Process for purifying isavuconazolium sulfate

Abstract

The present invention provides a method for purifying isavuconazonium sulfate, the method comprising the steps of: -(a) providing a mixture comprising a sulfate salt of a compound of formula (I) and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; -(b) allowing a first portion of the sulfate salt of the compound of formula (I) to crystallize from the mixture; and -(c) adding an aprotic organic solvent to the mixture and allowing another portion of the sulfate salt of the compound of formula (I) to precipitate from the mixture.

Description

[0001] The present invention provides a method for purifying isavuconazonium sulfate and its diastereomers.

[0002] Isavuconazolium sulfate is a prodrug of the broad-spectrum azole antifungal agent isavuconazole. It is being commercialized for the treatment of aspergillosis and mucormycosis and can be used as an oral formulation and an intravenous formulation. Isavuconazolium salts are described in WO 2001 / 32652, and a method for preparing isavuconazolium hydrochloride is given in Example 7. However, due to its sensitivity to moisture, isavuconazolium salts (such as the commercial product isavuconazolium sulfate) are difficult to purify from crude material in high yield.

[0003] Attempts have been made to purify isavuconazolium sulfate by crystallization. For example, CN 106565699 describes a method for preparing a crystalline form of isavuconazolium sulfate. The method involves step 1: dissolving isavuconazol hydrochloride in water, adjusting the pH to neutral with a base at low temperature, adding an organic solvent A for extraction, drying and concentrating, and then dissolving in an organic solvent B, adding concentrated sulfuric acid and hydrogen peroxide at low temperature, stirring and concentrating; step 2: adding the above concentrate to an organic solvent C, heating to dissolve, stirring and cooling to crystallize, and performing suction filtration to obtain crystals. However, this method is not suitable for commercial scale expansion. Specifically, the use of hydrogen peroxide leads to significant degradation of the product.

[0004] CN 106467534 also describes a method for preparing a crystalline form of isavuconazolium sulfate. The method involves (a) dissolving a crude isavuconazolium sulfate product in a mixed solution of water, an organic solvent A and an organic solvent B; (b) adding an organic solvent C dropwise to the isavuconazolium sulfate solution obtained in step (a); and (c) performing stirring crystallization and separation to obtain the isavuconazolium sulfate compound, wherein the organic solvent A refers to R1-O-CH2-CH2OH; the organic solvent B refers to R2-C(=O)-R3 and / or tetrahydrofuran; and the organic solvent C refers to R4-C(=O)O-R5; R1, R2, R3, R4 and R5 are independently selected from C1-3 alkyl.

[0005] However, as shown in the following comparative examples, we have found that the process described in CN106467534 results in low yields when the crude material has a lower purity. In addition, when starting from high purity material, CN106467534 produces an isavuconazolium sulfate product that is highly enriched in one of the two diastereomers, whereas the approved commercial product has a diastereomer molar ratio of 1.2:1 to 1:1.2.

[0006] Two diastereomers of isavuconazolium are depicted herein:

[0007]

[0008] The present invention provides a novel procedure for purifying isavuconazolium sulfate (referred to herein as the sulfate salt of the compound of Formula I).

[0009] In a first aspect, the present invention provides a method for purifying the sulfate salt of a compound of formula I

[0010]

[0011] The method comprises the following steps:

[0012] (a) providing a mixture comprising a sulfate salt of a compound of formula I and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6;

[0013] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture; and

[0014] (c) adding an aprotic organic solvent to the mixture and allowing a further portion of the sulfate salt of the compound of formula I to precipitate from the mixture.

[0015] The epimers of the sulfate salt of the compound of formula I are defined herein by reference to their retention times. Epimer A is the first epimer to elute from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenylcarbamate, wherein the mobile phase is a mixture of triethylammonium acetate and acetonitrile in a ratio of 40:60 at pH 6.5.

[0016] In general, the mixture provided in step (a) comprises a mixture of epimers A and epimers B of the sulfate of the compound of formula I in similar amounts. The portions obtained from step (b) and step (c) contain epimers A and epimers B in different proportions. Step (b) selectively crystallizes epimer B, while step (c) effectively precipitates epimer A remaining in solution. Therefore, in the absence of step (c), the crystalline form obtained from step (b) will tend to have a lower yield because a large portion of epimer A will still be in solution. In addition, for this reason, the ratio of epimers will generally not meet the ratio required for commercialization (i.e., a ratio of 1.2:1 to 1:1.2). When step (c) is included, a larger proportion of epimer A is precipitated, which can allow the ratio of epimer A to epimer B obtained to be within the limits required for commercial products.

[0017] The molar ratio of diastereomer B to diastereomer A in the portion of the sulfate salt of the compound of formula I obtained in step (b) is generally greater than 1:1, for example at least 1.3:1, for example at least 1.5:1, for example at least 2:1, for example at least 5:1, for example in the range of 1.3:1 to 100:1, for example in the range of 1.5:1 to 50:1, for example in the range of 2:1 to 20:1, for example in the range of 5:1 to 20:1.

[0018] The molar ratio of diastereomer A to diastereomer B in the portion of the sulfate salt of the compound of formula I obtained in step (c) is generally greater than 1:1, for example at least 1.3:1, for example at least 1.5:1, for example at least 2:1, for example at least 5:1, for example in the range of 1.3:1 to 100:1, for example in the range of 1.5:1 to 50:1, for example in the range of 2:1 to 20:1, for example in the range of 5:1 to 20:1.

[0019] The molar ratio of epimer A to epimer B in the combined fractions of the sulfate salt of the compound of Formula I from step (b) and step (c) combined may be from 2:1 to 1:2, such as from about 1.2:1 to about 1:1.2.

[0020] The mixture provided in step (a) can be prepared from a solid crude product obtained from the synthesis of a sulfate salt of a compound of formula I, which can be synthesized by a person skilled in the art according to known procedures. In one embodiment, the precursor of the compound of formula I is a sulfate salt of an analog of a Boc-protected compound of formula I (such as compound 6 depicted in CN 106916152 A), which can be deprotected using sulfuric acid using a suitable solvent (e.g., ethyl acetate) at a temperature in the range of 20°C to 25°C to give a sulfate salt of the compound of formula I. This sulfate salt can be allowed to precipitate (e.g., in water) to give a solid crude product, which can be optionally washed (e.g., with a protic organic solvent such as isopropanol).

