WO2004024707A2 - Procede permettant de preparer des benzofuranes a substitution amine - Google Patents

Procede permettant de preparer des benzofuranes a substitution amine Download PDF

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WO2004024707A2
WO2004024707A2 PCT/US2003/028396 US0328396W WO2004024707A2 WO 2004024707 A2 WO2004024707 A2 WO 2004024707A2 US 0328396 W US0328396 W US 0328396W WO 2004024707 A2 WO2004024707 A2 WO 2004024707A2
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formula
compound
group
cyanophenyl
alkyl
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PCT/US2003/028396
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WO2004024707A3 (fr
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Yi-Yin Ku
Yu-Ming Pu
Marlon D. Cowart
Timothy A. Grieme
Ashok K. Gupta
Daniel J. Plata
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Abbott Laboratories
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Priority claimed from US10/654,897 external-priority patent/US6822101B2/en
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Publication of WO2004024707A2 publication Critical patent/WO2004024707A2/fr
Publication of WO2004024707A3 publication Critical patent/WO2004024707A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to processes for preparing amine- substituted benzofuran compounds, and more particularly, 4-(2- ⁇ 2-[(2R)-2- methyl-1-pyrrolidinyl]ethyl ⁇ -1-benzofuran-5-yl)benzonitrile and salts thereof, as well as intermediates in such processes. Th ⁇ compounds have demonstrated activity as histamine-3 receptor ligands.
  • H 3 receptor ligands provide useful compounds for pharmaceutical products.
  • H 3 receptor ligands can be used for treatment of disorders related to cardiovascular processes, memory processes, such as Alzheimer's disease and attention-deficit hyperactivity disorder, neurological processes, cancer, sleep processes, and weight regulation, among other conditions.
  • Previous processes for preparing 2-(2-aminoethyl)-substituted benzofuran compounds generally involve halogenation of a starting phenol by treatment with sodium iodide and sodium hypochlorite, preferably in the presence of a base. The resulting iodinated phenol is subsequently converted into a functionalized benzofuran and the desired amine is appended. Many steps of the previous processes required chromatographic isolation and purification of intermediate compounds to provide a material possessing suitable qualities of purity and economy for the preparation of a pharmaceutical compound.
  • the invention relates to a process for preparing compounds of the formula (I)
  • A is heterocycle selected from pyrrolidinyl or piperidinyl, wherein the heterocycle is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl;
  • Ri is 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl of 4- cyanophenyl, aryl, or heteroaryl is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • the process comprises treating a compound of formula (II)
  • RA is selected from the group consisting of bromo, chloro, 4- cyanophenyl, aryl, and heteroaryl
  • the phenyl portion of the 4- cyanophenyl, the aryl, and the heteroaryl can be substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl, with a halogenating reagent selected from halogenating agents of the formula
  • X is bromo or iodo, N-iodoacetamide, N-bromoacetamide, N- iodophthalimide, N-bromophthalimide, iodine, bromine, ICI, IBr, BrCI, or an alkaline iodide or bromide with an oxidant, such as Nal and hydrogen peroxide, to provide a compound of formula (III)
  • R A is bromo, chloro, 4-cyanophenyl, aryl, or heteroaryl.
  • the phenyl moiety of 4-cyanophenyl and aryl and the heteroaryl can be substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • RA in a compound of formula (VI) is 4-cyanophenyl, aryl, or heteroaryl, the reaction provides compounds within the scope of formula (I).
  • Compounds of formula (III), (IV), (V), or (VI) wherein RA is bromo or chloro can be treated with a boronic acid reagent of formula (VIII)
  • Ri is 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl of 4- cyanophenyl, the aryl, and the heteroaryl are substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl; and R e and
  • Rt are each independently alkyl or R e and Rf are taken together to form a ring, wherein the ring is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl or aryl, which can be substituted as previously described for compounds of formula (I), to provide the corresponding product wherein R A is replaced by a substituent represented by Ri..
  • substituents selected from the group consisting of alkyl or aryl, which can be substituted as previously described for compounds of formula (I), to provide the corresponding product wherein R A is replaced by a substituent represented by Ri.
  • RA in a compound of formula (VI) is bromo or chloro, the reaction provides compounds within the scope of formula (I).
  • the invention relates to a process for preparing compounds of formula (I), as defined above, comprising at least the step of treating a compound of the formula:
  • RAI is selected from the group consisting of bromo, chloro, 4- cyanophenyl, aryl, and heteroaryl, and the phenyl portion of the 4- cyanophenyl, the aryl, and the heteroaryl can be substituted with 0, 1, 2, 3, or
  • a and R A ⁇ are as defined for compounds of formula (VII) and (lll-a), respectively.
