WO2024112610A2 - Preparation method of fasudil hydrochloride hemihydrate - Google Patents

Preparation method of fasudil hydrochloride hemihydrate Download PDF

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Publication number
WO2024112610A2
WO2024112610A2 PCT/US2023/080382 US2023080382W WO2024112610A2 WO 2024112610 A2 WO2024112610 A2 WO 2024112610A2 US 2023080382 W US2023080382 W US 2023080382W WO 2024112610 A2 WO2024112610 A2 WO 2024112610A2
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Prior art keywords
composition
isoquinoline
sulfonyl
hydrate
temperature
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PCT/US2023/080382
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French (fr)
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WO2024112610A3 (en
Inventor
Hong Chun
Xiaokai TIAN
Yuan Wang
Xungui He
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Woolsey Pharmaceuticals, Inc.
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Publication of WO2024112610A2 publication Critical patent/WO2024112610A2/en
Publication of WO2024112610A3 publication Critical patent/WO2024112610A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate), commonly referred to as “fasudil,” is a drug that has a wide range of indications. These indications include, for example, treatment of various diseases and conditions associated with senility. With an increasingly aging population, the use of fasudil is expected to rise, leading to a greater demand for this drug. There exists a need for new and more efficient methods of producing both fasudil and its intermediates. BRIEF SUMMARY [0004] The present disclosure addresses the need for new and more efficient methods of producing both fasudil and its intermediates.
  • composition (I) Disclosed is a method comprising mixing isoquinoline-5-sulfonic acid and thionyl chloride under an inert atmosphere in the absence of toluene to form a composition (I); mixing N,N-dimethylformamide with composition (I) under the inert atmosphere in the absence of toluene to form composition (II); heating composition (II) at a temperature of at least 40oC to form composition (III) comprising isoquinoline-5-sulfonyl chloride under the inert atmosphere in the absence of ⁇ ⁇ ⁇ toluene; and mixing composition (III) with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrogen chloride.
  • compositions (I), (II), and (III) are formed in a reaction vessel, the reaction vessel comprising the inert atmosphere prior to the introduction of the thionyl chloride, isoquinoline-5-sulfonate, and N,N- dimethylformamide to the reaction vessel.
  • composition (IV) comprising 1-(isoquinoline-5-sulfonyl) homopiperazine.
  • composition (IV) comprising 1-(isoquinoline-5-sulfonyl) homopiperazine.
  • a method of any preceding or following embodiment/feature/aspect further comprising precipitating the 1-(isoquinoline-5- sulfonyl) homopiperazine.
  • a method of any preceding or following embodiment/feature/aspect further comprising performing a plurality of extractions prior to precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine.
  • composition (IV) to form a composition (V); adjusting the pH of composition (V) to between 4.0 and 6.0; extracting an aqueous layer from composition (V) as composition (VI); adding an organic solvent to composition (VI) to form composition (VII); extracting an aqueous layer from composition (VII) as composition (VIII); adjusting the pH of composition (VIII) to between pH 9.5 and 12.5; and precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine.
  • composition (IX) a method of any preceding or following embodiment/feature/aspect, further comprising: mixing the 1-(isoquinoline-5-sulfonyl) ⁇ ⁇ ⁇ homopiperazine with water and hydrochloric acid to form composition (IX); precipitating a hydrate, or an anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate.
  • Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising raising the pH of composition (XI) above 5.0. [0029] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the pH is raised to between 5.5 and 7.0. [0030] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate, or an anhydrous form, or both of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride is precipitated from composition (XI).
  • composition (XII) with activated carbon to decolorize composition (XII) to form composition (XIII) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride.
  • ⁇ ⁇ ⁇ [0033]
  • Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising filtering composition (XIII) to remove the activated carbon to form composition (XIV) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride.
  • composition (XIV) Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated from composition (XIV).
  • the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30oC.
  • any preceding or following embodiment/feature/aspect wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature below 40oC.
  • the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of from about 20oC to about 35oC for a period for at least 8 hours.
  • any preceding or following embodiment/feature/aspect wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30oC to about 45oC for a second period for at least 36 hours , the period being a first period, the temperature being a second temperature, and the second temperature being greater than the first temperature.
  • the hydrate has a hydration of 1.0 or greater and the hemihydrate has a hydration of 0.5.
  • the reprecipitation comprises: adding a seed crystal to composition (XI), and mixing composition (XI) from about 2.0 to about 5.0 hours at a second temperature of from about 0oC to about 15oC.
  • a method comprising: mixing 1-(isoquinoline-5-sulfonyl) homopiperazine with water and hydrochloric acid; precipitating a hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate, wherein the heating comprises: a first period of at least 8 hours at a first temperature of from about 20oC to about 35oC, a second period of at least 36 hours at a second temperature of from about 30oC to about 45oC following the first period, and the second temperature is higher than the first temperature.
  • FIG.1A depicts an overall scheme for synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) in three Stages designated “A,” “B,” and “C.”
  • FIG.1B depicts a more specific scheme for the third stage “C” depicted in FIG.1, divided into Stages “C.1” and “C.2.”
  • FIG.2A depicts steps that can be performed in Stage A of the overall scheme depicted in FIG.1A.
  • FIG.2B depicts additional steps that can be performed in Stage A of the overall scheme depicted in FIG.1A.
  • FIG.3A depicts steps that can be performed in Stage B of the overall scheme depicted in FIG.1A.
  • FIG.3B depicts additional steps that can be performed in Stage B of the overall scheme depicted in FIG.1A.
  • FIG.4A depicts steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B.
  • FIG.4B depicts additional steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B.
  • FIG.4C depicts further steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B.
  • a method that can comprise one or more of the following steps to produce isoquinoline-5-sulfonyl chloride hydrogen chloride in Stage A, for example, as set forth in FIGS.1A, 2A, and 2B.
  • IQSA isoquinoline-5-sulfonic acid
  • thionyl chloride can be mixed together under an inert atmosphere in the absence of toluene to form a composition (I).
  • the mixing can be performed in a reaction vessel in which air has been removed and an inert atmosphere introduced.
  • the thionyl chloride can be added in molar equivalents excess to the isoquinoline-5- sulfonate.
  • the thionyl chloride can be added before or during addition of the IQSA, or both.
  • the thionyl chloride can act as both a reactant and a solvent. Less thionyl chloride can be used if one or more additional solvents are used.
  • the thionyl chloride can act as the solvent for the IQSA excluding one or more additional solvents, for example, toluene.
  • N,N-dimethylformamide can be mixed with composition (I) under the inert atmosphere in the absence of toluene to form composition (II).
  • composition (II) can be heated at a temperature of at least 40oC to form composition (III) comprising isoquinoline-5-sulfonyl chloride under the inert atmosphere in the absence of toluene.
  • the heating can be performed, for example, at a temperature of from about 65oC to about 75oC for from about 2.0 hours to about 8.0 hours.
  • the heating can be performed at from about 40oC to about 90oC, from about 45oC to about 85oC, from about 50oC to about 85oC, from about 55oC to about 80oC, from about 60oC to about 70oC, or from about 65oC to about 75oC, or any intervening value, or any range therebetween.
  • the heating can be performed from about 0.5 hours to about 12 hours, from about 1.0 hours to about ⁇ ⁇ ⁇ 10 hours, from about 1.5 hours to about 9.0 hours. from about 3.0 hours to about 6.0 hours, or from about 4.0 hours to about 5.0 hours, or any intervening time, or any duration therebetween.
  • composition III can be cooled subsequent to the heating, for example, to a temperature below 40oC and above 5oC, from about 10oC to about 30oC, from about 15oC to about 25oC, or from about 30oC to about 40oC, or any intervening value, or any range therebetween.
  • the cooling can be performed after mixing with an organic solvent, for example, methylene chloride.
  • the cooling can be performed, for example, from about 0.5 hours to about 3.5 hours, from about 0.1 hours to about 5.0 hours, from about 1.0 hours to about 4.0 hours, or from about 1.5 hours to about 3.0 hours, or any intervening time, or any duration therebetween.
  • Thionyl chloride can be removed from composition (III), for example, during Step A3.
  • thionyl chloride removed can be reused as a reactant and solvent in the earlier steps. This recycling of thionyl chloride can increase efficiency and diminishes the environmental impact of solvent that would otherwise be discarded.
