Process for producing triazine compound

Abstract

A process for producing the compound IV or a salt thereof by the reaction represented by the following scheme; wherein the symbol is the same as described in the description; a process for producing 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]- 5-(p-tolyl)-1,2,4-triazine by the reaction represented by the following scheme: and a process for producing 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]- 5-(p-tolyl)-1,2,4-triazine by the reaction represented by the following scheme: wherein the symbol is the same as described in the description.

Description

PROCESS FOR PRODUCING TRIAZINE COMPOUND

[0001] This application claims the priority of 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 publications are referenced, including referenced in parenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention.BACKGROUND OF THE INVENTION

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

[0004] PCT International Patent Application Publication No. WO 2022 / 059700 discloses the following method for producing the Triazine compound A.BRIEF SUMMARY OF THE INVENTION

[0005] The present invention relates to a process for producing a triazine compound or a production intermediate thereof which has an inhibitory action on aldosterone synthase and is useful as a drug, especially as a preventive or therapeutic drug for primary aldosteronism etc. More specifically, the present invention relates to a process for producing the following 3-[4-[[trans-4- (acetamino)cyclohexyl]carbamoylmethyl]piperazin-l-yl]-5-(p-tolyl)-l,2,4-triazine or a production intermediate thereof having excellent properties as an active pharmaceutical ingredient.Problems to be solved by the invention

[0006] An object of the present invention is to provide a process for producing the Triazine compound A or a production intermediate thereof which is one or more of more excellent in yield, production cost, number of production steps, convenience of purification, and the like, and more suitable for working in an industrial scale, as compared to conventional production processes.

[0007] Another object of the present invention is to provide a process for crystallizing the monohydrobromide salt of Triazine compound A which maximizes yield while allowing for particle size to be controlled.Means to solve the problems

[0008] The present inventors have earnestly studied to solve the above problems. As a result, they have found a production route through a production intermediate not requiring a protection reaction and a deprotection reaction from inexpensive starting materials, and successfully developed a process capable of producing the Triazine compound A or a production intermediate thereof in short steps and in a high yield using inexpensive reagents. Further, the present inventors have also successfully developed a production process in which a production intermediate is not isolated in a specific step and directly used in the next step, and completed the present invention.

[0009] Namely, the present invention provides the following:Process for producing a compound represented by Formula IV

[0010] (1) A process for producing a compound represented by Formula IV or a salt thereof:Formula IV wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule; the process comprising:(a) reacting a compound represented by Formula I or a salt thereof, an activating agent, and a compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof:Formula III wherein R1represents the same as defined above;Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group.

[0011] (2) The process according to (1), wherein reacting the compound represented byFormula I or a salt thereof, the activating agent, and the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof, is without isolating a compound represented by Formula II or a salt thereofFormula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group; andwherein R2and R3each independently represent a hydrogen atom or an amino protecting group.

[0012] (3) The process according to (1), wherein reacting the compound represented byFormula I or a salt thereof, the activating agent, and the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof, comprises isolating a compound represented by Formula II or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group.Process for producing a compound represented by Formula IV’

[0013] (4) The process according to any one of (1) to (3), wherein R1represents a hydrogen atom, for producing a compound of Formula IV’ :Formula IV’Process for producing a compound represented by Formula V

[0014] (5) A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula Vthe process comprising:(a) producing a compound represented by Formula IV’ or a salt thereof by a process of any one of (1) to (4):Formula IV’; and(b) reacting the compound represented by Formula IV’ or a salt thereof and a compound represented by Formula VI or a salt thereof to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula VI wherein X1represents a chlorine atom, a bromine atom, or a leaving group.Process for producing a compound represented by Formula VI or a salt thereof

[0015] (6) The process according to (5) further comprising 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:Formula VIIFormula VIIIwherein X1represents the same as defined above; and X2represents a chlorine atom, a bromine atom, or a leaving group.Process for producing a compound represented by Formula VII

[0016] (7) The process according to (6) further comprising subj ecting 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 IXProcess for producing a compound represented by Formula VII

[0017] (8) The process according to (6) further comprising subj ecting 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 thereofFormula XProcess for producing a compound represented by Formula VII

[0018] (9) A process for producing a compound represented by Formula VII, comprising subjecting a compound represented by Formula X to a reduction reaction.Formula X.Process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof

[0019] (10) A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereofFormula V the process comprising:(a) reacting a compound represented by Formula I or a salt thereof and an activating agent to produce and isolate a compound represented by Formula II or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group;(b) reacting the compound represented by Formula II or a salt thereof and a compound represented by Formula III or a salt thereof to produce a compound represented by Formula IV or a salt thereof:Formula III wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the moleculeFormula IV wherein R1represents 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 IXFormula VII.Process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof

[0020] (11) A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereofFormula V the process comprising:(a) reacting a compound represented by Formula I or a salt thereof and an activating agent to produce and isolate a compound represented by Formula II or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group;(b) reacting the compound represented by Formula II or a salt thereof and a compound represented by Formula III or a salt thereof to produce a compound represented by Formula IV or a salt thereof:Formula III wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the moleculeFormula IV wherein R1represents 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 thereofFormula VIIProcess for producing a compound represented by Formula V

[0021] (12) The process according to (10) or (11) further comprising:(a) reacting the 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 a compound represented by Formula VI or a salt thereof:Formula VIII wherein X1and X2each independently represent a chlorine atom, a bromine atom, or a leaving group;Formula VI wherein X1represents the same as defined above; and(b) reacting the compound represented by Formula IV or a salt thereof and the compound represented by Formula VI or a salt thereof to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof.

[0022] (13) The process according to any one of (7) to (12), wherein the reduction reaction is carried out by a reaction with a metal catalyst and hydrogen in a polar solvent.

[0023] (14) The process according to (13), wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.

[0024] (15) The process according to (13) or (14), wherein the metal catalyst is ruthenium — alumina (Ru / AhCh), ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, or nickel — diatomaceous earth nickel — alumina, or Raney nickel.

[0025] (16) The process according to (8) or (9), wherein the reduction reaction is carried out by reacting the compound represented by Formula X, a metal catalyst, and hydrogen in a polar solvent.

[0026] (17) The process according to (16), wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide, preferably methanol or tetrahydrofuran, more preferably a mixture of methanol and tetrahydrofuran.

[0027] (18) The process according to (16) or (17), wherein the metal catalyst is ruthenium — alumina, ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, nickel — diatomaceous earth, nickel — alumina, or Raney nickel, preferably Raney nickel.

[0028] (19) The process according to any one of (16) to (18), wherein the metal catalyst is washed with a polar aprotic solvent, preferably tetrahydrofuran (THF), prior to being combined with a solution of the compound represented by Formula X or salt thereof and a polar solvent, which polar solvent is preferably methanol.

[0029] (20) The process according to any one of (16) to (19), wherein the reduction reaction comprises stirring the compound represented by Formula X or salt thereof and metal catalyst in the polar solvent in the presence of hydrogen gas, preferably at 40-50°C under 0.35-0.50MPa of hydrogen gas, preferably for 2-6 hours.

[0030] (21) The process according to any one of (16) to (20), wherein a solid comprising a compound represented by Formula VII is formed by the reduction reaction.Formula VII

[0031] (22) The process according to (21), wherein the solid yields a peak area ratio of the compound represented by Formula X to the compound represented by Formula VII of less than or equal to 1% as measured by high pressure liquid chromatography (“HPLC”).

[0032] (23) The process according to (22), further comprising isolating the solid comprising the compound represented by Formula VII, preferably by steps of concentration, filtration, and washing, preferably wherein filtration is through diatomite, preferably wherein washing is with a polar aprotic solvent, more preferably THF, still more preferably wherein the isolating comprises a final step of concentration followed by washing with an organic solvent, preferably ethyl acetate, followed by drying.

[0033] (24) The process according to any one of (16) to (23), wherein the reaction yields the compound represented by Formula VII at a purity of greater than 94%, more preferably 95-97%, preferably wherein the reaction yields 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.Process for producing a compound represented by Formula V

[0034] (25) A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V; the process comprising reacting the compound represented by Formula II or a salt thereof and the compound represented by Formula XIII or a salt thereofFormula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group, preferably chlorine;Formula XIII.

[0035] (26) The process according to (25), wherein the compound represented by FormulaXIII or a salt thereof is produced by subjecting a compound represented by Formula XII or a salt thereof to a deprotection reaction, preferably wherein the deprotection reaction is a reduction reaction:Formula XII wherein Ri represents a protecting group, preferably an amino protecting group, more preferably a benzyloxy carbonyl group.

[0036] (27) The process according to (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:Formula XI wherein Ri represents an amino protecting group, preferably a benzyloxycarbonyl group;Formula VII.

[0037] (28) The process according to (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.

[0038] (29) The process 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 activating agent.Formula IProcesses for crystallizing the monohydrobromide salt of Compound V

[0039] (30) The process according to any one of (5) to (8) and (10) to (29) wherein the compound represented by Formula V free base is produced, further comprising a process for crystallizing the monohydrobromide salt of the compound represented by Formula V, the process comprising:(a) producing a solution of (1) the compound represented by Formula V free base, (2) a solvent such as ethanol or methanol, (3) water, and (4) hydrobromic acid, and(b) either:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and(c) collecting the resulting crystals.

[0040] (31 ) A process for crystallizing the monohydrobromide salt of a compound represented by Formula V:Formula V; the process comprising:(a) producing a solution of (1) the compound represented by Formula V free base, (2) a solvent such as ethanol or methanol, (3) water, and (4) hydrobromic acid, and(b) either:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and(c) collecting the resulting crystals.

[0041] (32) The process according to (30) or (31), comprising the following steps:(a) mixing the compound represented by Formula V free base with ethanol, water, and hydrobromic acid;(b) adding the resulting solution into acetone, preferably dropwise;(c) washing the resulting mixture with a mixed solution of ethanol and water;(d) cooling the resulting mixture and stirring;(e) collecting the resulting crystals; and(f) optionally washing the collected crystals with acetone;(g) optionally drying the washed crystals.

[0042] (33) The process according to (32), comprising one or more or all of the following features:(a) in step (a) the ratio by weight 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 into acetone at about 25-75°C, preferably about 50°C over 1 hour;(d) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00;(e) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours;(g) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and(h) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

[0043] (34) The process according to (30) or (31), comprising the following steps:(a) suspending the compound represented by Formula V free base in a solution of methanol and water to form a suspension of the compound represented by Formula V;(b) adding aqueous HBr 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) filtering the first solution;(e) charging acetone and crystallization seeds to the first solution to obtain a second mixture;(f) charging additional acetone to the second mixture to obtain a third mixture;(g) holding and cooling the third mixture;(h) filtering the third mixture to obtain a filter cake;(i) washing the filter cake to obtain crystals of the monohydrobromide salt of the compound represented by Formula V.

[0044] (35) The process according to (34), wherein the process comprises one or more or all of the following features:(i) step a) comprises suspending the compound represented by Formula V free base 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, aqueous HBr to the suspension of the compound represented by Formula V obtain the first mixture;(iii) step c) comprises heating the first mixture to about 45 to 60 °C, preferably about 50 °C, to obtain the first solution;(iv) step d) comprises filtering the first solution through a polish filter;(v) step e) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours;(vi) step f) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours, and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; ; and(x) the yield of the process is about 85%.Processes for recrystallizing the monohydrobromide salt of the compound represented by Formula V

[0045] (36) The process according to any one of (30) to (35), further comprising recrystallizing the monohydrobromide salt of the compound represented by Formula V, the process 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:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and(c) collecting the resulting crystals.

[0046] (37) A process for recrystallizing a monohydrobromide salt of a compound represented by Formula V:Formula V; the process comprising:(a) dissolving crystals of a monohydrobromide salt of the compound represented by Formula V in (1) a solvent such as ethanol or methanol, and (2) water, and(b) either:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and(c) collecting the resulting crystals.

[0047] (38) The process according to (36) or (37), comprising the following steps:(a) mixing crystals of the monohydrobromide salt of the compound represented by Formula V with ethanol and water;(b) adding the resulting solution into acetone, preferably dropwise;(c) washing the resulting mixture with a mixed solution of ethanol and water;(d) cooling the resulting mixture and stirring;(e) collecting the resulting crystals; and(f) optionally washing the collected crystals with acetone;(g) optionally drying the washed crystals.

[0048] (39) The process according to (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 into acetone at about 25-75°C, preferably about 50°C over 1 hour;(iii) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00;(iv) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours;(vi) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and(vii) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

[0049] (40) The process according to claim (36) or (37), comprising the following steps:(a) dissolving crystals of a monohydrobromide salt of the compound represented by Formula V in a solution of methanol and water to obtain a first solution;(b) filtering the first solution;(c) charging acetone and crystallization seeds to the first solution to obtain a second mixture;(d) charging additional acetone to the second mixture to obtain a third mixture;(e) holding and cooling the third mixture;(f) filtering the third mixture to obtain a filter cake;(g) washing the filter cake to obtain crystals of the monohydrobromide salt of the compound represented by Formula V.

[0050] (41) The process according to (40), wherein the process comprises one or more or all of the following features:(i) step a) comprises suspending crystals of a monohydrobromide salt 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) comprises heating to about 45 to 60 °C, preferably about 50 °C;(iii) step b) comprises filtering the first solution through a polish filter;(iv) step c) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours;(v) step d) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours, and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; and(ix) the yield of the process is about 85%.Processes according to any of one of the Aspects described herein

[0051] (42) A process substantially as described in any one of the Aspects described herein.Compounds and compositions produced according to the processes of the inventions

[0052] (43) A compound or composition produced according to a process of any one of (1) to(42).Effect of Invention

[0053] The processes for producing the Triazine compound A of the present invention are one or more of more excellent in yield, production cost, number of production steps, convenience of purification, and the like, and more suitable for working in an industrial scale, as compared to conventional production processes, and thus are useful as an industrial process for producing an active pharmaceutical ingredient.

[0054] The crystallization process of the present invention allows for a true crystallization of the monohydrobromide salt of Triazine compound A, where prior crystallization processes for Triazine compound A involved a slurry to slurry conversion. Further, the crystallization process of the present invention maximizes the yield of the product, in particular relative to the dihydrobromide salt, while allowing for particle size to be controlled.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0055] The definition of each group in the present description may be optionally combined with each other unless otherwise specified.

[0056] 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 the invention pertains. Although processes and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary processes and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, processes, and examples are illustrative only and are not intended to be necessarily limiting.

[0057] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word“or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins.

[0058] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.

[0059] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0060] In the description and claims of the present application, each of the verbs, “comprise,” “include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0061] In the present description, an alkyl group refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atom(s) (Ci -e), and especially a group having 1 to 4 carbon atom(s) (Ci .4 ) is preferable. Specific examples thereof include a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a t-butyl group, an i-amyl group, a n- pentyl group, and n-hexyl group, and preferable examples thereof include a methyl group, an ethyl group, an i-propyl group, and a t-butyl group.

