafluorophosphate), BOP (registered trademark) (1H-benzotriazol-1-yloxytris(dimethylamino)phospho-hexafluorophosphate), BOP-Cl (registered trademark) (bis(2-oxo-3-oxazolyl)phosphine chloride), T3P (registered trademark) (propylphosphonic anhydride), T4P (registered trademark) (butylphosphonic anhydride), CDI (1,1'-carbonyldiimidazole), and DPPCl (diphenylphosphine chloride). DPPCl is preferred when compound II or its salts, described later, are not separated. Compound II or its salts can be separated and used in the next step. When separated, preferred examples include chlorinating agents and brominating agents, with particularly preferred examples including chlorinating agents.

[0119] In this specific embodiment, examples of "chlorinating agents" include chlorine, thionyl chloride, thionyl chloride, phosphorus oxychloride, oxalyl chloride, 2,4,6-trichloro-1,3,5-triazine, trichloroisocyanuric acid, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, phosphorus trichloride, and phosphorus pentachloride, and preferred examples include thionyl chloride.

[0120] In this specific embodiment, examples of "brominating agents" include bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, and phosphorus tribromide.

[0121] In this specific embodiment, examples of "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms, and preferred examples include fluorine atoms, bromine atoms, and chlorine atoms.

[0122] In this specific embodiment, examples of "polar solvents" include alcohols, ethers, alkanes, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide. Preferred examples include propylene glycol methyl ether and 1,3-dimethylimidazolium ketone.

[0123] In this specific embodiment, "aprotic solvent" means a solvent that does not contain ionizable protons. Examples of "aprotic solvents" include N,N-dimethylformamide, N,N-methylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0124] In this specific embodiment, examples of "leaving groups" include methanesulfonyl, p-toluenesulfonyl, and nitrobenzenesulfonyl.

[0125] In this specific embodiment, examples of "metal catalysts" include ruthenium-alumina (Ru / Al2O3), ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, and nickel-diatomite, with preferred examples including ruthenium-alumina and Raney nickel.

[0126] In this specific embodiment, examples of "amino protecting groups" include protecting groups commonly used in the field of organic synthetic chemistry, and specific examples include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl (i.e., COCH3), trifluoroacetyl, p-toluenesulfonyl, and 2-nitrobenzenesulfonyl, and particularly preferred examples include tert-butoxycarbonyl and acetyl (i.e., COCH3).

[0127] In this specific embodiment, the term "separation" refers to operations such as concentration, filtration and washing, and also includes purification by recrystallization or various chromatographic methods, as well as drying of the obtained product.

[0128] In this specific embodiment, the compound represented by Formula I has tautomerism and includes the following two states.

[0129]

[0130] Therefore, in this specific embodiment, "carbonyl group in the compound represented by Formula I" refers to the same substituent as "hydroxyl group in the compound represented by Formula I".

[0131] The following table summarizes the chemical formulas used throughout this disclosure.

[0132] Table 1

[0133]

[0134]

[0135]

[0136]

[0137] Method of generating the present invention The method of this invention is a method for producing compound IV or a salt thereof, represented by the following scheme:

[0138] Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:

[0139] Where R 2 and R 3 Each element independently represents a hydrogen atom or an amino protecting group; and the wavy line indicates the connection point with the rest of the molecule.

[0140] According to this method, compound IV or its salt can be generated by reacting compound I or its salt, an activator, and compound III or its salt, without separating compound II or its salt.

[0141] Compound I or a salt thereof and compound III or a salt thereof are known or can be produced by known methods.

[0142] The amount of compound III or its salt to be used is typically 1 to 5 equivalents relative to compound I or its salt, and preferably 2 to 3 equivalents.

[0143] Examples of activators include chlorinating agents, brominating agents, PyBrop (registered trademark), BOP (registered trademark), BOP-Cl (registered trademark), T3P (registered trademark), and DPPCl, with preferred examples including PyBrop (registered trademark), BOP (registered trademark), BOP-Cl (registered trademark), T3P (registered trademark), T4P (registered trademark), and DPPCl, and particularly preferred examples including DPPCl.

[0144] Similarly, as shown in the following scheme, a compound represented by Formula II (hereinafter also referred to as "Compound II") or its salt can be separated and used in the next step to react with Compound III or its salt. Examples of separation include concentration, filtration, and washing. Purification by recrystallization, column chromatography, etc., and drying can also be performed.

[0145]

[0146] Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; and R 1 Same as described above.

[0147] When compound II or its salts are isolated, preferred examples of activators include chlorinating agents and brominating agents, with particularly preferred examples including chlorinating agents.

[0148] Unless otherwise stated, the following can be applied together to this production method, regardless of whether compound II or its salt is isolated.

[0149] The amount of activator to be used relative to compound I or its salt is typically 1.0 to 3.0 equivalents, and preferably 1.8 to 2.2 equivalents.

[0150] The step of generating compound IV or its salt without separating compound II or its salt, or step 1 (hereinafter also referred to as "this step") in the case of separating compound II or its salt, is generally carried out in a solvent. The solvent can be any solvent that does not affect this reaction, and examples include aromatic hydrocarbons (e.g., benzene, toluene, and xylene), aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), and ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and these can be suitably combined with each other. Preferred examples of these solvents include ethers and nitriles, and more preferred examples include dimethoxyethane and acetonitrile.

[0151] When PyBrop (registered trademark), BOP (registered trademark), BOP-Cl (registered trademark), T3P (registered trademark), T4P (registered trademark), CDI, or DPPCl is used as an activator, this step is carried out in the presence of a base. Examples of bases include organic bases such as triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and preferred examples include DBU.

[0152] The amount of base to be used relative to compound I or its salt is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents.

[0153] If necessary, step 1 can be carried out in the presence of a catalyst, provided that compound II or its salt has been separated. Examples of catalysts include dimethylformamide and N-methylpyrrolidone, with dimethylformamide being a preferred example.

[0154] The amount of catalyst to be used relative to compound I or its salt is typically 0.01 to 0.5 equivalents, and preferably 0.05 to 0.1 equivalents.

[0155] When compound II or its salt is separated, it is preferable to lower the reaction temperature to 0°C to 20°C, and more preferably 5°C to 10°C, after step 1, and to add water or the like to obtain compound II or its salt in crystalline form. As the mixture cools, triethylamine (TEA) can be added to adjust the pH of the mixture, preferably to about 4. After adding water (preferably about 12 L / kg), the resulting crystals can be filtered, washed, and dried.

[0156] In this reaction, the reaction temperature needs to be varied depending on the type of activator. When using activators such as PyBrop (registered trademark), BOP (registered trademark), BOP-Cl (registered trademark), T3P (registered trademark), T4P (registered trademark), and DPPCl, the reaction can be carried out at -40°C to 60°C, preferably at 0°C to 20°C. When using a chlorinating or brominating agent in the presence of a catalyst, the reaction temperature can be from 40°C to 100°C, preferably from 60°C to 90°C, and particularly preferably from 75°C to 85°C.

[0157] If compound II or its salt is isolated, step 2 is a step in which compound II or its salt is reacted with a compound represented by formula III (hereinafter also referred to as "compound III") or its salt to produce compound IV or its salt.

[0158] If compound II or its salt is separated, step 2 can be performed without step 1. In this case, compound II is the starting material of the method and can be obtained according to known methods.

[0159] Compound III or its salts are known, or can be produced by known methods.

[0160] The amount of compound III or its salt to be used is typically 1 to 5 equivalents relative to compound II or its salt, and preferably 2 to 3 equivalents. In the case where R1 is an amino protecting group such as tert-butoxycarbonyl, the amount of compound III or its salt to be used is preferably 1 to 1.5 equivalents, more preferably 1 to 1.1 equivalents.

[0161] Step 2 can usually be carried out in a solvent.

[0162] The solvent can be any solvent that does not affect the reaction, and examples include aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and alcohols (e.g., methanol, ethanol, and isopropanol), and these can be suitably combined with each other. Preferred examples of these solvents include aprotic solvents and alcohols, more preferred examples include N-methyl-2-pyrrolidone and methanol, and even more preferred examples include mixtures of N-methyl-2-pyrrolidone and methanol.

[0163] Step 2 can be carried out in the presence of a base, and examples of bases include: organic bases such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metal carbonates such as sodium carbonate and potassium carbonate, wherein preferred examples include triethylamine and N,N-diisopropylethylamine.

[0164] The amount of base to be used relative to compound II or its salt is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents.

[0165] This reaction can be carried out at 50°C to 100°C, and preferably at 50°C to 70°C.

[0166] The present invention also provides a composition comprising 99.1% to 99.9% of compound IV, wherein the composition preferably comprises 0.1% to 0.9%, preferably less than 0.9%, more preferably less than 0.1% of compound I, compound II and compound III, wherein the composition is preferably produced according to the method of the present invention, more preferably according to any one of the following aspects.

[0167] Aspects of the method for producing the present invention (the method for producing the present invention) The production method of the present invention (the production method of the present invention) includes the following aspects.

[0168] Aspect A1 The method of generating this invention, wherein R 1 (That is, compounds III and IV of the present invention) represent hydrogen atoms, alkyl groups optionally substituted with carboxyl or alkoxycarbonyl groups, amino protecting groups, or groups represented by the following formula:

[0169] Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule.

[0170] Aspect A2 The method of generating this invention, wherein R 1 It represents a hydrogen atom.

[0171] A3 The method of generating this invention, wherein R 1 This indicates an alkyl group that is optionally substituted with a carboxyl or alkoxycarbonyl group.

[0172] A4 The method of generating this invention, wherein R 1This indicates a methyl group that is optionally substituted with a carboxyl or methoxycarbonyl group.

[0173] A5 The method of generating this invention, wherein R 1 It indicates an amino protecting group.

[0174] A6 According to the method described in aspect A5, the amino protecting group represents tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, or 2-nitrobenzenesulfonyl.

[0175] A7 According to the method of aspect A5, the amino protecting group represents tert-butoxycarbonyl or benzyloxycarbonyl, preferably tert-butoxycarbonyl.

[0176] A8 The method of generating this invention, wherein R 1 Represents a group as shown by the following formula:

[0177] The symbols are the same as those described above.

[0178] A9 According to the method described in aspect A8, where R 2 and R 3 The amino protecting group in the text represents tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, or 2-nitrobenzenesulfonyl.

[0179] A10 According to the method described in aspect A8, where R 2 and R 3 The amino protecting group mentioned herein represents tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl.

[0180] Aspect A11 According to the method described in aspect A8, where R 2 and R 3 Each represents a hydrogen atom.

[0181] A12 The method according to any one of aspects A1 to A11, wherein the activator represents a chlorinating agent, a brominating agent, PyBrop (registered trademark), BOP (registered trademark), BOP-Cl (registered trademark), T3P (registered trademark), or DPPCl.

[0182] Aspect A13 The method according to any one of aspects A1 to A11, wherein the activator represents DPPC1, and the method includes the step of obtaining the compound represented by formula IV or a salt thereof without separating compound II or a salt thereof.

[0183] A14 The method according to any one of aspects A1 to A11, wherein the activator represents a chlorinating agent or a brominating agent, and compound II or a salt thereof is separated for use in the next step.

[0184] A15 The method according to any one of aspects A1 to A14 is carried out in a solvent.

[0185] Aspect A16 According to the method of aspect A15, the solvent is an ether or a nitrile.

[0186] A17 According to the method described in aspect A15, the solvent is dimethoxyethane or acetonitrile.

[0187] A18 According to the method described in aspect A15, the solvent is acetonitrile.

[0188] A19 The method according to any one of aspects A1 to A18 is carried out in the presence of an alkali.

[0189] A20 According to the method of aspect A19, the base is selected from one, two or more of the following: triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0190] A21 According to the method described in aspect A19, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0191] A22 The method according to any one of aspects A1 to A21 is carried out in the presence of a catalyst.

[0192] A23 According to the method described in aspect A22, the catalyst is dimethylformamide or N-methylpyrrolidone.

[0193] A24 According to the method described in aspect A22, the catalyst is dimethylformamide.

[0194] A25 The method according to aspect A7 is carried out in a solvent, preferably an aprotic solvent, more preferably dimethoxyethane (“DME”).

[0195] A26 The method according to aspect A7 or A25 is carried out in the presence of a base, such as potassium carbonate or triethylamine, preferably an amine base, more preferably triethylamine.

[0196] A27 According to the method of aspect A26, the reaction comprises stirring preferably at 10-40°C, more preferably at 20-30°C.

[0197] A28 The method according to any one of aspects A25 to A27 further comprises separating compound IV as an acid salt, preferably as compound IV • 2 hydrochloric acid (“HCl”).

[0198] A29 According to the method described in aspect A28, HCl is added to the reaction, preferably dropwise, and the reaction is then heated to preferably 40-70°C, more preferably 50-60°C, while stirring.

[0199] A30 According to the method described in aspect A29, wherein the amino protecting group is tert-butoxycarbonyl, and the addition of HCl first removes the tert-butoxycarbonyl, such that the tert-butoxycarbonyl is removed without the need for a subsequent separation step.

[0200] A31 The method according to any one of aspects A25 to A30 comprises separating compound IV substantially as described in Example 16 (method for producing compound 4).

[0201] A32 According to any one of aspects A25 to A31, the yield of compound IV in the reaction is at least 90%, preferably 90% to 95%, and the chemical purity is greater than 99%, preferably 99.1% to 99.9%.

[0202] Method for producing compound V (triazine compound A) The present invention also provides a method for producing a compound represented by formula V (hereinafter also referred to as "compound V") or a pharmacologically acceptable salt thereof, said method being represented by the following scheme:

[0203] Where X 1 It represents a chlorine atom, a bromine atom, or a leaving group.

[0204] This method is used to produce a compound represented by formula V or a pharmacologically acceptable salt thereof by reacting a compound represented by formula IV' (hereinafter also referred to as "compound IV'") with a salt thereof and a compound represented by formula VI (hereinafter also referred to as "compound VI") or a salt thereof.

[0205] Compound IV' or its salt can be produced, for example, by the method described in any one of aspects A1 to A32 above.

