Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-04-11
2001-11-13
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C564S442000, C568S588000
Reexamination Certificate
active
06316658
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an N-cyclopropyl-2-difluoromethoxy-3-halogenoaniline and an intermediate used for production thereof.
BACKGROUND ART
In an international publication, WO 97/29102 is disclosed a quinolonecarboxylic acid having a cyclopropyl group at the 1-position, an isoindolinyl group at the 7-position and a difluoromethoxy group at the 8-position, which is a synthetic antibacterial agent.
However, in the production method of the quinolonecarboxylic acid described in the above laid-open patent publication, 2,6-difluoroaniline which is difficult to synthesize and procure industrially, must be used as a starting material; many steps are employed; explosive sodium azide is used; and a diazotization step of low productivity is included. Thus, in carrying out the industrial production of the quinolonecarboxylic acid according to above method, there have been many problems in cost and safety.
The present inventors made studies on the intermediate for the quinolonecarboxylic acid and the process for production thereof. As a result, it was found out that by using a 2-difluoromethoxy-3-halognonitrobenzene (which is a novel substance) as a raw material, reducing the compound to corresponding aniline, subjecting the aniline to cyclopropylation to synthesize an N-cyclopropylaniline, and reacting it with a dialkyl alkoxymethylenemalonate typified by diethyl ethoxymethylenemalonate, a corresponding adduct was formed.
By subjecting the adduct to a ring-closing reaction according to a known method, there can be easily derived a precursor of the above-mentioned quinolonecarboxylic acid, i.e. an alkyl 1-cyclopropyl-4-oxo-7-halogeno-8-difluoro-methoxy-3-carboxylate. Therefore, it was confirmed that the above-mentioned intermediates (2-difluoromethoxy-3-halogenonitrobenzene, corresponding aniline and N-cyclopropylaniline) are important novel compounds in producing the above quinolonecarboxylic acid derivative at a low cost according to an industrially satisfactory method and are all easily synthesized industrially. Thus, the present invention has been completed.
DISCLOSURE OF THE INVENTION
The present invention provides a difluoromethoxybenzene derivative represented by the following formula (1):
wherein X is a halogen atom and Y is a nitro group or an amino group.
The present invention further provides an N-(1-alkoxycyclopropyl)-2-difluoromethoxy-3-halogenoaniline derivative represented by the following formula (2):
wherein X is a halogen atom and R
1
is a lower alkyl group; and an N-cyclopropyl-2-difluoromethoxy-3-halogenoaniline derivative represented by the following formula (3):
wherein X is a halogen atom and R is a hydrogen atom or a 2,2-di(alkoxycarbonyl)ethylene group represented by the following formula (4):
—CH═C(CO
2
R
2
)
2
(4)
(wherein R
2
is a lower alkyl group).
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail below.
To obtain the final objective compound of the present invention, first, one of the objective compounds of the present invention, i.e. a 2-difluoromethoxy-3-halogenonitrobenzene [a compound of the formula (1) wherein Y is a nitro group] is synthesized. As the raw material therefor, there can be used a 2-halogenophenol of good industrial availability such as 2-chlorophenol, 2-bromophenol, 2-iodophenol or the like. By nitrating the 2-halogenophenol according to a known method, there is obtained a 2-halogeno-6-nitrophenol such as 2-cloro-6-nitrophenol, 2-bromo-6-nitrophenol, 2-iodo-6-nitrophenol or the like.
In the above nitration, position isomers of nitro group are formed. However, an objective 2-halogeno-6-nitrophenol can be easily isolated at a high purity by using a purification means such as steam distillation, recrystallization or the like.
The 2-halogeno-6-nitrophenol can also be obtained by using an o-nitrophenol as a starting material and subjecting it to halogenation. Various other methods can also be used. In the present invention, there is no restriction as to the method for obtaining the 2-halogeno-6-nitrophenol.