[0062] In the present description, an alkoxy group refers to a monovalent group in which the above alkyl group is bound to an oxygen atom, and a group having 1 to 6 carbon atom(s) (Cue) is preferable, and a group having 1 to 4 carbon atom(s) (Ci .4 ) is more preferable. Specific examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, an i-propoxy group, a n- butoxy group, a t-butoxy group, an i-amyloxy group, a n-pentyloxy group, and a n-hexyloxy group,and preferable examples thereof include a methoxy group, an ethoxy group, an i-propoxy group, and a t-butoxy group.

[0063] In the present description, an alkoxy carbonyl group refers to a group in which the above alkoxy group is bound to a carbonyl group. Examples thereof include a straight or branched alkoxy carbonyl group having 2 to 7 carbon atoms (C2 - 7 ), and preferable examples thereof include an alkoxycarbonyl group having 1 to 4 carbon atoms (Ci .4 ) or in some cases 2 to 5 carbon atoms (C2 - 5 ). Specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an i-propoxycarbonyl group, a n-butoxy carbonyl group, and a t- butoxycarbonyl group.

[0064] In the present description, an aryl group refers to a 6 to 10 membered aromatic cyclic hydrocarbon group, and a monocyclic or bicyclic aryl group is preferable. Specific examples thereof include a phenyl group and a naphthyl group, and especially preferable examples thereof include a phenyl group.

[0065] In the present description, a sulfonate group refers to a group represented by the following formula:-X°'S"R4< wherein R4represents an optionally substituted alkyl group or an optionally substituted aryl group. Examples of substituent of the optionally substituted alkyl group include one or more substituent(s) selected from a halogen atom, a hydroxy group, a cyano group, and an alkoxy group, and preferable examples thereof include one or more halogen atom(s). Examples of substituent of the optionally substituted aryl group include an alkyl group and a nitro group, and preferable examples thereof include a methyl group and a nitro group. Preferable examples of aryl of the optionally substituted aryl group include a phenyl group.

[0066] In the present description, an “ester group” refers to a group represented by the following formula:wherein R5represents an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted amino group, preferably an optionally substituted alkyl group or an optionally substituted amino group, preferably wherein the optionally substituted alkyl group does not comprise a hydroxy substituent. Examples of substituent of the optionally substituted alkyl group and the optionally substituted alkoxy group include one or more substituent(s) selected from a halogen atom, a hydroxy group, a cyano group, and an alkoxy group, and preferable examples thereof include one or more halogen atom(s). Examples of substituent of the optionally substituted amino group include an alkyl group.

[0067] In the present description, a phosphate group refers to a group represented by the following formula:wherein R6and R7each independently represent an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkoxy group, -(OPO(R8))n- OH; wherein R8represents an alkyl group, and n represents any one integer of 1 to 6; and an optionally substituted amino group. Examples of substituent of the optionally substituted alkyl group and the optionally substituted alkoxy group include one or more substituent(s) selected from a halogen atom, a hydroxy group, a cyano group, and an alkoxy group. Examples of substituent of the optionally substituted amino group include an alkyl group.

[0068] In the present description, preferable examples of the “activating agent” include condensing agents, and specific examples thereof include chlorinating agents, brominating agents, PyBrop (registered trademark) (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), BOP (regi stered trademark) ( 1 H-benzotriazol- 1 -yl oxytri s(dimethyl ami no)phosphonium hexafluorophosphate), BOP-CI (registered trademark) (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), T3P (registered trademark) (propylphosphonic acid anhydride), T4P (registered trademark) (butylphosphonic acid anhydride), CDI (l,l'-Carbonyldiimidazole) and DPPC1 (diphenylphosphinic chloride). When Compound II to be described later or a salt thereof is notisolated, DPPC1 is preferable. Compound IT or a salt thereof may be isolated and used in the next step. When it is isolated, preferable examples thereof include chlorinating agents and brominating agents, and especially preferable examples thereof include chlorinating agents.

[0069] In the present description, examples of the “chlorinating agent” include chlorine, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, 2,4,6-trichloro-l,3,5- triazine, trichloroisocyanuric acid, N-chlorosuccinimide, l,3-dichloro-5,5-dimethylhydantoin, phosphorus trichloride, and phosphorus pentachloride, and preferable examples thereof include thionyl chloride.

[0070] In the present description, examples of the “brominating agent” include bromine, N- bromosuccinimide, l,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, and phosphorus tribromide.

[0071] In the present description, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferable examples thereof include a fluorine atom, a bromine atom, and a chlorine atom.

[0072] In the present description, examples of the “polar solvent” include alcohols, ethers, alkanes, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples thereof include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, tri ethyl amine, acetonitrile, and dimethylacetamide. Preferable examples thereof include propylene glycol methyl ether and 1,3 — dimethylimidazolidinone.

[0073] In the present description, the “aprotic solvent” means a solvent having no ionizable proton. Examples of the “aprotic solvent” include N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0074] In the present description, examples of the “leaving group” include a methanesulfonyl group, a p-toluenesulfonyl group, and a nitrobenzenesulfonyl group.

[0075] In the present description, examples of the “metal catalyst” include ruthenium — alumina (Ru / Ah Ch ), ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, and nickel — diatomaceous earth, and preferable examples thereof include ruthenium — alumina and Raney nickel.

[0076] In the present description, examples of the “amino protecting group” include protecting groups usually used in the field of organic synthetic chemistry, and specific examples thereof include a t-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2, 2, 2-trichloroethoxy carbonyl group, an allyloxycarbonyl group, an acetyl (i.e. COCH3) group, a trifluoroacetyl group, a p-toluenesulfonyl group, and a 2-nitrobenzenesulfonyl group, and especially preferable examples thereof include a t-butoxycarbonyl group and an acetyl (i.e. COCH3) group.

[0077] In the present description, the term of “isolation” refers to an operation such as concentration, filtration, and washing, and also includes purification by recrystallization or various chromatography etc. as well as drying the obtained product, and the like.

[0078] In the present description, the compound represented by Formula I has tautomerism, and includes both of the following states.

[0079] Thus, in the present description, “carbonyl group in the compound represented by Formula I” refers to the same substituent as “hydroxy group in the compound represented by Formula I”.

[0080] The following table summarizes the chemical formulas used throughout the present disclosure.Table 1Production process of the present invention

[0081] The production process of the present invention is a process for producing Compound IV or a salt thereof represented by the following scheme:wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule.

[0082] According to this production process, Compound IV or a salt thereof can be produced by reacting Compound I or a salt thereof, an activating agent, and Compound III or a salt thereof without isolating Compound II or a salt thereof.

[0083] Compound I or a salt thereof and Compound III or a salt thereof are known, or may be produced according to known method(s).

[0084] The amount of Compound III or a salt thereof to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound I or a salt thereof.

[0085] Examples of the activating agent include chlorinating agents, brominating agents, PyBrop (registered trademark), BOP (registered trademark), BOP-CI (registered trademark), T3P (registered trademark), and DPPC1, and preferable examples thereof include PyBrop (registered trademark), BOP (registered trademark), BOP-CI (registered trademark), T3P (registered trademark), T4P (registered trademark), and DPPC1, and especially preferable examples thereof include DPPC1.

[0086] Also, as shown in the following scheme, the compound represented by Formula TI (hereinafter also referred to as “Compound II”) or a salt thereof may be isolated, and used in the next step to be reacted with Compound III or a salt thereof. Examples of isolation include concentration, fdtration, and washing. Purification by recrystallization, column chromatography, or the like, as well as drying may also be carried out.wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group; and R1is the same as described above.

[0087] When Compound II or a salt thereof is isolated, preferable examples of the activating agent include chlorinating agents and brominating agents, and especially preferable examples thereof include chlorinating agents.

[0088] The following may be applied to this production process in common regardless of Compound II or a salt thereof being isolated or not, unless otherwise specified.

[0089] The amount of the activating agent to be used is usually 1.0 to 3.0 equivalent(s), and preferably 1.8 to 2.2 equivalents, relative to Compound I or a salt thereof.

[0090] The step of producing Compound IV or a salt thereof without isolating Compound II or a salt thereof or Step 1 in case Compound II or a salt thereof is isolated (hereinafter also referred to as “Present step”) is usually carried out in a solvent. The solvent may be any one as long as it does not affect this reaction, and examples thereof include aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert- butyl ether), and they may be appropriately combined with each other. Among them, preferable examples thereof include ethers and nitriles, and more preferable examples thereof include dimethoxy ethane and acetonitrile.

[0091] When PyBrop (registered trademark), BOP (registered trademark), BOP-CI (registered trademark), T3P (registered trademark), T4P (registered trademark), CDI or DPPC1 is used as the activating agent, the Present step is carried out in the presence of a base. Examples of the base include organic bases such as tri ethylamine, N,N-diisopropylethylamine, and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and preferable examples thereof include DBU.

[0092] The amount of the base to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound I or a salt thereof.

[0093] Step 1 in case Compound II or a salt thereof is isolated may be carried out in the presence of a catalyst, if necessary. Examples of the catalyst include dimethylformamide and N- methylpyrrolidone, and preferable examples thereof include dimethylformamide.

[0094] The amount of the catalyst to be used is usually 0.01 to 0.5 equivalent, and preferably 0.05 to 0.1 equivalent, relative to Compound I or a salt thereof.

[0095] When Compound II or a salt thereof is isolated, it is preferable that the reaction temperature is lowered to 0 to 20°C, and preferably to 5 to 10°C after Step 1, and water etc. is added thereto to obtain Compound II or a salt thereof as a crystal. When the mixture is cooled, triethylamine (TEA) may be added whereby the pH of the mixture is adjusted, preferably to a pH of about 4. After addition of water, preferably about 12 L / kg, the resulting crystals may be filtered, washed and dried.

[0096] In this reaction, it is necessary to change the reaction temperature depending on the type of the activating agent. When an activating agent such as PyBrop (registered trademark), BOP (registered trademark), BOP-CI (registered trademark), T3P (registered trademark), T4P (registered trademark), and DPPC1 is used, the reaction may be carried out at -40 to 60°C, and preferably at 0 to 20°C. The reaction temperature in case a chlorinating agent or a brominating agent is used in the presence of catalyst may be 40 to 100°C, preferably 60 to 90°C, and especially preferably 75 to 85°C.

[0097] Step 2 in case Compound II or a salt thereof is isolated is a step in which Compound II or a salt thereof is reacted with a compound represented by Formula III (hereinafter also referred to as “Compound III”) or a salt thereof to produce Compound IV or a salt thereof.

[0098] Step 2 in case Compound II or a salt thereof is isolated may be carried out in the absence of Step 1. In this case, Compound II is the starting material for the process and may be obtained according to known processes.

[0099] Compound III or a salt thereof is known, or may be produced according to known method(s).

[0100] The amount of Compound III or a salt thereof to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound II or a salt thereof. In the case that Ri isan amino protecting group such as a tert-butoxy carbonyl, the amount of Compound III or a salt thereof to be used is preferably 1 to 1.5 equivalents, more preferably 1 to 1.1 equivalents.

[0101] Step 2 may be usually carried out in a solvent.

[0102] The solvent may be any one as long as it does not affect this reaction, and examples thereof include aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl Zc / 7-butyl ether), and alcohols (for example, methanol, ethanol, and isopropanol), and they may be appropriately combined with each other. Among them, preferable examples thereof include aprotic solvents and alcohols, more preferable examples thereof include N-methyl-2-pyrrolidone and methanol, and further more preferable examples thereof include a mixed solvent of N-methyl-2-pyrrolidone and methanol.

[0103] Step 2 may be carried out in the presence of a base, and examples of the base include organic bases such as tri ethylamine, N,N-di isopropyl ethyl amine, and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metal carbonates such as sodium carbonate and potassium carbonate, and among them, preferable examples thereof include triethylamine and N,N-diisopropyl ethylamine.

[0104] The amount of the base to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound II or a salt thereof.

[0105] This reaction may be carried out at 50 to 100°C, and preferably at 50 to 70°C.

[0106] The present invention also provides a composition comprising 99.1% to 99.9% Compound IV, said composition preferably comprising 0.1% to 0.9%, preferably less than 0.9%, more preferably less than 0.1% Compound I, Compound II and Compound III, preferably wherein said composition is produced according to the Present production process, more preferably according to any of the below aspects.Aspects of the production process of the present invention (Present production process)

[0107] Aspects of the production process of the present invention (Present production process) include the following.Aspect A l

[0108] The Present production process, wherein R1(i.e. of Compound III and IV of the Present production process) represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule.Aspect A2

[0109] The Present production process, wherein R1represents a hydrogen atom.Aspect A3

[0110] The Present production process, wherein R1represents an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group.Aspect A4

[0111] The Present production process, wherein R1represents a methyl group optionally substituted with a carboxy group or a methoxycarbonyl group.Aspect A5

[0112] The Present production process, wherein R1represents an amino protecting group.Aspect A6

[0113] The process according to Aspect A5, wherein the amino protecting group represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, a p-toluenesulfonyl group, or a 2-nitrobenzenesulfonyl group.Aspect A 7

[0114] The process according to Aspect A5, wherein the amino protecting group represents a tert-butoxy carbonyl group or a benzyloxycarbonyl group, preferably a tert-butoxycarbonyl group.Aspect A8

[0115] The Present production process, wherein R1represents a group represented by the following formula:wherein the symbols are the same as described above.Aspect A9

[0116] The process according to Aspect A8, wherein the amino protecting group in R2and R3represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9- fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, a p-toluenesulfonyl group, or a 2- nitrobenzenesulfonyl group.Aspect Al 0

[0117] The process according to Aspect A8, wherein the amino protecting group in R2and R3represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or an acetyl group.Aspect All

[0118] The process according to Aspect A8, wherein R2and R3each represent a hydrogen atom.Aspect Al 2

[0119] The process according to any one of Aspects Al to Al 1, wherein the activating agent represents a chlorinating agent, a brominating agent, PyBrop (registered trademark), BOP (registered trademark), BOP-CI (registered trademark), T3P (registered trademark), or DPPC1.Aspect A l 3

[0120] The process according to any one of Aspects Al to Al 1, wherein the activating agent represents DPPC1, and the process comprises a step of obtaining the compound represented by Formula IV or a salt thereof without isolating Compound II or a salt thereof.Aspect Al 4

[0121] The process according to any one of Aspects Al to Al 1, wherein the activating agent represents a chlorinating agent or abrominating agent, and Compound II or a salt thereof is isolated to be used in the next step.Aspect Al 5

[0122] The process according to any one of Aspects Al to A14, which is carried out in a solvent.Aspect Al 6

[0123] The process according to Aspect A15, wherein the solvent is an ether or a nitrile.Aspect Al 7

[0124] The process according to Aspect A15, wherein the solvent is dimethoxyethane or acetonitrile.Aspect Al 8

[0125] The process according to Aspect A15, wherein the solvent is acetonitrile.Aspect A 19

[0126] The process according to any one of Aspects Al to A18, which is carried out in the presence of a base.Aspect A20

[0127] The process according to Aspect A19, wherein the base is one or two or more selected from triethylamine, N,N-diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Aspect A21

