WO2025217347A2 - Procédé de préparation de repotrectinib - Google Patents

Procédé de préparation de repotrectinib

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Publication number
WO2025217347A2
WO2025217347A2 PCT/US2025/023989 US2025023989W WO2025217347A2 WO 2025217347 A2 WO2025217347 A2 WO 2025217347A2 US 2025023989 W US2025023989 W US 2025023989W WO 2025217347 A2 WO2025217347 A2 WO 2025217347A2
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WO
WIPO (PCT)
Prior art keywords
compound
salt
give
reaction
range
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/US2025/023989
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English (en)
Other versions
WO2025217347A3 (fr
Inventor
Hester DANG
Adam Joseph Freitag
Bilal HOBLOS
Geoffrey Eugene PURDUM
Yichen TAN
Daniel S. Treitler
Jason Michael Stevens
Christopher Russell WILBERT
Troy Charles WILKENS
Steven R. WISNIEWSKI
Bin Zheng
Keming Zhu
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.)
Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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 Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of WO2025217347A2 publication Critical patent/WO2025217347A2/fr
Publication of WO2025217347A3 publication Critical patent/WO2025217347A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y206/00—Transferases transferring nitrogenous groups (2.6)
    • C12Y206/01—Transaminases (2.6.1)

Definitions

  • the present invention relates to methods for preparing the compound (75,13/?)- 11 -fluoro-7, 13 -dimethyl-6, 7, 13,14-tetrahy dro- 1,15- ethenopyrazolo[4, 3 - y][l,4,8,10]benzoxatriaza-cyclotridecin-4(5J7)-one and intermediates thereof.
  • the compound repotrectinib also known as (75,137?)-1 l-fhioro-7,13-dimethyl- 6,7,13,14-tetrahydro-l,15- ethenopyrazolo[4,3-/
  • the compound is also known as (3R,l lS)-6-Fluoro-3,l l-dimethyl-10-oxa- 2,13, 17,18,21-pentaazatetracyclo[13.5.2.0 4 ’ 9 .0 18 ’ 22 ]docosa-l(21),4,6,8,15(22),16,19- heptaen- 14-one (also herein referred to as "Compound I”) i s represented by F ormula ( I)
  • Compound (I) is a potent small-molecule multi-target kinase inhibitor showing activity against wild- type and mutant ALK (anaplastic lymphoma kinase), wild-type and mutant ROSI (ROSI proto- oncogene receptor tyrosine kinase), the TRK family of kinases (tropomyosin-related receptor tyrosine kinases), JAK2 of the Janus family of kinases, SRC (Src family of protein tyrosine kinases (SFKs)) and FAK (focal adhesion kinase).
  • ALK anaplastic lymphoma kinase
  • ROSI proto- oncogene receptor tyrosine kinase ROSI proto- oncogene receptor tyrosine kinase
  • TRK family of kinases tropomyosin-related receptor tyrosine kinases
  • JAK2 of the Janus
  • Compound (I) has properties, including anti-tumor properties, that are pharmacologically mediated through inhibition of tyrosine kinase receptors.
  • Compound (I) was disclosed in International Patent WO2015/112806 and in W02017/007759, which are incorporated herein by reference in its entirety.
  • Compound (I) has found application in treating disease associated with receptor tyrosine kinases, such as ALK, ROSI, TRK, JAK2, SRC and FAK. It is advantageous to have improved methods of preparation.
  • receptor tyrosine kinases such as ALK, ROSI, TRK, JAK2, SRC and FAK. It is advantageous to have improved methods of preparation.
  • the present invention provides methods of preparing the compound of formula (I), along with intermediates thereof.
  • the present invention also provides processes and intermediates for making the compounds of the present invention.
  • the present invention provides a process for making compound (D).
  • the present invention provides, a process for preparing a compound of formula (I): comprising the steps of:
  • the invention provides a process for preparing compound (D), or salt thereof comprising the steps of
  • a process for preparing a compound of formula (I), comprising treating compound (H) with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide either as a free base or as a hydrochloride salt
  • the asymmetric transamination (ATA) enzyme used in preparing compound (D) is SEQ ID 1.
  • the compound (D) can be prepared by using the transamination enzyme selected from, but not limited to, Codexis® ATA-025, Codexis® ATA-412, or Codexis® ATA-415. These enzymes are available from Codexis ® and are available from the ATA screening kit. The enzymes may be utilized in a powder form or in a solution form.