  • Thionyl chloride can be removed under negative pressure, for example, using a rotary evaporator.
  • a composition (III) can be mixed with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC).
  • IQSC isoquinoline-5-sulfonyl chloride hydrogen chloride
  • the isoquinoline-5-sulfonyl chloride hydrogen chloride can be contacted with a second organic solvent in the absence of toluene and acetonitrile.
  • the solvent can a first organic solvent and the second solvent can differ from the first organic solvent.
  • the first organic solvent can be, for example, thionyl chloride.
  • the second organic solvent can comprise, for example, methylene chloride (dichloromethane).
  • IQSC isoquinoline-5-sulfonyl chloride hydrogen chloride
  • the IQSC can be dried for from about 15oC to about 40oC, from about 20oC to about 35oC, from about 25oC to about 30oC, or any intervening temperature, or any range therebetween.
  • the drying can be performed for at least 2.0 hours, at least 3.0 hours , at least 4.0 hours, at least 4.5 hours, at least 5.0 hours, at least 5.5 hours, or at least 6 hours, or any intervening duration, or any range therebetween.
  • the inert atmosphere can comprise, for example, nitrogen, or a noble gas, or both. Examples of noble gasses include helium, neon, argon, krypton, and xenon.
  • the inert atmosphere can comprise, for example, less than 1.0 % by volume oxygen. ⁇ ⁇ ⁇
  • the inert atmosphere can comprise, for example, less than 1.0 % by volume water vapor.
  • compositions (I), (II), and (III) can be formed in a reaction vessel, the reaction vessel comprising the inert atmosphere prior to the introduction of the thionyl chloride, isoquinoline-5-sulfonate, and N,N-dimethylformamide to the reaction vessel.
  • Any step or combination of steps in any stage described herein can be performed under an inert atmosphere.
  • the inert atmosphere can be at, below, or above atmospheric pressure.
  • 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base) can be formed in a procedure comprising one or more of the steps depicted.
  • Step B1 isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC) and homopiperazine can be mixed to form composition (IV) comprising 1- (isoquinoline-5-sulfonyl) homopiperazine (FAS Base).
  • the IQSC and homopiperazine can be mixed in methylene chloride as the solvent.
  • the homopiperazine can be added to the methylene chloride before addition of the IQSC.
  • the mixture of homopiperazine and methylene chloride (or other suitable solvent) can be cooled before addition of the IQSC.
  • the mixture can be cooled to from about -20oC to about 20oC, from about -15oC to about 15oC, or from about - 10oC to about 0oC, or from about -5.0oC to about 5oC, or any intervening temperature, or any range therebetween.
  • a plurality of extractions can be performed prior to precipitating the 1- (isoquinoline-5-sulfonyl) homopiperazine, for example, as set forth in steps B2-B7. Any appropriate extraction procedure can be employed. Water can be added to composition (IV) to form a composition (V), for example, in Step B2.
  • composition (V) can be adjusted, for example, to between 3.0 and 7.0, between 4.0 and 6.0, between 4.5 and 5.5, or any intervening pH, or any range therebetween in Step B3.
  • An aqueous layer can be extracted from composition (V) as composition (VI), for example, in Step B4.
  • An organic solvent can be added to composition (VI) to form composition (VII), for example, in Step B5.
  • An aqueous layer can be extracted from composition (VII) as composition (VIII), for example, in Step B6.
  • the pH of composition (VIII) can be adjusted to, for example, between pH 9.0 and 13, between pH 9.5 and 12.5, between pH 10 and 11.5, or between pH 10.8 and 11.2, or any intervening pH, or any range therebetween in Step B7.
  • the 1-(isoquinoline-5- sulfonyl) homopiperazine (FAS Base) can be precipitated, for example, from Composition (VIII) in Step B8.
  • the 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS ⁇ ⁇ ⁇ Base) can be precipitated without an extraction procedure, for example, from Composition (IV).
  • Crystallization (precipitation) can comprise one or more cooling steps, for example, from about -10oC to about 25oC, from about 0oC to about 15oC, or from about 0oC to about 10oC, or any intervening temperature, or any range therebetween.
  • Stage C as set forth in FIGS.1, 4A, 4B, and 4C, 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate (FAS HCl Hemihydrate) can be formed in a procedure comprising one or more of the steps depicted. Stage C can be further divided into (Sub)Stages C.1 and C.2 (FIG.1B). FAS HCl can be first formed as a hydrate or an anhydrous form in Stage C.1 and then dissolved and reprecipitated in Step C.2 either as the hemihydrate or a higher order hydrate that is then modified to reach the hemihydrate.
  • composition (IX) The 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base) can be mixed with water and hydrochloric acid to form composition (IX), for example, in Step C1.
  • the mixing can be performed at a pH of, for example, from about 3.0 to about 6.0, from about 4.5 to about 5.5, from about 4.0 to about 5.0, or from about 4.3 to about 4.7.
  • composition (IX) can be heated and/or cooled with or without stirring.
  • composition (IX) can be heated, for example, to a temperature from about 35oC to about 55oC, or from about 40oC to about 50oC, or any intervening temperature, any temperature range therebetween.
  • the heating can be performed for about 10 minutes to about 60 minutes, from about 15 minutes to about 45 minutes, or about 30 minutes to about 40 minutes, or any intervening duration, or any range therebetween.
  • the cooling can be performed at from about 5oC to about 35oC, or from about 20oC to about 30oC, or any intervening temperature, or any range therein.
  • the cooling can be performed for from about 15 minutes to about 90 minutes, from about 20 minutes to about 75 minutes, or from about 30 minutes to about 60 minutes, or any intervening duration, or any other range therebetween.
  • a hydrate, an anhydrous form , or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) can be precipitated, for example, in Step C5.
  • the initial hydrate precipitated can be, for example, a hemihydrate or a trihydrate.
  • the FAS HCl can be precipitated as anhydrous FAS HCl.
  • the precipitated FAS HCl can be dry or wet.
  • wet FAS HCl can have from a water content of about 0.1% to about 90%, from about 1.0 to about 80%, from ⁇ ⁇ ⁇ about 5.0% to about 75%, from about 10% to about 65%, from about 20% to about 60%, from 25% to about 55%, or about 50%, or any intervening percentage, or any range therebetween on a weight percentage basis based on the total weight of the wet FAS HCl.
  • Stage C can be optionally performed using one or more extractions, or one or more recrystallizations, or both. These can be performed, for example, in Stage C.2 (FIG.1B).
  • composition (IX) can be mixed with an organic solvent to form composition (X) as in Step C2, and an aqueous layer can be extracted from composition (X) as composition (XI) as in Step C3.
  • the organic solvent can comprise, for example, methylene chloride (dichloromethane).
  • the pH of composition (XI) can be raised above 5.0, for example, from about 5.5 and to about 7.0, or from about 5.7 to about 6.5, or from about 5.8 to about 6.2, or any intervening pH, or any range therebetween in Step C4. Raising the pH can be performed at a temperature, for example, of from about 10oC to about 25oC, or from about 15oC to about 20oC, or any intervening temperature, or any range therebetween. Prior to precipitation, composition (XI) can be cooled.
  • composition (XI) can be cooled to from about -10oC to about 20oC, or from about -5.0oC to about 15oC, or from about 0oC to about 10oC, or any intervening temperature, or any range therebetween.
  • the cooling can be performed, with or without stirring, for about 1.0 hour to about 6 hours, from about 2.5 hours to about 5 hours, or from about 3.0 hours to about 4.0 hours.
  • the hydrate, or the anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be precipitated from composition (XI), for example, in Step C5.
  • composition (XII) can be redissolved to form composition (XII) as in Step C6.
  • the hydrate, or the anhydrous form, or both can be in a wet form before being redissolved.
  • composition (XII) can be heated to from about 30oC to about 60oC, from about 35oC to about 55oC, about 40oC to about 50oC, with or without stirring for up to about 30 minutes.
  • a hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated as in Step C7.
  • Composition (XII) can be contacted with activated carbon to decolorize ⁇ ⁇ ⁇ composition (XII) to form composition (XIII), as in Step C8, prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride.
