KR950009828B1 - Aryl amino thiazol acetic acid and process for preparing the same - Google Patents

Abstract

Arylaminothiazol acetic acid of formula (I) is perpd. by condensasion of the ketone cpd. of formula (II) and the amine cpd. of formula (III) in the mixed solvent comprising a polar solvent e.g. ethanol or methanol and water in the condition of 4-6 pH. pref. using an alkali metalic salts solution e.g. sodium hydroxide or sodium carbonate. In the formulas, R1 is H, formyl or trityl; R2 is carboxylic acid, C1-4 alkyl ester or carboxylic acid chloride; R3 and R4 are H, acetyl or para- methoxy benzyl; X and Y are H or halogen.

Description

Arylaminothiazole acetic acid and preparation method thereof

The present invention relates to a novel compound represented by the following general formula (I) which can be used as an intermediate useful in the preparation of Gram-positive bacteria, Gram-negative bacteria and a wide range of antimicrobial activities, and the preparation method thereof. More specifically, the present invention relates to an arylaminothiazole acetic acid of general formula (I) and a method for producing the same by reacting a ketone compound represented by the following general formula (II) with an amine compound represented by general formula (III).

In general formula (I) above, R ₁ refers to a hydrogen or a protecting group generally used in the synthesis of penicillin or cephalosporin compounds. That is, lower alkyl and alkyl groups such as benzyl, benzhydryl, trityl, tert-butoxycarbonyl, 2,2, -trichloromethoxycarbonyl, chloroacetyl, trichloroacetyl, benzyloxycarbonyl, para-meth Oxybenzyloxycarbonyl, formyl, and trifluoroacetyl. R ₂ refers to carboxylic acids, activated carboxylic acid derivatives useful for acylation reactions, lower esters having the function of carboxyl protecting groups. R <_3> , R <_4> is a protecting group or acyl group of hydrogen or phenolic hydroxyl group, R <_3> , R <_4> may be same or different from each other. Examples are acetyl, para-methoxybenzyl, benzyl, methylene and the like. X and Y are hydrogen or halogen atoms such as fluorine, chlorine, bromo and iodine, and X and Y may be the same as or different from each other. Heterocyclic structures such as 2-aminothiazole in general formula (I) are disclosed in Korean Patent Publication Nos. 8-860 and 81-950. In these aminothiazole structures, there may be two types of isomers of syn and anti conformation. Generally, syn isomers show much higher antimicrobial activity than anti isomers, considering the relationship between structure and antimicrobial activity. From the standpoint of its utility value, the syn isomer would be useful. Since these aminothiazole structures may also exist in tautomeric forms, they may also have a structure of 2-aminothiazolinyl, which is also included in the scope of the present invention. In general formula (II), R <_1> and R <_2> is mutually same as R <_1> and R <_2> of general formula (I), respectively. In the formula (Ⅲ), X, Y, R 3 and R ₄ are the same as each other and each of the general formula (Ⅰ) of X, Y, R ₃ and R _4.

That is, the present invention condenses a ketone compound of the general formula (II) and an amine compound of the general formula (III) to produce an arylaminothiazole acetic acid compound of the general formula (I). , Dimethyl sulfoxide, dimethylformamide, acetonitrile, methylene chloride, chloroform, ethyl acetate, and the like are possible, and the reaction is carried out by using a mixed solvent with 1 to 3 times water in proportion. In this condensation reaction, the pH of the reaction solution may be about 2 to 6, preferably, it is effective to maintain the pH of about 4-5. In order to maintain the pH of the reaction solvent, a base solution should be used. As a possible base, organic bases such as lower alkylamines can generally be used. In particular, alkali metal bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate Inorganic bases are possible. As reaction temperature, -10 degreeC-30 degreeC are suitable. The reaction time may be about 5 to 24 hours, preferably 12 to 18 hours.

The following examples will further illustrate the present invention but are not intended to limit the scope thereof.

Example 1

[3-[(3,4-Di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methylbromide]

3-[(3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methanol (2.1 g, 4.7 mmol) was dissolved in 67 ml of dry THF and sabromocarbon (3.1 g, 9.4 mmol) And triphenylphosphine (2.2g, 9.4mmol) were added sequentially under ice-cooling, stirred for several minutes, then the bath was removed and stirred at room temperature for 1 hour. Ethyl acetate was added, washed with saturated brine and dried over anhydrous magnesium sulfate. Let's do it. The dried organic solvent was concentrated and separated by 80 g of silica gel and an eluent (n-hexane: ethyl acetate = 3: 1). The obtained compound was suspended in isopropyl ether, filtered and dried to give 1.8 g of the target compound as a white solid. Get