  • the peptide coupling reagent used in preparing the compound of Formula (I) is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide either as the free base or as the hydrochloride salt.
  • the compound (D) is formed and isolated as a salt.
  • the compound (D) is formed and isolated as a tartaric acid, dibenzoyl tartaric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, sulfuric acid, hydrobromic acid, or hydrochloric acid salt.
  • the compound (D) is formed and isolated as the D-tartaric acid salt.
  • compound (D) is the D-tartaric acid salt of compound (D).
  • the reaction of compound A and B to give compound C may be performed in the presence of a base such as CS2CO3, K3PO4, K2CO3, KOH, NaOH, KOt-Bu, DBU, DIPEA, or KHMDS; in another embodiment, the reaction is run in the presence of K3PO4.Gr KOH.
  • the reaction is run in an organic solvent such as acetonitrile, THF, toluene, DMF, or MTBE/water; in another embodiment, the reaction is run in acetonitrile.
  • the reaction may be run at approximately 20- 55 °C, in another embodiment, the reaction is run at room temperature.
  • reaction of compound (C) to form compound (D) may be performed using an asymmetric transamination enzyme (ATA).
  • ATA asymmetric transamination enzyme
  • An asymmetric transamination enzyme is an enzyme used to prepare chiral amines in high enantiomeric purity.
  • An asymmetric transamination enzyme can catalyze an asymmetric reductive amination of carbonyl compounds to generate chiral amines.
  • the reaction is typically performed in a buffer to maintain the pH at 6-10, in another embodiment the pH is 8, in another embodiment, the reaction is run in a 0.1 M PB buffer at pH of 8, in another embodiment, the reaction is run in a borate buffer having pH 9.5.
  • the reaction may be run at approximately 20-60 °C, in another embodiment, the reaction is run at approximately 55 °C .
  • ATA enzymes that may be used, including, but not limited to, Codexis® ATA-025, Codexis® ATA-412, or Codexis® ATA-415 or the ATA enzyme SEQ ID. 1.
  • the compound (D) (as a salt; alternatively as a tartaric acid, dibenzoyl tartaric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, sulfuric acid, hydrobromic acid, or hydrochloric acid salt; or alternatively, the compound (D) as the D-tartaric acid salt) may then be reacted with compound (E) (the synthesis of compound (E) has been previously described) in the presence or absence of an amine, such as DBU, TMG, DMAP, pyridine, NMM, or DIPEA; in another embodiment, the reaction is run in the presence of N,N- diisopropylethylamine.
  • an amine such as DBU, TMG, DMAP, pyridine, NMM, or DIPEA
  • the reaction is run in a solvent, such as IP A, Toluene, EtOH, MeOH, THF, or MeTHF, the reaction may be run with or without water present; in another embodiment, the reaction is run in isopropyl alcohol.
  • the reaction may be run at about 60-82 °C, in another embodiment the reaction is run at approximately 70 °C .
  • Compound (F) may used in the next step without further isolation from the reaction.
  • the compound (F) may be reacted in the solution from the above paragraph, or in a separate reaction using solvents such as IP A, toluene, EtOH, MeOH, THF, or MeTHF, with aqueous base, such as NaOH, LiOH, KOH, TMAOH, or TBAOH, in another embodiment the reaction is with NaOH.
  • solvents such as IP A, toluene, EtOH, MeOH, THF, or MeTHF
  • aqueous base such as NaOH, LiOH, KOH, TMAOH, or TBAOH
  • the reaction is with NaOH.
  • the reaction is run at a temperature of approximately 60-90 °C, in another embodiment, the reaction is run at a temperature of approximately 75 °C, to hydrolyze the ester group.
  • toluene is added after the reaction is complete to isolate compound (G) as a toluene solvate.
  • the compound (G) is reacted with an acid to give the unprotected amine, compound (H).
  • the acid is HC1, TFA, MSA, HBr, H2SO4, or pTSA, in solvents such as methanol, ethanol, IP A, water, MeTHF, TFE, TFA, AcOH, or MeCN, the solvents being used either alone or in combination with each other;
  • the acid is HC1 in ethanol, dioxane, or water and IP A, in another embodiment the acid is concentrated aqueous HC1 in acetonitrile.
  • the reaction may be run at about 0-50 °C, alternatively, about 20-50 °C, in another embodiment, the reaction is run at about 20 °C until complete.
  • Compound (H) may be isolated as the di-HCl salt, the di-HCl salt of compound (H) may be isolated in either the anhydrous or monohydrate forms.
