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WO2024110862A9 - Procédé de préparation de zanubrutinib - Google Patents

Procédé de préparation de zanubrutinib Download PDF

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Publication number
WO2024110862A9
WO2024110862A9 PCT/IB2023/061735 IB2023061735W WO2024110862A9 WO 2024110862 A9 WO2024110862 A9 WO 2024110862A9 IB 2023061735 W IB2023061735 W IB 2023061735W WO 2024110862 A9 WO2024110862 A9 WO 2024110862A9
Authority
WO
WIPO (PCT)
Prior art keywords
acid
formula
zanubrutinib
compound
process according
Prior art date
Application number
PCT/IB2023/061735
Other languages
English (en)
Other versions
WO2024110862A1 (fr
Inventor
Barbara NOVO
Jacopo BONANOMI
Simona TRABACE
Jacopo LESMA
Original Assignee
Olon S.P.A.
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 Olon S.P.A. filed Critical Olon S.P.A.
Publication of WO2024110862A1 publication Critical patent/WO2024110862A1/fr
Publication of WO2024110862A9 publication Critical patent/WO2024110862A9/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for preparing Zanubrutinib .
  • Zanubrutinib is an active principle classified as a Bruton tyrosine kinase (BTK) inhibitor, currently approved by the Food and Drug Administration (FDA) for the treatment of mantle cell lymphoma (MCL) in patients who have received at least one previous therapy. It is marketed under the name Brukinsa®.
  • BTK Bruton tyrosine kinase
  • WO 2014/173289 in the name of Beigene LTD, describes Zanubrutinib and its preparation (compound 27) .
  • the Zanubrutinib synthesis process is also described in WO 2018/033135 (WO' 135) .
  • This process involves, among other steps, synthesis and isolation of an intermediate compound of formula (II) : formula II from an intermediate compound of formula (I) : formula I where X is Cl.
  • the compound of formula (II) was separated from the organic phase and isolated using methyl-t-butyl ether (MTBE) and n-heptane as anti-solvents causing its precipitation.
  • MTBE methyl-t-butyl ether
  • n-heptane anti-solvents
  • the Applicant has found that the compound of formula (II) has a tendency to react with anti-solvents, such as those used in WO' 135, forming impurities that are difficult to remove.
  • anti-solvents such as those used in WO' 135
  • the compound of formula (II) when isolated as described in WO' 135, has a certain amount of impurities, which are also found in the final product Zanubrutinib, often in quantities that do not meet the required specifications for this active principle.
  • the present invention concerns a process for preparing Zanubrutinib of formula A:
  • step (b) adding an aqueous medium to the reaction mixture obtained from step (a) ;
  • step (c) adding a base to the mixture obtained from step (b) up to obtain a pH higher than 8, preferably from 11 to 12; (d) optionally converting the compound of formula II into a salt thereof by reaction with an acid, preferably with an organic acid;
  • step (e) converting the compound of formula II, or the salt thereof, to Zanubrutinib; wherein the compound of formula II obtained from step (a) is not isolated.
  • the aqueous medium is water, or a mixture of water and a water-soluble organic solvent, e.g. an alcohol, particularly methyl alcohol or ethyl alcohol.
  • a water-soluble organic solvent e.g. an alcohol, particularly methyl alcohol or ethyl alcohol.
  • the compound of formula II is preferably reacted with an acid selected from: L-DBTA acid (L-dibenzoyltartaric) , D-DBTA (D- dibenzoyltartaric) , L-DTTA (di-p-toluyl-L-tartaric acid) , D- DTTA (di-p-toluyl-D-tartaric acid) , L-malic acid, D-malic acid, L-mandelic acid, D-mandelic acid, L-camphorsulphonic acid, D-camphorsulphonic acid, L-tartaric acid, D-tartaric acid.
  • the salt of the compound of formula II with L-DBTA is particularly preferred.
  • the molar ratio between acid and compound of formula II is from 1:2 to 1:1, more preferably the molar ratio is 1:2.
  • step (e) in which the compound of formula II, or a salt thereof, is converted to Zanubrutinib, is achieved by reacting the compound of formula II, or a salt thereof, with acryloyl chloride.
  • the Zanubrutinib obtained from step (e) can be in crystalline or amorphous form.
  • the Zanubrutinib obtained from step (e) is reacted with a coformer selected from 3-hydroxybenzoic acid, 2 , 4-dihydroxybenzoic acid, 4-aminobenzoic acid and 4-methylaminobenzoic acid, to obtain Zanubrutinib co-crystal .
  • a coformer selected from 3-hydroxybenzoic acid, 2 , 4-dihydroxybenzoic acid, 4-aminobenzoic acid and 4-methylaminobenzoic acid, to obtain Zanubrutinib co-crystal .
  • the Zanubrutinib co-crystal i s then converted to amorphous Zanubrutinib .
  • the conversion of Zanubrutinib co-crystal to amorphous Zanubrutinib occurs by treatment of the co-crystal in water at controlled pH, preferably at basic pH .
  • the pH is greater than or equal to 9 .