[0206] The reactions described above for producing compounds represented by formula V or their pharmacologically acceptable salts are typically carried out in a solvent, and if necessary, in the presence of a base.

[0207] The solvent can be any solvent that does not affect the reaction, and examples include aromatic hydrocarbons (e.g., benzene, toluene, and xylene), aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), and ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and these solvents can be suitably combined with each other. Preferred examples of these solvents include aprotic solvents, and more preferred examples include dimethyl sulfoxide.

[0208] Examples of bases include organic bases such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and preferred examples of which include N,N-diisopropylethylamine.

[0209] The amount of compound VI or a salt thereof to be used relative to compound IV' or a salt thereof is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents. Alternatively, compound VI may be present in only a slight excess relative to compound IV', i.e., 1 to 1.1 equivalents.

[0210] The amount of base to be used relative to compound IV' or its salt is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents.

[0211] This reaction can be carried out at 50°C to 100°C, and preferably at 50°C to 70°C.

[0212] The present invention also provides a composition comprising 99.9% of compound V or a salt thereof, wherein the composition preferably comprises 0.1%, more preferably less than 0.1% of compound IV' and compound VI, wherein the composition is preferably produced according to the method described above for producing compound V, and more preferably according to any one of the following aspects.

[0213] Various aspects of the methods used to produce compound V The aspects of methods for producing compound V or its salts include the following.

[0214] Aspect B1 A method for producing compound V or a pharmacologically acceptable salt thereof, the method comprising the step of reacting compound IV' or a salt thereof with compound VI or a salt thereof to produce a compound represented by formula V or a pharmacologically acceptable salt thereof.

[0215] Aspect B2 The method according to aspect B1 includes the step of producing compound IV' or a salt thereof by the method of the present invention according to any one of aspects A1 to A32 described above.

[0216] Aspect B3 According to the method described in aspect B1 or B2, where X 1 This represents a chlorine atom.

[0217] Aspect B4 According to the method described in aspect B1 or B2, where X 1 This represents a bromine atom.

[0218] Aspect B5 According to the method described in aspect B1 or B2, where X 1 Indicates a leaving group.

[0219] Aspect B6 According to the method described in aspect B1, B2 or B5, the leaving group represents a methanesulfonate group, a p-toluenesulfonate group or a nitrobenzenesulfonate group.

[0220] Aspect B7 The method according to any one of aspects B1 to B6, wherein the reaction for producing compound V or a pharmacologically acceptable salt thereof is carried out in a solvent in the presence of a base.

[0221] Aspect B8 According to the method described in aspect B7, the solvent is an aprotic solvent.

[0222] Aspect B9 According to the method described in aspect B8, the aprotic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone.

[0223] Aspect B10 According to the method described in aspect B7, the solvent is dimethyl sulfoxide.

[0224] Aspect B11 According to any one of aspects B7 to B10, the base is selected from one, two or more of the following: triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0225] Aspect B12 According to any one of aspects B7 to B10, the base is N,N-diisopropylethylamine.

[0226] Aspect B13 According to the method described in aspect B7, the solvent is tetrahydrofuran, preferably in the presence of water; more preferably a 2:1 solution of water and tetrahydrofuran.

[0227] Aspect B14 According to the method described in aspect B7 or B13, the base is potassium carbonate.

[0228] Aspect B15 According to any one of aspects B13 to B14, the method for producing compound V or its salt is carried out at a temperature of 20°C to 50°C, preferably 30-40°C, for 4-10 hours.

[0229] Aspect B16 The method according to any one of aspects B1 to B15 further comprises separating compound V as a free base, preferably substantially as described in Example 17 (method for producing a free base of compound 5).

[0230] Aspect B17 According to any one of aspects B1 to B16, the yield of compound V in the reaction is at least 80%, preferably 80% to 90%, and the chemical purity is greater than 99%, preferably up to 99.9%.

[0231] Method for generating compound VI The present invention also provides a method for producing compound VI or a salt thereof, represented by the following scheme:

[0232] Where X 1 and X 2 Each can independently represent a chlorine atom, a bromine atom, or a leaving group.

[0233] This method is used to produce compound VI or its salt by reacting a compound represented by formula VII (hereinafter also referred to as "compound VII"), a salt thereof, a base, and a compound represented by formula VIII (hereinafter also referred to as "compound VIII") or its salt in a solvent.

[0234] Compound VII or a salt thereof and compound VIII or a salt thereof are known or can be produced by known methods or methods described herein. For example, compound VII can be produced according to aspects D1 to D6, or alternatively according to aspects E1 to E12.

[0235] The solvent can be any solvent that does not affect the reaction, and examples include aromatic hydrocarbons (e.g., benzene, toluene, and xylene), aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), and ethers (e.g., diethyl ether, tetrahydrofuran, and dimethoxyethane), as well as chlorinated solvents (e.g., dichloromethane), and these solvents can be suitably combined with each other. Preferred examples of these solvents include aprotic solvents, and more preferred examples include N,N-dimethylformamide.

[0236] Examples of bases include: organic bases such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metal carbonates such as sodium carbonate and potassium carbonate, with preferred examples including potassium carbonate.

[0237] The amount of compound VIII or a salt thereof to be used is typically 1 to 5 equivalents relative to compound VII or a salt thereof, and preferably 2 to 3 equivalents. In X 1 and X 2 When each represents a bromine atom, the amount of compound VIII or its salt to be used is typically 1 to 5 equivalents relative to compound VII or its salt, and preferably 1.5 to 2.0 equivalents.

[0238] The amount of base to be used relative to compound VII or its salt is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents.

[0239] This reaction can be carried out at -10°C to 100°C, or 0°C to 100°C, and preferably at -10°C to 0°C or 0°C to 30°C.

[0240] The present invention also provides a composition comprising 98% to 99.5% of compound VI or a salt thereof, wherein the composition preferably comprises 0.5% to 2%, preferably less than 2%, more preferably less than 0.5% of compound VII and compound VIII, wherein the composition is preferably produced according to the method described above for producing compound VII, more preferably according to any one of the following aspects.

[0241] Various aspects of methods for producing compound VI or its salts The aspects of methods for producing compound VI or its salts include the following.

[0242] C1 A method for producing compound VI or a salt thereof, the method comprising the step of producing compound VI or a salt thereof by reacting compound VII or a salt thereof, a base and compound VIII or a salt thereof in a solvent.

[0243] C2 aspect According to the method described in aspect C1, where X 1 and X 2 Each can be represented independently as a chlorine atom or a bromine atom.

[0244] C3 aspect According to the method described in aspect C1, where X 1 and X 2 Each represents a chlorine atom.

[0245] C4 aspect According to the method described in aspect C1, where X 1 and X 2 Each represents a bromine atom.

[0246] C5 According to the method described in aspect C1, where X 1 Indicates a leaving group.

[0247] C6 According to the method described in aspect C1 or C5, where X 2 Indicates a leaving group.

[0248] C7 According to the method described in aspect C1, C5 or C6, the leaving group is a halogen atom, a sulfonate group or an alkoxy group.

[0249] C8 The method according to any one of aspects C1 to C7, wherein the solvent is an aprotic solvent.

[0250] C9 According to the method described in aspect C8, the aprotic solvent is N,N-dimethylformamide.

[0251] C10 The method according to any one of aspects C1 to C7, wherein the solvent is a chlorinated solvent, preferably dichloromethane, more preferably in the form of a 2:1 solution of dichloromethane and water.

[0252] C11 aspect According to any one of aspects C1 to C10, the alkali is an alkali metal carbonate.

[0253] C12 The method according to any one of aspects C1 to C11, wherein the base is potassium carbonate.

[0254] C13 The method according to any one of aspects C1 to C12 further comprises separating compound VI, preferably substantially as described in Example 3 (method for producing compound 6) or Example 15 (method for producing compound 6b).

[0255] C14 According to any one of aspects C1 to C13, the yield of compound VI in the reaction is at least 85%, preferably 85% to 95%, and the chemical purity is greater than 98%, preferably 98% to 99.5%.

[0256] Method for producing compound VII The present invention also provides a method for producing compound VII or a salt thereof by subjecting a compound represented by the following formula IX (hereinafter also referred to as "compound IX") or a salt thereof to a reduction reaction.

[0257]

[0258] This reduction reaction is typically carried out by reacting compound IX or its salt, a metal catalyst, and hydrogen in a polar solvent.

[0259] Compound IX or its salts are known, or can be produced by known methods.

[0260] Examples of polar solvents include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, and preferred examples include propylene glycol methyl ether and 1,3-dimethylimidazolium ketone.

[0261] Examples of metal catalysts include ruthenium-alumina (Ru / Al2O3), ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, and nickel-diatomite, with preferred examples including ruthenium-alumina.

[0262] The amount of metal catalyst to be used relative to compound IX or its salt is typically 0.01 to 0.5 wt equivalents, and preferably 0.05 to 0.1 wt equivalents.

[0263] The amount of hydrogen gas to be used relative to compound IX or its salt is typically 1 to 5 equivalents, and preferably 2 to 3 equivalents, more preferably 3 to 4 equivalents. When the hydrogen gas is in gaseous form, its pressure can be 3 to 5 MPa, preferably about 4 MPa.

[0264] This reaction can be carried out at 50°C to 200°C, and preferably at 100°C to 180°C.

[0265] The present invention also provides a composition comprising at least 60%, preferably 60% to 75% of compound VII or a salt thereof, said composition preferably comprising less than 40%, preferably 25-35% of compound 10, and 1% to 5%, preferably less than 5%, more preferably less than 3% of compound 11, wherein said composition is preferably produced according to the method described above for producing compound VII, more preferably according to any one of the following aspects.

[0266] Various aspects of the methods for producing compound VII or its salts The aspects of the methods for producing compound VII or its salts include the following.

[0267] aspect D1 A method for producing compound VII or a salt thereof, the method comprising subjecting compound IX or a salt thereof to a reduction reaction to produce compound VII or a salt thereof.

[0268] aspect D2 According to the method described in aspect D1, the reduction reaction is carried out by reacting compound IX or its salt, a metal catalyst, and hydrogen in a polar solvent.

[0269] Aspect D3 According to the method described in aspect D2, the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.

[0270] aspect D4 According to the method described in aspect D2, the polar solvent is propylene glycol methyl ether or 1,3-dimethylimidazolium ketone.

[0271] D5 According to any one of aspects D2 to D4, the metal catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, or nickel-diatomite.

[0272] aspect D6 The method according to any one of aspects D2 to D4, wherein the metal catalyst is ruthenium-alumina.

[0273] Alternative methods for producing compound VII The present invention also provides an alternative method for producing compound VII or a salt thereof by subjecting a compound represented by the following formula X (hereinafter also referred to as "compound X") or a salt thereof to a reduction reaction.

[0274]

[0275] This reduction reaction is typically carried out by reacting compound X, a metal catalyst, and hydrogen in a polar solvent.

[0276] Compound X can be produced using known methods.

[0277] Examples of polar solvents include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, with preferred examples including propylene glycol methyl ether and 1,3-dimethylimidazolium ketone. Methanol is the preferred polar solvent in this method.

[0278] Examples of metal catalysts include ruthenium-alumina (Ru / Al2O3), ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, nickel-diatomite, nickel-alumina, and Raney nickel. Preferred examples include nickel-alumina and Raney nickel.

[0279] The amount of metal catalyst to be used relative to compound X is typically 0.01 to 0.5 equivalents, and preferably 0.2 to 0.4 equivalents.

[0280] The hydrogen used is typically in gaseous form at a pressure of 0.25-0.75 MPa, preferably 0.35-0.50 MPa.

[0281] This reaction can be carried out at 35°C to 200°C, preferably at 40°C to 70°C, and more preferably at 40°C to 50°C.

[0282] The present invention also provides a composition comprising more than 94%, preferably 95-97%, of compound VII or a salt thereof, wherein the composition preferably comprises less than 5%, preferably 1-3%, of a cis isomer of compound VII, wherein the composition is preferably produced according to the method described above for producing compound VII, and more preferably according to any one of the following aspects.

[0283] Various aspects of alternative methods for producing compound VII The alternative methods for producing compound VII include the following aspects.

[0284] E1 A method for producing compound VII or a salt thereof, the method comprising subjecting compound X to a reduction reaction to produce compound VII or a salt thereof.

[0285] E2 aspect According to the method described in aspect E1, the reduction reaction is carried out by reacting compound X, a metal catalyst, and hydrogen in a polar solvent.

[0286] E3 According to the method described in aspect E2, the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.

[0287] E4 According to the method described in aspect E2, the polar solvent is methanol, tetrahydrofuran, or a mixture of methanol and tetrahydrofuran.

[0288] E5 The method according to any one of aspects E2 to E4, wherein the metal catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, nickel-diatomite, nickel-alumina, or Raney nickel.

[0289] E6 The method according to any one of aspects E2 to E4, wherein the metal catalyst is nickel-alumina, preferably Raney nickel.

[0290] E7 According to any one of aspects E2 to E6, the metal catalyst is washed with a polar aprotic solvent, preferably tetrahydrofuran (THF), before being combined with compound X or its salt in a solution containing a polar solvent. The polar solvent is preferably methanol.

[0291] E8 According to any one of aspects E2 to E7, the reduction reaction comprises, in the presence of hydrogen, preferably at 40-50°C under 0.35-0.50 MPa hydrogen, stirring the compound X or its salt and the metal catalyst in the polar solvent, preferably for 2-6 hours.

[0292] E9 According to any one of aspects E2 to E8, the solid containing compound VII is formed by the reduction reaction.

[0293] E10 According to the method described in aspect E9, the peak area ratio of compound X and compound VII produced by the solid is less than or equal to 1%, as measured by high-performance liquid chromatography (“HPLC”).

[0294] E11 According to the method of aspect E10, it further comprises separating the solid containing compound VII preferably by a concentration, filtration and washing step, preferably wherein the filtration is carried out with diatomaceous earth, preferably wherein the washing is carried out with a polar aprotic solvent, more preferably THF, and still more preferably wherein the separation comprises a final concentration step, followed by washing with an organic solvent, preferably ethyl acetate, followed by drying, and still more preferably wherein the separation is substantially as described in Example 7 (method for producing compound 7) or Example 8 (scale-up method for producing compound 7).

