Preparation method of fasudil hydrochloride semihydrate

Abstract

The invention discloses a method for synthesizing a fasudil hydrochloride semihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride semihydrate) and an intermediate thereof.

Description

[0001] Cross - reference to related applications

[0002] This is an international application under the Patent Cooperation Treaty, which claims the benefit of U.S. Provisional Application No. 63 / 384,634, filed on November 22, 2022. The content of the foregoing application is incorporated herein by reference in its entirety. Field of the invention

[0003] The present disclosure relates to a method for preparing fasudil hydrochloride hemihydrate. Background art

[0004] Fasudil hydrochloride hemihydrate (1 - (isoquinoline - 5 - sulfonyl) homopiperazine hydrochloride hemihydrate), commonly known as "fasudil", is a drug with a wide range of indications. These indications include, for example, the treatment of various diseases and disorders related to aging. With the increasing aging of the population, the use of fasudil is expected to increase, resulting in a greater demand for this drug. There is a need for new and more effective methods for producing both fasudil and its intermediates. Summary of the invention

[0005] The present disclosure addresses the need for new and more effective methods for producing both fasudil and its intermediates. Thus, the present disclosure includes, but is not limited to, the following aspects / embodiments / features in any order and / or any combination.

[0006] A method is disclosed that includes: mixing isoquinoline - 5 - sulfonic acid and thionyl chloride in the absence of toluene under an inert atmosphere to form Composition (I); mixing N,N - dimethylformamide with Composition (I) in the absence of toluene under the inert atmosphere to form Composition (II); heating Composition (II) at a temperature of at least 40 °C in the absence of toluene under the inert atmosphere to form Composition (III) containing isoquinoline - 5 - sulfonyl chloride; and mixing Composition (III) with an organic solvent in the absence of toluene to precipitate isoquinoline - 5 - sulfonyl chloride hydrochloride.

[0007] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further includes: cooling Composition (III) to a temperature below 40 °C and above 5 °C.

[0008] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein Composition (III) is cooled to a temperature of about 10 °C to about 30 °C.

[0009] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the cooling is carried out for about 0.5 hours to about 3.5 hours.

[0010] A method of any of the foregoing or following embodiments / features / aspects is further provided, which comprises: removing thionyl chloride from composition (III).

[0011] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the thionyl chloride is removed under negative pressure.

[0012] A method of any of the foregoing or following embodiments / features / aspects is further provided, which comprises: contacting the isoquinoline-5-sulfonyl chloride hydrochloride with a second organic solvent in the absence of toluene and acetonitrile; and drying the isoquinoline-5-sulfonyl chloride hydrochloride to remove the second organic solvent.

[0013] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the second organic solvent comprises dichloromethane.

[0014] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the solvent is a first organic solvent and the second solvent is different from the first organic solvent.

[0015] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the heating is carried out at a temperature of about 65 °C to about 75 °C for about 2.0 hours to about 8.0 hours.

[0016] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the inert atmosphere comprises nitrogen or a noble gas or both.

[0017] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the inert atmosphere comprises less than 1.0 vol% oxygen.

[0018] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein compositions (I), (II) and (III) are formed in a reaction vessel, and the reaction vessel contains the inert atmosphere before introducing the thionyl chloride, the isoquinoline-5-sulfonate and the N,N-dimethylformamide into the reaction vessel.

[0019] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the isoquinoline-5-sulfonate is added in solid form and the thionyl chloride and the N,N-dimethylformamide are added in liquid form.

[0020] A method of any of the foregoing or following embodiments / features / aspects is provided, wherein the thionyl chloride is added in a molar equivalent in excess relative to the isoquinoline-5-sulfonate.

[0021] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: mixing the isoquinoline-5-sulfonyl chloride hydrochloride and homopiperazine to form a composition (IV) comprising 1-(isoquinolin-5-ylsulfonyl)homopiperazine.

[0022] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: precipitating the 1-(isoquinolin-5-ylsulfonyl)homopiperazine.

[0023] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: performing multiple extractions before precipitating the 1-(isoquinolin-5-ylsulfonyl)homopiperazine.

[0024] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: adding water to the composition (IV) to form a composition (V); adjusting the pH of the composition (V) to between 4.0 and 6.0; extracting the aqueous layer from the composition (V) as a composition (VI); adding an organic solvent to the composition (VI) to form a composition (VII); extracting the aqueous layer from the composition (VII) as a composition (VIII); adjusting the pH of the composition (VIII) to between pH 9.5 and 12.5; and precipitating the 1-(isoquinolin-5-ylsulfonyl)homopiperazine.

[0025] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: mixing the 1-(isoquinolin-5-ylsulfonyl)homopiperazine with water and hydrochloric acid to form a composition (IX); precipitating the hydrate or anhydrous form or both of 1-(isoquinolin-5-ylsulfonyl)homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinolin-5-ylsulfonyl)homopiperazine hydrochloride to form 1-(isoquinolin-5-ylsulfonyl)homopiperazine hydrochloride hemihydrate.

[0026] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the mixing is carried out at a pH of about 4.0 to about 5.0.

