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WO2014206903A1 - Procédés pour la préparation de [1,2,4]triazolo[1,5-a]pyridines substituées - Google Patents

Procédés pour la préparation de [1,2,4]triazolo[1,5-a]pyridines substituées Download PDF

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Publication number
WO2014206903A1
WO2014206903A1 PCT/EP2014/063094 EP2014063094W WO2014206903A1 WO 2014206903 A1 WO2014206903 A1 WO 2014206903A1 EP 2014063094 W EP2014063094 W EP 2014063094W WO 2014206903 A1 WO2014206903 A1 WO 2014206903A1
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formula
compound
alkyl
mixture
water
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Mogens Larsen
Allan Carsten Dahl
John Mcparland
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Leo Pharma AS
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Leo Pharma AS
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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

Definitions

  • PCT/EP2012/076191 discloses [l,2,4]triazolopyridine compounds useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.
  • WO2010/069322 discloses novel triazolopyridines useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.
  • WO2008/125111 discloses triazolopyridines useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.
  • the present invention provides methods for the preparation of substituted
  • the present invention relates to a method for the preparation of a compound of formula (I)
  • R 2 represents Ci_ 6 alkyl
  • R 2 represents branced butyl. In another embodiment R 2 represents isobutyl.
  • Ci-6-alkyl is intended to mean a saturated, straight or branched hydrocarbon chain having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • "Ci- 6 -alkyl” is a Ci- 4 -alkyl group, e.g . methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl.
  • Ci- 3 -alkyl includes methyl, ethyl, propyl and isopropyl.
  • halogen is intended to mean one of fluoro, chloro, bromo and iodo. In one embodiment, the term “halogen” designates bromo or iodo. In another embodiment, the term “halogen” designates bromo.
  • the methods for the preparation of a compound of formula (I) includes the preparation of the starting material, a compound of formula (II)
  • a solvent e.g. selected from but not limited to methanol, ethanol, 2-propanol, acetone, ethyl acetate (EtOAc), and tetrahydrofuran (TH F), and mixtures thereof, in the presence of a catalyst, e.g. selected from the transition metals either in elemental form, as a chemical compound, or supported on an inert solid, such as, but not limited to, platinium(IV) oxide or palladium on carbon.
  • the solvent is selected as a mixture of ethyl acetate and methanol in the presence of palladium on carbon as catalyst.
  • the reaction is typically conducted under pressure in the range of 1-5 bars, such as in the range of 3-5 bar.
  • the reaction is typically conducted at a temperature in the range of 10-30 °C, such as in the range of 18-23°C.
  • the reaction is typically allowed to proceed for 1-48 hours, such as 3-24 hours.
  • reaction steps (a) and (b) are performed as a one-pot reaction indicating that the intermediate compound (IV) is not isolated.
  • the compound of formula (II) is not isolated.
  • X " represents an anion of the N-amination reagent, such as hydrogen sulfate, tosylate, mesityl sulfonate, phenolate, chloride; followed by the cyclising (b) of the above intermediate (IV) with a compound of formula (V)
  • each Ri independently is selected from Ci_ 6 alkyl, to form a compound of formula (VI)
  • the N-amination reagent is selected from the commercial available hydroxylamine-O- sulfonic acid, O-tosyl hydroxylamine, O-mesitylsulfonyl hydroxylamine, phenyl hydroxylamines, chloroamine. In one embodiment the N-amination reagent is hydroxylamine-O-sulfonic acid .
  • the reaction (a) is typically conducted in a polar solvent, e.g . selected from, but not limited to, methanol, ethanol, 2-propanol, or water, and mixtures thereof, in the presence of a base, e.g. selected from l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et 3 N), ⁇ , ⁇ -diisopropylethylamine (DIPEA), K 2 C0 3 and lithium methoxide (LiOMe).
  • the solvent is an alcohol with an organic amine as base.
  • methanol is used as solvent and l,8-diazabicyclo[5.4.0] undec-7-ene is used as base.
  • methanol is used as solvent and lithium methoxide is used as base.
  • reaction (a) is typically conducted at a temperature in the range of 20-70 °C, such as in the range of 38-70°C. The reaction is typically allowed to proceed for 3-48 hours.
  • the cyclising (b) is conducted by the addition of compound of formula (V).
  • the compound of formula (V) is commercial available for most of the possible combinations of Ri.
  • said compound of formula (V) is wherein Ri independently represents methyl or ethyl.
  • the compound is the commercial available dimethyl cyclopropane-1,1- dicarboxylate.
