WO2024089702A1 - Procédé amélioré pour la préparation de tucatinib et de son sel et de ses polymorphes - Google Patents

Procédé amélioré pour la préparation de tucatinib et de son sel et de ses polymorphes Download PDF

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Publication number
WO2024089702A1
WO2024089702A1 PCT/IN2023/050071 IN2023050071W WO2024089702A1 WO 2024089702 A1 WO2024089702 A1 WO 2024089702A1 IN 2023050071 W IN2023050071 W IN 2023050071W WO 2024089702 A1 WO2024089702 A1 WO 2024089702A1
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WIPO (PCT)
Prior art keywords
formula
compound
tucatinib
triflate
methyl
Prior art date
Application number
PCT/IN2023/050071
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English (en)
Inventor
Srinivasa Krishna Murthy Konduri
Srinivasulu GANGANAMONI
Phaneendra Gutala
Srinivas BODDULA
Subhash KUSUMBA
Laxmana Viswa Venkata Pavan Kumar MADDULA
Ankamanayudu Annadasu
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Limited
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Publication of WO2024089702A1 publication Critical patent/WO2024089702A1/fr

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  • the present invention relates to an improved process for the preparation of (N4- (4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine compound of formula- 1 exists as hemi ethanolate solvate which is represented by the following structural formula.
  • Tucatinib hemi ethanolate is referred as Tucatinib.
  • Tucatinib is chemically known as (N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6- diamine hemi ethanolate.
  • Tucatinib was developed by Array BioPharma and approved by USFDA as Tukysa tablets which is indicated for the treatment of metastatic HER2- positive breast cancer.
  • the present inventors have developed an improved process for the preparation of Tucatinib that avoids the usage of column chromatography techniques which are commercially not viable.
  • the present invention provides an efficient, economically viable, easily scalable process for the preparation of Tucatinib.
  • the first aspect of the present invention is to provide an improved process for the preparation of Tucatinib compound of formula- 1.
  • the second aspect of the present invention is to provide a novel crystalline form of Tucatinib Triflate of formula- 1 a hereinafter designated as “Form-N” and its process for the preparation.
  • the third aspect of the present invention is to provide process for making Tucatinib hemi ethanolate (1) from Tucatinib triflate salt of formula- la.
  • FIG.1 Illustrates the characteristic PXRD pattern of crystalline form-N of Triflate salt of Tucatinib compound of formula- 1 a.
  • FIG.2 Illustrates the DSC thermogram of crystalline form-N of Triflate salt of Tucatinib compound of formula- la.
  • FIG.3 Illustrates the characteristic PXRD pattern of crystalline form of Tucatinib obtained according to Example-6.
  • suitable solvent refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4- dioxane, monoxime, dioxime and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-
  • anti-solvent refers to a solvent which is used to precipitate the solid from a solution.
  • suitable acid refers to organic acids or inorganic acids.
  • the “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalen
  • suitable base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diiso
  • the first aspect of the present invention is to provide an improved process for the preparation of Tucatinib compound of formula- 1, comprising of: a) Reacting N4-[3-methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)phenyl] quinazoline-4,6-diamine compound of formula-6 with 4, 4-dimethyl-2- methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 in a suitable solvent followed by isolating the compound using addition of suitable anti-solvent to provide Tucatinib Triflate of formula- la, b) optionally, purifying the obtained compound with a suitable solvent mixture to provide pure Triflate salt of Tucatinib of formula- la, c) treating the Tucatinib triflate of formula- la with a suitable base in a suitable solvent followed by treatment of Tucatinib in ethanol to provide Tucatinib of formula
  • the suitable solvent & anti-solvent used is selected from benzene, toluene, xylene, pyridine, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) dichloromethane/methylene chloride, dichloroethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone acetonitrile, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol,
  • the suitable base used is selected from diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide or any other suitable base.
  • the preferred embodiment of the present invention provides an improved process for the preparation of Tucatinib of formula- 1, comprising of: a) Reacting N4-[3-methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)phenyl] quinazoline-4,6-diamine compound of formula-6 with 4, 4-dimethyl-2- methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 in pyridine followed by isolating the crude compound using n-butanol to provide Tucatinib Triflate of formula- la, b) purifying the obtained compound of formula- la in a solvent mixture comprising dimethylformamide and n-butanol to provide pure Tucatinib Triflate of formula- la, c) treating the compound of formula- la with triethylamine in methanol followed by further treatment with ethanol to provide Tucatinib of formula- 1.
  • the second aspect of the present invention is to provide a novel crystalline form-N of Tucatinib Triflate of formula- la, which is characterized by: i) Its powder X-ray diffractogram having peaks at about 5.3, 7.2, 10.6, 11.9, 16.0, 19.4, 21.4 and 22.7 ⁇ 0.2 degrees 2-theta. ii) Its powdered X-ray diffraction pattern as shown in figure- 1. iii) Its DSC thermogram as shown in figure-2.
  • the present invention also provides a process for the preparation of crystalline Form-N of Tucatinib Triflate of formula-la, comprising steps of: a) Reacting compound of formula-6 with compound of formula-7 in a suitable solvent and adding a suitable anti-solvent for the isolation of compound of formula- 1 a, b) dissolving the compound obtained in step-(a) in a suitable solvent, c) precipitating the compound of formula- 1 a using a suitable anti-solvent, d) filtering, washing and drying the compound to get the crystalline form-N of Tucatinib Triflate of formula- la.