  • Composition (XIII) can be filtered to remove the activated carbon to form composition (XIV), as in Step C9, prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride.
  • Composition (XIV) can be cooled, for example, from about 10oC to about 30oC, or from about 15oC to about 20oC, or any intervening temperature, or any range therebetween.
  • the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated from composition (XIV).
  • a seed crystal can be used for the reprecipitation, for example, a seed of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate.
  • Reprecipitation can comprise cooling composition (XIV) in one or more steps with or without stirring.
  • the cooling can be performed from about 2 hours to about 7 hours, or more.
  • a first cooling period can be at a first temperature and a second cooling period can be at a second temperature. The second temperature can be lower than the first temperature.
  • the first temperature can be from about 0oC to about 25oC, from about 5oC to about 20oC, or from about 10oC to about 15oC, or any intervening temperature, or range therebetween.
  • the second temperature can be from about - 10oC to about 20oC, from about -5.0oC to about 15oC, or from about 0oC to about 10oC, or any intervening temperature, or any range therebetween.
  • Each period can be from about 1.0 hour to about 8.0 hours, from about 2.0 hours to about 3.0 hours, from about 3.0 hours to about 4.0 hours, from about 4.0 hours to about 6.0 hours, or any intervening duration, or any range therebetween.
  • the heating can comprise heating the hydrate of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride to a temperature below 30oC or below 40oC, for example, in Step C10.
  • the heating can comprise heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of from about 20oC to about 35oC.
  • the heating can be performed for a period, for example, from about 1.0 hours to about 72 hours, or from about 2.5 hours to about 5.0 hours, or from about 6.0 hours to about 64 hours, or from about 10 hours to about 55 hours, or from about 14 hours to about 48 hours.
  • the heating can be performed in one or more periods, the period differing in temperature. For example, ⁇ ⁇ ⁇ a first period of at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 24 hours and a second period of at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 52 hours, at least 56 hours, or at least 60 hours.
  • the heating of the first period can be, for example, at a temperature of from about 15oC to about 40oC, or from about 25oC to about 30oC, or any intervening temperature, or any range therebetween.
  • the heating of the second period can be, for example, at a temperature for from about 25oC to about 50oC, or from about 35oC to about 40oC, or any intervening temperature, or any range therebetween.
  • the heating can comprise, for example, in Steps C10a,b, heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30oC to about 45oC for a second period from about 2.5 hours to about 8 hours, the period being a first period, the temperature being a second temperature, and the second temperature being greater than the first temperature.
  • the heating can comprise a first period of at least 3 hours at a first temperature of from about 20oC to about 35oC, for example in Step C10a, a second period of at least 36 hours at a second temperature of from about 30oC to about 45oC following the first period in Step C10b, such that the second temperature is higher than the first temperature.
  • the heating can dry the hydrate.
  • the heating in the second period can be done under saturated sodium chloride solution in the oven to maintain a relative humidity of between about 70-75%.
  • the hydrate resulting from the heating can have, for example, a hydration of 1.0 or greater and the hemihydrate has a hydration of 0.5.
  • the hydrate of the reprecipitate can have a hydration of 1.0 or greater and the hemihydrate have a hydration of 0.5.
  • the hydrate of the reprecipitate can have a hydration that is the same or that differs from the hydrate of the precipitate.
  • the precipitation, or the reprecipitation, or both can comprise adding a seed crystal. The use of a seed crystal is optional.
  • the use of a seed crystal of a desired hydrate can be used to facilitate crystallization of the desired hydrate, for example, the hemihydrate.
  • the reprecipitation can comprise cooling composition (XII) to a first temperature of from about 5oC to about 30oC, for example, in Step C7a, adding a seed crystal to composition (XI), for example, in Step C7b, and mixing composition (XI) from about 2.0 to about 5.0 hours at a second temperature of from about 0oC to about 15oC, for example, Step C7c.
  • ⁇ ⁇ ⁇ EXAMPLES [0068] The following examples demonstrate various aspects of the present disclosure. Variations on the same are within the scope of this disclosure and can be modified and combined with other aspects of this disclosure.
  • the resulting mixture is heated for upwards of four hours at 65-75oC.
  • the heated mixture is agitated.
  • IQSA/IQSC derivative is not more than 5.0%.
  • the heated mixture is cooled to 30oC to 40oC.
  • the mixture is concentrated at reduced pressure at 45-65oC.
  • the concentrated mixture is cooled to 30oC to 40oC.
  • Methylene chloride (CH2Cl2) is introduced to the cooled mixture at 15-25oC with stirring for two hours for precipitation.
  • the precipitated mixture is centrifuged.
  • the precipitate is washed with methylene chloride and then dried at 25-30oC for upwards of 5 hours.
  • the amount of thionyl chloride may impact processability and product purity.
  • Data presented in Table 4 indicate that with 6 equivalents (eq.) of thionyl chloride it was difficult to stir the reaction mixture, thus would impact the rection efficiency. Eight (8) eq. of thionyl chloride was sufficient to yield highly pure product with high yield. Additional amount of thionyl chloride did not result in higher yield or purity. Eight (8) eq. of thionyl chloride was the selected. Data presented in Table 4 also demonstrate that recycled thionyl chloride did not impact the product yield and purity. ⁇ ⁇ ⁇ Table 4.
  • Stage B of the synthetic scheme described herein Methylene chloride and homopiperazine are added to a reaction vessel and mixed therein with agitation. The mixture is cooled to -10-0oC. IQSC is added to the mixture. The resulting mixture is cooled to 0-10oC with agitation including stirring for 1 to 2 hours. The reaction end point control IQSA/FAS base is less than or equal to 2.0%. Purified water for washing is added with stirring at 15-30oC for 20-30 minutes. For phase separation the washed solution, is allowed to stand for 10-30 minutes.
  • Purified water is added to the organic layer for further washing and phase separation with stirring for 20-30 minutes at 15-30oC. Concentrated HCl is added for pH adjustment to 4.5 to 5.5. Upon phase separation, methylene chloride is added multiple times to aqueous phase for washing and phase separations. Purified water is added to the aqueous phase with agitation and cooling to 0-10oC. Sodium hydroxide solution is added for pH adjustment from 10.8 to 11.2. The pH-adjusted mixture is agitated at 0-10oC followed by centrifugation. Purified water is added for washing the 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base). The FAS base is weighed, packaged, and labelled.
  • FAS Base 1-(isoquinoline-5-sulfonyl) homopiperazine
  • Stage B of the synthetic scheme described herein in which the quantity of purified water during work-up was investigated. Based on the data presented in Table 7, washing the DCM phase twice with 3.0 volumes of purified water was found to be suitable. Table 7. Investigation on Wash Volume and Times of Purified Water in Work-up EXAMPLE 9 [0077] The following is an example of Stage B of the synthetic scheme described herein in which the quantity of DCM during work-up was investigated. Based on the data presented in Table 8, washing the aqueous phase twice with 5 volumes of DCM is the suitable condition to remove the dimer impurity. ⁇ ⁇ ⁇ Table 8.
  • Stage C.1 of the synthetic scheme described herein Purified water is added to a reaction water with agitation. Wet FAS base is added to the reaction vessel. The resulting composition is cooled to 15- 30oC. Concentrated HCl is added for pH adjustment to 4.3-4.7. The pH-adjusted composition is heated with agitation at 40-50oC for 30-40 minutes followed by cooling to 20-30oC for 30-60 minutes. Methylene chloride is added to the cooled composition for washing and let stand for about 60 minutes for phase separation. Sodium hydroxide solution is added to the resulting aqueous phase for pH adjustment to 5.8-6.2 at 15-20oC.
  • the pH-adjusted solution is cooled to 0-10oC with stirring for 3-4 hours.
  • the cooled composition is centrifuged and cooled purified water is then added for washing.
  • Water content control KF less than or equal to 50%.
  • the resulting hydrate, the anhydrous form , or both of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) is weighed, packaged, and labeled.
  • the composition is heated to 40-50oC. Activated carbon and purified water is added to the composition with stirring for up to 30 minutes at 40-50oC. Purified water is added and the composition is filtered resulting in a filtrate that is cooled to 15-20oC with agitation. A seed crystal of 1-(isoquinoline- 5-sulfonyl) homopiperazine hydrochloride hemihydrate is added. The composition is cooled to 10-15oC and stirred for 2-3 hours, and then cooled to 0-10oC for 3-4 hours. The cooled solution is centrifuged and cooled purified water added for washings of the 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (hemi)hydrate at 5- 10oC.
