EP2611803A1 - Procédé de fabrication de 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile - Google Patents

Procédé de fabrication de 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile

Info

Publication number
EP2611803A1
EP2611803A1 EP11757221.4A EP11757221A EP2611803A1 EP 2611803 A1 EP2611803 A1 EP 2611803A1 EP 11757221 A EP11757221 A EP 11757221A EP 2611803 A1 EP2611803 A1 EP 2611803A1
Authority
EP
European Patent Office
Prior art keywords
formula
salts
pyridine
pyrazolo
fluoro
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.)
Withdrawn
Application number
EP11757221.4A
Other languages
German (de)
English (en)
Inventor
Markus Follmann
Jens Ackerstaff
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.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
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 Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP2611803A1 publication Critical patent/EP2611803A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a process for the preparation of 5-fluoro-lH-pyrazolo [3,4-b] pyridine-3-carbonitrile of the formula (I)
  • WO 2009/018415 describes the synthesis of 5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine.
  • nicotinic acid A By selective dechlorination of nicotinic acid A to compound B, subsequent conversion into the amide C, its reduction to nitrile and the final cyclization with hydrazine hydrate, the 5-fluoro-lH-pyrazolo [3,4-b] pyridine core is built up.
  • the following Scheme 1 illustrates the synthesis.
  • the object of the present invention is to provide an efficient process with high yield for the preparation of 5-fluoro-lH-pyrazolo [3,4-b] pyridine-3-carbonitrile of the formula (I)
  • T 1 is (C 1 -C 4 ) -alkyl
  • the compound of the formula (II) is known from the literature and can be prepared in analogy to Example 20A in WO 00/06569.
  • the cyclization of the 5-aminopyrazole derivative of the compound ( ⁇ ) with the aldehyde of the compound ( ⁇ ) to the compound of the formula (IV) is carried out in an inert solvent optionally in the presence of trifluoroacetic acid in a temperature range from + 50 ° C to + 200 ° C, preferably at + 80 ° C to + 140 ° C, at atmospheric pressure, within for example 10 to 80 hours, preferably within 48 to 72 hours.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or Petroleum fractions or other solvents acetonitrile or N, N-dimethylformamide, or mixtures of solvents. Dioxane is preferred.
  • the formation of the amide (IV) - »(V) is carried out by reaction in an inert solvent with ammonia in a temperature range from 0 ° C to + 50 ° C, preferably from + 20 ° C to + 30 ° C, at atmospheric pressure or elevated Printing, within 24 to 72 hours.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol.
  • alcohols such as methanol, ethanol, n-propanol or isopropanol.
  • a solution of ammonia in methanol in a concentration of 5N to 7N is used.
  • the dehydration of the amide (V) to the nitrile (I) is carried out in an inert solvent in the presence of a suitable base with a suitable dehydrating agent such as trifluoroacetic anhydride, acetic anhydride or trifluoromethanesulfonic anhydride, in a temperature range of 0 ° C to + 60 ° C, preferably at + 20 ° C to + 30 ° C, within 12 to 36 hours.
  • a suitable dehydrating agent such as trifluoroacetic anhydride, acetic anhydride or trifluoromethanesulfonic anhydride
  • Inert solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or other solvents acetonitrile or N, N-dimethylformamide, or mixtures of solvents.
  • THF tetrahydrofuran
  • Suitable bases are, for example, organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). , Preference is given to pyridine.
  • organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN).
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1,5-diazabicyclo [4.3.0] non-5-ene
  • the compounds described in the context of the process according to the invention can also be present in the form of their salts, solvates or solvates of the salts.
  • Suitable salts in the context of the invention are physiologically acceptable salts of the compounds used and prepared in the process according to the invention.
  • Physiologically acceptable salts of the compounds used and prepared in the process according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds used and prepared in the process according to the invention also include salts of conventional bases such as, by way of example and by way of example, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylphosphine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine.
  • alkali metal salts eg sodium and potassium salts
  • alkaline earth salts eg calcium and magnesium salts
  • solvates are those forms of the compounds used and prepared in the process according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl, ⁇ -butyl and tert-butyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de fabrication de 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile de la formule (I) qui sert d'intermédiaire de synthèse pour la fabrication de médicaments, en particulier pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies cardiovasculaires.
EP11757221.4A 2010-09-03 2011-08-31 Procédé de fabrication de 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile Withdrawn EP2611803A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010040234A DE102010040234A1 (de) 2010-09-03 2010-09-03 Verfahren zur Herstellung von 5-Flour-1H-pyrazolo[3,4-b]pyridin-3-carbonitril
PCT/EP2011/065004 WO2012028645A1 (fr) 2010-09-03 2011-08-31 Procédé de fabrication de 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile

Publications (1)

Publication Number Publication Date
EP2611803A1 true EP2611803A1 (fr) 2013-07-10

Family

ID=44651701

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11757221.4A Withdrawn EP2611803A1 (fr) 2010-09-03 2011-08-31 Procédé de fabrication de 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile

Country Status (7)

Country Link
US (1) US20130211090A1 (fr)
EP (1) EP2611803A1 (fr)
JP (1) JP2013536826A (fr)
CN (1) CN103080110A (fr)
CA (1) CA2809912A1 (fr)
DE (1) DE102010040234A1 (fr)
WO (1) WO2012028645A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010021637A1 (de) 2010-05-26 2011-12-01 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung
DE102010043379A1 (de) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung
DE102010043380A1 (de) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Benzyl-substituierte Carbamate und ihre Verwendung
RS55387B1 (sr) 2011-11-25 2017-03-31 Adverio Pharma Gmbh Postupak za dobijanje supstituisanih (z)-alfa-fluoro-beta-amino-akrilaldehida
DE102012200349A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte annellierte Pyrimidine und Triazine und ihre Verwendung
MX2015010725A (es) 2013-02-21 2016-05-31 Adverio Pharma Gmbh Formas de metil {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo [3,4-b] piridino-3-il] pirimidino-5-il} metil carbamato.
US20160002267A1 (en) 2013-03-01 2016-01-07 Bayer Pharma Aktiengesellschaft Benzyl-substituted pyrazolopyridines and use thereof
JP2016523944A (ja) 2013-07-10 2016-08-12 バイエル・ファルマ・アクティエンゲゼルシャフト ベンジル−１Ｈ−ピラゾロ［３，４−ｂ］ピリジンおよびその使用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
DE10232572A1 (de) * 2002-07-18 2004-02-05 Bayer Ag Neue 2,5-disubstituierte Pyrimidinderivate
WO2009018415A1 (fr) 2007-07-31 2009-02-05 Vertex Pharmaceuticals Incorporated Procédé de préparation de la 5-fluoro-1h-pyrazolo[3,4-b]pyridin-3-amine et des dérivés de celle-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012028645A1 *

Also Published As

Publication number Publication date
CA2809912A1 (fr) 2012-03-08
DE102010040234A1 (de) 2012-03-08
CN103080110A (zh) 2013-05-01
US20130211090A1 (en) 2013-08-15
JP2013536826A (ja) 2013-09-26
WO2012028645A1 (fr) 2012-03-08

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