EP2611803A1 - Method for the production of 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile - Google Patents

Method for the production of 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile

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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
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Prior art keywords
formula
salts
pyridine
pyrazolo
fluoro
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German (de)
French (fr)
Inventor
Markus Follmann
Jens Ackerstaff
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Bayer Pharma AG
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Bayer Pharma AG
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    • 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.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

The invention relates to a method for producing 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile of formula (I) which is used as an intermediate synthesis compound for producing medicaments, in particular medicaments for the treatment and/or prevention of cardiovascular diseases.

Description

Verfahren zur Herstellung von 5-Fluor-lH-pyrazolo[3.4-b1pyridin-3-carbonitril  Process for the preparation of 5-fluoro-lH-pyrazolo [3,4-b1pyridine-3-carbonitrile
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 5-Fluor-lH-pyrazolo[3,4- b]pyridin-3-carbonitril der Formel (I) 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)
das als Synthese-Intermediat zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe von kardiovaskulären Erkrankungen, dient. which serves as a synthesis intermediate for the preparation of medicaments, in particular for the production of medicaments for the treatment and / or prophylaxis of cardiovascular diseases.
In WO 2009/018415 wird die Synthese von 5-Fluor-lH-pyrazolo[3,4-b]pyridin-3-amin beschrieben. Durch selektive Dechlorierung der Nikotinsäure A zur Verbindung B, anschliessende Überführung in das Amid C, dessen Reduktion zum Nitril und die abschliessende Zyklisierung mit Hydrazinhydrat wird das 5-Fluor-lH-pyrazolo[3,4-b]pyridin-Core aufgebaut. Das folgende Schema 1 veranschaulicht die Synthese. WO 2009/018415 describes the synthesis of 5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine. 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.
D E  D E
[i)Pd(OAc)2, PPh3, NEt3, HC02H; ii) 1) (COCl)2, CH2C12, cat. DMF, 2) NH3(g), Dioxan, iii) TFAA, NEt3; iv) H2NNH2x H20, n-BuOH] . Die Aufgabe der vorliegenden Erfindung ist es, ein effizientes Verfahren mit hoher Ausbeute zur Herstellung von 5-Fluor-lH-pyrazolo[3,4-b]pyridin-3-carbonitril der Formel (I) [i) Pd (OAc) 2 , PPh 3 , NEt 3 , HC0 2 H; ii) 1) (COCl) 2 , CH 2 Cl 2 , cat. DMF, 2) NH 3 (g), dioxane, iii) TFAA, NEt 3 ; iv) H 2 NNH 2 x H 2 O, n-BuOH]. 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)
bereitzustellen. Diese Aufgabe wird gemäß der vorliegenden Erfindung, wie folgt, gelöst. Das folgende Schema 2 veranschaulicht die einzelnen Reaktionsschritte. provide. This object is achieved according to the present invention as follows. The following Scheme 2 illustrates the individual reaction steps.
[a): TFA, Dioxan; b) NH3; c) TFAA]. Im einzelnen umfasst das erfindungsgemäße Verfahren zur Herstellung einer Verbindung der Formel (I) [a): TFA, dioxane; b) NH 3 ; c) TFAA]. In detail, the process according to the invention for preparing a compound of the formula (I) comprises
die Zyklisierung des 5-Aminopyrazol-Derivats (II) the cyclization of the 5-aminopyrazole derivative (II)
in welcher in which
T1 für (Ci-C4)-Alkyl steht, T 1 is (C 1 -C 4 ) -alkyl,
in Gegenwart einer geeigneten Säure mit dem Aldehyd (ΠΙ) in the presence of a suitable acid with the aldehyde (ΠΙ)
(in), zum Ester der Formel (IV) (in), to the ester of the formula (IV)
in welcher T1 die zuvor angegebene Bedeutung hat, dessen anschliessende Umsetzung mit Ammoniak zum Amid der Formel (V) in which T 1 has the meaning given above, the subsequent reaction with ammonia to give the amide of the formula (V)
und die darauffolgende Dehydratisierung zum Nitril (I). and the subsequent dehydration to the nitrile (I).
