Process for preparing...

Details Process for preparing... Process for preparing...

2000-11-06

2002-03-12

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...

Reexamination Certificate

active

06355801

ABSTRACT:

The present invention provides a process for preparing N-(4-hydroxyphenyl)-N′-(4′-aminophenyl)-piperazine.
BACKGROUND OF THE INVENTION
N-(4-hydroxyphenyl)-N′-(4′-aminophenyl)-piperazine is an intermediate useful for preparing triazolones having activity as antifungals. U.S. Pat. No. 5,625,064, for example, discloses the use of this compound to prepare the triazolones described therein. Published European Patent Application No. 0 331 232 discloses a process for N-arylating a piperazine of formula (III) to produce a di-aryl piperazine of formula (I):
wherein R
1
and R
2
are each independently hydrogen, C
1
-C
6
alkyl, or halo; R
3
and R
4
are each independently hydrogen, halo, amino, nitro or trifluoromethyl; Y is hydrogen, nitro, amino, mono- or di(C
1
-C
6
alkyl) amino, C
1
-C
6
alkylcarbonylamino, C
1
-C
6
alkyl, C
1
-C
6
alkylcarbonyl, hydroxy, halo, mono- or di(C
1
-C
6
alkyl) aminosulfonyl, or a heterocyclic radical; and W is halo, preferably fluoro or chloro. It also discloses that the compounds of formula (I) having a nitro substituent can be converted into the corresponding amines by catalytic hydrogenation. It further discloses that the N-arylation may be carried out at an elevated temperature in an appropriate solvent in the presence of an appropriate base such as, for example, an alkali metal hydride or carbonate. However, the reported yield for the N-arylation step is poor (see Example 17) and the product produced in this step has to be purified by extraction and salt formation, making this process unsuitable for large scale production.
The present invention solves this problem by providing an efficient, high-yielding N-arylation step employing an organic base which is suitable for large scale production.
SUMMARY OF THE INVENTION
A process is provided for producing a compound having the formula:
comprising:
(a) reacting a compound having the formula
 with a compound having the formula
 in the presence of an organic base selected from the group consisting of: triethylamine; N,N-diisopropylethylamine; 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); 1,5-diazabicyclo[4.3.0]non-5-ene; or 1,4-diazabicyclo[2.2.2]octane to form a compound having the formula
(b) reducing the compound of formula (4.0) to form the compound of formula (1.0), wherein X is Cl, Br, I or F.
DETAILED DESCRIPTION OF THE INVENTION
X is preferably Cl or F, most preferably Cl.
The organic base is preferably triethylamine or N,N-diisopropylethylamine (Hünig's base).
Certain solvents and reagents are referred to herein by the following abbreviations: N,N-diisopropylethylamine (Hünig's base); 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); ; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO); dimethyl sulfoxide (DMSO); N,N-dimethylformamide (DMF); N-methylpyrrolidone (NMP); and dimethyltetrahydropyrimidinone (DMPU).
Compounds (2.0) and (3.0) are commercially available, or may be prepared by methods known to those skilled in the art.
Step (a) is preferably carried out at a temperature of 50° C. to 140° C., more preferably 100° C. to 130° C., most preferably 120° C. to 125° C. Step (a) is preferably carried out in an organic solvent, more preferably an aprotic organic solvent. Examples of solvents that may be used include, but are not limited to alcohols, nitrobenzene, DMSO, DMF, NMP, and DMPU. DMSO, NMP and DMPU are particularly preferred. Preferably, the amount of the para-halo-nitrobenzene compound of formula (3.0) used in step (a) is 1 to 2 equivalents, more preferably 1 to 1.5 equivalents, most preferably 1.3 to 1.4 equivalents. Preferably, the amount of organic base used in step (a) is 1 to 3 equivalents, more preferably 1 to 2 equivalents, most preferably 1.2 to 1.5 equivalents.
The compound of formula (4.0) produced in step (a) is preferably recovered by precipitation, preferably induced by the addition of isopropanol or water. Isopropanol is particularly preferred, because it produces large crystals and excess para-halo-nitrobenzene stays in solution.
In step (b), the nitro-substituted compound of formula (4.0) is reduced to form the corresponding amine of formula (1.0). The reduction is preferably carried out by means of a catalytic hydrogenation or a catalytic hydrogen transfer reduction. Examples of catalysts that may be used for the catalytic hydrogenation include, but are not limited to, Pd, Ni and Pt. An example of a hydrogen transfer agent that can be used in the catalytic hydrogen transfer reduction includes, but is not limited to sodium phosphinite monohydrate with palladium on carbon (NaH
2
PO
2
.H
2
O/Pd/C).
The catalytic hydrogenation is preferably carried out at a pressure of 1-5 atm and at a temperature of 20° C. to 50° C., more preferably 20° C. to 30° C. Preferably, the catalytic hydrogenation is carried out in an organic solvent, more preferably, a protic organic solvent. Examples of solvents that may be used for the catalytic hydrogenation include, but are not limited to alcohols, such as methanol or ethanol; ethers such as THF; DMF; and NMP.
The catalytic hydrogen transfer reduction is preferably carried out at a temperature of 20° C. to 110° C., more preferably 70° C. to 75° C. The catalytic hydrogen transfer reduction is preferably carried out in an organic solvent, more preferably a protic organic solvent. Examples of solvents that may be used for the catalytic hydrogen transfer reduction include, but are not limited to methoxyethanol, n-butanol, DMF, and NMP.
Those skilled in the art will appreciate that unless stated otherwise, the compounds produced in the various process steps can, if desired, be separated from their reaction mixtures, and isolated and purified by techniques well known in the art. For example, separation can be accomplished by precipitation, chromatography, (e.g., column), phase separation (extraction) and distillation. The desired product can then be dried and purified by recrystallization.


REFERENCES:
patent: 4931444 (1990-06-01), Van Wauwe et al.
patent: 5688795 (1997-11-01), Pfister et al.
patent: 5710155 (1998-01-01), Schnorrenberg et al.
patent: 5780475 (1998-07-01), Baker et al.
patent: 0 331 232 (1989-02-01), None
Hepperle et al Tetrahedron Letters 40 (1999) 5655—5659.

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