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WO2025074394A1 - Processus de préparation de belzutifan et de ses nouveaux intermédiaires - Google Patents

Processus de préparation de belzutifan et de ses nouveaux intermédiaires Download PDF

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Publication number
WO2025074394A1
WO2025074394A1 PCT/IN2024/051950 IN2024051950W WO2025074394A1 WO 2025074394 A1 WO2025074394 A1 WO 2025074394A1 IN 2024051950 W IN2024051950 W IN 2024051950W WO 2025074394 A1 WO2025074394 A1 WO 2025074394A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
reacting
solvent
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/IN2024/051950
Other languages
English (en)
Inventor
Srinivasa Krishna Murthy Konduri
Jagan Mohan Reddy Sanapureddy
Ravi Kumar Remella
Srinivasulu GANGANAMONI
Annpurna Phani Yatam
Madhu Naik Moode
Govinda Raju POTHABATHULA
Santhosh Kumar KOKKU
Vinod Kumar AMASA
Balakrishna Reddy SIRIGIREDDY
Sriram RAMPALLI
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
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.)
Natco Pharma Ltd
Original Assignee
Natco Pharma Ltd
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 Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2025074394A1 publication Critical patent/WO2025074394A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • Belzutifan was approved by U.S. Food and Drug Administration (FDA) in August, 2021 which is a hypoxia-inducible factor inhibitor indicated for treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
  • FDA Food and Drug Administration
  • the second aspect of the present invention is to provide novel intermediate compounds of Belzutifan and its process for the preparation.
  • FIG.3 Thermogravimetric analysis of crystalline form of Belzutifan.
  • in another preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-9, comprising of: a) reacting the compound of formula-7 with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in acetonitrile to provide the compound of formula- 8, b) treating the compound of formula-8 with hydrochloric acid in DM water to provide the compound of formula-9, purifying the compound in ethyl acetate to provide the pure compound of formula-9.
  • a preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula- 12, comprising of reacting the compound of formula- 11 with perfluoro- 1 -butanesulfonyl fluoride (PBSF) in presence of 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in 1 ,2-dimethoxy ethane (DME) to provide the compound of formula- 12, purifying the compound in ethyl acetate and n-Heptane followed by isopropyl alcohol to provide the pure compound of formula- 12.
  • PBSF perfluoro- 1 -butanesulfonyl fluoride
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • DME 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • a process for the preparation of crystalline form of Belzutifan of Formula- 1 comprising of: a) Adding acetonitrile to Belzutifan crude compound of Formula- 1 , b) heating and treating the reaction mixture with charcoal, c) adding a mixture of isopropyl alcohol & water to the reaction mass, d) cooling and stirring the reaction mixture, e) filtering, washing the obtained solid with mixture of acetonitrile & aqueous isopropyl alcohol and drying the compound to get the crystalline form of Belzutifan compound of formula- 1.
  • the 4-Fluoro-7-methylsulfonyl-indan-l-one compound of formula-2 and 3- bromo-5 -fluorophenol compound of formula-4 are prepared from the processes known in the art.
  • DM water 8800 mL
  • aq. ammonia -20% solution; 2200 mL
  • DM water 8800 mL
  • aq. ammonia -20% solution; 2200 mL
  • the above filtrate was added slowly at 10-15°C and then stirred for 4 hrs at 10-15°C.
  • EDTA disodium salt 9.2 g
  • DM water 1000 mL
  • the obtained wet product (-340 g) was added at 25-30°C and stirred for 1 hour and filtered and dried the wet product under vacuum at 55-60°C for 12-14hrs.

Landscapes

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

Abstract

La présente invention concerne un processus de préparation d'un composé 3-[[(1S,2S,3R)-2,3-difluoro-2,3-dihydro-1-hydroxy-7-(méthylsulfonyl)- H-indén-4-yl]oxy]-5-fluorobenzonitrile de formule-1, qui est représenté par la formule structurale ci-après.
PCT/IN2024/051950 2023-10-06 2024-10-04 Processus de préparation de belzutifan et de ses nouveaux intermédiaires Pending WO2025074394A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341067140 2023-10-06
IN202341067140 2023-10-06

Publications (1)

Publication Number Publication Date
WO2025074394A1 true WO2025074394A1 (fr) 2025-04-10

Family

ID=95284358

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2024/051950 Pending WO2025074394A1 (fr) 2023-10-06 2024-10-04 Processus de préparation de belzutifan et de ses nouveaux intermédiaires

Country Status (1)

Country Link
WO (1) WO2025074394A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220388974A1 (en) * 2021-05-21 2022-12-08 Merck Sharp & Dohme Llc Novel synthetic pathway to belzutifan and crystalline phases of synthetic intermediates
CN115611847A (zh) * 2022-10-13 2023-01-17 南方科技大学坪山生物医药研究院 一种Belzutifan的中间体的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220388974A1 (en) * 2021-05-21 2022-12-08 Merck Sharp & Dohme Llc Novel synthetic pathway to belzutifan and crystalline phases of synthetic intermediates
CN115611847A (zh) * 2022-10-13 2023-01-17 南方科技大学坪山生物医药研究院 一种Belzutifan的中间体的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LUISETTO M, AHMADABADI NILI B, KHAN FARHAN AHMAD, ETTARHOUNI ZAINEB OMAR, BENZI CIPELLI RIC- CARDO, YESVI AHMED, RASOOL MASHORI GU: "Activated Charcoal and Derivate Materials in Drugs and Biopharmaceutical Purification: Impurity Aspects", JOURNAL OF MATERIALS SCIENCE AND NANOTECHNOLOGY, vol. 11, no. 1, 26 August 2023 (2023-08-26), pages 1 - 31, XP093301793, ISSN: 2348-9812 *

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