Die Verbindung der Formel (II) ist literaturbekannt und kann in Analogie zu Beispiel 20A in WO 00/06569 hergestellt werden. The compound of the formula (II) is known from the literature and can be prepared in analogy to Example 20A in WO 00/06569.
Die Verbindung der Formel (ΠΓ) ist literaturbekannt und kann wie in Justus Liebigs Ann. Chem. 1970, 99- 107 beschrieben, hergestellt werden. The compound of formula (ΠΓ) is known from the literature and can, as in Justus Liebigs Ann. Chem. 1970, 99-107.
Die Zyklisierung des 5-Aminopyrazol-Derivats der Verbindung (Π) mit dem Aldehyd der Verbindung (ΙΠ) zur Verbindung der Formel (IV) erfolgt in einem inerten Lösungsmittel gegebenenfalls in Gegenwart von Trifluoressigsäure in einem Temperaturbereich von +50°C bis +200°C, bevorzugt bei +80°C bis +140°C, bei Normaldruck, innerhalb von beispielsweise 10 bis 80 Stunden, bevorzugt innerhalb von 48 bis 72 Stunden. The cyclization of the 5-aminopyrazole derivative of the compound (Π) with the aldehyde of the compound (ΙΠ) 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.
Inerte Lösungsmittel sind beispielsweise Alkohole wie Methanol, Ethanol, n-Propanol oder iso- Propanol, Ether wie Diethylether, Dioxan, Tetrahydrofuran, Glykoldimethylether oder Diethylen- glykoldimethylether, Kohlenwasserstoffe wie Benzol, Toluol, Xylol, Hexan, Cyclohexan oder Erdölfraktionen oder andere Lösungsmittel Acetonitril oder NN-Dimethylformamid, oder Gemische von Lösungsmitteln. Bevorzugt ist Dioxan. 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.
Die Bildung des Amids (IV)— » (V) erfolgt durch Umsetzung in einem inertem Lösungsmittel mit Ammoniak in einem Temperaturbereich von 0°C bis + 50°C, bevorzugt von +20°C bis +30°C, bei Normaldruck oder erhöhtem Druck, innerhalb von 24 bis 72 Stunden. 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.
Inerte Lösungsmittel sind beispielsweise Alkohole wie Methanol, Ethanol, n-Propanol oder iso- Propanol. Bevorzugt wird eine Lösung von Ammoniak in Methanol in einer Konzentration von 5N bis 7N eingesetzt. Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol. Preferably, a solution of ammonia in methanol in a concentration of 5N to 7N is used.
Die Dehydratisierung des Amid (V) zum Nitril (I) erfolgt in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit einem geeigneten Dehydatisierungsmittel wie beispielsweise Trifluoressigsäureanhydrid, Essigsäureanhydrid oder Trifluormethansulfonsäureanhydrid, in einem Temperaturbereich von 0°C bis +60°C, bevorzugt bei +20°C bis +30°C, innerhalb von 12 bis 36 Stunden. 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.
Bevorzugt ist Trifluoressigsäureanhydrid. Inerte Lösungsmittel sind Ether wie Diethylether, Dioxan, Tetrahydrofuran (THF), Glykol- dimethylether oder Diethylenglykoldimethylether, Kohlenwasserstoffe wie Benzol, Toluol, Xylol, Hexan, Cyclohexan oder Erdölfraktionen oder andere Lösungsmittel Acetonitril oder N,N- Dimethylformamid, oder Gemische von Lösungsmitteln. Bevorzugt ist THF. Preference is given to trifluoroacetic 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. Preferred is THF.
Geeignete Basen sind beispielsweise organische Amine wie Triethylamin, Diisopropylethylamin, Pyridin, l,8-Diazabicyclo[5.4.0]undec-7-en (DBU) oder l,5-Diazabicyclo[4.3.0]non-5-en (DBN). Bevorzugt ist Pyridin. 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.
Die im Rahmen des erfindungsgemäßen Verfahrens beschriebenen Verbindungen können auch in Form ihrer Salze, Solvate oder Solvate der Salze vorliegen. 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.
Die im Rahmen des erfindungsgemäßen Verfahrens beschriebenen Verbindungen können in Abhängigkeit von der Struktur auch in Form ihrer Tautomere vorliegen. The compounds described in the context of the process according to the invention can also be present in the form of their tautomers, depending on the structure.
