This application claim the benefit of provisional application No. 60/411,210, filed 16 Sep. 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to processes for preparing amine-substituted benzofuran compounds, and more particularly, 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile and salts thereof, as well as intermediates in such processes. The compounds have demonstrated activity as histamine-3 receptor ligands.

2. Description of Related Technology

Benzofuran derivatives, particularly amine-substituted benzofuran derivatives such as 2-(2-aminoethyl)-substituted benzofuran compounds, have demonstrated activity as histamine-3 (H3) receptor ligands. Histamine-3 receptor ligands provide useful compounds for pharmaceutical products. For example, H3 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. One particular compound, having the structure

and the IUPAC name 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile demonstrates promising activity for use as a pharmaceutically active H3-receptor ligand. The compound has demonstrated promising activity for enhancing learning and cognition. The compound, related derivatives thereof, and processes for preparing the compound and derivatives are described in commonly-owned copending U.S. patent applications Ser. No. 09/810,648, filed Mar. 16, 2001; Ser. No. 10/044,495, filed Jan. 11, 2002; and Ser. No.10/081,207, filed Feb. 22, 2002.

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. Although such processes provide beneficial methods for preparing amine-substituted benzofuran compounds, and particularly, 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonit it would be beneficial to provide processes for preparing such compounds while reducing or eliminating isolation and purification steps and/or increasing reaction product yield. Such processes would provide for efficient, beneficial preparation of high-grade pharmaceutical compounds.

Accordingly, there remains a need to provide improved processes for making amine-substituted benzofurans. It would be beneficial to provide a process for preparing 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl) in particular, and salts thereof.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a process for preparing compounds of the formula (I)

or a salt thereof, wherein

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; and

R1 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)

wherein RA 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 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

wherein X is bromo or iodo, N-iodoacetamide, N-bromoacetamide, N-iodophthalimide, N-bromophthalimide, iodine, bromine, ICl, IBr, BrCl, or an alkaline iodide or bromide with an oxidant, such as Nal and hydrogen peroxide, to provide a compound of formula (III)

wherein RA and X are as previously defined.

Compounds of formula (III) are treated with 3-butyn-1-ol to provide a compound of formula (IV)

Compounds of formula (IV) are treated with a sulfonating reagent to provide a compound of formula (V)

wherein RB represents a toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate group. In addition, compounds of formula (III) are treated with a toluenesulfonyl butanol to provide (V), wherein RB represents a toluenesulfonate group, directly.

Compounds of formula (V) are treated with an amine reagent, preferably selected from the group consisting of pyrrolidine and piperidine, wherein the pyrrolidine or piperidine is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl to provide compounds of formula (VI),

wherein RA 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. Wherein 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)

(HO)2BR1(VIII)

or a boronate ester compound of the formula (VIII-a)

(ReO)(RfO)BR1(VIII-a),

wherein R1 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 Re and Rf are each independently alkyl or Re 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 RA is replaced by a substituent represented by R1. Wherein RA in a compound of formula (VI) is bromo or chloro, the reaction provides compounds within the scope of formula (I).

In another embodiment, 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:

wherein RA1 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 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl, and X is bromo or iodo, with a compound of formula (VII)

wherein A is a heterocyclic group selected from the group consisting of pyrrolidinyl and piperidinyl, and the heterocyclic group can be substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl, to provide a compound of formula (VI-a)

wherein A and RA1 are as defined for compounds of formula (VII) and (III-a), respectively. Typically, the reaction is carried out using a palladium catalyst, metal halide, and base, wherein the palladium catalyst can be a palladium(0) or a palladium(II) catalyst, for example, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetate)dipalladium, PdCl2(Ph3P)2, and the like.

Compounds of formula (VI-a), wherein RA1 is bromo or chloro, can be treated with a compound of formula (VIII)

(HO)2BR1(VIII),

or a compound of formula (VIII-a)

(ReO)(RfO)BR1(VIII-a),

wherein R1, Re and Rf are as previously described, to provide compounds of formula (I). Particularly, it is preferred that R1 is 4-cyanophenyl. Compounds of formula (VI-a), wherein RA1 is 4-cyanophenyl, aryl, or heteroaryl, are within the scope of compounds of formula (I), as previously described.

In yet another aspect, the invention relates to a process for preparing a compound useful in the preparation of 2-(2-aminoethyl)-substituted benzofuran compounds demonstrating activity as H3-receptor ligands. The process comprises the step of treating a compound of formula (II)

wherein RA is selected from the group consisting of bromo, chloro, 4-cyanophenyl, aryl, and heteroaryl, as previously defined, with a halogenating reagent of the formula:

wherein X is bromo or iodo, to provide a compound of formula (III)

wherein RA is as described for compounds of formula (II). The reaction is particularly useful in preparing a compound of formula (III) wherein X is iodo or bromo and RA is 4-cyanophenyl, which can be used in preparing 2-(2-aminoethyl)-substituted benzofuran compounds, particularly 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile.

