EP4298100A1 - Procédé d'obtention d'avapritinib et de ses intermédiaires - Google Patents

Procédé d'obtention d'avapritinib et de ses intermédiaires

Info

Publication number
EP4298100A1
EP4298100A1 EP22759019.7A EP22759019A EP4298100A1 EP 4298100 A1 EP4298100 A1 EP 4298100A1 EP 22759019 A EP22759019 A EP 22759019A EP 4298100 A1 EP4298100 A1 EP 4298100A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
reacted
iii
avapritinib
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
EP22759019.7A
Other languages
German (de)
English (en)
Inventor
Márta PORCS-MAKKAY
Ferenc Bertha
Enik MOLNÁR
Gábor NÉMETH
Simon HORVÁTH
Ildikó SZEBELÉDI
Beatrix BALI
Mónika TELLÉR
Katalin KÁTAINÉ FADGYAS
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.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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 Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP4298100A1 publication Critical patent/EP4298100A1/fr
Pending legal-status Critical Current

Links

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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
    • F24F5/00—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater
    • F24F5/0007—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning
    • F24F5/0017—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
    • F24F5/00—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater
    • F24F5/0007—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning
    • F24F5/0017—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice
    • F24F2005/0025—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice using heat exchange fluid storage tanks
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
    • F24F2221/00—Details or features not otherwise provided for
    • F24F2221/54—Heating and cooling, simultaneously or alternatively