  • the reaction is carried out using a palladium catalyst, metal halide, and base, wherein the palladium catalyst can be a palladium(O) or a palladium(ll) catalyst, for example, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetate)dipalladium, PdCI 2 (Ph 3 P) 2 , and the like.
  • the invention relates to a process for preparing a compound useful in the preparation of 2-(2-aminoethyl)-substituted benzofuran compounds demonstrating activity as H 3 -receptor ligands.
  • the process comprises the step of treating a compound of formula (II)
  • fluoroalkyl as used herein, means at least one fluorine atom is attached to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of fluoroalkyl include, but are not limited to, fluoromethyl, 2-fluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, and preferably 1 to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom, as defined herein.
  • Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl and hexylsulfanyl.
  • alkylthioalkyl refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group.
  • the alkylthio group typically is appended to the alkyl group via a sulfur atom.
  • Representative examples of alkylthio include, but are not limited to, methylsulfanylmethyl, ethylsulfanylmethyl, tert-butylsulfanylmethyl and hexylsulfanylmethyl.
  • aryl refers to a phenyl ring substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, and haloalkyl.
  • substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, and haloalkyl.
  • Examples of aryl include, but are not limited to, 4-cyanophenyl, 4- chlorophenyl, 4-methylphenyl, 4-phenylethanone, 4-trifluoromethyIphenyl, 4- trifluormethoxyphenyl, and the like.
  • cyano refers to a -CN group.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl refers to an aromatic five- or six- membered ring wherein 1 , 2, 3, or 4 heteroatoms are independently selected from N, O, or S.
  • the five-membered rings can have two double bonds or are a tautomer of a 5-membered ring having two double bonds.
  • the six- membered rings have three double bonds or are a tautomer of a 6-membered ring having three double bonds.
  • heteroaryl also includes bicyclic systems wherein the aromatic five- or six-membered ring is fused to a phenyl group.
  • heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • heteroaryl groups of the present invention are substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, and haloalkyl.
  • heterocycle refers to a saturated five- or six-membered ring containing a nitrogen atom.
  • the heterocycle can be substituted with 0, 1 , 2, 3, or 4 substituents selected from alkyl and fluoroalkyl.
  • Representative examples of heterocycle include, but are not limited to, 2-methylpyrrolidinyl, 2-fluoromethylpyrrolidinyl, pyrrolidinyl, and piperidinyl.
  • hydroxy refers to an -OH group.
  • the invention provides processes for preparing amine-substituted benzofuran derivatives and, more particularly, 2-(2-aminoethyl)-substituted benzofuran compounds.
  • the compounds prepared by the processes of the invention can have the formula (I),
  • A is a heterocycle selected from pyrrolidinyl or piperidinyl, wherein the heterocyclic group is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl; and Ri is 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl of 4-cyanophenyl and aryl, or the heteroaryl, is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • Such compounds have demonstrated activity as H 3 -receptor ligands.
  • the heterocyclic group for A is a saturated nitrogen ring, and preferably contains five or six members, including the nitrogen atom.
  • rings represented by the group A in a compound of formula (I) include, but are not limited to, pyrrolidinyl and piperidinyl.
  • the heterocyclic group, particularly the pyrrolidinyl group also can be substituted with substituents on the ring, for example, alkyl, fluoroalkyl, and the like.
  • substituted heterocyclic groups are 2-methylpyrrolidinyl, including (2R)-2-methylpyrroIidine and (2S)-2- methylpyrrolidine, 2-ethylpyrrolidinyl, and the like.
  • the preferred heterocyclic group for A in a compound of formula (I) is (2R)-2-methylpyrrolidine.
  • the heteroaryl group in compounds of formula (I), as represented by Ri represents an aromatic five- or six-membered ring wherein 1 , 2, 3, or 4 heteroatoms are independently selected from N, O, or S.
  • the five- membered rings have two double bonds or are tautomers of five-membered rings with two double bounds.
  • the six-membered rings have three double bonds or are tautomers of six-membered rings having three double bonds.
  • the invention also contemplates heteroaryl groups wherein the aromatic five- or six-membered ring is fused to a phenyl group.
  • heteroaryl groups suitable for compounds of formula (I) include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl, and the like.
  • the preferred heteroaryl groups are pyrimidinyl, pyrazinyl, and pyrazolyl.
  • heteroaryl groups of the present invention can be substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • the aryl group in compounds of formula (I), as represented by Ri can include, but are not limited phenyl groups substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • Examples of aryl include, but are not limited to, 4-cyanophenyl, 4- chlorophenyl, 4-methylphenyl, 4-phenylethanone, 4-trifluoromethylphenyi, 4- trifluormethoxyphenyl, and the like.
  • compounds of formula (II) can be treated with a halogenating reagent to provide a compound of formula (III).
  • Compounds of formula (II) are those wherein R A represents bromo, 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl portion of 4-cyanophenyl, the aryl, or the heteroaryl group can be substituted with various substituents.
