WO2013153055A1 - Procédé de préparation d'un inhibiteur de protéase virale sous forme amorphe - Google Patents

Procédé de préparation d'un inhibiteur de protéase virale sous forme amorphe Download PDF

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Publication number
WO2013153055A1
WO2013153055A1 PCT/EP2013/057373 EP2013057373W WO2013153055A1 WO 2013153055 A1 WO2013153055 A1 WO 2013153055A1 EP 2013057373 W EP2013057373 W EP 2013057373W WO 2013153055 A1 WO2013153055 A1 WO 2013153055A1
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WO
WIPO (PCT)
Prior art keywords
telaprevir
solvent
process according
amorphous
μηι
Prior art date
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PCT/EP2013/057373
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English (en)
Inventor
Pietro Allegrini
Enrico BRUNOLDI
Original Assignee
Dipharma Francis S.R.L.
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.)
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Publication date
Application filed by Dipharma Francis S.R.L. filed Critical Dipharma Francis S.R.L.
Publication of WO2013153055A1 publication Critical patent/WO2013153055A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a process for the preparation of (I S, 3aR, 6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinylcarbonyl) amino]acetyl]amino]-3,3-dimethylbutanoyl]-N-[(l S)-l-[(cyclopropylamino) (oxo)acetyl]butyl]-3,3a,4,5,6,6a-hexahydro- lH-cyclopenta[c]pyrrole-3- carboxyamide of formula (I), also known as telaprevir, in amorphous form.
  • Telaprevir or (I S, 3aR, 6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2- pyrazinylcarbonyl) amino]acetyl]amino]-3,3-dimethylbutanoyl]-N-[(l S)-l - [(cyclopropylamino)(oxo)acetyl]butyl]-3,3a,4,5,6,6a-hexahydro- lH- cyclopenta [c]pyrrole-3-carboxyamide, is a potent viral protease inhibitor used to treat hepatitis C infections.
  • telaprevir normally presents as a crystalline solid with a high melting point (246°C), characterised by very low solubility in water, i.e. only 4.7 mg/1, which is even less than that of marble.
  • Amorphous telaprevir is far more soluble in water and guarantees greater bioavailability, therefore it is used to prepare a pharmaceutical form as it is.
  • WO 2005/123076 only describes the preparation of telaprevir in amorphous form by the spray-drying technique, although the inventors state that amorphous telaprevir can also be prepared by other techniques, such as freeze-drying, rapid cooling of the molten product or evaporation of solvent in a rotary evaporator.
  • telaprevir all these techniques are rather expensive in practice and, to be conducted on a large scale, require specific industrial plants. Moreover, some of them cannot be used for telaprevir because of its high melting point or its high level of insolubility in many organic solvents, and in water. For example, the preparation of amorphous telaprevir by spray drying, described in WO 2005/123076, uses a solution of telaprevir in methylene chloride, a solvent which is unsuitable for industrial use because of its toxicity.
  • Figure 1 XRPD spectrum of amorphous telaprevir.
  • Figure 2 XRPD spectrum of crystalline telaprevir prepared as reported in EP 1934179, example 14.
  • Telaprevir in amorphous form has been characterised by X-ray powder diffraction (XRPD).
  • XRPD X-ray powder diffraction
  • the water content of the compounds was determined by titration with the Karl Fischer technique.
  • the particle size was determined by the well-known laser light scattering technique, using a Malvern Mastersizer MSI instrument under the following operating conditions: • 300RF mm lens with 2.4 mm laser beam length;
  • the subject of the invention is a process for the preparation of telaprevir in amorphous form which comprises:
  • Telaprevir used as starting material, can be in any crystalline form, i.e. anhydrous, hydrated or solvated.
  • the term "hydrated” means a form with any degree of hydration.
  • the first solvent used can be any solvent able to dissolve telaprevir.
  • a first solvent is preferably a polar aprotic solvent, such as dimethyl sulphoxide, dimethylacetamide, N-methyl pyrrolidone or acetonitrile; or a polar protic solvent, such as a C[-C 5 alkanol, preferably methanol, ethanol, isopropanol, trifluoroethanol or hexafluoroisopropanol; or an apolar aprotic solvent, typically a chlorinated solvent, preferably dichloromethane; or a mixture of two or more, preferably two or three, and more preferably two of said solvents able to dissolve telaprevir.
  • a polar aprotic solvent such as dimethyl sulphoxide, dimethylacetamide, N-methyl pyrrolidone or acetonitrile
  • a polar protic solvent such as a C[-C 5 alkanol, preferably methanol, ethanol, isopropanol, trifluoro
  • the concentration of telaprevir in the starting solution can range between approximately 2% and 80% w/w, preferably between about 5 and 50% w/w.
  • Telaprevir can be solubilised in a solvent at a temperature of up to about 40°C.
  • a telaprevir stabilizing agent such as an organic or inorganic acid, typically a Ci-C 7 carboxylic acid, preferably acetic acid or propionic acid, can optionally be added to the solution.
  • a second solvent is a solvent in which telaprevir is insoluble or scarcely soluble, herein also defined as "antisolvent". It is for example, water or an apolar aprotic solvent, preferably a cyclic or acyclic C 5 -C 12 saturated hydrocarbon, such as cyclopentane, cyclohexane, cycloheptane, pentane, hexane or heptane, or a mixture of two or more, typically two or three, and preferably two of said solvents.
  • apolar aprotic solvent preferably a cyclic or acyclic C 5 -C 12 saturated hydrocarbon, such as cyclopentane, cyclohexane, cycloheptane, pentane, hexane or heptane, or a mixture of two or more, typically two or three, and preferably two of said solvents.
  • the first solvent is dimethylsulphoxide and the second solvent is water or the first solvent is dichloromethane and the second solvent is heptane.
  • the solution of telaprevir in a first solvent can be mixed with the antisolvent, either by adding the solution to the antisolvent or the antisolvent to the solution, or substantially by mixing them together, preferably by adding the solution to the antisolvent.
  • the telaprevir solution can be mixed with an antisolvent in a variable time, ranging, for example, from very quickly, typically in less than 1 minute, to very slowly, typically up to several hours, for example in about 2 hours.
  • the temperature of the mixture containing the second solvent, namely the antisolvent is typically maintained at between about -80°C and about 60°C, preferably between about -20°C and about 40°C, to facilitate precipitation of the amorphous solid.
  • the solid can be recovered by known methods, such as filtration, and then dried, for example in a stove.
  • Telaprevir is obtained in amorphous form as proved by its XRPD, illustrated in Figure 1 , in which the absence of diffraction peaks can be observed.
  • Amorphous telaprevir thus obtained, can be anhydrous or have a variable water content, depending on whether the antisolvent is water or a mixture thereof with a further antisolvent as reported above.
  • the water content of amorphous telaprevir obtainable according to the invention, can subsequently be varied, depending on the operating conditions used for its drying.
  • the purity of the amorphous telaprevir obtained by the process according to the invention, evaluated by HPLC, is equal to or greater than 98%, and more preferably equal to or greater than 99.4%.
  • the particle size of the amorphous telaprevir thus obtained is characterised by a D(0.9) value of below 50 ⁇ . If desired, said value can be further reduced by micronisation or fine grinding.
  • a further aspect of the invention relates to amorphous telaprevir having a D(0.9) value of less than 10 ⁇ , preferably about 5 ⁇ .
  • telaprevir (1.8 g) is dissolved in dichloromethane (5 mL) at 30°C, and the solution thus obtained is dripped into heptane (150 mL) cooled to 0°C, the system being maintained under vigorous stirring. The resulting suspension is then filtered, and the white solid obtained is washed with heptane (10 mL) and dried at about 25°C under vacuum for 16 hours, to give amorphous telaprevir (1.5 g).
  • the product thus obtained has the XRPD spectrum shown in Figure 1.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention a pour objet un procédé de préparation d'un inhibiteur de protéase virale sous forme amorphe, employant une technique comprenant l'utilisation d'un système de solvants.
PCT/EP2013/057373 2012-04-13 2013-04-09 Procédé de préparation d'un inhibiteur de protéase virale sous forme amorphe WO2013153055A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2012A000608 2012-04-13
IT000608A ITMI20120608A1 (it) 2012-04-13 2012-04-13 Procedimento per la preparazione di un inibitore delle proteasi virali in forma amorfa

