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WO2024126771A1 - Procédé de préparation de (z)-3-(2-(5-bromo-1h-indol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile - Google Patents

Procédé de préparation de (z)-3-(2-(5-bromo-1h-indol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile Download PDF

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Publication number
WO2024126771A1
WO2024126771A1 PCT/EP2023/086010 EP2023086010W WO2024126771A1 WO 2024126771 A1 WO2024126771 A1 WO 2024126771A1 EP 2023086010 W EP2023086010 W EP 2023086010W WO 2024126771 A1 WO2024126771 A1 WO 2024126771A1
Authority
WO
WIPO (PCT)
Prior art keywords
bromo
methoxybenzonitrile
indol
indole
formyl
Prior art date
Application number
PCT/EP2023/086010
Other languages
English (en)
Inventor
Cécile BOUGERET
Daniel John FINNEMORE
Craig Aaron FISHER
Mahesh Jayantilal SANGANEE
Original Assignee
Evexta Bio
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 Evexta Bio filed Critical Evexta Bio
Publication of WO2024126771A1 publication Critical patent/WO2024126771A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom

Definitions

  • the present invention relates to the field of synthesis in organic and medicinal chemistry. More particularly, the present invention provides an improved process for preparing an anticancer agent, namely (Z)-3-(2-(5-bromo- lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile.
  • Kinesins are a superfamily of motor proteins that have ATP enzyme activity. They are involved in the normal biological activities of various cells, including mitosis, meiosis, and intracellular vesicle transport. Kinesin family member 20A (KIF20A, also known as MKlp2) is located on chromosome 5q31.2 and plays an important role in the occurrence and development of tumors. Recently, several studies have demonstrated that KIF20A may play an important role in the development and progression of many different types of cancer, such as melanoma, breast cancer, nasopharyngeal cancer, pancreatic cancer, hepatocellular carcinoma, lung cancer, and colorectal cancer.
  • WO 2014/086964 focusses on (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2- cyanovinyl)-4-methoxybenzonitrile (Example 38 of WO 2014/086964), for which it has been evaluated an efficient antitumor activity at a nanomolar efficiency on various human cancer cells, demonstrating thereby a strong interest to use this lead compound for treating a large panel of cancer including for instance acute myeloid leukemia, lymphoma, breast cancer, pancreatic cancer, lung cancer and colon cancer.
  • the inventors have developed new reactive conditions for preparing (Z)-3-(2- (5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile starting from tert-butyl 5- bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl-4-methoxybenzonitrile.
  • the inventors have shown that the replacement of sodium hydride dispersion with a more process-friendly reagent, namely sodium ethoxide solution, allows to obtain (Z)-
  • the present invention thus relates to a process for preparing (Z)-3-(2-(5-bromo- lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile comprising the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl-
  • sodium ethoxide solution is a sodium ethoxide/ethanol solution, preferably at a concentration of 21% w/w.
  • the step a) is reacted at a temperature ranging from 25 to 60 °C, preferably from 40 to 45 °C.
  • the step a) is reacted for a period from 1 to 3 hours, preferably about 2 hours.
  • the step a) is reacted at a temperature ranging from 40 to 45 °C for a period of about 2 hours.
  • sodium ethoxide solution, tert-butyl 5-bromo-3- (cyanomethyl)-lH-indole-l -carboxylate, and 3-formyl-4-methoxybenzonitrile are used at step a) in stoichiometric amount.
  • the step b) comprises the following steps: bl) adding water to mixture of step a), b2) filtering the mixture, then washing and drying the crude material, b3) optionally purifying the crude material with a MEK solution, and b4) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4- methoxybenzonitrile .
  • (Z)-3-(2-(5-bromo- lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (compound (6)) having the following formula: is an effective inhibitor of kinesin family member 20A (KIF20A, also known as MKlp2) , which can be used as a drug for treating, for instance, diseases or pathologies associated with dysregulation of KIF20A or its pathway, such as cancer.
  • KIF20A kinesin family member 20A
  • MKlp2 kinesin family member 20A
  • the present invention provides a simple and safe process for preparing this compound with a high yield and a high purity, starting from tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l- carboxylate and 3-formyl-4-methoxybenzonitrile, with sodium ethoxide solution.
  • the present invention relates to a process for preparing (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2- cyanovinyl)-4-methoxybenzonitrile comprising the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl- 4-methoxybenzonitrile with sodium ethoxide solution; and b) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile.
  • Sodium ethoxide also called sodium ethylate or sodium ethanolate, (CAS Number: 141-52-6) having the formula C2HsONa is a strong base, which can be dissolved in polar solvents such as methanol or ethanol.