  • the compound (H) is reacted with a peptide coupling reagent, such as, but not limited to, EDC, EDC/HOBt, HATU, TCFH, T3P, CDI, Vilsmeier reagent, or DPPC1; in another embodiment, the compound (H) is reacted with the peptide coupling reagent l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride; in another embodiment, the compound (H) is reacted with the peptide coupling reagent l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride in the presence of 1- hydroxybenzotriazole.
  • a peptide coupling reagent such as, but not limited to, EDC, EDC/HOBt, HATU, TCFH, T3P, CDI, Vilsmeier reagent, or DPPC1; in another embodiment, the compound (
  • the reaction may be run in a solvent such as THF, acetonitrile, DMF, NMP, DMAc, Water, Water+TPGS-750-M surfactant, EtOAc, alternatively, the solvent may be THF, or DMF, or a combination of these solvents.
  • the reaction is run in the presence of an amine, such as DIPEA, NMI, DBU, tert-butylTMG, NMM, pentamethylpiperidine, 2,6-lutidine, 1,4-dimethylpiperazine, or N,N- diisopropylethylamine; in another embodiment, the amine is A,A-diisopropylethylamine.
  • the reaction may be run at approximately -10 to 45 °C, in another embodiment, the reaction is run at approximately 2 °C.
  • Preparing the compound of Formula (I) from compound (H) using the present invention eliminates the use of pentafluorophenyl diphenylphosphinate (FDPP).
  • FDPP pentafluorophenyl diphenylphosphinate
  • the reagent FDPP is challenging to source and may not be readily available at all times, but the reagent l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is readily available.
  • the use of FDPP in this reaction produces byproducts which are challenging to remove from the final product. To remove these byproducts, a second crystallization is required. The elimination of the use of FDPP eliminates the need for the second crystallization.
  • the process of preparing compound (H) from compound (G) has the advantage that it produces a single form in a controlled way and via an alternate reaction / crystallization conditions.
  • the isolation of the single consistent form is not influenced by isolation or drying equipment and parameters, and it is amenable to different isolation technologies, e.g., centrifugation.
  • the process of preparing compound (D) produces the D-tartrate salt which is readily isolated.
  • the process of preparing compound (D) is 2 steps from compound (A), providing good overall yield, lower cycle time, and lower costs.
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • DIPEA 7V,7V-Diisopropylethylamine
  • DMAc dimethylacetamide
  • DMAP dimethylaminopyridine
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DPPC1 diphenylphosphinic chloride
  • EDAc or EDC l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • equiv equivalent(s)
  • EtOAc ethyl acetate
  • EtOH ethanol
  • HATU Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium
  • HC1 hydrogen chloride (usually as a solution)
  • HOBt Hydroxybenzotriazole
  • HPLC High Pressure Liquid Chromatography
  • NMI 1 -Methylimidazole
  • NMM A-Methylmorpholine
  • NMP n-methylpyrrolidine
  • PLP pyridoxal phosphate
  • pTSA p-toluenesulfonic acid
  • T3P Propanephosphonic acid anhydride
  • TBAOH Tetrabutylammonium hydroxide
  • tert-butylTMG 2-tert-Butyl-l,l,3,3-tetramethylguanidine
  • TPGS tocopheryl polyethylene glycol succinate
  • TMAOH tetramethylammonium hydroxide
  • HC1 solution (1.0 N, 76 mL) was slowly added at ⁇ 20 °C. The mixture was then warmed to 20 °C, and water (120 mL) was added to dissolve the solids. The biphasic mixture was aged until the sulfonic acid intermediate was consumed as determined by HPLC analysis. The aq. phase was then removed. Heptane (96 mL) was added into the organic phase, and the resulting solution was then washed with 4% aq. NaOH solution (72 mL x2) and 5% aq. KH2PO4 solution (24 mL), subsequently solvent exchanged to EtOH. The batch volume was adjusted to ca. 30 mL, and was then cooled to 0-5 °C.
  • the reaction was stirred vigorously for 30 min at 25 °C, then tert-butyl methyl ether (120 mL, 6 L/kg) [a range of 5.4-6.6 L/kg can be used] was added. The temperature was adjusted to 20 °C; the reaction was stirred 10 minand allowed to settle for 10 min. The aq layer was separated, and the organic layer was washed with 5 wt% aq. KOH (60 mL, 3L/kg) [a range of 2.7-3.3 L/kg can be used] twice. The aqueous layer was separated. The organic layer was washed with 5 wt% aq.
  • potassium dihydrogen phosphate 60 mL, 3 L/kg [a range of 2.7-3.3 L/kg can be used], and then the aq layer was separated.
  • the organic layer was stirred with activated carbon (Darco 100 mesh, 3.0 g, 3.0 equiv) for 15 min at 22 °C.