  • Factors during this step to obtain fasudil hydrochloride hemihydrate includes: 1) Preparation of fasudil hydrochloride hemihydrate from 2.5 v/w water, 0.2% (w/w) seeding of fasudil HCl hemihydrate; 2) Dry the solid product first at 25-30°C, and then continue to dry the product at 35-40°C under vacuum, over saturated sodium chloride solution to maintain a relative humidity of 70-75%. Drying time can depend on scale.

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Abstract

Disclosed are methods of synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) and intermediates thereof.

Description

^ ^^ PREPARATION METHOD OF FASUDIL HYDROCHLORIDE HEMIHYDRATE ^ CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is an international application under the Patent Cooperation Treaty, which claims the benefit of U.S. Provisional Application No.63/384,634, filed 22 November 2022. The content of the aforementioned application is herein incorporated by reference in its entirety. BACKGROUND Field [0002] The present disclosure relates to methods of preparing fasudil hydrochloride hemihydrate. Description of Related Art [0003] Fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate), commonly referred to as “fasudil,” is a drug that has a wide range of indications. These indications include, for example, treatment of various diseases and conditions associated with senility. With an increasingly aging population, the use of fasudil is expected to rise, leading to a greater demand for this drug. There exists a need for new and more efficient methods of producing both fasudil and its intermediates. BRIEF SUMMARY [0004] The present disclosure addresses the need for new and more efficient methods of producing both fasudil and its intermediates. Accordingly, the present disclosure includes without limitation the following aspects/embodiments/features in any order and/or in any combination. [0005] Disclosed is a method comprising mixing isoquinoline-5-sulfonic acid and thionyl chloride under an inert atmosphere in the absence of toluene to form a composition (I); mixing N,N-dimethylformamide with composition (I) under the inert atmosphere in the absence of toluene to form composition (II); heating composition (II) at a temperature of at least 40ºC to form composition (III) comprising isoquinoline-5-sulfonyl chloride under the inert atmosphere in the absence of ^^ ^ ^^ toluene; and mixing composition (III) with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrogen chloride. [0006] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising cooling composition (III) to a temperature below 40ºC and above 5ºC. [0007] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein composition (III) is cooled to a temperature of from about 10ºC to about 30ºC. [0008] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the cooling is performed from about 0.5 hours to about 3.5 hours. [0009] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising removing thionyl chloride from composition (III). [0010] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the thionyl chloride is removed under negative pressure. [0011] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising: contacting the isoquinoline-5- sulfonyl chloride hydrogen chloride with a second organic solvent in the absence of toluene and acetonitrile; and drying the isoquinoline-5-sulfonyl chloride hydrogen chloride to remove the second organic solvent. [0012] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the second organic solvent comprises methylene chloride. [0013] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the solvent is a first organic solvent and the second solvent differs from the first organic solvent. [0014] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the heating is performed at a temperature of from about 65ºC to about 75ºC for from about 2.0 hours to about 8.0 hours. [0015] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the inert atmosphere comprises nitrogen, or a noble gas, or both. ^^ ^ ^^ [0016] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the inert atmosphere comprises less than 1.0 % by volume oxygen. [0017] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein compositions (I), (II), and (III) are formed in a reaction vessel, the reaction vessel comprising the inert atmosphere prior to the introduction of the thionyl chloride, isoquinoline-5-sulfonate, and N,N- dimethylformamide to the reaction vessel. [0018] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the isoquinoline-5-sulfonate is added as a solid and the thionyl chloride and the N,N-dimethylformamide are added as liquids. [0019] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the thionyl chloride is added in molar equivalents excess to the isoquinoline-5-sulfonate. [0020] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising mixing the isoquinoline-5-sulfonyl chloride hydrogen chloride and homopiperazine to form composition (IV) comprising 1-(isoquinoline-5-sulfonyl) homopiperazine. [0021] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising precipitating the 1-(isoquinoline-5- sulfonyl) homopiperazine. [0022] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising performing a plurality of extractions prior to precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine. [0023] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising: adding water to composition (IV) to form a composition (V); adjusting the pH of composition (V) to between 4.0 and 6.0; extracting an aqueous layer from composition (V) as composition (VI); adding an organic solvent to composition (VI) to form composition (VII); extracting an aqueous layer from composition (VII) as composition (VIII); adjusting the pH of composition (VIII) to between pH 9.5 and 12.5; and precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine. [0024] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising: mixing the 1-(isoquinoline-5-sulfonyl) ^^ ^ ^^ homopiperazine with water and hydrochloric acid to form composition (IX); precipitating a hydrate, or an anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate. [0025] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the mixing is performed at a pH of from about 4.0 to about 5.0. [0026] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising, after the mixing and before the precipitating: mixing composition (IX) with an organic solvent to form composition (X); and extracting an aqueous layer from composition (X) as composition (XI). [0027] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the organic solvent comprises methylene chloride. [0028] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising raising the pH of composition (XI) above 5.0. [0029] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the pH is raised to between 5.5 and 7.0. [0030] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate, or an anhydrous form, or both of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride is precipitated from composition (XI). [0031] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising prior to the heating: redissolving the hydrate, or the anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form composition (XII); and reprecipitating a hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride. [0032] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising contacting composition (XII) with activated carbon to decolorize composition (XII) to form composition (XIII) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. ^^ ^ ^^ [0033] Disclosed is a method of any preceding or following embodiment/feature/aspect, further comprising filtering composition (XIII) to remove the activated carbon to form composition (XIV) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. [0034] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated from composition (XIV). [0035] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30ºC. [0036] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature below 40ºC. [0037] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of from about 20ºC to about 35ºC for a period for at least 8 hours. [0038] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30ºC to about 45ºC for a second period for at least 36 hours , the period being a first period, the temperature being a second temperature, and the second temperature being greater than the first temperature. [0039] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate has a hydration of 1.0 or greater and the hemihydrate has a hydration of 0.5. [0040] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate of the reprecipitate has a hydration of 1.0 or greater and the hemihydrate have a hydration of 0.5. [0041] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the hydrate of the reprecipitate has a hydration that differs from the hydrate of the precipitate. ^^ ^ ^^ [0042] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the precipitation, or the reprecipitation, or both comprises adding a seed crystal. [0043] Disclosed is a method of any preceding or following embodiment/feature/aspect, wherein the reprecipitation comprises: adding a seed crystal to composition (XI), and mixing composition (XI) from about 2.0 to about 5.0 hours at a second temperature of from about 0ºC to about 15ºC. [0044] Disclosed is a method comprising: mixing 1-(isoquinoline-5-sulfonyl) homopiperazine with water and hydrochloric acid; precipitating a hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate, wherein the heating comprises: a first period of at least 8 hours at a first temperature of from about 20ºC to about 35ºC, a second period of at least 36 hours at a second temperature of from about 30ºC to about 45ºC following