Process of purifying a drug used in the treatment of acid-related disorders

Abstract

Described herein is a method for purifying vonoprazan fumarate of formula (I).

Description

[0001] PROCESS OF PURIFYING A DRUG USED IN THE TREATMENT OF ACID-

[0002] RELATED DISORDERS

[0003] FIELD OF THE INVENTION

[0004] Described herein is a method for purifying vonoprazan fumarate.

[0005] STATE OF THE ART

[0006] Vonoprazan fumarate of formula (I):

[0007] (I), is a reversible inhibitor of the H+ / K+ATPase and represents a new pharmaceutical class for the treatment of diseases such as erosive esophagitis, gastro-esophageal reflux and gastrointestinal disorders and in combination with antibiotics, such as amoxicillin and clarithromycin, in the treatment of Helicobacter pylori infection. Vonoprazan fumarate of formula (I) has been shown to have a rapid and prolonged acid-suppressing action that is not affected by diet.

[0008] Example 8 of US 7,977,488 describes the preparation of vonoprazan fumarate of formula (I), which comprises dissolving vonoprazan in ethyl acetate and adding fumaric acid in methanol. The formed precipitate is separated by filtration providing the compound in a colorless crystalline form with a melting point of 201-203°C.

[0009] Example 5 of US 8,822,694 describes the purification of vonoprazan fumarate of formula (I) by dissolving the compound in a mixture of methanol and water at a temperature of 60-65°C. The mixture is then cooled down to 0-10°C providing a solid with a melting point of 203-205°C.

[0010] However, it has been found that maintaining solutions of vonoprazan fumarate of formula (I) at temperatures of 60-65°C leads to the formation of the impurity of formula (II):

[0011] Therefore, there is a need for a process for preparing vonoprazan fumarate of formula (I) with a degree of purity that meets the regulatory requirements with acceptable impurity values, which for instance does not lead to the formation of the impurity adduct of formula (II). Furthermore, the process has to be easily applicable on an industrial scale and has to provide the product at high yields in a cost-effective manner.

[0012] Now it has been surprisingly found that a new and safe method for the purification of vonoprazan fumarate of formula (I), which, due to its high yields and lower presence of impurities, is suitable for an industrial production. This new process, thanks to the specific conditions, provides a pure product, which is suitable to meet the regulatory requirements required for active pharmaceutical ingredients (APIs).

[0013] SUMMARY OF THE INVENTION

[0014] In a first aspect, the present invention is directed to a process for purifying vonoprazan fumarate of formula (I):

[0015] (I), comprising:

[0016] - dispersing and dissolving vonoprazan fumarate of formula (I) in a solvent mixture comprising an ether solvent and water at a temperature not exceeding 50°C;

[0017] - concentrating or cooling the solution to obtain a precipitate of vonoprazan fumarate of formula (I); and

[0018] - isolating the solid. DETAILED DESCRIPTION OF THE INVENTION

[0019] In a first aspect, the present invention is directed to a process for purifying vonoprazan fumarate of formula (I):

[0020] (I), comprising:

[0021] - dispersing and dissolving vonoprazan fumarate of formula (I) in a solvent mixture comprising an ether solvent and water at a temperature not exceeding 50°C;

[0022] - concentrating or cooling the solution to obtain a precipitate of vonoprazan fumarate of formula (I); and

[0023] - isolating the solid.

[0024] The term "comprising" means that additional reaction steps may be present, but which do not substantially modify the product obtained from the process. The term "comprising" also includes the terms "consisting of and "essentially consisting of.

[0025] Vonoprazan fumarate of formula (I) used as a starting material may be in any form. It may be amorphous or crystalline vonoprazan fumarate of formula (I). For instance, it may be an anhydrous, a hydrated or a solvated crystalline form. The compound is known and can be prepared according to the procedures described in US 7,977,488 or in US 8,822,694.

[0026] An ether solvent may be a cyclic ether.

[0027] In one aspect, the ether solvent is for instance tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (methyl-THF), or dioxane.

[0028] In a preferred aspect, the ether solvent is tetrahydrofuran.