  • the suitable solvent & anti-solvent used is selected from benzene, toluene, xylene, pyridine, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) dichloromethane/methylene chloride, dichloroethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone acetonitrile, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol,
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Tucatinib Triflate of formula- la, comprising steps of: a) Reacting compound of formula-6 with compound of formula-7 in pyridine followed by isolating the crude compound of formula- la using n-butanol to provide Tucatinib Triflate of formula- la, b) dissolving the compound obtained in step-(a) in N,N-dimethylformamide, c) precipitating the compound of formula- la using n-butanol, d) filtering, washing and drying the compound to get the crystalline form-N of Tucatinib Triflate of formula- 1 a.
  • the 2-Amino-5-nitro-benzonitrile compound of formula-2 can be prepared from the processes known in the art.
  • the preparation of 3-methyl-4- ([l,2,4]triazolo[l,5-a]pyridine-7-yloxy)aniline compound of formula-4 and 4, 4- dimethyl-2-methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 are prepared from the present invention or processes known in the art.
  • the present invention involves the usage of pyridine as a solvent which efficiently transforms the compound of formula-6 to compound of formula- la with improved yield and quality.
  • the present invention involves the transformation of compound of formula-6 to compound of formula- la at ambient temperatures which are suitable for commercial scale process.
  • the present invention successfully avoids chromatographic techniques which are commercially not viable.
  • the present invention involves the isolation Tucatinib as its triflate salt which enhances the purity of the desired compound i.e., Tucatinib by the removal of undesired impurities.
  • the present invention involves the usage of low cost reagents & solvents which reduce the cost of production and also best suitable for commercial scale process.
  • Tucatinib compound of formula- 1 is schematically represented as below:
  • reaction mass was cooled to 0-5 °C and stirred for 2 hrs at the same temperature.
  • the resultant precipitate was filtered and washed with methanol and dried to get the title compound (Yield: 82.4 g, 94.77%).
  • HPLC Purity 99.7%.
  • Exampe-4 Process for the preparation of N4-[3-methyl-4-([l,2,4]triazolo[l,5- a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine (F ormula-6)
  • the compound of formula-5 (65.0 g), methylene chloride (975 mL) and methanol (975 mL) were charged into the hydrogenator and stirred for 5-10 min at 25- 30°C.
  • the resulting reaction mass was charged with 10% Pd/C (0.075 % w/w) at 25- 30°C and temperature of the reaction mass was raised to 35-40 °C.
  • the resulting reaction mass was stirred at the same temperature for 8-9 hrs.
  • the resulting reaction mass was cooled to 25-30°C and filtered through hyflo bed, washed with methylene chloride and methanol mixture. The filtrate thus obtained was distilled at below 50 °C. Thereafter the resulting precipitate was co-distilled with methanol twice (5 V).
  • the compound of formula-6 (90.0 g) and pyridine (360 mL) were charged into a flask and stirred for 10 min at 25-30°C.
  • the resulting reaction mass was charged with 4, 4-dimethyl-2-methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 (103.94 g, 1.5 eq.) and the reaction mass was maintained for 48 hrs at 25-30°C.
  • the reaction mass was charged with n-butanol (2.25 Lt) and temperature of the reaction mass was cooled to 0-5°C.
  • the resulting slurry was maintained for 3.5-4 hrs at the same temperature.
  • the precipitated- out product was filtered and washed with n-butanol, dried to get the crude compound (118.4 g).
  • the PXRD of Tucatinib compound of formula- 1 is illustrated in figure-3.
  • the compound of formula- 10 reaction mass was treated with DMF-DMA (560 g, 2.4 m. eq.) in isopropyl alcohol (720 mL) at 80-85 °C for about 3-4 hrs. After completion of reaction, the reaction mass was cooled and the reaction mass containing compound of formula- 11 was used directly in the next stage without further isolation at step-(b) stage.
  • DMF-DMA 560 g, 2.4 m. eq.
  • isopropyl alcohol 720 mL
  • the compound of formula- 12 (125.0 g) was treated with trifluoroacetic anhydride (136.6 g, 1.5 m. eq.) in methylene chloride (6.0 Lt) at 32-36 °C for about 4- 5 hrs. After completion of reaction, the reaction mass was cooled and treated with aq. Sodium carbonate and the methylene chloride was distilled off under vacuum at about 45 °C. After distillation, the reaction mass was cooled to 25-30 °C and maintained for
  • the compound of formula- 13 (70.0 g) was hydrogenated in the presence of -10% Pd/C (3.5 g) and hydrogen pressure in methanol (1050 mL) at 45-50 °C for about 8-9 hrs. After completion of reaction, the catalyst was filtered, and methanol was partially distilled under vacuum at below 50 °C. After distillation, the reaction mass was cooled to room temperature and treated with aq. Ammonia solution (750 mL) for

Abstract

La présente invention concerne un procédé de préparation d'un composé de (N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-méthylphényl)-N6-(4,4-diméthyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine de formule 1 et ses sels et polymorphes qui est représenté par la formule structurelle suivante.
PCT/IN2023/050071 2022-10-28 2023-01-23 Procédé amélioré pour la préparation de tucatinib et de son sel et de ses polymorphes WO2024089702A1 (fr)

Applications Claiming Priority (2)

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IN202241061499 2022-10-28
IN202241061499 2022-10-28

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WO2024089702A1 true WO2024089702A1 (fr) 2024-05-02

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