FI57399B - FREEZING FOR ANTIBACTERIAL VERIFICATION OF IMMEDIATE FACTORS - Google Patents

Description

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Patent and registration duty Amekm utiajd och utUkriftan pubiicund 30.04.00 (32) (33) (31) Requested «tuolkMt —B * ftrd priorittt (71) Imperial Chemical Industries Limited, Imperial Chemical House, Millbank, London SW1, England-England ( GB) '(72) Philip Neil Edwards, Macclesfield, Cheshire, England-England (GB) (7U) Oy Kolster Ab (5U) Process for the preparation of antibacterial imidazole derivatives - Preparation of antibacterial active imidazole derivatives (6l) This invention relates to a process for the preparation of antibacterial imidazole derivatives according to patent 55 831 having the formula: R2 (r) r1 R1 v-r yf - A -. (X) f> 1

'u U

R R

1.2 ..1.2 wherein R and R are hydrogen atoms, or R and R together form a fused benzene ring; R is an alkyl group having 6 to 1 carbon atoms, a benzyl group having 0 to 5 chlorine substituents on the benzene ring, or 3-alkoxy-2-hydroxypropyl.

U

a pyyl group having U-8 carbon atoms in the alkoxy moiety; R is a hydrogen atom or 1-3 carbon

2Q

an atom-containing alkyl group; (x) 2 represents two monoanions and A is a bridging chain, 2 57399 of the formula - (CH 2 - CONH. (CH) -NH-CO (CH 2 -2 m 2 n 2 m where n is 2-12 and m is 1 or 2.

The process according to the invention is characterized in that the imidazolylalkanoic acid derivative of the formula S-

O I I 5 0 II

R -N'M N- (CH 2 -COOR? -YT Vx "· 2 ml · 1 2 3 1+. 5 where R, R, R, R and have the same meaning as above, R is hydrogen or 1-1 + carbon atoms an alkyl group, and ^ is a monoanion, is reacted with a diamine of the formula NH (CH) HH n, where n is as defined above.

The reaction may be carried out without a diluent or solvent, or most preferably in a diluent or solvent, e.g. toluene, ethanol or methanol or a mixture thereof. The reaction may be accelerated or supplemented by heating, e.g., at the boiling point of the diluent or solvent. When R 1 is hydrogen, the reaction is preferably carried out in the presence of an agent such as dicyclohexylcarbodiimide which provides a peptide bond in a diluent or solvent, e.g.

in ethyl acetate or dimethylformamide.

3. .

When R is an alkyl group, it is preferably a straight chain alkyl group, e.g.

an n-octyl, n-decyl or n-dodecyl group.

When R is an optionally substituted benzyl group, it is preferably a 1 + chloro or a 2,1 + dichlorobenzyl group.

3 ...

When R is a 3-alkoxy-2-hydroxypropyl group, it is preferably an alkoxy group having 1 + -8 carbon atoms in the straight chain, e.g. an n-heptyloxy group.

1 *.

When R is an alkyl group, it is preferably a methyl group.

is suitably a halide ion, e.g. a chloride ion or a bromide ion, or an anion derived from a sulphonic acid, e.g. a methanesulphonate or toluene p-sulphonate anion.

Preferably m is 1 and n is 1 +, 6,8,10 or 12.

Particularly preferably, 1.2 1 can be prepared by the method according to the invention.

compounds of formula I in which R and R are hydrogen atoms or R and 23 R together form a fused benzene ring; F is a chloro-chain alkyl group having 8 to 10 carbon atoms, a U-chlorobenzyl group or a 2,1 + dichlorobenzyl group; k 20 R is hydrogen or methyl; (X) ^ represents two chloride, bromide or methanesulfonate anions; and in the chain A m is 1 and n is 1 +, 6,8,10 or 12.

3,57399

Particularly preferred compounds which can be prepared by the process of the invention are 1,1'-decamethylene bis (carbamoylmethyl) -di- (3-n-octylimidazolium chloride) and 1,1'-dodecamethylene bis (carbamoylmethyl) -di- (3- n-octyl imidates (sodium chloride).

The imidazolylalkanoic acid derivative of formula II used as a starting material is prepared by reacting R 2 of formula R2

- III

reacting a compound of formula R3-n ny with a compound of formula X- (CH2) -COOR ^ 2 m „and, if hydrogen and it is desired to use a compound of formula II having an alkyl group, by esterification with an alcohol of formula formula R 1 OH, for example in the presence of thionyl chloride or an acidic ion exchange resin.

The products prepared by the method of the invention have valuable antibacterial properties, killing a wide variety of bacteria, both gram-positive and gram-negative, as shown by serial dilution experiments. They are therefore useful both as environmental antiseptics and anti-inflammatory agents and as pre-operative skin cleansers, they are also useful in oral hygiene, for example in resisting tartar formation or preventing gingivitis. The compounds of the invention do not have detectable toxic properties when administered orally to mice up to 250 mg / kg.

The invention is illustrated by the following examples.

Example 1 1-n-Octyl-3-methoxycarbonylmethylimidazolium chloride (1.0 g) dodecamethylenediamine (0.3 g) is stirred together in methanol (3.0 ml) for two hours and the methanol is removed by boiling under normal pressure. The residue is dissolved in water (5.0 ml), the pH is adjusted to 12, and extracted with chloroform (5 x 5 ml). The combined extracts are evaporated to dryness and the residue is triturated with acetone, whereupon the resulting white precipitate is filtered off, washed with acetone and dried. There is thus obtained 1,1'-dodecamethylene bis (carbamoylmethyl) di (3-n-octylimidazolium chloride), melting point 11 * 6-11 * 8 ° C.