Definitions

  • the present invention relates to process for obtaining avapritinib(l) and its intermediates.
  • GIST gastrointestinal stromal tumors
  • WO201 5058129 and W02020210293 disclose the synthesis of the compounds of the Formula (VI) and (V) which compounds contain the structural elements of avapritinib.
  • An alternative synthesis of avapritinib(l) is disclosed in the patent application No. CN1 10938077. The process according to the application does not require the separation on a chiral column, in contrast to that disclosed in the basic patent (WO 2015057873).
  • the compound of the Formula (VI) is resolved with L-dibenzoyltartaric acid (L-DBTA), and then the salt thus obtained [(ll) * L-DBTA] is reacted with the compound of the Formula (X) also disclosed in the basic patent (WO 2015057873).
  • L-dibenzoyl tartrate salt of avapritinib [(l) * L-DBTA] is formed, from which avapritinib (I) is released.
  • the Compound of the Formula (VI) was added to ethanol/water/acetic acid mixed solution (preparation method: mixing ethanol, water, Acetic acid was mixed according to the volume ratio of 7:3:1), heated to 70 ° C, and then kept at 70 ° C and added dropwise 1.2 eq. L-DBTA and ethanol/water/acetic acid (volume ratio 7:3: 1 ), the resulting solution was stirred at 70°C for 16 hours, then cooled to room temperature. However, no solids could be collected after cooling to room temperature. There was no crystallization even after stirring at lower temperature 0-5 °C or storing in freezer.
  • the patent application No. CN110950872 discloses another possible synthesis of avapritinib (I).
  • the starting material for the process is S-1-(4-fluorophenyl)-1-[2- (piperazin-1-yl)pyrimidin-5-yl]ethan-1 -amine (the compound of the Formula (II), which is the S enantiomer of the compound of the Formula (VI)).
  • the primary amino group of the starting material is protected with a tert- butyloxycarbonyl group (hereinafter Boc).
  • W0202021 0669 discloses a process for the manufacture of avapritinib which does not require a column chromatography process.
  • the diastereomeric mixture of the compound of the Formula (V) already known is prepared in a reaction medium from which mainly the S, S-diastereomer of the compound of the Formula (V) is precipitated, and the diastereomeric purity of the latter is increased by recrystallization from heptane-methanol.
  • the intermediate thus obtained is reacted with hydrochloric acid to simultaneously remove the two protecting groups to give the intermediate salt (ll * 3,5HCI). This is reacted with the compound of the Formula (X) to get the final avapritinib (I) product.
  • the present invention provides a novel process for the preparation of avapritinib (I) via the novel key intermediate the compound of the Formula (IV).
  • Another aspect of the invention is the compound of the Formula (IV).
  • the key intermediate, the compound of Formula (IV) is prepared by selectively introducing a Boc protecting group from the compound of Formula (VI) known in the literature or by removing the t-butylsulfinyl group from the compound of the Formula (V) also known in the literature (Scheme 1.).
  • Another object of the present invention is to provide a process for the preparation of avapritinib (I) via the novel intermediate the compound of the Formula (III).
  • a further object of the present invention is the compound of Formula (III), which is a diastereomeric salt of the S enantiomer of the compound of Formula (IV) with the compound of Formula (IX) wherein the meaning of R in Formula (IX) is FI or o-, m- or p- methyl group, and a process for obtaining the compound of the Formula (III), wherein the compound of Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) in which the meaning of R is FI or methyl in the o-, m- or p-position].
  • Another object of the present invention is a process for obtaining avapritinib (I) by converting the compound of the Formula (III) to avapritinib (I) in a one-pot process after removal of the resolving acid (Formula (IX)) and the Boc protecting group by reaction with the compound of Formula (X).
  • Another object of the present invention is a process for obtaining avapritinib (I) by 85 releasing the compound of Formula S-(IV) from the compound of Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removing the protecting group Boc in a one-pot process.
  • Another object of the present invention is a process for obtaining avapritinib (I) by 90 removing the resolving acid (Formula (IX)) and the Boc protecting group from the compound of the Formula (III) in a one-pot process, and then reacting the arising trihydrochloride monohydrate of the compound of Formula (II) (ll * 3HCI * H20) with the compound of Formula (X). Concentrated hydrochloric acid is used to remove the Formula (IX) and Boc, thereby a new, unknown form of the compound of Formula (II), 95 trihydrochloride monohydrate of Formula II (I l * 3HCI * H20) is obtained.
  • the present invention provides a novel process for the preparation of avapritinib (I) via loo the novel key intermediate of the compound of the Formula (IV).
  • the present invention further provides the compound of Formula (IV) and a process for obtaining the compound of the Formula (IV) as shown in Scheme 1.
  • the compound of the Formula (IV) can be prepared by two methods, from the starting material of compound (V) or (VI).
  • the compound of Formula (IV) is prepared by reacting a solution of the compound of the Formula (V) in an organic solvent with 1 to 6 equivalents, preferably 1 .5 to 2 equivalents of a strong acid, in which reaction the t-butylsulfinyl group can be selectively removed.
  • the compound of the Formula (V) is dissolved in an organic solvent, preferably THF, and then excess strong acid is added dropwise, preferably 1.5-2 equivalents of concentrated hydrochloric acid.
  • the reaction mixture is adjusted to an alkaline pH, the precipitated crystals are washed with water and, optionally, recrystallized from a C1 -C4 aliphatic alcohol, preferably ethanol, to obtain the compound of the Formula (IV).
  • a C1 -C4 aliphatic alcohol preferably ethanol
  • an organic solvent preferably THF
  • a base for example NaFIC03
  • the reaction mixture is cooled to 0-5 0 C and then a solution of di-tert-butyl dicarbonate in an organic solvent, preferably THF, is added dropwise. It is stirred for one hour at room temperature, then after addition of water it is stirred for additional half hour at 0-5 0 C. After the precipitated crystals are filtered off and washed with water, the compound of the Formula (IV) is obtained.
  • An object of the present invention is to provide a process for the preparation of avapritinib (I) via the new intermediate, the compound of the Formula (III).
  • An object of the present invention is the compound of the Formula (III) which is a diastereomeric salt of the compound of the Formula S-(IV) with compound (IX), wherein R means FI or methyl in the 0-, m- or p- position.
  • Another object of the present invention is a process for obtaining the compound of the Formula (III), wherein the compound of the Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) wherein R in the Formula (IX) means FI or methyl group in the 0-, m- or p-position] (Scheme 2.).
  • the compound of the Formula (IX) is preferably D-di-benzoyltartaric acid [(2S,3S)-2,3-bis(benzoyloxy)butanedioic acid (IXa)], or, more preferably D-di- toluyltartaric acid [(2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedicarboxylic acid (IXb)].
  • the resulting compound of the Formula (III) is preferably (2S,3S)-2,3-bis (benzoyloxy) butanedioic acid tert-butyl 4- ⁇ 5-[(1S)-1 -amino-1 -(4-fluorophenyl)ethyl]pyrimidine-2- yl ⁇ piperazine-1-carboxylate salt (1 :1) (Ilia), or, more preferably (2S,3S)-2,3-bis(4- methylbenzoyloxy) butanedioic acid tert-butyl4- ⁇ 5-[(1S))-1 -amino-1 -(4- fluorophenyl)ethyl]pyrimidin-2-yl ⁇ piperazine-1-carboxylate salt (1 : 1) (lllb).