the first period, and the second temperature is higher than the first temperature. BRIEF DESCRIPTION OF THE DRAWINGS [0045] For a further understanding of the nature, objects, and advantages of the present disclosure, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements. [0046] FIG.1A depicts an overall scheme for synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) in three Stages designated “A,” “B,” and “C.” [0047] FIG.1B depicts a more specific scheme for the third stage “C” depicted in FIG.1, divided into Stages “C.1” and “C.2.” [0048] FIG.2A depicts steps that can be performed in Stage A of the overall scheme depicted in FIG.1A. [0049] FIG.2B depicts additional steps that can be performed in Stage A of the overall scheme depicted in FIG.1A. [0050] FIG.3A depicts steps that can be performed in Stage B of the overall scheme depicted in FIG.1A. ^^ ^ ^^ [0051] FIG.3B depicts additional steps that can be performed in Stage B of the overall scheme depicted in FIG.1A. [0052] FIG.4A depicts steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B. [0053] FIG.4B depicts additional steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B. [0054] FIG.4C depicts further steps that can be performed in Stage C of the overall scheme depicted in FIGS.1A and 1B. DETAILED DESCRIPTION [0055] Disclosed is a method that can comprise one or more of the following steps to produce isoquinoline-5-sulfonyl chloride hydrogen chloride in Stage A, for example, as set forth in FIGS.1A, 2A, and 2B. In a Step A1, isoquinoline-5-sulfonic acid (IQSA) and thionyl chloride can be mixed together under an inert atmosphere in the absence of toluene to form a composition (I). The mixing can be performed in a reaction vessel in which air has been removed and an inert atmosphere introduced. The thionyl chloride can be added in molar equivalents excess to the isoquinoline-5- sulfonate. The thionyl chloride can be added before or during addition of the IQSA, or both. The thionyl chloride can act as both a reactant and a solvent. Less thionyl chloride can be used if one or more additional solvents are used. The thionyl chloride can act as the solvent for the IQSA excluding one or more additional solvents, for example, toluene. In a Step A2, N,N-dimethylformamide can be mixed with composition (I) under the inert atmosphere in the absence of toluene to form composition (II). The isoquinoline-5-sulfonate can be added as a solid and the thionyl chloride and the N,N-dimethylformamide can be added as liquids. [0056] In a Step A3, composition (II) can be heated at a temperature of at least 40ºC to form composition (III) comprising isoquinoline-5-sulfonyl chloride under the inert atmosphere in the absence of toluene. The heating can be performed, for example, at a temperature of from about 65ºC to about 75ºC for from about 2.0 hours to about 8.0 hours. The heating can be performed at from about 40ºC to about 90ºC, from about 45ºC to about 85ºC, from about 50ºC to about 85ºC, from about 55ºC to about 80ºC, from about 60ºC to about 70ºC, or from about 65ºC to about 75ºC, or any intervening value, or any range therebetween. The heating can be performed from about 0.5 hours to about 12 hours, from about 1.0 hours to about ^^ ^ ^^ 10 hours, from about 1.5 hours to about 9.0 hours. from about 3.0 hours to about 6.0 hours, or from about 4.0 hours to about 5.0 hours, or any intervening time, or any duration therebetween. The temperature of composition III can be cooled subsequent to the heating, for example, to a temperature below 40ºC and above 5ºC, from about 10ºC to about 30ºC, from about 15ºC to about 25ºC, or from about 30ºC to about 40ºC, or any intervening value, or any range therebetween. The cooling can be performed after mixing with an organic solvent, for example, methylene chloride. The cooling can be performed, for example, from about 0.5 hours to about 3.5 hours, from about 0.1 hours to about 5.0 hours, from about 1.0 hours to about 4.0 hours, or from about 1.5 hours to about 3.0 hours, or any intervening time, or any duration therebetween. [0057] Thionyl chloride can be removed from composition (III), for example, during Step A3. The thionyl chloride removed can be reused as a reactant and solvent in the earlier steps. This recycling of thionyl chloride can increase efficiency and diminishes the environmental impact of solvent that would otherwise be discarded. Thionyl chloride can be removed under negative pressure, for example, using a rotary evaporator. In a Step A4, a composition (III) can be mixed with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC). In a Step A5, the isoquinoline-5-sulfonyl chloride hydrogen chloride can be contacted with a second organic solvent in the absence of toluene and acetonitrile. The solvent can a first organic solvent and the second solvent can differ from the first organic solvent. The first organic solvent can be, for example, thionyl chloride. The second organic solvent can comprise, for example, methylene chloride (dichloromethane). In a Step A6, the isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC) can be dried to remove the second organic solvent. For example, the IQSC can be dried for from about 15ºC to about 40ºC, from about 20ºC to about 35ºC, from about 25ºC to about 30ºC, or any intervening temperature, or any range therebetween. The drying can be performed for at least 2.0 hours, at least 3.0 hours , at least 4.0 hours, at least 4.5 hours, at least 5.0 hours, at least 5.5 hours, or at least 6 hours, or any intervening duration, or any range therebetween. [0058] The inert atmosphere can comprise, for example, nitrogen, or a noble gas, or both. Examples of noble gasses include helium, neon, argon, krypton, and xenon. The inert atmosphere can comprise, for example, less than 1.0 % by volume oxygen. ^^ ^ ^^ The inert atmosphere can comprise, for example, less than 1.0 % by volume water vapor. Any or all of compositions (I), (II), and (III) can be formed in a reaction vessel, the reaction vessel comprising the inert atmosphere prior to the introduction of the thionyl chloride, isoquinoline-5-sulfonate, and N,N-dimethylformamide to the reaction vessel. Any step or combination of steps in any stage described herein can be performed under an inert atmosphere. The inert atmosphere can be at, below, or above atmospheric pressure. [0059] In Stage B, as set forth in FIGS.1, 3A, and 3B, 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base) can be formed in a procedure comprising one or more of the steps depicted. In Step B1, isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC) and homopiperazine can be mixed to form composition (IV) comprising 1- (isoquinoline-5-sulfonyl) homopiperazine (FAS Base). The IQSC and homopiperazine can be mixed in methylene chloride as the solvent. The homopiperazine can be added to the methylene chloride before addition of the IQSC. The mixture of homopiperazine and methylene chloride (or other suitable solvent) can be cooled before addition of the IQSC. For example, the mixture can be cooled to from about -20ºC to about 20ºC, from about -15ºC to about 15ºC, or from about - 10ºC to about 0ºC, or from about -5.0ºC to about 5ºC, or any intervening temperature, or any range therebetween. [0060] A plurality of extractions can be performed prior to precipitating the 1- (isoquinoline-5-sulfonyl) homopiperazine, for example, as set forth in steps B2-B7. Any appropriate extraction procedure can be employed. Water can be added to composition (IV) to form a composition (V), for example, in Step B2. The pH of composition (V) can be adjusted, for example, to between 3.0 and 7.0, between 4.0 and 6.0, between 4.5 and 5.5, or any intervening pH, or any range therebetween in Step B3. An aqueous layer can be extracted from composition (V) as composition (VI), for example, in Step B4. An organic solvent can be added to composition (VI) to form composition (VII), for example, in Step B5. An aqueous layer can be extracted from composition (VII) as composition (VIII), for example, in Step B6. The pH of composition (VIII) can be adjusted to, for example, between pH 9.0 and 13, between pH 9.5 and 12.5, between pH 10 and 11.5, or between pH 10.8 and 11.2, or any intervening pH, or any range therebetween in Step B7. The 1-(isoquinoline-5- sulfonyl) homopiperazine (FAS Base) can be precipitated, for example, from Composition (VIII) in Step B8. The 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS ^^ ^ ^^ Base) can be precipitated without an extraction procedure, for example, from Composition (IV). Crystallization (precipitation) can comprise one or more cooling steps, for example, from about -10ºC to about 25ºC, from about 0ºC to about 15ºC, or from about 0ºC to about 10ºC, or any intervening temperature, or any range therebetween. [0061] In Stage C, as set forth in FIGS.1, 4A, 4B, and 4C, 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate (FAS HCl Hemihydrate) can be formed in a procedure comprising one or more of the steps depicted. Stage C can be further divided into (Sub)Stages C.1 and C.2 (FIG.1B). FAS HCl can be first formed as a hydrate or an anhydrous form in Stage C.1 and then dissolved and reprecipitated in Step C.2 either as the hemihydrate or a higher order hydrate that is then modified to reach the hemihydrate. [0062] The 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base) can be mixed with water and hydrochloric acid to form composition (IX), for example, in Step C1. The mixing can be performed at a pH of, for example, from about 3.0 to about 6.0, from about 4.5 to about 5.5, from about 4.0 to about 5.0, or from about 4.3 to about 4.7. After addition of hydrochloric acid, composition (IX) can be heated and/or cooled