[0021] The solid crude product will contain impurities formed during the synthesis of the sulfate of the compound of formula I. The purity of the sulfate of the compound of formula I in the solid crude product that can be used in step (a) is typically, for example (before or after washing) at least 80% (i.e., the weight of the sulfate of the compound of formula I relative to the weight of the impurities), for example in the range of 80% to 100%, for example in the range of 90% to 100%, for example in the range of 90% to 99%, for example in the range of 90% to 98%, for example in the range of 90% to 97%, for example in the range of 90% to 96%, for example in the range of 90% to 95%, for example in the range of 93% to 100%, for example in the range of 93% to 98%. In other embodiments, the purity of the sulfate of the compound of formula I in the solid crude product that can be used in step (a) may not exceed 98%, for example not exceed 97%, for example not exceed 96%, not exceed 95%.

[0022] The mixture of step (a) can be provided by dissolving the solid crude product of the sulfate of the compound of formula I in an aliphatic alcohol. The aliphatic part is a non-aromatic hydrocarbon part, wherein the carbon atom constituting the aliphatic part can be straight-chain, branched or cyclic. The aliphatic alcohol according to the present invention contains one or two OH groups, provided that when there are two OH groups, there are three to six carbon atoms in the aliphatic part. The aliphatic alcohol can be a C2-C10 alkyl-OH or a C3-C10 cycloalkyl-OH (e.g., cyclopentanol, cyclohexanol, cycloheptanol) or a mixture thereof, particularly a C2-C10 alkyl-OH. In one embodiment, the aliphatic alcohol is an aliphatic alcohol selected from ethanol, propanol (including any isomer thereof, such as propan-1-ol, isopropanol), butanol (including any isomer thereof, such as n-butyl-1-ol, n-butyl-2-ol, tert-butyl-1-ol, tert-butyl-2-ol) and amyl alcohol (including any isomer thereof) or a mixture thereof. In another embodiment, the aliphatic alcohol is propanol or ethanol or a mixture thereof. In another embodiment, the aliphatic alcohol is ethanol or n-butanol. In another embodiment, the aliphatic alcohol is ethanol.

[0023] The v / w ratio (i.e. ml:g) of the aliphatic alcohol to the sulfate salt of the compound of formula I may be up to 100:1, for example up to 75:1, for example up to 40:1, for example up to 20:1, for example up to 10:1, for example up to 8:1, for example up to 6:1, for example up to 5:1, for example at least 1:1, for example at least 2:1, for example in the range of 1:1 to 100:1, for example in the range of 1:1 to 75:1, for example in the range of 1:1 to 40:1, for example in the range of 1:1 to 20:1, for example in the range of 1:1 to 10:1, for example in the range of 2:1 to 10:1, for example in the range of 2:1 to 8:1, for example in the range of 2:1 to 6:1, for example in the range of 3:1 to 5:1, for example about 4:1. For example, the v / w ratio of ethanol to the sulfate salt of the compound of formula I may be up to 100:1, such as up to 75:1, such as up to 40:1, such as up to 20:1, such as up to 10:1, such as up to 8:1, such as up to 6:1, such as up to 5:1, such as at least 1:1, such as at least 2:1, such as in the range of 1:1 to 100:1, such as in the range of 1:1 to 75:1, such as in the range of 1:1 to 40:1, such as in the range of 1:1 to 20:1, such as in the range of 1:1 to 10:1, such as in the range of 2:1 to 10:1, such as in the range of 2:1 to 8:1, such as in the range of 2:1 to 6:1, such as in the range of 3:1 to 5:1, such as about 4:1.

[0024] Optionally, the mixture in step (a) comprises water in addition to the aliphatic alcohol. The v / v ratio of the aliphatic alcohol to water may be up to 500:1, for example in the range of 1:1 to 50:1, for example in the range of 5:1 to 50:1, for example in the range of 5:1 to 30:1, for example in the range of 10:1 to 30:1, for example in the range of 15:1 to 25:1, for example about 20:1. For example, the v / v ratio of ethanol to water may be up to 500:1, for example in the range of 1:1 to 50:1, for example in the range of 5:1 to 50:1, for example in the range of 5:1 to 30:1, for example in the range of 10:1 to 30:1, for example in the range of 15:1 to 25:1, for example about 20:1.

[0025] In one embodiment, the mixture in step (a) is provided by obtaining a solid crude product comprising the sulfate salt of the compound of formula I and dissolving the solid crude product in an aliphatic alcohol and optionally water.

[0026] Dissolution of the solid crude product in an aliphatic alcohol and optionally water may result in a pH lower than the desired pH due to the presence of excess sulfuric acid. When adjusting the pH, it will generally be preferred to avoid the use of inorganic bases, as they may result in decomposition of the product. Alternative ways of adjusting (e.g., increasing) the pH include the use of anion exchange resins, such as those available from Commercially available weakly basic anion exchange resin. In one embodiment, the pH of the mixture in step (a) is provided to be about pH 3 to about pH 6, such as about pH 3.8 to about pH 6. In another embodiment, the pH is provided to be about pH 3 to about pH 5. In another embodiment, the pH is provided to be about pH 1 to about pH 5. In another embodiment, the pH is provided to be about pH 3 to about pH 4.5. In another embodiment, the pH is provided to be about pH 3.8 to about pH 4.5. In another embodiment, the pH is provided to be about 4. Generally speaking, the pH is increased to such a value that the mixture is not converted into an oil, but not too high that the sulfate of the compound of formula I becomes too soluble.

