Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-10-02
2003-04-08
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S341100, C548S346100, C514S399000, C514S400000, C514S397000, C504S139000
Reexamination Certificate
active
06545163
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the preparation of imidazole derivatives and more particularly to the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers.
BACKGROUND OF THE INVENTION
Imidazole derivatives, in particular, 1-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, commonly referred to as tioconazole, are known for their antifungal therapeutic properties. U.S. Pat. No. 4,062,966 discloses a process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers which employs arylation of an appropriate 1-aryl-2-(1-imidazolyl)alkanol or alkane thiol having the formula
wherein R
1
to R
4
are each H or C
1-6
alkyl, Ar is phenyl, or substituted phenyl wherein said substitutents are halogen, C
1-6
alkyl, C
1-6
alkoxy, thienyl, or halothienyl, and, Z is oxygen or sulfur. In accordance with US '966, the reaction comprises converting the alcohol or thiol in a suitable solvent to its alkali metal derivative by treatment with a strong base, such as an alkali metal amide or hydride, and reacting with the appropriate aralkyl halide of the formula
where n is 1 or 2, Y is an aromatic heterocyclic group or substituted heterocyclic group, wherein substitutents are halogen, C
1-6
alkyl, or C
1-6
alkoxy atoms, thienyl or halothienyl group, and X is a halogen, preferably chlorine. Tetrahydrofuran (THF) is the preferred solvent taught in US '966. Reaction temperatures may range from about 0° C. to reflux temperature of the solvent and reaction times range from about 1 hour to about 24 hours. The product is isolated with water, extracted with ether, and may be purified as the free base or converted to a salt, e.g. the hydrochloride, and purified by recrystallization.
A disadvantage of the process disclosed in US '966 is that THF is a peroxide generator which presents the potential for an explosion. From a commercial viewpoint, peroxide generators are not preferred due to the dangers associated therewith.
GB 1 522 848 discloses a process for the preparation of imidazoles useful as antifungal agents involving a labor intensive, multi-sequence reaction of an imidazole ether with a reactive ester. Like US '966, THF is employed presenting similar concerns in the synthesis of the desired imidazole product.
According to the Pharmaceutical Manufacturing Encyclopedia, tioconazole is prepared by dissolving 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol in THF and sodium hydride and heating to about 70° C. The resulting mixture is then contacted with 2-chloro-3-chloromethylthiophene and heated to reflux (about 67° C.). The resulting product is filtered, saturated with hydrogen chloride, triturated and recrystallized to obtain the purified tioconazole hydrochloride product having a melting point of about 170° C. This salt must then be freebased to form the product used in pharmaceutical formulations. This route, like those discussed above, also presents the dangers of a potential explosion.
There is thus a continuing need for a commercially viable, synthetic route for the production of imidazoles, in particular tioconazole.
SUMMARY OF THE INVENTION
The present invention relates broadly to a novel process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers comprising (a) alpha bromination of an aromatic or a heterocyclic compound, or more particularly a thiophene derivative under suitable reaction conditions; and, (b) coupling under suitable reaction conditions the product of step (a) with an imidazole, preferably an imidazolyl ethanol derivative.
For exemplary purposes, the present invention is described in particular detail with respect to the preparation of tioconazole. It is to be understood that the process is applicable to other aromatic or heterocyclic compounds, e.g. econazole or miconazole.
Relative to the preparation of tioconazole, it is preferred that the product of step (b) be converted to a bisulfate salt for ease of isolation and purification of the final product. Reaction conditions for step (a) include free radical alpha bromination, preferably employing n-bromosuccinimide (NBS) in a refluxing aliphatic solvent such as cyclohexane. Reaction conditions for step (b) include a temperature range of about 15° C. to about 30° C., use of an alcohol or short chain (e.g., C
5-10
) aliphatic hydrocarbon as solvent, and employing a reaction time of from about 1 to about 24 hours.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates broadly to a process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers comprising
(a) alpha brominating an aromatic or heterocyclic compound, preferably a thiophene derivative under suitable reaction conditions; and,
(b) coupling the product of step (a) with an imidazole, preferably an imidazolyl ethanol derivative under suitable reaction conditions. Purification of the product of step (b) is preferably accomplished as the bisulfate salt.
More specifically, the present invention relates to a process for the preparation of tioconazole comprising (a) alpha bromination of 2-chloro-3-methylthiophene, using NBS in the presence of a peroxide and aliphatic solvent under suitable reaction conditions; and, (b) contacting the product solution of step (a) with 1-(2,4-dichlorphenyl)-2-(1-imidazolyl)ethanol under suitable reaction conditions.
The reaction will be described below relative to each reaction step.
Step A
Alpha Bromination:
One embodiment of the present invention involves, as step (a), alpha bromination with a brominating agent in the presence of an aliphatic solvent and a free radical initiator. Any suitable brominating agent may be employed. Suitable brominating agents include but are not limited to NBS, molecular bromine, 1,3-dibromo-5,5-dimethyl hydantoin, n-bromoacetamide. N-bromosuccinimide is the preferred brominating agent.
The process may be employed to brominate the alkyl side chain of alkyl-substituted heterocyclic or aromatic compounds. The alkyl side chain can have from 1 to about 4 carbon atoms and is preferably a saturated hydrocarbyl radical. Typical of such alkyl side chains include methyl, ethyl, propyl and butyl radicals. Preferably, the alkyl radical is a methyl radical.
Typical of the aryl or heterocyclic compounds with which the brominated intermediate (produced by the process of step (a)) can be employed include toluene, thiophene, furan, pyridine, 2-methylpyridine, lutidine, methylquinoline, dimethylfuran and similar heterocyclic compounds. Thiophene compounds are of particular interest. Most preferred are 2- and 3-methyl thiophene and most particularly preferred is 3-methyl thiophene.
The molar ratio of brominating agent to aryl or heterocyclic is preferably 1:1. However, an excess of starting heterocyclic material above stoichiometric can be employed.
The alpha bromination is preferably carried out in a solvent that facilitates the alpha bromination. Prior art studies have shown that certain brominators take place with more facility in one solvent versus another solvent. It has been found that aliphatic solvents, such as hexane, and in particular cycloaliphatic solvents such as cyclohexane show good selectivity. It has also been found that satisfactory selectivity and yield can be obtained by carrying out the process of step (a) with an initial concentration of heterocyclic of about 5 to about 20 percent (%) by weight (wt) in the solvent.
The time of the reaction is only that necessary to complete the reaction and the reaction can generally be carried out at elevated temperature (e.g., refluxing cyclohexane) under atmospheric conditions. Generally, reaction times for step (a) comprise about 1 hour to about 12 hours. More generally the reaction is performed in about 4 hours.
In general, suitable organic peroxides may be employed as free radical initiators. Suitable initiators include but are not limited to peracetic acid, perbenzoic acid, perbutyric acid, toluenesulfonic acid, benzoyl peroxide, azobisisobutyronitrile, and the like, with benzoyl peroxide being the preferred i
Burke Brian David
Chiou Huh-Sun
Fruchey Olan Stanley
Nichols Michele L.
McKane Joseph K.
Napp Technologies
Pennie & Edmonds LLP
Shameem Golam M. M.
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