Process for the preparation diaryl-4-amino-piperidinyl...

Details Process for the preparation diaryl-4-amino-piperidinyl... Process for the preparation diaryl-4-amino-piperidinyl...

2003-06-04

2004-12-28

Chang, Celia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S224000, C546S193000

Reexamination Certificate

active

06835840

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to a new process for the preparation of 1-substituted diaryl-4-amino-piperidinyl compounds. In further aspects, the present invention also relates to new intermediates used in said process.
BACKGROUND AND PRIOR ART
WO 98/28270 discloses a group of compounds, and processes for their preparation, to which 1-substituted diaryl-4-amino-piperidinyl compounds belongs.
WO 99/33806 discloses 4[aryl(piperidin-4-yl)]aminobenzamide compounds and processes for their preparation. The core of the process disclosed in WO99/33806 consists of a reductive amination followed by a second step wherein the previously prepared N-aryl-piperidineamine is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide in the presence of a palladium catalyst a phosphine ligand and a base to give said (N-aryl, N-piperidin-4-yl)aminobenzamide.
The first reaction step (reductive amination) is performed using an appropriate solvent/reducing agent combination such as 1,2-chloroethane or acetonitrile/NaBH(OAc)
3
+acid catalyst; methanol/NaBH
3
CN+acid catalyst; titanium isopropoxide/NaBH
3
CN; methanol, ethanol or isopropanol/NaBH
4
; alcoholic solvent/H
2
+noble metal catalyst or 1,2-dichloroethane or acetonitrile/NaBH(OAc)
3
+acid catalyst. The product of the first step is thereafter isolated and purified before the second step is performed. The second step is thereafter performed in a different solvent.
Thomas et al. in J. Med. Chem. discloses 4-[aryl(piperidin-4-yl)]aminobenzamide of similar structure as WO 99/33806. The compounds are prepared by a reductive amination step followed by a nucleophilic aromatic substitution step.
The process of the present invention provides 1-substituted diaryl-4-amino-piperidinyl compounds in an improved and simplified manufacturing process that, e.g. uses only commercially available starting materials and reagents, has less reaction and purification steps, gives easier purification of the final and intermediate compounds, uses only one solvent system throughout the whole process.
Thus, the object of the present invention is to provide a novel process suitable for use in large-scale synthesis. A further object of the present invention is to provide a process containing as few reaction steps as possible.
OUTLINE OF THE INVENTION
The present invention provides a new process for preparation of 1-substituted diaryl-4-amino piperidinyl compounds, hereinafter referred to as compounds of the invention. The compounds of the invention are useful in therapy, and in particular for the treatment of pain.
The process for preparing of 1-substituted diaryl-amino-piperidinyl compounds is schematically shown in Scheme 1 below.
wherein
R
1
and R
2
are independently selected from the group consisting of hydrogen, hydroxy, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
acyl, C
1
-C
6
acyloxy, cyano, amino, nitro, C
1
-C
6
acylamino, C
1
-C
6
alkylamino, (C
1
-C
6
alkyl)
2
amino, C
1
-C
6
alkylthio, C
1
-C
6
alkylsulfonyl, halogenated C
1
-C
6
alkyl, halogenated C
1
-C
6
alkoxy, CO—NR
8
R
9
and C
1
-C
6
alkoxycarbonyl;
R
3
, R
4
, R
5
and R
6
are independently selected from hydrogen and C
1
-C
6
alkyl;
R
7
is selected from the group consisting of imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl, all optionally and independently mono-, di-, or tri-substituted with a R′ group;
R
8
and R
9
are independently selected from hydrogen, C
1
-C
6
alkyl, halogenated C
1
-C
6
alkyl, phenyl, benzyl, all optionally and independently mono-, di-, or tri-substituted with a R″ group;
Ar— is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R
2
groups;
R′ is independently selected from the group consisting of hydroxy, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