  • the reaction (b) is typically conducted by add ing a base in combination with the compound of formula (V), e.g. selected from l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), triethylamine (Et 3 N), ⁇ , ⁇ -diisopropylethylamine (DIPEA), K 2 C0 3 and lithium methoxide (LiOMe).
  • a base e.g. selected from l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), triethylamine (Et 3 N), ⁇ , ⁇ -diisopropylethylamine (DIPEA), K 2 C0 3 and lithium methoxide (LiOMe).
  • a base e.g. selected from l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), triethylamine (Et 3 N), ⁇ , ⁇ -diiso
  • the reaction (b) is typically conducted at a temperature in the range of 60-75°C, such as in the range of 65-75°C.
  • the reaction is typically allowed to proceed for 6-24 hours, such as 16-18 hours.
  • a base e.g . a metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, e.g . sodium hydroxide, is added to the mixture.
  • the resulting crude product (VI) may be isolated by conventional means, e.g. by filtration .
  • the compound of formula (VI) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, or tertiary butyl . In another embodiment the compound of formula (VI) is wherein R is hydrogen . In another embodiment the compound of formula (VI) is wherein R is isobutyl.
  • R represents hydrogen or Ci- 6 alkyl
  • Hal represents halogen
  • the reaction is typically conducted in an aprotic polar solvent or mixtures thereof, e.g . selected from acetonitrile (MeCN), ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF) and methyl tert-butyl ether (MTBE) and mixtures thereof.
  • the solvent is a mixture of acetonitrile and N,N-dimethylformamide.
  • the halogenating agent is typically selected from N-bromosuccinimide, N-iodosuccin- imide and N-chlorosuccinimide. In one embodiment the halogenating agent is N- bromosuccinimide.
  • the reaction is typically conducted at a temperature in the range of 50-70 °C, such as in the range of 55-68°C.
  • the resulting crude product (VIII) may be recovered by conventional means, known to those skilled in the art.
  • the compound of formula (VIII) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl.
  • the compound of formula (VIII) is wherein Hal is iodo or bromo.
  • the compound of formula (VIII) is wherein R is hydrogen and Hal is bromo.
  • compound of formula (VIII) is wherein R is isobutyl and Hal is bromo.
  • aprotic polar solvent or mixtures thereof e.g. selected from acetonitrile (MeCN), ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF), methyl-tert-butylether (MTBE), and dioxane or mixtures thereof, preferably DMF or dioxane.
  • a base e.g.
  • the reaction is catalysed by a catalyst based on a transition metal, e.g. palladium(II)acetate or and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane.
  • a catalyst based on a transition metal e.g. palladium(II)acetate or and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane.
  • the solvent is ⁇ , ⁇ -dimethylformamide (DMF)
  • the base is potassium carbonate
  • the catalyst is palladium(II)acetate.
  • the solvent is dioxane
  • the base is potassium acetate
  • the catalyst is and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane.
  • the resulting crude product (IX) may be isolated by conventional means, known to those skilled in the art.
  • the resulting crude product (IX) is re-precipitated by dissolving the product in a polar solvent, preferably ethyl acetate, filtering through silicagel, and concentration of the resulting solution.
  • the crude product (IX) is washed by trituration in an unpolar solvent, preferably cyclohexane, followed by filtration.
  • the Suzuki coupling reaction is performed by reacting the above compound of formula (VIII) wherein R represents hydrogen or d- 6 alkyl, and Hal represents halogen, with the above compound of formula (IX), catalysed by a Pd catalyst in the presence of a base, to form a compound of formula XI)
  • R represents hydrogen or Ci_ 6 alkyl.
  • the Pd catalyst is typically selected from, but not limited to, bis(triphenylphosphine)- palladium(II)dichloride, tetrakis(triphenylphosphine)palladium(0) or [l, l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.
  • the reactive catalyst is formed by mixing a source of Pd, such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0) and bis(dibenzylideneacetone)- palladium(O), with a ligand such as, but not limited to, tricyclohexylphosphine.
  • a source of Pd such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0) and bis(dibenzylideneacetone)- palladium(O)
  • a ligand such as, but not limited to, tricyclohexylphosphine.
  • the Pd catalyst is bis(triphenylphosphine)palladium(II)dichloride.
  • the Pd catalyst is [l, l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II), complex with dichloromethane.
  • the Pd catalyst is
  • the reaction is typically conducted in a mixture of dioxane and water.