Yield: 75%

¹ H-NMR (CDCl ₃ ): δ3.82 (6H, s, OCH ₃ ), 4.47 (2H, CH ₂ Br), 5.13 (4H, s, CH ₂ O), 6.53 (1H, s, isoxazole -H), 6.6-7.6 (11H, m, phenyl-H)

Example 2

[N-{3-[(3,4-Di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxy} phthalimide]

3-[(3,4-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxy bromide (1.5 g, 2.94 mmol) and N-hydroxyphthalimide (0.58 g, 3.53 mmol) It is dissolved in a mixed solvent of 18 ml of THF and 6 ml of dimethylformamide, and 0.50 ml of triethylamine is added dropwise at room temperature, followed by stirring at room temperature for 5 hours. 100 ml of ethyl acetate was added to the reaction mixture, washed with water (30 ml × 5), dried over anhydrous magnesium sulfate, concentrated, and added to isopropyl ether. The mixture was stirred well, filtered and dried to give 1.4 g of the desired compound as pale yellow. Obtained as a solid.

Yield: 80%

¹ H-NMR (CDCl ₃ ): δ 3.80 (6H, s, OCH ₃ ), 5.10 (4H, d, OCH ₂ ), 5.37 (2H, s, CH ₂ ON-phthalimide), 6.8-7.5 ( 11H, m, phenyl-H), 7.86 (4H, s, phenyl-H of phthalimide)

Example 3

[3-[(3,4-Para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxyamine]

N- {3-[(3,4-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxy} phthalimide (1.4 g, 2.36 mmol) was dissolved in 45 ml of methylene chloride and -15 After cooling to ˜10 ° C., hydrazine monohydrate (0.32%, 6.39 mmol) is dissolved in 4.5 ml of ethanol and stirred at room temperature for 1.5 hours. The resulting white solid is removed by filtration, the filtrate is washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to obtain about 1 g of the target compound. This compound is used for the next reaction without purification.

¹ H-NMR (CDCl ₃ ): δ 3.76 (6H, s, OCH ₃ ), 4.81 (2H, s, OCH ₂ ONH ₂ ), 5.61 (4H, s, CH ₂ Ar), 6.53 (1H, s, Isoxazole-H), 6.70-7.70 (11H, m, phenyl-H)

Example 4

[3-[(2,5-Dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methylbromide]

[3- (2,5-Dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methanol (0.95 g, 1.84 mmol) was dissolved in 25 ml of tetrahydrofuran and ice-cooled. Sabromocarbon (1.2 g, 3.62 mmol) and triphenylphosphine (0.85 g, 3.76 mmol) were added thereto, followed by stirring at room temperature for 4 hours. The reaction is filtered and the filtrate is diluted with 50 ml of ethyl acetate, washed with 25 ml of water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was separated by column chromatography (silica gel / eluent; hexane: ethyl acetate = 3: 1) to yield 0.65 g of the desired compound as a yellow solid.

Yield: 61%

¹ H-NMR (CDCl ₃ ): δ3.83 (6H, s, OCH ₃ ), 4.53 (2H, CH ₂ Br), 5.03, 5.10 (4H, d, OCH ₂ Ar), 6.77 (1H, s, iso Oxazole-H), 6.80-7.57 (8H, m, phenyl-H), 7.60 (1H, s, dichlorophenyl-H)

Example 5

[N- [3- (2,5-Dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxyphthalimide]

To a mixed solution of 7.5 ml of tetrahydrofuran and 2.5 ml of dimethylformamide, [3- (2,5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methyl Bromides (6.0 g, 1.03 mmol) are dissolved, and with N-hydroxyphthalimide (0.2 g, 1.24 mmol), 0.18 ml of triethylamine is added immediately, followed by stirring at room temperature for 18 hours. 100 ml of ethyl acetate was added to the reaction, washed with water several times, dried over anhydrous magnesium sulfate and concentrated to obtain 0.51 g of the target compound as a pale yellow solid. It is used for the next reaction without purification.

Yield: 89%

¹ H-NMR (CDCl ₃ ): δ3.9 (6H, s, CH ₃ O), 5.1 (4H, d, CH ₂ PMB), 5.4 (2H, s, NOCH ₂ ), 7.1 (1H, s, iso Oxazole-H), 6.9-7.5 (8H, m, PMB), 7.6 (1H, s, chlorophenyl-H), 7.9 (4H, s, phenyl-H of phthalimide)

Example 6

[N- [3- (2,5-Dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxyamine]

[3- (2,5-Dichloro) isoxazol-5-yl] methylphthalimide (0.6 g, 1.91 mmol) was added to 25 ml of dichloromethane, and cooled to -15 to -10 ° C. Hydrazine monohydrate 125 mg is added dropwise in 2 ml of ethanol and stirred at room temperature for 1.5 hours. The reaction mixture was filtered to remove solids, 50 ml of dichloromethane was added to the filtrate, washed with water, dried over anhydrous magnesium sulfate, concentrated and used for the next reaction as it was.