[0295] E12 According to the method described in aspects E1 to E11, the method produces compound VII with a purity greater than 94%, more preferably 95-97%, preferably less than 5% cis isomers of compound VII, more preferably 1-3% cis isomers of compound VII.

[0296] Method for producing compound XII The present invention also provides a method for producing compound XII or a salt thereof, represented by the following scheme:

[0297] R1 represents an amino protecting group, preferably benzyloxycarbonyl.

[0298] This method is used to produce compound XII or its salt by reacting compound VII or its salt, a base, and a compound represented by formula XI (hereinafter also referred to as "compound XI") or its salt in a solvent in the presence of a condensing agent.

[0299] Compound XI or its salts are known, or can be produced by known methods.

[0300] The solvent can be any solvent that does not affect the reaction, and examples include polar organic solvents (e.g., ethanol and methanol), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and dichloromethane), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), and ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and these solvents can be suitably combined with each other. Preferred examples of these solvents include aprotic solvents, and more preferred examples include dichloromethane.

[0301] Examples of bases include: organic bases such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metal carbonates such as sodium carbonate and potassium carbonate, with preferred examples including potassium carbonate.

[0302] Examples of bases include nonnucleophilic bases, and preferred examples include diisopropylethylamine.

[0303] Condensing agents can be any condensing agent capable of forming amide or peptide bonds. Condensing agents capable of forming amide or peptide bonds are described in the following literature: El-Faham, A. and Albericio, F. (2011). Peptide coupling reagents, more than a letter soup. Chemical Review (…). Chemical Reviews )》, 111 (11), 6557-6602, the contents of which are specifically incorporated herein by reference for their description of condensing agents capable of forming amide or peptide bonds. Preferred examples of such condensing agents include propylphosphonic anhydride (“T3P”) and butylphosphonic anhydride (“T4P”). Such condensing agents are preferably soluble in a polar solvent, preferably ethyl acetate. The amount of condensing agent to be used can be from 1 to 2 equivalents, preferably 1.3 to 1.7 equivalents.

[0304] The amount of compound VII or its salt to be used is typically 1.0 to 1.1 equivalents relative to compound XI or its salt.

[0305] The amount of base to be used relative to compound XI or its salt is typically 1 to 10 equivalents, and preferably 4 to 5 equivalents.

[0306] This reaction can be carried out at 0°C to 100°C, preferably at 0°C to 30°C, and more preferably at 0°C to 10°C.

[0307] The present invention also provides a composition comprising at least 99%, preferably 99.1% to 99.9% of compound XII or a salt thereof, wherein the isomer purity of the composition is preferably at least 99.5%, preferably 99.5% to 99.9%, and preferably wherein the composition is produced according to the method described above for producing compound XII, more preferably according to any one of the following aspects.

[0308] Various aspects of the methods for producing compound XII The aspects of the methods for producing compound XII include the following.

[0309] F1 A method for producing compound XII or a salt thereof, the method comprising the step of producing compound XII or a salt thereof by reacting compound VII or a salt thereof, a base, and compound XI or a salt thereof in a solvent in the presence of a condensing agent.

[0310] F2 According to the method described in aspect F1, the solvent is an aprotic solvent.

[0311] F3 According to the method described in aspect F2, the aprotic solvent is dichloromethane.

[0312] F4 The method according to any one of aspects F1 to F3, wherein the base is non-nucleophilic.

[0313] F5 According to the method described in aspect F4, the nonnucleophilic base is diisopropylethylamine.

[0314] F6 According to any one of aspects F1 to F5, the condensing agent capable of forming amide or peptide bonds is preferably selected from the condensing agents described in the following literature: El-Faham, A. and Albericio, F. (2011). Peptide Coupling Agents, Not Just Letter Soup. Chemical Reviews, 111 (11), 6557-6602, the contents of which are specifically incorporated herein by reference for their description of condensing agents capable of forming amide or peptide bonds.

[0315] F7 According to the method of aspect F6, the condensing agent is propylphosphonic anhydride or butylphosphonic anhydride, preferably butylphosphonic anhydride, preferably wherein the propylphosphonic anhydride or butylphosphonic anhydride is present in an amount of 1 to 2 equivalents, preferably 1.3 to 1.7 equivalents.

[0316] F8 According to any one of aspects F6 to F7, the condensing agent is preferably added to the solution of the solvent, the base, compound VII and compound XI within one hour or longer.

[0317] F9 According to the method described in aspect F8, the solution is cooled, preferably to 0-10°C, before the condensing agent is added.

[0318] F10 The method according to any one of aspects F1 to F9 further comprises separating compound XII.

[0319] F11 According to the method of aspect F10, the separation of compound XII includes concentration, filtration and washing steps, preferably substantially as described in Example 9 (method for producing compound 15) or Example 10 (scale-up method for producing compound 15).

[0320] F12 According to the method described in aspects F1 to F11, the yield of compound XII in the reaction is at least 90%, preferably 91% to 96%, the chemical purity is greater than 99%, preferably 99.1% to 99.9%, and / or the isomer purity is at least 99.5%, preferably 99.5% to 99.9%.

[0321] Method for producing compound XIII The present invention also provides a method for producing compound XIII or a salt thereof by subjecting a compound represented by the following formula XII (hereinafter also referred to as "compound XII") or a salt thereof to a reaction involving the removal of R1:

[0322] Wherein R1 represents a protecting group, preferably an amino protecting group, more preferably a benzyloxycarbonyl group;

[0323] Compound XIII.

[0324] When R1 represents a protecting group (such as benzyloxycarbonyl) that can be removed by a reduction reaction, the method comprises subjecting compound XII to a reduction reaction.

[0325] This reduction reaction is typically carried out by reacting compound XII or its salt, a metal catalyst, and hydrogen in a polar solvent.

[0326] Examples of polar solvents include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, with methanol being a preferred example.

[0327] Examples of metal catalysts include ruthenium-alumina (Ru / Al2O3), ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, and nickel-diatomite, with palladium-carbon being a preferred example.

[0328] The amount of metal catalyst to be used relative to compound XII or its salt is typically 0.01 to 0.5 equivalents, and preferably 0.05 to 0.1 equivalents. When the catalyst is palladium-carbon, it can be wetted with water at 50% concentration; in this case, the preferred amount relative to compound XII is 0.02 to 0.04 wt equivalents. In the case of a dry palladium-carbon catalyst, the preferred amount can be readily determined based on the preferred amount of a 50% wet palladium-carbon catalyst.

[0329] This reaction can be carried out at 10-50°C, and preferably at 20°C to 35°C.

[0330] This reaction can be carried out under hydrogen gas at 0.1-0.5 MPa, preferably 0.25-0.4 MPa.

[0331] The present invention also provides a composition comprising at least 99%, preferably 99.1% to 99.9% of compound XIII or a salt thereof, wherein the composition preferably comprises less than 0.9% of compound XII, preferably 0.1% to 0.9% of compound XIII, wherein the composition is preferably produced according to the method described above for producing compound XIII, and more preferably according to any one of the following aspects.

[0332] Various aspects of the methods used to produce compound XIII The aspects of the methods used to produce compound XIII include the following.

[0333] G1 A method for producing compound XIII or a salt thereof, the method comprising subjecting compound XII or a salt thereof to a reaction to remove a protecting group in order to produce compound XIII or a salt thereof.

[0334] G2 According to the method of aspect G1, the protecting group is a protecting group that can be removed by a reduction reaction, preferably an amino protecting group, more preferably a benzyloxycarbonyl group, and the reaction for removing the protecting group is a reduction reaction.

[0335] G3 The method according to aspect G1 or G2 includes the step of producing compound XII or a salt thereof by means of the above-described method for producing compound XII, preferably according to any one of aspects F1 to F12.

[0336] G4 According to the method described in aspect G2 or G3, the reduction reaction is carried out by reacting compound XII or its salt, a metal catalyst, and hydrogen in a polar solvent.

[0337] G5 According to the method described in aspect G4, the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide, preferably methanol.

[0338] G6 According to any one of aspects G4 to G5, the catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, or nickel-diatomite, preferably palladium-carbon.

[0339] G7 According to any one of aspects G4 to G6, the reduction reaction comprises, in the presence of hydrogen, preferably at 20-35°C and 0.27-0.35 MPa hydrogen, stirring the compound XII and the metal catalyst in the polar solvent for 3-7 hours.

[0340] G8 The method according to any one of aspects G4 to G7 further comprises generating a suspension of compound XIII.

[0341] G9 According to the method of aspect G8, the suspension of said compound XIII is generated by: concentrating said compound XIII in a solvent to form concentrated compound XIII; cooling said concentrated compound XIII, preferably to -15°C to 10°C; and adding an organic solvent, preferably methyl tert-butyl ether (“MTBE”).

[0342] G10 The method according to any one of aspects G7 to G9 further comprises stirring the suspension of compound XIII at a cooling temperature, preferably at -15°C to 10°C, for at least 10 hours, preferably for 15-25 hours.

[0343] G11 The method according to any one of aspects G8 to G10 further comprises filtering a suspension of the compound XIII to produce a filter cake, preferably further comprising washing the filter cake with a solvent, preferably with MTBE.

[0344] G12 According to any one of aspects G1 to G11, compound XIII is isolated substantially as described in Example 11 (method for producing compound 16) or Example 12 (scale-up method for producing compound 16).

[0345] G13 According to any one of aspects G1 to G12, the yield of compound XIII in the reaction is at least 90%, preferably 90% to 95%, and the chemical purity is greater than 99%, preferably 99.1% to 99.9%.

[0346] Method for producing compound V (triazine compound A) The present invention also provides an alternative method for producing a compound represented by formula V (hereinafter also referred to as "compound V") or a pharmacologically acceptable salt thereof, said alternative method being represented by the following scheme:

[0347] Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group, preferably chlorine.

[0348] This method is used to produce a compound represented by formula V or a pharmacologically acceptable salt thereof by reacting a compound represented by formula II (also known as "compound II") or a salt thereof with a compound represented by formula XIII (also known as "compound XIII") or a salt thereof.

[0349] Compound II or a salt thereof is known, or can be produced by known methods. Compound II can be produced, for example, according to step 1 of the above-described "method of production of the present invention," i.e., by producing compound II or a salt thereof from compound I or a salt thereof. Therefore, compound II can be produced, for example, according to any of the above aspects A1 to A32, provided that these aspects are applicable to the production of compound II or a salt thereof from compound I or a salt thereof.

[0350] Compound XIII can be produced, for example, by the method for producing compound XIII as described herein, specifically according to any one of aspects G1 to G12 above.

[0351] The reactions described above for producing compounds represented by formula V or their pharmacologically acceptable salts are typically carried out in a solvent, and if necessary, in the presence of a base.

[0352] The solvent can be any solvent that does not affect the reaction, and examples include polar organic solvents (e.g., ethanol and methanol), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and dichloromethane), nitriles (e.g., acetonitrile), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate), and ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and these can be suitably combined with each other. Preferred examples of these solvents include aprotic solvents, preferably polar aprotic solvents. A preferred example of a solvent for this reaction is dichloromethane.

[0353] Examples of bases include: inorganic bases, such as alkali metal carbonates, including sodium carbonate and potassium carbonate; organic bases, such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and wherein preferred examples include triethylamine.

[0354] The amount of compound II or its salt to be used is typically 1 to 2 equivalents relative to compound XIII or its salt, and preferably 1.0 to 1.5 equivalents, more preferably 1.2 to 1.22 equivalents.

[0355] The amount of base to be used relative to compound XIII or its salt is typically 1 to 5 equivalents, and preferably 1.4 to 1.6 equivalents.

[0356] This reaction can be carried out at temperatures ranging from 20°C to 100°C, and preferably at temperatures ranging from 25°C to 40°C.

[0357] The present invention also provides a composition comprising 99.9% of compound V or a salt thereof, wherein the composition preferably comprises 0.1%, more preferably less than 0.1% of compound II and compound XIII, wherein the composition is preferably produced according to the method described above for producing compound V, and more preferably according to any one of the following aspects.

[0358] Various aspects of the methods used to produce compound V The aspects of methods for producing compound V or its salts include the following.

[0359] H1 A method for producing compound V or a pharmacologically acceptable salt thereof, the method comprising the step of reacting compound II or a salt thereof with compound XIII or a salt thereof to produce a compound represented by formula V or a pharmacologically acceptable salt thereof.

[0360] H2 aspect The method according to aspect H1 includes the step of producing compound XIII or a salt thereof by means of the above-described method for producing compound XIII, preferably according to any one of aspects G1 to G13.

[0361] H3 aspect According to the method of aspect H2, the generation of compound XIII or a salt thereof comprises the step of generating compound XII or a salt thereof by means of the above-described method for generating compound XII, preferably according to any one of aspects F1 to F12.

[0362] Aspect H4 The method according to any one of aspects H1 to H3 includes step 1 of the above-described "method of production of the present invention", preferably the step of producing compound II or a salt thereof according to any one of aspects A1 to A32, provided that these aspects are applicable to the production of compound II or a salt thereof from compound I or a salt thereof.

[0363] H5 aspect The method according to any one of aspects H1 to H4, wherein X represents a chlorine atom.

[0364] H6 The method according to any one of aspects H1 to H5, wherein X represents a bromine atom.

[0365] H7 The method according to any one of aspects H1 to H6, wherein the reaction for producing compound V or a pharmacologically acceptable salt thereof is carried out in a solvent in the presence of a base.

[0366] H8 According to the method described in aspect H7, the solvent comprises one or more aprotic solvents, preferably dichloromethane and / or N 2-Methyl-2-pyrrolidone (NMP).

[0367] H9 According to the method described in aspect H7 or H8, the solvent comprises one or more polar protic solvents, preferably methanol.

[0368] H10 According to any one of aspects H7 to H9, the solvent comprises a mixture of two or more solvents, preferably a mixture of one or more aprotic solvents and one or more polar protic solvents, more preferably methanol, NA mixture of 2-methyl-2-pyrrolidone (NMP) and dichloromethane.