[0027] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: after the mixing and before the precipitation: mixing the composition (IX) with an organic solvent to form a composition (X); and extracting the aqueous layer from the composition (X) as a composition (XI).

[0028] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the organic solvent comprises dichloromethane.

[0029] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: raising the pH of the composition (XI) to above 5.0.

[0030] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the pH is raised to between 5.5 and 7.0.

[0031] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is precipitated from composition (XI).

[0032] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: before said heating: redissolving the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to form composition (XII); and reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride.

[0033] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: before reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride, contacting composition (XII) with activated carbon to decolorize composition (XII), thereby forming composition (XIII).

[0034] A method of any of the foregoing or following embodiments / features / aspects is disclosed, which further comprises: before reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride, filtering composition (XIII) to remove the activated carbon, thereby forming composition (XIV).

[0035] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated from composition (XIV).

[0036] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein said heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30 °C.

[0037] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein said heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature below 40 °C.

[0038] A method of any of the foregoing or following embodiments / features / aspects is disclosed, wherein said heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of about 20 °C to about 35 °C for a period of at least 8 hours.

[0039] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein said heating comprises: heating the hydrate of 1-(isoquinolin-5-sulfonyl) homopiperazine hydrochloride at a second temperature of from about 30 °C to about 45 °C for a second period of at least 36 hours, said period being a first period, said temperature being a second temperature, and said second temperature being higher than said first temperature.

[0040] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein the degree of hydration of the hydrate is 1.0 or greater, and the degree of hydration of the hemihydrate is 0.5.

[0041] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein the degree of hydration of the reprecipitated hydrate is 1.0 or greater, and the degree of hydration of the hemihydrate is 0.5.

[0042] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein the degree of hydration of the reprecipitated hydrate is different from the degree of hydration of the precipitated hydrate.

[0043] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein said precipitation or said reprecipitation or both comprise: adding a seed crystal.

[0044] Disclosed is a method of any of the foregoing or following embodiments / features / aspects, wherein said reprecipitation comprises: adding a seed crystal to composition (XI); and mixing composition (XI) at a second temperature of from about 0 °C to about 15 °C for from about 2.0 hours to about 5.0 hours.

[0045] Disclosed is a method comprising: mixing 1-(isoquinolin-5-sulfonyl) homopiperazine with water and hydrochloric acid; precipitating a hydrate of 1-(isoquinolin-5-sulfonyl) homopiperazine hydrochloride; and heating the hydrate of 1-(isoquinolin-5-sulfonyl) homopiperazine hydrochloride to form 1-(isoquinolin-5-sulfonyl) homopiperazine hydrochloride hemihydrate, wherein said heating comprises: a first period of at least 8 hours at a first temperature of from about 20 °C to about 35 °C, after which a second period of at least 36 hours at a second temperature of from about 30 °C to about 45 °C, and said second temperature is higher than said first temperature. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] To further understand the nature, objects, and advantages of the present disclosure, reference should be made to the following detailed description read in conjunction with the following drawings, in which like reference numerals denote like elements.

[0047] Figure 1ADepicts the overall scheme for synthesizing fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) in three stages designated as "A", "B", and "C".

[0048] Figure 1B Depicts a more specific scheme for stage "C" of the third stage depicted in Figure 1, which is divided into stages "C.1" and "C.2".

[0049] Figure 2A Depicts steps that can be carried out in stage A of the overall scheme depicted in Figure 1A

[0050] Figure 2B Depicts additional steps that can be carried out in stage A of the overall scheme depicted in Figure 1A

[0051] Figure 3A Depicts steps that can be carried out in stage B of the overall scheme depicted in Figure 1A

[0052] Figure 3B Depicts additional steps that can be carried out in stage B of the overall scheme depicted in Figure 1A

[0053] Figure 4A Depicts steps that can be carried out in stage C of the overall scheme depicted in Figure 1A and 1B

[0054] Figure 4B Depicts additional steps that can be carried out in stage C of the overall scheme depicted in Figure 1A and 1B

[0055] Figure 4C Depicts additional steps that can be carried out in stage C of the overall scheme depicted in Figure 1A and 1B Detailed Description

[0056] Discloses a method that can include one or more of the following steps to produce isoquinoline-5-sulfonyl chloride hydrochloride in stage A, for example, as Figure 1A , 2AAs shown in FIGS. 2A and 2B. In step A1, isoquinoline-5-sulfonic acid (IQSA) and thionyl chloride can be mixed together in the absence of toluene under an inert atmosphere to form composition (I). The mixing can be carried out in a reaction vessel in which air has been removed and an inert atmosphere has been introduced. Thionyl chloride can be added in a molar equivalent in excess relative to the isoquinoline-5-sulfonate. Thionyl chloride can be added before or during or both during the addition of IQSA. Thionyl chloride can act as both a reactant and a solvent. If one or more additional solvents are used, less thionyl chloride can be used. Thionyl chloride can act as a solvent for IQSA, excluding one or more additional solvents such as toluene. In step A2, N,N-dimethylformamide can be mixed with composition (I) in the absence of toluene under the inert atmosphere 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.