  • the mixture was filtered, and the filter cake was rinsed with 20 mL MTBE.
  • the filtrate was concentrated to a final volume of 60 mL (3 L/kg) at 280 mbar with jacket temp up to 50 °C.
  • the jacket temp was adjusted to -9 °C, and the reaction was seeded with seeds of compound D (200 mg) [a range of 0.9-1. lwt% can be used].
  • the mixture was aged for 20 min. Water (90 mL, 4.5 L/kg) [a range of 4.0-5.0 L/kg can be used] was stirred in dropwise over the course of ⁇ 30 min. The mixture was aged for 15 h at -2 °C.
  • the batch was filtered and the reactor and cake were rinsed with cold (0 °C) 2: 1 water: EtOH (60 mL, 3 L/kg) [a range of 2.7-3.3 L/kg can be used], then the cake was rinsed with water (60 mL, 3 L/kg) [a range of 2.7-3.3 L/kg can be used].
  • the solid was dried under vacuum with N2 purge for 48 h at 25 °C, affording 22.93 g (86.5% yield as-is) as a white powder.
  • Step 2 can be performed as follows.
  • a 0.1 M borate buffer pH 9.5 (125 mL, 25 vol), isopropylamine hydrochloride (15.4g, 10 equiv), PLP (0.5g, 10 wt%) and ATA enzyme having SEQ ID NO1 (0.5 g, 10 wt%) were charged into the reactor and dissolved by stirring.
  • Compound (C) (5.0 g, LR) was dissolved in DMSO (25 mL, 5 vol), and the solution was added to the enzyme solution. Note: precipitation formation was observed due to poor solubility of compound C in aq buffer.
  • the reaction mixture was stirred at 45 °C for 48 hours with continuous N2 bubbling.
  • Step 2 can be performed as follows:
  • Triethanolamine hydrochloride (0.6 g) and pyridoxyl-L-phosphate (8.0 mg) were dissolved in 20 mL of water. To this solution was added isopropylamine (2.5 mL) or isopropylamine hydrochloride (2.9 g), and the pH was adjusted to pH 8.0 using 5 M NaOH or HC1 (Solution A).
  • Compound C 150 mg was dissolved in DMSO (3 mL).
  • Solution A 450ul
  • Solution of Compound (C) (50ul) was added to each vial of ATA enzyme. The vials were sealed and agitated at 600 RPM at 30 °C for 18 hours.
  • Compound (C) was prepared using this process and the ATA enzymes Codexis® ATA-025, Codexis® ATA-412, or Codexis® ATA-415. Yields of compound C was 2-
  • N,N-Diisopropylethylamine (DIPEA; 2.5 equiv.; 236 mL; 175 g) was added [a range of 2.25-2.75 equiv DIPEA can be charged], followed by IPA (0.25 L/kg; 62.5 mL; 49.1 g) as a rinse.
  • Compound (E) (1.10 equiv.; 134.2 g) [a range of 1.03-1.21 equiv E can be charged] was then added, and IPA (0.75 L/kg; 188 mL; 147 g) was again added as a rinse.
  • the subsequent slurry was warmed to 70 °C for 12 hours (a range of 60-79 °C, with longer reaction times needed for lower temperature).
  • the reaction was cooled to 40 °C and sampled for conversion to compound (F) as judged by UPLC.
  • Compound (F) was then directly transformed without isolation.
  • To the reaction was added 25 wt% aqueous NaOH (10.0 equiv.; 679 mL; 865 g) [a range of 2.43-2.97 L/kg of 25 wt% aqeous NaOHcan be charged] and the biphasic solution was then warmed to 70 °C for 12 hours (a range of 65-79 °C, with longer reaction times needed for lower temperature).
  • the organic phase was then iteratively washed with 20 wt% aqueous NaCl (7.0 L/kg; 1750 mL; 2010 g) [a range of 6.3-7.7 L/kg can be charged] followed by 20 wt% aqueous citric acid (3.0 L/kg; 750 mL; 814 g) [a range of 2.7-3.3 L/kg 20 wt% aqueous citric acid can be charged].
  • Toluene (10.0 L/kg; 2500 mL; 2180 g) [a range of 9-11 L/kg toluene can be charged] and water (1.0 L/kg; 250 mL; 250 g) [a range of 0.9-1.1 L/kg water can be charged] were then added, and the biphasic mixture was stirred for 30 minutes. After discarding the aqueous layer, the solution was distilled under reduced pressure (100-300 mBar) to a residual volume of 5.95-8.05 L/kg (end point: 1750 mL). At 50 °C (range of 45-60 °C), the solution was then seeded with 1.0 wt% (a range of 0.25 - 2.15 wt% seeds can be charged) compound (G). Following the addition of toluene (8 L/kg; 2000 mL;
  • the resultant slurry was cooled to -5 °C, and N,N-diisopropylethylamine (8.5 mL, 48.4 mmol, 2.25 equiv) [a range of 2.02-2.48 equiv DIPEA can be charged] was added, followed by compound (H) (10.0 g, 21.5 mmol, limiting reagent).
  • the resultant mixture was aged for 24 h at an internal temperature of 3 °C (range of -10 to 30 °C, with longer reaction times needed for lower temperature).
  • Additional water 80 mL, 8 L/kg [a range of 7-9 L/kg water can be charged] was charged slowly over the course of 2 h, followed by 2 h of additional age at 35 °C. The slurry was cooled to 20 °C over the course of 2 h, aged for 16 h more, then filtered.

