JPH1180145A - Production of propoxynitrobenzenes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for producing a synthetic antimicrobial agent by reacting a dihalogenated nitrophenol with glycidyl alcohol protected with a specific substituent group. SOLUTION: A propoxynitrobenzene of formula I (X<1> and X<2> are each a halogen) is obtained by reacting a compound of formula II with a compound of formula III. 2,3-Difluoro-6-nitrophenol, etc., may be cited as the compound of formula II. The optically active substance of the compound of formula III is readily obtainable and the compound of formula I can be obtained. (R)- Glycidyl tosilate, etc., may be cited as the compound of formula III. 2, 3- Difluoro-6-nitro[(R)-2,3-epoxypropyloxy]benzene, etc., may be cited as the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound represented by the following general formula (3) useful as an intermediate for producing a synthetic antibacterial drug:

[0002]

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Wherein X ¹ and X ² are each independently
A halogen atom), and a process for producing 2-oxiranylmethyloxy-3,4-dihalogenonitrobenzene.

[0004]

2. Description of the Related Art Ofloxacin (OFLX) is a synthetic antibacterial agent having excellent antibacterial activity, pharmacokinetics and high safety, and is widely used. Further, subsequent studies have revealed that the optically active form DR-3355 has a higher antibacterial activity and safety than racemic ofloxacin, and is a more useful compound as an antibacterial agent (Japanese Patent Application Laid-Open (JP-A) No. 9-110572). JP-A-57-46986 and JP-A-62-25
No. 2790).

[0005]

Accordingly, the present invention has been intensively studied to provide an industrially advantageous process for producing the compound of the general formula (3), and as a result, the present invention has been completed.

[0006]

The present invention is represented by the following reaction formula.

[0007]

Embedded image

Wherein X ¹ and X ² are each independently
In other words, the present invention provides a compound of the general formula (1)
Is a method for producing a compound of the general formula (3) by reacting the compound of the formula (3).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound of formula (2), examples of the substituted sulfonyloxy group include a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a paratoluenesulfonyloxy group.

The reaction between the compounds (1) and (2) is carried out under basic conditions. Examples of the base used in the reaction include inorganic bases such as sodium hydride, lithium hydride, sodium amide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo. Organic bases such as [5,4,0] -7-undecene (DBU) and Triton B, metal alkoxides such as potassium tert-butoxide, sodium ethoxide and sodium methoxide, and lithium reagents such as butyllithium and phenyllithium. And these may be 1 to 1
It is preferable to use about 0 equivalent.

Examples of the solvent used in the reaction include hydrocarbon solvents such as benzene, toluene, xylene and n-hexane;
Alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and n-butanol; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; ketones such as acetone and methyl ethyl ketone Examples of the solvent include amide solvents such as dimethylacetamide and dimethylformamide, chlorine solvents such as dichloromethane, dichloroethane and chloroform, and dimethylsulfoxide and sulfolane.

The reaction is preferably carried out in a temperature range from -78 ° C. to the boiling point of the solvent, the reaction time is from about 10 minutes to several days, and sometimes it may be desirable to carry out the reaction under anhydrous conditions. When potassium iodide, sodium iodide, crown ether, etc. are added in an amount of about 1/100 to equivalent, these reactions may be promoted.

As for the compound of the formula (2) as a raw material, its optically active substance can be easily obtained [References]
J. Org. Chem. 43 , 4876 (1978),
52 , 3710 (1986), Angew. Che
m. Int. Ed. Engl. 17 , 937 (197)
8), Synthesis 316 (1982);
Org. Chem. 46 , 3348 (1981), Ca
n. J. Chem. 57, 233 (1979)]. By using this optically active substance, an optically active substance of the compound represented by the formula (3) can be obtained.

[0014]

Next, an embodiment will be described.

Example 1 2,3-difluoro-6-nitro-[(R) -2,3-
Epoxypropyloxy] benzene ((3): X ¹ = X ²
= F) 2,3-difluoro-6-nitrophenol ((1):
After dissolving 700.4 mg of (X ¹ = X ² = F) in 4 ml of anhydrous DMF, add 304.1 mg of K ₂ CO _{3 and} stir at 70 ° C. for 30 minutes. Catalytic amount of 18-crown-6-ether, KI
242.4 mg and (R) -glycidyl tosylate 1
g, and the mixture is heated and stirred at the same temperature for 6 hours. After the reaction, ethyl acetate was added, and the organic layer was washed with water, dried (MgSO ₄ ), and evaporated, and the residue obtained was subjected to silica gel column chromatography.
7 mg, yield 55%. NMR (CDCl ₃ ) δ: 2.72 (1H, d, d, J = 2.7 and 4.8 Hz, proton at the 3rd position of the epoxypropyl group) 2.89 (1H, d, d, J = 4.8 and 4.8 Hz, 3rd position of the epoxypropyl group) 3.42 (1H, multiple line with 18 Hz width, methylene proton at the 2nd position of epoxypropyl group) 4.21 (1H, d, d, d, J = 1.2, 6.0 and 7.2 Hz, proton at the 1st position of epoxypropyl group) 4.53 (1H, d, d, d, J = 1.2,3.6 and 4.8Hz, 1st position of epoxypropyl group proton) 7.07 (1H, d, d, d, J = 7.2,9.0 and 9.6Hz, 4th position proton) 7.74 (1H, d, d, d, J = 2.4,5.4 and 7.2Hz, 5-position proton)

[0016]

According to the method of the present invention, a compound of the general formula (3) useful as an intermediate for producing a synthetic antibacterial drug can be obtained in high yield.

Claims (3)

[Claims] 1. A compound of the general formula (1) Wherein X ¹ and X ² each independently represent a halogen atom, to a compound represented by the formula (2): Wherein the compound represented by the general formula (3) is reacted: (Wherein X ¹ and X ² each independently represent a halogen atom). 2. The method according to claim 1, wherein the substituted sulfonyloxy group is a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a paratoluenesulfonyloxy group. 3. The method according to claim 1, wherein X ¹ and X ² are each a fluorine atom.