  • suitable substituents can include, for example, alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • the compound of formula (II) is purchased commercially or prepared from commercially available 4-bromophenol.
  • 4- bromophenol can be treated with heteroarylboronic acids or heteroaryl boronate esters and a palladium complex and a phosphine in the presence of a base to provide suitable starting materials for the process, wherein RA is 4- cyanophenyl or heteroaryl.
  • Examples of palladium complexes suitable for preparing a compound of formula (II) include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) and palladium acetate.
  • the phosphine can include, but is not limited to, 2-(dicyclohexylphosphino)biphenyl and 2-(dicyclohexylphosphino)biphenyl.
  • the reaction is carried out in the presence of a base for example, sodium carbonate or potassium phosphate, at above room temperature.
  • a base for example, sodium carbonate or potassium phosphate
  • Examples of more specific conditions for accomplishing the reaction include treating the 4-bromophenol with a heteroarylboronic acid, tetrakis(triphenylphosphine)palladium(0) and
  • the reaction typically is accomplished in about 1 to about 36 hours.
  • heteroarylboronic acids are 4- cyanophenyl boronic acid, pyridine-3-boronic acid, and the like.
  • halogenating reagent selected from N-iodosuccinimide or N- bromosuccinimide and an acid as shown in Scheme 1.
  • Alternative halogenating agents include, but are not limited to, N-iodoacetamide, N- bromoacetamide, N-iodophthalimide, N-bromopthalimide, iodine, bromine, ICI, IBr, BrCI, an alkaline iodide or bromide with an oxidant such as with Nal and hydrogen peroxide.
  • the amount of halogenating reagent suitable for the reaction can include from about 1 to about 3 molar equivalents relative to the amount of compound having the formula (II).
  • a preferred amount of halogenating reagent is from about 0.90 to about 1 molar equivalent of the succinimide.
  • about 1 mole of halogenating reagent is used for each mole of the compound of formula (II).
  • the reaction is accomplished in an organic solvent or in a weak acid in the presence of a catalytic amount of strong acid.
  • a specific example of a suitable solvent is acetonitrile.
  • a weak acid suitable for the reaction is acetic acid in the presence of a strong acid, for example, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • a strong acid for example, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • N-iodosuccinimide is reacted with the compound of formula (II) in acetic acid in the presence of a stronger acid, such as sulfuric acid, while maintaining the reaction at or below room temperature, for example at or less than 27 °C.
  • a preferred amount of concentrated sulfuric acid is from about 0.025 to about 0.075 molar equivalents, relative to the starting material of formula (II). The preferred amount of sulfuric acid is about 0.05 equivalents.
  • the preferred alkynol is 3-butyn-1-ol, but compounds that provide alcohols equivalent to the 3-butyn-1-ol also can be used, for example alkynes that include protected forms of 3-butyn-1-ol, R p OCH 2 CH 2 C ⁇ CH, where the R p is a protecting group.
  • Typical protecting groups are described for instance in Green and Wuts, "Protecting Groups in Organic Synthesis", 3rd edition, published by John Wiley and Sons, New York (1999), and which may be appended onto the 3-butyn-1-ol, and subsequently removed by the methods therein. In this case, removal of the protecting group R p in the product will generate compounds of structure (IV).
  • Examples of specific protecting groups represented by R p include, but are not limited to, triethylsilyl, acetyl, benzoyl, and tetrahydropyran-2-yl. Typically, from about 1 to about 2 equivalents of the alkynol are used relative to one mole of the compound of formula (II).
  • suitable palladium sources include, but are not limited to, palladium(ll) acetate, tetrakis(triphenylphosphine)palladium, and tris(dibenzylideneacetate)dipalladium.
  • the preferred palladium catalyst is palladium (II) acetate.
  • a phosphine suitable for the reaction can be triphenylphosphine.
  • Other examples of phosphines suitable for the reaction can include, triphenylphosphine, bis(diphenylphosphine)methane, bis(diphenylphosphine)ethane, tri(o-tolyl)phosphine, and the like.
  • the ratio of palladium catalyst to phosphine generally ranges from about 1 :1 to about 1:8 relative to the palladium source. Preferably, about two molar equivalents of phosphine are used for one mole of the palladium source.
  • a useful metal halide is copper(l) iodide.
  • Alternative and additional halides can include, but are not limited to, copper(l) bromide.
  • the amount of metal halide used ranges from about 1 :1 to about 1 :2 relative to the phosphine.
  • the reaction preferably is carried out in the presence of a base.
  • Suitable bases include, but are not limited to, diisopropylamine, diethylamine, dipropylamine, triethylamine, isopropylethylamine, pyrrolidine, or piperidine, in a solvent including, but not limited to, isopropyl acetate to provide compounds of formula (IV).