  • the compound of the Formula (IV) is suspended in a C1- C4 aliphatic alcohol, preferably ethanol, and heated to reflux, and a solution of the compound of Formula (IX) in a C1- C4 aliphatic alcohol, preferably ethanol, is added and stirred at room temperature for 24 hours.
  • a solution of the compound of Formula (IX) in a C1- C4 aliphatic alcohol, preferably ethanol is added and stirred at room temperature for 24 hours.
  • the precipitated crystals of the compound of the Formula (III) are filtered off, washed with a C1-C4 aliphatic alcohol, preferably ethanol, and then recrystallized from ethanol / C1-C4 aliphatic alcohol.
  • the preparation of the compound of the Formula (III) is of key importance, since by the reaction of Scheme 2., the S enantiomer of the compound of the Formula (IV) (S-(IV)) can be separated selectively and on an industrial scale via the compound of the Formula (III), so that avapritinib (I) can be produced without the use of a chromatographic purification step. As a result of the reaction shown in Scheme 2., the S:R ratio of the resulting compound of the Formula (III) is at least 98:2.
  • Avapritinib (I) may be prepared from the compound of Formula (III) in three alternative ways according to the present invention.
  • the compound of the Formula (III) is reacted with the compound of the Formula (X) after removal of the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process.
  • the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid.
  • a base preferably N, N-diisopropylethylamine (DIPEA) is added dropwise to the organic phase, and then compound of the Formula (X) is added.
  • DIPEA N-diisopropylethylamine
  • the reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaHCC>3 solution is added.
  • the phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated.
  • the residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off.
  • the crude final product may be purified by recrystallization.
  • avapritinib (I) may be prepared by setting free the Formula S-(IV) from the compound of the Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removal of the Boc protecting group in a one-pot process.
  • the compound of Formula (III) is stirred in a mixture of a water-immiscible organic solvent and water, preferably dichloromethane and water, until dissolved at room temperature and then the mixture is made alkaline.
  • the aqueous phase is extracted with a water- immiscible organic solvent, preferably dichloromethane, and the combined organic phases are washed, dried and then concentrated in vacuum.
  • the residue is dissolved in an organic solvent, preferably TFIF or ethyl acetate, more preferably TFIF, at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid.
  • a strong acid is added dropwise, preferably concentrated hydrochloric acid.
  • the reaction mixture is stirred for 1 - 24 hours, then water is added, and the mixture is made alkaline.
  • the phases are separated, a base, preferably DIPEA, is added dropwise to the organic phase, then the compound of the Formula (X) is added.
  • the reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaFIC03 solution is added.
  • the phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated. The residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off.
  • the crude final product may be purified by recrystallization.
  • a third method of preparing avapritinib (I) from the compound of the Formula (III) is to remove the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process; isolating the arising compound: trihydrochloride monohydrate of the compound of the Formula (II) (ll * 3HCI * H20) which is a new salt of the compound of the Formula (II), and then converting the said compound to avapritinib (I) by reaction with the compound of the Formula (X).
  • the compound of the Formula (III) is reacted with a mixture of concentrated hydrochloric acid and an organic solvent to obtain the compound of the Formula (N * 3FICrFl20).
  • the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid, preferable concentrated hydrochloric acid is added dropwise. After stirring the reaction mixture for 1 -24 hours, the precipitated crystals are filtered and after washing with water, the compound of the Formula (M * 3FICI * Fl20) can be collected. Then, by reacting the compound of the Formula (I l * 3HCI * H20) and the compound of the Formula (X), avapritinib (I) is obtained as the final product in the reaction shown in Scheme 4.
  • an organic solvent preferably TFIF at room temperature
  • a strong acid preferable concentrated hydrochloric acid
  • the previously collected salt of the compound of the Formula (II) is suspended in a C1-C4 aliphatic alcohol, preferably ethanol, and then a base, preferably a tertiary amine, more preferably DIPEA, is added dropwise.
  • a base preferably a tertiary amine, more preferably DIPEA
  • the compound of the Formula (X) is added while stirring, and after stirring for 2.5 hours, water is added. After stirring for an additional 1 hour, the precipitated crystalline avapritinib (I) is filtered and washed with water.
  • the crude final product can be purified by recrystallization.
  • the crude product is recrystallized from ethanol.
  • Example 2 Preparation of tert-Butyl 4-15-H -amino-1 -(4-fluorophenyl)ethyllpyrimidin-2- yl)piperazine-1 -carboxylate (IV) with Method B: 5.0 g (16.59 mmol) of 1 - (4-fluorophenyl)-1 -[2- (piperazin-1 -yl) pyrimidin-5-yl] ethan-1 - amine (VI) is dissolved in 32.5 ml of THF with stirring, then 1.53 g (18.25 mmol) of NaHC03 dissolved in 16 ml of water is added.
  • the reaction mixture is cooled to 0-5 ° C and a solution of di-tert-butyl-dicarbonate (3.62 g, 16.59 mmol) in THF (12 ml) is added dropwise. After stirring for 1 hour at room temperature, 50 ml of water is added and the mixture is stirred for further 30 minutes at 0-5 ° C. The precipitated crystals are filtrated and washed with water to obtain 5.76 g (86.5%) of white crystals.
  • Example 9 Preparation of Avapritinib (I) with the 3. method: 1.05 g (2.45 mmol) of (1S)-1 -(4-fluorophenyl)-1 -[2- (piperazin-1 -yl)pyrimidin-5- yl]ethan-1 -amine trihydrochloride-hydrate (ll * 3HCI * H20) is suspended in 9.1 ml of ethanol with vigorous stirring at room temperature, then 1.7 ml (1.29 g; 10.0 mmol) of DIPEA is added dropwise, stirred until complete dissolution, and 0.57 g (2.45 mmol) of 4- ⁇ 4-chloropyrrolo [2,1 -f] [1 ,2, 4]triazin-6-yl ⁇ -1 -methyl-1 H-pyrazole (X) is added with stirring.
  • the Compound (X) gradually dissolves and meantime the product begins to precipitate.
  • the reaction mixture is stirred at room temperature for 2.5 hours, then water (13 ml) is added, and the mixture is stirred for an additional 1 hour.
  • the crystals are filtered off and washed with water to obtain 1 .13 g (92.6%) of crude product which is recrystallized from acetonitrile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Sustainable Development (AREA)
  • Combustion & Propulsion (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un procédé d'obtention d'avapritinib de formule (I) et de ses intermédiaires. L'avapritinib est utilisé pour le traitement de tumeurs stromales gastro-intestinales (GIST) et pour des tumeurs de l'estomac et des intestins.
EP22759019.7A 2021-02-26 2022-02-28 Procédé d'obtention d'avapritinib et de ses intermédiaires Pending EP4298100A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP2100077A HU231413B1 (hu) 2021-02-26 2021-02-26 Eljárás avapritinib és intermedierek előállítására
PCT/HU2022/050019 WO2022180416A1 (fr) 2021-02-26 2022-02-28 Procédé d'obtention d'avapritinib et de ses intermédiaires

