CS267798B1 - Imidazole Derivatives and Preparation - Google Patents

Abstract

The solution concerns the imidazole group. derivatives of the general formula I, where R. represents alkyl C. to C. and R represents straight or branched alkyl O. to C-, a benzyl group substituted in the aromatic part by a chlorine atom, a methoxycarbonylmethyl group; 2-ethoxycarbonylethyl group and X represents a hydrogen or bromine atom. The substances are prepared by alkylating a compound of the general formula H and a 4-halogen derivative of 3-oxobutanoic acid of the formula ΤΠ, where R. and R have the above meaning. The mentioned substances are used as intermediates for the preparation of biologically useful substances.

Description

The invention relates to novel imidazole derivatives which are intermediates in the production of biologically active substances and to a process for their preparation. Substituted iridazoles are highly antifungal fungicides and antiracotics as disclosed in e.g. Buchol, U.K. Fungicide Chemistry, Advances and Practical Application / Green, B.H., Spilter, D.A. eds./ American Chom. Soo. Washington D.C. 1986 /. Trihaloimidazole derivatives are described in VS patents 3501286 η 4506598, which also discloses their herbicidal activity.

The invention relates to imidazole derivatives of the general formula I

CH -CO-C- CO.R, ¹ II

N ⁱⁿ OR where X is hydrogen or bromine, R _f represents alkyl to and R represents straight or branched alkyl C 1 to Οθ, a benzyl group substituted in the aromatic part by a chlorine atom in the o-, m- or p- position, a methoxyxarbonylmethyl group, 2 -ethoxycarbonylethyl group and their quaternary salts and a process for their preparation which consists in that 0.9 to 1.0 molar part of the imidazole of the general formula II

H, as X is as defined above, is reacted with 0.9 to 3 molar parts of an .beta.-halo-.beta.-oxobutanoic acid derivative of the general formula III

V- CH.-CO-C-CO.R,

wherein R and R ₁ are as defined above and Y is a halogen atom, at -10 ° C to 165 ° C in an aprotic solvent for 0.5 to 12 hours. Said compounds of formula I include syn- and anti-isomers as well as a mixture of these isomers. The reaction is carried out in the presence of a base. In a special case, the addition of base is replaced by carrying out the reaction in a basic solvent or by using 2 equivalents of a compound of formula II.

The compounds are used as modifying products for the preparation of other biologically active substances. The processes for the preparation of the compounds according to the invention are carried out by adding an organic base to 1 molar part of the imidazole of the formula II in an aprotic organic solvent selected from the group consisting of ketones, acetone, esters such as ethyl oleate, ethers such as tetrahydrofuran, nitriles for example. triethylamine or inorganic, potassium carbonate and 0.9 to 1.3 molar parts of a 4-halogen-3-oxobutanoic acid derivative. The mixed component of the alkylation fraction is carried out at a temperature of 10 DEG C. to 5 DEG C. 3 followed by a reaction at a temperature of 35 DEG C. to 165 DEG C. The required time is 0.5 to 12 hours for doraacovaiiijo. The isolation of the compounds aa is carried out by known procedures, by filtration, followed by purification, crystallization or olmo-ore. In the following, the subject matter of the invention is described in the examples without being limited thereto.

Example 1

E-

To a suspension of 0.83 g (0.035 mol) of sodium hybrid in 50 ml of tetrahydrofuran was added a solution of 10 g (0.03 mol) of 2,4,5-tribrominitrile, daxel in 50 ml of tetrahydrofuran at 10 ° C. 7.56 g (0.03 mol) of 4-bromo-2-hydroxyimino-3-oxobutanoic acid are then added to the solution. The mixture was heated from reflux for 6 hours. The reaction mixture was filtered, and the concentrated filtrate was purified by silica gel column chromatography. 12.8 g of ethyl 4- (2,4,5-tribromimidazol-1-yl) -2-methoxyquino-3-oxo-butyrate are obtained, m.p. 116-118 ° C. 1 H-NMR (acetone-D 6) c = 1.25 (t), 4.19 (s), 4.31 (g), 5.47 (s).