[0029] In another aspect, the solvent mixture does not comprise a linear or branched Ci-Ce alcohol.

[0030] In another aspect, the solvent mixture comprising an ether solvent and water does not comprise methanol, ethanol, n-propanol, / .wpropanol or n-butanol.

[0031] In one aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture comprising an ether solvent and water, wherein the ratio of the ether solvent and water is from 30:70 (v:v) to 90: 10 (v:v), for example from 40:60 (v:v) to 90:10 (v:v), from 50:50 (v: v) to 90: 10 (v:v), from 50:50 (v:v) to 80:20 (v:v), or from 60:40 (v:v) to 70:30 (v:v).

[0032] In one aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture, wherein the ratio of the ether solvent and water is 30:70 (v:v), 40:60 (v:v), 50:50 (v:v), 60:40 (v:v), 67:33 (v:v), 70:30 (v:v), 80:20 (v:v), or 90: 10 (v:v).

[0033] In a preferred aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture, wherein the ratio of the ether solvent and water is from 40:60 (v:v) to 90: 10 (v:v).

[0034] In a particularly preferred aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture, wherein the ratio of the ether solvent and water is from 50:50 (v:v) to 80:20 (v:v), for example at a ratio of 60:40 (v:v), of 67:33 (v:v), or of 70:30 (v:v).

[0035] In one aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture comprising tetrahydrofuran (THF) and water, wherein the ratio of tetrahydrofuran (THF) and water is from 30:70 (v:v) to 90: 10 (v:v), for example from 40:60 (v:v) to 90:10 (v:v), from 50:50 (v: v) to 90: 10 (v:v), from 50:50 (v:v) to 80:20 (v:v), or from 60:40 (v:v) to 70:30 (v:v).

[0036] In one aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture comprising tetrahydrofuran (THF) and water, wherein the ratio and tetrahydrofuran (THF) and water is 30:70 (v:v), 40:60 (v:v), 50:50 (v:v), 60:40 (v:v), 67:33 (v:v), 70:30 (v:v), 80:20 (v: v), or 90: 10 (v:v).

[0037] In a preferred aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture comprising tetrahydrofuran (THF) and water, wherein the ratio of tetrahydrofuran (THF) and water is from 40:60 (v:v) to 90: 10 (v:v).

[0038] In a particularly preferred aspect, the dispersion and dissolution of vonoprazan fumarate of formula (I) may be carried out in a solvent mixture comprising tetrahydrofuran (THF) and water, wherein the ratio of tetrahydrofuran (THF) and water is from 50:50 (v:v) to 80:20 (v:v), for example at a ratio of 60:40 (v:v), of 67:33 (v:v), or of 70:30 (v: v).

[0039] The dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion to a temperature not exceeding 50°C, for example at about 45°C, at about 40°C, at about 35°C, at about 30°C, at about 25°C, at about 20°C or at about 15°C.

[0040] In one aspect, the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion from 20°C to 50°C, for example from 20°C to 40°C or from 20°C to 30°C.

[0041] In a preferred aspect, the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion to a temperature not exceeding 40°C.

[0042] In a preferred aspect, the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion from 20°C to 40°C or from 20°C to 30°C, for example at 25°C.

[0043] In a particularly preferred aspect, the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion at 25°C.

[0044] The dissolution of vonoprazan fumarate of formula (I) may be advantageously carried out within 15 minutes or in more than 15 minutes, for example in 30 minutes, in 45 minutes, in 1 hour, in 2 hours, in 3 hours, in 4 hours, in 5 hours, in 6 hours, in 7 hours, in 8 hours, in 9 hours, in 10 hours, in 11 hours, in 12 hours or in 18 hours.

[0045] The concentration of the vonoprazan fumarate of formula (I) used as starting material may be chosen based on the temperature and the solvent mixture.

[0046] In one aspect, at 25°C the starting concentration of vonoprazan fumarate of formula (I) is typically from about 1 g / L to about 70 g / L of vonoprazan fumarate of formula (I) in the solvent mixture comprising an ether solvent and water.