[0128] The process according to Aspect Al 9, wherein the base is 1,8- di azabi cyclo [ 5.4.0] undec- 7-ene (DBU) .Aspect A 22

[0129] The process according to any one of Aspects Al to A21, which is carried out in the presence of a catalyst.Aspect A23

[0130] The process according to Aspect A22, wherein the catalyst is dimethylformamide or N-methy 1 py rroli done .Aspect A24

[0131] The process according to Aspect A22, wherein the catalyst is dimethylformamide.Aspect A25

[0132] The process according to Aspect A7, which is carried out in a solvent, preferably an aprotic solvent, more preferably dimethoxyethane (“DME”).Aspect A26

[0133] The process according to Aspect A7 or A25, which is carried out in the presence of a base such as potassium carbonate or tri ethyl amine, preferably an amine base, more preferably triethylamine.Aspect A27

[0134] The process according to Aspect A26, wherein the reaction comprises stirring, preferably at 10-40 °C, more preferably 20-30 °C.Aspect A28

[0135] The process according to any one of Aspects A25 to A27, further comprising isolating Compound IV as an acid salt, preferably as Compound IV • 2 hydrochloric acid (“HQ”).Aspect A29

[0136] The process according to Aspect A28, wherein HC1 is added to the reaction, preferably dropwise, wherein the reaction is then warmed while stirring, preferably to 40-70°C, more preferably 50-60°C.Aspect A 30

[0137] The process according to Aspect A29, wherein the amino protecting group is a tertbutoxycarbonyl group and the addition of HC1 first removes the tert-butoxy carbonyl group such that the tert-butoxycarbonyl group is removed without the need for a subsequent isolation step.Aspect A31

[0138] The process according to Aspect any one of Aspects A25 to A30, comprising isolating Compound IV substantially as described in Example 16 (Process for producing Compound 4).Aspect A32

[0139] The process according to Aspect any one of Aspects A25 to A31, wherein the reaction has a yield of Compound IV of at least 90%, preferably 90 to 95%, at a chemical purity of greater than 99%, preferably 99.1 to 99.9%.Process for producing Compound V (Triazine compound A)

[0140] The present invention also provides a process for producing the compound represented by Formula V (hereinafter also referred to as “Compound V”) or a pharmacologically acceptable salt thereof represented by the following scheme:wherein X1represents a chlorine atom, a bromine atom, or a leaving group.

[0141] This production process is a process for producing the compound represented by Formula V or a pharmacologically acceptable salt thereof by reacting the compound represented by Formula IV’ (hereinafter also referred to as “ Compound IV’ “) or a salt thereof and the compound represented by Formula VI (hereinafter also referred to as “Compound VI”) or a salt thereof.

[0142] Compound IV’ or a salt thereof may be produced by, for example, the Present production process according to any one of the above Aspects Al to A32.

[0143] The reaction to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof represented by the above scheme is usually carried out in a solvent, in the presence of a base if necessary.

[0144] The solvent may be any one as long as it does not affect this reaction, and examples thereof include aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, dimethoxyethane and methyl tert-butyl ether), and they may be appropriately combined with each other. Among them, preferable examples thereof include aprotic solvents, and more preferable examples thereof include dimethyl sulfoxide.

[0145] Examples of the base include organic bases such as triethylamine, N,N- diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and among them, preferable examples thereof include N,N-diisopropylethylamine.

[0146] The amount of Compound VI or a salt thereof to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound IV’ or a salt thereof. Alternatively, Compound VI may be present in only a slight excess relative to Compound IV’, i.e. 1 to 1.1 equivalents.

[0147] The amount of the base to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound IV’ or a salt thereof.

[0148] This reaction may be carried out at 50 to 100°C, and preferably at 50 to 70°C.

[0149] The present invention also provides a composition comprising 99.9% Compound V or a salt thereof, said composition preferably comprising 0.1%, preferably less than 0.1% Compound IV’ and Compound VI, preferably wherein said composition is produced according to the above process for producing Compound V, more preferably according to any of the below aspects.Aspects of the process for producing Compound V

[0150] Aspects of the process for producing Compound V or a salt thereof include the following.Aspect Bl

[0151] A process for producing Compound V or a pharmacologically acceptable salt thereof, which comprise a step of reacting Compound IV’ or a salt thereof and Compound VI or a salt thereof to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof.Aspect B2

[0152] The process according to Aspect B l, which comprises a step of producing Compound IV’ or a salt thereof by the above Present production process according to any one of Aspects Al to A32.Aspect B3

[0153] The process according to Aspect Bl or B2, wherein X1represents a chlorine atom.Aspect B4

[0154] The process according to Aspect Bl or B2, wherein X1represents a bromine atom.Aspect B5

[0155] The process according to Aspect Bl or B2, wherein X1represents a leaving group.Aspect B6

[0156] The process according to Aspect Bl, B2, or B5, wherein the leaving group represents a methanesulfonate group, a p-toluenesulfonate group, or a nitrobenzenesulfonate group.Aspect B7

[0157] The process according to any one of Aspects Bl to B6, wherein the reaction to produce Compound V or a pharmacologically acceptable salt thereof is carried out in a solvent in the presence of a base.Aspect B8

[0158] The process according to Aspect B7, wherein the solvent is an aprotic solvent.Aspect B9

[0159] The process according to Aspect B8, wherein the aprotic solvent is N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone.Aspect BIO

[0160] The process according to Aspect B7, wherein the solvent is dimethyl sulfoxide.Aspect Bl 1

[0161] The process according to any one of Aspects B7 to BIO, wherein the base is one or two or more selected from tri ethylamine, N,N-diisopropylethylamine, and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).Aspect B 12

[0162] The process according to any one of Aspects B7 to BIO, wherein the base is N,N- diisopropylethylamine.Aspect Bl 3

[0163] The process according to Aspect B7, wherein the solvent is tetrahydrofuran, preferably in tetrahydrofuran in the presence of water; more preferably a 2: 1 solution of water: tetrahydrofuran.Aspect B 14

[0164] The process according to Aspect B7 or B 13, wherein the base is potassium carbonate. Aspect Bl 5

[0165] The process according to any one of Aspects B13 to B14, wherein the reaction to produce Compound V or a salt thereof is carried out for 4-10 hours at a temperature of 20 to 50°C, preferably 30-40°C.Aspect B 16

[0166] The process according to any one of Aspects Bl to Bl 5, further comprising isolating Compound V as a free base, preferably substantially as described in Example 17 (Process for producing Compound 5 free base).Aspect Bl 7

[0167] The process according to any one of Aspects Bl to Bl 6, wherein the reaction has a yield of Compound V of at least 80%, preferably 80% to 90%, at a chemical purity of greater than 99%, preferably 99.9%.Process for producing Compound VI

[0168] The present invention also provides a process for producing Compound VI or a salt thereof represented by the following scheme:wherein X1and X2each independently represent a chlorine atom, a bromine atom, or a leaving group.

[0169] This production process is a process for producing Compound VI or a salt thereof by reacting the compound represented by Formula VII (hereinafter also referred to as “Compound VII”) or a salt thereof, a base, and the compound represented by Formula VIII (hereinafter also referred to as “Compound VIII”) or a salt thereof in a solvent.

[0170] Compound VII or a salt thereof and Compound VIII or a salt thereof are known, or may be produced according to known method(s) or the processes described herein. For example, Compound VII may be produced according to Aspects DI to D6, or alternatively according to Aspects El to El 2.

[0171] The solvent may be any one as long as it does not affect this reaction, and examples thereof include aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2 -pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), and chlorinated solvents (for example, di chloromethane), and they may be appropriately combined with each other. Among them, preferable examples thereof include aprotic solvents, and more preferable examples thereof include N,N- dimethylformamide.

[0172] Examples of the base include organic bases such as triethylamine, N,N- diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metalcarbonates such as sodium carbonate and potassium carbonate, and preferable examples thereof include potassium carbonate.

[0173] The amount of Compound VIII or a salt thereof to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound VII or a salt thereof. In the case X1and X2each represent a bromine atom, the amount of Compound VIII or a salt thereof to be used is usually 1 to 5 equivalent(s), and preferably 1.5 to 2.0 equivalents, relative to Compound VII or a salt thereof.

[0174] The amount of the base to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to Compound VII or a salt thereof.

[0175] This reaction may be carried out at -10 to 100°C, or 0 to 100°C, and preferably at -10 to 0°C or 0 to 30°C.

[0176] The present invention also provides a composition comprising 98% to 99.5% Compound VI or a salt thereof, said composition preferably comprising 0.5% to 2%, preferably less than 2%, more preferably less than 0.5% Compound VII and Compound VIII, preferably wherein said composition is produced according to the above process for producing Compound VII, more preferably according to any of the below aspects.Aspects of the process for producing Compound VI or a salt thereof

[0177] Aspects of the process for producing Compound VI or a salt thereof include the following.Aspect Cl

[0178] A process for producing Compound VI or a salt thereof, which comprises a 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.Aspect C2

[0179] The process according to Aspect Cl, wherein X1and X2each independently represent a chlorine atom or a bromine atom.Aspect C3

[0180] The process according to Aspect Cl, wherein X1and X2each represent a chlorine atom.Aspect C4

[0181] The process according to Aspect Cl, wherein X1and X2each represent a bromine atom.Aspect C5

[0182] The process according to Aspect Cl, wherein X1represents a leaving group.Aspect C6

[0183] The process according to Aspect Cl or C5, wherein X2represents a leaving group.Aspect C 7

[0184] The process according to Aspect Cl, C5, or C6, wherein the leaving group is a halogen atom, a sulfonate group, or an alkoxy group.Aspect C8

[0185] The process according to any one of Aspects Cl to C7, wherein the solvent is an aprotic solvent.Aspect C9

[0186] The process according to Aspect C8, wherein the aprotic solvent is N,N- dimethylformamide.Aspect CIO

[0187] The process according to any one of Aspects Cl to C7, wherein the solvent is a chlorinated solvent, preferably dichloromethane, more preferably in the form of a 2: 1 solution of di chi orom ethane : water.Aspect CllThe process according to any one of Aspects Cl to CIO, wherein the base is an alkali metal carbonate.Aspect C 12

[0188] The process according to any one of Aspects Cl to Cl 1, wherein the base is potassium carbonate.Aspect Cl 3

[0189] The process according to any one of Aspects Cl to Cl 2, further comprising isolating Compound VI, preferably substantially as described in Example 3 (Process for producing Compound 6) or Example 15 (Process for producing Compound 6b).Aspect C14

[0190] The process according to any one of Aspects Cl to C13, wherein the reaction has a yield of Compound VI of at least 85%, preferably 85% to 95%, at a chemical purity of greater than 98%, preferably 98% to 99.5%.Process for producing Compound VII

[0191] The present invention also provides a process for producing Compound VII or a salt thereof by subjecting the compound represented by the following Formula IX (hereinafter also referred to as “Compound IX”) or a salt thereof to a reduction reaction.

[0192] This reduction reaction is usually carried out by reacting Compound IX or a salt thereof, a metal catalyst, and hydrogen in a polar solvent.

[0193] Compound IX or a salt thereof is known, or may be produced according to known method(s).

[0194] Examples of the polar solvent include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples thereof include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone,1.3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, and preferable example thereof include propylene glycol methyl ether and1.3 — dimethylimidazolidinone.

[0195] Examples of the metal catalyst include ruthenium — alumina (Ru / Ah Ch ), ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, and nickel — diatomaceous earth, and preferable examples thereof include ruthenium — alumina.

[0196] The amount of the metal catalyst to be used is usually 0.01 to 0.5 weight equivalent, and preferably 0.05 to 0.1 weight equivalent, relative to Compound IX or a salt thereof.

[0197] The amount of hydrogen to be used is usually 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, more preferably 3 to 4 equivalents, relative to Compound IX or a salt thereof. In the case where the hydrogen is present in the form of a gas, it may be at a pressure of 3 to 5 MPa, preferably about 4 MPa.

[0198] This reaction may be carried out at 50 to 200°C, and preferably at 100 to 180°C.

[0199] The present invention also provides a composition comprising at least 60% preferably 60% to 75% Compound VII or a salt thereof, said composition preferably comprising less than 40%, preferably 25-35% Compound 10, and 1 to 5%, preferably less than 5%, more preferably less than 3% Compound 11, preferably wherein said composition is produced according to the above process for producing Compound VII, more preferably according to any of the below aspects.Aspects of the process for producing Compound VII or a salt thereof

[0200] Aspects of the process for producing Compound VII or a salt thereof include the following.Aspect DI

[0201] A process for producing Compound VII or a salt thereof, which comprises a step of subjecting Compound IX or a salt thereof to a reduction reaction to produce Compound VII or a salt thereof.Aspect D2

[0202] The process according to Aspect DI, wherein the reduction reaction is carried out by reacting Compound IX or a salt thereof, a metal catalyst, and hydrogen in a polar solvent.Aspect D3

[0203] The process according to Aspect D2, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.Aspect D4

[0204] The process according to Aspect D2, wherein the polar solvent is propylene glycol methyl ether or 1,3 — dimethylimidazolidinone.Aspect D5

[0205] The process according to any one of Aspects D2 to D4, wherein the metal catalyst is ruthenium — alumina, ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, or nickel — diatomaceous earth.Aspect D6

[0206] The process according to any one of Aspects D2 to D4, wherein the metal catalyst is ruthenium — alumina.Alternative Process for producing Compound VII

[0207] The present invention also provides an alternative process for producing Compound VII or a salt thereof by subjecting the compound represented by the following Formula X (hereinafter also referred to as “Compound X”) or a salt thereof to a reduction reaction.X

[0208] This reduction reaction is usually carried out by reacting Compound X, a metal catalyst, and hydrogen in polar solvent.

[0209] Compound X may be produced according to known method(s).

[0210] Examples of the polar solvent include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples thereof include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone,1.3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, and preferable example thereof include propylene glycol methyl ether and1.3 — dimethylimidazolidinone. A preferable polar solvent in this process is methanol.

[0211] Examples of the metal catalyst include ruthenium — alumina (Ru / Ah Ch ), ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, nickel — diatomaceous earth, nickel — alumina, and Raney nickel. Preferable examples thereof include nickel — alumina, and Raney nickel.

[0212] The amount of the metal catalyst to be used is usually 0.01 to 0.5 equivalent, and preferably 0.2 to 0.4 equivalent, relative to Compound X.

[0213] The hydrogen to be used is usually present as a gas at a pressure of 0.25-0.75Mpa, preferably 0.35-0.50 Mpa.

[0214] This reaction may be carried out at 35 to 200°C, preferably at 40 to 70°C, and more preferably 40 to 50 °C.