[0027] In general, the solid crude product is dissolved in an aliphatic alcohol (and optionally water) at a suitable temperature that is high enough to achieve dissolution, but not so high that the compound of formula I decomposes (e.g., by hydrolysis). For example, the dissolution temperature may be in the range of -70°C to 50°C, e.g., in the range of 0°C to 40°C, e.g., in the range of 15°C to 30°C, e.g., in the range of 20°C to 25°C, e.g., at least -70°C, e.g., at least 0°C, e.g., at least 15°C, e.g., up to 50°C, e.g., up to 40°C, e.g., up to 30°C, e.g., up to 25°C. The mixture may be allowed to remain at these temperatures for up to 48 hours, e.g., up to 30 hours, e.g., up to 24 hours, e.g., in the range of 1 to 48 hours, e.g., in the range of 5 to 30 hours, e.g., in the range of 12 to 24 hours, and may be stirred during this time.

[0028] Step (b) may comprise allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture by cooling the mixture. For example, the mixture may be cooled from a starting temperature (e.g., dissolution temperature) to a temperature in the range of -25°C to 20°C (e.g., at least -25°C, e.g., up to 20°C), e.g., in the range of -15°C to 20°C (e.g., at least -15°C, e.g., up to 20°C), e.g., in the range of 5°C to 20°C (e.g., at least 5°C, e.g., up to 20°C), e.g., to a temperature in the range of 5°C to 15°C (e.g., at least 5°C, e.g., up to 15°C), e.g., to a temperature of about 10°C. The starting temperature (e.g., typically the dissolution temperature) may be in the range of 5°C to 40°C (e.g., at least 5°C, e.g., up to 40°C), e.g., in the range of 20°C to 40°C (e.g., at least 20°C, e.g., up to 40°C), e.g., in the range of 20°C to 30°C (e.g., at least 20°C, e.g., up to 30°C). Taking into account that prolonged time at higher temperatures may result in decomposition, the time for cooling the mixture may be, for example, 10 minutes to 48 hours, such as in the range of 5 to 15 hours, such as in the range of 8 to 12 hours.

[0029] Examples of cooling rates that can be used are, for example, not more than 3°C / hour, such as not more than 2°C, such as not more than 1.5°C / hour, such as not more than 1°C / hour, such as in the range of 0.2°C to 3°C / hour, such as in the range of 0.5°C to 1.5°C / hour, such as about 1°C / hour.

[0030] In step (b), the mixture may be allowed to stand for a suitable period of time, such as up to 10 days, such as in the range of 1 to 10 days, at a temperature in the range of -10°C to 20°C (e.g. at least -10°C, such as up to 20°C), such as in the range of 0°C to 15°C (e.g. at least 0°C, such as up to 15°C), such as about 10°C. Longer standing times (e.g. at least 3 days, such as in the range of 4 to 10 days, such as in the range of 4 to 5 days) may allow for an increase in yield while avoiding oily products. The time for which the mixture is allowed to stand may be shortened by adding seed crystals.

[0031] In step (c), the aprotic organic solvent can be a C4-C10 alkyl or a C4-C10 alkenyl or a mixture thereof. Specific examples include hexane and heptane or a mixture thereof, such as n-hexane or n-heptane or a mixture thereof. In one embodiment, the aprotic solvent is n-heptane. Other specific examples include hexene and heptene, such as 1-hexene or 1-heptene. In another embodiment, the aprotic solvent is 1-hexene.

[0032] The volume of the aprotic organic solvent used in step (c) may be up to 8 times, such as up to 6 times, such as up to 4 times, such as at least 0.05 times, such as at least 0.1 times, such as at least 0.5 times, such as at least 1 times, such as at least 3 times, such as in the range of 0.05 to 8 times, such as in the range of 0.1 to 8 times, such as in the range of 0.5 to 6 times, such as in the range of 1 to 6 times, such as in the range of 3 to 5 times, the volume of the mixture in step (a).

[0033] The aprotic organic solvent may be added to the mixture over a suitable period of time, for example in the range of 10 minutes to 48 hours, for example in the range of 1 to 30 hours, for example in the range of 2 to 12 hours. The temperature during this time may be in the range of -10°C to 20°C (for example at least -10°C, for example up to 20°C), for example in the range of 0°C to 15°C (for example at least 0°C, for example up to 15°C), for example about 10°C. The mixture may be stirred during this time.

[0034] After adding the aprotic solvent, the mixture may be allowed to stand for a suitable time (e.g. up to 5 days, e.g. in the range of -10°C to 20°C (e.g. at least -10°C, e.g. up to 20°C), e.g. in the range of 0°C to 15°C (e.g. at least 0°C, e.g. up to 15°C), e.g. about 10°C. The product may be dried.

[0035] Step (a) may comprise providing a mixture comprising a sulfate salt of a compound of formula I and ethanol and optionally water; and step (c) may comprise adding propanol (including any isomer thereof, such as propan-1-ol, isopropanol) and / or butanol (including any isomer thereof, such as n-butan-1-ol, n-butan-2-ol, tert-butan-1-ol, tert-butan-2-ol) (preferably isopropanol) and an aprotic organic solvent (preferably n-heptane) selected from hexane and heptane and mixtures thereof to the mixture, and allowing a further portion of the sulfate salt of the compound of formula I to precipitate from the mixture. The propanol and / or butanol may be added to the mixture prior to the aprotic organic solvent, and after the propanol and / or butanol are added, the mixture may be allowed to stand before the aprotic organic solvent is added, for example to allow a portion of the sulfate salt of the compound of formula I to precipitate from the mixture before the aprotic solvent is added.

[0036] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0037] (a) providing a mixture comprising a sulfate salt of the compound of formula I and ethanol and optionally water, wherein the pH of the mixture is in the range of about pH 1 to about pH 6;

[0038] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture;

[0039] (c1) adding propanol and / or butanol to the mixture and allowing a further portion of the sulfate salt of the compound of formula I to precipitate from the mixture; and

[0040] (c2) adding hexene, heptene, hexane or heptane or a mixture thereof to the mixture and allowing yet a further portion of the sulfate salt of the compound of formula I to precipitate from the mixture.

