SU411687A3 - - Google Patents

Description

METHOD FOR PRODUCING IMIDLZOLE DERIVATIVES

iidoopeTeiiue relates to the field of obtaining new compounds that can be widely used in the pharmaceutical industry and have improved properties compared with the known compounds of similar effect.

It is known that glyoxal derivatives are reacted with ammonia and formaldehyde to form substituted imidazoles.

A method for the preparation of new imidazole derivatives of the general formula based on a known method is proposed.

where RI is an alkyl group with 2-6 carbon atoms or a cycloalkyl group with 3- G carbon atoms;

Rii is a methyl, methoxy, hydroxy or methylsulfonyl group;

Ks is methyl or methoxy, hydrogen or chlorine, or their salts.

The way is

that compound is a formula

R;

where Ra and Hz have the indicated values, react with an excess of ammonia (at least two molar; ammonia amount) or with an excess of form and an aldehyde of the formula

N.

) C - R, (W)

r, i.e., Ri has the indicated meanings

or with their mixture. Target product you;, e; 1 are in free form or n, than salts by known methods.

With ammonia, the reaction is usually carried out in a lower alkanoic acid, preferably in acetic acid or formic acid, or carbonyl RI-COOH, and at the temperature of the boiling point of the reaction mixture. In this case, ammonia 1 is removed in large excess in the form of the corresponding alkanoic acid salt. Aldehyde can be used in a proper way in equimolarly to the amount of substituted benzyl or in excess in order to achieve the best result in each case, taking into account the availability of starting materials and purification of the final product.

The reaction time is between 1 and 24 hours.

The modified modifier indicated that a substituted benzyl of the general formula I is heated with a large excess of formamide and an aldehyde of the general formula III is preferably from 180 to 200 ° C and the resulting imidazole derivative is converted into an additive with an inorganic or organic acid as desired. In this embodiment of the process, a portion of the formamide decomposes into ammonia, and thus the formation of imidazole derivatives of general formula I in a manner similar to the above mentioned variant. For the reaction, for example, substituted benzyl of general formula II is boiled with an equimolar amount or an excess of aldehyde of general formula III in formamide, the amount of which is approximately 5-25 times the amount of other reaction components or with a mixture of formamide and dimethylformamide for 2 -6 hours with reflux.

Example 1. A mixture of 13.5 g (0.050 mol) of panisyl, 3.96 g (0.055 mol) of isobutyraldegnd, 27.0 g (0.35 mol) of ammonium acetate and 130 ml of ice vinegar is boiled for 15 hours reflux and then, with a strong displacement, pour 350 g of ice and 270 ml of concentrated aqueous ammonia into a mixture of ice.

The combination of crystals and mother liquor is extracted with ethyl acetate and the organic phase is washed with a solution of sodium chloride until neutral and evaporated. The residue is recrystallized from ethnyl acetate and dried under high vacuum at 100 °. 2-isopropyl-4,5-bis- (p-methoxyphenyl) -nmindazole is obtained in the form of white crystals; m.p. 195-196 ° C, yield 8.8 g, 55% of theoretical.

The following imidazole derivatives are prepared analogously, using 0.055 mole of the corresponding aldehydes instead of isobutyraldehyde:

2-ethyl-4,5-bis- / g-methoxyphenyl) -imidazole; m.p. 170-172C (nz toluene), using 3.19 g of propionaldehyde;

2-pronyl-4,5-bis - ("-methoxyphenyl) -imidazole; m.p. 180-182 ° C (from ethyl acetate), using 3.96 g of butyraldehyde;

2-butyl-4,5-bis- (l-methoxyphenyl) -imidazole; m.p. 175-176 ° C (from ethyl acetate), with the help of 4.73 g of valeraldehyde;

2-isobutyl-4,5-bis- (p-methoxyphenyl) -imidazole; m.p. (from benzene), with the help of 4.73 g of isovaleraldehyde;

butyl-4,5-bis- (p-methoxyphenyl) -imidazole; m.p. 167-168 ° C (IZ benzene), with the help of 4.73 g of pivalaldehyde;

2-nentyl-4,5-bis- (methoxyphenyl) -imidazole; m.p. 137-138 ° C (from ethyl acetate), using 5.50 g of hexanal;

2-hexyl-4,5-bis- (l-methoxyphenyl) -imidazole; m.p. 145-147 ° C (from toluene), with the help of 6.27 g of heptanal;

2- (1,1-dimethylbutyl) -4,5-bis- (p-methoxyphenyl) -imidazole; m.p. 120-121 ° C. (from toluene-petroleum ether), using 6.27 g of 2,2-dimethyl-valeraldehyde;

2-cyclopropyl-4,5-bis - (p-methoxyphenyl) imidazole; m.p. 189-19GS (from toluene), with

relief 3.85 g of cyclopropanecarboxaldehyde;

2 - cyclohexyl - 4,5 - bis - (p - methoxyphenyl) imidazole; m.p. 194-195 ° C (from benzene), with

Aid 6,16 g of cyclohexanecarboncaldehyde.

