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WO2007089193A1 - Procédé de synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1h-indole-5-carbonitrile sous forme de base libre ou de ses sels - Google Patents

Procédé de synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1h-indole-5-carbonitrile sous forme de base libre ou de ses sels Download PDF

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Publication number
WO2007089193A1
WO2007089193A1 PCT/SE2007/000088 SE2007000088W WO2007089193A1 WO 2007089193 A1 WO2007089193 A1 WO 2007089193A1 SE 2007000088 W SE2007000088 W SE 2007000088W WO 2007089193 A1 WO2007089193 A1 WO 2007089193A1
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process according
halogen
compound
solvent
palladium
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Silke Erbeck
Martin Hedberg
Thomas Nussbaumer
Per Ryberg
Andrea Zistler
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a new process for the manufacture of the compound 2- hydroxy-3-[5-(rnorpholrn-4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile as a free base and pharmaceutically acceptable salts thereof and to new intermediates prepared therein suitable for large scale manufacturing of said compounds.
  • the invention also relates to a new robust process for large scale cyanation to produce 2-hydroxy-3-[5-(morphol ⁇ i-4- ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile under mild conditions.
  • the invention also relates to the use of new palladium catalysts for metal-catalysed cyanation of aryl halides.
  • WO 03/082853 discloses a process for the preparation of 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile as a free base and the hydrochloride salt thereof.
  • 5-cyanooxindole is reacted with a 2-halopyridin-iV-oxide derivative in an inert organic solvent such as tetrahydrofuran, dioxane, dimethylformamide or N- methylpyrrolidin-2-one.
  • the presence of a base is advantageous for the coupling.
  • a temperature range of 0- 13O 0 C was disclosed.
  • the N-oxide could be removed with phosphorus trichloride in a suitable solvent such as methylene chloride, toluene or ethyl acetate to furnish 2-hydroxy-3-[5-(morpholin-4-yl- methyl)pyridin-2-yl]l//-indole-5-carbonitrile.
  • a suitable solvent such as methylene chloride, toluene or ethyl acetate
  • the 5-cyano- oxindole is expensive and is not available as a commercial bulk substance.
  • 13O 0 C the starting 5-cyanooxindole decomposes.
  • the use of N-oxides on large scale is of concern due to their potential explosive properties. Purification to achieve a pharmaceutically acceptable quality material could only be achieved by column chromatography. This purification technique is not the most
  • WO 03/082853 discloses the preparation of 5-bromo-3-[5-(morpholin-4-ylmethyl)pyridin- 2-yl]l/f-indol-2-ol which was prepared analogously as 2-hydroxy ⁇ 3-[5-(morpholin-4-yl- methyl)pyridin-2-yl]lH-indole-5-carbonitrile however using 5-bromooxindole instead of 5-cyanooxindole.
  • the present invention is directed to a new process for manufacturing of the compound (2- hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl] lH-indole-5-carbonitrile as a free base and pharmaceutically acceptable salts thereof, particularly the citrate salt.
  • Rl is halogen, where halogen is chloro, bromo or iodo
  • X is halogen, where halogen is chloro, bromo or iodo.
  • Rl is bromo and X is chloro.
  • the new manufacturing process of the present invention may be described in the following way: A process for the preparation of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl] IH- indole-5-carbonitrile as a free base and pharmaceutically acceptable salts thereof, by a) reacting a compound of formula (I) wherein Rl is halogen, where the halogen is chloro,
  • step 1 process step a above and in claim 1 of the manufacturing process a compound of formula (EI)
  • Rl is halogen, where halogen is chloro, bromo or iodo, is prepared by reacting compounds of formula (I), wherein Rl is halogen, where halogen is chloro, bromo or iodo,
  • a step 1 using a compound of formula (I) wherein Rl is bromo and a compound of formula (II) wherein X is chloro is particularly suitable.
  • the starting compound of formula (I) wherein Rl is bromo may be prepared in a known manner described in the prior art, e.g. reacting oxindole with bromine and potassium bromide ( J. Am. Chem. Soc, 1945, 67, 1656).
  • the chloro analogue may be synthesized as disclosed in the prior art (Synthesis, 1991, 10, 871) and the iodo analogue may be synthesized as disclosed in the prior art (Heterocyclic Communications, 1997, 3(3), 207).