[0215] The present invention also provides a composition comprising greater than 94% preferably 95-97% Compound VII or a salt thereof, said composition preferably comprising less than 5%, preferably 1-3% of the cv.s-isomer of Compound VII, preferably wherein said composition is produced according to the above process for producing Compound VII, more preferably according to any of the below aspects.Aspects for the alternative process for producing Compound VII

[0216] Aspects for the alternative process for producing Compound VII include the following. Aspect El

[0217] A process for producing Compound VII or a salt thereof, which comprises a step of subjecting Compound X to a reduction reaction to produce Compound VII or a salt thereof.Aspect E2

[0218] The process according to Aspect El, wherein the reduction reaction is carried out by reacting Compound X, a metal catalyst, and hydrogen in a polar solvent.Aspect E 3

[0219] The process according to Aspect E2, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide.Aspect E4

[0220] The process according to Aspect E2, wherein the polar solvent is methanol, tetrahydrofuran, or a mixture of methanol and tetrahydrofuran.Aspect E5

[0221] The process 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 — diatomaceous earth, nickel — alumina, or Raney nickel.Aspect E6

[0222] The process according to any one of Aspects E2 to E4, wherein the metal catalyst is nickel — alumina, preferably Raney nickel.Aspect E7

[0223] The process according to any one of Aspects E2 to E6, wherein the metal catalyst is washed with polar aprotic solvent, preferably tetrahydrofuran (THF), prior to being combined with Compound X or salt thereof in a solution with a polar solvent, which polar solvent is preferably methanol.Aspect E8

[0224] The process according to any one of Aspects E2 to E7, wherein the reduction reaction comprises stirring the Compound X or salt thereof and metal catalyst in the polar solvent in the presence of hydrogen gas, preferably at 40-50°C under 0.35-0.50Mpa of hydrogen gas, preferably for 2-6 hours.Aspect E9

[0225] The process according to any one of Aspects E2 to E8, wherein a solid comprising Compound VII is formed by the reduction reaction.Aspect E10

[0226] The process according to Aspect E9, wherein the solid yields a peak area ratio of Compound X to Compound VII of less than or equal to 1% as measured by high pressure liquid chromatography (“HPLC”).Aspect Ell

[0227] The process according to Aspect E10, further comprising isolating the solid comprising Compound VII, preferably by steps of concentration, fdtration, and washing, preferably wherein filtration is through diatomite, preferably wherein washing is with a polar aprotic solvent, more preferably THF, still more preferably wherein the isolating comprises a final step of concentration followed by washing with an organic solvent, preferably ethyl acetate, followed by drying, still more preferably wherein isolating is substantially as described in Example 7 (Process for producing Compound 7) or Example 8 (Scaled up process for producing Compound 7).Aspect El 2

[0228] The process according to Aspect El to El 1, wherein the process yields Compound VII at a purity of greater than 94%, more preferably 95-97%, preferably wherein the process yields less than 5% of the c / .s-i sorrier of Compound VII, more preferably 1-3% of the c / .s-isomer of Compound VII.Process for producing Compound XII

[0229] The present invention also provides a process for producing Compound XII or a salt thereof represented by the following scheme:wherein Ri represents an amino protecting group, preferably a benzyloxycarbonyl group.

[0230] This production process is a process for producing Compound XII or a salt thereof by reacting Compound VII or a salt thereof, a base, and the compound represented by Formula XI(hereinafter also referred to as “Compound XI”) or a salt thereof in a solvent, in the presence of a condensing agent.

[0231] Compound XI or a salt thereof is known, or may be produced according to known method(s).

[0232] The solvent may be any one as long as it does not affect this reaction, and examples thereof include polar organic solvents (for example ethanol and methanol), aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and dichloromethane), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and they may be appropriately combined with each other. Among them, preferable examples thereof include aprotic solvents, and more preferable examples thereof include dichloromethane.

[0233] Examples of the base include organic bases such as triethylamine, N,N- diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metal carbonates such as sodium carbonate and potassium carbonate, and preferable examples thereof include potassium carbonate.

[0234] Examples of the base include non-nucleophilic bases, and preferable examples thereof include diisopropylethylamine.

[0235] The condensing agent may be any condensing agent capable of forming an amide or peptide bond. Condensing agents capable of forming an amide or peptide bond are described in El-Faham, A., & Albericio, F. (2011). Peptide coupling reagents, more than a letter soup. Chemical Reviews, 777(11), 6557-6602, the contents of which are specifically incorporated by reference herein for its description of condensing agents capable of forming an amide or peptide bond. Preferable examples of such condensing agents include propylphosphonic anhydride (“T3P”) and butylphosphonic anhydride (“T4P”). Such a condensing agent is preferably dissolved in polar solvent which is preferably ethyl acetate. The amount of the condensing agent to be used may be 1 to 2 equivalents, preferably 1.3-1.7 equivalents.

[0236] The amount of Compound VIT or a salt thereof to be used is usually 1.0 to 1.1 equivalents relative to Compound XI or a salt thereof.

[0237] The amount of the base to be used is usually 1 to 10 equivalent(s), and preferably 4 to 5 equivalent(s), relative to Compound XI or a salt thereof.

[0238] This reaction may be carried out at 0 to 100 °C, preferably at 0 to 30°C, and more preferably 0 to 10 °C.

[0239] The present invention also provides a composition comprising at least 99% preferably 99.1% to 99.9% Compound XII or a salt thereof, said composition preferably comprising an isomeric purity of at least 99.5%, preferably 99.5% to 99.9%, preferably wherein said composition is produced according to the above process for producing Compound XII, more preferably according to any of the below aspects.Aspects of the process for producing Compound XII

[0240] Aspects for the process for producing Compound XII include the following.Aspect Fl

[0241] A process for producing Compound XII or a salt thereof, which comprises a 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.Aspect F2

[0242] The process according to Aspect Fl, wherein the solvent is an aprotic solvent.Aspect F3

[0243] The process according to Aspect F2, wherein the aprotic solvent is dichloromethane.Aspect F4

[0244] The process according to any one of Aspects Fl to F3, wherein the base is non- nucleophilic.Aspect F5

[0245] The process according to Aspect F4, wherein the non-nucleophilic base is diisopropylethylamine.Aspect F 6

[0246] The process according to any one of Aspects Fl to F5, wherein the condensing agent capable of forming an amide or peptide bond, preferably selected from those described in El- Faham, A., & Albericio, F. (2011). Peptide coupling reagents, more than a letter soup. Chemical Reviews, 7 / 7(11), 6557-6602, the contents of which are specifically incorporated by reference herein for its description of condensing agents capable of forming an amide or peptide bond.Aspect F7

[0247] The process according to Aspect F6, wherein 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 1.3-1.7 equivalents.Aspect F8

[0248] The process according to any one of Aspects F6 to F7, wherein the condensing agent is added to a solution of the solvent, the base, Compound VII, and Compound XI, preferably over the course of an hour or longer.Aspect F9

[0249] The process according to Aspect F8, wherein the solution is chilled, preferably to 0- 10°C, prior to the condensing agent being added.Aspect F JO

[0250] The process according to any one of Aspects Fl to F9, further comprising isolating Compound XII.Aspect Fl 1

[0251] The process according to Aspect Fl 0, wherein isolating Compound XII comprises steps of concentration, filtration, and washing, preferably substantially as described in Example 9 (Process for producing Compound 15) or Example 10 (Scaled up process for producing Compound 15).Aspect FI 2

[0252] The process according to Aspect Fl to Fl 1, wherein the reaction has a yield of Compound XII of at least 90%, preferably 91% to 96%, at a chemical purity of greater than 99%, preferably 99.1 to 99.9% and / or an isomeric purity of at least 99.5%, preferably 99.5% to 99.9%.Process for producing Compound XIII

[0253] The present invention also provides a process for producing Compound XIII or a salt thereof by subjecting the compound represented by the following Formula XII (hereinafter also referred to as “Compound XII”) or a salt thereof to a reaction which removes Ri:XII wherein Ri represents a protecting group, preferably an amino protecting group, more preferably a benzyloxy carbonyl group;Compound XIII.

[0254] When Ri represents a protecting group that can be removed by a reduction reaction, such as a benzyloxy carbonyl group, the process comprises subjecting Compound XII to a reduction reaction.

[0255] This reduction reaction is usually carried out by reacting Compound XII or a salt thereof, a metal catalyst, and hydrogen in a polar solvent.

[0256] Examples of the polar solvent include alcohols, ethers, esters, ketones, carboxylic acids, amines, nitriles, and amides, and specific examples thereof include methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone,1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, and dimethylacetamide, and preferable example thereof include methanol.

[0257] Examples of the metal catalyst include ruthenium — alumina (Ru / Ah Ch ), ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, and nickel — diatomaceous earth, and preferable examples thereof include palladium — carbon.

[0258] The amount of the metal catalyst to be used is usually 0.01 to 0.5 equivalent, and preferably 0.05 to 0.1 equivalent, relative to Compound XII or a salt thereof. Where the catalyst is palladium — carbon, the catalyst may be 50% wet with water, in which case the preferred amount, relative to Compound XII is 0.02 to 0.04 weight equivalents. Where the palladium — carbon catalyst is dry, the preferred amount can be readily determined based on the preferred amount of 50% wet palladium — carbon catalyst.

[0259] This reaction may be carried out at 10-50°C, and preferably at 20 to 35°C.

[0260] This reaction may be carried out under 0.1-0.5 Mpa hydrogen, preferably 0.25-0.4 Mpa hydrogen.

[0261] The present invention also provides a composition comprising at least 99% preferably 99.1% to 99.9% Compound XIII or a salt thereof, said composition preferably comprising less than 0.9% Compound XII, preferably 0.1 to 0.9% Compound XII, preferably wherein said composition is produced according to the above process for producing Compound XIII, more preferably according to any of the below aspects.Aspects of the process for producing Compound XIII

[0262] Aspects for the process for producing Compound XIII include the following.Aspect G1

[0263] A process for producing Compound XIII or a salt thereof, which comprises a step of subjecting Compound XII or a salt thereof to a reaction which removes the protecting group, to produce Compound XIII or a salt thereof.Aspect G2

[0264] The process according to Aspect G1 wherein the protecting group is protecting group that can be removed by a reduction reaction, preferably an amino protecting group, more preferably a benzyloxy carbonyl group, and the reaction to remove the protecting group is a reduction reaction. Aspect G3

[0265] The process according to Aspect G1 or G2, which comprises a step of producing Compound XII or a salt thereof by the above process for producing Compound XII, preferably according to any one of aspects Fl to Fl 2.Aspect G4

[0266] The process according to Aspect G2 or G3, wherein the reduction reaction is carried out by reacting Compound XII or a salt thereof, a metal catalyst, and hydrogen in a polar solvent. Aspect G5

[0267] The process according to Aspect G4, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or dimethylacetamide, preferably methanol.Aspect G6

[0268] The process according to any one of Aspects G4 to G5, wherein the catalyst is ruthenium — alumina, ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, or nickel — diatomaceous earth, preferably palladium — carbon.Aspect G7

[0269] The process according to any one of Aspects G4 to G6, wherein the reduction reaction comprises stirring the Compound XII and metal catalyst in the polar solvent in the presence of hydrogen gas, preferably at 20-35°C under 0.27-0.35Mpa hydrogen for 3-7 hours.Aspect G8

[0270] The process according to any one of Aspects G4 to G7, further comprising producing a suspension of Compound XIII.Aspect G9

[0271] The process according to Aspect G8, wherein the suspension of Compound XIII is produced by concentrating the Compound XIII in solvent to form concentrated Compound XIII, chilling the concentrated Compound XIII, preferably to -15 to 10°C, and adding an organic solvent, preferably methyl tert-butyl ether (“MTBE”).Aspect GIO

[0272] The process according to any one of Aspects G7 to G9, further comprising stirring the suspension of Compound XIII at a chilled temperature, preferably at -15 to 10°C for at least 10 hours, preferably for 15-25 hours.Aspect Gil

[0273] The process according to any one of Aspects G8 to GIO, further comprising filtering the suspension of Compound XIII to produce a filter cake, preferably further comprising washing the filter cake with a solvent, preferably with MTBE.Aspect GJ 2

[0274] The process according to any one of Aspects G1 to Gi l, wherein Compound XIII is isolated substantially as described in Example 11 (Process for producing Compound 16) or Example 12 (Scaled up process for producing Compound 16).Aspect G13

[0275] The process according to any one of Aspects G1 to G12, wherein the reaction has a yield of Compound XIII of at least 90%, preferably 90 to 95%, at a chemical purity of greater than 99%, preferably 99.1 to 99.9%.Process for producing Compound V (Triazine compound A)

[0276] The present invention also provides an alternative process for producing the compound represented by Formula V (hereinafter also referred to as “Compound V”) or a pharmacologically acceptable salt thereof represented by the following scheme:wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group, preferably chlorine.

[0277] This production process is a process for producing the compound represented by Formula V or a pharmacologically acceptable salt thereof by reacting the compound represented by Formula II (also referred to as “ Compound II“) or a salt thereof and the compound represented by Formula XIII (also referred to as “Compound XIII”) or a salt thereof.

[0278] Compound II or a salt thereof is known, or may be produced according to known method(s). Compound II may be produced, for example, according to Step 1 of the above “Production process of the present invention”, i.e. by producing Compound II or a salt thereof from Compound I or a salt thereof. Thus, Compound II may be produced, for example, according to any one of the above Aspects Al to A32 to the extent these aspects apply to producing Compound II or a salt thereof from Compound I or a salt thereof.

[0279] Compound XIII may be produced by, for example, according to the process for producing Compound XIII described herein, in particular according to any one of the above Aspects G1 to G12.

[0280] The reaction to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof represented by the above scheme is usually carried out in a solvent, in the presence of a base if necessary.

[0281] The solvent may be any one as long as it does not affect this reaction, and examples thereof include polar organic solvents (for example ethanol and methanol), aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and dichloromethane), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, dimethoxyethane, and methyl tert-butyl ether), and they may be appropriatelycombined with each other. Among them, preferable examples thereof include aprotic solvents, preferably polar aprotic solvents. One preferable example of a solvent for this reaction is dichloromethane.

[0282] Examples of the base include inorganic bases such as alkali carbonates including sodium carbonate and potassium carbonate, organic bases such as tri ethyl amine, N,N- diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and among them, preferable examples thereof include tri ethyl amine.

[0283] The amount of Compound II or a salt thereof to be used is usually 1 to 2 equivalent(s), and preferably 1.0 to 1.5 equivalents, more preferably 1.2 to 1.22 equivalents, relative to Compound XIII or a salt thereof.

[0284] The amount of the base to be used is usually 1 to 5 equivalent(s), and preferably 1.4-1.6 equivalents, relative to Compound XIII or a salt thereof.

[0285] This reaction may be carried out at 20 to 100°C, and preferably at 25 to 40°C.