  • the compound of formula (IV) can be isolated and separated by column chromatography, it is not necessary to isolate or purify the product to provide a useful starting material for the hydroxy protection step of preparing a compound of formula (V), which follows.
  • Compounds of formula (IV) can be treated with a sulfonating reagent in basic conditions to provide compounds of formula (V).
  • the sulfonating reagent provides a toluenesulfonyl group to activate the hydroxy group of a compound of formula (IV) as shown in Scheme 1.
  • suitable sulfonating reagents can include, but are not limited to, para- toluensulfonic chloride and para-toluenesulfonic anhydride.
  • Alternative sulfonating agents also can provide similarly reactive and useful products related to compounds of formula (V) when reacted with compounds of formula (IV).
  • Such sulfonating agents can include, but are not limited to, methane sulfonic anhydride, methane sulfonyl chloride, and triflic anhydride, wherein the toluenesulfonyl moiety of a compound of formula (V) is replaced with a methansulfonyl or trifluoromethanesulfonyl group.
  • Basic conditions to accomplish the reaction include, for example, treating the compound of formula (IV) with N,N-dimethylaminopyridine and a base.
  • Suitable bases for the reaction can include, for example, triethylamine, pyridine, and the like. The preferred base is triethylamine.
  • Suitable solvents for the reaction typically are aprotic solvents, for example acetonitrile, tetrahydrofuran, dichloromethane, and the like.
  • the sulfonating reagent is reacted with the compound of formula (IV) in a range of from about 1 :1 to about 1 :5 molar equivalents, relative to the compound of formula (IV).
  • about 3 molar equivalents of sulfonating reagent are used for each mole of the compound of formula (IV).
  • the reaction can be carried out in at least room temperature. Typically, the reaction will be accomplished in from about 1 to 2 hours.
  • the product of formula (V) can be, but need not be, isolated and purified according to conventional methods for use in reaction attaching the amine.
  • the preferred reagent is a cyclic amine reagent, for example pyrrolidine or piperidine.
  • the reaction can be accomplished in a solvent, for example, acetonitrile, ethanol, methanol, isopropyl alcohol or a mixture thereof.
  • the pyrrolidine or piperidine reagent can include 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl.
  • Suitable amine reagents can be provided as the amine compound, for example, 2-methylpyrrolidine, or as a salt of the amine compound, such as 2-methylpyrrolidine tartrate. Examples of suitable amine reagents include, but are not limited to, 2-methylpyrrolidine, 2-ethylpyrrolidine,
  • 2-fluoromethyIpyrrolidine and the salts thereof.
  • suitable salts of the amine reagent include, but are not limited to, tartrate, lactate, chloride, and succinate salts.
  • the reaction typically is accomplished in the presence of a weak base, for example, potassium carbonate, and the like.
  • the preferred amine reagent for the reaction is pyrrolidine, including the (2R)-2- methylpyrrolidine enantiomer and the (2S)-2-methylpyrrolidine enantiomer. The more preferred enantiomer is (2R)-2-methylpyrrolidine.
  • the invention provides processes for preparing amine- substituted benzofuran compounds as shown below in Scheme 2.
  • 3-butynyl-4-methylbenzenesulfonate is reacted with an amine reagent of formula AH, wherein A represents a heterocyclic group selected from pyrrolidinyl or piperidinyl.
  • A represents a heterocyclic group selected from pyrrolidinyl or piperidinyl.
  • the pyrrolidinyl group or the piperidinyl group can be substituted as previously described for the compound of formula (I).
  • the 3-butynyl-4-methylbenzenesulfonate, or 3-butynyl-4- toluenesulfonate is prepared by treating 3-butyn-1-ol with a sulfonating reagent including, but not limited to, para-toluensulfonic chloride or para- toluenesulfonic anhydride, and a base.
  • a sulfonating reagent including, but not limited to, para-toluensulfonic chloride or para- toluenesulfonic anhydride
  • bases for the reaction can include, but not is limited to, triethylamine, as previously described.
  • Suitable solvents for the reaction can include, but is not limited to, acetonitrile, tetrahydrofuran, or mixtures thereof.
  • the conditions for the reaction are similar to those previously described for the protection of the compound of formula (IV) in Scheme 1 , from which a compound of formula (V) is obtained.
  • 3-Butynyl-4-methylbenzenesulfonate can be treated with the amine reagent in an aprotic solvent, preferably in the presence of base, to provide compounds of formula (VII).
  • the reaction conditions are similar to those described for providing compounds of formula (VI) in Scheme 1.
  • the preferred base is potassium carbonate.
  • the preferred solvent for the reaction includes, but is not limited to, acetonitrile, ethanol, methanol, isopropyl alcohol or a mixture thereof.