[0369] H11 According to any one of aspects H7 to H10, the base is selected from one, two or more of the following: triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and potassium carbonate.

[0370] H12 According to any one of aspects H7 to H11, the base is preferably triethylamine and / or potassium carbonate.

[0371] H13 The method according to any one of aspects H1 to H12 comprises separating the salt of compound V by filtration, thereby producing a filter cake containing the salt of said compound V.

[0372] H14 According to the method in aspect H13, the filtration comprises concentrating a salt of the compound V in a solvent to form a concentrated salt of compound V, cooling the concentrated salt of compound V, preferably to -15°C to -5°C, and then filtering to thereby produce the filter cake.

[0373] H15 According to the method described in aspect H14, the filter cake is washed with an organic solvent, preferably methanol.

[0374] H16 The method according to any one of aspects H1 to H15 further comprises separating the free base of compound V.

[0375] H17 According to the method described in aspect H16, separating the free base of compound V comprises dissolving a salt of compound V in an extraction solution, increasing the pH of the extraction solution, and filtering the extraction solution, thereby producing a filter cake containing the free base of compound V.

[0376] H18 According to the method described in method H17, where: (a) The extraction solution contains an organic solvent, preferably a 50:50 mixture of methanol and dichloromethane; (b) The pH of the extraction solution is raised to pH 11-13 by adding an alkaline solution, preferably 3% potassium carbonate; (c) After the pH of the extraction solution is raised, the extraction solution is stirred at 20-50°C, preferably 30-35°C, for 1-5 hours, preferably wherein any alkaline solution is removed before stirring the extraction solution; (d) After the pH of the extraction solution increases, add additional water, stir, and remove; and (e) After the pH of the extraction solution is raised, an additional solvent, preferably an organic solvent, and more preferably N-methyl-2-pyrrolidone, is added dropwise.

[0377] H19 The method according to any one of aspects H1 to H18 comprises the separation of compound V as substantially as described in Example 13 (method for producing free base of compound 5) or Example 14 (scale-up method for producing compound 5).

[0378] H2O According to any one of aspects H1 to H19, the yield of compound V in the reaction is at least 85%, preferably 85% to 90%, and the chemical purity is greater than 99%, preferably up to 99.9% or greater.

[0379] Method for producing compound V or its salt Similarly, when using the separation of compound II or its salt to produce compound V or its salt, the production method preferably includes the step of subjecting compound IX or its salt to a reduction reaction to produce compound VII or its salt. Alternatively, the production method includes the step of subjecting compound X to a reduction reaction to produce compound VII or its salt. Examples of such production methods include the following.

[0380] A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0381] Formula V The method includes the following steps: Step 1 Reacting a compound represented by Formula I or a salt thereof with an activator to produce a compound represented by Formula II or a salt thereof:

[0382] Formula I

[0383] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group.

[0384] In one aspect of step 1, a compound represented by formula II or a salt thereof is produced without subsequent separation. Alternatively, in another aspect of step 1, a compound represented by formula II or a salt thereof is produced, and then separation is performed.

[0385] Step 2 React the compound represented by Formula II or a salt thereof with the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof:

[0386] Formula III Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:

[0387] Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule.

[0388] Formula IV Where R 1 This indicates that it is the same as described above.

[0389] Step 3 (Option 1) To subject a compound or salt thereof represented by formula IX to a reduction reaction to produce a compound or salt thereof represented by formula VII:

[0390] Formula IX

[0391] Formula VII.

[0392] Step 3 (Option 2) An alternative step for producing a compound represented by formula VII involves subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof:

[0393] Formula X

[0394] Formula VII.

[0395] The above method further includes the following steps: Step 4 The compound represented by formula VII or a salt thereof, a base, and a compound represented by formula VIII or a salt thereof are reacted in a solvent to produce a compound represented by formula VI or a salt thereof:

[0396] Formula VIII Where X 1 and X 2 Each can independently represent a chlorine atom, a bromine atom, or a leaving group;

[0397] Style VI Where X 1 This indicates that it is the same as described above.

[0398] Step 5 The compound represented by formula IV or a salt thereof produced in step 2 is reacted with the compound represented by formula VI or a salt thereof produced in step 4 to produce the compound represented by formula V or a pharmacologically acceptable salt thereof.

[0399] aspect Steps 1 and 2 can be performed according to the above-described method for producing compound II or a salt thereof by generating compound II or a salt thereof from compound I or a salt thereof, and then reacting compound II or a salt thereof with compound III or a salt thereof to produce compound IV or a salt thereof, and can be performed, for example, according to any one of the above-described aspects A1 to A32.

[0400] Step 3 can be carried out according to the method described above for producing compound VII or its salt by subjecting compound IX or its salt to a reduction reaction, and can be carried out, for example, according to any one of the above aspects D1 to D6.

[0401] Alternatively, step 3 can be carried out according to the method described above for producing compound VII or its salt by subjecting compound X to a reduction reaction, and can be carried out according to, for example, the production method according to any one of aspects E1 to E12 above.

[0402] Step 4 can be carried out according to the method described above for producing compound VI or its salt by reacting compound VII or its salt with compound VIII or its salt, and can be carried out, for example, according to any one of the production methods described in aspects C1 to C14 above.

[0403] Step 5 can be performed according to the above-described method for generating compound V or a pharmacologically acceptable salt thereof by reacting compound IV' or a salt thereof with compound VI or a salt thereof, and can be performed, for example, according to any one of aspects B1 to B17 above.

[0404] Alternative methods for producing compound V or its salts The present invention also provides alternative methods for producing compound V or its salts. Examples of such alternative production methods include the following.

[0405] A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof:

[0406] Formula V The method includes the following steps: Step 1 Reacting a compound represented by Formula I or a salt thereof with an activator to produce a compound represented by Formula II or a salt thereof:

[0407] Formula I

[0408] Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group.

[0409] In one aspect of step 1, a compound represented by formula II or a salt thereof is produced without subsequent separation. Alternatively, in another aspect of step 1, a compound represented by formula II or a salt thereof is produced, and then separation is performed.

[0410] Step 2 (Option 1) To subject a compound or salt thereof represented by formula IX to a reduction reaction to produce a compound or salt thereof represented by formula VII:

[0411] Formula IX

[0412] Formula VII.

[0413] Step 2 (Option 2) An alternative step for producing a compound represented by formula VII involves subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof:

[0414] Formula X

[0415] Formula VII.

[0416] Step 3 The compound represented by formula XI is reacted with the compound represented by formula VII to produce the compound represented by formula XII:

[0417] Formula XI R1 represents an amino protecting group, preferably benzyloxycarbonyl.

[0418]

[0419] Formula XII R1 is the same as that in equation XI above.

[0420] Step 4 To reduce a compound represented by formula XII or a salt thereof to produce a compound represented by formula XIII:

[0421] Formula XIII.

[0422] Step 5 The compound represented by formula II or a salt thereof produced in step 2 is reacted with the compound represented by formula XIII or a salt thereof produced in step 4 to produce the compound represented by formula V or a pharmacologically acceptable salt thereof.

[0423] aspect Step 1 can be performed according to step 1 of the above-described "Method of Production of the Invention," that is, by producing compound II or a salt thereof from compound I or a salt thereof. Therefore, step 1 can be performed, for example, according to aspects A1 to A32, as long as these aspects are applicable to producing compound II or a salt thereof from compound I or a salt thereof.

[0424] Step 2 can be carried out according to the method described above for producing compound VII or its salt by subjecting compound IX or its salt to a reduction reaction, and can be carried out, for example, according to any one of the above aspects D1 to D6.

[0425] Alternatively, step 2 can be carried out according to the method described above for producing compound VII or its salt by subjecting compound X to a reduction reaction, and can be carried out according to, for example, the production method according to any one of aspects E1 to E12 above.

[0426] Step 3 can be carried out according to the method described above for producing compound XII or its salt by reacting compound XI with compound VII, and can be carried out, for example, according to any one of the production methods described in aspects F1 to F12 above.

[0427] Step 4 can be carried out according to the method described above for producing compound XIII or its salt by subjecting compound XII or its salt to a reduction reaction, and can be carried out, for example, according to any one of aspects G1 to G13 above.

[0428] Step 5 can be carried out according to the method described above for producing compound V or its salt by reacting compound XIII and compound II, and can be carried out according to, for example, the production method according to any one of aspects H1 to H20 above.

[0429] Crystallization method of monohydrobromide of compound V This invention provides a method for crystallizing the monohydrobromide of compound V, the method comprising: (a) A solution is produced by: (1) the free base of compound V; (2) a solvent, such as ethanol or methanol; (3) water; and (4) hydrobromic acid; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of compound V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of compound V; and (c) Collect the obtained crystals.

[0430] On one hand, the present invention provides a method for crystallizing the monohydrobromide of compound V, the method comprising: (a) Mix the free base of compound V with ethanol, water and hydrobromic acid; (b) Add the resulting solution to acetone, preferably dropwise; (c) Wash the resulting mixture with a mixture of ethanol and water; (d) Cool and stir the resulting mixture; (e) Collect the obtained crystals; and (f) Optionally wash the collected crystals with acetone; (g) Optionally, dry the washed crystals.

[0431] The above method may include one or more, or all, of the following features: (i) In step (a), the weight ratio of compound V: ethanol: water: hydrobromic acid is approximately 15:14.22:11.91:2.69; (ii) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; (iii) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, over 1 hour; (iv) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; (v) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; (vi) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2 to 24 hours, preferably about 18 hours; (vii) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and (viii) The yield of the method is at least 90%, preferably at least 93%, more preferably 93% to 97%.

[0432] On the other hand, the present invention also provides a method for crystallizing the monohydrobromide of compound V, the method comprising: (a) The free base of compound V is suspended in a solution of methanol and water to form a suspension of compound V; (b) Add an aqueous HBr solution to a suspension of compound V to obtain a first mixture; (c) Heating the first mixture to obtain a first solution; (d) Filter the first solution; (e) Acetone and seed crystals are added to the first solution to obtain a second mixture; (f) Add additional acetone to the second mixture to obtain a third mixture; (g) Maintain and cool the third mixture; (h) Filter the third mixture to obtain a filter cake; (i) Wash the filter cake to obtain crystals of monohydrobromide of compound V.

[0433] The above method may include one or more, or all, of the following features: (i) Step a) comprises suspending the free base of compound V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, of about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water; (ii) Step b) comprises adding about 1.00 to 1.025 molar equivalents, preferably about 1.01 molar equivalents, of an aqueous HBr solution to a suspension of the compound V to obtain the first mixture; (iii) Step c) comprises heating the first mixture to about 45°C to 60°C, preferably about 50°C, to obtain the first solution; (iv) Step d) includes filtering the first solution through a fine filter; (v) Step e) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; (vi) Step f) comprises loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, to obtain the third mixture; (vii) Step g) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, followed by cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; (viii) Step h) comprises filtering the third mixture to form a filter cake; (ix) Step i) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and (x) The yield of the method is approximately 85%.

[0434] In the above method, the particle size can be controlled by adding seed crystals to a supersaturated liquid and then performing slow addition, aging and cooling steps, thereby allowing preferential particle growth rather than nucleation.

[0435] This invention provides a method for recrystallizing the monohydrobromide of compound V, the method comprising: (a) Dissolving crystals of the monohydrobromide salt of compound V in (1) a solvent, such as ethanol or methanol and (2) water; and (b) Either of the following two: (i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of compound V; or (ii) Adding acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of compound V; and (c) Collect the obtained crystals.

[0436] On one hand, the present invention provides a method for recrystallizing the monohydrobromide of compound V, the method comprising: (a) Mixing crystals of the monohydrobromide salt of compound V with ethanol and water; (b) Add the resulting solution to acetone, preferably dropwise; (c) Wash the resulting mixture with a mixture of ethanol and water; (d) Cool and stir the resulting mixture; (e) Collect the obtained crystals; and (f) Optionally wash the collected crystals with acetone; (g) Optionally, dry the washed crystals.

[0437] The above method may include one or more, or all, of the following features: (i) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; (ii) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, over 1 hour; (iii) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; (iv) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; (v) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2-24 hours, preferably about 18 hours; (vi) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and (vii) The yield of the method is at least 90%, preferably at least 93%, and more preferably 93% to 97%.

[0438] On the other hand, the present invention also provides a method for recrystallizing the monohydrobromide of compound V, the method comprising: (a) Dissolve crystals of the monohydrobromide salt of compound V in a solution of methanol and water to obtain a first solution; (b) Filter the first solution; (c) Acetone and seed crystals are added to the first solution to obtain a second mixture; (d) Add additional acetone to the second mixture to obtain a third mixture; (e) Maintain and cool the third mixture; (f) Filter the third mixture to obtain a filter cake; (g) Wash the filter cake to obtain crystals of monohydrobromide of compound V.

[0439] The above method may include one or more, or all, of the following features: (i) Step a) comprises suspending crystals of monohydrobromide of compound V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, of about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water; (ii) Step a) involves heating to about 45°C to 60°C, preferably about 50°C; (iii) Step b) includes filtering the first solution through a fine filter; (iv) Step c) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; (v) Step d) includes loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, to obtain the third mixture; (vi) Step e) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, followed by cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; (vii) Step f) comprises filtering the third mixture to form a filter cake; (viii) Step g) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and (ix) The yield of the method described is approximately 85%.

[0440] In the above method, the particle size can be controlled by adding seed crystals to a supersaturated liquid and then performing slow addition, aging and cooling steps, thereby allowing preferential particle growth rather than nucleation.

[0441] The present invention also provides a composition comprising crystals of monohydrobromide of compound V produced according to any of the methods described above.

[0442] Overview With respect to the foregoing embodiments, each embodiment disclosed herein is intended to be applicable to each of the other disclosed embodiments. Furthermore, each aspect described herein, including each combination of aspects contemplated through one or more cross-references to other aspects, is considered an embodiment of the invention.

[0443] If necessary, the compounds produced in each step of the invention can be produced as salts. The salt can be any type of salt, as long as it is generally industrially usable, and examples include: inorganic acid salts, such as hydrochlorides, sulfates, phosphates, and hydrobroms; organic acid salts, such as acetates, fumarates, oxalates, citrates, methanesulfonates, benzenesulfonates, toluenesulfonates, succinates, and maleates; and alkali metal salts, such as sodium and potassium salts. Conversion to such salts can be carried out using conventional methods.