Publications (1)

Publication Number Publication Date
EP4298100A1 true EP4298100A1 (fr) 2024-01-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP22759019.7A Pending EP4298100A1 (fr) 2021-02-26 2022-02-28 Procédé d'obtention d'avapritinib et de ses intermédiaires

Country Status (3)

Country Link
EP (1) EP4298100A1 (fr)
HU (1) HU231413B1 (fr)
WO (1) WO2022180416A1 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2706235C2 (ru) * 2013-10-17 2019-11-15 Блюпринт Медсинс Корпорейшн Композиции, пригодные для лечения расстройств, связанных с kit
DK3856341T3 (da) * 2019-04-12 2023-12-04 Blueprint Medicines Corp Krystallinske former af (s)-1-(4-fluorphenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amin og fremgangsmåder til fremstilling deraf
CN110938077B (zh) * 2019-12-25 2021-04-27 武汉九州钰民医药科技有限公司 合成Avapritinib的方法
CN110950872A (zh) * 2019-12-25 2020-04-03 武汉九州钰民医药科技有限公司 制备靶向抗癌药avapritinib的方法

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Publication number Publication date
HUP2100077A1 (hu) 2022-08-28
WO2022180416A1 (fr) 2022-09-01
HU231413B1 (hu) 2023-08-28

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