  • the starting compound of formula (II) wherein X is chloro may be prepared in a known manner described in the prior art, e.g. formation of the acid chloride of 6-chloronicotinic acid and subsequent reaction with morpholine (Ann. Pharm. Fr. 1977, 35(5-6), 197).
  • the other halogen analogue of compound of formula (II) could be prepared by someone skilled in the art starting from the corresponding 6-halonicotinic acid i.e. 6-fluoro- (J. Med. Chem., 1990, 33(6), 1667, 6-bromo- (Synthesis, 2003, 4, 551), 3394, 6-iodo-nictonic acid (J. Am. Chem. Soc, 1950, 72, 1032), respectively.
  • Step 1 is performed in a solvent and in the presence of a base.
  • the solvent may be selected from the group comprising of ethers such as tetrahydrofuran, methyltetrahydrofuran, diethyleneglycol dimethyl ether or 1,4-dioxane, or a polar aprotic solvent such as N, N-dimethylacetamide, iV-methyl-2-pyrrolidinone, dimethylformamide, dimethylsulfoxide, l,3-dimethyl-tetrahydro-2(lH)-pyrimidinone or mixtures thereof.
  • the preferred solvents are polar aprotic solvents, particularly preferred is N-methyl-2- pyrrolidinone.
  • the total amount of solvents used in the coupling process step 1, may vary between 2 to 4.
  • a suitable base may be an organic amine base such as diazabicyclo[5.4.0]undec-7-ene, or alkali metal salts such as sodium carbonate; or alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal alkoxides as lithium tert-butoxide; or alkali metal amides such as potassium bis(trimethylsilyl) amide, lithium diisopropylamide or sodium amide.
  • the preferred base is lithium hydride.
  • the amount of base used in the coupling process step a) may vary between 1 to 5 mole equivalents of compound of formula (I).
  • the preferred equivalent of base ranges from 2 to 3 mole equivalents of compound of formula (I).
  • the temperature of the coupling step a) may be between -100 0 C to +180°C, preferably between room temperature and +140 0 C.
  • the mole equivalent of compound of formula (II) compared to compound of formula (I) may be between 1 and 5 mole equivalents, preferably between 1 and 2.5 mole equivalents.
  • the work up may be performed by methods known by someone skilled in the art, for example by quenching with water, ammonium chloride either as a solid or as a solution in water of varying concentration or by an organic or inorganic acid.
  • Other protic solvents of low molecular weight could also be used as quenching agent e.g. methanol, ethanol, propan ⁇ l or butanol, or mixtures thereof as long as the pH is adjusted by the addition of an acid.
  • the compound of formula (III) obtained in step 1 has a chromatographic purity of at least 90%, preferably more than 95%.
  • Step 2 process step b above and in claim 1 of the manufacturing process of a compound of formula (IV) wherein the Rl is halogen, where halogen is chloro, bromo or iodo
  • the reducing agent used for the formation of compound (IV) may be selected from the group comprising of boranes e.g. borane tetrahydrofuran complex, borane dimethyl- sulphide complex, borane-morpholine complex and borane-NJV-diethylaniline.
  • Preferred reducing agents are borane tetrahydrofuran complex or borane dimethylsulphide complex, particularly preferred is borane tetrahydrofuran complex.
  • the mole equivalent of the reducing agent compared to compound of formula (III) may be between 1 and 5 mole equivalents, preferably between 3 and 4 mole equivalents.
  • a suitable polar, aprotic solvent in step 2), stage i) is preferably ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, or diethyleneglycol dimethyl ether, or mixtures thereof.
  • the preferred solvent is tetrahydrofuran.
  • the total amount of solvents may vary between 1 to 100 (v/w) volume parts per weight of starting material, preferably between 5 to 20 (v/w) volume parts per weight of starting material.
  • stage i) may be between -100 0 C to +100°C.
  • the o temperature is preferably kept between -1O 0 C to +4O 0 C.
  • the formed borane complex of compound of formula (IV) is usually not isolated.