[0444] In this specific embodiment, examples of "pharmacologically acceptable salts" include: inorganic acid salts, such as hydrochlorides, sulfates, phosphates, and hydrobroms; and organic acid salts, such as acetates, fumarates, oxalates, citrates, methanesulfonates, benzenesulfonates, toluenesulfonates, succinates, and maleates. Preferred examples include sulfates, hydrobroms, succinates, benzenesulfonates, and toluenesulfonates; more preferred examples include benzenesulfonates and hydrobroms; and particularly preferred examples include hydrobroms.

[0445] As used herein, all headings are for organization purposes only and are not intended to limit this disclosure in any way. The content of any single section may equally apply to all sections. All combinations of the various elements disclosed herein are within the scope of this invention.

[0446] Further objects, advantages, and novel features of the invention will become apparent to those skilled in the art after studying the following examples, which are intended to be non-limiting. Additionally, each of the various embodiments and aspects of the invention as described above and claimed in the following claims section finds experimental support in the following examples.

[0447] It should be understood that, for clarity, certain features of the invention described in the context of a single embodiment may also be provided in combination in a single embodiment. Conversely, for simplicity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination or, where appropriate, in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments are invalid without those elements.

[0448] Examples are provided below to facilitate a more comprehensive understanding of the invention. The following examples illustrate exemplary modes of preparing and practicing the invention. However, the scope of the invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only.

[0449] Example The present invention will be described in detail below through examples, but the present invention is not limited to these examples. In this specific embodiment, "equivalent" means "molar equivalent".

[0450] Methods in Examples 1-6 The results of HPLC / LRMS (High Performance Liquid Chromatography / Low Resolution Mass Spectrometry) and GC (Chromatography) described in Examples 1-6 were measured under the following conditions.

[0451] HPLC / LRMS Device: Manufactured by Waters Operating conditions: (a) Column: X Bridge C18, 5 μm 3.0 mm x 50 mm (b) Solvents: A: Water (0.05% trifluoroacetic acid), B: Acetonitrile (0.05% trifluoroacetic acid) (c) Gradient: B: 10% (1 minute) → 30% (1.5 minutes) → 70% (4.5 minutes) → 90% (5.0 minutes) → 90% (6.0 minutes) → 10% (6.2 minutes) → 10% (7 minutes) (d) Flow rate: 1.27 mL / min (e) Wavelength range: 210 nm to 400 nm (f) Measurement range: 0 minutes to 7 minutes GC Device: Manufactured by Agilent Technologies Operating conditions: (a) Column: CP-Sil 8 CB for amines, length: 30.0 m, inner diameter: 0.25 mm, membrane thickness: 0.50 μm (b) Detector temperature: 300℃ (c) Heating program: 50℃ (0 minutes) → rate: 10℃ / min → 250℃ (0 minutes) → rate: 20℃ / min → 300℃ (15 minutes) Example 1 (Method 1 for producing compound 4)

[0452] Compound 3 (13.80 g) was suspended in acetonitrile (35 mL), and the resulting mixture was heated to 70 °C to obtain a solution. Compound 1 (10.03 g) and DBU (8.96 g) were suspended in acetonitrile (40 mL), and DPPCl (15.79 g) was added dropwise over approximately 30 minutes at -1 °C to 0 °C. The resulting suspension was then added dropwise to the solution over approximately 30 minutes. The container was washed with acetonitrile (5 mL), and the washings were added dropwise to the reaction solution. After 1 hour, the temperature was raised to 20 °C to 25 °C, and concentrated hydrochloric acid (25.63 g) was then added dropwise over approximately 30 minutes. After stirring for approximately 1 hour, the resulting crystals were collected by filtration and washed with acetonitrile (60 mL). The resulting crystals were suspended in water (40 mL), and an 8 N sodium hydroxide aqueous solution (40 mL) was added dropwise over 10 minutes at approximately 45 °C. After stirring for about 30 minutes, the reaction mixture was stirred at 5°C for 16 hours. The resulting crystals were collected by filtration and washed with water (100 mL). The crystals were dried at 50°C to give compound 4 (8.05 g) (yield: 59%).

[0453] Compound 4: 1 H NMR (DMSO-d6) 9.24 (s, 1H), 8.14 (d, 2H), 7.38 (d, 2H), 3.82 (t, 4H), 2.81 (t, 4H), 2.40 (s, 3H), C 14 H 17 The calculated MS value for N5 is 255.1, m / z 256 [M+H]. + .

[0454] Example 2 (Method 2 for producing compound 4)

[0455] (1) Step 1 (Generation of compound 2 from compound 1) Compound 1 (50.00 g), 1,2-dimethoxyethane (281.81 g), and dimethylformamide (1.95 g) were mixed under an inert atmosphere, and the resulting mixture was stirred at 83 °C. Thionyl chloride (63.99 g) was added dropwise to the mixture at 80 °C to 83 °C, and the mixture was stirred for 3 hours. Then, water (250.00 g) was added dropwise to the mixture at 8 °C to 10 °C, and the mixture was stirred for 16 hours. The resulting crystals were filtered and washed with water (750.01 g). The crystals were stirred in ethanol (118.50 g) at 20 °C to 22 °C for 2 hours. The crystals were filtered and washed with ethanol (118.50 g). The crystals were dried under reduced pressure at an external temperature of 30 °C to give compound 2 (42.50 g, yield: 77%).

[0456] Compound 2: 1 H NMR (DMSO-d6, 500 MHz): δ2.43 (s, 3H), 7.46 (d, J = 7.9Hz, 2H), 8.25 (d, J = 8.3 Hz, 2H), 10.12 (s, 1H).

[0457] C 10 The calculated MS value for H8ClN3 is 205.0, and the experimental value is 206 m / z [M+H]. + .

[0458] (2) Step 2 (compound 4 is generated from compound 2) At 55°C, a solution of compound 2 (20.0 g) in N-methylpyrrolidone (103 g) was added dropwise to a solution of compound 3 (42.0 g) in methanol (79.2 g) and stirred for 1.5 hours. After stirring at 55°C for 3 hours, water (200 mL) was added, and the resulting mixture was stirred at 55°C for 20 hours. The resulting insoluble substances were removed by filtration, and the resulting residue was washed with water (100 mL). Water (300 mL) was added to the resulting filtrate, and the resulting mixture was stirred at 20°C for 16 hours. The resulting crystals were collected by filtration and washed with water (200 mL). The crystals were dried at 50°C to give compound 4 (17.6 g) (yield: 79%).

[0459] Compound 4: 1 H NMR (CDCl3) 8.97 (s, 1H), 8.00 (d, 2H), 7.32 (d, 2H), 3.98-4.00 (t, 4H), 2.99-3.01 (t, 4H), 2.44 (s, 3H), C14 H 17 The calculated MS value for N5 is 255.1, and the experimental value is 256 m / z [M+H]. + .

[0460] Example 3 (Method for producing compound 6)

[0461] At room temperature, N,N-dimethylformamide (14.2 g) was added to a mixture of compound 7 (1.50 g) and potassium carbonate (2.92 g), and the resulting mixture (suspension) was cooled to 10 °C. A solution of compound 8 (2.71 g) in N,N-dimethylformamide (2.83 g) was added dropwise over 1.5 hours. A mixture of 4 N hydrochloric acid (10 mL) and saturated brine (20 mL) was added at 10 °C, and the resulting mixture was stirred at 10 °C for 19 hours. The resulting crystals were collected by filtration and washed twice with water (15 mL). The crystals were dried at 50 °C to give compound 6 (1.81 g) (yield: 81%).

[0462] Compound 6: 1 H NMR (DMSO-d6) 8.12 (d, 1H), 7.74 (d, 1H), 4.00 (s, 3H), 3.42-3.52 (m, 2H), 1.75-1.79 (m, 7H), 1.15-1.28 (m, 4H), C 10 H 17 The MS value of ClN₂O₂ is 232.1, m / z 233 [M+H]. + .

[0463] Example 4 (Method for producing compound 7)

[0464] Compound 9 was subjected to reduction in a solvent at 60°C to 160°C under pressure and a hydrogen atmosphere (4 MPa) in the presence of a metal catalyst. Ruthenium-alumina (Ru / Al₂O₃), rhodium-carbon, palladium-carbon, or nickel-diatomaceous earth were used as metal catalysts, and methanol, propylene glycol methyl ether, or 1,3-dimethylimidazolium ketone were used as solvents. In this reaction, in addition to the target compound 7 (trans isomer), compounds 10 (cis isomer) and 11 (dimerization product) were produced as major byproducts. Tables 2 and 3 show the combinations of metal catalysts and solvents, the ratios of each product, and the ratio of compound 7 to compound 10 (GC area %). The reaction described in Table 2 was carried out using methanol as a solvent. The reaction described in Table 3 was carried out using ruthenium-alumina as a metal catalyst.

[0465] Table 2

[0466] Table 3

[0467] As clearly demonstrated by the results shown in Table 2, target compounds 7 and 10 were produced while suppressing the formation of compound 11 when inexpensive and readily available ruthenium-alumina was used as the metal catalyst. Similarly, as clearly demonstrated by the results shown in Table 3, target compound 7 (trans isomer) was preferentially produced relative to compound 10 (cis isomer) when propylene glycol methyl ether or 1,3-dimethylimidazolium ketone was used as the solvent.

[0468] Example 5 (Method for producing compound 5 (triazine compound A))

[0469] A mixture of compound 4' (1.51 g), compound 6 (1.45 g), N,N-diisopropylethylamine (0.91 g), and dimethyl sulfoxide (33.2 g) was stirred at 60 °C for 24 hours. Water (30 mL) was added to the mixture at 60 °C, and the resulting mixture was stirred at 60 °C for 2 hours. The resulting crystals were collected by filtration and washed with water (15 mL). The crystals were dried at 50 °C to give compound 5 (2.54 g) (yield: 96%).

[0470] Example 6 (Method for producing a salt of compound 5 (triazine compound A))

[0471] Compound 5 (15.00 g) was dissolved in a mixture of ethanol (14.22 g), water (9.00 g), and 48% hydrobromic acid (5.60 g) at 75 °C. The resulting solution was then added dropwise to acetone (237.00 g) over 1 hour at 50 °C. The container and funnel used were washed with a mixture of ethanol (9.48 g) and water (1.12 g), and the resulting mixture was cooled to 0 °C and stirred for 18 hours. The resulting crystals were collected by filtration and washed with acetone (59.25 g). The crystals were dried at 50 °C to give compound 12 (16.38 g) (yield: 93%).

[0472] Example 7 (Method for producing compound 7)

[0473] Wash Raney Ni (0.3 wt equivalents) three times with THF, and then add THF (6 volumes). Perform Karl Fischer titration to confirm that the water content in the Raney Ni is <0.4%. If <0.4%, wash the Raney Ni again with THF until the water content is <0.4%. Purge the container with nitrogen and add Compound 13 to a solution of MeOH (6 volumes). Then purge the container with hydrogen to a pressure of 0.35–0.5 MPa (50–72 psi) and then heat the mixture to 40–50 °C. Stir the mixture at 40–50 °C for 2–6 hours and then filter through diatomite (0.2–2.0 wt equivalents). Wash the filter cake with THF (5–10 volumes). Evaporate the filtrate and switch to 3.5–4.5 volumes of THF. Confirm that the residual MeOH content is <0.5%. Ethyl acetate (3.5-4.5 volumes) was slowly added at 20-30°C. The reaction mixture was heated to 60-70°C and then stirred at 60-70°C for 1-2 hours. The reaction mixture was then cooled to 22-28°C over 8 hours, stirred at 22-28°C for 12-18 hours, and then filtered. The wet filter cake was washed with ethyl acetate (1-3 volumes) and then dried under vacuum at 40-50°C for 20-24 hours to give compound 7 as a white solid. The yield was determined to be 43.4%, the purity 95.1%, and the cis isomer 2.7%. This level is tolerable in downstream processing.

[0474] Example 8 (Scale-up method for producing compound 7)

[0475] The following procedure is used to begin with 2.35 kg of compound 13.

[0476] 1) Load methanol (3.9-4.0X) into R1.

[0477] 2) Compound 13 (1.0X) is loaded into R1.

[0478] 3) Adjust R1 to 20-30℃.

[0479] 4) Stir R1 at 20-30℃ for 1-2 hours until it becomes clear.

[0480] 5) Obtain a MeOH solution of compound 13.

[0481] 6) Replace the air with nitrogen three times in R2.

[0482] 7) Load Raney nickel (0.25-0.35X) into R2.

[0483] 8) Add tetrahydrofuran (10-16X) into R2.

[0484] 9) Replace the air with nitrogen three times in R2.

[0485] 10) Stir R2 at 20-30℃ for 15-30 minutes.

[0486] 11) Let R2 stand for 0.5-1 hour.

[0487] 12) Siphon out the THF (5-15X) of R2.

[0488] 13) Add tetrahydrofuran (5-15X) into R2.

[0489] 14) Stir R2 at 20-30℃ for 15-30 minutes.

[0490] 15) Let R2 stand for 0.5-1 hour.

[0491] 16) Siphon out THF (5-15X) from R2 (keep 6V THF in R2).

[0492] 17) Add tetrahydrofuran (5-15X) into R2.

[0493] 18) Stir R2 at 20-30℃ for 15-30 minutes.

[0494] 19) Let R2 stand for 0.5-1 hour.

[0495] 20) Siphon out THF (5-15X) from R2 (keep 6V THF in R2).

[0496] 21) IPC (Process Control): Check water content (%w / w, specification: ≤ 0.4%).

[0497] 22) Transfer the material in R1 to R2.

[0498] 23) R1 was rinsed with methanol (0.7-0.9X).

[0499] 24) Transfer the material in R1 to R2.

[0500] 25) Replace the air with nitrogen three times.

[0501] 26) Replace nitrogen with hydrogen.

[0502] 27) Adjust R2 to 0.35-0.50 MPa using H2.