The processes, and compounds prepared by the processes, including intermediate compounds, are further described herein.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

A number of terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended.

The term 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.

The term alkoxy, as used herein, 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.

The term alkoxyalkyl, as used herein, 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.

The term alkyl, as used herein, 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.

The term alkylthio, as used herein, 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.

The term alkylthioalkyl, as used herein, 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.

The term aryl, as used herein, 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. Examples of aryl include, but are not limited to, 4-cyanophenyl, 4-chlorophenyl, 4-methylphenyl, 4-phenylethanone, 4-trifluoromethylphenyl, 4-trifluormethoxyphenyl, and the like.

The term cyano, as used herein, refers to a CN group.

The term haloalkoxy, as used herein, 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.

The term haloalkyl, as used herein, 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.

The term heteroaryl, as used herein, 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. The term heteroaryl also includes bicyclic systems wherein the aromatic five- or six-membered ring is fused to a phenyl group. Representative examples of 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. The 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.

The term heterocycle or heterocyclic group, as used herein, 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.

The term hydroxy, as used herein, 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),

wherein 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 R1 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 H3-receptor ligands.

The heterocyclic group for A is a saturated nitrogen ring, and preferably contains five or six members, including the nitrogen atom. Examples of 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. Examples of substituted heterocyclic groups are 2-methylpyrrolidinyl, including (2R)-2-methylpyrrolidine 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 R1, represents an aromatic five- or six-membered ring wherein 1, 2, 3, or 4 heteroatoms are independently selected from N, O, or S. Typically, the five-membered rings have two double bonds or are tautomers of five-membered rings with two double bounds. Typically, 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. Examples of 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.

The heteroaryl groups of the present invention can be substituted with 0,1, 2, 3, or 4 substituents independently selected from alkoxy, alkoxyalkyl, alkyl, alkylthio, aikylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.

The aryl group in compounds of formula (I), as represented by R1, 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. Examples of aryl include, but are not limited to, 4-cyanophenyl, 4-chlorophenyl, 4-methylphenyl, 4-phenylethanone, 4-trifluoromethylphenyl, 4-trifluormethoxyphenyl, and the like.

The compounds are described, inter alia, in commonly-owned copending U.S. patent applications Ser. No. 09/810,648, filed Mar. 16, 2001; Ser. No. 10/044,495, filed Jan. 11, 2002; and Ser. No. 10/081,207, filed Feb. 22, 2002, each of which is incorporated by reference herein. The processes of the invention particularly are useful for preparing 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile having the structure

and salts thereof including, but not limited to, tartrate salts, for example (L)-tartrate.

Examples of processes of the invention are described herein in the following Schemes 1-7. The Schemes are intended to illustrate a process of the invention and are not meant to limit the scope of the invention in any way. Isomeric forms of compounds described in the Schemes also are contemplated and considered within the scope of the invention.

Abbreviations used in the descriptions of the Schemes and the Examples that follow are: DMSO for dimethylsulfoxide; EtOH for ethanol; IPAC for isopropyl acetate; HPLC for high pressure liquid chromatography; Ph for phenyl; and TsO for toluenesulfonate.

As shown in Scheme 1, 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 RA 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. Examples of suitable substituents can include, for example, alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl.

Typically, the compound of formula (II) is purchased commercially or prepared from commercially available 4-bromophenol. For example, 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-(d icyclohexylphosphino)biphenyl and 2-(dicyclohexylphosphino)biphenyl. Preferably, the reaction is carried out in the presence of a base for example, sodium carbonate or potassium phosphate, at above room temperature. Examples of more specific conditions for accomplishing the reaction include treating the 4-bromophenol with a heteroarylboronic acid, tetrakis(triphenylphosphine)palladium(0) and 2-(dicyclohexylphosphino)biphenyl in a solvent mixture of water and 1,2-dimethoxyethane, isopropyl alcohol, or toluene, at about 40 C. to about 100 C. The reaction typically is accomplished in about 1 to about 36 hours. Examples of commercially available heteroarylboronic acids are 4-cyanophenyl boronic acid, pyridine-3-boronic acid, and the like.

Compounds of formula (II), wherein RA represents bromo, chloro, 4-cyanophenyl, or heteroaryl, as described above, can be treated with a 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, ICl, IBr, BrCl, 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. Preferably, about 1 mole of halogenating reagent is used for each mole of the compound of formula (II). Preferably, 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. Particularly, 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.