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Abstract

L'invention concerne un procédé de préparation de repotrectinib, un composé de formule (I) et un procédé de préparation d'un composé (D). Formule (I) et formule (D).
PCT/US2025/023989 2024-04-11 2025-04-10 Procédé de préparation de repotrectinib Pending WO2025217347A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463632580P 2024-04-11 2024-04-11
US63/632,580 2024-04-11

Publications (2)

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WO2025217347A2 true WO2025217347A2 (fr) 2025-10-16
WO2025217347A3 WO2025217347A3 (fr) 2025-11-20

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015112806A2 (fr) 2014-01-24 2015-07-30 Tp Therapeutics, Inc. Macrocycles de diaryle en tant que modulateurs de protéines kinases
WO2017007759A1 (fr) 2015-07-06 2017-01-12 Tp Therapeutics, Inc. Polymorphe de macrocycle de diaryle

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT3733187T (lt) * 2015-07-21 2024-12-10 Turning Point Therapeutics, Inc. Chiralinis diarilo makrociklas ir jo panaudojimas vėžio gydymui
WO2021027503A1 (fr) * 2019-08-12 2021-02-18 罗欣药业(上海)有限公司 Composé tricyclique, procédé de préparation, intermédiaire et utilisation associés
CN114763360A (zh) * 2021-01-15 2022-07-19 广州百霆医药科技有限公司 手性大环化合物作为蛋白激酶抑制剂及其用途
CN113336774B (zh) * 2021-06-25 2023-05-23 江南大学 作为trk抑制剂的取代的手性二芳基大环化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015112806A2 (fr) 2014-01-24 2015-07-30 Tp Therapeutics, Inc. Macrocycles de diaryle en tant que modulateurs de protéines kinases
WO2017007759A1 (fr) 2015-07-06 2017-01-12 Tp Therapeutics, Inc. Polymorphe de macrocycle de diaryle

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