[0503] 28) Adjust R2 to 40-50℃.

[0504] 29) Stir R2 at 40-50℃ under hydrogen (0.35-0.50 MPa) for 2-6 hours.

[0505] 30) IPC: Sampling and submission for HPLC testing. Compound 13 / Compound 7 (HPLC, area / area%, specification ≤ 1.0%, if not meeting specification, proceed to steps 31 and 32, otherwise proceed to step 33); Purity of Compound 7 (HPLC, area%, specification: report).

[0506] 31) Stir R2 at 40-50℃ under hydrogen (0.35-0.50 MPa) for 2-6 hours.

[0507] 32) IPC: Sampling and submission for HPLC testing. Compound 13 / Compound 7 (HPLC, area / area%, specification ≤ 1.0%), Purity of Compound 7: Report (HPLC, area%, specification: Report).

[0508] 33) Filter the reaction mixture through diatomaceous earth (0.2-2.0X) and transfer the filtrate to R3.

[0509] 34) Wash R2 and the filter cake twice with tetrahydrofuran (3-5X). Transfer the filter to R3.

[0510] 35) Concentrate R3 to 3-5V under vacuum at a temperature below 40°C.

[0511] 36) Add tetrahydrofuran (4-5X) into R3.

[0512] 37) Concentrate R3 to 3-5V under vacuum at a temperature below 40°C.

[0513] 38) Sampling for analysis: PS11814-47-A-RS.

[0514] 39) Add tetrahydrofuran (4-5X) into R3.

[0515] 40) Concentrate R3 to 3-5V under vacuum at a temperature below 40°C.

[0516] 41) Adjust R3 to 20-30℃.

[0517] 42) At 20-30℃, EtOAc (3-4X) is loaded into R3.

[0518] 43) Adjust R3 to 60-70℃.

[0519] 44) Stir R3 at 60-70℃ for 0.5-1.5 hours.

[0520] 45) Cool R3 to 15-25°C within 8 hours.

[0521] 46) Stir R3 at 15-25℃ for 2-6 hours.

[0522] 47) Filter the filter cake and wash it with (1-3 X) EtOAc.

[0523] 48) Dry the wet filter cake at 40-50℃ for 16-24 hours.

[0524] The yield was 932 g (43.2%), containing 3.9% of the cis isomer.

[0525] Example 9 (Method for producing compound 15)

[0526] Add diisopropylethylamine (5.0 equivalents) to a suspension of compound 14 (limiting reagent) in dichloromethane (10 volumes). Stir the mixture at 20–30 °C until a solution is obtained, and then cool to 0–10 °C. Add compound 7 (1.05–1.10 equivalents), and then add dropwise a 50% ethyl acetate solution of T4P* (1.5–1.7 equivalents) at 0–10 °C. Stir the mixture at 0–10 °C until the reaction is complete. Add water (5 volumes), and then stir and separate. Extract the aqueous phase with dichloromethane (5 volumes). Combine the organic phases and wash twice with 7% sodium bicarbonate (5 volumes) and then with water (5 volumes). Concentrate the resulting organic phase to 6 volumes, and then add MTBE (15 volumes) dropwise at 15–25 °C. The mixture was cooled to -5–5°C, stirred at -5–5°C for 5–10 hours, and then filtered and washed with MTBE (1–3 volumes). The filter cake was dried under vacuum at 40–50°C for 10–18 hours. The obtained compound 15 had a separated yield of 79.3%, a chemical purity of 99.50%, and an isomer purity of 99.46%.

[0527] *T3P can be used as a substitute for T4P. It is speculated that T3P and T4P behave similarly, since T4P simply has a butyl side chain instead of a propyl side chain.

[0528] Example 10 (Scale-up method for producing compound 15)

[0529] This step is performed on a scale of 600 g, as follows: 1) Load 11.3-12.6X (8.5-9.5V) dichloromethane into R1.

[0530] 2) 1.0X (0.99-1.01X, 1.0 equivalent) of compound 14 was loaded into R1.

[0531] 3) Adjust R1 to 15-25℃.

[0532] 4) Stir R1 at 15-25℃ for 10-30 minutes.

[0533] 5) At 15-25℃, (1.7-2.3X, 4-5 equivalent) N,N-diisopropylethylamine (DIPEA) is loaded into R1.

[0534] 6) Adjust R1 to 0-10℃.

[0535] 7) At 0-10°C, 0.50-0.55X (1.0-1.1 equivalents) of compound 7 is loaded into R1.

[0536] 8) Stir R1 at 0-10℃ for 15-35 minutes.

[0537] 9) Slowly fill T4P solution (50%, in ethyl acetate) (3.0-3.9X, 1.3-1.7 equivalents) into R1 at 0-10℃ over 1 hour.

[0538] 10) Rinse the tube with DCM (0.2-1.5V).

[0539] 11) Stir R1 at 0-10℃ for 2-8 hours.

[0540] 12) IPC: Compound 14 / Compound 15 (%, area / area) ≤ 2.0%, purity of Compound 15 (area%, specification: report).

[0541] 13) At 0-10℃, process water (7.5-8.5X) is added to R1.

[0542] 14) Adjust R1 to 15-25℃.

[0543] 15) Stir R1 at 15-25℃ for 15-35 minutes.

[0544] 16) Let R1 stand for 15-30 minutes.

[0545] 17) Separate the organic layer into T1.

[0546] 18) Load 6-7X dichloromethane into R1.

[0547] 19) Stir R1 at 15-25℃ for 15-35 minutes.

[0548] 20) Let R1 stand for 15-30 minutes.

[0549] 21) Separate the bottom organic layer and the middle layer to T1, and separate the top layer to T2.

[0550] 22) Transfer the organic phase in T1 to R1.

[0551] 23) Add 7% NaHCO3 aqueous solution (6.5-7.5X) into R1.

[0552] 24) Stir R1 at 15-25℃ for 15-35 minutes.

[0553] 25) Filter R1 into F1 (0.2X diatomaceous earth), and then transfer the filtrate back into R1.

[0554] 26) Let R1 stand for 15-30 minutes.

[0555] 27) Separate the bottom organic layer and the middle layer to T1, and separate the top layer to T3.

[0556] 28) Transfer the organic phase in T1 to R1.

[0557] 29) Add 7% NaHCO3 aqueous solution (6.5-7.5X) into R1.

[0558] 30) Stir R1 at 15-25℃ for 15-35 minutes.

[0559] 31) Filter R1 into F1 (0.2X diatomaceous earth) and wash the filter cake with 2-3X DCM. Then transfer the filtrate to R1.

[0560] 32) Let R1 stand for 15-30 minutes.

[0561] 33) Separate the bottom organic layer to T1, and separate the middle and top layers to T3.

[0562] 34) Transfer the organic phase in T1 to R1.

[0563] 35) Add process water (4.5-5.5X) into R1.

[0564] 36) Stir R1 at 15-25℃ for 20-40 minutes.

[0565] 37) Let R1 stand for 15-30 minutes.

[0566] 38) Separate the bottom organic layer to T1, and separate the middle and top layers to T4.

[0567] 39) Transfer the organic phase in T1 to R1.

[0568] 40) At 15-25℃, filter the organic layer in R1 twice through CUNO (activated carbon (0.08-0.22X)).

[0569] 41) Wash CUNO twice with 6-7X DCM for 60 minutes to 0.5-2 hours. Add the washed items to R1.

[0570] 42) Concentrate R1 in batches to 5-6V under vacuum at temperatures below 45°C.

[0571] 43) Adjust R1 to 15-25℃.

[0572] 44) At 15-25℃, slowly fill MTBE (10.5-11.5X, 15V) into R1.

[0573] 45) Adjust R1 to -5-5℃ within 2 hours.

[0574] 46) Stir R1 at -5 to -5℃ for 5 to 15 hours.

[0575] 47) IPC: Residual compound 15 in supernatant (% w / w, specification: ≤ 0.3%), purity of wet filter cake of compound 15 (area %): report, chirality of wet filter cake of compound 15 (area %), specification: ≥ 99.0%.

[0576] 48) Filtration: Wash the filter cake with MTBE (2.0-5.0X) and then transfer the filtrate to T4.

[0577] 49) Dry the wet filter cake under vacuum at 40-50℃ for 17-24 hours.

[0578] 50) IPC: Water content of compound 15 (% w / w, specification ≤ 0.5%), residual DCM (% w / w, specification: report), residual MTBE (% w / w, specification: report), residual EA (% w / w, specification: report).

[0579] The yield was 724.0 g (91.2% yield determined, 99.3% chemical purity, and 99.7% isomer purity). The latter value indicates that the percentage of the cis isomer (compound 10) in the starting monoacetyldiamine is tolerable in downstream chemistry.

[0580] Example 11 (Method for producing compound 16)

[0581] A mixture of MeOH (12 volumes), compound 15 (limiting reagent), and 10% wet Pd / C (0.02–0.04 wt / wt) was stirred at 20–30 °C under hydrogen (40–50 psi) until the reaction was complete. The mixture was then filtered, and the filter cake was washed with MeOH (5 volumes). The filtrate was concentrated to 2–3 volumes, and then MTBE (10V) was added dropwise at -15 °C to -10 °C. The resulting suspension was stirred at the same temperature for 18 hours and then filtered. The wet filter cake was washed with MTBE (2 volumes) and then dried under vacuum to give solid C. The yield was approximately 90%.

[0582] Example 12 (Scale-up method for producing compound 16)

[0583] This reaction was carried out on a scale of 674 g, as follows: 1) Load methanol (9-10X) into R1.

[0584] 2) Compound 15 (1.0X) is loaded into R1.

[0585] 3) Replace R1 with nitrogen three times.

[0586] 4) Adjust R1 to 20-30℃.

[0587] 5) Stir R1 at 20-30℃ for 0.5-1 hour until it becomes clear.

[0588] 6) Load 0.04X palladium / activated carbon (10% Pd / C, 0.02-0.04X, 50% water-wetted) into R1.

[0589] 7) Adjust R1 to 20-30℃.

[0590] 8) Replace R1 with hydrogen.

[0591] 9) At 20-35℃, adjust R1 to 0.27-0.35 MPa (40-50 psi) hydrogen.

[0592] 10) Stir R1 under hydrogen at 0.27-0.35 MPa (40-50 psi) at 20-35°C for 3-7 hours.

[0593] 11) IPC: Sampling to check the purity of compound 15 / compound 16 (area%, specification: ≤ 0.5%) and compound 16 (area%, specification: report).

[0594] 12) Filter the material with diatomaceous earth (0.2-2X) and transfer the liquid to a clean bucket.

[0595] 13) Rinse the wet filter cake twice with 3-7X MeOH and transfer the liquid to a clean container.

[0596] 14) Transfer the filtrate (compound 16 MeOH solution) to R2.

[0597] 15) Concentrate R2 to 2-3V under vacuum at temperatures below 50°C.

[0598] 16) At 15-20°C, add methyl tert-butyl ether (7.2-7.6X) dropwise to R2.

[0599] 17) Adjust R2 to -15℃ to -5℃.

[0600] 18) Stir R2 at -15℃ to -5℃ for 10-16 hours.

[0601] 19) IPC: Residual compound 16 in supernatant (%, w / w, specification: ≤ 0.5%), purity of compound 16 in filtered solids (area, specification: report).

[0602] 20) Filter the filter cake and wash it with MTBE (3-5X).

[0603] 21) Dry the wet filter cake at 40-50℃ under vacuum for 16-24 hours.

[0604] The yield was 419 g (91.8%), and the purity was 99.2%.

[0605] Example 13 (Method for generating free base of compound 5)

[0606] At 15-25°C, triethylamine (1.5 equivalents) was added to a solution of compound 16 (limiting reagent) in MeOH (10 volumes) / dichloromethane (10 volumes). Then, a solution of compound 2 (1.2 equivalents) in NMP (4 volumes) was slowly added at 30-35°C. The reaction mixture was stirred at 30-35°C until the reaction was complete. The mixture was then concentrated to 7-10 volumes, cooled to -15°C to -5°C, and filtered. The filter cake was washed with methanol (1-3 volumes) and then dissolved in MeOH (13 volumes) / dichloromethane (13 volumes). A 3% aqueous solution of potassium carbonate (0.5-1.5 wt / wt) was added to adjust the pH to 11-13, and the mixture was then stirred at 30-35°C for 1-5 hours. [Preferably, the alkaline aqueous layer is separated first.] Water (12-15 volumes) was added, stirred, and then separated. Then, MeOH (5 volumes) and NMP (5 volumes) were added dropwise to the resulting organic phase, and the mixture was concentrated to 7-10 volumes. The resulting slurry was cooled, stirred at -15°C to -5°C for 1 hour, and then filtered. The filter cake was washed with MeOH (1-3 volumes) and then dried under vacuum to give compound 5.

[0607] Example 14 (Scale-up method for producing compound 5)

[0608] The following method was performed twice on a scale of approximately 200 g. After the reaction was complete, the two batches were combined for post-processing.

[0609] 1) Load 3.90-4.31X N-methylpyrrolidone into R2.

[0610] 2) Load 0.86-0.88X (1.20-1.22 equivalents) of compound 2 into R2.

[0611] 3) Rinse R2 with 0.10X-0.21X NMP.

[0612] 4) Stir R2 at 15-25℃ for 0.5-1 hour until the solution is clear.

[0613] 5) Load 7.51-8.30X methanol into R1.

[0614] 6) Load 0.99-1.01X of compound 16 into R1.

[0615] 7) Load 13.0-13.6X dichloromethane into R1.

[0616] 8) Load 0.51-0.57X triethylamine into R1.

[0617] 9) Rinse R1 with 0.08X-0.16X MeOH.

[0618] 10) Adjust R1 to 30-35℃.

[0619] 11) The solution of R2 is added dropwise to R1 within 3 hours.

[0620] 12) R2 was rinsed with 0.10X-0.21X NMP, and then the solution of R2 was added dropwise to R1.

[0621] 13) Stir R1 at 30-35℃ for 2-6 hours.

[0622] 14) IPC: Samples were taken to check the IPC purity (area%, specification ≤ 0.2%) of compound 16.