[0286] The present invention also provides a composition comprising 99.9% Compound V or a salt thereof, said composition preferably comprising 0.1%, preferably less than 0.1% Compound II and Compound XIII, preferably wherein said composition is produced according to the above process for producing Compound V, more preferably according to any of the below aspects.Aspects of the process for producing Compound V

[0287] Aspects of the process for producing Compound V or a salt thereof include the following.Aspect Hl

[0288] A process for producing Compound V or a pharmacologically acceptable salt thereof, which comprise a step of reacting Compound II or a salt thereof and Compound XIII or a salt thereof to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof.Aspect H 2

[0289] The process according to Aspect Hl, which comprises a step of producing Compound XIII or a salt thereof by the above process for producing Compound XIII, preferably according to any one of Aspects G1 to G13.Aspect H3

[0290] The process according to Aspect H2, wherein producing Compound XIII or a salt thereof comprises a step of producing Compound XII or a salt thereof by the above process of producing Compound XII, preferably according to any one of Aspects Fl to Fl 2.Aspect H4

[0291] The process according to any one of Aspects Hl to H3, which comprises a step of producing Compound II or a salt thereof according to Step 1 of the above “Production process of the present invention”, preferably according to any one of Aspects Al to A32 to the extent these aspects apply to producing Compound II or a salt thereof from Compound I or a salt thereof.Aspect H5

[0292] The process according to any one of Aspects Hl to H4, wherein X represents a chlorine atom.Aspect H6

[0293] The process according to any one of Aspects Hl to H5, wherein X represents a bromine atom.Aspect H7

[0294] The process according to any one of Aspects Hl to H6, wherein the reaction to produce Compound V or a pharmacologically acceptable salt thereof is carried out in a solvent in the presence of a base.Aspect H8

[0295] The process according to Aspect H7, wherein the solvent comprises one or more aprotic solvent(s), preferably wherein the aprotic solvent(s) is / are dichloromethane and / or A-Methyl-2- pyrrolidone (NMP).Aspect H 9

[0296] The process according to Aspect H7 or H8, wherein the solvent comprises one or more polar protic solvent(s), preferably methanol.Aspect H 10

[0297] The process according to any one of Aspects H7 to H9, wherein 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 a mixture of methanol, A-Methyl-2-pyrrolidone (NMP), and dichloromethane.Aspect Hl 1

[0298] The process according to any one of Aspects H7 to H10, wherein the base is one or two or more selected from tri ethyl amine, N,N-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), and potassium carbonate.Aspect Hl 2

[0299] The process according to any one of Aspects H7 to Hl l, wherein the base(s) is / are preferably triethylamine and / or potassium carbonate.Aspect Hl 3

[0300] The process according to any one of Aspects Hl to H12, comprising separation of a salt of Compound V via fdtration to thereby produce a fdter cake which contains the salt of Compound V.Aspect H 14

[0301] The process of Aspect H13, wherein filtration comprises concentrating the salt of Compound V in solvent to form concentrated Compound V salt, chilling the concentrated Compound V salt, preferably to -15 to -5°C, followed by filtration to thereby produce the filter cake.Aspect Hl 5

[0302] The process of Aspect Hl 4, wherein the filter cake is washed with an organic solvent, preferably methanol.Aspect H16

[0303] The process according to any one of Aspects Hl to Hl 5, further comprising isolating the free base of Compound V.Aspect Hl 7

[0304] The process of Aspect H16, wherein isolating the free base of Compound V comprises dissolving Compound V salt in an extraction solution, raising the pH of the extraction solution, and filtering the extraction solution, thereby producing a filter cake containing the free base of Compound V.Aspect H18

[0305] The process of Aspect Hl 7, wherein:(a) the extraction solution comprises a 50:50 mixture of organic solvents, preferably methanol and dichloromethane;(b) the pH of the extraction solution is raised to pH 11-13 by adding a basic 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 prior to stirring the extraction solution, any basic solution is removed;(d) after the pH of the extraction solution is raised, additional water is added, stirred, and removed; and(e) after the pH of the extraction solution is raised, additional solvent, preferably organic solvent, more preferably N-methyl-2-pyrrolidone, is added, preferably dropwise.Aspect H19

[0306] The process according to any one of Aspects Hl to H18, comprising isolating Compound V substantially as described in Example 13 (Process for producing Compound 5 free base) or Example 14 (Scaled up process for producing Compound 5).Aspect H 20

[0307] The process according to any one of Aspects Hl to H19, wherein the reaction has a yield of Compound V of at least 85%, preferably 85% to 90%, at a chemical purity of greater than 99%, preferably 99.9% or greater.Process for producing Compound V or a salt thereof

[0308] Also, in case of isolating Compound II or a salt thereof is used to produce Compound V or a salt thereof, the production process preferably includes a step of subjecting Compound IX or a salt thereof to a reduction reaction to produce Compound VII or a salt thereof. Alternatively, the production process includes a step of subjecting Compound X to a reduction reaction to produce Compound VII or a salt thereof. Examples of such production processes include the following production process.

[0309] A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V the process comprising the following steps:Step 1

[0310] Reacting a compound represented by F ormula I or a salt thereof and an activating agent to produce a compound represented by Formula II or a salt thereof:Formula IFormula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group.

[0311] In one aspect of step 1, the compound represented by Formula II or a salt thereof is produced without being subsequently isolated. In an alternative aspect of step 1, the compound represented by Formula II or a salt thereof is produced and then isolated.Step 2

[0312] Reacting the compound represented by Formula II or a salt thereof and a compound represented by Formula III or a salt thereof to produce a compound represented by Formula IV or a salt thereof:Formula III wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxycarbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule;Formula IV wherein R1represents the same as described above.Step 3 (option 1)

[0313] 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 IXFormula VII.Step 3 (option 2)

[0314] An alternative step to produce a compound represented by Formula VII comprises 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 VII.

[0315] The above process further comprising the following steps:Step 4

[0316] Reacting the 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 a compound represented by Formula VI or a salt thereof:Formula VIII wherein X1and X2each independently represent a chlorine atom, a bromine atom, or a leaving group;Formula VI wherein X1represents the same as described above.Step 5

[0317] Reacting the compound represented by Formula IV or a salt thereof produced in Step 2 and 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.Aspects

[0318] Step 1 and Step 2 may be carried out according to the above process for producing Compound IV or a salt thereof by producing Compound II or a salt thereof from Compound I or a salt thereof, and then reacting Compound II or a salt thereof and Compound III or a salt thereof, and may be carried out, for example, according to the production process according to any one of the above Aspects Al to A32.

[0319] Step 3 may be carried out according to the above process for producing Compound VTI or a salt thereof by subjecting Compound IX or a salt thereof to a reduction reaction, and may be carried out, for example, according to the production process according to any one of the above Aspects DI to D6.

[0320] Alternatively, Step 3 may be carried out according to the above process for producing Compound VII or a salt thereof by subjecting Compound X to a reduction reaction, and may be carried out, for example, according to the production process according to any one of the above Aspects El to El 2.

[0321] Step 4 may be carried out according to the above process for producing Compound VI or a salt thereof by reacting Compound VII or a salt thereof and Compound VIII or a salt thereof, and may be carried out, for example, according to the production process according to any one of the above Aspects Cl to C14.

[0322] Step 5 may be carried out according to the above process for producing Compound V or a pharmacologically acceptable salt thereof by reacting Compound IV’ or a salt thereof and Compound VI or a salt thereof, and may be carried out, for example, according to the production process according to any one of the above Aspects Bl to Bl 7.Alternative process for producing Compound V or a salt thereof

[0323] The present invention also provides an alternative process for producing Compound V or a salt thereof. Examples of such alternative production process include the following production process.

[0324] A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V the process comprising the following steps:Step 1

[0325] Reacting a compound represented by Formula I or a salt thereof and an activating agent to produce a compound represented by Formula II or a salt thereof:Formula IFormula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group.

[0326] In one aspect of step 1, the compound represented by Formula II or a salt thereof is produced without being subsequently isolated. In an alternative aspect of step 1, the compound represented by Formula II or a salt thereof is produced and then isolated.Step 2 (option 1)

[0327] 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 IXFormula VIIStep 2 (option 2)

[0328] An alternative step to produce a compound represented by Formula VII comprises 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 VIIStep 3

[0329] Reacting a compound represented by Formula XI with a compound represented by Formula VII, to produce a compound represented by Formula XII.Formula XI wherein Ri represents an amino protecting group, preferably a benzyloxycarbonyl group.Formula XII wherein Ri is the same as in Formula XI above.Step 4

[0330] Subjecting a compound represented by Formula XII or a salt thereof to a reduction reaction to produce a compound represented by Formula XIII.Formula XIIIStep 5

[0331] Reacting the compound represented by Formula II or a salt thereof produced in Step 2 and 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.Aspects

[0332] Step 1 may be carried out according to Step 1 of the above “Production process of the present invention”, i.e. by producing Compound II or a salt thereof from Compound I or a salt thereof. Thus, Step 1 may be carried out, for example, according to Aspects Al to A32 to the extent these aspects apply to producing Compound II or a salt thereof from Compound I or a salt thereof.

[0333] Step 2 may be carried out according to the above process for producing Compound VII or a salt thereof by subjecting Compound IX or a salt thereof to a reduction reaction, and may be carried out, for example, according to the production process according to any one of the above Aspects DI to D6.

[0334] Alternatively, step 2 may be carried out according to the above process for producing Compound VII or a salt thereof by subjecting Compound X to a reduction reaction, and may be carried out, for example, according to the production process according to any one of the above Aspects El to E12.

[0335] Step 3 may be carried out according to the above process for producing Compound XII or a salt thereof by reacting Compound XI with Compound VII, and may be carried out, forexample, according to the production process according to any one of the above Aspects Fl to F12.

[0336] Step 4 may be carried out according to the above process for producing Compound XIII or a salt thereof by subjecting Compound XII or a salt thereof to a reduction reaction, and may be carried out, for example, according to the production process according to any one of the above Aspects G1 to G13.

[0337] Step 5 may be carried out according to the above process for producing Compound V or a salt thereof by reacting Compound XIII and Compound II, and may be carried out, for example, according to the production process according to any one of the above Aspects Hl to H20.Crystallization processes of monohydrobromide salt of Compound V

[0338] The present invention provides a process for crystallizing the monohydrobromide salt of Compound V, the process comprising:(a) producing a solution of (1) Compound V free base, (2) a solvent such as ethanol or methanol, (3) water, and (4) hydrobromic acid, and(b) either:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of Compound V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of Compound V; and(c) collecting the resulting crystals.

[0339] In one aspect, the present invention provides a process for crystallizing the monohydrobromide salt of Compound V, the process comprising:(a) mixing Compound V free base with ethanol, water, and hydrobromic acid;(b) adding the resulting solution into acetone, preferably dropwise;(c) washing the resulting mixture with a mixed solution of ethanol and water;(d) cooling the resulting mixture and stirring;(e) collecting the resulting crystals; and(f) optionally washing the collected crystals with acetone;(g) optionally drying the washed crystals.

[0340] The above process may comprise one or more or all of the following features:(i) in step (a) the ratio by weight of Compound 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 into acetone at about 25-75°C, preferably about 50°C over 1 hour;(iv) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00;(v) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours;(vii) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and(viii) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

[0341] In an another aspect, the present invention also provides a process for crystallizing the monohydrobromide salt of Compound V, the process comprising:(a) suspending Compound V free base in a solution of methanol and water to form a suspension of Compound V;(b) adding aqueous HBr to the suspension of Compound V to obtain a first mixture;(c) heating the first mixture to obtain a first solution;(d) filtering the first solution;(e) charging acetone and crystallization seeds to the first solution to obtain a second mixture;(f) charging additional acetone to the second mixture to obtain a third mixture;(g) holding and cooling the third mixture;(h) filtering the third mixture to obtain a filter cake;(i) washing the filter cake to obtain crystals of the monohydrobromide salt of Compound V.

[0342] The above process may comprise one or more or all of the following features:(i) step a) comprises suspending Compound V free base 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, aqueous HBr to the suspension of Compound V obtain the first mixture;(iii) step c) comprises heating the first mixture to about 45 to 60 °C, preferably about 50 °C, to obtain the first solution;(iv) step d) comprises filtering the first solution through a polish filter;(v) step e) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours;(vi) step f) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours, and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; and(x) the yield of the process is about 85%.

[0343] In the above process, particle size can be controlled by the addition of seeds to a supersaturated liquid and subsequent slow addition, aging, and cooling steps, allowing for preferential particle growth over nucleation.

[0344] The present invention provides a process for recrystallizing the monohydrobromide salt of Compound V, the process comprising:(a) dissolving crystals of a monohydrobromide salt of Compound V in (1) a solvent such as ethanol or methanol, and (2) water, and(b) either:(i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of Compound V; or(ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of Compound V; and(c) collecting the resulting crystals.

[0345] In one aspect, the present invention provides a process for recrystallizing the monohydrobromide salt of Compound V, the process comprising:(a) mixing crystals of the monohydrobromide salt of Compound V with ethanol and water;(b) adding the resulting solution into acetone, preferably dropwise;(c) washing the resulting mixture with a mixed solution of ethanol and water;(d) cooling the resulting mixture and stirring;(e) collecting the resulting crystals; and(f) optionally washing the collected crystals with acetone;(g) optionally drying the washed crystals.

[0346] The above process may comprise 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 into acetone at about 25-75°C, preferably about 50°C over 1 hour;(iii) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00;(iv) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours;(vi) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and(vii) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

[0347] In an another aspect, the present invention also provides a process for recrystallizing the monohydrobromide salt of Compound V, the process comprising:(a) dissolving crystals of a monohydrobromide salt of Compound V in a solution of methanol and water to obtain a first solution;(b) filtering the first solution;(c) charging acetone and crystallization seeds to the first solution to obtain a second mixture;(d) charging additional acetone to the second mixture to obtain a third mixture;(e) holding and cooling the third mixture;(f) filtering the third mixture to obtain a filter cake;(g) washing the filter cake to obtain crystals of the monohydrobromide salt of Compound V.

[0348] The above process may comprise one or more or all of the following features:(i) step a) comprises suspending crystals of a monohydrobromide salt 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) comprises heating to about 45 to 60 °C, preferably about 50 °C;(iii) step b) comprises filtering the first solution through a polish filter;(iv) step c) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours;(v) step d) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours,and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; and(ix) the yield of the process is about 85%.

[0349] In the above process, particle size can be controlled by the addition of seeds to a supersaturated liquid and subsequent slow addition, aging, and cooling steps, allowing for preferential particle growth over nucleation.

[0350] The present invention also provides a composition comprising crystals of the monohydrobromide salt of Compound V produced according to any of the above processes.General

[0351] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Further, every Aspect described herein, including every combination of Aspects contemplated by way of one or more cross- references to other Aspects is considered to be an embodiment of the invention.

[0352] Compounds produced in each step of the present invention may be produced as a salt if necessary. The salt may be any one as long as it may be usually industrially used, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide; organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, succinate, and maleate; and alkali metal salts such as sodium salts and potassium salts. Conversion to such salts may be carried out according to conventional method(s).

[0353] In the present description, examples of the “pharmacologically acceptable salt” include inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide; and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, succinate, and maleate. Preferable examples thereof include sulfate, hydrobromide, succinate, benzenesulfonate, and tosylate, more preferable examples include benzenesulfonate and hydrobromide, and especially preferable examples thereof include hydrobromide.

[0354] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.