Examples 2 to 10

The following derivatives of formula I were prepared analogously to the procedure of Example 1

Example X ^R 1 R M.p. (° C) hl NMR (-n-ch ₂ -) 2 Dr c ₂ n ₅ propyl 132 to 135 5.23 3 Br ^C 2 ^H 5 n-propyl 81 to 82 5.23 4 Br ^C 2 ^H 5 n-octyl 69 to 73 5.24 5 II ^C 2 ⁿ 5 -CH 2 solidifying oil 5.35 6 Br ^C 2 ⁿ 5 -ch ₂ - / o \ -Cl 179 to 82 5, 18 7 II ^C 4 ^H 9 -ch ₃ 58 to 62 5, 18 8 Br c ₂ h ₅ -01 ^ 0020 ^ solidifying oil 5, 19 9 Br C 2 5 -CH (CH 2) CO, C _? H ^ solidifying oil 5.20 10 II C., 11 -CII _O - “1 Cl 120 to 123 5, 19

CS 267 798 B1 3

Example 1 1

Ethyl 4- [imidozol-1H-1-yl] -2-thioxyminino-3-oxobutyrate

A solution of 2.7 g of imidazole (0.38 mol) and 5 g (0.013 mol) of ethyl 4-bromo-2-methoxyimino-3-oxo-butyrate is refluxed in 50 ml of chloroform for 1 hour. After cooling, the reaction mixture was washed with 25 ml of water, and the solvent was distilled off under reduced pressure. 1.8 g of live oil are obtained, 1 H-NMR (CDCl 3 = t, 29 (t) _), 4.25 (g), 2.39 , 15 ₍ 7.90 (s)).

No. spectrum (c = o) = 1720, 1745 cm -1

Example 12

Ethyl 4- (2,4,5-tribroninildazol-1H-1-yl) -2-methoxycarbonylmethoxylmino-3-oxo-butyrate

To a solution of 1.4 g (0.035 mol) of sodium hydroxide in 50 ml of ethanol solution was added 10 g (0.03 mol) of 2,4,5-tribromimidazole, and the mixture was then concentrated in vacuo. To the residue was added 70 L of benzene and then 9.3 L (0.03 mol) of ethyl 4-bromo-2-n-ethoxycarbonylmethoxylamino-3-oxobutyrate. The reaction mixture was heated to reflux for 12 hours. By operating as in example 1, 18 g of ethyl 4 / 2,4,5-tribromimidazol Η-1-yl-1 / ^R-2-methoxy carbonylmethoxyimino-3-oxo-butyrate as a solidifying oil ¹ H-NMR (CDCl 1 ^) = 1.3 ² (t), 4.36 (g), 3.8 (s), 4.87 (s),

5.19 (s).

Example 13

Ethyl 4- (2,4,5-tribromimidazol-1H-1-yl) -2- (3-chlorophenylmethoxyimino) -3-oxobutyrate hydrochloride.

A solution of 10 g (0.03 mol) of 43,5-tribromimidazole and 9.57 g (0.03 mol) of ethyl 4-chloro-2- (3-chlorophenylmethoxyimino) -3-oxobutyrate is heated in 80 ml of dimethylformamide at 165 ° C in an oil bath for 1.5 hours. The reaction mixture is decolorized by the addition of activated carbon and, after filtration, the solvent is distilled off in vacuo. The resulting oil was triturated with the addition of ether (200 ml). The precipitated crystalline substance was filtered off and crystallized from ethanol. 12 g of ethyl 4- [2,5-tribromimidazol-1H-1-yl] -2- (1-chlorophenylmethoxyimino) -3-oxobutyrate are obtained, m.p. 199-201 ° C as the hydrochloride.