  • the ratio of waten dioxane is typically in the range 30 : 70 to 5: 95 w/w, preferable in the range 25 : 75 to 15 : 85 w/w. In one embodiment, the ratio of waten dioxane is 20 : 80 w/w.
  • the reaction is typically conducted in the presence of a base e.g. selected from triethylamine, K 3 P0 4 , Na 2 C0 3 and K 2 C0 3 .
  • the base is triethylamine.
  • the reaction is typically conducted at a temperature in the range of 70°C to reflux of the solvent mixture, preferably in the range 80-85°C.
  • the compound of formula (XI) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl.
  • the compound of formula (XI) is wherein R is hydrogen.
  • the compound of formula (XI) is wherein R is is isobutyl.
  • R represents hydrogen or Ci_ 6 alkyl
  • the Pd catalyst in the reaction (i) is typically selected from, but not limited to, bis(triphenylphosphine)palladium(II)dichloride, tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloro- methane.
  • the reactive catalyst is formed by mixing a source of Pd, such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0) and
  • the Pd catalyst is bis(triphenylphosphine)- palladium(II)dichloride.
  • the Pd catalyst is [l,l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.
  • the Pd catalyst is formed by mixing tris(dibenzylideneacetone)- dipalladium(O) with tricyclohexylphosphine.
  • the reaction (i) is typically conducted in a mixture of dioxane and water in the presence of a base e.g . selected from triethylamine, K 3 P0 4 , Na 2 C0 3 and K 2 C0 3 .
  • a base e.g . selected from triethylamine, K 3 P0 4 , Na 2 C0 3 and K 2 C0 3 .
  • the base is K 3 P0 4 . In another embodiment the base is K 2 C0 3 .
  • the reaction (i) is typically conducted at a temperature in the range of 70°C to reflux of the solvent mixture, preferably in the range 80-85°C.
  • the resulting crude product (X) may be isolated by conventional means, known by those skilled in the art.
  • the reaction (ii) is typically conducted in an aprotic polar solvent, e.g . an ether or a cyclic ether selected from dioxane, diethyl ether, tert-butyl methyl ether, in the presence of an acid, e.g . sulphuric acid .
  • an aprotic polar solvent e.g . an ether or a cyclic ether selected from dioxane, diethyl ether, tert-butyl methyl ether
  • an acid e.g . sulphuric acid
  • the solvent is dioxane and the acid is sulphuric acid.
  • the reaction (ii) is typically conducted at reflux of the reaction mixture.
  • Another alternative way of preparing the compound of formula (XI) is by performing the preparation of the compound of formula (IX) and step (d) as a one-pot reaction, indicating that work-up of the compound of formula (IX) is circumvented .
  • a further advantage is that the expensive Pd catalyst is used for both reactions, reducing the cost of Pd catalyst for the production.
  • R represents hydrogen or Ci_ 6 alkyl, and Hal represents halogen, to the reaction mixture containing the compound of formula (IX), and letting the compounds of formula (VIII) and (IX) react to form the compound of formula (XI)
  • R represents hydrogen or Ci_ 6 alkyl.
  • the resulting crude product (XI) may be isolated by conventional means, known by those skilled in the art.
  • the reaction (i) is typically conducted in an aprotic polar solvent or mixtures thereof, e.g. selected from acetonitrile (MeCN), ⁇ , ⁇ -dimethylformamide (DM F), tetrahydrofuran (THF), methyl-tert-butylether (MTBE), and dioxane or mixtures thereof, preferably DMF or dioxane.
  • aprotic polar solvent or mixtures thereof e.g. selected from acetonitrile (MeCN), ⁇ , ⁇ -dimethylformamide (DM F), tetrahydrofuran (THF), methyl-tert-butylether (MTBE), and dioxane or mixtures thereof, preferably DMF or dioxane.
  • a base e.g . selected from potassium acetate, potassium carbonate, potassium phosphate, preferably potassium carbonate or potassium acetate.
  • the reaction is catalysed by a suitable Pd catalyst.
  • the solvent is dioxane
  • the base is potassium acetate
  • the catalyst is [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.
  • the reaction (ii) is typically conducted by adding a compound of the formula (VIII) to the reaction mixture resulting from reaction (i), optionally in combination with the addition of water to the reaction mixture. In one embodiment, water is added in combination with the compound of formula (VIII).
  • the reaction (i) is typically performed at elevated temperature, such as 50-105°C, preferably 70-90°C, most preferably at 73-81°C.
  • the reaction (ii) is typically performed at elevated temperature, such as 50-105°C, preferably 60-80°C, most preferably 68-75°C.
  • the compound of formula (VIII) is wherein Hal represents bromine, and R represents hydrogen.
  • R represents hydrogen in the compound of formula (XI)
  • the following alkylation step (e) is conducted to form the compound of formula (I) wherein R 2 represents Ci- 6 alkyl, by reacting said compound of formula (XI) with an alkylating agent (XII), R 2 -Hal, wherein R 2 represents Ci- 6 alkyl and Hal represents halogen.