Analogously, the following imidazoles are obtained by condensing 0.050 mol of substituted benzyls with 0.055 mol of aldehydes:

2-Ethyl-4 (5) - (p - methoxyphenyl) - 5 (4) - phenylimidazole; m.p. 161-163 ° C (from toluene), from 12.0 g of 4-methoxybenzyl and 3.19 g of propionaldehyde;

2-isopropyl-4 (5) - (l-methoxyphenyl) -5 (4) -phenylimidazole; m.p. 189-191 ° C (from toluene), from 12.0 g of 4-methoxybenzyl and 3.96 g of isobutyraldehyde;

2-butyl-4 (5) - (l-methoxyphenyl) -5 (4) -phenylimidazole; m.p. 162-163 ° C (from ethanol), from 12.0 g of 4-methoxybenzyl and 4.73 g of valeraldehyde;

2-cyclopropyl-4 (5) - (l-methoxyphenyl) -5 (4) phenylimidazole; m.p. 192-193 ° C (from toluene), from 12.0 g of 4-methoxybenzyl and 4.73 g of valeraldehyde;

2-cyclopropyl-4 (5) - (l-methoxyphenyl) -5 (4) phenylimidazole; m.p. 192-193 ° C (from toluene), from 12.0 g of 4-methoxybepzil and 3.85 g of cyclopropanecarboxaldehyde;

2-g. Butyl - 4,5 - bns - (l-tolyl) -imidazole; m.p. 204–206 ° С (from toluene), from 11.9 g of l-tolyl and 4.73 g of pivalaldehyde;

2-isonropyl-4 (5) - (l-tolyl) -5 (4) -phenylimidazole; m.p. 209-210 ° C (from toluene), from 11.2 g of 4-methylbenzyl and 3.96 g of isobutyraldehyde; 2-g / 7.butyl-4 (5) - (l-tolyl) -5 (4) -phenylimidazole; m.p. 154-156 ° C (from toluene), from 11.2 g of 4-methylbenzyl and 4.73 g of pivalaldehyde;

2-isopropyl-4 (5) - (l-methoxyphenyl) -5 (4) - (ltolyl) -imidazole; m.p. 200-20 ° C, from 12.7 g of 4-methoxy-4-methiobenzyl and 3.96 g of isobutyraldehyde;

2- (1-methylpropyl) -4,5-bis- (l-methoxyphenyl) imidazole; m.p. 170-17GS, from 13.5 g of l-anisyl and 4.73 g of 1-methylbutyraldehyde;

2- (1-ethylpropyl) -4,5-bis- (l-methoxyphenyl) imidazole; m.p. 168-169 ° C, from 13.5 g of l-anisyl and 5.5 g of 1-ethylbutyraldehyde;

2-cyclopentyl-4,5-bis - (l-methoxyphenyl) imide ol; m.p. 170-172 ° C, from 13.5 g of l-anisyl and 5.5 g of cyclopentanecarboxaldehyde;

2 - cyclobutyl - 4,5 - bis - (l - methoxyphenyl) imidazole; m.p. 176-178 ° C, from 13.5 g of l-anisyl and 4.62 g of cyclobutylcarboxaldehyde;

2-g / 9.butyl-4 (5) - (l-methoxyphenyl) -5 (4) - (ochlorophenyl) -imidazole; m.p. 169-171 ° C, from

13.7 g of 4-methoxy-3-chlorobenzyl and 4.73 g of pivalaldehyde;

2-treg. Butyl-4 (5) - (-methoxyphenyl) -5 (4) - (phlorphenyl) -imidazole; m.p. : 148-150 ° С, from 13.7 g of 4-m & toxi-4-chlorobenzyl and 4.73 g of pivalaldehyde;

2-isopropyl-4 (5) - (l-methoxyphenyl) -5 (4) - (mhlorphenyl) -imidazole; m.p. 167-170 ° C, from 13.7 g of 4-methoxy-3; Chloro-111yl and 3.96 g of isobutyraldehyde;

2-tert.butyl-4 (5) - (l-methoxyphenyl) -5 (4) - (ptolyl) -imidazole; m.p. 171-7US (from toluene), from 12.7 g of 4-methoxy-4-methylbenzyl- and 4.73 g of pivalaldehyde;

2-greg.butyl-4 (5) (g-methoxyphenyl) -5 (4) - (lgtolyl) -imidazole; m.p. 185-187 ° C (from toluene), from 12.7 g of 4-methoxy-3-methylbenzyl, and 4.73 g of pivalaldehyde;

- 2-7reg. Butyl-4 (5) - (l-methoxyphenyl) -5 (4) - (otolyl) -imidazole; m.p. 156-158 ° C (from toluene), from 12.7 g of 4-methoxy-2-methylbenzyl and 4.73 g of pivalaldehyde.

