JPH035391B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel oxazole derivative represented by the following general formula (I). [In the formula, R ₁ is an aryl group or a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms and with or without a lower alkyl group as a substituent, and R ₂ is a lower alkyl group. The group is 0 or 1
or an integer of 2. ] In the above general formula (I), the aryl group represented by R ₁ includes a phenyl group, a naphthyl group, etc.
Specific examples of the 5- or 6-membered aromatic heterocyclic group containing one or two nitrogen atoms include a pyrazolyl group, an imidazolyl group, a pyridyl group, and the like. In addition, the lower alkyl group in R ₁ and R ₂ is an alkyl group having 1 to 6 carbon atoms, such as a linear group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl group, etc. Alternatively, it can represent a branched alkyl group. The compound represented by the general formula (I) of the present invention is a new compound that has not been described in any literature, and is, for example, a compound that has antibacterial and antibacterial effects and is useful as a medicine. Compound (I) of the present invention can be produced, for example, by the method shown below. <Method A> General formula [In the formula, X represents a halogen atom, and R ₂ represents the above meaning. ] and a compound represented by the general formula R ₁ S(O)mM () [wherein M is an alkali metal atom or a silver atom,
R ₁ has the above meaning, and m represents an integer of 0 or 2. ]
A compound represented by is reacted. In the general formula (), examples of the halogen atom of X include chlorine, bromine, and iodine atoms.
The compound represented by the general formula () is a new compound, and can be produced, for example, by reacting the compound represented by the following general formula () with a halogenating agent. [In the formula, R ₂ has the above meaning. ] The details of the method for producing the compound of general formula () will be described in detail in Reference Examples below. Furthermore, examples of the alkali metal atom represented by M in the general formula () include lithium, sodium, potassium, and the like. The reaction of compounds () and () is preferably carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally includes ethers such as tetrahydrofuran, dioxane, and dimethoxymethane, and aprotic polar solvents such as dimethyl sulfoxide and dimethylformamide. The usage ratio of compound () and () may be appropriately selected, and it is generally preferable to use 1 mol to 2 molar equivalents of compound () with respect to compound (). The reaction temperature is also determined appropriately, but is usually preferably from -20°C to the reflux temperature of the solvent, and the reaction is generally sufficiently completed in about 1 to 24 hours.
The reaction is promoted by adding a catalytic amount of a crown ether such as 18-crown-6. <Method B> General formula [In the formula, R ₁ and R ₂ have the above meanings. ] By reacting the compound represented by the general formula with an oxidizing agent, [In the formula, n is an integer of 1 or 2, and R ₁ and R ₂ have the above meanings. ] The compound of the present invention can be produced. Various types of oxidizing agents can be used,
For example, peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, hydrogen peroxide, ozone, peroxides such as benzoyl peroxide, chromic acid,
Examples include metal oxides such as potassium permanganate, hypohalous acids such as sodium hypochlorite, and sodium metaperiodate. This reaction is preferably carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but water, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as methylene chloride are used. The proportion of the oxidizing agent to be used is appropriately determined depending on the desired compound of the present invention and is not limited. For example, when producing a sulfoxide compound in which n is 1 in the general formula (), it is usually best to use an equimolar amount to the compound represented by the general formula (V), and if desired, a slight excess amount may be used. You can also do it. On the other hand, when producing a sulfone compound in which n is 2 in the general formula (), the proportion of the oxidizing agent used is about twice or more, usually about 2 to It is preferable to use 3 times the molar amount. The reaction temperature is determined appropriately, but is usually -40℃~
The boiling point temperature of the solvent is preferably within a range, and a reaction time of about 1 to 24 hours is generally sufficient. After completion of the reaction, the target compound can be easily isolated and purified by known methods such as extraction, recrystallization, column chromatography, etc. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples. Further, Table 1 shows the compounds of the present invention and their physicochemical properties. The compound numbers in each example correspond to the numbers listed in Table 1. Reference example 2-methyloxazole-4-carboxylic acid-t
- 7.32 g of butyl ester, 10.68 g of N-bromosuccinimide, 60 mg of benzoyl peroxide, and charcoal tetrachloride.
Pour into 200ml and reflux for 4 hours under light irradiation.