Compounds of formula (III), wherein X is bromo or iodo and RA is as defined above, for example of formula (II), can be treated with an alkynol or a toluenesulfonyl alkynol, to provide benzofuran derivatives of formulae (IV) or (V), respectively. The coupling reaction is accomplished using a palladium source, a phosphine ligand for the palladium, and a metal halide in the presence of a base. 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, RpOCH2CH2CCH, where the Rp 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 Rp in the product will generate compounds of structure (IV). Examples of specific protecting groups represented by Rp 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). Examples of suitable palladium sources include, but are not limited to, palladium(II) 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(I) iodide. Alternative and additional halides can include, but are not limited to, copper(I) bromide. Typically, 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). Although 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). Preferably, the sulfonating reagent provides a toluenesulfonyl group to activate the hydroxy group of a compound of formula (IV) as shown in Scheme 1. Examples of 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. Typically, 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). Preferably, 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.

Compounds of formula (V) can be reacted with an amine reagent to provide compounds of formula (VI). 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-fluoromethylpyrrolidine, and the salts thereof. Examples of 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.

In addition, the invention provides processes for preparing amine-substituted benzofuran compounds as shown below in Scheme 2.

As shown in Scheme 2, 3-butynyl4-methylbenzenesulfonate is reacted with an amine reagent of formula AH, wherein 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).

Typically, 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. Examples of 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. Particularly, 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. Typically, 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 (III-a), wherein RA1 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 (VI-a), wherein RA1 is as defined for compounds of formula (III-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(II) catalyst in combination with a phosphine ligand for the palladium. Typically the reaction is carried out using a metal halide and a base. Examples of palladium catalysts can include, for example, Pd(Ph3P)4, Pd(dba), Pd2(dba)3, Pd(Pcy3)2, Pd(dppe), Pd(dppf), PdCl2(Ph3P)2, PdCl2(dppf)2, PdCl2(dppe)2, and PdCl2(CH3CN)2. As used herein, the preceding designations are intended to refer to the following: Pd(Ph3P)4 for tetrakis(triphenylphosphine)palladium, Pd(dba) for (dibenzylideneacetate)palladium, Pd2(dba)3 for tris(dibenzylideneacetate)d ipalladium, Pd(Pcy3)2 for bis(tricyclohexylphosphine)palladium, Pd(dppe) for (2-(diphenylphosphino)ethyl)palladium, Pd(dppf) for (1,1-bis(diphenylphosphino)ferrocene)palladium, PdCl2(Ph3P)2 for bis(triphenylphosphine)dichloropalladium, PdCl2(dppf)2 for bis(1,1-bis(diphenylphosphino)ferrocene)palladium, PdCl2(dppe)2 for bis(2-(diphenylphosphino)ethyl)dichloropalladium, and PdCl2(CH3CN)2 for dichlorobis(acetonitrile)palladium. More specifically, preferred palladium sources include, but are not limited to, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetate)dipalladium, and PdCl2(Ph3P)2. Preferably, the palladium catalyst is PdCl2(Ph3P)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. Typically, palladium catalysts already coordinated with a phosphine ligand are not used in combination with additional phosphine ligands.

Although copper(I) chloride and copper(I) bromide may be suitable, the preferred metal halide is copper(I) iodide. 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. Typically, the amine of formula (VII) is reacted with the compound of formula (III-a) in an amount of from about 1:1 to about 1:3 molar equivalents, relative to the compound of formula (III-a). It is preferred that two molar equivalents of amine are reacted with one molar equivalent of a compound of formula (III-a). Under the preferred conditions, the reaction is carried out with copper(I) iodide in diisopropylamine in the presence of a PdCl2(Ph3P)2 catalyst.

One with skill in the art may understand that compounds of formulae (III), (III-a), (IV), (V), (VI), and (VI-a ), wherein RA or RA1 is bromo or chloro, can be treated with a boronic acid of the formula:

(HO)2BR1(VIII),

wherein R1 is 4-cyanophenyl, aryl, or heteroaryl, to provide a corresponding compound of each respective formula, wherein RA 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 R1 is 4-cyanophenyl.

Boronic acid esters of formula (VII-a) also can be substituted for boronic acids of formula (VIII)

(ReO)(RfO)BR1(VIII-a).