[0623] 15) Concentrate R1 to 7-10V under vacuum at a temperature below 45°C.

[0624] 16) Adjust R1 to -15℃ to -5℃.

[0625] 17) Stir R1 at -15℃ to -5℃ for 3-18 hours.

[0626] 18) Filter the filter cake and wash it with 2.28-2.52X methanol.

[0627] 19) Load the wet filter cake into R1.

[0628] 20) Load 16.5-17.5X dichloromethane into R1.

[0629] 21) Load 10-10.5X methanol into R1.

[0630] 22) Add 4-5 x 3% K2CO3 aqueous solution to R1 to adjust the pH to 11-12.

[0631] 23) Adjust R1 to 25-35℃.

[0632] 24) Stir R1 at 25-35℃ for 1-5 hours.

[0633] 25) Load the 9-11X process water into R1.

[0634] 26) Separation. The organic phase is transferred to R1, and the aqueous layer is transferred to T1.

[0635] 27) Adjust R1 to -10-0℃.

[0636] 28) Add 15.68-17.33X N-methylpyrrolidone dropwise into R1.

[0637] 29) Stir R1 at 20-30℃ for 1-3 hours.

[0638] 30) Concentrate R1 to 15-16V under vacuum at temperatures below 45°C.

[0639] 31) Adjust R1 to -15℃ to -5℃.

[0640] 32) Stir R1 at -15℃ to -5℃ for 1-5 hours.

[0641] 33) Filter the filter cake and wash it with 2.57-2.84X dichloromethane.

[0642] 34) Dry under vacuum at 40-50℃ for 4-12 hours.

[0643] The yield was 535 g (85.8%), and the purity was 99.9%.

[0644] Example 15 (Method for producing compound 6b)

[0645] The following steps are performed on a scale of 350 g.

[0646] 1) Load the 9.50-10.50X process water into R2.

[0647] 2) Add 1.71-1.89X potassium carbonate (2.0 equivalent) to R2.

[0648] 3) Rinse R2 with 0.10X-0.21X process water.

[0649] 4) Stir R2 at 15-25℃ for 0.5-1 hour until the solution is clear.

[0650] 5) Load 1.0X compound 7 into R1.

[0651] 6) Load 25.2-27.9X dichloromethane into R1.

[0652] 7) Replace R1 with nitrogen three times.

[0653] 8) Adjust R1 to -5-0℃.

[0654] 9) Load the solution of R2 into R1 within 0.5 hours.

[0655] 10) Under N2 protection, at -5 to 0°C for 30 minutes, 1.81-2.00X compound 8b (1.5 equivalents) was loaded into R1.

[0656] 11) Stir R1 at -5 to 0℃ for 30 to 60 minutes.

[0657] 12) IPC: Samples were taken to check the IPC purity (area%, specification ≤ 2.0%) of compound 7.

[0658] 13) If necessary, under N2 protection, at -5 to 0°C for 10 minutes, charge 0.60-0.70X compound 8b (0.5 equivalents) into R1.

[0659] 14) Stir R1 at -5 to 0℃ for 30 to 60 minutes.

[0660] 15) IPC: Samples were taken to check the IPC purity (area%, specification ≤ 2.0%) of compound 7.

[0661] 16) Filter the reaction mixture.

[0662] 17) Wash the wet filter cake with 10X water.

[0663] 18) Dry under vacuum at 35-45℃ for 14-28 hours.

[0664] The yield was 590.1 g (the determined yield was 86.1%, and the chemical purity was 98.4%).

[0665] Example 16 (Method for producing compound 4)

[0666] This reaction was carried out on a scale of 400 g.

[0667] 1) Load 1.0X (0.99-1.01X, 1.0 equivalent) of compound 2 into R1.

[0668] 2) Load 8.7X (8.6-8.8X) 1,2-dimethoxyethane into R1.

[0669] 3) Adjust R1 to 20-30℃.

[0670] 4) Stir R1 at 20-30℃ for 0.5-1 hour until it becomes clear.

[0671] 5) Add 0.74X (0.72-0.76X) 1.50 equivalents of triethylamine to R1.

[0672] 6) At 20-30℃, 1.04X(1.00-1.10X)1.10 equivalents of 1-Boc-piperazine are loaded into R1.

[0673] 7) Stir R1 at 20-30℃ for 3-16 hours.

[0674] 8) Sampling for analysis: purity of compound 2 (area%, specification ≤ 1.0%).

[0675] 9) If necessary, at 20-30°C, add 0.05 x (0.03-0.06 x) 0.05 equivalents of 1-Boc-piperazine to R1.

[0676] 10) Stir R1 at 20-30℃ for 2-5 hours.

[0677] 11) Sampling for analysis: purity of compound 2 (area%, specification ≤ 1.0%).

[0678] 12) If necessary, at 20-30°C, 0.05 x (0.03-0.06 x) 0.05 equivalents of 1-Boc-piperazine are loaded into R1.

[0679] 13) Stir R1 at 20-30℃ for 2-5 hours.

[0680] 14) Samples were taken for analysis of the purity of compound 2 (area%, specification ≤ 1.0%).

[0681] 15) Add 7.5X (7.3-7.7X) process water to R2.

[0682] 16) At 20-50℃, add 2.6X (2.5-2.7X) 35% hydrochloric acid into R2.

[0683] 17) Adjust R2 to 20-30℃.

[0684] 18) Stir R2 at 20-30℃ for 10-30 minutes to obtain a 9% HCl aqueous solution.

[0685] 19) At 20-50℃, add the 9% HCl aqueous solution of R2 dropwise into R1.

[0686] 20) Adjust R1 to 50-60℃.

[0687] 21) Stir R1 at 50-60℃ for 3-10 hours.

[0688] 22) Adjust R1 to 10-20℃.

[0689] 23) Stir R1 at 10-20℃ for 2-10 hours.

[0690] 24) Filter the wet filter cake and wash it with 2-7V DME.

[0691] 25) Dry the wet filter cake at 45-55℃ for 20-24 hours.

[0692] The yield was 588.4 g (91.2%), and the purity was 99.8%.

[0693] Example 17 (Method for producing a free base of compound 5)

[0694] The following steps are performed on a scale of approximately 420 g.

[0695] 1) Add 20X (19.00-21.00X) of purified water to R2.

[0696] 2) Add 1.5X (3.0-3.5 equivalent) potassium carbonate to R2.

[0697] 3) Adjust R2 to 20-30℃.

[0698] 4) Stir R2 at 20-30℃ for 0.5-1 hour until the solution is clear.

[0699] 5) Add 8.9X (8.7-9.1X) tetrahydrofuran into R1.

[0700] 6) 1.1X (1.09-1.11X, 1.05 equivalent) of compound 4 was loaded into R1.

[0701] 7) Stir R1 at 20-30℃ for 0.5 hours.

[0702] 8) At 20-30℃, add the K2CO3 aqueous solution of R2 dropwise into R1.

[0703] 9) Stir R1 at 20-30℃ for 0.5 hours until it becomes clear.

[0704] 10) At 20-30°C, 0.99-1.01X (1.0 equivalent) of compound 6b was loaded into R1.

[0705] 11) Adjust R1 to 30-40℃.

[0706] 12) Stir R1 at 30-40℃ for 4-10 hours.

[0707] 13) IPC: Samples were taken to check the IPC purity (area%, specification ≤ 1.0%) of compound 6b.

[0708] 14) Adjust R1 to 20-30℃.

[0709] 15) Stir R1 at 20-30℃ for 2-6 hours.

[0710] 16) Filter the wet filter cake and wash it with MeOH (1-3X).

[0711] 17) Load the wet filter cake into R1.

[0712] 18) Add 16.5-17.5X dichloromethane to R1.

[0713] 19) Load 10-10.5X methanol into R1.

[0714] 20) Add 4-5 x 5% K2CO3 aqueous solution to R1 to adjust the pH to 11-12.

[0715] 21) Adjust R1 to 30-40℃.

[0716] 22) Stir R1 at 30-40℃ for 5-15 hours.

[0717] 23) Load the 10-15X process water into R1.

[0718] 24) Stir R1 at 20-30℃ for 0.5 hours.

[0719] 25) Separation. The organic phase is transferred to R1, and the aqueous layer is transferred to T1.

[0720] 26) Adjust R1 to 20-30℃.

[0721] 27) At 20-30℃, 4-5X MeOH is loaded into R1.

[0722] 28) Add 14-18X 2.2% HBr aqueous solution (1.2 equivalent 40% HBr aqueous solution in 15V process water) to R1 to adjust the pH to 1-2.

[0723] 29) Stir R1 at 20-30℃ for 0.5 hours.

[0724] 30) Separation. The organic phase is transferred to T2, and the aqueous layer is transferred to R1.

[0725] 31) Load 16.5-17.5X dichloromethane into R1.

[0726] 32) Load 4-5X methanol into R1.

[0727] 33) Add 6.5-7.5 x 10% K2CO3 aqueous solution to R1 to adjust the pH to 9-11.

[0728] 34) Stir R1 at 20-30℃ for 0.5 hours.

[0729] 35) Separation. The organic phase is transferred to R1 and the aqueous layer is transferred to T3.

[0730] 36) Load 9-11X N-methylpyrrolidone into R1.

[0731] 37) Concentrate R1 to 10-12V under vacuum at a temperature below 45°C.

[0732] 38) Adjust R1 to -15℃ to -5℃.

[0733] 39) Stir R1 at -15℃ to -5℃ for 1-5 hours.

[0734] 40) Filter the filter cake and wash it with MeOH (1-3V).

[0735] 41) Dry under vacuum at 40-50℃ for 16-24 hours.

[0736] The yield was 568 g (81.4%), and the purity was 99.9%.

[0737] Example 18 (An alternative method for producing compound 2 from compound 1)

[0738] Under an inert atmosphere, compound 1 (1 equivalent), 1,2-dimethoxyethane (6.5 volumes), and dimethylformamide (0.01 equivalents) were mixed and stirred at 68–70 °C. At 68–70 °C, thionyl chloride (2.0 equivalents) was added, and the mixture was stirred for 3 hours. After sampling to check the completion of the reaction, the mixture was cooled to 0 °C, and 3.5 equivalents of triethylamine (TEA) were added. The pH was measured, and approximately 1 equivalent of TEA was added to adjust the pH of the mixture to 4. Next, 12 L / kg water was added. The resulting crystals were filtered, washed, and dried.

[0739] Example 19 (Method for crystallizing compound 12)

[0740] Crystals of compound 12 were produced using the following steps: (a) Suspend MLS-101 free base in 5 L / kg of 80:20 (v / v) methanol:water (b) Add 1.01 equivalents of HBr aqueous solution (c) Heating to 50°C to obtain a solution (d) Fine filter (e) Load 1 L / kg acetone and 0.005 kg / kg seed crystals. Keep this mixture for 2 hours. (f) Load 19 L / kg acetone below the liquid level within 12 hours to avoid scaling on the reactor walls. (g) Keep this mixture for 5 hours to ensure conversion to crystal form A. (h) Cool to 25°C within 3 hours and maintain for 3 hours. (i) Filter and wash twice with 2 L / kg acetone. The yield of this method is approximately 85%.

[0741] The methanol / water ratio maximizes recovery while ensuring the product remains in solution during polishing and filtration.

[0742] The amount of acetone was optimized for recovery while keeping the total volume as low as possible.

[0743] Particle size can be controlled by adding seed crystals to a supersaturated liquid followed by slow addition, aging, and cooling steps, thus allowing preferential particle growth rather than nucleation.

[0744] Example 20 (Method for recrystallization of hydrobromide of compound V) The hydrobromide of compound V was prepared into a slurry at 25°C in 4 L / kg MeOH / H2O 80 / 20 (by volume), and then heated to 60°C. A solution was formed at approximately 58°C.

[0745] The solution was cooled to 50°C, and no precipitate was observed.

[0746] 2 L / kg of acetone was added to the solution, followed by the addition of 0.5% seed crystals.

[0747] Solids nucleate from solution.

[0748] Then, the solution was stirred at 50°C for 16 hours.

[0749] Another 14 L / kg of acetone was added over 1.2 hours, followed by cooling to 25°C over 2 hours, and then stirring at 25°C for 4 hours.

[0750] The mixture was then filtered and washed twice with 2 L / kg acetone, and then dried under vacuum at 50°C for 16 hours. An 86.8% yield was obtained.

[0751] Industrial applicability According to the method of production of the present invention, triazine compound A or its intermediate that can be used as an active pharmaceutical ingredient can be produced from inexpensive starting materials via a production route that does not require protection and deprotection reactions, and therefore can be produced with inexpensive reagents, in fewer steps and in high yield.

Claims

1. A method for producing a compound represented by formula IV or a salt thereof: Formula IV Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula: Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule. The method comprises reacting a compound represented by Formula I or a salt thereof, an activator, and a compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof: Formula I Formula III Where R 1 This indicates that it is the same as the definition above.

2. The method of claim 1, wherein reacting the compound represented by formula I or a salt thereof, the activator, and the compound represented by formula III or a salt thereof to produce the compound represented by formula IV or a salt thereof is carried out without separating the compound represented by formula II or a salt thereof: Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; and Where R 2 and R 3 Each can independently represent a hydrogen atom or an amino protecting group.

3. The method of claim 1, wherein the step of reacting the compound or salt thereof represented by Formula I, the activator, and the compound or salt thereof represented by Formula III to produce the compound or salt thereof represented by Formula IV comprises isolating the compound or salt thereof represented by Formula II: Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group.

4. The method according to any one of claims 1 to 3, wherein R 1 Representing hydrogen atoms, the method is used to produce compounds of formula IV': Formula IV'.

5. A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof: Formula V The method includes: a) Producing a compound or a salt thereof represented by formula IV' by any one of claims 1 to 4: Formula IV'; as well as b) Reacting the compound represented by formula IV' or a salt thereof with a compound represented by formula VI or a salt thereof to produce the compound represented by formula V or a pharmacologically acceptable salt thereof: Style VI Where X 1 It represents a chlorine atom, a bromine atom, or a leaving group.