[0355] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0356] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0357] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only.EXAMPLES

[0358] Hereinafter, the present invention is specifically illustrated by means of Examples and the like, but the present invention is not limited to them. In the present description, “equivalent” means “molar equivalent”.Methods for Examples 1-6

[0359] 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.HPLC / LRMS

[0360] Device: manufactured by Waters

[0361] Operating conditions:(a) Column: X Bridge C18, 5pm 3.0 mm x 50 mm(b) Solvent: A: water (0.05% trifluoroacetic acid), B: acetonitrile (0.05% trifluoroacetic acid)(c) Gradient: B: 10% (1 min) 30% (1.5 min) 70% (4.5 min) — 90% (5.0 min)— 90% (6.0 min) — 10% (6.2 min) 10% (7 min)(d) Flow rate: 1.27 mL / min(e) Wavelength range: 210 to 400 nm(f) Measurement range: 0 to 7 minGC

[0362] Device: manufactured by Agilent

[0363] Operating conditions:(a) Column: CP-Sil 8 CB for Amines, Length: 30.0 m, Inner diameter: 0.25 mm, Film thickness: 0.50 pm(b) Detector temperature: 300°C(c) Heating program: 50°C (0 min.) — > rate: 10°C / min. — > 250°C (0 min.) — > rate: 20°C / min 300°C (15 min.)Example 1 (Process 1 for producing Compound 4)

[0364] 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 DPPC1 (15.79 g) was added dropwise thereto at -1 to 0°C over about 30 minutes, the resulting suspension was added dropwise to the solution over about 30 minutes,the container was washed with acetonitrile (5 mL), and the wash liquid was added dropwise to the reaction solution. After 1 hour, the temperature was raised to 20 to 25°C, and then concentrated hydrochloric acid (25.63 g) was added dropwise thereto over about 30 minutes. After stirring for about 1 hour, the resulting crystals were collected by filtration, and said crystals were washed with acetonitrile (60 mL). The resulting crystals were suspended in water (40 mL), and an 8 N aqueous solution of sodium hydroxide (40 mL) was added dropwise thereto at about 45°C over 10 minutes. 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 said crystals were washed with water (100 mL). The crystals were dried at 50°C to give Compound 4 (8.05 g) (yield: 59%).

[0365] Compound 4: ‘ 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), MS calcd for Ci 4H17N5 255.1, m / z 256 [M+H]+Example 2 (Process 2 for producing Compound 4)(1) Step 1 (Production of Compound 2 from Compound 1)

[0366] Under an inert atmosphere, Compound 1 (50.00 g), 1,2-dimethoxy ethane (281.81 g), and dimethylformamide (1.95 g) were mixed, and the resulting mixture was stirred at 83°C. Thionyl chloride (63.99 g) was added dropwise thereto at 80 to 83°C, and the resulting mixture was stirred for 3 hours. Then, water (250.00 g) was added dropwise thereto at 8 to 10°C, and the resulting mixture was stirred for 16 hours. The resulting crystals were filtered, and washed with water (750.01 g). Said crystals were stirred in ethanol (118.50 g) at 20 to 22°C for 2 hours. The crystals were filtered, and washed with ethanol ( 118.50 g). Said crystals were dried under reduced pressure at an outside temperature of 30°C to give Compound 2 (42.50 g, yield: 77%).

[0367] Compound 2:1H NMR (DMSO-d6, 500 MHz): 82.43 (s, 3H), 7.46 (d, J = 7.9 Hz, 2H), 8.25 (d, J = 8.3 Hz, 2H), 10.12 (s, 1H).

[0368] MS calcd for Ci o H8C1N3205.0, found m / z 206 [M+H]+.(2) Step 2 (Production of Compound 4 from Compound 2)

[0369] To a solution of Compound 3 (42.0 g) in methanol (79.2 g) was added dropwise a solution of Compound 2 (20.0 g) in N-methylpyrrolidone (103 g) at 55°C with stirring over 1.5 hours. After stirring at 55°C for 3 hours, water (200 mL) was added thereto, 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). To the resulting filtrate was added water (300 mL), and the resulting mixture was stirred at 20°C for 16 hours. The resulting crystals were collected by filtration, and said crystals were washed with water (200 mL). The crystals were dried at 50°C to give Compound 4 (17.6 g) (yield: 79%).

[0370] Compound 4:1H NMR (CDC13) 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), MS calcd for Ci4HI 7N5 255.1, found m / z 256 [M+H]+Example 3 (Process for producing Compound 6)

[0371] To a mixture of Compound 7 (1.50 g) and potassium carbonate (2.92 g) was added N,N-dimethylformamide (14.2 g) at room temperature, 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 thereto over 1.5 hours. A mixed solution of 4 N hydrochloric acid (10 mL) and saturated brine (20 mL) was added thereto at 10°C, and the resulting mixture was stirred at 10°C for 19 hours. The resulting crystals were collected by filtration, and said crystals were washed with water (15 mL) twice. The crystals were dried at 50°C to give Compound 6 (1.81 g) (yield: 81%).

[0372] Compound 6:1HNMR (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), MS calcd for C10 H17 CIN2 O2 232.1, m / z 233 [M+H]+Example 4 (Process for producing Compound 7)

[0373] Compound 9 was subjected to a reduction reaction in a solvent in the presence of a metal catalyst under pressure and hydrogen atmosphere (4 Mpa) at 60 to 160°C. As the metal catalyst, ruthenium — alumina (Ru / Ah Ch ), rhodium — carbon, palladium — carbon, or nickel — diatomaceous earth was used, and as the solvent, methanol, propylene glycol methyl ether, or 1,3-dimethylimidazolidinone was used. In this reaction, in addition to the target Compound 7 (trans isomer), Compound 10 (cis isomer) and Compound 11 (dimerized product) are produced as the main by-products. The combination of the metal catalyst and the solvent, and the ratio of each product and the ratio of Compound 7 relative to Compound 10 (GC Area %) are shown in Table 2 and Table 3. The reactions described in Table 2 were carried out by using methanol as the solvent. The reactions described in Table 3 were carried out by using ruthenium-alumina as the metal catalyst.Table 2Table 3

[0374] As clearly demonstrated by the results shown in Table 2, when inexpensively purchasable ruthenium — alumina was used as the metal catalyst, the target Compounds 7 and 10 were produced with suppressing the production of Compound 11. Also, as clearly demonstrated by the results shown in Table 3, when propylene glycol methyl ether or 1,3- dimethylimidazolidinone was used as the solvent, the target Compound 7 (trans isomer) was preferentially produced relative to Compound 10 (cis isomer).Example 5 (Process for producing Compound 5 (Triazine compound A))

[0375] A mixture of Compound 4’ (1. 1 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 thereto at 60°C, and the resulting mixture was stirred at 60°C for 2 hours. The resulting crystals were collected by filtration, and said crystals ware washed with water (15 mL). The crystals were dried at 50°C to give Compound 5 (2.54 g) (yield: 96%).Example 6 (Process for producing salt of Compound 5 (Triazine compound A))

[0376] Compound 5 (15.00 g) was mixed with ethanol (14.22 g), water (9.00 g), and 48% hydrobromic acid (5.60 g), dissolved therein at 75°C, and then the resulting solution was added dropwise to acetone (237.00 g) at 50°C over 1 hour. The used container and funnel was washed with a mixed solution of ethanol (9.48 g) and water (1.12 g), and the resulting mixture cooled to 0°C, and stirred for 18 hours. The resulting crystals were collected by filtration, and said crystals were washed with acetone (59.25 g). The crystals were dried at 50°C to give Compound 12 (16.38 g) (yield: 93%).Example 7 (Process for producing Compound 7)

[0377] Raney Ni (0.3 wt. equiv.) was washed with THF three times and then THF (6 vol) added. A Karl Fischer titration was conducted to confirm water in Raney Ni <0.4%. If <0.4%, the Raney Ni was washed with THF again until water<0.4%. The vessel was purged with nitrogen, and Compound 13 added in a solution of MeOH (6 vol). The vessel was then purged with hydrogen to 0.35-0.5 Mpa (50-72 psi) pressure and then the mixture warmed to 40-50 °C. The mixture was stirred at 40-50 °C for 2-6 hr and then filtered through diatomite (Celite, 0.2-2.0 wt. equiv.). The cake was washed with THF (5-10 vol). The filtrate was evaporated and switched to 3.5-4.5 vol THF. Residual MeOH was confirmed to be <0.5%. Ethyl acetate was added (3.5-4.5 vol) slowly at 20-30 °C. The reaction mixture was warmed to 60-70 °C and then stirred at 60-70 °C for 1-2 hr. The reaction mixture was then cooled to 22-28 °C over 8 hr, stirred at 22-28 °C for 12-18 hr, and then filtered. The wet cake was washed with ethyl acetate (1-3 vol) and then dried under vacuum at 40-50 °C for 20-24 hrs to give Compound 7 as white solid. The assay yield was 43.4% with 95.1% purity and 2.7% of the c / .s-isomer. This level was tolerated in downstream processing.Example 8 (Scaled up process for producing Compound 7)

[0378] The following procedure was used starting with 2.35 kg of Compound 13.1) Charge methanol (3.9-4. OX) into Rl.2) Charge Compound 13 (1.0X) into Rl.3) Adjust Rl to 20-30°C.4) Stir Rl at 20-30°C for l-2h until clear.) Obtain MeOH solution of Compound 13. ) Replace air with nitrogen for three times in R2. ) Charge Raney Ni (0.25-0.35X) into R2. ) Charge tetrahydrofuran(10-16X) into R2. ) Replace air with nitrogen for three times in R2 0) Stir R2 at 20-30°C for 15-30min. 1) Stand R2 for 0.5- Ih. 2) THF(5-15X) of R2 was siphoned off. 3) Charge tetrahydrofuran(5-15X) into R2. 4) Stir R2 at 20-30°C for 15-30min. 5) Stand R2 for 0.5-lh. 6) THF (5-15X) of R2 was siphoned off (Keep 6V THF in R2). 7) Charge tetrahydrofuran(5-15X) into R2. 8) Stir R2 at 20-30°C for 15-30min. 9) Stand R2 for 0.5-lh. 0) THF (5-15X) of R2 was siphoned off. (Keep 6V THF in R2). 1) LPC (in process control): check water content (%w / w, spec. : < 0.4%). 2) Transfer the material in R1 into R2. 3) Rinse R1 with methanol (0.7-0.9X). 4) Transfer the material in R1 into R2. 5) Replace air with nitrogen three times. 6) Replace nitrogen with hydrogen. 7) Adjust R2 to 0.35-0.50Mpa with H2. 8) Adjust R2 to 40-50°C.) Stir R2 under hydrogen (O.35-O.5OMpa) at 40-50°C for 2-6h. ) IPC: Take a sample and submit for HPLC test. Compound 13 / Compound 7 (HPLC, %area / area, spec. <1.0%, if out of the spec, do step 31,32, otherwise, go to step 33); Purity of Compound 7 (HPLC, %area, spec.: report). ) Stir R2 at 40-50°C for 2-6h under hydrogen (O.35-O.5OMpa). ) IPC: Take a sample and submit for HPLC test. Compound 13 / Compound 7 (HPLC, %area / area, spec. <1.0%) , Purity of Compound 7: report (HPLC, %area, spec.: report). ) Filter the reaction mixture through diatomite (0.2-2. OX), transfer the filtrate into R3) Wash R2 and the filter cake with tetrahydrofuran (3-5X) twice. Transfer the filtration into R3. ) Concentrate R3 under vacuum to 3-5V below 40°C. ) Charge tetrahydrofuran (4-5X) into R3. ) Concentrate R3 under vacuum to 3-5V below 40°C. ) Take sample for analysis:PSl 1814-47-A-RS. ) Charge tetrahydrofuran (4-5X) into R3. ) Concentrate R3 under vacuum to 3-5V below 40°C. ) Adjust R3 to 20-30°C. ) Charge EtOAc (3-4X) into R3 at 20-30°C. ) Adjust R3 to 60-70°C. ) Stir R3 at 60-70°C for 0.5-1.5hrs. ) Cool R3 to 15-25°C over 8hrs. ) Stir R3 at 15-25°C for 2-6hrs. ) Filter and wash cake with (1-3 X) EtOAc. ) Dry the wet cake at 40-50 °C for 16-24 hr.

[0379] The yield was 932 g (43.2%) containing 3.9% of the cZs-isomer.Example 9 (Process for producing Compound 15)

[0380] To suspension of Compound 14 (limiting reagent) in methylene chloride (10 vol) was added diisopropylethylamine (5.0 equiv.). The mixture was stirred at 20-30 °C until a solution was obtained, and then cooled to 0-10 °C. Compound 7 (1.05-1.10 equiv.) was added and then 50% T4P* in ethyl acetate solution (1.5-1.7 equiv.) was added dropwise at 0-10 °C. The mixture was stirred at 0-10 °C until the reaction was complete. Water (5 vol) was charged and then stirred and separated. The aqueous phase was extracted with methylene chloride (5 vol). The organic phases were combined and washed with 7% sodium bicarbonate (5 vol) twice and water (5 vol). The resulting organic phase was concentrated to 6 vol and then MTBE (15 vol) was added dropwise at 15-25 °C. The mixture was cooled to -5-5 °C, stirred at -5-5 °C for 5-10 hr, and then filtered and washed with MTBE (1-3 vol). The cake was dried at 40-50 °C for 10-18 hr under vacuum. Compound 15 was obtained in 79.3% isolated yield with 99.50% chemical purity and 99.46% isomeric purity.