  • the decomplexation reaction of the formed borane complex of the compound of formula (TV) may be performed by quenching with either an inorganic acid e.g. s hydrochloric acid, sulphuric acid, phosphoric acid or an organic acid e.g. acetic acid, or a protic solvent which includes water, methanol, ethanol, propanol, butanol or triethanolamine, or mixture thereof.
  • an inorganic acid e.g. s hydrochloric acid, sulphuric acid, phosphoric acid or an organic acid e.g. acetic acid, or a protic solvent which includes water, methanol, ethanol, propanol, butanol or triethanolamine, or mixture thereof.
  • the acids may be used in the gas or fluid phase and may optionally be mixed with water and/or any of the protic solvents mentionad above.
  • the reagent for free basing of the salt of compound of formula (IV) is selected from aqueous hydroxides such as sodium hydroxide, lithium hydroxide or other inorganic bases such as sodium hydrogen carbonate, potassium carbonate, or organic bases such as amines e.g. triethylamine, diisopropylamine or ammonia optionally in combination with water and/or a protic solvent, preferably one of the protic solvent mentioned above.
  • the preferred quench agent for step 2, stage u) is water and/or methanol.
  • stage ii) may be between -1O 0 C to +15O 0 C, preferably between room temperature and +8O 0 C.
  • Compounds of formula (IV) are normally obtained with a purity of at least 85%. Compounds of formula (IV) may optionally be further purified by recrystallisation from a mixture of an organic solvent using a hydrocarbon as antisolvent to obtain a purity of at least 95%.
  • Suitable solvents for crystallisation may include polar solvents such as dimethylsulphoxide, JV ⁇ -methylpyrrolidinone, 1,4-dioxane and a hydrocarbon solvent such as toluene, cumene, xylenes, ligroin, petroleum ether, halobenzenes, heptanes, hexanes, octanes, cyclohexanes, cycloheptanes, or mixtures thereof.
  • polar solvents such as dimethylsulphoxide, JV ⁇ -methylpyrrolidinone, 1,4-dioxane and a hydrocarbon solvent such as toluene, cumene, xylenes, ligroin, petroleum ether, halobenzenes, heptanes, hexanes, octanes, cyclohexanes, cycloheptanes, or mixtures thereof.
  • Step 3 process step c above and in claim 1, the cyanation reaction, of the manufacturing process of a compound of formula (V), 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2- yl] lH-indole-5-carbonitrile
  • the catalyst is based on a metal where the metal may be selected from the group comprising of palladium, nickel or copper, or mixtures thereof, preferably palladium, or alternatively it may be based on the combination of a metal and a ligand where the metal may be palladium, nickel or copper, or mixtures thereof, preferably palladium, and where the ligand may be a tertiary phosphine or di-phosphine, secondary or tertiary amine or di- amine, a tertiary arsine or a JV-heterocyclic carbene, or combinations thereof.
  • the ligand is selected from tri-tert-butylphosphine, tri- ⁇ rt/zo-tolylphosphine or 1,2,3,4,5- pentaphenyl-r-(di-tert-butylphosphino)ferrocene.
  • a preferred source of palladium is a complex between palladium and dibenzylideneacetone.
  • the catalyst is preferably selected from the group comprising of di- ⁇ -bromobis(tri-tert-butylphosphine)dipalladium(I) ([BrPdP(t-Bu) 3 ]2), a combination of tris(dibenzylideneacetone)di-palladium(0) or bis(dibenzylideneacetone)palladium(0) and tri-ter ⁇ butylphosphine, a combination of tris(dibenzylideneacetone)dipalladium(0) or bis(diben2ylideneacetone)palladium(0) and tri-or ⁇ o-tolylphosphine, a combination of tris(diben2ylideneacetone)dipalladium(0) or bis(dibenzylideneacetone)palladium(0) and 1,2,3,4,5-pentaphenyl-l '-(di-terf- butylphosphino)ferrocene, bis(tri-tert-but
  • the mole equivalents of the catalyst compared to compound of formula W may be from 0.0001 to 0.1 mole equivalents, preferably between 0.001 to 0.05 mole equivalents.
  • the ligand is tri-fert-butylphosphine or l,2,3,4,5-pentaphenyl-r-(di-fert-butyl- phosphino)ferrocene or a 2-(dialkylphosphino)biphenyl
  • the ligand to metal ratio may be from 0.5:1 to 2:1 but preferably from 0.9:1 to 1.2:1.