  • the reaction is carried out at above room temperature, for example in a temperature of from about 80 °C to about 100 °C.
  • the preferred temperature for the reaction is about 85 °C.
  • the amine reagents also are similar to those previously described for coupling the amine group to compounds of formula (V) in Scheme 1.
  • the preferred amine reagent is 2-methylpyrrolidine and, more particularly, the 2-methylpyrrolidine tartrate salt.
  • Compounds of formula (VII) can be treated with compounds of formula (lll-a), wherein R A ⁇ is bromo or 4-cyanophenyl and the phenyl of 4- cyanophenyl is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl, to provide compounds of formula (Vl-a), wherein RAI is as defined for compounds of formula (lll-a).
  • the reaction is accomplished in a manner similar to the conditions described for the preparation of a compound of formula (IV) as previously described.
  • the reaction is accomplished in the presence of a palladium catalyst, preferably a Pd(0) or Pd(ll) catalyst in combination with a phosphine ligand for the palladium.
  • a palladium catalyst preferably a Pd(0) or Pd(ll) catalyst in combination with a phosphine ligand for the palladium.
  • the reaction is carried out using a metal halide and a base.
  • palladium catalysts can include, for example, Pd(Ph 3 P) 4 , Pd(dba), Pd 2 (dba) 3 , Pd(Pcy 3 ) 2 , Pd(dppe), Pd(dppf), PdCI 2 (Ph 3 P) 2 , PdCI 2 (dppf) 2 , PdCI 2 (dppe) 2 , and PdCI 2 (CH 3 CN) 2 .
  • Pd(Ph 3 P) for tetrakis(triphenylphosphine)palladium
  • Pd(dba) for (dibenzylideneacetate)palladium
  • Pd 2 (dba) 3 for tris(dibenzylideneacetate)dipalladium
  • Pd(Pcy 3 )2 for bis(tricyclohexylphosphine)palladium
  • Pd(dppe) for (2- (diphenylphosphino)ethyl)palladium
  • Pd(dppf) for (1 ,1 - bis(diphenylphosphino)ferrocene)palladium
  • PdCI 2 (Ph 3 P) 2 for bis(triphenylphosphine)dichloropalladium
  • PdCI 2 (dppf) 2 for bis(1 ,1'- bis(diphenylphosphino)ferrocene)
  • preferred palladium sources include, but are not limited to, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetate)dipalladium, and PdCI 2 (Ph 3 P) 2 .
  • the palladium catalyst is PdCI 2 (Ph 3 P) 2 .
  • Suitable phosphine ligands that can be coordinated with the palladium catalyst are, for example, triphenylphosphine, bis(diphenylphosphine)methane, bis(diphenylphosphine)ethane, tri(o- tolyl)phosphine, and the like.
  • the reaction may, but need not, include the use of a phosphine ligand, depending on the palladium catalyst used.
  • palladium catalysts already coordinated with a phosphine ligand are not used in combination with additional phosphine ligands.
  • Suitable bases for the reaction can include, but are not limited to, diisopropylamine, diethylamine, dipropylamine, triethylamine, isopropylethylamine, pyrrolidine, piperidine, or mixtures thereof.
  • the preferred base is diisopropylamine.
  • Suitable solvents for the reaction can include, but are not limited to, acetonitrile, ethyl acetate, isopropyl acetate, tetrahydrofuran, and mixtures thereof. The preferred solvent is acetonitrile.
  • the amine of formula (VII) is reacted with the compound of formula (lll-a) in an amount of from about 1 :1 to about 1 :3 molar equivalents, relative to the compound of formula (lll-a). It is preferred that two molar equivalents of amine are reacted with one molar equivalent of a compound of formula (lll-a). Under the preferred conditions, the reaction is carried out with copper(l) iodide in diisopropylamine in the presence of a PdCI 2 (Ph 3 P) 2 catalyst.
  • R is 4-cyanophenyl, aryl, or heteroaryl, to provide a corresponding compound of each respective formula, wherein R A is 4-cyanophenyl, aryl, or heteroaryl.
  • the phenyl portion of the 4-cyanophenyl, the aryl, and the heteroaryl can be substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, and haloalkyl, as previously described for compounds of formula (I). More particularly, the process is preferred for compounds wherein Ri is 4- cyanophenyl.
  • Boronic acid esters of formula (Vlll-a) also can be substituted for boronic acids of formula (VIII) (Vlll-a).
  • the R e and R f in compounds of formula (Vlll-a) are alkyl, or alternatively R e and R f taken together to form a ring, preferably a C C 6 ring, wherein the ring can be substituted with 0, 1, 2, 3, or 4 alkyl or aryl groups and Ri is as defined for compounds of formula (VIII).
  • suitable compounds of formula (Vlll-a) include, but are not limited to, (CH 3 O) 2 BPh, (4- cyanomethylphenyl)boronic acid, pinacol ester (CombiBlocks Inc., San Diego).