Als Salze sind im Rahmen der Erfindung physiologisch unbedenkliche Salze der im erfindungsgemäßen Verfahren eingesetzten und hergestellten Verbindungen bevorzugt. 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.
Physiologisch unbedenkliche Salze der im erfindungsgemäßen Verfahren eingesetzten und hergestellten Verbindungen umfassen Säureadditionssalze von Mineralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfonsäure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure und Benzoesäure. 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.
Physiologisch unbedenkliche Salze der im erfindungsgemäßen Verfahren eingesetzten und hergestellten Verbindungen umfassen auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kaliumsalze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C-Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Me&ylmorpholin, Dihydroabiethylamin, Arginin, Lysin, Ethylendiamin und Methylpiperidin. 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.
Als Solvate werden im Rahmen der Erfindung solche Formen der im erfindungsgemäßen Verfahren eingesetzten und hergestellten Verbindungen bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungsmittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt. In the context of the invention, 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.
Im Rahmen der vorliegenden Erfindung haben die Substituenten, soweit nicht anders spezifiziert, die folgende Bedeutung: Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkylrest mit 1 bis 4 Kohlenstoffatomen. Beispielhaft und vorzugsweise seien genannt: Methyl, Ethyl, w-Propyl, Isopropyl, w-Butyl, iso-Butyl, jec.-Butyl und tert.- tyl. In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, ω-propyl, isopropyl, ω-butyl, isobutyl, γ-butyl and tert-butyl.
Die vorliegende Erfindung wird nachstehend anhand von nicht einschränkenden bevorzugten Beispielen und Vergleichsbeispielen näher dargestellt. Soweit nicht anderweitig angegeben, beziehen sich alle Mengenangaben auf Gewichtsprozente. The present invention will now be described in more detail by way of non-limiting preferred examples and comparative examples. Unless otherwise stated, all quantities are by weight.
A. Beispiele A. Examples
Abkürzungen: Abbreviations:
Ac Acetyl Ac acetyl
CI chemische Ionisation (bei MS)  CI chemical ionization (in MS)
DCI direkte chemische Ionisation (bei MS)  DCI direct chemical ionization (in MS)
DMF Dimethylformamid  DMF dimethylformamide
DMSO Dimethylsulfoxid  DMSO dimethyl sulfoxide
d. Th. der Theorie (bei Ausbeute) d. Th. Of theory (at yield)
eq. Äquivalente) eq. equivalents)
ESI Elektrospray-Ionisation (bei MS)  ESI electrospray ionization (in MS)
Et Ethyl  Et ethyl
GC/MS Gaschromatographie-gekoppelte Massenspektrometrie ges. Gesättigt  GC / MS gas chromatography-coupled mass spectrometry sat. Saturated
h Stunde(n) h hour (s)
HPLC Hochdruck-, Hochleistungsflüssigchromatographie  HPLC high pressure, high performance liquid chromatography
HV Hochvakuum  HV high vacuum
konz. Konzentriert conc. Concentrated
LC/MS Flüssigchromatographie-gekoppelte Massenspektrometrie LC / MS liquid chromatography-coupled mass spectrometry
Me Methyl Me methyl
min Minute(n) min minute (s)
MS Massenspektrometrie  MS mass spectrometry
NMR Kernresonanzspektrometrie  NMR nuclear magnetic resonance spectrometry
rac racemisch / Racemat rac racemic / racemate
Rf Retentionsfaktor (bei Dünnschichtchromatographie auf Kieselgel) RT Raumtemperatur R f Retention factor (in thin-layer chromatography on silica gel) RT room temperature
Rt Retentionszeit (bei HPLC)  Retention time (on HPLC)
SFC Supercritical Fluid Chromatography  SFC Supercritical Fluid Chromatography
THF Tetrahydrofuran THF tetrahydrofuran
UV Ultraviolett-Spektrometrie UV ultraviolet spectrometry
v/v Volumen zu Volumen-Verhältnis (einer Lösung) LC/MS-. HPLC- und GC/MS-Methoden: v / v volume to volume ratio (of a solution) LC / MS. HPLC and GC / MS methods:
Methode 1 (LC-MS): Method 1 (LC-MS):
Instrument: Waters ACQUITY SQD UPLC System; Säule: Waters Acquity UPLC HSS T3 1,8μ 50 x 1mm; Eluent A: 1 1 Wasser + 0.25 ml 99%ige Ameisensäure , Eluent B: 1 1 Acetonitril + 0.25 ml 99%ige Ameisensäure; Gradient: 0.0 min 90% A 1.2 min 5% A 2.0 min 5% A; Ofen: 50°C; Fluss: 0.40 ml/min; UV-Detektion: 210 - 400 nm. Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8μ 50 x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A 1.2 min 5% A 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.