[0057] In step A3, composition (II) can be heated in the absence of toluene under the inert atmosphere at a temperature of at least 40 °C to form composition (III) containing isoquinoline-5-sulfonyl chloride. The heating can be carried out, for example, at a temperature of about 65 °C to about 75 °C for about 2.0 hours to about 8.0 hours. The heating can be carried out at about 40 °C to about 90 °C, about 45 °C to about 85 °C, about 50 °C to about 85 °C, about 55 °C to about 80 °C, about 60 °C to about 70 °C, or about 65 °C to about 75 °C, or any intermediate value or any range therebetween. The heating can be carried out for about 0.5 hours to about 12 hours, about 1.0 hours to about 10 hours, about 1.5 hours to about 9.0 hours, about 3.0 hours to about 6.0 hours, or about 4.0 hours to about 5.0 hours, or any intermediate time or any duration therebetween. The temperature of composition III can be cooled after heating, for example, cooled to a temperature below 40 °C and above 5 °C, about 10 °C to about 30 °C, about 15 °C to about 25 °C, or about 30 °C to about 40 °C, or any intermediate value or any range therebetween. The cooling can be carried out after mixing with an organic solvent such as dichloromethane. The cooling can be carried out, for example, for about 0.5 hours to about 3.5 hours, about 0.1 hours to about 5.0 hours, about 1.0 hours to about 4.0 hours, or about 1.5 hours to about 3.0 hours, or any intermediate time or any duration therebetween.

[0058] For example, during step A3, thionyl chloride can be removed from composition (III). The removed thionyl chloride can be reused as a reactant and a solvent in a previous step. This recycling of thionyl chloride can improve efficiency and reduce the environmental impact of the solvent that would otherwise be discarded. Thionyl chloride can be removed, for example, using a rotary evaporator under reduced pressure. In step A4, composition (III) can be mixed with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrochloride (IQSC). In step A5, isoquinoline-5-sulfonyl chloride hydrochloride can be contacted with a second organic solvent in the absence of toluene and acetonitrile. The solvent can be the first organic solvent, and the second solvent can be different 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 step A6, isoquinoline-5-sulfonyl chloride hydrochloride (IQSC) can be dried to remove the second organic solvent. For example, IQSC can be dried at about 15 °C to about 40 °C, about 20 °C to about 35 °C, about 25 °C to about 30 °C, or any intermediate temperature or any range therebetween. The drying can be carried out 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 intermediate duration or any range therebetween.

[0059] The inert atmosphere can comprise, for example, nitrogen or a noble gas or both. Examples of noble gases include helium, neon, argon, krypton, and xenon. The inert atmosphere can comprise, for example, less than 1.0 volume % oxygen. The inert atmosphere can comprise, for example, less than 1.0 volume % water vapor. Any one or all of compositions (I), (II), and (III) can be formed in a reaction vessel that contains the inert atmosphere before introducing the thionyl chloride, the isoquinoline-5-sulfonate, and the N,N-dimethylformamide into the reaction vessel. Any step or combination of steps in any of the stages described herein can be carried out under an inert atmosphere. The inert atmosphere can be at, below, or above atmospheric pressure.

[0060] In stage B, as shown in FIGS. 1, 3A and 3B, 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS base) can be formed in a procedure that includes one or more of the depicted steps. In step B1, isoquinoline-5-sulfonyl chloride hydrochloride (IQSC) and homopiperazine can be mixed to form a composition (IV) that includes 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS base). IQSC and homopiperazine can be mixed in dichloromethane as a solvent. Homopiperazine can be added to dichloromethane before adding IQSC. Before adding IQSC, the mixture of homopiperazine and dichloromethane (or other suitable solvent) can be cooled. For example, the mixture can be cooled to from about -20°C to about 20°C, from about -15°C to about 15°C, or from about -10°C to about 0°C, or from about -5.0°C to about 5°C, or any intermediate temperature or any range therebetween.

[0061] Before precipitating the 1-(isoquinoline-5-sulfonyl) homopiperazine, multiple extractions can be performed, for example, as shown in steps B2 - B7. Any suitable extraction method can be employed. For example, in step B2, water can be added to composition (IV) to form composition (V). In step B3, the pH of composition (V) can be adjusted to, for example, between 3.0 and 7.0, between 4.0 and 6.0, between 4.5 and 5.5, or any intermediate pH or any range therebetween. For example, in step B4, the aqueous layer can be extracted from composition (V) as composition (VI). For example, in step B5, an organic solvent can be added to composition (VI) to form composition (VII). For example, in step B6, the aqueous layer can be extracted from composition (VII) as composition (VIII). In step B7, 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 intermediate pH or any range therebetween. In step B8, 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS base) can be precipitated, for example, from composition (VIII). 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS base) can be precipitated from, for example, composition (IV) without an extraction procedure. Crystallization (precipitation) can include one or more cooling steps, for example, from about -10°C to about 25°C, from about 0°C to about 15°C, or from about 0°C to about 10°C, or any intermediate temperature or any range therebetween.