6. The method of claim 5, further comprising reacting a compound of formula VII or a salt thereof, a base, and a compound of formula VIII or a salt thereof in a solvent to produce the compound of formula VI or a salt thereof: Equation VII Formula VIII Where X 1 This indicates that it is the same as defined above; and X 2 It represents a chlorine atom, a bromine atom, or a leaving group.

7. The method of claim 6, further comprising subjecting a compound represented by formula IX or a salt thereof to a reduction reaction to produce the compound represented by formula VII or a salt thereof: Formula IX.

8. The method of claim 6, further comprising subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce the compound represented by formula VII or a salt thereof: Formula X.

9. A method for producing a compound represented by formula VII or a salt thereof, said method comprising subjecting a compound represented by formula X or a salt thereof to a reduction reaction: Equation VII; Formula X.

10. A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof: Formula V The method includes: a) Reacting a compound represented by formula I or a salt thereof with an activator to produce and isolate a compound represented by formula II or a salt thereof: Formula I Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; b) React the compound represented by Formula II or a salt thereof with the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof: Formula III Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula: Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule. Formula IV Where R 1 This indicates that it is the same as defined above; and c) subjecting a compound represented by formula IX or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof: Formula IX Equation VII.

11. A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof: Formula V The method includes: a) Reacting a compound represented by formula I or a salt thereof with an activator to produce and isolate a compound represented by formula II or a salt thereof: Formula I Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group; b) React the compound represented by Formula II or a salt thereof with the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof: Formula III Where R 1 Represents a hydrogen atom, an alkyl group optionally substituted with a carboxyl or alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula: Where R 2 and R 3 Each element independently represents a hydrogen atom, acetyl group, or amino protecting group; and the wavy line indicates the connection point with the rest of the molecule. Formula IV Where R 1 This indicates that it is the same as defined above; and c) subjecting a compound represented by formula X or a salt thereof to a reduction reaction to produce a compound represented by formula VII or a salt thereof: Formula X Equation VII.

12. The method according to claim 10 or 11, further comprising: a) React the compound represented by formula VII or a salt thereof, a base, and the compound represented by formula VIII or a salt thereof in a solvent to produce the compound represented by formula VI: Formula VIII Where X 1 and X 2 Each can independently represent a chlorine atom, a bromine atom, or a leaving group; Style VI Where X 1 This indicates that it is the same as defined above. or its salt; and b) Reacting the compound represented by formula IV or a salt thereof with the compound represented by formula VI or a salt thereof to produce the compound represented by formula V or a pharmacologically acceptable salt thereof.

13. The method according to any one of claims 7 to 12, wherein the reduction reaction is carried out by reacting with a metal catalyst and hydrogen in a polar solvent.

14. The method according to claim 13, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.

15. The method according to claim 13 or 14, wherein the metal catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, nickel-diatomite, nickel-alumina, or Raney nickel.

16. The method according to claim 8 or 9, wherein the reduction reaction is carried out by reacting the compound represented by formula X, the metal catalyst, and hydrogen in a polar solvent.

17. The method according to claim 16, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3-dimethylimidazolium ketone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide, preferably methanol or tetrahydrofuran, more preferably a mixture of methanol and tetrahydrofuran.

18. The method according to claim 16 or 17, wherein the metal catalyst is ruthenium-alumina, ruthenium-carbon, rhodium-carbon, palladium-carbon, platinum-carbon, nickel-diatomite, nickel-alumina, or Raney nickel, preferably Raney nickel.

19. The method according to any one of claims 16 to 18, wherein the metal catalyst is washed with a polar aprotic solvent, preferably tetrahydrofuran (THF), prior to combination with the compound represented by formula X or a salt thereof in a solution containing a polar solvent, wherein the polar solvent is preferably methanol.

20. The method according to any one of claims 16 to 19, wherein the reduction reaction comprises, in the presence of hydrogen, preferably at 40-50°C under 0.35-0.50 MPa hydrogen, stirring the compound represented by formula X or a salt thereof and the metal catalyst in the polar solvent, preferably for 2-6 hours.

21. The method according to any one of claims 16 to 20, wherein the solid comprising the compound represented by formula VII is formed by said reduction reaction: Equation VII.

22. The method of claim 21, wherein the ratio of the peak area of ​​the compound represented by formula X to the compound represented by formula VII, as measured by high-performance liquid chromatography, generated by the solid is less than or equal to 1%.

23. The method of claim 22, further comprising preferably separating the solid containing the compound represented by formula VII by a concentration, filtration and washing step, preferably wherein the filtration is carried out with diatomaceous earth, preferably wherein the washing is carried out with a polar aprotic solvent, more preferably THF, and still more preferably wherein the separation comprises a final concentration step, followed by washing with an organic solvent, preferably ethyl acetate, and then drying.

24. The method according to any one of claims 16 to 23, wherein the reaction produces the compound represented by formula VII with a purity greater than 94%, more preferably 95-97%, preferably wherein the reaction produces less than 5% of the cis isomer of the compound represented by formula VII, more preferably 1-3% of the cis isomer of the compound represented by formula VII.

25. A method for producing a compound represented by formula V or a pharmacologically acceptable salt thereof: Formula V; The method comprises reacting a compound represented by formula II or a salt thereof with a compound represented by formula XIII or a salt thereof: Formula II Where X represents a halogen atom, a sulfonate group, an ester group, or a phosphate ester group, preferably chlorine; Formula XIII.

26. The method of claim 25, wherein the compound represented by formula XIII or a salt thereof is produced by subjecting the compound represented by formula XII or a salt thereof to a deprotection reaction, preferably wherein the deprotection reaction is a reduction reaction: Formula XII R1 represents a protecting group, preferably an amino protecting group, and more preferably a benzyloxycarbonyl group.

27. The method of claim 26, wherein the compound represented by formula XII is produced in the presence of a condensing agent by reacting a compound represented by formula VII or a salt thereof, a base, and a compound represented by formula XI or a salt thereof in a solvent: Formula XI Wherein R1 represents an amino protecting group, preferably a benzyloxycarbonyl group; Equation VII.

28. The method of claim 27, wherein the compound represented by formula VII or a salt thereof is produced by subjecting a compound represented by formula X or a salt thereof to a reduction reaction: Formula X.

29. The method according to any one of claims 25 to 28, wherein the compound represented by formula II or a salt thereof is produced by reacting a compound represented by formula I or a salt thereof with an activator: Formula I.

30. The method according to any one of claims 5 to 8, 10, 11, 14, 15, 17 to 23 and 25 to 28, wherein a free base of the compound represented by formula V is produced, the method further comprising a method for crystallizing the monohydrobromide salt of the compound represented by formula V, the method comprising: a) A solution is produced that contains: (1) a free base of the compound represented by formula V; (2) a solvent, such as ethanol or methanol; (3) water; and (4) hydrobromic acid; and b) Any one of the following two: i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or ii) Add acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; as well as c) Collect the obtained crystals.

31. A method for crystallizing the monohydrobromide of a compound represented by formula V: Formula V; The method includes: a) A solution is produced that contains: (1) a free base of the compound represented by formula V; (2) a solvent, such as ethanol or methanol; (3) water; and (4) hydrobromic acid; and b) Any one of the following two: i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or ii) Add acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; as well as c) Collect the obtained crystals.

32. The method according to claim 30 or 31, comprising the following steps: a) Mix the free base of the compound represented by formula V with ethanol, water and hydrobromic acid; b) Add the resulting solution to acetone, preferably dropwise; c) Wash the resulting mixture with a mixture of ethanol and water; d) Cool and stir the resulting mixture; e) The collected crystals; and f) Optionally wash the collected crystals with acetone; g) Optionally, dry the washed crystals.

33. The method of claim 32, comprising one or more, or all, of the following features: i) In step (a), the weight ratio of the compound represented by formula V: ethanol: water: hydrobromic acid is about 15:14.22:11.91:2.69; ii) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; iii) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, for 1 hour; iv) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; v) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; vi) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2-24 hours, preferably about 18 hours; vii) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and viii) The yield of the method is at least 90%, preferably at least 93%, and more preferably 93% to 97%.

34. The method according to claim 30 or 31, comprising the following steps: a) Suspend the free base of the compound represented by formula V in a solution of methanol and water to form a suspension of the compound represented by formula V; b) Add an aqueous HBr solution to the suspension of the compound represented by formula V to obtain a first mixture; c) Heating the first mixture to obtain a first solution; d) Filter the first solution; e) Add acetone and seed crystals to the first solution to obtain a second mixture; f) Add additional acetone to the second mixture to obtain a third mixture; g) Maintain and cool the third mixture; h) Filter the third mixture to obtain a filter cake; i) Wash the filter cake to obtain crystals of the monohydrobromide of the compound represented by formula V.

35. The method of claim 34, wherein the method comprises one or more, or all, of the following features: i) Step a) comprises suspending the free base of the compound represented by formula V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, of about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water; ii) Step b) comprises adding about 1.00 to 1.025 molar equivalents, preferably about 1.01 molar equivalents, of an aqueous HBr solution to the suspension of the compound represented by formula V to obtain a first mixture; iii) Step c) comprises heating the first mixture to about 45°C to 60°C, preferably about 50°C, to obtain a solution; iv) Step d) includes filtering the first solution through a fine filter; v) Step e) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; vi) Step f) includes loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, preferably within about 12 hours, to obtain the third mixture; vii) Step g) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, then cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; viii) Step h) comprises filtering the third mixture to form a filter cake; (i) Step i) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and The yield of the method described in ix) is approximately 85%.

36. The method according to any one of claims 30 to 35, further comprising recrystallizing the monohydrobromide of the compound represented by formula V, the method comprising: a) Dissolving the crystals of the monohydrobromide of the compound represented by formula V in (1) a solvent, such as ethanol or methanol and (2) water; and b) Any one of the following two: i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or ii) Add acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; as well as c) Collect the obtained crystals.

37. A method for recrystallizing the monohydrobromide of a compound represented by formula V: Formula V; The method includes: a) Dissolving crystals of the monohydrobromide salt of the compound represented by formula V in (1) a solvent, such as ethanol or methanol and (2) water; and b) Any one of the following two: i) The solution is added to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide of the compound represented by formula V; or ii) Add acetone and seed crystals to the solution, followed by cooling to produce crystals of the monohydrobromide of the compound represented by formula V; as well as c) Collect the obtained crystals.

38. The method according to claim 36 or 37, comprising the following steps: a) Mix the crystals of the monohydrobromide of the compound represented by formula V with ethanol and water; b) Add the resulting solution to acetone, preferably dropwise; c) Wash the resulting mixture with a mixture of ethanol and water; d) Cool and stir the resulting mixture; e) The collected crystals; and f) Optionally wash the collected crystals with acetone; g) Optionally, dry the washed crystals.

39. The method of claim 38, comprising one or more, or all, of the following features: i) In step (a), the solution is mixed at about 50-100°C, preferably about 75°C; ii) In step (b), the solution from step (a) is added to acetone at about 25-75°C, preferably about 50°C, over 1 hour; iii) In step (b), the weight ratio of the solution from step (a) to acetone is approximately 43.82:237.00; iv) In step (c), the weight ratio of ethanol to water in the ethanol-water mixture is approximately 9.48:1.12; v) In step (d), the mixture is cooled to about 0°C to 5°C, preferably about 0°C, and stirred for about 2-24 hours, preferably about 18 hours; vi) In step (g), the crystal is dried at about 25°C to 75°C, preferably at about 50°C; and vii) The yield of the method is at least 90%, preferably at least 93%, and more preferably 93% to 97%.

40. The method of claim 36 or 37, comprising the following steps: a) Dissolve the crystals of the monohydrobromide of the compound represented by formula V in a solution of methanol and water to obtain a first solution; b) Filter the first solution; c) Add acetone and seed crystals to the first solution to obtain a second mixture; d) Add additional acetone to the second mixture to obtain a third mixture; e) Maintain and cool the third mixture; f) Filter the third mixture to obtain a filter cake; g) Wash the filter cake to obtain crystals of the monohydrobromide of the compound represented by formula V.

41. The method of claim 40, wherein the method comprises one or more, or all, of the following features: i) Step a) comprises suspending crystals of the monohydrobromide of the compound represented by formula V in about 4 L / kg to 5 L / kg, preferably about 5 L / kg, in about 75:25-85:15 (v / v) methanol:water, preferably about 80:20 (v / v) methanol:water. ii) Step a) involves heating to about 45°C to 60°C, preferably about 50°C; iii) Step b) includes filtering the first solution through a fine filter; iv) Step c) comprises adding about 1-4 L / kg, preferably about 2.5 L / kg acetone and about 0.005-0.05 kg / kg, preferably about 0.005 kg / kg seed crystals to the filtrate to obtain a second mixture, and maintaining the second mixture for about 2-16 hours, preferably about 16 hours; v) Step d) includes loading about 12-19 L / kg acetone, preferably about 17.5 L / kg acetone, below the liquid surface within about 12 hours, to obtain the third mixture; vi) Step e) comprises holding the third mixture for about 1-5 hours, preferably about 1 hour, followed by cooling the third mixture to about 15-20°C, preferably about 20°C, for about 2-3 hours, preferably about 2 hours, and holding it for another about 3-16 hours, preferably another about 16 hours; vii) Step f) comprises filtering the third mixture to form a filter cake; (ii) Step g) comprises washing the filter cake preferably with acetone, more preferably with about 2.5 L / kg acetone; and viii) The yield of the method described is approximately 85%.

42. A method that is substantially as described in any of the aspects described herein.

43. A compound or composition produced by the method according to any one of claims 4 to 11, 14, 15, 17 to 23, 25 to 28, 31 to 33, 35, 37 to 39, 41 and 42.

44. A compound or composition produced by the method according to claim 12.

45. A compound or composition produced by the method according to claim 11.

46. ​​A compound or composition produced by the method according to claim 16.

47. A compound or composition produced by the method according to claim 24.

48. A compound or composition produced by the method according to claim 29.

49. A compound or composition produced by the method according to claim 30.

50. A compound or composition produced by the method according to claim 34.

51. A compound or composition produced by the method according to claim 36.

52. A compound or composition produced by the method according to claim 40.

Images