Ausführungsbeispiele embodiments
Beispiel 1 example 1
Ethyl-5-fluor- 1 -(2-fluorbenzyl)- lH-pyrazolo[3 ,4-b]pyridin-3-carboxylat Ethyl 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylate
13.487 g (51.228 mmol) Emyl-5-amino-l-(2-fluorbenzyl)-lH-pyrazol-3-carboxylat (Darstellung beschrieben für Beispiel 20A in WO 00/06569) wurden in 300 ml Dioxan vorgelegt und bei RT mit 6 g (51.228 mmol) 3-(Dimethylamino)-2-fluoracrylaldehyd (Darstellung beschrieben in Justus Liebigs Annalm der Chemie 1970; 99 - 107) versetzt. Anschliessend wurden 4.736 ml (61.473 mmol) Trifluoressigsäure zugegeben und der Ansatz wurde für 3 Tage unter Rühren zum Rückfluss erhitzt. Nach Abkühlen wurde im Vakuum eingeengt und der Rückstand mit Wasser und Essigsäureethylester versetzt. Die Phasen wurden getrennt und die organische Phase wurde zweimal mit Wasser gewaschen. Die vereinigten wässrigen Phasen wurden anschliessend zweimal mit Essigsäureethylester extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, filtriert und im Vakuum eingeengt. Der Rückstand (22 g) wurde anschliessend durch Chromatographie an Kieselgel (Laufmittel: Dichlormethan) gereinigt. Man erhielt 5.67 g (35 % d. Th.) der Titelverbindung. 13487 g (51.228 mmol) of emyl-5-amino-1- (2-fluorobenzyl) -1H-pyrazole-3-carboxylate (preparation described for Example 20A in WO 00/06569) were initially charged in 300 ml of dioxane and at RT with 6 g (51,228 mmol) of 3- (dimethylamino) -2-fluoroacrylaldehyde (described in Justus Liebigs Annalm der Chemie 1970, 99-107). Subsequently, 4,736 ml (61,473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux for 3 days with stirring. After cooling, the mixture was concentrated under reduced pressure and the residue was combined with water and ethyl acetate. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue (22 g) was then purified by chromatography on silica gel (eluent: dichloromethane). 5.67 g (35% of theory) of the title compound were obtained.
LC-MS (Methode 1): Rt = 1.17 min LC-MS (Method 1): R t = 1.17 min
MS (ESIpos): m z = 318 (M+H) MS (ESIpos): mz = 318 (M + H)
Ή-NMR (400 MHz, DMSO-dg): δ = 1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15 - 7.27 (m, 3H), 7.36 - 7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H). Beispiel 2 Ή NMR (400 MHz, DMSO-dg): δ = 1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15 - 7.27 (m, 3H), 7.36 - 7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H). Example 2
5-Fluor-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin-3-carboxamid 5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamide
1.00 g (3.152 mmol) der unter Beispiel 1 erhaltenen Verbindung wurden in 10 ml einer 7N Lösung von Ammoniak in Methanol bei RT für drei Tage gerührt. Anschliessend wurde im Vakuum eingeengt. Man erhielt 908 mg (99 % d. Th.) der Titelverbindung. 1.00 g (3.152 mmol) of the compound obtained in Example 1 were stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. It was then concentrated in vacuo. 908 mg (99% of theory) of the title compound were obtained.