[0041] The propanol and / or butanol may be added to the mixture over a period of time in the range of 10 minutes to 48 hours (e.g., in the range of 1 to 30 hours, e.g., in the range of 2 to 24 hours). The temperature during this period may be in the range of -10°C to 20°C (e.g., at least -10°C, e.g., up to 20°C), e.g., in the range of 0°C to 15°C (e.g., at least 0°C, e.g., up to 15°C), e.g., about 10°C. The mixture may be stirred during this period of time. After the propanol and / or butanol are added, the mixture may be allowed to stand for a suitable period of time (e.g., up to 5 days, e.g., 1 hour to 5 days), e.g., at a temperature in the range of -10°C to 20°C (e.g., at least -10°C, e.g., up to 20°C), e.g., in the range of 5°C to 15°C (e.g., at least 0°C, e.g., up to 15°C), e.g., about 10°C, before the aprotic solvent is added.

[0042] The volume of propanol and / or butanol can be up to 8 times, such as up to 6 times, such as up to 5 times, such as at least 0.05 times, such as at least 0.1 times, such as at least 1 times, such as at least 4 times, such as in the range of 0.05 to 8 times, such as in the range of 0.1 to 6 times, such as in the range of 1 to 6 times, such as in the range of 4 to 6 times, the volume of the mixture in step (a).

[0043] The v / v ratio of the aprotic organic solvent to propanol and / or butanol may be, for example, 1:10 to 10:1, such as 1:5 to 5:1, such as 1:2 to 2:1.

[0044] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0045] (a) providing a mixture comprising a sulfate salt of a compound of formula I and an aliphatic alcohol, wherein the aliphatic alcohol is a C2-C10 alkyl-OH or a C3-C10 cycloalkyl-OH or a mixture thereof, wherein the v / w ratio of the aliphatic alcohol to the sulfate salt of a compound of formula I is in the range of 1:1 to 100:1 (e.g., 1:1 to 10:1), and wherein the pH of the mixture is in the range of about pH 3 to about pH 5;

[0046] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture; and

[0047] (c) adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is a C4-C10 alkyl, or a C4-C10 alkenyl or a mixture thereof, wherein the volume of the aprotic organic solvent used in step (c) is in the range of 0.05 to 8 times the volume of the mixture in step (a), and allowing an additional portion of the sulfate of the compound of formula I to precipitate from the mixture.

[0048] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0049] (a) providing a mixture comprising the sulfate salt of the compound of formula I and an aliphatic alcohol, wherein the aliphatic alcohol is ethanol, propanol, butanol or pentanol or a mixture thereof, wherein the v / w ratio of the aliphatic alcohol to the sulfate salt of the compound of formula I is in the range of 1:1 to 100:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5;

[0050] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture; and

[0051] (c) adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is hexane or heptane or a mixture thereof, wherein the volume of the aprotic organic solvent is in the range of 0.5 to 6 times the volume of the mixture in step (a), and allowing an additional portion of the sulfate salt of the compound of formula I to precipitate from the mixture.

[0052] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0053] (a) providing a mixture comprising the sulfate salt of the compound of formula I and an aliphatic alcohol, wherein the aliphatic alcohol is ethanol, propanol, butanol or pentanol or a mixture thereof, wherein the v / w ratio of the aliphatic alcohol to the sulfate salt of the compound of formula I is in the range of 2:1 to 6:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5;

[0054] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture; and

[0055] (c) adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is hexane or heptane or a mixture thereof, wherein the volume of the aprotic organic solvent is in the range of 1 to 6 times the volume of the mixture in step (a), and allowing an additional portion of the sulfate salt of the compound of formula I to precipitate from the mixture.

[0056] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0057] (a) providing a mixture comprising the sulfate salt of the compound of formula I, water and ethanol, wherein the v / w ratio of the ethanol to the sulfate salt of the compound of formula I is in the range of 2:1 to 6:1, wherein the v / v ratio of ethanol to water is 15:1 to 25:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5;

[0058] (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture;

[0059] (c1) adding propanol and / or butanol to the mixture, wherein the volume of propanol and / or butanol is 1 to 6 times the volume of the mixture in step (a), and allowing an additional portion of the sulfate salt of the compound of formula I to precipitate from the mixture; and

[0060] (c2) adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is hexane or heptane or a mixture thereof, wherein the volume of the aprotic organic solvent is in the range of 1 to 6 times the volume of the mixture in step (a), and allowing yet another portion of the sulfate salt of the compound of formula I to precipitate from the mixture.

[0061] According to an embodiment, the present invention provides a method for purifying a sulfate salt of a compound of formula I, the method comprising the following steps:

[0062] (a) providing a mixture comprising the sulfate salt of the compound of formula I, water and ethanol, wherein the v / w ratio of the ethanol to the sulfate salt of the compound of formula I is in the range of 2:1 to 6:1, wherein the v / v ratio of ethanol to water is 15:1 to 25:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5;

[0063] (b) cooling the mixture and allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture, wherein the cooling rate does not exceed 3° C. / hour;

[0064] (c1) adding propanol and / or butanol to the mixture, wherein the volume of propanol and / or butanol is 1 to 6 times the volume of the mixture in step (a), and allowing an additional portion of the sulfate salt of the compound of formula I to precipitate from the mixture; and

[0065] (c2) adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is hexane or heptane or a mixture thereof, wherein the volume of the aprotic organic solvent is in the range of 1 to 6 times the volume of the mixture in step (a), and allowing yet another portion of the sulfate salt of the compound of formula I to precipitate from the mixture;

[0066] and wherein the diastereomers in the combined fraction of the sulfate salt of the compound of formula I from step (b) and steps (c1) and (c2) taken together

[0067]

[0068] The molar ratio is in the range of 1:2 to 2:1.

[0069] In another aspect, the present invention provides a process for preparing epimer B of the sulfate salt of the compound of formula I in crystalline form, wherein epimer B is eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate.

[0070]

[0071] The method comprises the following steps:

[0072] (a) providing a mixture comprising a sulfate salt of the compound of formula I and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; and

[0073] (b) allowing epimer B to crystallize from the mixture.

