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WO2025181220A1 - Procédé de purification d'un médicament utilisé dans le traitement de troubles liés à l'acidité - Google Patents

Procédé de purification d'un médicament utilisé dans le traitement de troubles liés à l'acidité

Info

Publication number
WO2025181220A1
WO2025181220A1 PCT/EP2025/055317 EP2025055317W WO2025181220A1 WO 2025181220 A1 WO2025181220 A1 WO 2025181220A1 EP 2025055317 W EP2025055317 W EP 2025055317W WO 2025181220 A1 WO2025181220 A1 WO 2025181220A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
vonoprazan fumarate
water
hours
vonoprazan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/055317
Other languages
English (en)
Inventor
Michela ZUFFO
Lorenzo BISCONTI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dipharma Francis SRL
Original Assignee
Dipharma Francis SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dipharma Francis SRL filed Critical Dipharma Francis SRL
Publication of WO2025181220A1 publication Critical patent/WO2025181220A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Described herein is a method for purifying vonoprazan fumarate.
  • (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.
  • 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.
  • 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.
  • the present invention is directed to a process for purifying vonoprazan fumarate of formula (I):
  • the present invention is directed to a process for purifying vonoprazan fumarate of formula (I):
  • 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.
  • An ether solvent may be a cyclic ether.
  • the ether solvent is for instance tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (methyl-THF), or dioxane.
  • the ether solvent is tetrahydrofuran.
  • the solvent mixture does not comprise a linear or branched Ci-Ce alcohol.
  • the solvent mixture comprising an ether solvent and water does not comprise methanol, ethanol, n-propanol, /.wpropanol or n-butanol.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • THF tetrahydrofuran
  • 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
  • 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).
  • THF tetrahydrofuran
  • 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).
  • 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).
  • 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.
  • 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.
  • the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion to a temperature not exceeding 40°C.
  • 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.
  • the dissolution of vonoprazan fumarate of formula (I) may be carried out by heating the dispersion at 25°C.
  • 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.
  • the concentration of the vonoprazan fumarate of formula (I) used as starting material may be chosen based on the temperature and the solvent mixture.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the solution may be cooled down slowly, for example at a rate of about 0.1°C to 0.5°C per minute.
  • 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.
  • 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.
  • the solution comprising vonoprazan fumarate of formula (I) may be concentrated and then cooled down.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the solid vonoprazan fumarate of formula (I) is isolated by filtration.
  • 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.
  • vonoprazan fumarate of formula (I) does not contain the impurities of formula (HI) and of formula (IV).
  • the J H 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).
  • 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 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de purification de fumarate de vonoprazan de formule (I).
PCT/EP2025/055317 2024-02-29 2025-02-27 Procédé de purification d'un médicament utilisé dans le traitement de troubles liés à l'acidité Pending WO2025181220A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT202400004474 2024-02-29
IT102024000004474 2024-02-29

Publications (1)

Publication Number Publication Date
WO2025181220A1 true WO2025181220A1 (fr) 2025-09-04

Family

ID=90924133

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/055317 Pending WO2025181220A1 (fr) 2024-02-29 2025-02-27 Procédé de purification d'un médicament utilisé dans le traitement de troubles liés à l'acidité

Country Status (1)

Country Link
WO (1) WO2025181220A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7977488B2 (en) 2005-08-30 2011-07-12 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8822694B2 (en) 2009-02-25 2014-09-02 Takeda Pharmaceutical Company Limited Process for producing pyrrole compound
CN104926790A (zh) * 2015-06-29 2015-09-23 江苏奥赛康药业股份有限公司 一种高纯度 Vonoprazan Fumarate化合物及其中间体、杂质以及它们的制备方法
CN106892900A (zh) * 2017-04-10 2017-06-27 山东裕欣药业有限公司 一种富马酸沃诺拉赞及其制备方法
CN106905216A (zh) * 2017-04-19 2017-06-30 刘德鹏 一种质子泵抑制剂药物化合物及其制备方法
CN107586288A (zh) * 2017-10-19 2018-01-16 上海博志研新药物技术有限公司 一种富马酸沃诺拉赞的纯化方法
CN114853728A (zh) * 2022-05-07 2022-08-05 四川制药制剂有限公司 一种富马酸伏诺拉生片及其制备方法
CN110590746B (zh) * 2019-09-23 2023-08-29 吉林汇康制药有限公司 一种低杂质富马酸沃诺拉赞的制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7977488B2 (en) 2005-08-30 2011-07-12 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8436187B2 (en) * 2005-08-30 2013-05-07 Takeda Pharmaceutical Company Limited 1-heterocyclylsulfonyl, 3-aminomethyl, 5- (hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
US8822694B2 (en) 2009-02-25 2014-09-02 Takeda Pharmaceutical Company Limited Process for producing pyrrole compound
CN104926790A (zh) * 2015-06-29 2015-09-23 江苏奥赛康药业股份有限公司 一种高纯度 Vonoprazan Fumarate化合物及其中间体、杂质以及它们的制备方法
CN106892900A (zh) * 2017-04-10 2017-06-27 山东裕欣药业有限公司 一种富马酸沃诺拉赞及其制备方法
CN106905216A (zh) * 2017-04-19 2017-06-30 刘德鹏 一种质子泵抑制剂药物化合物及其制备方法
CN107586288A (zh) * 2017-10-19 2018-01-16 上海博志研新药物技术有限公司 一种富马酸沃诺拉赞的纯化方法
CN110590746B (zh) * 2019-09-23 2023-08-29 吉林汇康制药有限公司 一种低杂质富马酸沃诺拉赞的制备方法
CN114853728A (zh) * 2022-05-07 2022-08-05 四川制药制剂有限公司 一种富马酸伏诺拉生片及其制备方法

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