  • the alkylating agent is the compound of formula (XII) wherein R 2 represents Ci- 6 alkyl, e.g. methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl, and Hal represents bromo or iodo. In another embodiment R 2 represents isobutyl and Hal represents iodo.
  • the reaction is typically conducted in an aprotic polar solvent or mixtures thereof, e.g. selected from acetonitrile (MeCN), ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF) and methyl-tert-butylether (MTBE) and mixtures thereof in the presence of a base, e.g. selected from, but not limited to, Cs 2 C0 3 or potassium carbonate.
  • a base e.g. selected from, but not limited to, Cs 2 C0 3 or potassium carbonate.
  • the solvent is ⁇ , ⁇ -dimethylformamide (DMF) and the base is Cs 2 C0 3 .
  • the solvent is ⁇ , ⁇ -dimethylformamide and the base is potassium carbonate.
  • the resulting crude product (crude I/XI) may advantageously be purified by
  • the resulting crude I/XI is crystallized in water/DMF/citric acid; isolated by filtration and dried; subsequently dissolved in CH 2 CI 2 and treated with PL- DETA resin; filtered through celite; after exchange of solvent to EtOH, the product is crystallized from EtOH/water and isolated by filtration and dried.
  • the product was crystallized from ethanol with 3-10% V/V water by heating to reflux, followed by cooling to typically 18-20°C over eight hours, and then aging of the crystals at that temperature for at least 12 hours. Finally, the product is isolated by filtration and dried.
  • the present invention relates to intermediates which are useful in the preparations of a compound of the formula (I) wherein R 2 represents Ci_ 6 alkyl .
  • the invention relates to the intermediate compound of formula (VI)
  • R represents hydrogen or d- 6 alkyl.
  • R represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, or tertiary butyl.
  • R represents hydrogen.
  • R represents isobutyl.
  • R represents hydrogen or d- 6 alkyl, and Hal represents halogen.
  • R represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl and Hal represents iodo or bromo.
  • R represents hydrogen and Hal represents bromo.
  • R represents isobutyl and Hal represents bromo.
  • 3-Methoxypyridin-2-amine (25g, 201mmol) was stirred with methanol (375mL), and hydroxylamine-O-sulphonic acid (22.8g, 202mmol) was added portion wise over approximately 10 minutes, keeping the temperature between 20 - 25°C. Transfer was ensured with a rinse of methanol (30mL). After stirring for another 15 minutes, 1,8- diazabicyclo[5.4.0]undec-7-ene (30.6g, 201mmol) was added slowly over approximately 5 minutes. The mixture was heated to reflux for 4-6 hours, and cooled to approximately 40°C.
  • the two combined reaction mixtures were concentrated on a rotary evaporator applying a vacuum and using a water bath for heating; 720-740mL distillate was collected.
  • the mixture was diluted with water (380ml_) and extracted twice with MTBE (300ml_).
  • MTBE was removed using a rotary evaporator applying a vacuum and using a water bath for heating.
  • the mixture was cooled with an ice-water bath, and sulfuric acid (6M, 140- 145mL) was added slowly, keeping the temperature below 20°C. Then pH was approximately 3 as determined using a pH test strip.
  • the mixture was cooled to ambient temperature giving a mixture with two liquid phases; the phases were separated.
  • the organic phase was filtered, and concentrated to a final volume of 300-400ml_ using a rotary evaporator applying a vacuum and using a water bath for heating.
  • the residue was added 2M sodium hydroxide (200mL) and stirred for approximately 1.5 hours.
  • the mixture was extracted twice with MTBE (200mL).
  • the resulting aqueous solution was filtered, and MTBE was removed using a rotary evaporator applying a vacuum and using a water bath for heating.
  • Concentrated sulfuric acid was added to the aqueous solution under stirring until pH was approximately 3, as determined using a pH test strip; 25ml_ concentrated sulfuric acid was added. The mixture was stirred over night at ambient temperature. A solid was isolated by filtration and dried to some extent in an oven at elevated temperature and applying a vacuum, giving 287g of material.
  • More water is removed from the material by adding dioxane (500mL) and concentrating the mixture using a rotary evaporator, applying a vacuum (approximately 250mbar) and using a water bath for heating (bath temperature: 60°C). This is repeated two times more.
  • Dioxane (2.5L) was added to the residue and the mixture was heated to reflux for approximately 5 minutes, and cooled to 17°C over approximately 1.5 hours.
  • the raw product was isolated by filtration, washed with dioxane (lOOmL), and dried in an oven at 40°C applying a vacuum, giving 124g of material.