acyl, C
1
-C
6
acyloxy, cyano, amino, nitro, C
1
-C
6
acylamino, C
1
-C
6
alkylamino, (C
1
-C
6
alkyl)
2
amino, C
1
-C
6
alkylthio, C
1
-C
6
alkylsulfonyl, halogenated C
1
-C
6
alkyl, halogenated C
1
-C
6
alkoxy;
R″ is independently selected from the group consisting of hydroxy, halogen, C
1
-C
6
alkyl C
1
-C
6
alkoxy, cyano, amino, nitro, C
1
-C
6
alkylthio, halogenated C
1
-C
6
alkyl, halogenated C
1
-C
6
alkoxy; and
n is 1, 2, 3, 4, 5, or 6.
A preferred embodiment of the present invention is the process according to Scheme 1, wherein
R
1
and R
2
are independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, cyano, amino, CO—NR
8
R
9
and C
1
-C
6
alkoxycarbonyl;
R
3
, R
4
, R
5
and R
6
are independently selected from hydrogen and C
1
-C
4
alkyl;
R
7
is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl, and phenyl;
R
8
and R
9
are independently selected from hydrogen, C
1
-C
6
alkyl, phenyl or benzyl; and
n is an integer from 1 to 6.
A more preferred embodiment of the present invention is the process according to Scheme 1, wherein
R
1
and R
2
are independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, cyano, amino, CO—NR
8
R and C
1
-C
6
alkoxycarbonyl;
R
3
, R
4
, R
5
and R
6
are hydrogen;
R
7
is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R
8
and R
9
are independently selected from hydrogen, ethyl and isopropyl, and
n is 1.
An even more preferred embodiment of the present invention is the process according to Scheme 1, wherein
R
1
and R
2
are independently selected from hydrogen, hydroxy, halogen, cyano, amino, CO—NR
8
R
9
and C
1
-C
6
alkoxycarbonyl;
R
3
, R
4
, R
5
and R
6
are hydrogen;
R
7
is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R
8
and R
9
are independently selected from hydrogen, ethyl and isopropyl, and
n is 1.
Most preferred embodiment of the present invention is the process according to Scheme 1, wherein
R
1
and R
2
are independently selected from hydrogen, halogen, cyano CO—NR
8
R
9
and C
1
-C
6
alkoxycarbonyl;
R
3
, R
4
, R
5
and R
6
are hydrogen;
R
7
is selected from the group consisting of imidazolyl, pyridinyl, and furanyl;
R
8
and R
9
are independently selected from hydrogen, ethyl and isopropyl; and
n is 1.
Thus the process of the present invention can be described as comprising a one-pot double arylation step. It will be apparent for the skilled person that an optional deprotection step might have to be introduced after the one-pot double arylation step, due to interference/reactivity of the substituents. Reference is made to “Protective Groups in Organic Synthesis”, 2nd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1991). Example of a substituent that might need to be protected is hydroxy. A hydroxy substituent preferably protected as its methyl ether. Such methyl ether would then have to be cleaved after the one-pot double arylation step. This could for example be done by treating the product of the one-pot double arylation step with BBr
3
under standard conditions, such as 2-5 molar equivalents of BBr
3
in dichloromethane at −78° C.
The One-Pot Double Arylation Step
A one-pot double arylation step is a reaction that is performed in one pot but consists of two separate and distinct reaction steps (arylation couplings) that are performed consecutively without the need for any purification of intermediate compounds, work-up procedure, or change of solvent. The two reagents are added separately and the addition of the reagents is so timed as to allow the first reaction step to be completed before the next reagent is added to start the second reaction step.
The one-pot double arylation step of the present invention is performed by reacting 4-amino-piperidine of Formula II
wherein R
3
to R
7
, n, and R′ are as described above in Scheme 1, with a first bromo compound of Formula III,
wherein R
1
, R
8
, R
9
, and R″ are as decribed above in Scheme 1, in the presence of a strong base, a palladium catalyst and a phosphine ligand. U

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