  • the ligand is i ⁇ -ortho-tolyl- phosphine the ligand to metal ratio may be from 1 : 1 to 4 : 1 but preferably from 1.8 : 1 to 2.5:1.
  • the source of cyanide may be selected by a person skilled in the art of organic synthesis.
  • Examples of cyanide sources so far used in cyanation are inorganic salts or organic compounds.
  • Inorganic salts used include sodium cyanide, potassium cyanide, zinc cyanide, lithium cyanide, copper cyanide, calcium cyanide and tetrapotassium hexacyanoferrate(II).
  • Examples of organic compounds that can be used as cyanide sources are acetone cyanohydrin or other cyanohydrins.
  • the preferred cyanide source is zinc cyanide.
  • the mole equivalents of the cyanide ions compared to compound of formula TV may be between 1 and 3 mole equivalents, preferably between 1 and 2 mole equivalents.
  • the reaction may be performed in a solvent selected from the group comprising of polar aprotic solvents e.g. JV,JV-dialkylamides such as JV, N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone and dimethylsulphoxide, ethers such as tetrahydrofuran or 1,4-dioxane, ketones such as acetone or methyl wo-butyl ketone, nitriles such as acetonitrile or propionitrile, or mixtures thereof.
  • polar aprotic solvents e.g. JV,JV-dialkylamides such as JV, N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone and dimethylsulphoxide
  • ethers such as tetrahydrofuran or 1,4-dioxane
  • ketones such as acetone or methyl wo-butyl ket
  • the total volume of solvents used may vary between 1 to 100 (v/w) volume parts per weight of starting material. Preferably between 2 to 40 (v/w) volume parts per weight of starting material.
  • the reaction is performed by adding the cyanide source to a preheated mixture of the other reaction components in the reaction medium under inert conditions, which means under an atmospere of inert gases such as nitrogen, argon or helium, preferably nitrogen, excluding air/oxygen.
  • the temperature of the reaction may be between room temperature and +150 0 C, preferably between +35°C and +8O 0 C.
  • the additives may be selected from the group comprising of zinc-dust, acetic acid or a metal acetate such as zinc acetate, lithium acetate, sodium acetate, potassium acetate or magnesium acetate, a base such as sodium carbonate, potassium carbonate, an oxide such as calcium oxide or magnesium oxide or an amine such as N,N' '-dimethyl ethylenediamine, triethylamine, ethylenediamine, or mixtures thereof.
  • the reaction may be carried out without the additive also.
  • the preferred additive is zinc-dust as such or zinc dust in combination with zinc acetate.
  • the mole equivalent of the additive may be from 0 to 1.0 equivalents, preferably between 0 to 0.5 mole equivalents.
  • the new improved cyanation reaction is more advantangeous than prior known cyanation reactions since it can be performed in relatively short time under mild conditions such as low temperatures, which is particularly valuable in large scale manufacturing processes of complex and/or sensitive molecules.
  • Compound of formula (V) may be purified by a sequence where the reaction mixture is treated with a metal scavenger e.g. an extractive metal chelating agent, an organo- functionalised polysiloxane or polymer, activated carbon, or mixtures thereof.
  • a metal scavenger e.g. an extractive metal chelating agent, an organo- functionalised polysiloxane or polymer, activated carbon, or mixtures thereof.
  • the amount of metal scavenger to compound of formula (V) may be between 10% (w/w) and 100%(w/w), preferably between 10% (w/w) to 40% (w/w).
  • a satisfactory purity of the compound of formula (V) is in the range of 96 to 99%, preferably at least 98%.
  • the solid product is then obtained by precipitation by adding water or an aqueous solution of a metal chelating agent selected from the group comprising of ethylenediamine- tetraacetic acid, oxalic acid, citric acid or one of their metal salts e.g. sodium, potassium, calcium salts, or mixtures thereof.
  • a metal chelating agent selected from the group comprising of ethylenediamine- tetraacetic acid, oxalic acid, citric acid or one of their metal salts e.g. sodium, potassium, calcium salts, or mixtures thereof.