Next, the 2-halogeno-6-nitrophenol is reacted with a difluoromethylation agent, for example, chlorodifluoromethane, whereby can be obtained a 2-difluoromethoxy-3-halogenonitrobenzene [a compound of the formula (1) wherein Y is a nitro group], such as 2-difluoromethoxy-3-chloronitrobenzene, 2-difluoromethoxy-3-bromonitrobenzene, 2-difluoromethoxy-3-iodonitrobenzene or the like.
The above difluoromethylation can be conducted by reacting the 2-halogeno-6-nitrophenol with a difluoromethylation agent (e.g. chlorodifluoromethane) in the presence of a base. In this reaction, there may be used a solvent such as halogenated solvent (e.g. dichloromethane or dichloroethane), ether type solvent (e.g. 1,4-dioxane, tetrahydrofuran, dimethoxyethane or diethylene glycol dimethyl ether), aprotic polar solvent (e.g. dimethylformamide, dimethylacetamide or dimethyl sulfoxide) or the like.
The temperature of the difluoromethylation must be room temperature or higher. The reaction can be conducted in a temperature range up to the boiling point of the solvent used, at ordinary pressure. The reaction may be conducted under a pressure which is generated spontaneously in a closed vessel. The temperature is specifically from room temperature to 150° C., preferably from 50 to 120° C.
The amount of the difluoromethylation agent (e.g. chlorodifluoromethane) used is 1 to 20 moles, preferably 1 to 5 moles per mole of the 2-halogeno-6-nitrophenol. The base used can be exemplified by inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. Of these, sodium hydroxide, potassium hydroxide or the like is preferred.
Incidentally, the difluoromethylation may be conducted in the presence of a phase transfer catalyst such as tetra-n-butylammonium bromide, benzyltrimethylammonium chloride or the like.
Next, the above-obtained 2-difluoromethoxy-3-halogenonitrobenzene is reduced to obtain a 2-difluoromethoxy-3-halogenoaniline [a compound of the formula (1) wherein Y is an amino group], which is one objective compound of the present invention. A known technique can be used in this reduction reaction.
There can be specifically used reduction using a metal (e.g. iron powder, zinc or tin); catalytic reduction; reduction using a metal hydride (e.g. aluminum lithium hydride or sodium boron hydride); or reduction using a sulfur compound (e.g. sodium hydrosulfide or sodium dithionite). Reduction using an iron powder is preferred.
The above-obtained 2-difluoromethoxy-3-halogenoaniline is subjected to cyclopropylation, whereby can be synthesized an N-cyclopropoyl-2-difluoromethoxy-3-halogenoaniline [a compound of the formula (3) wherein R is a hydrogen atom], which is one objective compound of the present invention. The cyclopropylation can be conducted by, as reported in J. Chem. Soc. Chem. Comm. 897 (1987), reacting the 2-difluoromethoxy-3-halogenoaniline with 1-bromo-1-ethoxycyclopropane and then reacting the reaction product with sodium boron hydride and boron trifluoride etherate.
Or, the cyclopropylation may be conducted by, as described in JP-A-10-87584, reacting the 2-difluoromethoxy-3-halogenoaniline with a 1-alkoxy-1-trimethylsilyloxy-cyclopropane (e.g. 1-ethoxy-1-trimethylsilyloxycyclopropane) in the presence of an organic acid (e.g. formic acid or acetic acid) or an inorganic acid (e.g. hydrochloric acid or sulfuric acid) in a straight chain or branched chain alcohol type solvent having 1 to 6 carbon atoms, and then reducing the reaction product with, for example, sodium boron hydride, preferably in the presence of boron trifluoride etherate or the like.
Incidentally, when there is adopted, for example, the above-mentioned reaction of 2-difluoromethoxy-3-halogenoaniline with 1-alkoxy-1-trimethylsilyloxycyclopropane (e g. 1-ethoxy-1-trimethylsilyloxycyclopropane), there is derived an N-(1-alkoxycyclopropyl)-2-difluoromethoxy-3-halogenoaniline derivative represented by the formula (2):
which is one obje
Takeuchi Hiroaki
Yoshida Yasuo
Ihara Chemical Industry Co. Ltd.
Kubovcik & Kubovcik
Raymond Richard L.
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