[0062] In stage C, as shown in FIGS. 1, 4A, 4B and 4C, 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate (FAS HCl hemihydrate) can be formed in a procedure that includes one or more of the depicted steps. Stage C can be further divided into (sub) stages C.1 and C.2 (Figure 1B )。FAS HCl can first be formed in the form of a hydrate or anhydrous form in stage C.1, and then dissolved and reprecipitated as a hemihydrate or higher-order hydrate in step C.2, and then modified to obtain a hemihydrate.

[0063] For example, in step C1, 1-(isoquinoline-5-sulfonyl) homopiperazine (FAS base) can be mixed with water and hydrochloric acid to form composition (IX). The mixing can be carried out at a pH of, for example, about 3.0 to about 6.0, about 4.5 to about 5.5, about 4.0 to about 5.0, or about 4.3 to about 4.7. After adding hydrochloric acid, composition (IX) can be heated and / or cooled with or without stirring. For example, composition (IX) can be heated to a temperature of, for example, about 35°C to about 55°C, or about 40°C to about 50°C, or any intermediate temperature, any temperature range therebetween. The heating can be carried out for about 10 minutes to about 60 minutes, about 15 minutes to about 45 minutes, or about 30 minutes to about 40 minutes, or any intermediate duration or any range therebetween. The cooling can be carried out at about 5°C to about 35°C, or about 20°C to about 30°C, or any intermediate temperature or any range therein. The cooling can be carried out for about 15 minutes to about 90 minutes, about 20 minutes to about 75 minutes, or about 30 minutes to about 60 minutes, or any intermediate duration or any other range therebetween.

[0064] For example, in step C5, a hydrate, anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) can be precipitated. The initially precipitated hydrate can be, for example, a hemihydrate or a trihydrate. FAS HCl can be precipitated as anhydrous FAS HCl. The precipitated FAS HCl can be dry or wet. For example, based on the weight percentage of the total weight of wet FASHCl, the water content of wet FAS HCl can be about 0.1% to about 90%, about 1.0% to about 80%, about 5.0% to about 75%, about 10% to about 65%, about 20% to about 60%, 25% to about 55%, or about 50%, or any intermediate percentage or any range therebetween. For example, in step C10, a hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be heated to form 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate (FAS HCl hemihydrate).

[0065] Stage C can optionally be carried out using one or more extractions, or one or more recrystallizations, or both. For example, these can be carried out in stage C.2 ( Figure 1B)。For example, after mixing and before precipitation, as in step C2, the composition (IX) can be mixed with an organic solvent to form a composition (X), and as in step C3, the aqueous layer can be extracted from the composition (X) as a composition (XI). The organic solvent can include, for example, dichloromethane (methylene chloride). In step C4, the pH of the composition (XI) can be raised to above 5.0, for example, from about 5.5 to about 7.0, or from about 5.7 to about 6.5, or from about 5.8 to about 6.2, or any intermediate pH or any range therebetween. Raising the pH can be carried out at a temperature of, for example, about 10°C to about 25°C, or about 15°C to about 20°C, or any intermediate temperature or any range therebetween. Before precipitation, the composition (XI) can be cooled. For example, the composition (XI) can be cooled to about -10°C to about 20°C, or about -5.0°C to about 15°C, or about 0°C to about 10°C, or any intermediate temperature or any range therebetween. Cooling can be carried out for about 1.0 hour to about 6 hours, about 2.5 hours to about 5 hours, or about 3.0 hours to about 4.0 hours, with or without stirring.

[0066] For example, in step C5, the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be precipitated from composition (XI). As in step C6, the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be redissolved to form composition (XII). The hydrate or anhydrous form or both can be in a wet form before redissolution. After redissolution, with or without stirring, composition (XII) can be heated to about 30°C to about 60°C, about 35°C to about 55°C, about 40°C to about 50°C for up to about 30 minutes. As in step C7, the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated. As in step C8, before the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated, composition (XII) can be contacted with activated carbon to decolorize composition (XII) so as to form composition (XIII). As in step C9, before the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated, composition (XIII) can be filtered to remove the activated carbon so as to form composition (XIV). Composition (XIV) can be cooled, for example, from about 10°C to about 30°C, or from about 15°C to about 20°C, or any intermediate temperature or any range therebetween. The hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride can be reprecipitated from composition (XIV). Seeds can be used for reprecipitation, such as seeds of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate. The reprecipitation can include: cooling composition (XIV) in one or more steps with or without stirring. For example, the cooling can be carried out for about 2 hours to about 7 hours or longer. The first cooling period can be at a first temperature, and the second cooling period can be at a second temperature. The second temperature can be lower than the first temperature. The first temperature can be about 0°C to about 25°C, about 5°C to about 20°C, or about 10°C to about 15°C, or any intermediate temperature or range therebetween. The second temperature can be about -10°C to about 20°C, about -5.0°C to about 15°C, or about 0°C to about 10°C, or any intermediate temperature or any range therebetween. Each period can be about 1.0 hour to about 8.0 hours, about 2.0 hours to about 3.0 hours, about 3.0 hours to about 4.0 hours, about 4.0 hours to about 6.0 hours, or any intermediate duration or any range therebetween. After cooling, centrifugation can be carried out, followed by washing with cooled pure water at about 0°C to about 15°C, or about 5°C to about 10°C, or any intermediate temperature or any range therebetween.

