Method of preparing oxoquazepam

Details Method of preparing oxoquazepam Method of preparing oxoquazepam

1999-10-01

2001-06-26

Berch, Mark L (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06252067

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of preparing oxoquazepam which is an intermediate material for quazepam shown by the following formula (3) which is important in medicines such as sedatives.
2. Description of the Background
Oxoquazepam is considered to be prepared by the trifluoroethylation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one as shown by the following formula.
However, trifluoroethylation of this compound does not proceed due to the strong attraction to electrons of a fluorine atom when using conventional halides such as 2,2,2-trifluoroethyl iodide.
Perfluoroalkylsulfonate which possesses higher reactivity, specifically, 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate has been found as a trifluoroethylation agent instead of such conventional halides (Japanese Patent Publication No. 60663/1990).
However, 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate used as the trifluoroethylation agent is a special compound which cannot be produced on an industrial level and is expensive.
The use of anhydrous polar neutral solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane, or mixed solvents of these solvents with other solvents such as hydrocarbons (for example, benzene or toluene), halogenated hydrocarbons (for example, methylene dichloride or chloroform), and ethers (for example, diethyl ether or dioxane) has been disclosed as an effective method of the trifluoroethylation reaction using 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate (Japanese Patent Publication No. 24807/1990). Such a solvent is used to promote N-alkylation reaction in the reaction involving a compound containing both an amine and a carbonyl group, because the ratio of N-alkylation to O-alkylation is controlled by the polarity of a reaction medium in such a reaction.
Oxoquazepam used as an intermediate material for medicines must include only a small amount of impurities, in particular, only a small amount of analogous materials. Therefore, a method of preparing high purity oxoquazepam with a high yield has been demanded.
Accordingly, an object of the present invention is to provide a method of preparing high purity oxoquazepam with a high yield using a trifluoroethylation agent which is readily available and cheap.
In view of the above-described situation, the present inventors have conducted extensive studies. As a result, the present inventors have found that high purity oxoquazepam can be prepared at high yield by the trifluoroethylation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one using commercially available 2,2,2-trifluoroethyl trifluoromethanesulfonate (J. Org. Chem. 30, 4322. (1965)) as a trifluoroethylation agent in tetrahydrofuran or ethyl acetate as a solvent in the presence of potassium carbonate under reflux. This finding has led to the completion of the present invention.
SUMMARY OF THE INVENTION
Specifically, an object of the present invention is to provide a method of preparing oxoquazepam shown by the following formula (2),
which comprises reacting 2,2,2-trifluoroethyl trifluoromethanesulfonate with 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one shown by the following formula (1) in tetrahydrofuran or ethyl acetate in the presence of potassium carbonate under reflux.
Other objects, features and advantages of the invention will hereinafter become more readily apparent from the following description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The amount of 2,2,2-trifluoroethyl trifluoromethanesulfonate used in the present invention is preferably equimolar with or slightly more than the amount of the compound (1) in a molar ratio. The amount of 1.15-1.2 times mol of the compound (1) is sufficient.
The amount of potassium carbonate used in the present invention is preferably more than 2,2,2-trifluoroethyl trifluoromethanesulfonate in a molar ratio, in particular, about 1.5-3 times mol of 2,2,2-trifluoroethyl trifluoromethanesulfonate.
In the present invention, ethyl acetate or tetrahydrofuran is used as a solvent. If a solvent having a polarity higher than that of these compounds such as acetone, acetonitrile, or dimethylformamide is used, O-alkylates are produced at about a 30% yield. If a solvent having a polarity lower than that of these compounds such as toluene is used, the reaction scarcely proceeds and the raw materials are left unreacted. It is preferable to use ethyl acetate or tetrahydrofuran in an amount so that the polarity of the solvent is not affected by the polarity of the solute, specifically, 5 times or more of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one.
According to the method of the present invention using ethyl acetate or tetrahydrofuran, the raw materials disappear after being refluxed for 8-20 hours to obtain an N-alkylate, specifically, oxoquazepam. The ratio of the resulting by-product O-alkylates is 3% or less.
After the reaction, potassium carbonate is removed and the reactant is crystallized from a saturated hydrocarbon solvent to obtain high purity oxoquazepam.
According to the method of the present invention, high purity oxoquazepam can be manufactured at high yield at a low cost.


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