Publications (1)

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WO2013153055A1 true WO2013153055A1 (fr) 2013-10-17

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PCT/EP2013/057373 WO2013153055A1 (fr) 2012-04-13 2013-04-09 Procédé de préparation d'un inhibiteur de protéase virale sous forme amorphe

Country Status (2)

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IT (1) ITMI20120608A1 (fr)
WO (1) WO2013153055A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123076A2 (fr) 2004-06-08 2005-12-29 Vertex Pharmaceuticals, Inc. Compositions pharmaceutiques
EP1934179A2 (fr) 2005-08-19 2008-06-25 Vertex Pharmaceuticals Incorporated Procedes et intermediaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123076A2 (fr) 2004-06-08 2005-12-29 Vertex Pharmaceuticals, Inc. Compositions pharmaceutiques
EP1934179A2 (fr) 2005-08-19 2008-06-25 Vertex Pharmaceuticals Incorporated Procedes et intermediaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANASS ZNABET ET AL: "A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions", CHEMICAL COMMUNICATIONS, vol. 46, no. 42, 1 January 2010 (2010-01-01), pages 7918, XP055027224, ISSN: 1359-7345, DOI: 10.1039/c0cc02823a *
NATURE BIOTECHNOLOGY, vol. 29, 2011, pages 993

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