  • step 4 the salt formation, of the manufacturing process of the compound (VI), 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridm-2-yl]lH- indole-5-carbonitrile citrate salt, is performed by mixing the compound (V) with citric acid in the presence of a solvent.
  • the equivalent of citric acid may vary between 1 and 3 mole equivalents, preferably between 1 to 1.5 mole equivalent.
  • the reaction of step 4 may be performed in a solvent
  • suitable solvents are ethers such as 1,4-dioxane, diethyl ether or alcohols such as methanol, ethanol, propanol, or ketones such as acetone, isobutylmethylketone, or acetates such as ethyl acetate, butylacetate, or organic acids such as acetic acid, or mixtures thereof, optionally using water as an additive.
  • the total volume of solvents used may vary between 1 (v/w) to 100 (v/w) volume parts per weight of starting material, preferably between 10 (v/w) and 45 (v/w) volumes parts per weight of starting material.
  • the temperature of the reaction may be between -30 and 150 0 C, preferably between -5°C and 100 0 C.
  • Pure compound of formula (VI), 2-b.ydroxy-3-[5-(morpholm-4-yhnethyl)pyridin-2-yl] IH- indole-5-carbonitrile citrate, may be obtained by crystallising with or without an additive in suitable solvents to obtain a crystalline solid having a purity of about 95% and preferably about 98%.
  • the new synthetic route for the manufacture of (2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]l/f-indole-5-carbonitrile as a free base is performed as described in the three Steps 1 to 3 below, preferably wherein Rl is bromo and X is chloro.
  • room temperature means a temperature between 18 0 C and 25 0 C
  • halogen refers to fluoro, chloro, bromo or iodo
  • large scale means a manufacturing scale in the range of about 10 gram to 1 ton.
  • solvents may be used as pure solvents, or mixtures with other solvents in the steps in question.
  • the skilled person will appreciate that the different reaction steps need different reaction times.
  • the new large scale manufacturing process is more advantageous than the known processes with respect to commercial potential, safety, yield, and robustness.
  • a process of the present invention the use of potential explosive intermediates such as pyridine-N- oxides is avoided.
  • the present invention is also directed to new intermediates, namely intermediates of the compound of formula (III)
  • Rl is halogen, where halogen is chloro, bromo or iodo.
  • Especially preferred new intermediate is the compound of the formula (III) where Rl is bromo.
  • Another object of the present invention relates to the use of the compound of formula (III), wherein Rl is halogen, where halogen is chloro, bromo or iodo, preferably where the halogen is bromo, as an intermediate for the manufacturing of a pharmaceutically active compound.
  • Yet another object of the present invention relates to the use of the compound of formula (III), wherein Rl is halogen, where halogen is chloro, bromo or iodo, preferably where the halogen is bromo, as an intermediate for the manufacturing of 2-hydroxy-3-[5-(morpholin- 4-ylmethyl)pyridin-2-yl] lH-indole-5-carbonitrile and pharmaceutically acceptable salts thereof, particularly the citrate salt thereof.
  • Yet another object of the present invention is the selective reduction of the amide functional group in compounds of formula (III), wherein Rl is halogen, where halgen is chloro, bromo or iodo, preferably where the halogen is bromo, to form compounds of formula (IV) wherein Rl is halogen, where halgen is chloro, bromo or iodo, preferably where the halogen is bromo.
  • Yet another object of the present invention is the catalytic cyanation of compounds of formula (TV), wherein Rl is halogen, where the halogen is chloro, bromo or iodo, preferably where the halogen is bromo, under mild reaction conditions on a large scale manufacturing process.
  • Yet another object of the present invention is the development of a robust process for the catalytic cyanation of compounds of formula (IV) where the source of cyanide is added to a preheated mixture of compound of formula (IV), wherein Rl is halogen, where the halogen is chloro, bromo or iodo, preferably where the halogen is bromo, the catalyst and optional additive(s) in an appropriate solvent.
  • Yet another object of the present invention is the catalytic cyanation of compounds of formula (TV), wherein the Rl may be halogen, where the halogen is chloro, bromo or iodo for the manufacture 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]lH-indole-5- carbonitrile and pharmaceutically acceptable salts thereof, particularly the citrate salt thereof.