[0047] In one aspect, at 25°C the starting concentration of vonoprazan fumarate of formula (I) is typically from about 1 g / L to about 70 g / L of vonoprazan fumarate of formula (I) in the solvent mixture comprising THF and water.

[0048] In one aspect, at 25°C the starting concentration of vonoprazan fumarate of formula (I) is typically from about 1 g / L to about 70 g / L of vonoprazan fumarate of formula (I) in THF and water.

[0049] The solution comprising vonoprazan fumarate of formula (I) may be concentrated by distillation. The distillation may be carried out at ambient pressure or at reduced pressure.

[0050] In one aspect, at 25°C the concentration of vonoprazan fumarate of formula (I) after concentration of the solution is typically > 80 g / L of vonoprazan fumarate of formula (I) in the solvent mixture comprising an ether solvent and water, for example the concentration is 90 g / L, 100 g / L, 120 g / L or 150 g / L.

[0051] In one aspect, at 25 °C the concentration of vonoprazan fumarate of formula (I) after concentration of the solution is typically > 80 g / L of vonoprazan fumarate of formula (I) in the solvent mixture comprising THF and water, for example the concentration is 90 g / L, 100 g / L, 120 g / L or 150 g / L. In one aspect, at 25 °C the concentration of vonoprazan fumarate of formula (I) after concentration of the solution is typically > 80 g / L of vonoprazan fumarate of formula (I) in THF and water, for example the concentration is 90 g / L, 100 g / L, 120 g / L or 150 g / L.

[0052] In one aspect, the ratio of the ether solvent and water is typically < 50:50 (v:v), for example the ratio is 40:60 (v:v), 35:65 (v:v), 30:70 (v:v), 25:75 (v:v), 20:80 (v:v), 15:85 (v:v), 10:90 (v:v) or 5:95 (v:v) after concentration of the solution.

[0053] In one aspect, the ratio of tetrahydrofuran (THF) and water is typically < 50:50 (v:v), for example the ratio is 40:60 (v:v), 35:65 (v:v), 30:70 (v:v), 25:75 (v:v), 20:80 (v:v), 15:85 (v:v), 10:90 (v:v) or 5:95 (v:v) after concentration of the solution.

[0054] The solution may be cooled down below about 20° C to obtain a precipitate of vonoprazan fumarate of formula (I), for example to from about -10°C to about 15°C.

[0055] In a preferred aspect, the solution may be cooled down to from about -10°C to about 10°C or to from about 0°C to about 15°C.

[0056] In a further preferred aspect, the solution may be cooled down to below about 15°C to obtain a precipitate of vonoprazan fumarate of formula (I), for example to about 10°C, to about 5°C, to about 0°C or to about -5°C.

[0057] The cooling of the solution to provide a precipitate of vonoprazan fumarate of formula (I) may be carried out within approximately one hour to 48 hours, for example in 2 hours, 5 hours, 8 hours, 12 hours, 18 hours, 24 hours, or 36 hours.

[0058] The solution may be cooled down slowly, for example at a rate of about 0.1°C to 0.5°C per minute.

[0059] In one aspect, the solution comprising vonoprazan fumarate of formula (I) in THF and water may be cooled down to a temperature below about 20°C, for example to from about -10°C to about 10°C or to from about 0°C to about 15°C.

[0060] In one aspect, the solution comprising vonoprazan fumarate of formula (I) in THF and water may be cooled down at a rate of approximately 0.1 to 0.5°C per minute.

[0061] In one aspect, the solution comprising vonoprazan fumarate of formula (I) may be concentrated and then cooled down.

[0062] In one aspect, the solution comprising vonoprazan fumarate of formula (I) may be concentrated and cooled down, for example to a temperature below about 20°C, for example to from about -10°C to about 10°C or to from about 0°C to about 15°C.

[0063] In one aspect, the solution comprising vonoprazan fumarate of formula (I) may be concentrated and cooled down, for example to a temperature below about 15°C, for example to about 10°C, to about 5°C, to about 0°C or to about -5°C. In one aspect, the solution comprising vonoprazan fumarate of formula (I) may be concentrated and cooled down within approximately one hour to 48 hours, for example in 2 hours, 5 hours, 8 hours, 12 hours, 18 hours, 24 hours, or 36 hours. The solution may be cooled down slowly, for example at a rate of about 0.1°C to 0.5°C per minute.