  • the pH is from 9 to 12 .
  • the conversion step allows the precipitation of amorphous Zanubrutinib .
  • the process according to the present invention avoids the formation of impurities from the interaction of the compound of formula I T with the antisolvents used for the crystallisation thereof .
  • the process o f the invention makes it possible to avoid, or in any event to control , the formation of the following impurities :
  • the impurity of formula I T T which is formed by the addition of MTBE to the product of formula I I , is particularly critical , as it remains in the finished product even after sequential crystallisation .
  • the basic solution was slowly dripped into the reaction while maintaining the temperature less than or equal to 5°C (internal) , until a pH between 11 and 12 was reached. The mixture was brought back to 20°C and left to stir for 10 minutes. The organic phase was separated from the aqueous phase, which was then re-extracted with dichloromethane (50 ml) . The organic phases were combined and concentrated to a residual volume of 50 ml. Demineralised water (50 ml) was added to the solution. The solution was concentrated under reduced pressure to a residual volume of 50 ml. Methanol (100 ml) was slowly added and the solution was heated to 30°C. A solution consisting of L-DBTA monohydrate (4.38 g, 11.64 mmol) and methanol (50 ml) was prepared in another flask. The solution was stirred at 25°C until complete dissolution of the product.
  • Figure 1 shows the hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR) of the compound of formula IT thus obtained (in salt form with L-DBTA) (spectrum obtained with NMR300 Mercury 300 spectrometer, at 25°C, with solvent D2O) .
  • Demineralised water (25 ml) , NaHCCh 1.2 g (3 eq) and L-tartaric acid 358 mg (0.5 eq) were then loaded into the flask.
  • the temperature was raised to -2°C and acryloyl chloride (564 mg, 1.3 eq) was dripped.
  • isopropyl acetate (12 ml) was added and the phases were separated.
  • the organic phase was washed with 5 % NaHCCh aq. and isopropyl acetate (40 ml) and the coformer selected from 3-hydroxybenzoic acid (1.1 eq) were loaded onto the organic phase .
  • the organic phase was concentrated to a small volume then more isopropyl acetate was added until the acetonitrile was removed. The final solution was brought to 40°C and triggered. When abundant precipitate was observed, it was filtered and washed with 2 ml isopropyl acetate. The co-crystal was dried in a vacuum oven at 45°C for 6 hours.
  • the co-crystal Zanubrutinib obtained from Example 2 (2 g) and DMSO (6 ml) were loaded into a flask. The mixture was stirred until completely dissolved. A 70 ml solution of NaHCCh 5% aq. was prepared in another flask and the DMSO solution was slowly dripped onto the aqueous solution, while maintaining vigorous stirring . The suspension was left stirring for 1 hour , then filtered and washed with water . The solid was discharged and dissolved in 6 ml of DMSO . A 70 ml solution of NaHCCh 5% aq . was prepared in another flask and the DMSO solution was slowly dripped onto the aqueous solution, while maintaining vigorous stirring .
  • the suspension was stirred for 1 hour, then filtered and washed with water .
  • the solid was discharged and washed with 2 slurries in water for 1 hour each .
  • the final amorphous solid was dried in an oven at 35 ° C for 16 hours .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de zanubrutinib, dans lequel l'intermédiaire de formule (II) n'est pas du milieu réactionnel, de sorte qu'il n'est pas nécessaire d'utiliser des anti-solvants qui peuvent compromettre la stabilité du composé de formule (II) et générer des sous-produits indésirables.
PCT/IB2023/061735 2022-11-24 2023-11-21 Procédé de préparation de zanubrutinib WO2024110862A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102022000024192 2022-11-24
IT102022000024192A IT202200024192A1 (it) 2022-11-24 2022-11-24 Processo per la preparazione di Zanubrutinib.

Publications (2)

Publication Number Publication Date
WO2024110862A1 WO2024110862A1 (fr) 2024-05-30
WO2024110862A9 true WO2024110862A9 (fr) 2024-11-28

Family

ID=85122691

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2023/061735 WO2024110862A1 (fr) 2022-11-24 2023-11-21 Procédé de préparation de zanubrutinib

Country Status (2)

Country Link
IT (1) IT202200024192A1 (fr)
WO (1) WO2024110862A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG11201901141WA (en) * 2016-08-16 2019-03-28 Beigene Ltd Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
EP4353747A3 (fr) 2016-08-19 2024-06-26 BeiGene Switzerland GmbH Combinaison de zacuturinib avec un anticorps anti-cd20 ou anti-pd-1 pour une utilisation dans le traitement du cancer

Also Published As

Publication number Publication date
WO2024110862A1 (fr) 2024-05-30
IT202200024192A1 (it) 2024-05-24

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