  • Yet another object of the present invention is the use of 2-hydroxy-3-[5-(morpholin ⁇ 4- ylmethyl)pyridin-2-yl]lH ' -indole-5-carbonitrile and pharmaceutically acceptable salts thereof, particularly the citrate salt thereof prepared according to a process described above under step a, b, c and optionally d for the manufacturing of a medicament for the treatment of cognitive disorders, Alzheimer's disease, dementias, chronic and acute neurodegenerative diseases, bipolar disorders, schizophrenia, diabetes, hair loss and all the listed disorders described in WO 03/082853.
  • Another object of the present invention is the new use in catalytic cyanation of aryl halides of prior disclosed Pd-catalyst such as di- ⁇ -bromobis(tri-tert-butylphosphine)dipalladium(I) ([BrPdP(t-Bu) 3 ] 2 ), the combination of tris(dibenzylideneacetone)dipalladium(0) or bis(dibenzylideneacetone)palladium(0) and tri- ⁇ r ⁇ o-tolylphosphine, the combination of tris(dibenzylideneacetone)dipalladium(0) or bis(dibenzylideneacetone)palladium(0) and 1 ,2,3,4,5-pentaphenyl-l '-(di-ferf-butylphosphino)ferrocene, bis(tri-terf-butylphosphine)- palladium(O) (Pd[P(t-Bu)3] 2 ), the combination
  • the reaction mixture was cooled to o 5O 0 C and saturated aqueous ammonium chloride solution (119L) was added over 2 h at such a rate that the internal temperature was kept in the range of 5O 0 C.
  • the resulting suspension was stirred for 1 h at 5O 0 C and then cooled down to an inner temperature of 15 0 C over 4 h and held there for 5 h.
  • the solid was filtered and the filter cake washed with water (3x16 L), then with cooled (5 0 C) methanol (2 x 6L) and washed with cooled (5°C) 5 TBME (6 L).
  • the mixture was stirred at I 0 C for 5 h and it was then allowed to warm to room temperature over 5 h and stirred there for an additional H h.
  • the resulting solution was cooled to -I 0 C and mixed with water/methanol (5.5 L/20.9 L) within 55 min keeping the inner temperature below 2 0 C.
  • After 1 h at 3 0 C the mixture was heated to 6O 0 C for 3 h.
  • the solvent (135 L) was then distilled off at 6O 0 C and the resulting suspension was cooled to an inner temperature of 4O 0 C before mixing with water (65 L).
  • the resulting suspension was stirred at 4O 0 C for 5 h and then cooled to an inner temperature of 3 0 C over 5 h and held there for 2h.
  • the schlenk tube was sealed with a rubber septum and then evacuated and re-filled with nitrogen gas twice.
  • Degassed dimethylformamide 14 mL was then added with a syringe.
  • the mixture was then heated under stirring to 50 0 C and kept there for 4 minutes before zinc cyanide (339 mg, 2.83 mmol) was charged against a positive flow of nitrogen.
  • the mixture was stirred at 5O 0 C for 3 h at which point of HPLC (high performance liquid chromatography) analysis showed 100% conversion and then cooled to room temperature and filtered through a sintered glass filter.
  • 3-Mercaptopropyl functionalized silica 0.3 g was then added to the filtrate and the mixture was stirred at 40 0 C over night and then filtered.
  • the schlenk tube was sealed with a rubber septum and then evacuated and re-filled with nitrogen gas twice.
  • Degassed dimethylformamide (7 mL) was then added with a syringe followd by t ⁇ -tert- butylphosphine (65 ⁇ L of a 20% w/v solution in toluene, 0.064 mmol).
  • the mixture was then heated under stirring to 50°C and kept there for 4 minutes before zinc cyanide (169 mg, 1.42 mmol) was charged against a positive flow of nitrogen.
  • the mixture was stirred at 5O 0 C for 3 h at which point HPLC analysis showed 100% conversion and then cooled to room temperature and filtered through a sintered glass filter.
  • Degassed dimethylformamide (0.7 mL) was then added with a syringe. The mixture was then heated under stirring to 5O 0 C and kept there for 5 minutes before zinc cyanide (17 mg, 0.14 mmol) was charged against a positive flow of nitrogen. The mixture was stirred at 5O 0 C for 2 h at which point of HPLC analysis showed 100% conversion and then cooled to room temperature and filtered through a sintered glass filter. 3-Mercaptopropyl functionalized silica (0.03 g) was then added to the filtrate and the mixture was stirred at 40 0 C over night and then filtered.