[0067] For example, in step C10, heating may include: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30 °C or below 40 °C. For example, heating may include: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of about 20 °C to about 35 °C. The heating may be carried out for a period of, for example, about 1.0 hour to about 72 hours, or about 2.5 hours to about 5.0 hours, or about 6.0 hours to about 64 hours, or about 10 hours to about 55 hours or about 14 hours to about 48 hours. The heating may be carried out in one or more periods that differ in terms of 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 in the first stage may be carried out at a temperature of, for example, about 15 °C to about 40 °C, or about 25 °C to about 30 °C, or any intermediate temperature or any range therebetween. The heating in the second stage may be carried out at a temperature of, for example, about 25 °C to about 50 °C, or about 35 °C to about 40 °C, or any intermediate temperature or any range therebetween. Heating may include, for example: in steps C10a,b, heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of about 30 °C to about 45 °C for a second period of about 2.5 hours to about 8 hours, said period being the first period, said temperature being the second temperature, and said second temperature being higher than the first temperature. Heating may include, for example: in step C10a, a first period of at least 3 hours at a first temperature of about 20 °C to about 35 °C, and in step C10b, a second period of at least 36 hours at a second temperature of about 30 °C to about 45 °C after the first period, such that the second temperature is higher than the first temperature. Heating may dry the hydrate. The heating in the second period may be carried out in an oven under a saturated sodium chloride solution to maintain a relative humidity of about 70 - 75%.

[0068] The hydration of the hydrate produced by heating can be 1.0 or greater, and the hydration of the hemihydrate is 0.5. Similarly, the hydration of the hydrate of the reprecipitate can be 1.0 or greater, and the hydration of the hemihydrate is 0.5. The hydrate of the reprecipitate can have the same or different hydration as the hydrate of the precipitate. The precipitation or the reprecipitation or both can include: seeding. The use of seeds is optional. The use of seeds of the desired hydrate can be used to promote the crystallization of the desired hydrate (e.g., hemihydrate). The reprecipitation can include: for example, in step C7a, cooling the composition (XII) to a first temperature of about 5°C to about 30°C, for example, in step C7b, adding seeds to the composition (XI), and for example, in step C7c, mixing the composition (XI) at a second temperature of about 0°C to about 15°C for about 2.0 to about 5.0 hours.

[0069] Examples

[0070] The following examples illustrate various aspects of the present disclosure. Variations thereof are within the scope of the present disclosure and can be modified and combined with other aspects of the present disclosure. Table 1 provides a list of codes and abbreviations.

[0071] Table 1 List of Codes and Abbreviations

[0072]

[0073] Example 1

[0074] The following is an example of Stage A of the synthesis scheme described herein. A nitrogen atmosphere is introduced into the reaction vessel (reactor) to remove air. Thionyl chloride (SOCl2) is first added to the reaction vessel as both a solvent and a reactant. Next, isoquinoline-5-sulfonic acid (IQSA) is added to the reaction vessel. IQSA and thionyl chloride are mixed in the reaction vessel by stirring. Next, 7 wt% of N,N-dimethylformamide (DMF) based on the total weight of the resulting mixture is added to the reaction vessel. The resulting mixture is heated at 65 - 75 °C for more than four hours. The heated mixture is stirred. For reaction endpoint control, the IQSA / IQSC derivative does not exceed 5.0%. The heated mixture is cooled to 30 °C to 40 °C. After transfer from the reaction vessel (with a brief exposure to air), the mixture is concentrated under reduced pressure in a rotary evaporator at 45 - 65 °C. The concentrated mixture is cooled to 30 °C to 40 °C. Dichloromethane (CH2Cl2) is introduced into the mixture cooled at 15 - 25 °C while stirring for two hours for precipitation. The precipitated mixture is centrifuged. The precipitate is washed with dichloromethane and then dried at 25 - 30 °C for more than five hours. At the end of drying, the LOD does not exceed 2.0%. The resulting isoquinoline-5-sulfonyl chloride hydrochloride (IQSC) is weighed, packaged, and labeled.

[0075] Example 2

[0076] The following is an example of Stage A of the synthesis scheme described herein, in which the reaction solvent was studied. 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 hours. Since thionyl chloride is a liquid solvent, the investigation excluded the use of toluene and SOCl2 was used as both a reagent and a solvent. Without using toluene, the target intermediate IQSC with a purity of not less than 98% was obtained. The data are shown in Table 2. This investigation demonstrated that the pure reaction (without using toluene) provided a higher yield and higher purity compared to using toluene.

[0077] Table 2. Investigation of the reaction solvent

[0078]

[0079] Example 3

[0080] The following is an example of Stage A of the synthesis scheme described herein, in which the reaction temperature and reaction time of the pure reaction were studied. The effects of reaction temperature and time on the yield and purity were investigated. Based on the data presented in Table 3, a reaction temperature of 65 - 75 °C and a reaction time of 3 - 4 hours were selected.