  • the assay by NMR (method A) was 59wt% (average of two determinations) with regard to the title compound.
  • a reactor was charged with methanol (80L), ethyl acetate (80L), and 3-methoxy-2- nitropyridine (15.85kg, 102.8mol) and the mixture was stirred at 18-23°C until a solution was formed. Then 5wt% Pd on Carbon (50% wet, 274g) was added. The reactor was pressurized and purged three times with nitrogen and then pressurized and purged three times with hydrogen. The reactor was pressurized with hydrogen to 3 bars, and the mixture was stirred at 18-23°C until completion of the reaction (as determined by TLC, eluent: ethyl acetate). The reactor was vented and then pressurized and purged three times with nitrogen. The catalyst was removed by filtration, and the filter cake was washed with a mixture of methanol (24L) and ethyl acetate (24L), and the filtrates were combined.
  • the solution contained 12.41kg of the product (yield 97%), ⁇ -NMR conformed to NMR of the small batch of 3-methoxypyridin-2-amine above.
  • the temperature of the mixture was adjusted to 20-25°C and water (46kg) and ethyl acetate (55.5kg) were added. The mixture was stirred for approximately 15 minutes, and then the phases were allowed to settle. The phases were separated and the water phase was extracted with another portion of ethyl acetate (55.5kg), and the phases were separated.
  • the temperature of the water phase was adjusted to 20-25°C and 6M sulfuric acid (65.4kg) was added with cooling over at least 60 minutes keeping the temperature below 25°C, pH of the mixture was then ⁇ 1.
  • the mixture was stirred at 18-22°C for at least four hours.
  • the raw product of the title compound was isolated by filtration, washed with water (20kg), and dried on the filter with vacuum for at least two hours.
  • a reactor was charged with dioxane (36.0kg), l-(5-bromo-8-methoxy-[l,2,4]triazolo- [l,5-a]pyridin-2-yl)cyclopropanecarboxylic acid (4.63kg, 14.8mol), 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-l-one (4.25kg, 16.3mol), water (9.26kg), triethylamine (6.02kg, 59.5mol), and [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), complex with dichloromethane (306g, 0.375mol), and the mixture was heated to 80-85°C. The reaction was followed by UPLC, and when the reaction was complete, the mixture was cooled to 20-25°C.
  • Citric acid (5wt% in water, approximately 10kg) was added slowly to the water phase with stirring to lower the pH to 4-4.5, and then the mixture was stirred at 20-25°C for at least two hours.
  • the product was isolated by filtration, washed with water (47kg), and dried at elevated temperature under vacuum. Yield 3.72kg (69%).
  • ⁇ -NMR conforms to NMR of the small batch above.
  • ⁇ /,/V-Dimethylformamide (35.5kg), l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (3.69kg, lO. lmol), potassium carbonate (2.79kg, 20.2mol), and l-iodo-2-methylpropane (2.79kg, 15.2mol) were charged to a reactor, and the mixture was heated to 70-75°C until completion of the reaction as determined by UPLC. The temperature of the mixture was adjusted to 20-25°C and the mixture was discharged from the reactor and divided in two portions.
  • Citric acid (5wt% in water, 70kg) was charged to a reactor and half of the reaction mixture was added at 20-25°C (effervescence). The transfer of as much as possible of this portion of reaction mixture was ensured with a rinse of citric acid solution (5wt% in water, 3.8kg). After stirring for an additional two hours, the raw product was isolated by filtration, washed with water (9kg), and drained on the filter. This procedure was repeated with the second half of the reaction mixture. The two portions of raw product were dried at elevated temperature under vacuum giving a total of 4.26kg of solid.
  • 3-Methoxypyridin-2-amine (10. Og, 80.6mmol) was stirred with methanol (150mL), and hydroxylamine-O-Sulphonic acid (9.12g, 80.6mmol) was added portion wise over 4 minutes keeping the temperature between 20 - 25°C. Transfer was ensured with a rinse of methanol (4mL). Then lithium methoxide (3.07g, 80.9mmol) was added portion wise over 4 minutes keeping the temperature between 19 - 25°C. The mixture was heated to reflux for 16-18 hours, and cooled to approximately 30°C.
  • Lithium methoxide (3.07g, 80.9mmol) and dimethyl cyclopropane-l,l-dicarboxylate (25.5g, 161mmol) were added, and the mixture was heated to reflux for 16-18 hours.
  • the mixture was cooled with an ice-water bath, and a mixture of 32% sodium hydroxide (62.5g) and water (57.5g) was added slowly keeping the temperature below 22°C. Stirring for two hours at ambient temperature gave full conversion of the intermediate methyl l-(8-methoxy-[l,2,4]- triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxylate to the title compound (according to LC-MS, method A).