[0064] In one aspect, the solution comprising vonoprazan fumarate of formula (I) in THF and water may be concentrated and cooled down to a temperature below about 20°C, for example to from about -10°C to about 10°C or to from about 0°C to about 15°C.

[0065] In one aspect, the solution comprising vonoprazan fumarate of formula (I) in THF and water may be concentrated and cooled down at a rate of approximately 0.1 to 0.5°C per minute.

[0066] The solid vonoprazan fumarate of formula (I) obtained after the concentration and / or cooling step may be isolated by known techniques, for example by filtration or centrifugation

[0067] In a preferred aspect, the solid vonoprazan fumarate of formula (I) is isolated by filtration.

[0068] Vonoprazan fumarate of formula (I) obtainable according to the present process, has a high purity, typically > 99.8%, for example 99.91%, 99.95% or 99.99% measured at 220 nm in HPLC, and impurities are present in an amount < 0.04%, preferably < 0.01% measured at 220 nm in HPLC.

[0069] It has been surprisingly found that the herein disclosed purification process of vonoprazan fumarate of formula (I) does not lead to the formation of the impurity of formula (II):

[0070] (II).

[0071] Furthermore, the present purification process of vonoprazan fumarate of formula (I) in a mixture of THF and water and in the absence of a linear or branched Ci-Ce alcohol, for example methanol, does not lead to the formation of the corresponding mono- and diesters of the impurity of formula (II). In fact, it has been found that crystallizing vonoprazan fumarate of formula (I) in a mixture of methanol and water under reflux leads to the formation of the impurities of formula (III) and of formula (IV):

[0072] (III) (IV)

[0073] Thanks to the employed conditions described herein, vonoprazan fumarate of formula (I) does not contain the impurities of formula (HI) and of formula (IV).

[0074] The examples below further illustrate, but do not limit, the disclosure.

[0075] Experimental part

[0076] TheJH NMR spectra were acquired with a Varian 500 MHz instrument. The chemical shifts are expressed in parts per million (ppm). The coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).

[0077] HPLC analyses of vonoprazan fumarate of formula (I) were carried out on a Waters Alliance or Agilent 1260 HPLC at the following conditions: Sunfire C18 (250 x 4.6 mm, 5 pm) column; solvent 1 : H3PO4 0.1% in water, solvent 2: methanol or acetonitrile; flow rate: 1.0 mL / min; UV detector at 220 nm.

[0078] Example 1: Purification of Vonoprazan Fumarate of Formula (I)

[0079] 42.5 g (92.1 mmol) of vonoprazan fumarate of formula (I) is placed in a 1 L reactor comprising a mechanical stirrer, a thermometer, a Claisen distillation flask, and a connection to a vacuum line. 20 volumes of a 2:1 (v:v) demineralized THF / water mixture (566 mL + 283 mL, respectively) are then added and the mixture is stirred at 25°C until the solid is completely dissolved. The vacuum is then activated, adjusted by means of a pressure switch, and the solution is concentrated to a volume of about 460 mL, while maintaining an internal temperature of 15-20°C and a maximal external temperature of 25°C. Once the desired residual volume is obtained, the vacuum is stopped, and the mixture is heated to 25°C. The Claisen flask is then replaced with a refrigerant and the mixture is kept under inert atmosphere. The mixture is maintained for 5 minutes at 25°C, and then cooled down to 0°C within 5 hours (outside temperature, the temperature of the solution is about 3-4°C) and maintained for 8-13 hours at 0°C. The obtained solid is then filtered off, and washed with a 30:70 THF / water mixture, which has been previously cooled down to 0-5°C. The solid is dried for 19-24 hours under vacuum at 40°C to provide 32.7 g vonoprazan fumarate of formula (I) as an off-white / very light yellow solid (yield of 73%). The purity of the product is 99.84% (HPLC detector at 220 nm). No formation of the impurity of formula (II) is observed and the impurities formula of (III) and of formula (IV) are not detected neither.