[0081] Table 3. Investigation of the reaction temperature and time

[0082]

[0083] Example 4

[0084] The following is an example of Stage A of the synthesis scheme described herein, in which the amount of thionyl chloride and recycling were studied. The amount of thionyl chloride may affect processability and product purity. The data presented in Table 4 indicate that with 6 equivalents (eq) of thionyl chloride, it was difficult to stir the reaction mixture, thus potentially affecting the reaction efficiency. Eight (8) equivalents of thionyl chloride were sufficient to obtain a high-purity product in high yield. Additional amounts of thionyl chloride did not result in higher yields or purity. Eight (8) equivalents of thionyl chloride were selected. The data presented in Table 4 also demonstrated that recycled thionyl chloride did not affect product yield and purity.

[0085] Table 4. Study of Recycling of Thionyl Chloride Equivalents

[0086]

[0087] Example 5

[0088] The following is an example of Stage B of the synthesis scheme described herein. Dichloromethane and homopiperazine were added to a reaction vessel and mixed in the reaction vessel with stirring. The mixture was cooled to -10 - 0 °C. IQSC was added to the mixture. The resulting mixture was cooled to 0 - 10 °C with stirring, including stirring for 1 to 2 hours. The reaction end point was controlled such that IQSA / FAS base was less than or equal to 2.0%. Purified water for washing was added while stirring at 15 - 30 °C for 20 - 30 minutes. For phase separation, the washed solution was allowed to stand for 10 - 30 minutes. Purified water was added to the organic layer and stirred at 15 - 30 °C for 20 - 30 minutes for further washing and phase separation. Concentrated HCl was added to adjust the pH to 4.5 to 5.5. At phase separation, dichloromethane was added to the aqueous phase multiple times for washing and phase separation. Purified water was added to the aqueous phase with stirring and cooled to 0 - 10 °C. Sodium hydroxide solution was added to adjust the pH from 10.8 to 11.2. The mixture with adjusted pH was stirred at 0 - 10 °C and then centrifuged. Purified water was added to wash 1-(isoquinoline-5-sulfonyl)homopiperazine (FAS base). The FAS base was weighed, packaged, and labeled. A water content (KF) report was generated.

[0089] Example 6

[0090] The following are examples of Stage B of the synthesis scheme described herein, where the addition temperature of IQSC and the reaction temperature were studied. For the preparation of fasudil free base, the effects of the addition temperature of IQSC and the reaction temperature on the yield and purity were studied. Based on the data presented in Table 5, it was confirmed that an addition temperature of IQSC of -10 - 0 °C and a reaction temperature of 0 - 10 °C were optimal for the preparation of fasudil free base with a purity of 97% - 98% and a yield exceeding 90%.

[0091] Table 5. Study on the addition temperature and reaction temperature

[0092]

[0093]

[0094] Example 7

[0095] The following are examples of Stage B of the synthesis scheme described herein, where the amount of dichloromethane (DCM: dichloromethane) was studied. It was found that the reaction solvent volume affected the purity and yield of FAS base. When the solvent volume of DCM was reduced from 25 volumes to 20 volumes or less, more dimer impurities were formed during this step. Based on the data presented in Table 6, 25 volumes of DCM were selected for the preparation of fasudil hydrochloride free base.

[0096] Table 6. Study on the amount of DCM

[0097]

[0098] Example 8

[0099] The following are examples of Stage B of the synthesis scheme described herein, where the amount of pure water during the treatment was studied. Based on the data presented in Table 7, it was found that it was appropriate to wash the DCM phase twice with 3.0 volumes of pure water.

[0100] Table 7. Study on the washing volume and number of washes of pure water during the treatment

[0101]

[0102] Example 9

[0103] The following are examples of Stage B of the synthesis scheme described herein, where the amount of DCM during the treatment was studied. Based on the data presented in Table 8, washing the aqueous phase twice with 5 volumes of DCM was the appropriate condition for removing dimer impurities.

[0104] Table 8. Study on the DCM washing volume and number of washes

[0105]

[0106] Example 10

[0107] The following is an example of stage C.1 of the synthesis scheme described herein. Pure water is added to the reaction water with stirring. Wet FAS base is added to the reaction vessel. The resulting composition is cooled to 15 - 30 °C. Concentrated HCl is added to adjust the pH to 4.3 - 4.7. The pH-adjusted composition is heated at 40 - 50 °C with stirring for 30 - 40 minutes and then cooled to 20 - 30 °C for 30 - 60 minutes. Dichloromethane is added to the cooled composition for washing, and it is allowed to stand for about 60 minutes for phase separation. Sodium hydroxide solution is added to the resulting aqueous phase, and the pH is adjusted to 5.8 - 6.2 at 15 - 20 °C. With stirring for 3 - 4 hours, the pH-adjusted solution is cooled to 0 - 10 °C. The cooled composition is centrifuged, and then cooled pure water is added for washing. For related substances (TLC): the standard solution (0.1%) shows no spots; related substances (HPLC). Any individual impurity does not exceed 0.1%. The total impurities do not exceed 0.3%. Water content control: KF is less than or equal to 50%. The resulting hydrate, anhydrous form, or both of 1-(isoquinolin-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) are weighed, packaged, and labeled.

[0108] Example 11

[0109] The following is an example of stage C.1 of the synthesis scheme described herein, in which the reaction conditions are studied. Based on the data presented in Table 9, for the preparation of fasudil HCl, a combination of 1.09 equivalents of concentrated HCl and 1.9 volumes of pure water is suitable for salt formation.

