Process for preparing (hetero) aromatic substituted benzene...

Details Process for preparing (hetero) aromatic substituted benzene... Process for preparing (hetero) aromatic substituted benzene...

2000-02-22

2001-08-07

Riley, Jezia (Department: 1656)

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

Organic compounds

Amino nitrogen containing

C564S305000, C564S412000, C564S446000, C564S449000

Reexamination Certificate

active

06271418

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains to the field of pharmaceutical chemistry and provides advantageous processes for substituted benzene derivatives. More specifically, the process relate to the preparation of (hetero)aromatic substituted benzene derivatives by aromatizing cyclohexenone derivatives.
BACKGROUND OF THE INVENTION
Conventionally, biphenyl derivatives have been prepared by a coupling reaction under various reacting condition.
Ann. (1904), 332, 38 and JP4-257564 discloses Ullman coupling reaction of halobenzene derivatives in the presence of metal, Na or Cu etc.
Bull. Chem. Soc. Jpn. (1976), 49, 1958 teaches a nickel-phosphine complex catalyzed coupling of aryl Grignard reagent with haloaryl derivative.
JP6-9536 discloses a cross coupling reaction of 2-chlorobenzonitrile and aryl Grignard reagent in the presence of MnCl
2
.
Synth. Commun. (1981), 11, 513 teaches palladium catalyzed coupling reaction of aryl iodide, aryl bromide or aryl trifulate with aryl boronic acid derivative.
A major disadvantage of coupling processes in the art is 1) use of expensive starting material and catalyst, 2) low selectivity of the reaction resulted in a mixture of homo and cross coupling products, 3) difficulty in isolation and purification processes, 4) handling of highly reactive reagents, Grignard reagent etc.
Construction of benzene ring is another method to prepare biphenyl derivatives. JP9-87238 discloses a cycloaddition reaction of &agr;-cyanocinnamate derivative with butadiene to afford benzene substituted cyclohexene derivative followed by aromatization. This method needs high pressure and temperature in the cycloaddition process.
The present invention provides an industrial process by which biphenyl derivatives can be prepared in a high selectivity and yield and which is free from the above-mentioned disadvantages.
SUMMARY OF THE INVENTION
The present invention provides three processes for preparing substituted benzene derivatives represented by the formula (I):
wherein X represents a phenyl group, a naphthyl group or a heteroaromatic group which are optionally substituted with (C
1
-C
4
)alkyl group(s), (C
1
-C
4
)alkoxy group(s), halogen atom(s) or nitro group(s); Y represents a (C
1
-C
4
)alkoxycarbonyl group, a cyano group, a nitro group or a (C
1
-C
4
)alkoxysulfonyl group; R
1
, R
2
and R
3
each independently represent a hydrogen atom, a (C
1
-C
4
)alkyl group, a (C
1
-C
4
)alkoxy group or a phenyl group which is optionally substituted with (C
1
-C
4
)alkyl group(s), (C
1
-C
4
)alkoxy group(s) or halogen atom(s); which comprise aromatizing cyclohexenone derivatives represented by the formula (II):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above.
The first process comprises chlorinating a cyclohexenone derivative represented by the formula (II):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above, to obtain a halocyclohexadiene derivative or a mixture of isomers represented by the formula (IIIA and/or IIIB):
wherein X, Y, R
1
, R
2
and R
3
are as defined above and W represents a halogen atom, followed by dehydro-, dehalogenation to a benzene derivative represented by the formula (1):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above.
The second process comprises halogenating a cyclohexenone derivative represented by the formula (II):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above, to obtain a halocyclohexadiene derivative or a mixture of isomers represented by the formula (IIIA and/or IIIB):
wherein X, Y, W, R
1
, R
2
and R
3
have the same meanings as defined above, followed by dehydrogenation and reduction to a benzene derivative represented by the formula (I):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above.
The third process comprises reducing a cyclohexenone derivative represented by the formula (II):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above, to obtain a cyclohexenol derivative represented by the formula (V):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above, followed by dehydration and dehydrogenation to a benzene derivative represented by the formula (I):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described in detail below.
In this document, all temperatures are stated in degrees Celsius. All amounts, ratios, concentrations, proportions and the like are stated in weight units unless otherwise stated, except for ratios of solvents which are in volume units.
The first process is summarized in the scheme 1 as showed below.
A cyclohexenone derivative represented by the formula (II):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above, is reacted with a halogenating agent in a solvent to obtain a halocyclohexadiene derivative or a mixture of isomers represented by the formula (IIIA and/or IIIB):
wherein X, Y, W, R
1
, R
2
and R
3
have the same meanings as defined above.
Any ratio of the isomers (IIIA and IIIB) may be employed.
As the halogenating agent, there may be used chlorinating agent such as thionyl chloride, oxalyl chloride, phosgen, phosphorus oxychloride, phosphorus pentachloride, etc. and brominating agent such as thionyl bromide, phosphorus oxybromide, etc. The agent may be used in a stoichiometrical amount or 0.5 to 10 times the stoichiometrical amount, but preferably a stoichiometrical amount or 0.8 to 5 times the stoichiometrical amount.
As the solvent, any solvent inert to a reactant and a reagent may be used. There may be mentioned aliphatic hydrocarbons such as n-hexane, n-heptane, etc., aromatic hydrocarbons such as toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, chlorobenzene, etc., aliphatic esters such as ethyl acetate, butyl acetate, etc., and ethers such as tetrahydrofuran, etc., but preferably aliphatic hydrocarbons, aromatic hydrocarbons and halogenated hydrocarbons. A mixed solvent of the above may be used. And this step also may be carried out without a solvent.
The reaction can be carried out at a temperature from−20° C. to the boiling point of the solvent, but preferably in the range from 0° C. to the boiling point of the solvent.
If necessary, a catalyst such as N,N-dimethylformamide may be added to the reaction system. The catalyst may be used in a stoichiometrical amount or 0.01 to 5 times the stoichiometrical amount, but preferably a stoichiometrical amount or 0.05 to 3 times the stoichiometrical amount.
A halocyclohexadiene derivative or a mixture of isomers represented by the formula (IIIA and/or IIIB):
wherein X, Y, W, R
1
, R
2
and R
3
have the same meanings as defined above, is reacted with a dehydro-, dehalogenating agent in a solvent to obtain a benzene derivative represented by the formula (I):
wherein X, Y, R
1
, R
2
and R
3
have the same meanings as defined above.
As the dehydro-, dehalogenating agent, a base may be used. There may be used alkaline metal hydroxides such as potassium hydroxide, sodium hydroxide, etc., alkaline metal carbonates such as potassium carbonate, sodium carbonate, etc., alkaline metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., alkaline metal hydrides such as sodium hydride etc. and organic bases such as pyridine, triethylamine, etc., but preferably alkaline metal hydroxides. The base may be used in a stoichiometrical amount or 0.5 to 20 times the stoichiometrical amount, but preferably a stoichiometrical amount or 0.8 to 10 times the stoichiometrical amount.
As the solvent, any solvent inert to a reactant and a reagent may be used. There may be mentioned aliphatic alcohols such as methanol, ethanol, etc., aromatic hydrocarbons such as toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, chlorobenzene, etc., ethers such as tetrahydrofuran, etc., amides such as N,N-dimethylformamide etc., sulfoxides such as dimethylsulfoxide, etc. and water, but preferably aliphatic alcohol,

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