with or without stirring. For example, composition (IX) can be heated, for example, to a temperature from about 35ºC to about 55ºC, or from about 40ºC to about 50ºC, or any intervening temperature, any temperature range therebetween. The heating can be performed for about 10 minutes to about 60 minutes, from about 15 minutes to about 45 minutes, or about 30 minutes to about 40 minutes, or any intervening duration, or any range therebetween. The cooling can be performed at from about 5ºC to about 35ºC, or from about 20ºC to about 30ºC, or any intervening temperature, or any range therein. The cooling can be performed for from about 15 minutes to about 90 minutes, from about 20 minutes to about 75 minutes, or from about 30 minutes to about 60 minutes, or any intervening duration, or any other range therebetween. [0063] A hydrate, an anhydrous form , or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) can be precipitated, for example, in Step C5. The initial hydrate precipitated can be, for example, a hemihydrate or a trihydrate. The FAS HCl can be precipitated as anhydrous FAS HCl. The precipitated FAS HCl can be dry or wet. For example, wet FAS HCl, can have from a water content of about 0.1% to about 90%, from about 1.0 to about 80%, from ^^^ ^ ^^ about 5.0% to about 75%, from about 10% to about 65%, from about 20% to about 60%, from 25% to about 55%, or about 50%, or any intervening percentage, or any range therebetween on a weight percentage basis based on the total weight of the wet FAS HCl. The hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be heated to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate (FAS HCl hemihydrate), for example, in Step C10. [0064] Stage C can be optionally performed using one or more extractions, or one or more recrystallizations, or both. These can be performed, for example, in Stage C.2 (FIG.1B). For example, after the mixing and before the precipitating, composition (IX) can be mixed with an organic solvent to form composition (X) as in Step C2, and an aqueous layer can be extracted from composition (X) as composition (XI) as in Step C3. The organic solvent can comprise, for example, methylene chloride (dichloromethane). The pH of composition (XI) can be raised above 5.0, for example, from about 5.5 and to about 7.0, or from about 5.7 to about 6.5, or from about 5.8 to about 6.2, or any intervening pH, or any range therebetween in Step C4. Raising the pH can be performed at a temperature, for example, of from about 10ºC to about 25ºC, or from about 15ºC to about 20ºC, or any intervening temperature, or any range therebetween. Prior to precipitation, composition (XI) can be cooled. For example, composition (XI) can be cooled to from about -10ºC to about 20ºC, or from about -5.0ºC to about 15ºC, or from about 0ºC to about 10ºC, or any intervening temperature, or any range therebetween. The cooling can be performed, with or without stirring, for about 1.0 hour to about 6 hours, from about 2.5 hours to about 5 hours, or from about 3.0 hours to about 4.0 hours. [0065] The hydrate, or the anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be precipitated from composition (XI), for example, in Step C5. The hydrate, or the anhydrous form, or both of 1-(isoquinoline- 5-sulfonyl) homopiperazine hydrochloride can be redissolved to form composition (XII) as in Step C6. The hydrate, or the anhydrous form, or both can be in a wet form before being redissolved. After being redissolved, composition (XII) can be heated to from about 30ºC to about 60ºC, from about 35ºC to about 55ºC, about 40ºC to about 50ºC, with or without stirring for up to about 30 minutes. A hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated as in Step C7. Composition (XII) can be contacted with activated carbon to decolorize ^^^ ^ ^^ composition (XII) to form composition (XIII), as in Step C8, prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. Composition (XIII) can be filtered to remove the activated carbon to form composition (XIV), as in Step C9, prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. Composition (XIV) can be cooled, for example, from about 10ºC to about 30ºC, or from about 15ºC to about 20ºC, or any intervening temperature, or any range therebetween. The hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated from composition (XIV). A seed crystal can be used for the reprecipitation, for example, a seed of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride hemihydrate. Reprecipitation can comprise cooling composition (XIV) in one or more steps with or without stirring. For example, the cooling can be performed from about 2 hours to about 7 hours, or more. A first cooling period can be at a first temperature and a second cooling period can be at a second temperature. The second temperature can be lower than the first temperature. The first temperature can be from about 0ºC to about 25ºC, from about 5ºC to about 20ºC, or from about 10ºC to about 15ºC, or any intervening temperature, or range therebetween. The second temperature can be from about - 10ºC to about 20ºC, from about -5.0ºC to about 15ºC, or from about 0ºC to about 10ºC, or any intervening temperature, or any range therebetween. Each period can be from about 1.0 hour to about 8.0 hours, from about 2.0 hours to about 3.0 hours, from about 3.0 hours to about 4.0 hours, from about 4.0 hours to about 6.0 hours, or any intervening duration, or any range therebetween. After cooling, centrifugation can be performed followed by washing with cooled purified water at from about 0ºC to about 15ºC, or from about 5ºC to about 10ºC, or any intervening temperature, or any range therebetween. [0066] The heating can comprise heating the hydrate of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride to a temperature below 30ºC or below 40ºC, for example, in Step C10. For example, the heating can comprise heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of from about 20ºC to about 35ºC. The heating can be performed for a period, for example, from about 1.0 hours to about 72 hours, or from about 2.5 hours to about 5.0 hours, or from about 6.0 hours to about 64 hours, or from about 10 hours to about 55 hours, or from about 14 hours to about 48 hours. The heating can be performed in one or more periods, the period differing in temperature. For example, ^^^ ^ ^^ a first period of at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 24 hours and a second period of at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 52 hours, at least 56 hours, or at least 60 hours. The heating of the first period can be, for example, at a temperature of from about 15ºC to about 40ºC, or from about 25ºC to about 30ºC, or any intervening temperature, or any range therebetween. The heating of the second period can be, for example, at a temperature for from about 25ºC to about 50ºC, or from about 35ºC to about 40ºC, or any intervening temperature, or any range therebetween. The heating can comprise, for example, in Steps C10a,b, heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30ºC to about 45ºC for a second period from about 2.5 hours to about 8 hours, the period being a first period, the temperature being a second temperature, and the second temperature being greater than the first temperature. The heating can comprise a first period of at least 3 hours at a first temperature of from about 20ºC to about 35ºC, for example in Step C10a, a second period of at least 36 hours at a second temperature of from about 30ºC to about 45ºC following the first period in Step C10b, such that the second temperature is higher than the first temperature. The heating can dry the hydrate. The heating in the second period can be done under saturated sodium chloride solution in the oven to maintain a relative humidity of between about 70-75%. [0067] The hydrate resulting from the heating can have, for example, a hydration of 1.0 or greater and the hemihydrate has a hydration of 0.5. Similarly, the hydrate of the reprecipitate can have a hydration of 1.0 or greater and the hemihydrate have a hydration of 0.5. The hydrate of the reprecipitate can have a hydration that is the same or that differs from the hydrate of the precipitate. The precipitation, or the reprecipitation, or both can comprise adding a seed crystal. The use of a seed crystal is optional. The use of a seed crystal of a desired hydrate can be used to facilitate crystallization of the desired hydrate, for example, the hemihydrate. The reprecipitation can comprise cooling composition (XII) to a first temperature of from about 5ºC to about 30ºC, for example, in Step C7a, adding a seed crystal to composition (XI), for example, in Step C7b, and mixing composition (XI) from about 2.0 to about 5.0 hours at a second temperature of from about 0ºC to about 15ºC, for example, Step C7c. ^^^ ^ ^^ EXAMPLES [0068] The following examples demonstrate various aspects of the present disclosure. Variations on the same are within the scope of this disclosure and can be modified and combined with other aspects of this disclosure. Table 1 provides a list of codes and abbreviations. Table 1 List of Codes and Abbreviations
Figure imgf000015_0001