Example 14

Ethyl 4- (2,4,5-tribromimidazol-1H-yl) -3-oxo-2- (4-chlorophenylmethoxyimino) butyrate

Step A

Ethyl 3- [2- (4-chlorophenylmethoxyimino) butyrate

To 12 g of ethyl 3-oxo-2- (hydroxyimino) -butyrate (0.075 M) in 50 ml of acetone and 10 g of potassium carbonate are added 13.3 g (0.075 mol) of 4-chlorobenzyl chloride. After stirring for 12 hours, the reaction mixture is poured into 400 ml of water and extracted with ethyl acetate. Distilling off the solvent in vacuo gave 20.7 g of ethyl 3-oxo-2- (4-chlorophenylmethoxyimino) butyrate.

Step D

Ethyl 4-bromo-3-oxo-2- (4-chlorophonomethoxyimino) butyrate

To 13.7 g of the product from step A in 40 ml of dichloromethane are added 0.2 g of boron trifluoride etherate and 2.7 ml of bromine. The reaction mixture is heated to reflux for 5 hours. The reaction mixture is washed with water, sodium bisulfite solution and dried over magnesium sulfate and distilling off the solvent in vacuo, 14.5 g of ethyl 4-bromo-3-oxo-2- / 4-chlorfonylmotoxyimino / - b butyrate mp 60-64 ° C; 'H-NMR (acetone-D ₆₎ C £ t , 31 (t), 4.29 (s), 4.35 (e), 5.29 (s), 7.25 (n).

Step C

A mixture of 5.7 g (0.09 mol) of 2,4,5-tribromimidazole, 7.5 DEG C. of the product from step B and 5 g of potassium carbonate is heated in 80 ml of dimethylformamide at 16 DEG C. for 6 hours. . The reaction mixture was poured into 200 ml of water and the substance was purified by crystallization from cyclohexane bonzene (3: 1). Gained aa. 6 g of ethyl 4- (2,4,5-tribromomiazol-1H-yl) -3-oxo-2- (4-chlorophonylmethoxylinino) butyrate, m.p. 182 ° C) ¹ H-NMR (aootone-D ₆ ) c T = 1.32 (t), 4.37 (g), 5.18 (s), 5Ό5 (s), 7.25 - 7.40 ( m).

Claims (5)

The CS 267,798 of potassium was heated in 80 ml of dimethylformamide at 0 ° C for 6 hours. The reaction mixture is poured into 200 ml of water and the precipitate is purified by crystallization from cyclohexane bonzone (3: 1). 6 g of ethyl 4- (2,4,5-tribiimidazol-1 H-yl) -3- (2-oxo-2-propyl) -ylotoxyimino / butyrate were obtained with mp 179-182 ° C. aootone-D6) cf = 1.32 (t), 4.37 (e), 5.18 (a), 5-5 (a), 7.25-7.40 (m). 1. Imidazole derivatives of general formula (1) CM-CO-C-Co R (11 N OR where X m is hydrogen or bromine atoms, R 1 is C1 to alkyl and R is equal to -8 'by chlorine atom at O, m, p, methoxycarbonylmethyl, 2- ethoxycarbonyl-alkyl or branched C 1 -C 6 alkyl, benzyl substituted in the chloro aromatic moiety in the moiety, m, moiety and quaternary salts thereof; 1.0 molar portion of imidazole of formula H (i) wherein X is as defined above, it is reacted with 0.9 to 1.3 molar parts of the 4-halo-3-oxo-butanoic acid derivative of the general formula (III); R 1 and R 1 are as defined above, and Y is a halogen atom, at-10 ° C to 165 ° C for 0.5 to 2 hours, 3. A method according to claim 2, characterized in that the extraction is carried out in the presence of a base. 4. Process according to claim 2, characterized in that the extraction is carried out in basic solvent. 5. Process according to claim 2, characterized in that the compound of formula II is used.