Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-07-13
2001-11-06
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S393000, C544S394000
Reexamination Certificate
active
06313297
ABSTRACT:
The present invention relates to a novel process for preparing 1-aryl-4-(arylethyl)piperazines.
Arylpiperazines are, as building blocks for a large number of pharmaceutically active compounds, of industrial interest. In this context, 1-aryl-4-(arylethyl)piperazines are of particular importance as active compounds in medicinal chemistry. Thus, this class of compounds is the subject of a large number of patents and publications.
1-aryl-4-(arylethyl)piperazines are mainly prepared by reacting the corresponding arylpiperazines with 1-arylethyl-2-bromide. Another route is the reaction of anilines with N,N-bis-2-chloroethylanilines.
In both reaction routes, halogenated starting materials are used, giving stoichiometric amounts of salt by-products. The latter is ecologically disadvantageous. In addition, the alkylations are insufficiently selective, so that product yields of only 50-70% are obtained.
It is an object of the present invention to provide a process for preparing 1-aryl-4-(arylethyl)piperazines from simple starting materials under mild reaction conditions which can be carried out on an industrial scale and does not produce any salt by-products.
This object is achieved by a process for preparing a 1-aryl-4-(arylethyl)piperazine of the formula (I)
by reacting a 1-arylpiperazine of the formula (II)
with an aromatic olefin of the formula (III)
Ar′CR
1
═CHR
2
(III)
in an inert solvent in the presence of at least one basic catalyst, where in the formulae (I) to (III)
Ar and Ar′ independently of one another are an aryl radical, selected from the group of the fused and unfused C
6
-C
22
-aromatics and the fused or unfused C
5
-C
22
-heteroaromatics which have at least one nitrogen, oxygen or sulfur atom in the ring; and
R
1
and R
2
independently of one another are a hydrogen atom, a C
1
-C
8
-alkyl radical or an aryl radical Ar.
It is furthermore possible to prepare the product of the formula (I) by extending the intermolecular coupling between the aromatic olefin of the formula (III) and the arylpiperazine of the formula (II) by an intramolecular amination of a corresponding compound.
It is an essential property of the process according to the invention that, for the first time, the arylpiperazines react with aromatic olefins under base catalysis, generally in good to very good yields of from 90 to 99%. Salt by-products are not formed.
The inert solvent can be selected from the group consisting of aromatic hydrocarbons, such as toluene, xylenes, anisole, tetraline, and aliphatic ethers, such as tetrahydrofuran, dimethoxyethane, dioxane, tetrahydropyran, formaldehyde acetals. Examples of the aryl radical Ar are phenyl, naphthyl, anthryl, phenanthryl and diphenyl, pyridyl, furfuryl or pyrazolyl radicals.
The basic catalyst can be selected from the group consisting of
alkali metal and alkaline earth metal hydrocarbons, such as, for example, phenyllithium or butyllithium;
alkali metal and alkaline earth metal amides, such as, for example, potassium amide, potassium dimethylamide, potassium diisopropylamide, potassium propylamide, potassium isopropylamide, sodium amide, sodium dimethylamide, sodium diisopropylamide, sodium propylamide, sodium isopropylamide, lithium amide, lithium dimethylamide, lithium diisopropylamide, lithium propylamide or lithium isopropylamide;
alkali metals and alkaline earth metals, such as, for example, sodium or potassium; and
alkali metal hydrides, such as, for example, sodium hydride or potassium hydride.
In addition, the basic catalyst used can also be a mixture of the catalysts described above with one another or with alkali metal or alkaline earth metal silazides, such as, for example, potassium hexamethyidisilazide, sodium hexamethyldisilazide, lithium hexamethyidisilazide.
Preferred basic catalysts are alkali metal and alkaline earth metal hydrocarbons and alkali metal and alkaline earth metal amides.
Studies have shown that alkali metal amides and alkali metal hydrocarbons are particularly effective catalysts.
The basic catalyst can be employed directly in the form of one of the compounds mentioned or similar compounds. However, in some cases it is advantageous, owing to the stability of the basic catalyst, to prepare the active compound in situ from suitable precursors.
The basic catalyst can be employed in an amount of from 0.01 to 20 mol %, in particular from 0.1 to 5 mol %, based on the arylpiperazine of the formula (II).
The aryl radicals Ar or Ar′ in the formulae (I) and (III) can, independently of one another, have up to 8 identical or different substituents from the group consisting of hydrogen, fluorine, chlorine, bromine or iodine atoms and C
1
-C
8
-alkyl, C
1
-C
8
-alkoxy, C
1
-C
8
-acyloxy, HO—, O
2
N—, CN—, HOC(O)—, HC(O)—, HOS(O)
2
—, R
4
S(O)
2
—, R
4
S(O)—, H
2
N—, R
4
N(H)—, R
4
2
N—, R
4
C(O)N(H)—, R
4
C(O)—, (OCH)HN—, Ar″C(O)—, ArC(O)O—, CF
3
—, H
2
NC(O)—, R
4
OC(O)C(H)═C(H)—, Ar″
2
P(O)—, R
4
2
P(O)—, R
4
3
Si— or heteroaryl radicals having 5 or 6 atoms in the aryl ring, where R
4
is a C
1
-C
12
-alkyl radical and Ar″ is selected from the group of the fused or unfused C
6
-C
22
-aromatics and the fused or unfused C
5
-C
22
-heteroaromatics which have at least one nitrogen, oxygen or sulfur atom in the ring.
The reaction is carried out at temperatures of from 0 to 200° C., in particular at from 10 to 150° C. and preferably at from 20 to 120° C.
Owing to the tendency to undergo oligomerization or polymerization side reactions, it may, in the case of some aromatic olefins of the formula (III), be advantageous to add a polymerization inhibitor. For this purpose, it is possible to employ the customary polymerization inhibitors, such as, for example, p-quinone.
REFERENCES:
patent: 85 503 (1965-12-01), None
Beller, Matthias, et al,Tetrahedron 54:6359-6368, “Base-Catalyzed Hydroamination of Aromatic Olefins—An Efficient Route to 1-Aryl-4-(Arylethyl) Piperazines” (1998).
Beller Matthias
Breindl Claudia
Herwig Jurgen
Aventis Research & Technologies
Connolly Bove & Lodge & Hutz LLP
Raymond Richard L.
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