Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2002-06-14
2003-06-03
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C549S434000
Reexamination Certificate
active
06573397
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing 3,4-dihydroxybenzonitrile. More particularly, the present invention relates to a process for producing 3,4-dihydroxybenzonitrile from 3,4-methylenedioxybenzonitrile.
The target 3,4-dihydroxybenzonitrile is useful as a starting material for synthesis of medicines or agricultural chemicals, particularly for synthesis of quinazoline compounds usable as an anticancer agent.
BACKGROUND ART
As a conventional process for producing 3,4-dihydroxybenzonitrile from 3,4-methylenedioxybenzonitrile, for example, J. Org. Chem., 62, 4097 (1977) discloses a process in which 3,4-methylenedioxybenzonitrile is reacted with lithium diisopropylamide in an excess molar amount (five times by mole or more) in a reaction medium consisting of 1,3-dimethyl-2-imidazolidinone at a high temperature of 185° C., to produce 3,4-dihydroxybenzonitrile with a yield of 94%. This process is, however, disadvantageous as an industrial process in that lithium diisopropylamide, which has a high ignition property, must be employed, and the reaction conditions are very severe and a complicated after-treatment is necessary.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a process for producing 3,4-dihydroxybenzonitrile with a high yield from 3,4-methylenedioxybenzonitrile by simple and easy procedures suitable for industrial practice.
The above-mentioned object can be attained by the process of the present invention for producing 3,4-dihydroxybenzonitrile, which comprises the steps of:
chlorinating 3,4-methylenedioxybenzonitrile with at least one member selected from the group consisting of sulfuryl chloride and mixtures of molecular chlorine with a chlorination-promoter consisting of at least one member selected from phosphorus trichloride, phosphorus pentachloride, sulfuryl chloride, thionyl chloride, and nitrosyl chloride, to prepare 2-chloro-benzo[1,3]dioxole-5-carbonitrile, and
hydrolyzing 2-chloro-benzo[1,3]dioxole-5-carbonitrile by contacting it with water to produce 3,4-dihydroxybenzonitrile.
In the process of the present invention, the chlorination procedure is preferably carried out in a reaction medium comprising at least one chlorination-resistive solvent.
Also, in the process of the present invention, the reaction medium for the chlorination procedure is preferably present in an amount of 1 to 50 ml per g of 3,4-methylenedioxybenzonitrile.
Additionally, in the process of the present invention, the chlorination procedure is preferably carried out at a temperature of 5 to 150° C.
Further, in the process of the present invention, the chlorination procedure using the molecular chlorine-chlorination promoter mixture, a chlorination reaction mixture is preferably prepared by introducing a molecular chlorine gas into a mixture of 3,4-methylenedioxybenzonitrile with the chlorination-promoter.
Yet further, in the process of the present invention, the molecular chlorine in the chlorination reaction mixture is preferably present in an amount of 1 to 50 moles per mole of 3,4-methylenedioxybenzonitrile.
Still further, in the process of the present invention, the chlorination promoter in the chlorination reaction mixture is preferably present in an amount of 0.05 to 5 moles per mole of 3,4-methylenedioxybenzonitrile.
Moreover, in the process of the present invention, the chlorination procedure is preferably carried out by using sulfuryl chloride in an amount of 1 to 50 moles per mole of 3,4-methylenedioxybenzonitrile.
In addition, in the process of the present invention, the chlorination procedure with sulfuryl chloride is preferably carried out in an inert gas atmosphere under a gauge pressure of 0 to 1000 kPa at a temperature of 5 to 100° C.
Furthermore, in the process of the present invention, the hydrolysis procedure is preferably carried out at a temperature of 5 to 100° C.
Finally, in the process of the present invention, the hydrolysis procedure, water is preferably present in an amount of 1 to 50 g per g of 3,4-methylenedioxybenzonitrile.
The process of the present invention optionally comprises a step of collecting the resultant 3,4-dihydroxybenzonitrile from the reaction mixture of hydrolysis procedure by at least one procedure selected from precipitation, recrystallization, distillation and column chromatography.
BEST MODE OF CARRYING OUT THE INVENTION
In the first step of the process of the present invention for producing 3,4-dihydroxybenzonitrile, a starting compound, namely 3,4-methylenedioxybenzonitrile represented by the formula (1):
is chlorinated with at least one member selected from the group consisting of (A) sulfuryl chloride and (B) mixtures of (a) molecular chlorine with (b) a chlorination-promoter consisting of at least one member selected from phosphorus trichloride, phosphorus pentachloride, sulfuryl chloride, thionyl chloride and nitrosyl chloride, to produce an 2-chloro-benzo[1,3]dioxole-5-carbonitrile represented by the formula (2):
In the next step, the reaction mixture discharged from the chlorination step and containing the resultant 2-chloro-benzo[1,3]dioxole-5-carbonitrile is brought into contact with water to hydrolyze this compound into 3,4-dihydroxybenzonitrile represented by the formula (3):
The 2-chloro-benzo[1,3]dioxole-5-carbonitrile of the formula (2) is a novel compound prepared for the first time by the present invention.
In an embodiment (1) of the process of the present invention, the chlorination of 3,4-methylenedioxybenzonitrile is carried out by using, as a chlorination agent, a mixture of molecular chlorine with a chlorination promoter.
The chlorination promoter consists of at least one member selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, sulfuryl chloride, thionyl chloride (SOCl
2
) and nitrosyl chloride (NOCl), preferably phosphorus trichloride and phosphorus pentachloride. The above-mentioned compounds for the chlorination promoter can be employed alone or in a mixture of two or more thereof.
In this embodiment (1), the molecular chlorine is preferably employed in an amount of 1 to 50 moles, more preferably 1 to 10 moles, per mole of 3,4-methylenedioxybenzonitrile, and the chlorination promoter is preferably employed in an amount of 0.05 to 5 moles, more preferably 0.1 to 2 moles per mole of 3,4-methylenedioxybenzonitrile.
In the embodiment (1), the chlorination procedure is preferably carried out in a reaction liquid medium. There is no limitation to the type of compounds usable for the reaction liquid medium, as long as the compounds do not hinder the chlorination reaction of 3,4-methylenedioxybenzonitrile and are resistive to chlorination with the mixture of the molecular chlorine with the chlorination promoter.
The reaction liquid medium preferably comprises, as a main component, at least one member selected from aromatic hydrocarbons, for example, benzene, toluene, xylene, ethylbenzene, tert-butylbenzene; halogenated aromatic hydrocarbons, for example, chlorobenzene; aliphatic hydrocarbons, for example, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, cycloheptane, cyclooctane; halogenated aliphatic hydrocarbons, for example, methylenechloride, chloroform, tetrachloromethane, and dichloroethane; ethers, for example, diethylether, diisopropylether, tetrahydrofuran, and dioxane; and carboxylate esters, for example ethyl acetate, and butyl acetate. Preferably, the aromatic hydrocarbons, halogenated aromatic hydrocarbons, and carboxylate esters, more preferably, the aromatic hydrocarbons, and carboxylate esters are employed for the reaction liquid medium. These compounds for the reaction liquid medium may be employed alone or in a mixture of two or more thereof.
The amount of the reaction medium is controlled, in consideration of the uniformity of the reaction mixture and ease of stirring the reaction mixture, in preferably 1 to 50 ml, more preferably 2 to 20 ml per g of 3,4-methylenedioxybenzonitrile in the reaction mixture.
In the chlorination step of the embodiment
Furuya Toshio
Shiba Koji
Shirai Masashi
Arent Fox Kintner & Plotkin & Kahn, PLLC
Ube Industries Ltd.
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