[0080] H NMR (500 Hz, DMSO) 5: 8.87-8.85 (m, 1H), 8.54 (d, .J 2.0 Hz, 1H), 7.87-7.85 (m, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.61-7.58 (m, 1H), 7.51 -7.48 (m, 1H), 7.23-7.20 (m, 2H), 7.10- 7.06 (m, 1H), 6.47-6.46 (m, 3H), 3.86 (s, 2H), 2.42 (s, 3H).

[0081] Example 2: Crystallization of Vonoprazan Fumarate of Formula (I) in Water and Methanol

[0082] 5.00 g (10.8 mmol) of vonoprazan fumarate of formula (I) is suspended in 50 mL of a methanol / water mixture (8:2, v:v) and the mixture is heated to reflux (60-67°C) to solubilize the solid. After 30 minutes, the mixture is allowed to cool down to room temperature (25°C) and then within another hour to 10°C. The obtained solid is filtered off and dried under vacuum at 40 / 45°C for 16 hours to provide 4.24 g (yield of 84.8%) of vonoprazan fumarate of formula (I). The purity of the product is 99.81% (HPLC detector at 220nm), the amount of the impurity of formula (II) is 0.12%, the impurity of formula (III) is 0.08%, while the impurity of formula (IV) is not detected.

[0083] Example 3: Crystallization of Vonoprazan Fumarate of Formula (I) in Water and Methanol

[0084] It was observed that maintaining the mixture comprising vonoprazan fumarate of formula (I), prepared as described in Example 2, under reflux for 16 hours in a methanol / water mixture (8:2, v:v), thus under prolonged conditions compatible to the ones of industrial applications, provides vonoprazan fumarate of formula (I) with a purity of 95.30% (HPLC detector at 220 nm). The amount of the impurity of formula (II) is 3.86%, the impurity of formula (III) is 0.20%, and the impurity of formula (IV) is 0.14% (HPLC at 220 nm).

Claims

CLAIMS1. A process for purifying vonoprazan fumarate of formula (I):(I), comprising:- dispersing and dissolving vonoprazan fumarate of formula (I) in a solvent mixture comprising an ether solvent and water at a temperature not exceeding 50°C;- concentrating or cooling the solution to obtain a precipitate of vonoprazan fumarate of formula (I); and- isolating the solid.

2. The process according to claim 1, wherein the ether solvent is tetrahydrofuran (THF), 2 -methyl -tetrahydrofuran or dioxane.

3. The process according to claim 1, wherein the ether solvent is tetrahydrofuran (THF).4 The process according to claims 1 to 3, wherein the solvent mixture does not comprise methanol, ethanol, n-propanol, / .wpropanol or n-butanol.

5. The process according to claims 1 to 4, wherein the dispersion and dissolution of vonoprazan fumarate of formula (I) is carried out in a solvent mixture comprising an ether solvent and water, wherein the ratio of the ether solvent and water is from 40:60 v:v to 90: 10 v:v.

6. The process according to claim 5, wherein the ratio of the ether solvent and water is from 50:50 v:v to 70:30 v:v.

7. The process according to claims 1 to 6, wherein the dissolution of vonoprazan fumarate of formula (I) is carried out by heating the dispersion of vonoprazan fumarate of formula (I) at a temperature not exceeding 50°C.

8. The process according to claim 7, wherein the dissolution of vonoprazan fumarate of formula (I) is carried out by heating the dispersion of vonoprazan fumarate of formula (I) at a temperature not exceeding 40°C.

9. The process according to claim 7, wherein the dissolution of vonoprazan fumarateof formula (I) is carried out by heating the dispersion of vonoprazan fumarate of formula (I) at 25 °C.

10. The process according to claims 1 to 9, wherein after concentration of the solution, the ratio of the ether solvent and water is < 50:50 v:v.

11. The process according to claims 1 to 10, wherein the cooling of the solution is carried out at a temperature from -10°C to 10°C.

12. The process according to claims 1 to 11, wherein the solution comprising vonoprazan fumarate of formula (I) is concentrated and cooled.

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