[0110] Table 9. Study of reaction conditions

[0111]

[0112] Example 12

[0113] The following is an example of Stage C.2 of the synthesis scheme described herein. The wet hydrate, wet anhydrous form, or both of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (FAS HCl) and pure water are added to a reaction chamber and stirred. The composition is heated to 40 - 50 °C. Activated carbon and pure water are added to the composition while stirring at 40 - 50 °C for up to 30 minutes. Pure water is added, and the composition is filtered. The resulting filtrate is cooled to 15 - 20 °C with stirring. Seeds of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate are added. The composition is cooled to 10 - 15 °C and stirred for 2 - 3 hours, and then cooled to 0 - 10 °C for 3 - 4 hours. The cooled solution is centrifuged, and cooled pure water is added for washing 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (hemi)hydrate at 5 - 10 °C. The drying of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride (hemi)hydrate is carried out in two stages, including heating to 25 - 30 °C in a saturated sodium chloride solution for at least 14 hours (water content control, KF: 5 - 15%), and then heating to 35 - 40 °C for at least 48 hours (water content control, KF 2.5 - 3.3%). The resulting 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate is sieved, weighed, packaged, and labeled. The yield of the final fasudil product can be at least 36%.

[0114] Example 13

[0115] The following is an example of Stage C.2 of the synthesis scheme described herein, in which the preparation of fasudil hydrochloride hemihydrate was studied. The conditions for the formation of fasudil hydrochloride hemihydrate were studied. The data are shown in Table 10. The factors for obtaining fasudil hydrochloride hemihydrate during this step include: 1) preparing fasudil hydrochloride hemihydrate from 2.5 v / w water and 0.2% (w / w) fasudil HCl hemihydrate seeds; 2) drying the solid product first at 25 - 30 °C and then continuing to dry the product at 35 - 40 °C under vacuum over a saturated sodium chloride solution to maintain a relative humidity of 70 - 75%. The drying time depends on the scale.

[0116] Table 10: Preparation of Fasudil (HCl) Hemihydrate

[0117]

[0118]

[0119] Example 14

[0120] Based on the specific results of the studies generally described in the above examples and the disclosure, a protocol for the synthesis of fasudil hydrochloride hemihydrate (1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride hemihydrate) and its intermediates can be established, which represents a significant improvement over existing synthetic protocols. The disclosed protocol can provide purities and yields that were previously unattainable. Parameters for examples of the synthetic protocol according to the present disclosure are provided in Table 11.

[0121] Table 11. Established Optimal Operating Parameters

[0122]

[0123]

[0124] Based on the synthetic protocol, an increase in batch scale can be achieved, for example, as shown in Table 12.

[0125] Table 12: Batch Results of Increased Scale of Fasudil Hydrochloride Hemihydrate

[0126] Batch size 7.28 kg Determination, based on anhydrous 99.8％ Impurities 0.04％ Water content 2.8％ Residue on ignition (RoI) 0.04％ Residual solvents Not detected Hydrate Hemihydrate

[0127] The present disclosure can include any combination of these various features or embodiments as shown above and / or below, such as in sentences and / or paragraphs. Any combination of the features disclosed herein is considered part of the present disclosure. Further, when an equivalent, concentration, or other value or parameter is given as a list of a range or upper and lower limit values, all ranges formed by any pair of an upper range limit or value and any lower range limit or value are also disclosed, whether or not the ranges are separately disclosed. Where a numerical range is recited herein, unless otherwise stated, the range is intended to include its endpoints, as well as all sub-ranges, integers, and fractions within the range. The scope of the present disclosure is not limited to the specific values recited within the range. All documents cited in this specification are incorporated herein by reference as if each document was specifically and individually indicated to be incorporated by reference. Each of the elements described herein, or two or more together, is also within the scope of the present disclosure.

Claims

1. A method, comprising: Mixing isoquinoline-5-sulfonic acid and thionyl chloride in the absence of toluene under an inert atmosphere to form Composition (I); Mixing N,N-dimethylformamide with Composition (I) in the absence of toluene under the inert atmosphere to form Composition (II); Heating Composition (II) at a temperature of at least 40 °C under the inert atmosphere in the absence of toluene to form Composition (III) comprising isoquinoline-5-sulfonyl chloride; and Mixing Composition (III) with an organic solvent in the absence of toluene to precipitate isoquinoline-5-sulfonyl chloride hydrochloride.

2. The method according to claim 1, further comprising: cooling Composition (III) to a temperature below 40 °C and above 5 °C.

3. The method according to claim 2, wherein Composition (III) is cooled to a temperature of about 10 °C to about 30 °C.

4. The method according to claim 2, wherein the cooling is carried out for about 0.5 hour to about 3.5 hours.

5. The method according to claim 1, further comprising: removing thionyl chloride from Composition (III).

6. The method according to claim 5, wherein the thionyl chloride is removed under negative pressure.

7. The method according to claim 1, further comprising: Contacting the isoquinoline-5-sulfonyl chloride hydrochloride with a second organic solvent in the absence of toluene and acetonitrile; and Drying the isoquinoline-5-sulfonyl chloride hydrochloride to remove the second organic solvent.