¹ H-NMR (CDCl ₃ ): δ3.84 (6H, OCH ₃ ), 4.83 (2H, s, ONH ₂ ), 5.03, 5.06 (4H, d, ONH ₂ Ar), 5.71 (2H, brs, NH 2), 6.75 (1H, s, isoxazole-H), 6.8-7.5 (8H, m, ph-H), 7.59 (1H, s, ph-H)

Example 7

[2 [2-aminothiazol-4-yl] -2 (z)-[3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl) methoxyimino] acetic acid ]

About 1 g of 3-[(3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxyamine obtained in the above reaction was dissolved in 3 ml of methylene chloride and 8.5 ml of ethanol and water under stirring 8.5 ml are added. To this mixture was added 2-[(N-formylamino) thiazol-5-yl] -2-oxoacetic acid (476 mg, 2.38 mmol) in small portions, adjusted to pH = 5 with 5 N aqueous sodium hydroxide solution, at room temperature. Stir for 18 hours. After confirming that all amine compounds disappeared on TLC, 30 ml of saturated salt was added to the reaction, extracted with ethyl acetate (50 ml × 5), dried over anhydrous magnesium sulfate, and concentrated to give 1.06 g of the target compound as a pale yellow solid.

Yield: 73%

¹ H-NMR (DMSO): δ 3.77 (6H, s, OCH ₃ ), 5.10 (4H, s, OCH ₂ Ar), 5.26 (2H, s, = N-OCH ₂ ), 6.76-7.70 (13H, m, phenyl-H, thiazole-H, isoxazole-H)

Example 8

[2 [-(2-aminothiazol-4-yl) -2 (Z)-{-3 (2,5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazole -5-yl} methoxyimino] acetic acid]

In 1.7 ml of dichloromethane [3- (2,5-disfluoro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl] methoxyamine (from the previous reaction ), 3.4 ml of ethanol and 3.4 ml of water are added to the mixture under stirring, and 2- (2-N-formylaminothiazol-4-yl) -2-oxoacetic acid (200 mg, 0.99 mmol) is added to the reaction mixture, and 5N-hydroxyl is added. Adjust to pH = 5.0-5.5 with sodium and stir at room temperature for 18 hours. After stirring, saturated brine was added, extracted with ethyl acetate (30ml × 2), dried over anhydrous magnesium sulfate, and concentrated to obtain 0.40 g of the target compound as a yellow solid.

Yield: 52%

¹ H-NMR (DMSO-d ⁶ ): δ 3.77 (6H, s, OCH ₃ ), 5.03, 5.07 (4H, d, OCH ₂ Ar), 5.27 (2H, s, = N-OCH ₂ ), 6.821 (1H, s, isoxazole-H), 6.90-7.50 (11H, m, phenyl-H, thiazole-1H, -NH ₂ ), 7.59 (1H, s, ph-H)

Claims (8)

Arylaminothiazole acetic acid represented by the following general formula (I); In which R ₁ is hydrogen, formyl or trityl; R ₂ carboxylic acid, C _1-4 alkyl ester or carboxylic acid chloride; R ₃ and R ₄ are each hydrogen, acetyl or para-methoxybenzyl; X and Y are each hydrogen or a halogen atom. The arylaminothiazole acetic acid of claim 1, wherein R ₁ is hydrogen, R ₂ is carboxylic acid, R ₃ and R ₄ are both para-methoxybenzyl, and X and Y are each hydrogen or chlorine. A process for producing arylaminothiazole acetic acid represented by the general formula (I), which comprises condensing a ketone compound represented by the following general formula (II) with an amine compound represented by the following general formula (III); In which R ₁ is hydrogen, formyl or trityl; R ₂ is a carboxylic acid, C _1-4 alkyl ester or carboxylic acid chloride; R ₃ and R ₄ are each hydrogen, acetyl or para-methoxybenzyl; X and Y are each hydrogen or a halogen atom. The method of claim 3, wherein the condensation reaction is carried out in a mixed solvent of a polar solvent and water. The method for producing arylaminothiazole acetic acid according to claim 4, wherein the polar solvent is ethanol or methanol. The method for preparing arylaminothiazole acetic acid according to claim 3, wherein the condensation reaction is performed at pH 4 to 6. The method for producing arylaminothiazole acetic acid according to claim 3, wherein an aqueous solution of an alkali metal base is used as a base in the condensation reaction. The method for producing arylaminothiazole acetic acid according to claim 7, wherein the aqueous solution of the alkali metal base is sodium hydroxide or sodium carbonate.