After cooling, insoluble matter is filtered off, and the filtrate is washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off carbon tetrachloride is purified by silica gel column chromatography to obtain 4.35 g of 2-bromomethyl-oxazole-4-carboxylic acid t-butyl ester as a colorless oil. Boiling point 115-118℃/0.1mmHg ¹ H-NMR (100MHz, CDCl ₃ ) δ: 1.58 (9H, s, -COO-t-Bu) 4.47 (2H, s, -CH ₂ -) 8.14 (1H, s, Proton at position 5 of oxazole ring) MS (M ⁺ ) 261 C ₉ H ₁₂ NO ₃ Br Calculated value m/e 261.000 Actual value m/e 261.003 Example 1 670 mg of 50% sodium hydride, 27 ml of dry tetrahydrofuran 1.43 ml of benzenethiol is added dropwise to the suspension under ice cooling in a nitrogen stream. After stirring at the same temperature for 5 minutes, 3.33 g of 2-bromomethyl-oxazole-4-carboxylic acid t-butyl ester,
A solution of dried 18-crown-6 (100 mg) dissolved in 10 ml of tetrahydrofuran was added dropwise to the above reaction solution, and the mixture was further stirred at the same temperature for 1.5 hours. Tetrahydrofuran was distilled off, the residue was extracted with diethyl ether, the extract was dried over anhydrous sodium sulfate, the diethyl ether was distilled off, and the residue was purified by silica gel column chromatography to obtain an oily product. was crystallized from petroleum ether, and the crystals were recrystallized from ether-petroleum ether to give a melting point of 64.5~
3.1 g (yield: 81%) of 2-phenylthiomethyl-oxazole-4-carboxylic acid t-butyl ester (compound 1) was obtained as colorless fine needle-like crystals at 65.5°C. Example 2 Compounds 4 and 7 were obtained in the same manner as in Example 1 except that the raw materials were selected to obtain Compounds 4 and 7 listed in Table 1. Example 3 2.1 g of 2-bromomethyl-oxazole-4-carboxylic acid t-butyl ester was added to 3.2 g of sodium benzenesulfinate at room temperature under a nitrogen atmosphere.
20 ml of an acetonitrile solution containing 18-crown-6 (50 mg) was added dropwise and stirred for 8 hours. Acetonitrile was distilled off and the residue was extracted with methylene chloride and dried over anhydrous sodium sulfate. Methylene chloride was distilled off, ether was added to the residue, the crystals were collected by filtration, and recrystallized from ethanol to give 2-benzenesulfonylmethyl-oxazole-4-carboxylic acid-t as colorless fine needle-like crystals with a melting point of 180-181°C. -Butyl ester (compound 3) 1.99g (yield 76%) was obtained. Example 4 A solution of Compound 1 (846 mg) and 7 ml of methylene chloride was cooled with ice under a nitrogen stream, and a solution of 752 mg of 70% m-chloroperbenzoic acid and 14 ml of methylene chloride was added dropwise, followed by stirring at the same temperature for 30 minutes. Insoluble materials are removed by filtration, and the filtrate is washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. After drying, methylene chloride was distilled off, the resulting residue was purified by silica gel column chromatography, and the resulting oil was crystallized from ether and recrystallized from ether-petroleum ether to give a product with a melting point of 129-130°C. 743 mg of 2-benzenesulfinylmethyl-oxazole-4-carboxylic acid t-butyl ester (compound 2) in the form of fine platelets
(yield 83%). Example 5 Compounds 5 and 8 were obtained in the same manner as in Example 4 except that the raw materials were selected to obtain Compounds 5 and 8 listed in Table 1. Example 6 2-(pyridyl-2-thiomethyl)-oxazole-4-carboxylic acid-t-butyl ester 584 mg
was dissolved in 5 ml of dichloromethane, cooled on ice under a nitrogen stream, 1.08 g of m-chloroperbenzoic acid was dissolved in 20 ml of dichloromethane, the solution was added dropwise, and the mixture was heated at the same temperature for 30 mL.
Stir for 5 minutes and then at room temperature for 5 hours. Insoluble matters are removed by filtration and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography and recrystallized from ethanol to give 2-(α-pyridinesulfonylmethyl)-oxazole-4-carboxylic acid in the form of colorless fine needles with a melting point of 173-174°C. 447 mg (yield 69%) of t-butyl ester (compound 6) was obtained. Example 7 Compounds 3 and 9 were obtained in the same manner as in Example 6 except that the raw materials were selected to obtain Compounds 3 and 9 listed in Table 1.

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Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is an aryl group or a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms and with or without a lower alkyl group as a substituent, and R ₂ is a lower alkyl group. The group is 0 or 1
or an integer of 2. ] An oxazole derivative represented by