[0074] Where possible, the above description of steps (a) and (b) in relation to the first aspect of the invention also applies to steps (a) and (b) of this aspect of the invention.

[0075] In another aspect, the present invention provides a process for preparing epimer A of the sulfate salt of the compound of formula I in solid form, wherein epimer A is eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate.

[0076]

[0077] The method comprises the following steps:

[0078] (c) adding an aprotic organic solvent to a mixture comprising a sulfate salt of epimer A and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; and allowing the sulfate salt of epimer A to precipitate from the mixture; wherein the molar amount of epimer A in the precipitate from step (c) is greater than the molar amount of epimer B.

[0079] Where possible, the above description of step (c) in relation to the first aspect of the invention (including the description of step (c) as steps (c1) and (c2)) also applies to step (c) of this aspect of the invention.

[0080] In another aspect, the present invention provides a process for preparing a pharmaceutical composition, the process comprising formulating a sulfate salt of a compound of formula I, wherein the sulfate salt of the compound of formula I has been purified by a process as described herein, with one or more pharmaceutical excipients.

[0081] In another aspect, the present invention provides a pharmaceutical composition comprising a sulfate salt of a compound of formula I and one or more pharmaceutical excipients, wherein the sulfate salt of the compound of formula I has been purified by a process as defined as described herein.

[0082] Pharmaceutical compositions comprising the sulfate salt of the compound of formula I can be prepared according to the common knowledge of those skilled in the art using conventionally available pharmaceutical excipients. The pharmaceutical formulation can be a powder for injection or a capsule for oral administration. For example, isavuconazolium sulfate is commercially available as a lyophilized powder for intravenous administration containing the excipients mannitol and sulfuric acid for pH adjustment; and is commercially available as capsules for oral administration containing the excipients trimagnesium dicitrate, microcrystalline cellulose, talc, colloidal silicon dioxide, and stearic acid.

[0083] The sulfate salt of the compound of formula I purified as described herein can be directly formulated into a pharmaceutical composition or can undergo further processing steps before being formulated into a pharmaceutical composition. For example, it can be reprecipitated, for example, to produce an amorphous form, for example, as used in an approved formulation for oral administration. For example, it can be dissolved in a suitable solvent and lyophilized, for example, as used in an approved formulation for injection.

[0084] Alkyl and alkenyl groups can be straight or branched. The term "about" means a variation of + / - 5%, preferably 2%, more preferably 1% of a given value. All ranges mentioned include the starting point and the end point of the specified range. Where possible, all aspects and embodiments of the invention described herein can be combined in any combination.

[0085] Various publications are cited herein in order to more fully describe and disclose the present invention and the state of the art in the field to which the present invention pertains. Each of these references is hereby incorporated by reference into the present disclosure in its entirety, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0086] Specific embodiments of the present invention are described in the following examples, which are intended to illustrate the present invention in more detail and should not be construed as limiting the present invention in any way.

[0087] Figure 1

[0088] Figure 1 The XRPD diffraction pattern of Form I of the sulfate salt of the compound of Formula I is shown.

[0089] Figure 2

[0090] Figure 2 The XRPD diffraction pattern of Form II of the sulfate salt of the compound of Formula I is shown.

[0091] Examples

[0092] Example 1

[0093] 30 g of the crude sulfate of the compound of formula I (HPLC purity 93.7%) was dissolved in a mixture of 90 mL of ethanol and 10 mL of water, the pH value of the solution being 3.5. The resulting solution was then cooled from 10° C. to -20° C. (-1° C. / hour). The mixture was stirred at -20° C. for 16 hours, and then warmed to 5° C. The mixture was then stirred at 5° C. for 16 hours. After filtration and drying, 5 g of the sulfate of the compound of formula I as white crystalline form I with a yield of 16.6% and a HPLC purity of 98.5% was obtained (the diastereoisomer ratio was not determined).

[0094] Example 2

[0095] 75 g of the crude sulfate of the compound of formula I (HPLC purity 94.8%) was dissolved in a mixture of 225 mL of ethanol and 25 mL of water (pH 2.8) and stirred for 2 days at 8° C. After filtration and drying, 18 g of the sulfate of the compound of formula I with a yield of 24% and a HPLC purity of 98% were obtained as white crystalline form I (the diastereoisomer ratio was not determined).

[0096] Example 3

[0097] 1 g of crude sulfate of the compound of formula I (HPLC purity 85.2%) was dissolved in 3.6 mL of ethanol and 0.4 mL of water, pH 5.1. The solution was cooled from 25° C. to 19° C., and 0.55 g of a white precipitate of sulfate of the compound of formula I with a yield of 55% and a HPLC purity of 92% was formed. XRPD analysis showed that the sulfate of the compound of formula I was obtained as crystalline form II (the diastereoisomer ratio was not determined).

[0098] Example 4

[0099] 0.9 g of the crude sulfate of the compound of formula I (HPLC purity 85.2%) was dissolved in 4.5 mL of ethanol and 0.5 mL of water, and the pH was adjusted to 3.7 with concentrated sulfuric acid. The solution was cooled from 20° C. to −10° C. over 15 hours, and a precipitate of the sulfate of the compound of formula I was formed. The precipitate was filtered and dried to give 0.36 g of crystalline form II (diamer ratio not determined) with a yield of 36% and a HPLC purity of 98%.

[0100] Example 5

[0101] 6 g of the crude sulfate of the compound of formula I (HPLC purity 85.2%) were dissolved in 36 mL of ethanol and 4 mL of water, pH 4.2. The solution was then cooled from 20° C. to −10° C. over 15 hours, and a precipitate of the sulfate of the compound of formula I was formed. The precipitate was filtered and dried to give 0.36 g of crystalline form II (diamer ratio not determined) in a yield of 35%.