  • Boronic acids of formula (VIII) are commercially available or can be prepared by methods well known to those skilled in the art of synthetic organic chemistry.
  • Takagi et al. (Tetrahedron Letters, (2002) 43, 5649- 5651) describe preparing heteroaryl pinacolborane esters of formula (Vlll-a) using heteroaromatic compounds and reaction with bis(pinacolborane) in the presence of an iridium catalysis of lrCI[COD]2-(4, 4'-di-t-butyl-2,2'-bipyridine) in octane.
  • Miyaura reaction described in: Ishiyama, Tatsuo; Ishida, Kousaku; Miyaura, Norio; Tetrahedron (2001) 9813 - 9816, in which aryl and heteroaryl halides are reacted with bis(pinacolborane), KOAc, and Pd 2 dba 3 and tris-cyclohexylphosphine or PdCI 2 dppf (Ishiyama, et al. Tetrahedron (2001) 9813-9816).
  • boronic acids include, but are not limited to, 4-cyanophenylboronic acid, pyridine-3-boronic acid, pyrimidine-5-boronic acid pinacol ester, and the like.
  • the preferred boronic acid is 4-cyanophenylboronic acid.
  • RA2 in compounds of formula (lll-c), (IV-c), and (V- c) and Ri in compounds of formula (I) in Schemes 3-6 represent a 4- cyanophenyl group, aryl, or a heteroaryl group.
  • the process of the invention is particularly beneficial for compounds wherein RA2 or Ri is 4-cyanophenyl.
  • RA 4-cyanophenyl, aryl, or heteroaryl and A is as previously defined can be, but need not be, isolated and purified to provide compounds of formula (I).
  • the compound of formula (VI) or (Vl-a) can be isolated and purified, typically by chromatographic methods, using conventional methods in the art to provide a desired compound.
  • Examples of conventional methods for isolating and purifying compounds of formula (VI) or (Vl-a) can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and
  • a compound of formula (VI) can be treated with an acid to form a desired salt.
  • a compound of formula (VI) or (Vl-a) is reacted with an acid at above room temperature to provide the desired salt.
  • acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, or hydroxybutyric acid, and the like.
  • a preferred acid is tartaric acid and, more specifically, (L)-tartaric acid.
  • the reaction is accomplished at above room temperature.
  • the reaction is carried out in a temperature of from about 50 °C to about 75 °C.
  • the preferred temperature for the reaction is about 60 °C.
  • the desired salt can be isolated by filtration in pure form. The recrystallization procedure may be repeated to afford product of even higher purity.
  • the processes of the invention are particularly useful for preparing 4- (2- ⁇ 2-[(2R)-2-methyl-1 -pyrro!idinyl]ethyl ⁇ -1 -benzofuran-5-yl)benzonitrile and salts thereof.
  • a particular example of a process for preparing 4-(2- ⁇ 2-[(2R)-2- methyl-1-pyrrolidinyl]ethyl ⁇ -1-benzofuran-5-yl)benzonitrile, and salts thereof, comprises the steps of:
  • Yet another aspect of the invention relates to preparing a compound of formula (III), which provides useful intermediates in the preparation of amine- substituted benzofuran derivatives described herein.
  • Such process comprises the step of reacting a phenol of formula (II) with a suitable halogenating reagent, as shown in Scheme 7, below.
  • R c is 4-cyanophenyl, wherein the phenyl portion of 4-cyanophenyl is substituted with 0, 1 , 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.
  • R c is 4- cyanophenyl without additional subsituents on the phenyl moiety.
  • the compound can be used as an intermediate or starting material for preparing compounds of formula (I), which also is contemplated as an aspect of the invention.
  • (2R)-2-methylpyrrolidine hydrobromide also is a suitable source of (2R)-2-methyIpyrrolidine, and was prepared from L-prolinol (which also called (S)-(+)-pyrrolidinemethanol, Chemical Abstracts number 23356-96-9, Aldrich Chemical Co., Milwaukee, Wis.) using the procedure described by Nijhuis, Walter H.N., et al., J.Org.Chem., 54(1): 209-216, 214 (1989). Other procedures describing the synthesis of R-2-methylpyrrolidine and salts thereof can be found in Andres,
  • (2S)-2-Methylpyrrolidine can be substituted for (2R)-2- methylpyrrolidine in the experimental procedures provided herein.
  • the (2S)- 2-methylpyrrolidine can be prepared by procedures described in Kim, Mahn-
  • the mixture was then treated with diisopropylamine (1.97 kg, 19.37 mol), by addition over about 30 minutes. After 2 hours, the suspension was heated to about 40 °C. After about 8 hours, the reaction mixture was cooled to room temperature and filtered through a pad of Celite ® . The pad was washed with isopropyl acetate (12 kg) and the filtrate was washed with 5% NaHCO 3 solution and then washed with water. The organic layer was then distilled to dryness. The residue (2.03 kg, 80% assayed yield) was carried onto the tosylation step. A small sample was purified by silica gel chromatography.