[0381] *T3P may be used instead of T4P. It is presumed that T3P and T4P will behave similarly because T4P simply has butyl side chains instead of propyl.Example 10 (Scaled up process for producing Compound 15)

[0382] This step was run on 600 g scale, as follows:1) Charge 11.3-12.6X (8.5-9.5V) dichloromethane into Rl.2) Charge 1. OX (0.99-1.01X, l.Oeq.) Compound 14 into Rl.) Adjust Rl to 15-25 °C. ) Stir R1 for 10-30min at 15-25 °C ) Charge (1.7-2.3X, 4-5eq.) N, N-diisopropylethylamine (DIPEA) into R1 at 15-25 °C.) Adjust R1 to 0-10 °C. ) Charge 0.50-0.55X (1.0-l.leq.) Compound 7 into R1 at 0-10 °C. ) Stir R1 for 15-35min at 0-10 °C. ) Charge T4P solution (50% in ethyl acetate) (3.0-3.9X, 1.3-1.7eq) into R1 slowly over Ih at 0-10 °C. 0) Rinse the pipe with DCM (0.2- 1.5V) 1) Stir R1 at 0-10°C for 2-8h. 2) IPC: Compound 14 / Compound 15 (%, area / area) <2.0%, Purity of Compound 15 (% area, spec.: report ) 3) Charge process water (7.5-8.5X) into R1 at 0-10°C. 4) Adjust R1 to 15-25 °C. 5) Stir R1 for 15-35min at 15-25°C. 6) Stand R1 for 15-30min. 7) Separate the organic layers into Tl. 8) Charge 6-7X di chloromethane into Rl. 9) Stir Rl for 15-35min at 15-25°C. 0) Stand Rl for 15-30min. 1) Separate the bottom organic layer and middle layer to Tl, the upper layer to T2.2) Transfer the organic phase in Tl to Rl. 3) Charge 7% aq. NaHCCh (6.5-7.5X) into Rl. 4) Stir Rl for 15-35min at 15-25°C. 5) Filter Rl through Fl (0.2X diatomite) and then transfer the filter liquor back into Rl.) Stand R1 for 15-30min. ) Separate the bottom organic layer and middle layer to Tl, the upper layer to T3.) Transfer the organic phase in Tl to R1. ) Charge 7% aq. NaHCCh (6.5-7.5X) into R1 ) Stir Rl for 15-35min at 15-25°C. ) Filter R1 through Fl (0.2X diatomite) and wash cake with 2-3X DCM. And then transfer the fdter liquor into R1. ) Stand R1 for 15-30min. ) Separate the bottom organic layer to Tl, the middle layer and upper layer to T3.) Transfer the organic phase in Tl to Rl. ) Charge process water (4.5-5.5X) into Rl. ) Stir Rl for 20-40min at 15-25°C ) Stand Rl for 15-30min. ) Separate the bottom organic layer to Tl, the middle layer and upper layer to T4.) Transfer the organic phase in Tl to Rl . ) Filter through organic layer in Rl through CUNO (active carbon (0.08-0.22X)) at 15- 25°C twice. ) Wash CUNO with 6-7X DCM for 60min 0.5-2hr twice. Add the washes to Rl. ) Concentrate Rl to 5-6V below 45°C under vacuum in portions. ) Adjust Rl to 15-25 °C. ) Charge MTBE (10.5-11.5X, 15V) slowly into Rl at 15-25 °C. ) Adjust Rl to -5-5 °C over 2hr. ) Stir Rl for 5-15h at -5-5 °C.47) IPC: Residual Compound 15 of supernatant liquor (% w / w, spec.: <0.3%), Purity Compound 15wet cake (% area): Report, Chiral of Compound 15 wet cake (% area, spec.: >99.0%).48) Filter, wash the cake with MTBE (2.0-5. OX) and then transfer the filtrate into T4.49) Dry the wet cake at 40-50 °C for 17-24 h under vacuum.50) IPC: water content of Compound 15 (%w / w, spec.<0.5%, residual DCM (% w / w spec.: report), residual MTBE (% w / w spec.: report), residual EA (%w / w, spec.: report).

[0383] Yield 724.0 g (91.2% assay yield, 99.3% chemical purity, 99.7% isomeric purity). The latter value indicates that the percentage of the cA-isomer (Compound 10) in the starting monoacetyl diamine was tolerated in downstream chemistry.Example 11 (Process for producing Compound 16)

[0384] A mixture of MeOH (12 vol), 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. Next, the mixture was filtered and the cake rinsed with MeOH (5 vol). The filtrate was concentrated to 2-3 vol and then MTBE (10V) added dropwise at -15 to-10°C. The resulting suspension was stirred at this same temperature for 18hr, and then filtered. The wet cake was washed with MTBE (2 vol) and then dried under vacuum to give solid C. The yield was about 90%.Example 12 (Scaled up process for producing Compound 16)

[0385] This reaction was run on 674 g scale, as follows:1) Charge methanol (9-1 OX) into R1 .2) Charge Compound 15 (1.0X) into Rl.3) Swap Rl with nitrogen three times.4) Adjust Rl to 20-30 °C.5) Stir Rl for 0.5-1 hr at 20-30 °C until clear.6) Charge palladium on activated carbon 0.04X (10% Pd / C, 0.02-0.04X, 50% water wet) into Rl.7) Adjust Rl to 20-30 °C.8) Swap Rl with hydrogen.9) Adjust Rl to 0.27-0.35Mpa (40-50 psi) hydrogen at 20-35°C.10) Stir Rl for 3-7 hr at 20-35 °C under hydrogen at 0.27-0.35Mpa (40-50 psi).11) IPC: take a sample to check Compound 15 / Compound 16 (% area, spec.: <0.5%) and purity of Compound 16 (% area, spec.: report).12) Filter the material by diatomite (0.2-2X) and transfer the liquor into clean drum.13) Rinse wet cake with 3-7X MeOH twice, transfer the liquor into clean drum.14) Transfer the filtrate (Compound 16 MeOH solution) into R2.15) Concentrate R2 to 2-3 V below 50°C under vacuum.16) Charge methyl-tert-butyl ether (7.2-7.6X) into R2 dropwise at 15-20°C.17) Adjust R2 to -15 to -5 °C.18) Stir R2 for 10-16 hr at -15 to -5 °C.19) IPC: Residual Compound 16 in supernatant liquor (%, w / w, spec.: <0.5%), purity of Compound 16 filter solid (% area, spec.: report).20) Filter and wash cake with MTBE (3-5X).21) Dry the wet cake at 40-50 °C for 16-24 hr under vacuum.

[0386] Yield 419 g (91.8%) with 99.2% purity.Example 13 (Process for producing Compound 5 free base)

[0387] To a solution of Compound 16 (limiting reagent) in MeOH (10 vol) / dichloromethane (lOvol) was added triethylamine (1.5 equiv.) at 15-25 °C. Then a solution of Compound 2 (1.2 equiv.) in NMP (4 vol) was added slowly at 30-35 °C. The reaction was stirred at 30-35 °C until the reaction was complete. Then the mixture was concentrated to 7-10 vol, cooled to -15 to -5 °C, and filtered. The cake was washed with methanol (1-3 vol) and then dissolved in MeOH (13 vol) / dichloromethane (13vol). 3% Aqueous potassium carbonate (0.5-1.5 wt / wt) was added to adjust the pH to 11-13 and then the mixture stirred at 30-35 °C for 1- 5hr. [Preferably, the basic water layer is separated first.] Water (12-15 vol) was added, stirred, and then separated. To the resulting organic phase was then added MeOH (5 vol) and NMP (5 vol) dropwise, and then the mixture was concentrated to 7-10 vol. The resulting slurry was cooled, stirred at -15 to -5 °C for 1 h and then filtered. The cake was rinsed with MeOH (1-3 vol) and then dried under vacuum to give Compound 5.Example 14 (Scaled up process for producing Compound 5)

[0388] The following process was run twice on approximately 200 g scale. After completion of the reaction, the two batches were combined for workup.1) Charge 3.90-4.3 IX N-methyl pyrrolidone into R2.) Charge 0.86-0.88X (1 .20-1 .22 eq.) Compound 2 into R2. ) Rinse R2 with 0.10X-0.21X NMP. ) Stir R2 at 15-25°C for 0.5-lh until the solution is clear. ) Charge 7.51-8.3 OX methanol into Rl. ) Charge 0.99-1.01X Compound 16 into Rl. ) Charge 13.0-13.6X dichloromethane into Rl. ) Charge 0.51-0.57X triethylamine into Rl. ) Rinse Rl with 0.08X-0.16X MeOH. 0) Adjust Rl to 30-35 °C. 1) Charge the solution of R2 into Rl dropwise over 3h. 2) Rinse R2 with 0.10X-0.21X NMP and then charge the solution of R2 into Rl dropwise. 3) Stir Rl for 2-6 hr at 30-35 °C. 4) IPC: Take sample to check IPC purity of Compound 16 (% area, spec. <0.2%)5) Concentrate Rl to 7-10V below 45 °C under vacuum. 6) Adjust Rl to -15 to -5 °C. 7) Stir Rl for 3-18 hr at -15 to -5 °C. 8) Filter and wash cake with 2.28-2.52X methanol. 9) Charge the wet cake into Rl . 0) Charge 16.5-17.5X di chloromethane into Rl. 1) Charge 10-10.5X methanol into Rl. 2) Charge 4-5X 3% aq. K2CO3 into Rl to adjust pH to 11-12. 3) Adjust Rl to 25-35 °C. 4) Stir Rl for 1-5 hr at 25-35 °C. 5) Charge 9-1 IX process water into Rl.26) Separate. Transfer the organic phase into R1 and transfer the aqueous layer into T1 .27) Adjust R1 to-10-0 °C.28) Charge 15.68-17.33X N-methyl pyrrolidone into R1 dropwise.29) Stir R1 for 1-3 hr at 20-30 °C.30) Concentrate R1 to 15-16V below 45 °C under vacuum.31) Adjust R1 to -15 to -5 °C.32) Stir R1 for 1-5 hr at -15 to -5 °C.33) Filter and wash cake with 2.57-2.84X dichloromethane.34) Dry at 40-50 °C under vacuum for 4-12 hr.

[0389] Yield 535 g (85.8%) with 99.9% purity.Example 15 (Process for producing Compound 6b)

[0390] The following steps were run on 350 g scale.1) Charge 9.50- 10.5 OX process water into R2.2) Charge 1.71-1.89X potassium carbonate (2.0 eq.) into R2.3) Rinse R2 with 0.10X-0.21X process water.4) Stir R2 at 15-25°C for 0.5-lhr until the solution is clear.5) Charge 1 ,0X Compound 7 into R1.6) Charge 25.2-27.9X dichloromethane into R1.7) Swap R1 with nitrogen under three times.8) Adjust R1 to -5-0 °C.9) Charge the solution of R2 into R1 over 0.5 h.10) Charge 1.81-2.00X Compound 8b (1.5 eq.) into R1 at -5-0 °C over 30 min under N2 protection.11) Stir Rl for 30-60 min at -5-0 °C.12) IPC: Take sample to check IPC purity of Compound 7 (% area, spec. <2.0%)13) If necessary, charge 0.60-0.70X Compound 8b (0.5 eq.) into Rl at -5-0°C over 10 min under N2 protection.14) Stir Rl for 30-60 min at -5-0 °C.15) IPC: Take sample to check IPC purity of Compound 7 (% area, spec. <2.0%)16) Filter the reaction mixture.17) Wash the wet cake with 10X water.18) Dry at 35-45 °C under vacuum for 14-28 hrs.

[0391] Yield 590.1 g (86.1% assay yield, 98.4% chemical purity).Example 16 (Process for producing Compound 4)

[0392] This reaction was run on 400 g scale.1) Charge 1. OX (0.99-1.01X, l.Oeq.) Compound 2 into Rl.2) Charge 8.7X (8.6-8.8X) 1, 2-dimethoxyethane into Rl.3) Adjust Rl to 20-30°C.4) Stir Rl for 0.5 -Ihr at 20-30 °C until clear.5) Charge 0.74X (0.72-0.76X) 1.50eq triethylamine into Rl.6) Charge 1 04X (1 .00-1 .1 OX) 1 .1 Oeq 1 -Boc-piperazine into Rl at 20-30 °C.7) Stir Rl for 3-16hr at 20-30 °C.8) Take sample for analysis: Purity of Compound 2 (% area, spec <1.0%).9) If necessary, charge 0.05X (0.03-0.06X) 0.05q 1 -Boc-piperazine into Rl at 20-30 °C.10) Stir R1 for 2-5hr at 20-30 °C.11) Take sample for analysis: Purity of Compound 2 (% area, spec.< 1.0 %)12) If necessary, charge 0.05X (0.03-0.06X) 0.05q 1-Boc-piperazine into R1 at 20-30 °C.13) Stir R1 for 2-5hr at 20-30 °C.14) Take sample for analysis: Purity of Compound 2 (% area, spec. <1.0%).15) Charge 7.5X (7.3 -7.7X) process water into R2.16) Charge 2.6X (2.5-2.7X) hydrochloric acid 35% into R2 at 20-50°C.17) Adjust R2 to 20-30 °C.18) Stir R2 for 10-30min at 20-30 °C to give 9% aq. HC1 solution.19) Charge 9% aq. HC1 solution of R2 into R1 dropwise at 20-50 °C.20) Adjust R1 to 50-60 °C.21) Stir R1 for 3-10hr at 50-60 °C.22) Adjust R1 to 10-20 °C.23) Stir R1 for 2-10hr at 10-20 °C.24) Filter and wash wet cake with 2-7V DME.25) Dry the wet cake at 45-55 °C for 20-24 hr.

[0393] Yield 588.4 g (91.2%) with 99.8% purity.Example 17 (Process for producing Compound 5 free base)

[0394] The following steps were run on approximately 420 g scale.1) Charge 20X (19.00-21.00X) purified water into R2.) Charge 1 ,5X (3.0-3.5eq.) potassium carbonate into R2. ) Adjust R2 to 20-30 °C. ) Stir R2 at 20-30°C for 0.5-lh until the solution is clear. ) Charge 8.9X (8.7-9. IX) tetrahydrofuran into R1. ) Charge 1. IX (1.09-1.1 IX, 1 ,05eq.) Compound 4 into R1. ) Stir Rl for 0.5 hr at 20-30 °C. ) Charge the aq. K2CO3 solution of R2 into R1 dropwise at 20-30 °C. ) Stir R1 for 0.5 hr at 20-30 °C until clear. 0) Charge 0.99-1.01X (l.Oeq.) Compound 6b into R1 at 20-30 °C. 1) Adjust R1 to 30-40 °C. 2) Stir R1 at 30-40°C for 4-1 Oh. 3) IPC: Take sample to check IPC purity of Compound 6b (% area, spec.<1.0%).4) Adjust R1 to 20-30 °C. 5) Stir Rl at 20-30°C for 2-6h. 6) Filter and wash wet cake with MeOH(l-3X). 7) Charge the wet cake into R1. 8) Charge 16.5-17.5X di chloromethane into Rl. 9) Charge 10-10.5X methanol into Rl. 0) Charge 4-5X 5% aq. K2CO3 into Rl to adjust pH to 11-12. 1) Adjust Rl to 30-40 °C. 2) Stir Rl for 5-15 hr at 30-40 °C. 3) Charge 10-15X process water into Rl. 4) Stir Rl for 0.5 hr at 20-30 °C. 5) Separate. Transfer the organic phase into Rl and transfer the aqueous layer into T1.26) Adjust R1 to 20-30 °C.27) Charge 4-5X MeOH into R1 at 20-30 °C.28) Charge 14-18X 2.2% aq. HBr (1.2 eq. 40% aq. HBr in 15V process water) into R1 to adjust pH to 1-2.29) Stir R1 for 0.5 hr at 20-30 °C.30) Separate. Transfer the organic phase into T2 and transfer the aqueous layer into Rl.31) Charge 16.5-17.5X di chloromethane into Rl.32) Charge 4-5X methanol into Rl.33) Charge 6.5-7.5X 10% aq. K2CO3 into Rl to adjust pH to 9-11.34) Stir Rl for 0.5 hr at 20-30 °C.35) Separate. Transfer the organic phase into Rl and transfer the aqueous layer into T3.36) Charge 9-1 IX N-methyl pyrrolidone into Rl.37) Concentrate Rl to 10- 12V below 45 °C under vacuum.38) Adjust Rl to -15 to-5 °C.39) Stir Rl for 1-5 hr at -15 to-5 °C.40) Filter and wash cake with MeOH (1-3 V).41) Dry at 40-50 °C under vacuum for 16-24 hr.