[0102] Example 6

[0103] 101g of the crude sulfate of the compound of formula I (HPLC purity 95.6%) was dissolved in 400mL ethanol and 20mL water, and the pH value was 4.0. 1.0g of crystalline form I was added as a seed. The mixture was then stirred at 20°C-25°C for 16 hours, cooled to 10°C over 10 hours, and allowed to stand at 0°C-10°C for 5 days. During this period of time, a precipitate was formed, giving a 35% yield, and the ratio of diastereomer A to diastereomer B was 1:11. Then 1.5L of isopropanol was added over 21 hours, and 2L of n-heptane was added over 12 hours. After filtering and drying, 52g of the sulfate of the compound of formula I as crystalline form I with a purity of 97.4% was obtained, giving a 71.7% total yield, and the ratio of diastereomer A to diastereomer B was 1:1.18.

[0104] Example 7

[0105] 10 g of the crude sulfate of the compound of formula I (HPLC purity 95.6%) was dissolved in 40 mL of ethanol and 2 mL of water, pH 4.0. 0.05 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 10° C. over 10 hours, and allowed to stand at 10° C. for 5 days. After filtration and drying, 2.2 g of a sulfate of the compound of formula I as crystalline form I with a purity of 99.0% was obtained with a yield of 35%, wherein the ratio of diastereomer A to diastereomer B was 1:10.8.

[0106] Example 8

[0107] 2.8 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 100 mL of cyclohexanol and 5 mL of water, and the pH was adjusted to 4.1. 0.03 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 5 days. 75 mL of isopropanol was then added over 2 hours, and 100 mL of n-heptane was added over 3 hours. After filtration and drying, 0.71 g of the sulfate of the compound of formula I as crystalline form I with a purity of 98.1% was obtained, giving a total yield of 40.5%, and the ratio of diastereomer A to diastereomer B was 1.89.

[0108] Example 9

[0109] 2 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 100 mL of n-butanol and 5 mL of water, and the pH was adjusted to 4.0. 0.02 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 5 days. 75 mL of isopropanol was then added over 21 hours, and 100 mL of n-heptane was added over 12 hours. After filtration and drying, 0.61 g of the sulfate of the compound of formula I as crystalline form I with a purity of 98.2% was obtained, giving a total yield of 48.8%, and the ratio of diastereomer A to diastereomer B was 2.26.

[0110] Example 10

[0111] 4 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 200 mL of anhydrous ethanol. The pH was adjusted to 4.5. 0.08 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 5 days. 150 mL of isopropanol was then added over 18 hours, and 200 mL of n-heptane was added over 12 hours. After filtration and drying, 1.25 g of the sulfate of the compound of formula I as crystalline form I with a purity of 97.4% was obtained, giving a total yield of 49.6%, and the ratio of diastereomer A to diastereomer B was 1.18.

[0112] Example 11

[0113] 10 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 80 mL of ethanol and 4 mL of water, and the pH was adjusted to 4.4. 0.10 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 6 days. 200 mL of n-heptane was then added over 7 hours. The mixture was then stirred at 0° C.-5° C. for 48 hours. After filtration and drying, 2.72 g of the sulfate of the compound of formula I with a purity of 95.8% was obtained, giving a total yield of 36.0%, and the ratio of diastereomer A to diastereomer B was 0.80.

[0114] Example 12

[0115] 5 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 40 mL of ethanol and 2 mL of water, and the pH was adjusted to 4.4. 0.05 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 6 days. 100 mL of n-hexane was then added over 8 hours. The mixture was then stirred at 0° C.-5° C. for 48 hours. After filtration and drying, 1.95 g of the sulfate of the compound of formula I with a purity of 96.6% was obtained, giving a total yield of 53.2%, and the ratio of diastereomer A to diastereomer B was 1.19.

[0116] Example 13

[0117] 5 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 40 mL of ethanol and 2 mL of water, and the pH was adjusted to 4.4. 0.05 g of crystalline form I was added as a seed. The mixture was then stirred at 20°C-25°C for 16 hours, cooled to 5°C-10°C over 10 hours, and allowed to stand at 5°C for 6 days. 100 mL of 1-hexene was then added over 11 hours. The mixture was then stirred at 0°C-5°C for 48 hours. After filtration and drying, 1.88 g of the sulfate of the compound of formula I with a purity of 96.9% was obtained, giving a total yield of 51.5%, and the ratio of diastereomer A to diastereomer B was 1.20.

[0118] Example 14

[0119] 5 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 40 mL of ethanol and 2 mL of water, and the pH was adjusted to 4.2. 0.05 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 6 days. 75 mL of isopropanol was then added over 8 hours, followed by 20 mL of n-heptane over 4 hours. The mixture was then stirred at 0° C.-5° C. for 48 hours. After filtration and drying, 1.92 g of the sulfate of the compound of formula I with a purity of 97.8% was obtained, giving a total yield of 55.7%, and the ratio of diastereomer A to diastereomer B was 1.89.

[0120] Example 15

[0121] 5 g of the crude sulfate of the compound of formula I (BAL0008557-002) (HPLC purity 94.9%) was dissolved in 40 mL of ethanol and 2 mL of water, and the pH was adjusted to 4.2. 0.05 g of crystalline form I was added as a seed. The mixture was then stirred at 20° C.-25° C. for 16 hours, cooled to 5° C.-10° C. over 10 hours, and allowed to stand at 5° C. for 6 days. 20 mL of n-heptane was then added over 4 hours. The mixture was then stirred at 0° C.-5° C. for 48 hours. After filtration and drying, 1.30 g of the sulfate of the compound of formula I with a purity of 97.6% was obtained, giving a total yield of 37.1%, and the ratio of diastereomer A to diastereomer B was 2.59.

[0122] Example 16: Preparation of crude sulfate salt of compound of formula I

[0123] 13 g of the crude sulfate of the compound of formula I (93% area HPLC purity) were dissolved in a mixture of 45 mL ethanol and 5 mL water, pH 2.3. The solution was cooled to -20°C and allowed to stand in a refrigerator for 14 days for recrystallization. After filtration and drying, 5 g of the sulfate of the compound of formula I as crystalline form I with a yield of 41% and an area HPLC purity of 97.8% were obtained (the diastereoisomer ratio was not determined).