LC-MS (Methode 1): Rt = 0.85 min LC-MS (Method 1): R t = 0.85 min
MS (ESIpos): m/z = 289 (M+H)+ MS (ESIpos): m / z = 289 (M + H) +
Ή-NMR (400 MHz, DMSO-d6): δ = 5.87 (s, 2H), 7.12 - 7.26 (m, 3H), 7.34 - 7.40 (m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H). Ή-NMR (400 MHz, DMSO-d 6 ): δ = 5.87 (s, 2H), 7.12- 7.26 (m, 3H), 7.34-7.40 (m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H).
Beispiel 3 Example 3
5-Fluor-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin-3-carbonitril 5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carbonitrile
900 mg (3.122 mmol) der unter Beispiel 2 erhaltenen Verbindung wurden in THF (14 ml) gelöst und mit 0.646 ml (7.993 mmol) Pyridin versetzt. Danach wurden unter Rühren 1.129 ml (7.993 mmol) Trifluoressigsäureanhydrid langsam zugetropft und anschliessend über Nacht bei RT gerührt. Danach wurde das Reaktionsgemisch auf Wasser gegossen und dreimal mit Essigsäureethylester extrahiert. Die vereinigten organischen Phasen wurden mit gesättigter wässriger Natriumhydrogencarbonat-Lösung und IN Salzsäure extrahiert und danach mit gesättigter wässriger Natriumchlorid-Lösung gewaschen. Die organische Phase wurde über900 mg (3.122 mmol) of the compound obtained in Example 2 were dissolved in THF (14 ml) and treated with 0.646 ml (7.993 mmol) of pyridine. Then, with stirring, 1.129 ml (7.993 mmol) of trifluoroacetic anhydride were slowly added dropwise and then stirred at RT overnight. Thereafter, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases became with saturated aqueous sodium bicarbonate solution and IN hydrochloric acid and then washed with saturated aqueous sodium chloride solution. The organic phase was over
Natriumsulfat getrocknet, filtriert und eingeengt. Man erhielt 850 mg (99 % d. Th.) der Titelverbindung. LC-MS (Methode 1 ): Rt = 1.06 min Dried sodium sulfate, filtered and concentrated. 850 mg (99% of theory) of the title compound were obtained. LC-MS (Method 1): R t = 1.06 min
MS (ESIpos): m/z = 271 (M+H)+ MS (ESIpos): m / z = 271 (M + H) +
Ή-NMR (400 MHz, DMSO-dg): δ = 5.87 (s, 2H), 7.17 - 7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H). Ή NMR (400 MHz, DMSO-dg): δ = 5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H).

Claims

Patentansprüche: claims:
1. Verfahren zur Herstellung einer Verbindung der Formel (I) 1. Process for the preparation of a compound of the formula (I)
umfassend die Dehydratisierung des Amids der Formel (V) comprising the dehydration of the amide of the formula (V)
Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung der Formel (V) durch Umsetzung eines Esters der Formel (IV) Process according to Claim 1, characterized in that the compound of the formula (V) is obtained by reacting an ester of the formula (IV)
in welcher in which
T1 für (CrC4)-Alkyl steht, mit Ammoniak hergestellt wird. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass ein Ester der Formel (IV) durch Zyklisierung des 5-Aminopyrazol-Derivats (II) T 1 is (C r C 4 ) -alkyl, prepared with ammonia. Process according to Claim 1 or 2, characterized in that an ester of the formula (IV) is obtained by cyclization of the 5-aminopyrazole derivative (II)
in welcher  in which
T1 für (CrC4)-Alkyl steht, T 1 is (C r C 4 ) -alkyl,
in Gegenwart einer geeigneten Säure mit dem Aldehyd (III) in the presence of a suitable acid with the aldehyde (III)
hergestellt wird.  will be produced.
4. Verbindung der Formel (V)  4. Compound of formula (V)
sowie ihre Salze, Solvate und Solvate der Salze. and their salts, solvates and solvates of the salts.
5. Verbindung der Formel (IV) 5. Compound of the formula (IV)
in welcher T1 die zuvor angegebene Bedeutung hat, sowie ihre Salze, Solvate und Solvate der Salze. in which T 1 has the meaning given above, and their salts, solvates and solvates of the salts.
EP11757221.4A 2010-09-03 2011-08-31 Method for the production of 5-fluoro-1h-pyrazolo[3,4-b]pyridine-3-carbonitrile Withdrawn EP2611803A1 (en)

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