  • the schlenk tube was sealed with a rubber septum and then evacuated and re-filled with nitrogen gas twice.
  • Degassed dimethylformamide (0.7 mL) was then added with a syringe.
  • the mixture 0 was then heated under stirring to 5O 0 C and kept there for 5 minutes before zinc cyanide (17 mg, 0.14 mmol) was charged against a positive flow of nitrogen.
  • the mixture was stirred at 5O 0 C for 2 h at which point of HPLC analysis showed 100% conversion and then cooled to room temperature and filtered through a sintered glass filter.
  • 3-Mercaptopropyl functionalized silica (0.03 g) was then added to the filtrate and the mixture was stirred at 40°C over night and then filtered.
  • Degassed dimethyl- formamide (0.7 mL) was then added with a syringe. The mixture was then heated under stirring to 50 0 C and kept there for 5 minutes before zinc cyanide (17 mg, 0.14 mmol) was charged against a positive flow of nitrogen. The mixture was stirred at 5O 0 C for 2 h at which point of HPLC analysis showed 100% conversion and then cooled to room temperature and filtered through a sintered glass filter. 3-Mercaptopropyl functionalized silica (0.03 g) was then added to the filtrate and the mixture was stirred at 40 0 C over night and then filtered.
  • Example 12 2-Hydroxy-3-[5-(morpholin-4- ⁇ lmethyl ' )pyridin-2-yl11H-indole-5-carbonitrile using bisftri-?er/-butylphosphine)palladium(0), addition of zinc cyanide from the beginning 5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]lH-indol-2-ol (0.192 g, 0.505 mmol), zinc-dust (6 mg, 0.09 mmol), zinc cyanide (32 mg, 0.53 mmol)and bis(t ⁇ -tert- butylphosphine)palladium(O) (6.4 mg, 0.013 mmol) were added to a 10 mL schlenk tube with a magnetic stirbar.
  • the schlenk tube was sealed with a rubber septum and then evacuated and re-filled with nitrogen gas twice.
  • Degassed dimethylformamide 1.5 mL was then added with a syringe. The mixture was then stirred at 55 0 C for 1 h at which point HPLC analysis showed only starting material and no product.
  • Di- ⁇ -bromobis(tri-tert-butylphosphine)dipalladium(I) (0.168 kg was added to the slurry and the vessel was made inert by evacuation and refilling with nitrogen. The mixture was heated to 40 0 C and zinc cyanide (1.109 kg) was added to the suspension in one portion and the system was made inert again. The resulting mixture was heated to an inner temperature of 50°C and stirred for 3 h. HPLC indicated full conversion at this point.
  • the reaction mixture was filtered at an inner temperature of 5O 0 C and the filter cake was washed with dimethylformamide (3 L), mercaptopropyl functionalised silica (1.458 kg, 25%w/w) was added to the filtrate and the mixture was stirred for 82 h at an inner temperature of 5O 0 C.
  • the scavenger was filtered off and the filtrate was concentrated in vacuo.
  • aqueous ethylenediamine tetraacetic acid tetrasodium salt solution (0.3 M, 142 L) was added at an inner temperature of 40°C and the resulting mixture was stirred for 1 h keeping the inner temperature at 4O 0 C.

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Abstract

La présente invention concerne un nouveau procédé de fabrication du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1H-indole-5-carbonitrile sous forme de base libre ou de ses sels de qualité pharmaceutique, en particulier le citrate de 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1H-indole-5-carbonitrile, l'emploi desdits composés dans la fabrication d'un médicament pour le traitement des troubles cognitifs, de la maladie d'Alzheimer, des démences, des maladies neurodégénératives chroniques et aiguës, des troubles bipolaires, de la schizophrénie, du diabète, de l'alopécie, entre autres. La présente invention concerne également de nouveaux intermédiaires ainsi qu'un mode opératoire robuste de cyanation catalytique pour la synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1H-indole-5-carbonitrile sous forme de base libre et de ses sels de qualité pharmaceutique, de même qu'un nouvel intermédiaire synthétisé lors dudit procédé et adapté à la fabrication à grande échelle desdits composés. La présente invention concerne également une nouvelle application à la réaction de cyanation des catalyseurs au palladium.