EXAMPLE 1 [0069] The following is an example of Stage A of the synthetic scheme described herein. A nitrogen atmosphere is introduced into a reaction vessel (reactor) such that the air is removed. Thionyl chloride (SOCl2) is first added to the reaction vessel as both a solvent and a reactant. Isoquinoline-5-sulfonic acid (IQSA) is next added to the reaction vessel. The IQSA and thionyl chloride are mixed through agitation in the reaction vessel. N,N-Dimethylformamide (DMF) at 7 wt% of the total weight of ^^^ ^ ^^ the resulting mixture is next added to the reaction vessel. The resulting mixture is heated for upwards of four hours at 65-75ºC. The heated mixture is agitated. For a reaction end-point control, IQSA/IQSC derivative is not more than 5.0%. The heated mixture is cooled to 30ºC to 40ºC. At reduced pressure in a rotary evaporator after transfer from the reaction vessel (with brief exposure to air), the mixture is concentrated at reduced pressure at 45-65ºC. The concentrated mixture is cooled to 30ºC to 40ºC. Methylene chloride (CH2Cl2) is introduced to the cooled mixture at 15-25ºC with stirring for two hours for precipitation. The precipitated mixture is centrifuged. The precipitate is washed with methylene chloride and then dried at 25-30ºC for upwards of 5 hours. At the end of drying, the LOD is not more than 2.0%. The resulting isoquinoline-5-sulfonyl chloride hydrogen chloride (IQSC) is weighed, packaged, and labeled. EXAMPLE 2 [0070] The following is an example of Stage A of the synthetic scheme described herein in which reaction solvent was investigated. The use of toluene as a solvent for the reaction was investigated. The starting material IQSA was difficult to dissolve in toluene in about 22 hrs. Because thionyl chloride is a liquid solvent, it was investigated to eliminate the use of toluene and use SOCl2 as a reagent and solvent. The target intermediate IQSC was obtained with purity not less than 98% without the use of toluene. The data are presented in Table 2. This investigation demonstrates that neat reaction (without the use of toluene) afforded higher yield and higher purity compared to using toluene. Table 2. Investigation on Reaction Solvent
Figure imgf000016_0001
^^^ ^ ^^
Figure imgf000017_0001
EXAMPLE 3 [0071] The following is an example of Stage A of the synthetic scheme described herein in which reaction temperature and reaction time for a neat reaction were investigated. Reaction temperature and time were investigated for their effects on yield and purity. Based on the data presented in Table 3, reaction temperature of 65-75°C and reaction time of 3-4 hours was selected. Table 3. Investigation on Reaction Temperature and Time
Figure imgf000017_0002
EXAMPLE 4 [0072] The following is an example of Stage A of the synthetic scheme described herein in which the quantity and recycling of thionyl chloride was investigated. The amount of thionyl chloride may impact processability and product purity. Data presented in Table 4 indicate that with 6 equivalents (eq.) of thionyl chloride it was difficult to stir the reaction mixture, thus would impact the rection efficiency. Eight (8) eq. of thionyl chloride was sufficient to yield highly pure product with high yield. Additional amount of thionyl chloride did not result in higher yield or purity. Eight (8) eq. of thionyl chloride was the selected. Data presented in Table 4 also demonstrate that recycled thionyl chloride did not impact the product yield and purity. ^^^ ^ ^^ Table 4. Investigation on Equivalent of Thionyl Chloride and Recycling
Figure imgf000018_0001
EXAMPLE 5 [0073] The following is an example of Stage B of the synthetic scheme described herein. Methylene chloride and homopiperazine are added to a reaction vessel and mixed therein with agitation. The mixture is cooled to -10-0ºC. IQSC is added to the mixture. The resulting mixture is cooled to 0-10ºC with agitation including stirring for 1 to 2 hours. The reaction end point control IQSA/FAS base is less than or equal to 2.0%. Purified water for washing is added with stirring at 15-30ºC for 20-30 minutes. For phase separation the washed solution, is allowed to stand for 10-30 minutes. Purified water is added to the organic layer for further washing and phase separation with stirring for 20-30 minutes at 15-30ºC. Concentrated HCl is added for pH adjustment to 4.5 to 5.5. Upon phase separation, methylene chloride is added multiple times to aqueous phase for washing and phase separations. Purified water is added to the aqueous phase with agitation and cooling to 0-10ºC. Sodium hydroxide solution is added for pH adjustment from 10.8 to 11.2. The pH-adjusted mixture is agitated at 0-10ºC followed by centrifugation. Purified water is added for washing the 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS Base). The FAS base is weighed, packaged, and labelled. A water content (KF) report is generated. ^^^ ^ ^^ EXAMPLE 6 [0074] The following is an example of Stage B of the synthetic scheme described herein in which the addition temperature of IQSC and reaction temperature were investigated. For the preparation of fasudil free base, addition temperature of IQSC and reaction temperature were investigated for their effects on the yield and purity. Based on the data presented in Table 5, the addition temperature of IQSC at -10-0°C and reaction temperature at 0-10°C are confirmed optimal for the preparation of fasudil free base with purity of 97%-98% and yield of over 90%. Table 5. Investigation on Addition Temperature and Reaction Temperature
Figure imgf000019_0001
EXAMPLE 7 [0075] The following is an example of Stage B of the synthetic scheme described herein in which the amount of dichloromethane (DCM; methylene chloride) was investigated. The reaction solvent volume was found to affect the purity and yield of FAS Base. When the solvent amount of DCM was decreased from 25 volumes to 20 or fewer volumes much more dimer impurity formed during this step. Based on the data presented in Table 6, 25 volumes of DCM was the selected for the preparing of fasudil hydrochloride free base. ^^^ ^ ^^ Table 6. Investigation on Amount of DCM
Figure imgf000020_0001
EXAMPLE 8 [0076] The following is an example of Stage B of the synthetic scheme described herein in which the quantity of purified water during work-up was investigated. Based on the data presented in Table 7, washing the DCM phase twice with 3.0 volumes of purified water was found to be suitable. Table 7. Investigation on Wash Volume and Times of Purified Water in Work-up
Figure imgf000020_0002
EXAMPLE 9 [0077] The following is an example of Stage B of the synthetic scheme described herein in which the quantity of DCM during work-up was investigated. Based on the data presented in Table 8, washing the aqueous phase twice with 5 volumes of DCM is the suitable condition to remove the dimer impurity. ^^^ ^ ^^ Table 8. Investigation on DCM Wash Volume and Wash Times
Figure imgf000021_0001
EXAMPLE 10 [0078] The following is an example of Stage C.1 of the synthetic scheme described herein. Purified water is added to a reaction water with agitation. Wet FAS base is added to the reaction vessel. The resulting composition is cooled to 15- 30ºC. Concentrated HCl is added for pH adjustment to 4.3-4.7. The pH-adjusted composition is heated with agitation at 40-50ºC for 30-40 minutes followed by cooling to 20-30ºC for 30-60 minutes. Methylene chloride is added to the cooled composition for washing and let stand for about 60 minutes for phase separation. Sodium hydroxide solution is added to the resulting aqueous phase for pH adjustment to 5.8-6.2 at 15-20ºC. The pH-adjusted solution is cooled to 0-10ºC with stirring for 3-4 hours. The cooled composition is centrifuged and cooled purified water is then added for washing. For related substances (TLC): no spots from the standard solution (0.1%); related substances (HPLC). Any individual impurity not more than 0.1%. Total impurities not more than 0.3%. Water content control: KF less than or equal to 50%. The resulting hydrate, the anhydrous form , or both of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) is weighed, packaged, and labeled. EXAMPLE 11 [0079] The following is an example of Stage C.1 of the synthetic scheme described herein in which reaction conditions were investigated. Based on the data ^^^ ^ ^^ presented in Table 9, for the preparation of Fasudil HCl, the combination of 1.09 eq. of conc. HCl and 1.9 volumes of purified water is suitable for the salt formation. Table 9. Investigation on Reaction Conditions
Figure imgf000022_0001
EXAMPLE 12 [0080] The following is an example of Stage C.2 of the synthetic scheme described herein. Wet hydrate, wet anhydrous form, or both of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride (FAS HCl) and purified water is added to a reaction chamber and agitated. The composition is heated to 40-50ºC. Activated carbon and purified water is added to the composition with stirring for up to 30 minutes at 40-50ºC. Purified water is added and the composition is filtered resulting in a filtrate that is cooled to 15-20ºC with agitation. A seed crystal of 1-(isoquinoline- 5-sulfonyl) homopiperazine hydrochloride hemihydrate is added. The composition is cooled to 10-15ºC and stirred for 2-3 hours, and then cooled to 0-10ºC for 3-4 hours. The cooled solution is centrifuged and cooled purified water added for washings of the 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (hemi)hydrate at 5- 10ºC. Drying of the 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (hemi)hydrate is performed in two stages including heating to 25-30ºC for at least 14 hours (water content control, KF: 5-15%) and then heating to 35-40ºC for at least 48 hours (water content control, KF 2.5-3.3%) under saturated sodium chloride solution. The resulting 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate is sieved, weighed, packaged, and labelled. The yield of final fasudil product can be at least 36%. ^^^ ^ ^^ EXAMPLE 13 [0081] The following is an example of Stage C.2 of the synthetic scheme described herein in which the preparation of fasudil hydrochloride hemihydrate was investigated. The conditions for fasudil hydrochloride hemihydrate formation were investigated. The data are presented in Table 10. Factors during this step to obtain fasudil hydrochloride hemihydrate includes: 1) Preparation of fasudil hydrochloride hemihydrate from 2.5 v/w water, 0.2% (w/w) seeding of fasudil HCl hemihydrate; 2) Dry the solid product first at 25-30°C, and then continue to dry the product at 35-40°C under vacuum, over saturated sodium chloride solution to maintain a relative humidity of 70-75%. Drying time can depend on scale. Table 10: Preparation of Fasudil (HCl) Hemihydrate