[0124] Example 17: Separation of epimers of the sulfate salt of the compound of formula I

[0125] The HPLC column used is a Shiseido chiral CD-Ph 5 μm column with a size of 250mm x 4.6mm. The HPLC detector wavelength is 290nm, and the column is maintained at a temperature of 40 ℃ ± 5 ℃. The HPLC sample is prepared by dissolving 10mg of the product in a 50mL dissolving mixture (containing water, acetonitrile and trifluoroacetic acid, in a ratio of 100:100:0.1, which is shaken to homogenize the mixture). The HPLC mobile phase is a mixture (pH 6.5) of triethylammonium acetate and acetonitrile in proportion 40:60. The mixture is shaken to homogenize and degas. The injection volume is 10 μL, and the flow velocity is 1mL / min.

[0126] The retention times of the epimers are as follows:

[0127] Epimer A: 80 minutes

[0128] Epimer B: 84 minutes

[0129] Example 18: Characterization of Form I and Form II of the Sulfate Salt of the Compound of Formula I

[0130] XRPD patterns were obtained using a high throughput XRPD setup. The plate was mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform used silver behenate to calibrate long d-spacings, and corundum to calibrate short d-spacings. Data collection was performed using monochromatic CuKα radiation in the 2θ region between 1.5° and 41.5° (the region being the most unique part of the XRPD pattern) at room temperature. The diffraction patterns of each hole were collected in two 2θ ranges (1.5°≤2θ≤21.5° for the first frame, and 19.5°≤2θ≤41.5° for the second frame), with an exposure time of 90 seconds for each frame. No background subtraction or curve smoothing was applied to the XRPD pattern. The support material used during the XRPD analysis was transparent to X-rays and contributed only slightly to the background.

[0131] Figure 1 The XRPD of Form I at room temperature is shown in , and its diffraction peaks are shown in Table 1. Figure 2 The XRPD of Form II at room temperature is shown in , and its diffraction peaks are shown in Table 2.

[0132] Table 1: List of XRPD peak positions of Form I

[0133]

[0134]

[0135] Table 2: List of XRPD peak positions for Form I

[0136]

[0137] Comparative Example 1 (CN 106565699)

[0138] 5 g of the crude sulfate of the compound of formula I was dissolved in 50 mL of water, and at 0 ° C, the solution was treated with saturated sodium bicarbonate to adjust the pH to 7. The solution was then extracted with 50 mL of dichloromethane, and the organic phase was concentrated to dryness. At -5 ° C, the crude product was dissolved in 10 mL of methanol, and the solution was then treated with 6.7 g of sulfuric acid and 8.3 g of 30% aqueous hydrogen peroxide for 30 min, then concentrated to dryness. The product decomposed significantly, and no crystalline solid was formed.

[0139] Comparative Example 2 (CN 106467534)

[0140] In a 250mL flask, 62mL of acetone, 2.65mL of pure water and 5mL of 2-methoxyethanol were added. 5g of crude sulfate of the compound of formula I with an HPLC purity of 97.2% was added, wherein the ratio of epimer A to epimer B was 1:1. The solution was stirred at 0°C-10°C for 1 hour, then 41mL of ethyl acetate was added dropwise, and the solution was stirred at 0°C-5°C for 10 hours. The mixture was filtered under nitrogen, and the filter cake was dried for 30 minutes to give 4g of sulfate of the compound of formula I with an HPLC purity of 98.9% and a yield of 13% as crystalline form I. The epimer ratio of epimer A to epimer B was 1:2.

[0141] Comparative Example 3 (CN 106467534)

[0142] In a 250mL flask, 62mL of acetone, 2.65mL of pure water and 5mL of 2-methoxyethanol were added. Then 5g of crude sulfate of the compound of formula I with a HPLC purity of 92.8%, wherein the ratio of epimer A to epimer B was 3.2:1. The solution was stirred at 0°C-10°C for 1 hour, and then 41mL of ethyl acetate was added dropwise, and the solution was stirred at 0°C-5°C for 10 hours. The mixture was filtered under nitrogen, and the filter cake was dried for 30 minutes to give 0.7g of sulfate of the compound of formula I with a HPLC purity of 96.3% and a yield of 71.6% as crystalline form I. The epimer ratio of epimer A to epimer B was 1:16.

Claims

1. A method for purifying the sulfate salt of a compound of formula I The Method The following steps are involved: (a) providing a mixture comprising a sulfate salt of a compound of Formula I and an aliphatic alcohol, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture by cooling the mixture and allowing the mixture to stand for a suitable period of time; as well as (c) adding an aprotic organic solvent to the mixture and allowing an additional portion of the sulfate salt of the compound of formula I to precipitate from the mixture; wherein the aliphatic alcohol is ethanol, propanol, butanol, pentanol, cyclopentanol, cyclohexanol or a mixture thereof; wherein the aprotic organic solvent is a C4-C10 alkane or a C4-C10 alkene or a mixture thereof; The term "about" herein means + / - 5% of a given value.

2. The method according to claim 1, in, The mixture provided in step (a) comprises a mixture of the following diastereomers of the sulfate salt of the compound of formula I wherein epimer A is the first epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, and epimer B is the second epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, wherein the mobile phase is a mixture of triethylammonium acetate and acetonitrile in a ratio of 40:60 at pH 6.5; wherein step (b) selectively crystallizes epimer B, and step (c) effectively precipitates epimer A remaining in solution.

3. The method according to claim 1, in, The mixture provided in step (a) comprises a mixture of the following diastereomers of the sulfate salt of the compound of formula I wherein epimer A is the first epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, and epimer B is the second epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, wherein the mobile phase is a mixture of triethylammonium acetate and acetonitrile in a ratio of 40:60 at pH 6.5; And wherein the molar ratio of the epimer B to the epimer A in the sulfate salt of the compound of formula I obtained in step (b) is greater than 1:

1.