  • Example 1C 2-[5-(4-cvanophenyl)-1-benzofuran-2-yl1ethyl 4-methylbenzenesulfonate
  • the product from Example 1B (2.03 kg, 7.71 mol) in acetonitrile (31.8 kg) was treated in succession with triethylamine (1.86 kg, 18.34 mol), 4-(dimethylamino)pyridine 0.10 kg, 0.87 mol), and p-toluenesulfonyl chloride (3.50 kg, 17.99 mol).
  • the reaction mixture was distilled to a minimum volume and treated with isopropyl alcohol (24.1 kg).
  • Potassium carbonate powder (2.28 kg, 16.5 mol, 325 mesh) and milled (2R)-2-methylpyrrolidine tartrate (1.78 kg, 7.48 mol) were combined in acetonitrile (37.4 kg) and heated at 55 °C with agitation for 36 hours.
  • the mixture was chilled to about 25 °C, and the product from Example 1C (2.07 kg, 4.98 mol) was added to the mixture in portions.
  • the reaction mixture was heated at 65 °C with agitation for about 48 hours.
  • the mixture was cooled to about 25 °C, filtered, and the filtrate was concentrated to a volume of about 10 L.
  • the mixture was partitioned between toluene (32.3 kg) and 5% NaHCO 3 solution (23.7 kg).
  • the organic phase was separated and washed with 5% NaHCO 3 solution (23.7 kg).
  • the organic phase was then extracted with a mixture of CH 3 SO 3 H:N-methylpyrrolidinone:H 2 O (10:20:70 v/v/v) (32 kg, 8.0 kg respectively).
  • the extract was treated with isopropyl acetate (32.5 kg) and the pH adjusted to about 12 with 50% NaOH solution (about 4.9 kg) at about 30 °C.
  • the organic phase was separated and the aqueous phase was extracted with isopropyl acetate (IPAC) (6.0 kg).
  • IPAC isopropyl acetate
  • the organic phases were combined, washed with 5% NaHCO 3 (33 kg x3), distilled water (33 kg x2), distilled to a volume of about 10 L, and chased with IPAC (15.6 kg) to about 10 L.
  • the mixture was diluted with isopropyl alcohol (14.5 kg) and concentrated to 10 L. Additional 14.5 kg of isopropyl alcohol was added and the solution concentrated to a volume of 10 L.
  • the solution was treated with active carbon (Darco KB-B, 0.125 kg) and heated at 30 °C with stirring for 1 hour.
  • the mixture was filtered through a pad of Celite ® and the Celite ® washed with isopropyl alcohol (6.3 kg). The filtrate (about 13 kg) was used directly in the next step (1.17 kg).
  • Example 1 D The solution from Example 1 D was diluted with absolute ethanol (5.0 kg), heated at 65 °C, and treated with a solution of (L)-tartaric acid (0.56 kg, 3.73 mol) in absolute ethanol (8.0 kg) slowly. The mixture was cooled to about 25 °C, agitated for about 16 hours, cooled to 0 °C for 2 hours, and filtered. The filter cake was washed with isopropyl alcohol (5.0 kg), dried at 60 °C for about 24 hours to provide 1.46 kg of the title compound as a solid (61% isolated yield from the tosylate).
  • Example 2A The solution from Example 2A (3.02g, 22.0 mmol) in CH 3 CN (49.5 mL) was purged with nitrogen and treated with the product from Example 1 A (3.21 g, 10.0 mmol), Cul (38 mg, 0.2 mmol), PdCI 2 (Ph 3 P) 2 (70 mg, 0.2 mmol), and diisopropylamine (8.4 ml, 60 mmol).
  • the mixture was stirred at room temperature under nitrogen until reaction was near complete by HPLC.
  • the reaction mixture was concentrated to about 30 mL, treated with toluene (100 mL), washed with 5% NaHCO 3 (2X100 mL), and 10% NH 4 CI (2X100 mL).
  • the organic layer was separated, filtered through a pad of Celite ® , and extracted with (CH 3 SO 3 H:N-methylpyrrolidinone:H 2 O, 10:20:70) (2X100 mL).
  • the aqueous layer was extracted with IPAC (2X100 mL), basified with 50%
  • potassium carbonate (1.38 g, 10.0 mmol) were combined in acetonitrile (20 mL) and heated at 60 °C for 1 hour.
  • the mixture was treated with 3-butynyl 4- methylbenzenesulfonate (673 mg, 3.0 mmol) and heated at about 60 °C overnight.