Figure imgf000023_0001
^^^ ^ ^^
Figure imgf000024_0001
EXAMPLE 14 [0082] Based on the specific results from the investigations described in the above examples and the disclosure generally, a protocol for synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) and intermediates thereof can be established that constitutes a significant improvement over existing synthetic protocols. The disclosed protocol can provide purities and yields not previously achievable. Parameters for an ^^^ ^ ^^ example of the synthetic protocol in accordance with the present disclosure are provided in Table 11. Table 11. Established Optimal Operating Parameters
Figure imgf000025_0001
^^^ ^ ^^
Figure imgf000026_0002
[0083] Based on the synthetic protocol, a batch scale-up can be achieved, for example, as set forth in Table 12. Table 12: Fasudil Hydrochloride Hemihydrate Scale up batch Results
Figure imgf000026_0001
[0084] The present disclosure can include any combination of these various features or embodiments above and/or below as set forth in sentences and/or paragraphs. Any combination of disclosed features herein is considered part of the present disclosure. Further, when an amount, concentration, or other value or parameter is given as either a range, or a list of upper values and lower values, all ranges formed from any pair of any upper range limit or value and any lower range limit or value are also disclosed, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all subranges, integers, and fractions within the range. The scope of the disclosure is not limited to the specific values recited in a range. All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. Each of the elements described herein, or two or more together, are also within the scope of the present disclosure. ^^^

Claims

^ CLAIMS What is claimed is: 1. A method comprising: mixing isoquinoline-5-sulfonic acid and thionyl chloride under an inert atmosphere in the absence of toluene to form a composition (I); mixing N,N-dimethylformamide with composition (I) under the inert atmosphere in the absence of toluene to form composition (II); heating composition (II) at a temperature of at least 40ºC to form composition (III) comprising isoquinoline-5-sulfonyl chloride under the inert atmosphere in the absence of toluene; and mixing composition (III) with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrogen chloride. 2. The method of claim 1, further comprising cooling composition (III) to a temperature below 40ºC and above 5ºC. 3. The method of claim 2, wherein composition (III) is cooled to a temperature of from about 10ºC to about 30ºC. 4. The method of claim 2, wherein the cooling is performed from about 0.5 hours to about 3.5 hours. 5. The method of claim 1, further comprising removing thionyl chloride from composition (III). 6. The method of claim 5, wherein the thionyl chloride is removed under negative pressure. 7. The method of claim 1, further comprising: contacting the isoquinoline-5-sulfonyl chloride hydrogen chloride with a second organic solvent in the absence of toluene and acetonitrile; and drying the isoquinoline-5-sulfonyl chloride hydrogen chloride to remove the second organic solvent.
^^^ ^ ^ 8. The method of claim 7, wherein the second organic solvent comprises methylene chloride. 9. The method of claim 7, wherein the solvent is a first organic solvent and the second solvent differs from the first organic solvent. 10. The method of claim 1, wherein the heating is performed at a temperature of from about 65ºC to about 75ºC for from about 2.0 hours to about 8.0 hours. 11. The method of claim 1, wherein the inert atmosphere comprises nitrogen, or a noble gas, or both. 12. The method of claim 1, wherein the inert atmosphere comprises less than 1.0 % by volume oxygen. 13. The method of claim 1, wherein compositions (I), (II), and (III) are formed in a reaction vessel, the reaction vessel comprising the inert atmosphere prior to the introduction of the thionyl chloride, isoquinoline-5-sulfonate, and N,N- dimethylformamide to the reaction vessel. 14. The method of claim 13, wherein the isoquinoline-5-sulfonate is added as a solid and the thionyl chloride and the N,N-dimethylformamide are added as liquids. 15. The method of claim 13, wherein the thionyl chloride is added in molar equivalents excess to the isoquinoline-5-sulfonate. 16. The method of claim 1, further comprising mixing the isoquinoline-5-sulfonyl chloride hydrogen chloride and homopiperazine to form composition (IV) comprising 1-(isoquinoline-5-sulfonyl) homopiperazine. 17. The method of claim 16, further comprising precipitating the 1-(isoquinoline-5- sulfonyl) homopiperazine.
^^^ ^ ^ 18. The method of claim 17, further comprising performing a plurality of extractions prior to precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine. 19. The method of claim 16, further comprising: adding water to composition (IV) to form a composition (V); adjusting the pH of composition (V) to between 4.0 and 6.0; extracting an aqueous layer from composition (V) as composition (VI); adding an organic solvent to composition (VI) to form composition (VII); extracting an aqueous layer from composition (VII) as composition (VIII); adjusting the pH of composition (VIII) to between pH 9.5 and 12.5; and precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine. 20. The method of claim 16, further comprising: mixing the 1-(isoquinoline-5-sulfonyl) homopiperazine with water and hydrochloric acid to form composition (IX); precipitating a hydrate, or an anhydrous form, or both of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate. 21. The method of claim 20, wherein the mixing is performed at a pH of from about 4.0 to about 5.0. 22. The method of claim 20, further comprising, after the mixing and before the precipitating: mixing composition (IX) with an organic solvent to form composition (X); and extracting an aqueous layer from composition (X) as composition (XI). 23. The method of claim 22, wherein the organic solvent comprises methylene chloride. 24. The method of claim 22, further comprising raising the pH of composition (XI) above 5.0.
^^^ ^ ^ 25. The method of claim 24, wherein the pH is raised to between 5.5 and 7.0. 26. The method of claim 24, wherein the hydrate, or the anhydrous form, or both of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride is precipitated from composition (XI). 27. The method of claim 20, further comprising prior to the heating: redissolving the hydrate, or the anhydrous form, or both of 1-(isoquinoline-5- sulfonyl) homopiperazine hydrochloride to form composition (XII); and reprecipitating a hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. 28. The method of claim 27, further comprising contacting composition (XII) with activated carbon to decolorize composition (XII) to form composition (XIII) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. 29. The method of claim 28, further comprising filtering composition (XIII) to remove the activated carbon to form composition (XIV) prior to reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride. 30. The method of claim 29, wherein the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated from composition (XIV). 31. The method of claim 20, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30ºC. 32. The method of claim 20, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature below 40ºC. 33. The method of claim 20, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of from about 20ºC to about 35ºC for a period for at least 8 hours.
^^^ ^ ^ 34. The method of claim 33, wherein the heating comprises heating the hydrate of 1- (isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30ºC to about 45ºC for a second period for at least 36 hours, the period being a first period, the temperature being a second temperature, and the second temperature being greater than the first temperature. 35. The method of claim 20, wherein the hydrate has a hydration of 1.0 or greater and the hemihydrate has a hydration of 0.5. 36. The method of claim 27, wherein the hydrate of the reprecipitate has a hydration of 1.0 or greater and the hemihydrate have a hydration of 0.5. 37. The method of claim 27, wherein the hydrate of the reprecipitate has a hydration that differs from the hydrate of the precipitate. 38. The method of claim 27, wherein the precipitation, or the reprecipitation, or both comprises adding a seed crystal. 39. The method of claim 27, wherein the reprecipitation comprises: adding a seed crystal to composition (XI), and mixing composition (XI) from about 2.0 to about 5.0 hours at a second temperature of from about 0ºC to about 15ºC. 40. A method comprising: mixing 1-(isoquinoline-5-sulfonyl) homopiperazine with water and hydrochloric acid; precipitating a hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate, wherein the heating comprises: a first period of at least 8 hours at a first temperature of from about 20ºC to about 35ºC,
^^^ ^ ^ a second period of at least 36 hours at a second temperature of from about 30ºC to about 45ºC following the first period, and the second temperature is higher than the first temperature.
^^^ ^
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