  • the mixture was concentrated on a rotary evaporator applying a vacuum and using a water bath for heating. Concentration was stopped when 125mL distillate was collected. Water (76mL) and MTBE (60ml_) were added to the residue, and the mixture was stirred for 5-10 minutes at ambient temperature. The phases were separated, and the water phase was stirred with MTBE (60mL) for 5-10 minutes. The phases were separated. MTBE was removed from the water phase using a rotary evaporator applying a vacuum and using a water batch for heating : 13mL distillate was collected. The residue was stirred with cooling on an ice-water batch and cone, sulfuric acid was added slowly keeping the temperature below 20°C.
  • the mixture was cooled to ambient temperature and stirred with water (lOOmL) and ethyl acetate (lOOmL), and triethyl amine was added until pH 8 was reach in the water phase (pH test strip, 13ml_ triethyl amine was used).
  • the mixture was filtered and the filter cake was washed with water (20mL).
  • the combined filtrates were transferred to a separatory funnel, mixed by shaking, and allowed to settle.
  • the phases were separated and the water phase was stirred for 20 minutes with ethyl acetate (lOOmL).
  • the mixture was filtered, and the tiny filter cake was washed with water (15mL).
  • the combined filtrates were transferred to a separatory funnel, mixed by shaking, and allowed to settle. The phases were separated.
  • R 2 represents Ci- 6 alkyl, comprising carrying out one or more of the following reaction steps : (a) N-aminating a compound of formula (II)
  • X " represents an anion of an N-amination reagent
  • R represents hydrogen or Ci_ 6 alkyl
  • R represents hydrogen or Ci- 6 alkyl, and Hal represents halogen
  • R represents hydrogen or Ci- 6 alkyl; and when R in formula (XI) represents hydrogen
  • R 2 represents Ci- 6 alkyl and Hal represents halogen, to form the compound of formula (I) wherein R 2 represents Ci_ 6 alkyl .
  • step (a) is conducted in a polar solvent in the presence of a base.
  • step (a) the solvent is methanol and the base is l,8-diazabicyclo[5.4.0] undec-7-ene.
  • step (b) is conducted in the presence of a base.
  • step (b) is conducted in the presence of a base.
  • the base is l,8-diazabicyclo[5.4.0]- undec-7-ene.
  • step (c) is selected from N-bromosuccinimide, N-iodosuccinimide and N-chlorosuccinimide.
  • Clause 10 The method according to clause 9 wherein the halogenating agent is N- bromosuccinimide.
  • step (c) is conducted in an aprotic polar solvent or mixtures thereof.
  • the solvent is a mixture of acetonitrile (MeCN) and ⁇ , ⁇ -dimethylformarriide (DMF).
  • step (d) is conducted in a mixture of dioxane and water in the presence a Pd catalyst and a base.
  • Clause 14 The method according to clause 13 wherein the ratio of watendioxane is ratio of watendioxane is 20: 80 w/w. Clause 15. The method according to clause 13 wherein the Pd catalyst is
  • step (e) is conducted in an aprotic polar solvent in the presence of a base.
  • R represents hydrogen or d- 6 alkyl.
  • R represents hydrogen or Ci_ 6 alkyl
  • R represents hydrogen or Ci- 6 alkyl, and Hal representshalogen; comprising step (c) as defined in clause 1.
  • R 2 represents Ci- 6 alkyl, comprising step (a) and (b) as defined in clause 1.
  • Clause 32. A method for preparing a compound of formula (I)
  • R 2 represents Ci_ 6 alkyl, comprising step (a), (b) and (c) as defined in clause 1.
  • Clause 33 A method for preparing a compound of formula (XI)
  • R represents hydrogen or d- 6 alkyl
  • step (d) as defined in clause 1.
  • R represents hydrogen or d- 6 alkyl; comprising :
  • R represents hydrogen or Ci- 6 alkyl, and Hal represents halogen; with the compound of formula (IX)
  • step (i) is conducted in an mixture of dioxane and water in the presence of a Pd catalyst and a base.
  • step (i) the Pd catalyst is formed by mixing tricyclohexylphosphine and
  • Clause 37 The method according to any one of the preceding clauses 34-36 wherein, in step (i), the base is K 3 P0 4 .
  • step (ii) is conducted in an aprotic polar solvent in the presence of an acid .
  • Clause 39 The method according to clause 38 wherein, in step (ii), the solvent is dioxane and the acid is sulphuric acid.
  • Clause 40 A method for preparing a compound of formula (XI)
  • R represents hydrogen or d- 6 alkyl
  • R represents hydrogen or Ci_ 6 alkyl
  • Hal represents halogen
  • step (i) is conducted in dioxane in the presence of a Pd catalyst and a base.
  • step (i) the Pd catalyst is [ l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.
  • Clause 43 The method according to any one of the preceding clauses 40-42 wherein, in step (i), the base is potassium acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux procédés pour la préparation de [1,2,4]triazolo[1,5-a]pyridines substituées et d'intermédiaires pour ces composés. Ces composés sont utiles en tant qu'inhibiteurs de la PDE4.
PCT/EP2014/063094 2013-06-25 2014-06-23 Procédés pour la préparation de [1,2,4]triazolo[1,5-a]pyridines substituées Ceased WO2014206903A1 (fr)