  • the mixture was cooled to about 5 °C and filtered.
  • Example 4A 2-(5-bromo-1-benzofuran-2-yl)ethanol The product from Example 3A (14.95 g, 50 mmol), palladium(ll) acetate
  • Example 4B 2-(5-bromo-1 -benzofuran-2-yl)ethyl 4-methylbenzenesulfonate
  • the product from Example 4A (1.21 g, 5.0 mmol), 4-dimethylaminopyridine (0.06 g, 0.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) were combined in dichloromethane (20 mL) stirred briefly and treated with para-toluenesulfonyl chloride (1.91 g, 10.0 mmol) in dichloromethane (2 mL) over about 5 minutes.
  • (2R)-2-Methylpyrrolidine tartrate (0.70 g, 3.0 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were combined in acetonitrile (12 mL).
  • the slurry was heated at 60 °C for 1 hour, treated with the product from Example 4B (790 mg, 2.0 mmol).
  • the mixture was heated at about 60 °C for 6 hours, cooled to 25 °C, and diluted with toluene (30 mL).
  • Example 4D 4-(2- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinyllethyl)-1-benzofuran-5-yl)benzonitrile
  • the title compound can be prepared using the procedure described in Example 3C.
  • Example 5 4-[2-(2-hvdroxyethyl)-1-benzofuran-5-vnbenzonitrile
  • the product from Example 4A (241 mg, 1.0 mmol), 4-cyanophenylboronic acid (221 mg, 1.5 mmol), tetrakis(triphenylphosphine) palladium (0) (57.5 mg, 0.05 mmol), 2-(dicyclohexyl phosphino)biphenyl (35.0 mg, 0.10 mmol), and sodium carbonate (160 mg, 1.5 mmol) were combined in 1 ,2-dimethoxyethane (16 mL) and water (6 mL) and heated at 80 °C overnight.
  • Example 6 4-(2- ⁇ 2-f(2S)-2-methyl-1-pyrrolidinvnethyl)-1-benzofuran-5-yl)benzonitrile 4- ⁇ 2-[2-(2(S)-Methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl ⁇ -benzonitrile can be prepared by the method described in Examples 2A and 2B, except that (S)-2-methylpyrrolidine tartrate is used in the place of (2R)-2- methylpyrrolidine tartrate in step 2A.
  • Examples 7-15 The following compounds can be prepared by using the methods described in Example 3c, but substituting the corresponding boronic acid and boronic acid ester compounds in place of 4-cyanophenylboronic acid as shown below in Table 1.

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Abstract

La présente invention concerne des procédés permettant de préparer des benzofuranes à substitution amine, et plus particulièrement, du 4-(2-{2-[(2R)-2-méthyl-1-pyrrolidinyl]éthyl}-1-benzofurane-5-yl)benzonitrile, et des sels associés. Les composés préparés selon les procédés décrits dans cette invention présentent une activité en tant que ligands des récepteurs de l'histamine-3.
PCT/US2003/028396 2002-09-16 2003-09-10 Procede permettant de preparer des benzofuranes a substitution amine WO2004024707A2 (fr)

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WO2008137087A1 (fr) * 2007-05-03 2008-11-13 Cephalon, Inc. Procédé de préparation de la (r)-2-méthylpyrrolidine, de la (s)-2-methylpyrrolidine et de leurs tartrates
WO2024033454A1 (fr) * 2022-08-12 2024-02-15 F. Hoffmann-La Roche Ag Composés hétéroaryle pour le traitement du cancer

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EP0567967A1 (fr) * 1992-04-28 1993-11-03 Dr. Karl Thomae GmbH Composés marqués au tritium utilisé comme antagonistes de récepteur de fibrinogen et leur préparation
EP0721947A1 (fr) * 1995-01-11 1996-07-17 Adir Et Compagnie Nouveaux composés (hétéro)cycliques alkylés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
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EP0721947A1 (fr) * 1995-01-11 1996-07-17 Adir Et Compagnie Nouveaux composés (hétéro)cycliques alkylés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US20020183309A1 (en) * 2001-03-16 2002-12-05 Cowart Marlon D. Novel amines as histamine-3 receptor ligands and their therapeutic applications
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WO2008137087A1 (fr) * 2007-05-03 2008-11-13 Cephalon, Inc. Procédé de préparation de la (r)-2-méthylpyrrolidine, de la (s)-2-methylpyrrolidine et de leurs tartrates
JP2010526142A (ja) * 2007-05-03 2010-07-29 セファロン、インク． （ｒ）−２−メチルピロリジンおよび（ｓ）−２−メチルピロリジンならびにその酒石酸塩を調製するための方法
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WO2024033454A1 (fr) * 2022-08-12 2024-02-15 F. Hoffmann-La Roche Ag Composés hétéroaryle pour le traitement du cancer

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