4. The method according to claim 1, in, The mixture provided in step (a) comprises a mixture of the following diastereomers of the sulfate salt of the compound of formula I wherein epimer A is the first epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, and epimer B is the second epimer eluted from a chiral HPLC column functionalized with β-cyclodextrin esterified with phenyl carbamate, wherein the mobile phase is a mixture of triethylammonium acetate and acetonitrile in a ratio of 40:60 at pH 6.5; And wherein the molar ratio of the epimer A to the epimer B in the sulfate salt of the compound of formula I obtained in step (c) is greater than 1:

1.

5. The method according to claim 1, in, The diastereomers in the combined fractions of the sulfate salt of the compound of formula I from step (b) and step (c) combined The molar ratio is in the range of 1:2 to 2:

1.

6. The method according to claim 1, in, The molar ratio of the epimers ranged from 1:1.2 to 1.2:

1.

7. The method according to claim 1, in, The aliphatic alcohol is ethanol, propanol, butanol or pentanol or a mixture thereof.

8. The method according to claim 1, in, The aliphatic alcohol is ethanol.

9. The method according to claim 1, in, The v / w ratio of the aliphatic alcohol to the sulfate salt of the compound of formula I is in the range of 2:1 to 6:

1.

10. The method according to claim 1, in, The mixture in step (a) comprises the sulfate salt of the compound of formula I, an aliphatic alcohol and water.

11. The method according to claim 10, in, The v / v ratio of the aliphatic alcohol to water is in the range of 5:1 to 50:

1.

12. The method according to claim 1, in, The pH of the mixture in step (a) is in the range of about pH 3 to about pH 5.

13. The method according to claim 12, in, The pH of the mixture in step (a) is in the range of about pH 3.8 to about pH 4.

5.

14. The method according to claim 1, in, Step (b) comprises cooling the mixture, and wherein the cooling rate does not exceed 3°C / hour.

15. The method according to claim 1, in, The aprotic organic solvent is hexene, heptene, hexane or heptane or a mixture thereof.

16. The method according to claim 15, in, The aprotic organic solvent is n-heptane.

17. The process according to any one of claims 1 to 6 and 9 to 14, wherein the aliphatic alcohol is ethanol, propanol, butanol, pentanol, cyclopentanol, cyclohexanol or a mixture thereof, and wherein the aprotic organic solvent is hexane, heptane, hexene, heptene or a mixture thereof.

18. The process according to claim 17, wherein the aliphatic alcohol is ethanol, butanol, cyclohexanol or a mixture thereof, and wherein the aprotic organic solvent is hexane, heptane, hexene, heptene or a mixture thereof.

19. The process according to claim 18, wherein the aliphatic alcohol is ethanol, n-butanol, cyclohexanol or a mixture thereof, and wherein the aprotic organic solvent is n-hexane, n-heptane, 1-hexene or a mixture thereof.

20. The process according to claim 19, wherein the aliphatic alcohol is ethanol, n-butanol or cyclohexanol, and wherein the aprotic organic solvent is n-hexane, n-heptane or 1-hexene.

21. The method according to claim 1, in, The volume of the aprotic organic solvent used in step (c) is in the range of 0.05 to 8 times the volume of the mixture in step (a).

22. The method according to claim 1, in, The method includes (a) providing a mixture comprising a sulfate salt of the compound of formula I and ethanol and optionally water, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; (b) allowing a first portion of the sulfate salt of the compound of formula I to crystallize from the mixture; (c1) Add propanol and / or butanol to the mixture and allow a further portion of the sulfate of the compound of formula I to precipitate from the mixture; and (c2) Add hexane or heptane or a mixture thereof to the mixture and allow a further additional portion of the sulfate of the compound of formula I to precipitate from the mixture.

23. The method according to claim 1, the method comprising the steps of: (a) Providing a mixture comprising the sulfate of the compound of formula I and an aliphatic alcohol, wherein the aliphatic alcohol is ethanol, propanol, butanol, pentanol, cyclopentanol, cyclohexanol or a mixture thereof, wherein the v / w ratio of the aliphatic alcohol to the sulfate of the compound of formula I is in the range of 1:1 to 100:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5; (b) Allowing a first portion of the sulfate of the compound of formula I to crystallize from the mixture; and (c) Adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is a C4-C10 alkane, or a C4-C10 alkene or a mixture thereof, wherein the volume of the aprotic organic solvent used in step (c) is in the range of 0.05 times to 8 times the volume of the mixture in step (a), and allowing a further portion of the sulfate of the compound of formula I to precipitate from the mixture.

24. The method according to claim 1, the method comprising the steps of: (a) Providing a mixture comprising the sulfate of the compound of formula I, water and ethanol, wherein the v / w ratio of the ethanol to the sulfate of the compound of formula I is in the range of 2:1 to 6:1, wherein the v / v ratio of ethanol to water is 15:1 to 25:1, and wherein the pH of the mixture is in the range of about pH 3 to about pH 5; (b) Cooling the mixture and allowing a first portion of the sulfate of the compound of formula I to crystallize from the mixture, wherein the cooling rate does not exceed 3 °C / hour; (c1) Adding propanol and / or butanol to the mixture, wherein the volume of propanol and / or butanol is 1 times to 6 times the volume of the mixture in step (a), and allowing a further portion of the sulfate of the compound of formula I to precipitate from the mixture; and (c2) Adding an aprotic organic solvent to the mixture, wherein the aprotic organic solvent is hexane or heptane or a mixture thereof, wherein the volume of the aprotic organic solvent is in the range of 1 times to 6 times the volume of the mixture in step (a), and allowing a further additional portion of the sulfate of the compound of formula I to precipitate from the mixture; and wherein the epimers in the combined portion of the sulfate of the compound of formula I from steps (b) and (c1) and (c2) together have a molar ratio in the range of 1:2 to 2:

1.

25. A method for preparing a pharmaceutical composition comprising the sulfate of the compound of formula I as defined in claim 1, the method comprising (i) purifying the sulfate of the compound of formula I by the method as defined in any one of claims 1 to 24, and (ii) formulating the sulfate of the compound of formula I together with one or more pharmaceutical excipients.

Images