Applications Claiming Priority (2)

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EP13173482.4 2013-06-25

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WO2014206903A1 true WO2014206903A1 (fr) 2014-12-31

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Cited By (1)

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CN114805286A (zh) * 2022-05-06 2022-07-29 深圳职业技术学院 一种萘并氧硫杂卓类衍生物的制备方法

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2008125111A1 (fr) 2007-04-16 2008-10-23 Leo Pharma A/S Triazolopyridines comme inhibiteurs de phosphodiestérases pour le traitement de maladies dermiques
WO2010069322A1 (fr) 2008-12-19 2010-06-24 Leo Pharma A/S Triazolopyridines en tant qu'inhibiteurs de phosphodiestérase pour le traitement de maladies du derme
WO2013092739A1 (fr) * 2011-12-21 2013-06-27 Leo Pharma A/S [1,2,4] triazolopyridines et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase

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WO2008125111A1 (fr) 2007-04-16 2008-10-23 Leo Pharma A/S Triazolopyridines comme inhibiteurs de phosphodiestérases pour le traitement de maladies dermiques
WO2010069322A1 (fr) 2008-12-19 2010-06-24 Leo Pharma A/S Triazolopyridines en tant qu'inhibiteurs de phosphodiestérase pour le traitement de maladies du derme
WO2013092739A1 (fr) * 2011-12-21 2013-06-27 Leo Pharma A/S [1,2,4] triazolopyridines et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase

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AKOKA, S.; BARANTIN, L.; TRIERWEILER, M., ANAL. CHEM., vol. 71, 1999, pages 2554 - 2557

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805286A (zh) * 2022-05-06 2022-07-29 深圳职业技术学院 一种萘并氧硫杂卓类衍生物的制备方法
CN114805286B (zh) * 2022-05-06 2023-06-16 深圳职业技术学院 一种萘并氧硫杂卓类衍生物的制备方法

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