8. The method according to claim 7, wherein the second organic solvent comprises dichloromethane.

9. The method according to claim 7, wherein the solvent is a first organic solvent and the second solvent is different from the first organic solvent.

10. The method according to claim 1, wherein the heating is carried out at a temperature of about 65 °C to about 75 °C for about 2.0 hours to about 8.0 hours.

11. The method according to claim 1, wherein the inert atmosphere comprises nitrogen or a noble gas or both.

12. The method according to claim 1, wherein the inert atmosphere comprises less than 1.0 volume % of oxygen.

13. The method according to claim 1, wherein Compositions (I), (II) and (III) are formed in a reaction vessel, and the reaction vessel contains the inert atmosphere before introducing the thionyl chloride, the isoquinoline-5-sulfonate and the N,N-dimethylformamide into the reaction vessel.

14. The method according to claim 13, wherein the isoquinoline-5-sulfonate is added in solid form and the thionyl chloride and the N,N-dimethylformamide are added in liquid form.

15. The method according to claim 13, wherein the thionyl chloride is added in a molar equivalent in excess relative to the isoquinoline-5-sulfonate.

16. The method according to claim 1, further comprising: mixing the isoquinoline-5-sulfonyl chloride hydrochloride and homopiperazine to form a composition (IV) comprising 1-(isoquinoline-5-sulfonyl)homopiperazine.

17. The method according to claim 16, further comprising: precipitating the 1-(isoquinoline-5-sulfonyl)homopiperazine.

18. The method according to claim 17, further comprising: performing multiple extractions before precipitating the 1-(isoquinoline-5-sulfonyl)homopiperazine.

19. The method according to claim 16, further comprising: adding water to composition (IV) to form composition (V); adjusting the pH of composition (V) to between 4.0 and 6.0; extracting the aqueous layer from composition (V) as composition (VI); adding an organic solvent to composition (VI) to form composition (VII); extracting the 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 according to claim 16, further comprising: mixing the 1-(isoquinoline-5-sulfonyl)homopiperazine with water and hydrochloric acid to form composition (IX); precipitating the hydrate or 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 according to claim 20, wherein the mixing is carried out at a pH of about 4.0 to about 5.

0.

22. The method according to claim 20, further comprising: after the mixing and before the precipitation: mixing composition (IX) with an organic solvent to form composition (X); and extracting the aqueous layer from composition (X) as composition (XI).

23. The method according to claim 22, wherein the organic solvent comprises dichloromethane.

24. The method according to claim 22, further comprising: raising the pH of composition (XI) to above 5.

0.

25. The method according to claim 24, wherein the pH is raised to between 5.5 and 7.

0.

26. The method according to claim 24, wherein the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl)homopiperazine hydrochloride are precipitated from composition (XI).

27. The method according to claim 20, further comprising: before the heating: redissolving the hydrate or anhydrous form or both of 1-(isoquinoline-5-sulfonyl)homopiperazine hydrochloride to form composition (XII); and re-precipitating the hydrate of 1-(isoquinoline-5-sulfonyl)homopiperazine hydrochloride.

28. The method according to claim 27, further comprising: before reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride, contacting the composition (XII) with activated carbon to decolorize the composition (XII), thereby forming a composition (XIII).

29. The method according to claim 28, further comprising: before reprecipitating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride, filtering the composition (XIII) to remove the activated carbon, thereby forming a composition (XIV).

30. The method according to claim 29, wherein the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride is reprecipitated from the composition (XIV).

31. The method according to claim 20, wherein the heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride to a temperature below 30°C.

32. The method according to claim 20, wherein the heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature below 40°C.

33. The method according to claim 20, wherein the heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a temperature of about 20°C to about 35°C for a period of at least 8 hours.

34. The method according to claim 33, wherein the heating comprises: heating the hydrate of 1-(isoquinoline-5-sulfonyl) homopiperazine hydrochloride at a second temperature of about 30°C to about 45°C for a second period of at least 36 hours, the period being the first period, the temperature being the second temperature, and the second temperature being higher than the first temperature.

35. The method according to claim 20, wherein the degree of hydration of the hydrate is 1.0 or greater, and the degree of hydration of the hemihydrate is 0.

5.

36. The method according to claim 27, wherein the degree of hydration of the reprecipitated hydrate is 1.0 or greater, and the degree of hydration of the hemihydrate is 0.

5.

37. The method according to claim 27, wherein the degree of hydration of the reprecipitated hydrate is different from the degree of hydration of the precipitated hydrate.

38. The method according to claim 27, wherein the precipitation or the reprecipitation or both comprise: adding a seed crystal.

39. The method according to claim 27, wherein the reprecipitation comprises: adding a seed crystal to the composition (XI); and mixing the composition (XI) at a second temperature of about 0°C to about 15°C for about 2.0 hours to about 5.0 hours.

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 20°C to about 35°C, after said first period, a second period of at least 36 hours at a second temperature of from about 30°C to about 45°C, and said second temperature is higher than said first temperature.

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