The Re and Rf in compounds of formula (VIII-a) are alkyl, or alternatively Re and Rf taken together to form a ring, preferably a C1-C6 ring, wherein the ring can be substituted with 0, 1, 2, 3, or 4 alkyl or aryl groups and R1 is as defined for compounds of formula (VIII). Examples of suitable compounds of formula (VIII-a) include, but are not limited to, (CH3O)2BPh, (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. For example, Takagi et al. (Tetrahedron Letters, (2002) 43, 5649-5651) describe preparing heteroaryl pinacolborane esters of formula (VIII-a) using heteroaromatic compounds and reaction with bis(pinacolborane) in the presence of an iridium catalysis of IrClCOD2-(4,4-di-t-butyl-2,2-bipyridine) in octane. Other methods have been described wherein aryl halides and triflates and heteroaryl halides and triflates are reacted with alkyl lithiums or Grignard reagents, treated with trialkylborate esters, and then treated with acid to produce compounds of the formula (Vil) or (VIII-a). See, for example, B. T. O'Neill, et al. Organic Letters (2000), 2, 4201; M. D. Sindkhedkar, et al. Tetrahedron (2001), 57, 2991; W. C. Black, et al. Journal of Medicinal Chemistry (1999), 42, 1274; Letsinger; Dandegaonker; J. Amer. Chem. Soc. (1959), 81, 498, 501; Carroll, F. Ivy, et al. J. Med. Chem. (2001) 2229 -2237. Another well-known method is the 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 Pd2dba3 and tris-cyclohexylphosphine or PdCl2dppf (Ishiyama, et al. Tetrahedron (2001) 9813-9816). Examples of suitable 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. The reaction provides the corresponding compound wherein the bromo substituent is replaced with a 4-cyanophenyl, aryl, or heteroaryl, as shown below:

Schemes 3-6

The group represented by RA2 in compounds of formula (III-c), (IV-c), and (V-c) and R1 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 R1 is 4-cyanophenyl.

In addition, compounds of formula (VI)

wherein RA is 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). In one aspect, the compound of formula (VI) or (VI-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 (VI-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 Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

Alternatively, and more preferably, a compound of formula (VI) can be treated with an acid to form a desired salt. For example, a compound of formula (VI) or (VI-a) is reacted with an acid at above room temperature to provide the desired salt. Examples of 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. Typically, the reaction is accomplished at above room temperature. Preferably, 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. After cooling, 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-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile and salts thereof. A particular example of a process for preparing 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-l -benzofuran-5-yl)benzon itrile, and salts thereof, comprises the steps of:

(a) treating 4-hydroxy-1,1-biphenyl4-carbonitrile with N-iodosuccinimide and an acid, such as sulfuric acid, to provide 4-hydroxy-3-iodo-1,1-biphenyl-4-carbonitrile;

(b) treating 4-hydroxy-3-iodo-1,1-biphenyl-4-carbonitrile with 3-butyn-1-ol, a palladium source with a phosphine for the palladium and a metal halide in the presence of a base, for example using palladium(ll) acetate, triphenylphosphine, copper(I) iodide in the presence of diisopropylamine, in isopropyl acetate to provide 4-2-(2-hydroxyethyl)-1-benzofuran-5-ylbenzonitrile;

(c) reacting 4-2-(2-hyd roxyethyl)-1-benzofuran-5-ylbenzonitrile with para-toluenesulfonyl chloride and N,N-dimethylaminopyridine, in the presence of a base, such as triethylamine, to provide 2-5-(4-cyanophenyl)-1-benzofuran-2-ylethyl 4-methylbenzenesulfonate; and

(d) treating 2-5-(4-cyanophenyl)-1-benzofuran-2-ylethyl 4-methylbenzenesulfonate with (2R)-2-methylpyrrolidine, preferably in the presence of potassium carbonate and in an acetonitrile solvent, to provide 4-(2-2-(2R)-2-methyl-1-pyrrolidinylethyl-1-benzofuran-5-yl)benzonitrile.

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.

As shown in Scheme 7, compounds of formula (II) wherein RA is selected from the group consisting of bromo, chloro, 4-cyanophenyl, aryl, and heteroaryl, as previously described with compounds of formula (II) can be reacted with a halogenating reagent selected from N-bromosuccinimide and N-iodosuccinimide. The reagents and conditions are as described for preparing compounds of formula (III) according to Scheme 1. The compound of formula (III) suitably can be used to prepare compounds of formula (I), for example by processes described herein.

Yet another aspect of the invention relates to compounds of formula (V), wherein RB is toluenesulfonate, particularly wherein RA is 4-cyanophenyl, and compounds of formulae (I), (III), (VI), and (VI-a) prepared by the processes described above.

Still yet another aspect of the invention relates to a compound of the formula (IX),

wherein X is bromo or iodo and Rc 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. Preferably, Rc 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.

The processes of the invention, and intermediates and products prepared by the processes, can be better understood in connection with the following examples, which are merely intended to illustrate the invention and should not be construed to limit the invention in any way.

REFERENCE EXAMPLE

Preparation of (2R)-2-methylpyrrolidine and

(2S)-2-methylpyrrolidine

(2R)-2-Methylpyrrolidine tartrate was prepared by the resolution of racemic (/) 2-methylpyrrolidine with L-tartaric acid (which is also called (2R,3R)-()-tartaric acid,