Process for preparing amine-substituted benzofurans

Details Process for preparing amine-substituted benzofurans Process for preparing amine-substituted benzofurans

2003-09-05

2004-11-23

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S196000

Reexamination Certificate

active

06822101

ABSTRACT:

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-pyrrolidinyl]ethyl}-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 (H
3
) receptor ligands. Histamine-3 receptor ligands provide useful compounds for pharmaceutical products. For example, 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. One particular compound, having the structure
and the IUPAC name 4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile demonstrates promising activity for use as a pharmaceutically active H
3
-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-pyrrolidinyl]ethyl}-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-pyrrolidinyl]ethyl}-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
R
1
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 R
A
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 R
A
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 R
B
represents a toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate group. In addition, compounds of formula (III) are treated with a toluenesulfonyl butanol to provide (V), wherein R
B
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 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. Wherein R
A
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 R
A
is bromo or chloro, can be treated with a boronic acid reagent of formula (VIII)
(HO)
2
B—R
1
  (VIII)
or a boronate ester compound of the formula (VIII-a)
(R
e
O)(R
f
O)B—R
1
  (VIII-a),
wherein R
1
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 R
f
are each independently alkyl or R
e
and R
f
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 R
1
. Wherein R
A
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 R
A1
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 R
A1
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, PdCl
2
(Ph
3
P)
2
, and the like.

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