PCT/SE2007/000088 2006-02-02 2007-01-31 Procédé de synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1h-indole-5-carbonitrile sous forme de base libre ou de ses sels Ceased WO2007089193A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US20100267720A1 (en) * 2007-07-30 2010-10-21 Astrazeneca Ab Crystalline Forms of 2-Hydroxy-3- [5- (Morpholin- 4- Ylmethyl) Pyridin-2-YL] IH- Indole- 5 -Carbonitrile Citrate
US8101750B2 (en) 2007-04-18 2012-01-24 Astrazeneca Ab Process for the manufacturing of the compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile 701
WO2012084855A2 (fr) 2010-12-21 2012-06-28 Bayer Cropscience Ag Procédé de préparation d'oxindoles substitués par triazinyle
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille

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EP0771786A1 (fr) * 1995-10-31 1997-05-07 Eli Lilly And Company Procédé de préparation de nitriles d'aryl et vinyl
WO2000026187A1 (fr) * 1998-11-02 2000-05-11 Synthon B.V. Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants
WO2002011883A1 (fr) * 2000-08-07 2002-02-14 Yale University Catalyseur pour formation de liaisons aromatiques c-o, c-n, et c-c
DE10113976A1 (de) * 2001-03-22 2002-09-26 Degussa Verfahren zur katalytischen Herstellung von aromatischen oder heteroaromatischen Nitrilen
WO2003082853A1 (fr) * 2002-03-28 2003-10-09 Astrazeneca Ab Nouveaux composes
US20040215020A1 (en) * 2001-01-04 2004-10-28 Rafael Foguet Process for preparing (+)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
EP1554266B1 (fr) * 2002-10-14 2006-03-22 Clariant Life Science Molecules (Italia) S.p.A. Procede d'elaboration de 3-alkylthiophenes a disubstitution en 2,5

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GB1012618A (en) * 1961-06-27 1965-12-08 Sterling Drug Inc Indolylalkyl piperidines and preparation thereof
EP0771786A1 (fr) * 1995-10-31 1997-05-07 Eli Lilly And Company Procédé de préparation de nitriles d'aryl et vinyl
WO2000026187A1 (fr) * 1998-11-02 2000-05-11 Synthon B.V. Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants
WO2002011883A1 (fr) * 2000-08-07 2002-02-14 Yale University Catalyseur pour formation de liaisons aromatiques c-o, c-n, et c-c
US20040215020A1 (en) * 2001-01-04 2004-10-28 Rafael Foguet Process for preparing (+)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
DE10113976A1 (de) * 2001-03-22 2002-09-26 Degussa Verfahren zur katalytischen Herstellung von aromatischen oder heteroaromatischen Nitrilen
WO2003082853A1 (fr) * 2002-03-28 2003-10-09 Astrazeneca Ab Nouveaux composes
EP1554266B1 (fr) * 2002-10-14 2006-03-22 Clariant Life Science Molecules (Italia) S.p.A. Procede d'elaboration de 3-alkylthiophenes a disubstitution en 2,5

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8101750B2 (en) 2007-04-18 2012-01-24 Astrazeneca Ab Process for the manufacturing of the compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile 701
US20100267720A1 (en) * 2007-07-30 2010-10-21 Astrazeneca Ab Crystalline Forms of 2-Hydroxy-3- [5- (Morpholin- 4- Ylmethyl) Pyridin-2-YL] IH- Indole- 5 -Carbonitrile Citrate
WO2012084855A2 (fr) 2010-12-21 2012-06-28 Bayer Cropscience Ag Procédé de préparation d'oxindoles substitués par triazinyle
US8962828B2 (en) 2010-12-21 2015-02-24 Bayer Intellectual Property Gmbh Method for producing triazinyl-substituted oxindoles
US9522904B2 (en) 2010-12-21 2016-12-20 Bayer Intellectual Property Gmbh Method for producing triazinyl-substituted oxindoles
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille

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