The starting 1-n-octyl-3-methoxycarbonylmethylimidazolium chloride can be prepared as follows:

Chloroacetic acid (112 g) and 1-n-octylimidazole (11 + 5 g) are heated and stirred under a nitrogen atmosphere for 1 * 5 min, then allowed to cool. When the mixture

It 57399 has cooled to 150 ° C, acetonitrile (1 + 00 ml) is added (initially very slowly), then acetone (500 ml) is added. On further cooling, the precipitate crystallizes, which is filtered, washed with acetone and dried to give 1-n-octyl-3-hydroxycarbonylmethylimidazolium chloride, m.p. 120-122 ° C.

1-n-Octyl-3-hydroxycarbonylacetylimidazolium chloride (1.0 g) is added to a mixture of methanol (1.5 ml) and thionyl chloride (0.1 + 35 g), and the mixture thus obtained is stirred for 3 hours. All volatiles are evaporated in vacuo to give gummy 1-n-octyl-3-methoxycarbonylmethylimidazole chloride. On the other hand, the 1-n-octyl-3-methoxycarbonylimidazolium chloride used as a starting material can be prepared as follows: 1-n-octylimidazole (10.0 g), methyl chloroacetate (10 ml) and methanol (50 ml) are refluxed under a nitrogen atom for 18 hours. . Evaporation of methanol and excess chloroacetate in vacuo gives a thick oily 1-n-octyl-3-methoxycarbonylmethylimidazolium chloride which cannot be crystallized. Thin layer chromatographic analysis (silica gel; eluent isopropanol / water / acetic acid (3: 1: 1)) »shows mainly one spot with traces of starting material.

On the other hand, the intermediate 1-n-octyl-3-hydroxycarbonylmethylimidazolium chloride can be prepared as follows: 1-n-octylimidazole (18.0 g), sodium chloroacetate (1U, 5 g) -methanol (1 + 0 ml) and sufficient water to dissolve the sodium salt mixture is heated at reflux for 20 hours, maintaining the pH at 7 by the addition of sodium carbonate. The cooled mixture is evaporated, dissolved in water (150 ml) and washed with toluene. The aqueous phase is evaporated and the residue is triturated with acetone. The resulting precipitate is filtered from a mixture of oil and water and all oil is carefully removed. The oil is separated, triturated with ethereal hydrogen chloride and the precipitate obtained is filtered off and dried in a desiccator. The dry precipitate is dissolved in as little chloroform as possible, the residual precipitate is filtered off, the chloroform solution is evaporated and the residue is triturated with acetone. The solid is filtered, dried and recrystallized from acetonitrile to give 1-n-octyl-3-hydroxycarbonylmethylimidazolium chloride, mp 120.5-121.5 ° C.

Example 2 To a solution of 1-n-octyl-3-ethoxycarbonylmethylimidazolium chloride (65 g) in ethanol (500 ml) and toluene (1 + 00 ml) is added dodecamethylenediamine (1 + 0 g) and the resulting solution is heated at reflux for 2b hours. I drive.

57399 5

The solvents are evaporated in vacuo and the residue is crystallized from acetone containing a little water to give 1,1'-dodecamethylene bis (carbamoylmethyl) -di (3-n-octylimidazolium chloride), m.p. 13 DEG-1 DEG C.

A solution of 1-n-octyl-3-ethoxycarbonylmethylimidazolium chloride used as starting material can be prepared as follows:

The 1-n-octyl-3-hydroxycarbonylmethylimidazolium chloride prepared according to Example 1 (180 g) and the sulfonated polystyrene resin catalyst are heated and mixed with ethanol (500 ml) and toluene (i + 00 ml), azeotropically removing water. 1-n-Octyl-3-ethoxycarbonylmethylimidazolium chloride is completely formed after two hours, after which the resin is filtered off.

a *

Claims (1)

57399 Claim: A process for the preparation of the antibacterially active imidazole derivatives of the patent 55 831 having the formula: h 'V-γ ν-γ R3-NVs ^ ^ N-A-N-R3 Ax) f Ui, R R ^ • 1.2. .1.2 wherein R and R are hydrogen atoms, or R and R together form a fused benzene ring; R is an alkyl group having 6 to 0 carbon atoms, a benzyl group having 0 to 5 chlorine substituents on the benzene ring, or a 3-alkoxy-2-hydroxypropyl group having U to 8 carbon atoms in the alkoxy moiety; R ** is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; (X) ^ represents two monoanions and A is a bridge chain of the formula - (CH_) -COHH (CH) -NH-CO (CHo) -2 mdn 2 m where n is 2-12 and m is 1 or 2, known that an imidazolylalkanoic acid derivative of the formula R2 R1> - (3. i® I e R -N2 - (CH2) -mC00R? JT * ί 1 2 3 It. ς wherein R, R, R, R and m is as defined above, R is hydrogen or an alkyl group containing 1-U carbon atoms, and O is a monoanion, is reacted with a diamine of the formula NHg (CH2), where n is as defined above.