[0395] Yield 568 g (81.4%) with 99.9% purity.Example 18 (Alternative Process for producing Compound 2 from Compound 1)

[0396] Under inert atmosphere, Compound 1 (1 equivalent), 1 ,2-dimethoxyethane (6.5 vol), and dimethylformamide (0.01 equivalents) were mixed, and the resulting mixture was stirred at 68-70°C. Thionyl chloride (2.0 equivalents) was added thereto at 68 to 70°C, and the resulting mixture was stirred for 3 hours. After sampling to check reaction completion, the mixture was cooled to 0 °C and 3.5 equivalents of triethylamine (TEA) was added. The pH was measured and about 1 equivalent of TEA was added to adjust the pH of the mixture to 4. Next, 12 L / kg of water was added. The resulting crystals were filtered, washed and dried.Example 19 (Process for crystallization of Compound 12)

[0397] The following steps were used to produce crystals of Compound 12:(a) Suspend MLS-101 freebase in 5 L / kg of 80:20 (v / v) methanol: water(b) Add 1.01 equiv. aq. HBr(c) Heat to 50 °C to obtain a solution(d) Polish filter(e) Charge 1 L / kg acetone and 0.005 kg / kg seeds. Hold this mixture for 2 hours(f) Charge 19 L / kg of acetone over 12 hours below the liquid surface to avoid scale on reactor walls(g) Hold this mixture for 5 hours to ensure conversion to Form A(h) Cool to 25 °C over 3 hours and hold for 3 hours(i) Filter and wash twice with 2 L / kg acetone

[0398] The yield of this process is about 85%.

[0399] The ratio of methanol / water maximizes recovery while ensuring the product remains in solution during polish filtration.

[0400] The amount of acetone obtains the best recovery while keeping the overall volume as low as practically possible.

[0401] Particle size can be controlled by the addition of seeds to a supersaturated liquid and subsequent slow addition, aging, and cooling steps, allowing for preferential particle growth over nucleation.Example 20 (Process for recrystallization of hydrobromide salt of Compound V)

[0402] The hydrobromide salt of Compound V was slurried in 4 L / kg MeOH / LLO 80 / 20 (by volume) at 25°C, then heated to 60 C. A solution was formed at approximately 58 °C.

[0403] The solution was cooled to 50 °C and no precipitate was observed.

[0404] 2 L / kg of Acetone was charged to the solution, followed by 0.5% seeds.

[0405] Solids nucleated from the solution.

[0406] The solution was then stirred for 16 hours at 50 °C.

[0407] A further 14 L / kg Acetone was charged over 1.2 hours, followed by cooling to 25 °C over 2 hours, followed by stirring at 25 °C for 4 hours.

[0408] This mixture was then filtered and washed with 2 L / kg Acetone twice, then dried at 50°C under vacuum for 16 hours. A yield of 86.8% was obtained.INDUSTRIAL APPLICABILITY

[0409] According to the production process of the present invention, the Triazine compound A, which is useful as an active pharmaceutical ingredient, or a production intermediate thereof can be produced by a production route through a production intermediate not requiring a protection reaction and a deprotection reaction from inexpensive starting materials, and thus the Triazine compound A or a production intermediate thereof can be produced in a short number of steps and in a high yield using inexpensive reagents.

Claims

CLAIMSWhat is claimed is:

1. A process for producing a compound represented by Formula IV or a salt thereof:Formula IV wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule; the process comprising reacting a compound represented by Formula I or a salt thereof, an activating agent, and a compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof:Formula IFormula III wherein R1represents the same as defined above.

2. The process according to claim 1, wherein reacting the compound represented by Formula I or a salt thereof, the activating agent, and the compound represented by Formula III or a salt thereof to produce the compound represented by Formula IV or a salt thereof, is without isolating a compound represented by Formula II or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group; and wherein R2and R3each independently represent a hydrogen atom or an amino protecting group.

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

4. The process according to any one of claims 1 to 3, wherein R1represents a hydrogen atom, for producing a compound of Formula IV’ :Formula IV’.

5. A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V the process comprising: a) producing a compound represented by Formula IV’ or a salt thereof by a process of any one of claims 1 to 4:b) reacting the compound represented by Formula IV’ or a salt thereof and a compound represented by Formula VI or a salt thereof to produce the compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula VI wherein X1represents a chlorine atom, a bromine atom, or a leaving group.

6. The process according to claim 5 further comprising 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:Formula VIIFormula VIII wherein X1represents the same as defined above; and X2represents a chlorine atom, a bromine atom, or a leaving group.

7. The process according to 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 IX8. The process according to 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.A process for producing a compound represented by Formula VII or a salt thereof, comprising subjecting a compound represented by Formula X or a salt thereof to a reduction reaction:Formula X.A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V the process comprising: a) reacting a compound represented by Formula I or a salt thereof and an activating agent to produce and isolate a compound represented by Formula II or a salt thereof:Formula IT wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group; b) reacting the compound represented by Formula II or a salt thereof and a compound represented by Formula III or a salt thereof to produce a compound represented by Formula IV or a salt thereof:Formula III wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule;Formula IV wherein R1represents 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 VII11. A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereof:Formula V the process comprising: a) reacting a compound represented by Formula I or a salt thereof and an activating agent to produce and isolate a compound represented by Formula II or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group; b) reacting the compound represented by Formula II or a salt thereof and a compound represented by Formula III or a salt thereof to produce a compound represented by Formula IV or a salt thereof:Formula ITT wherein R1represents a hydrogen atom, an alkyl group optionally substituted with a carboxy group or an alkoxy carbonyl group, an amino protecting group, or a group represented by the following formula:wherein R2and R3each independently represent a hydrogen atom, an acetyl group, or an amino protecting group; and the wavy line represents the point of attachment to the rest of the molecule;Formula IV wherein R1represents 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 thereofFormula VII.

12. The process according to claim 10 or 11, further comprising:a) reacting the 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 a compound represented by Formula VI:Formula VIII wherein X1and X2each independently represent a chlorine atom, a bromine atom, or a leaving group;Formula VI wherein X1represents the same as defined above or a salt thereof; and b) reacting the compound represented by Formula IV or a salt thereof and 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 process according to any one of claims 7 to 12, wherein the reduction reaction is carried out by a reaction with a metal catalyst and hydrogen in a polar solvent.

14. The process according to claim 13, wherein the polar solvent is methanol, tetrahydrofuran, propylene glycol methyl ether, heptane, ethyl acetate, acetone, 1,3 — dimethylimidazolidinone, acetic acid, triethylamine, acetonitrile, or di methyl acetami de .

15. The process according to claim 13 or 14, wherein the metal catalyst is ruthenium — alumina, ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, nickel — diatomaceous earth, nickel — alumina, or Raney nickel.

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

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

18. The process according to claim 16 or 17, wherein the metal catalyst is ruthenium — alumina, ruthenium — carbon, rhodium — carbon, palladium — carbon, platinum — carbon, nickel — diatomaceous earth, nickel — alumina, or Raney nickel, preferably Raney nickel.

19. The process 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 being combined with the compound represented by Formula X or salt thereof in a solution with a polar solvent, which polar solvent is preferably methanol.

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

21. The process according to any one of claims 16 to 20, wherein a solid comprising a compound represented by Formula VII is formed by the reduction reaction:Formula VII.

22. The process according to claim 21, wherein the solid yields a peak area ratio of the compound represented by Formula X to the compound represented by Formula VII of less than or equal to 1% as measured by high pressure liquid chromatography.

23. The process according to claim 22, further comprising isolating the solid comprising the compound represented by Formula VII, preferably by steps of concentration, filtration, and washing, preferably wherein filtration is through diatomite, preferably wherein washing iswith a polar aprotic solvent, more preferably THF, still more preferably wherein the isolating comprises a final step of concentration followed by washing with an organic solvent, preferably ethyl acetate, followed by drying.

24. The process according to any one of claims 16 to 23, wherein the reaction yields the compound represented by Formula VII at a purity of greater than 94%, more preferably 95-97%, preferably wherein the reaction yields less than 5% of the c / .s-iso er of the compound represented by Formula VII, more preferably 1-3% of the c / s-isomer of the compound represented by Formula VII.

25. A process for producing a compound represented by Formula V or a pharmacologically acceptable salt thereofFormula V; the process comprising reacting a compound represented by Formula II or a salt thereof and a compound represented by Formula XIII or a salt thereof:Formula II wherein X represents a halogen atom, a sulfonate group, an ester group, or a phosphate group, preferably chlorine;Formula XIII.

26. The process according to claim 25 wherein the compound represented by Formula XIII or a salt thereof is produced by subjecting a compound represented by Formula XII or a salt thereof to a deprotection reaction, preferably wherein the deprotection reaction is a reduction reaction:Formula XII wherein Ri represents a protecting group, preferably an amino protecting group, more preferably a benzyloxy carbonyl group.

27. The process according to claim 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:Formula XI wherein Ri represents an amino protecting group, preferably a benzyloxycarbonyl group;Formula VII.

28. The process according to 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 process 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 activating agent:Formula I.

30. The process according to any one of claims 5 to 8, 10, 11, 14, 15, 17 to 23, and 25 to 28, wherein the compound represented by Formula V free base is produced, further comprising a process for crystallizing the monohydrobromide salt of the compound represented by Formula V, the process comprising: a) producing a solution of (1) the compound represented by Formula V free base, (2) a solvent such as ethanol or methanol, (3) water, and (4) hydrobromic acid, and b) either: i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and c) collecting the resulting crystals.

31. A process for crystallizing the monohydrobromide salt of a compound represented by Formula V:Formula V; the process comprising: a) producing a solution of (1) the compound represented by Formula V free base, (2) a solvent such as ethanol or methanol, (3) water, and (4) hydrobromic acid, and b) either: i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and c) collecting the resulting crystals.

32. The process according to claim 30 or 31, comprising the following steps: a) mixing the compound represented by Formula V free base with ethanol, water, and hydrobromic acid; b) adding the resulting solution into acetone, preferably dropwise; c) washing the resulting mixture with a mixed solution of ethanol and water; d) cooling the resulting mixture and stirring; e) collecting the resulting crystals; and f) optionally washing the collected crystals with acetone; g) optionally drying the washed crystals.

33. The process according to claim 32, comprising one or more or all of the following features: i) in step (a) the ratio by weight 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 into acetone at about 25-75°C, preferably about 50°C over 1 hour; iv) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00; v) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours; vii) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and viii) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

34. The process according to claim 30 or 31, comprising the following steps: a) suspending the compound represented by Formula V free base in a solution of methanol and water to form a suspension of the compound represented by Formula V; b) adding aqueous HBr 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) filtering the first solution; e) charging acetone and crystallization seeds to the first solution to obtain a second mixture; f) charging additional acetone to the second mixture to obtain a third mixture; g) holding and cooling the third mixture; h) filtering the third mixture to obtain a filter cake; i) washing the filter cake to obtain crystals of the monohydrobromide salt of the compound represented by Formula V.

35. The process according to claim 34, wherein the process comprises one or more or all of the following features:i) step a) comprises suspending the compound represented by Formula V free base 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, aqueous HBr to the suspension of the compound represented by Formula V obtain a first mixture; iii) step c) comprises heating the first mixture to about 45 to 60 °C, preferably about 50 °C, to obtain a solution; iv) step d) comprises filtering the first solution through a polish filter; v) step e) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours; vi) step f) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours, and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; and ix) the yield of the process is about 85%.

36. The process according to any one of claims 30 to 35, further comprising recrystallizing the monohydrobromide salt of the compound represented by Formula V, the process 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:i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and c) collecting the resulting crystals.

37. A process for recrystallizing a monohydrobromide salt of a compound represented byFormula V:Formula V; the process comprising: a) dissolving crystals of a monohydrobromide salt of the compound represented by Formula V in (1) a solvent such as ethanol or methanol, and (2) water, and b) either: i) adding the solution to acetone, preferably dropwise, followed by washing and cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; or ii) adding acetone and crystallization seeds to the solution, followed by cooling to produce crystals of the monohydrobromide salt of the compound represented by Formula V; and c) collecting the resulting crystals.

38. The process according to claim 36 or 37, comprising the following steps: a) mixing crystals of the monohydrobromide salt of the compound represented by Formula V with ethanol and water; b) adding the resulting solution into acetone, preferably dropwise; c) washing the resulting mixture with a mixed solution of ethanol and water;d) cooling the resulting mixture and stirring; e) collecting the resulting crystals; and f) optionally washing the collected crystals with acetone; g) optionally drying the washed crystals.

39. The process according to 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 into acetone at about 25-75°C, preferably about 50°C over 1 hour; iii) in step (b) the ratio by weight of the solution from step (a) to amount of acetone is about 43.82:237.00; iv) in step (c) the ratio by weight of ethanol to water in the mixed solution of ethanol and water is about 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 is for about 2-24 hours, preferably about 18 hours; vi) in step (g) the crystals are dried at about 25°C to 75 °C, preferably at about 50°C; and vii) the yield of the process is at least 90%, preferably at least 93%, more preferably 93% to 97%.

40. The process according to claim 36 or 37, comprising the following steps: a) dissolving crystals of a monohydrobromide salt of the compound represented by Formula V in a solution of methanol and water to obtain a first solution; b) filtering the first solution; c) charging acetone and crystallization seeds to the first solution to obtain a second mixture; d) charging additional acetone to the second mixture to obtain a third mixture; e) holding and cooling the third mixture; f) filtering the third mixture to obtain a filter cake; g) washing the filter cake to obtain crystals of the monohydrobromide salt of the compound represented by Formula V.41 . The process according to claim 40, wherein the process comprises one or more or all of the following features: i) step a) comprises suspending crystals of a monohydrobromide salt 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) comprises heating to about 45 to 60 °C, preferably about 50 °C; iii) step b) comprises filtering the first solution through a polish filter; iv) step c) comprises charging 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, crystallization seeds into the filtrate to obtain a second mixture, and holding this second mixture for about 2 - 16 hours, preferably about 16 hours; v) step d) comprises charging about 12 - 19 L / kg of acetone, preferably about 17.5 L / kg of acetone, over about 1 - 12 hours, preferably over about 12 hours, preferably below the liquid surface, 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 to about 20 °C, over about 2 - 3 hours, preferably about 2 hours, and holding for an additional about 3 - 16 hours, preferably an additional 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 of acetone; and viii) the yield of the process is about 85%.

42. A process substantially as described in any of the Aspects described herein.

43. A compound or composition produced according to a process of 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 according to a process of claim 12.

45. A compound or composition produced according to a process of claim 11.

46. A compound or composition produced according to a process of claim 16.

47. A compound or composition produced according to a process of claim 24.

48. A compound or composition produced according to a process of claim 29.

49. A compound or composition produced according to a process of claim 30.

50. A compound or composition produced according to a process of claim 34.

51. A compound or composition produced according to a process of claim 36.

52. A compound or composition produced according to a process of claim 40.

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