  • sodium ethoxide is dissolved in ethanol to form sodium ethoxide/ethanol solution, preferably at a concentration of 21% w/w. It is understood that the sodium ethoxide/ethanol solution can be easily prepared by a skilled person or commercially purchased.
  • the step a) is reacted at a temperature ranging from 25 to 60 °C, from 30 to 55 °C, from 35 to 50 °C, preferably from 40 to 45 °C.
  • the step a) is reacted for a period from 1 to 3 hours, from 1.5 to 2.5 hours, preferably for a period of about 2 hours.
  • the term “about” will be understood by these skilled in the art and can vary to a certain extent according to the context in which it used. If some uses of this term are not clear for those skilled in the art depending on the context, “about” means plus or minus 30%, 20%, preferably plus or minus 10%, more preferably plus or minus 5% of the specific term.
  • the invention relates to a process for preparing (Z)-3-(2-(5-bromo- lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile comprising the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl- 4-methoxybenzonitrile with sodium ethoxide/ethanol solution at a temperature ranging from 40 to 45 °C for a period of about 2 hours; and b) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile.
  • sodium ethoxide solution, tert-butyl 5-bromo-3- (cyanomethyl)-lH-indole-l -carboxylate, and 3-formyl-4-methoxybenzonitrile at step a) are used in stoichiometric amounts.
  • each of sodium ethoxide/ethanol solution, tert-butyl 5-bromo-3- (cyanomethyl)-lH-indole-l -carboxylate and 3 -formyl-4- methoxybenzonitrile is used at 1.00- 1.05 equivalents relative to the others.
  • 1.00 equivalent of tert-butyl 5-bromo-3- (cyanomethyl)-lH-indole-l -carboxylate, 1.00 equivalent of sodium ethoxide/ethanol solution, and 1.02 equivalents of 3-formyl-4-methoxybenzonitrile are used in the step a) as defined herein.
  • Step b) of the process of the invention relating to the recovering of (Z)-3-(2-(5-bromo-lH- indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile can be easily performed by a skilled person including non-exhaustive steps of quenching, filtering, washing, purifying and drying steps.
  • step b) of the process of the invention may further comprise the following steps: bl) adding water to mixture of step a), b2) filtering the mixture, then washing and drying the crude material, b3) optionally purifying the crude material with a MEK solution, and b4) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4- methoxybenzonitrile .
  • the process of the invention comprises the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl- 4-methoxybenzonitrile with sodium ethoxide/ethanol solution; and bl) adding water to mixture of step a), b2) filtering the mixture, then washing and drying the crude material, b3) optionally purifying the crude material with a MEK solution, and b4) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4- methoxybenzonitrile .
  • the process of the invention comprises the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl- 4-methoxybenzonitrile wit sodium ethoxide/ethanol solution, at a temperature ranging from 40 to 45 °C for a period of about 2 hours; and bl) adding water to mixture of step a), b2) filtering the mixture, then washing and drying the crude material, b3) optionally purifying the crude material with a MEK solution, and b4) recovering (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4- methoxybenzonitrile .
  • tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l -carboxylate and 3-formyl- 4-methoxybenzonitrile can be prepared by a skilled person thanks to any known methods of synthesis including any chemical synthesis currently used in organic chemistry. These starting materials can even be commercially purchased (tert-butyl 5-bromo-3-(cyanomethyl)-lH- indole-1 -carboxylate, CAS Number: 1419874-03-5; and 3-formyl-4-methoxybenzonitrile, (CAS Number: 21962-53-8).
  • tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate and 3-formyl-4- methoxybenzonitrile can be prepared by procedures of synthesis disclosed by WO 2014/086964.
  • tert-butyl 5-bromo-3-(cyanomethyl)-lH-indole-l-carboxylate is prepared by a process comprising the following steps of:
  • 3-formyl-4-methoxybenzonitrile is prepared by a process comprising the following steps of:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile comprenant la mise en réaction de tert-butyl-5-bromo-3-(cyanométhyl)-1H-indole-1-carboxylate, de 3-formyl-4-méthoxybenzonitrile et d'une solution d'éthoxyde de sodium.
PCT/EP2023/086010 2022-12-16 2023-12-15 Procédé de préparation de (z)-3-(2-(5-bromo-1h-indol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile WO2024126771A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22306921 2022-12-16
EP22306921.2 2022-12-16

Publications (1)

Publication Number Publication Date
WO2024126771A1 true WO2024126771A1 (fr) 2024-06-20

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WO (1) WO2024126771A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014086964A1 (fr) 2012-12-07 2014-06-12 Biokinesis Nouveaux dérivés d'indole utiles dans le traitement du cancer, des infections virales et des maladies pulmonaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014086964A1 (fr) 2012-12-07 2014-06-12 Biokinesis Nouveaux dérivés d'indole utiles dans le traitement du cancer, des infections virales et des maladies pulmonaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
no. 1419874-03-5

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