Example 2. A mixture of 11.5 g (0.048 mol) of 4methoxybenzyl, 5.45 g (0.063 mol) of pivalaldehyde, 50.0 g (0.65 mol) of ammonium acetate and 100 ml of glacial vinegar is boiled for 15 hours with reverse refrigerator and then poured with vigorous stirring on a mixture of 300 g of ice and 240 ml of concentrated aqueous ammonia. The combination of crystals and mother liquor is extracted, the organic phase is washed until neutral with help, and sodium chloride solution, dried with sodium sulfate and evaporated. The residue is crystallized from toluene and dried under high vacuum at 110 ° C to obtain 2-greg-butyl-4 (5) - (l-methoxyphenyl) -5 (4) -phenylimidazole; m.p. 193-194 ° C.

Example 3. A mixture of 4.0 g (0.015 mol) of panisyl; 1.08 g (0.015 mol) of isobutyraldehyde and 100 ml of formamide are boiled for 3 hours under reflux and then poured onto 200 ppm of water. The dark precipitate is filtered on a putch and taken up in chloroform, the insoluble part is filtered off and the organic phase is separated, dried over sodium sulfate and evaporated. Recrystallization from ethyl acetate gives 2 isopropyl-4, 5-bis - (l-methoxyphenyl) -imidazole; m.p. 195-196 ° C.

Example 4. To a solution of 30.84 g (0.10 mol) of 2-ethyl-4,5-bis- (l-methoxyfepyl) -imidazole in 900 ml of acetone at 20-25 ° C was added 9.61 g (6 , 5 ml, 0.10 mol) of methanesulphonic acid and then move about 15 hours. White crystals are filtered on suction. By recrystallization from ethanol-ether, 2-ethyl-4,5-bis- (l-methoxy-feil) -imidazolmethanesulfonate is obtained, melting at 149-15PC.

Example 5. To 15.0 g of 2-isopropyl-4,5-bic (lmethoxyphenyl) -imidazol were added 400 ml of ethyl acetate and 100 ml of ether and filtered. In a separatory funnel, the filtrate is shaken with 70 ml of 2 p. Of hydrochloric acid. The precipitated hydrochloride is then filtered on suction and the filtering product on suction is maintained for an hour in a high vacuum at 80 ° C, recrystallized from an absolute ethanylether, and, times. property, BbtcoKOM. vacuum at 1.10 ° C. - Idal-scientist: 2LISO: propll-4,5bis- (l-methoxyphenyl) -Emidazole - hydrochloride

melts at 264-: 267 ° C. ,, ....-

Example 6, a Mixture of 5.8, .g - (0.02 mol). 4-methylsulfonylbenzyl,. L7 g; (0.02 mol) of pivaldehyde, 10.0 g (0.13 mol) of ammonium tetatate and 50 ml of ice vinegar are boiled for 15 hours with reflux condenser and then poured into

150g ice The yellow solution is basified with an aqueous solution of ammonia and extracted with ethyl acetate. The organic phase is separated, dried over sodium sulfate and evaporated. The residue is recrystallized from toluene and dried under high vacuum at, whereby 2-treg-butyl-4 (5) - (l-methylsulfonyl) -fecyl-5 (4) -imidazole is obtained; m.p. 215-217 ° C. Similarly, 2-isopropyl-4 (5) - (lmethylsulfonyl) - phenyl - 5 (4) - phenylimidazole is obtained; m.p. 207-208 ° С (from toluene), outcome

from 5.8 g (0.02 mol) of 4-methylsulfonylbenyl and 1.4 g (0.02 mol) of isobutyraldehyde.

Example 7. A mixture of 4.5 g (0.02 mol) of 4-hydroxybenzyl, 1.72 g (0.02 mol) of pivalaldehyde, 10.0 g (0.13 mol) of ammonium acetate and 60 ml of glacial vinegar is boiled for 18 hours, with a reversible refrigerator and then, with vigorous stirring, pour the mixture

150 g of ice and 120 ml of an aqueous solution of concentrated ammonia. The combination of crystals and mother liquor is extracted with ethyl acetate, the organic phase is washed until neutral with a saturated solution of sodium chloride, dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate-petroleum ether and dried under high vacuum at, and get 2-t / 7.butyl-4 (5) - (lihydroxyphenyl) -5 (4) -phenylimidazole; m.p. 190-192 ° C.

Similarly, 2-g / 7et.butyl-4 (5) - (; methomethoxyphenyl) -5 (4) - (l-gndroxyphenyl) -imidazole are obtained; m.p. 216-218 ° C from ether-pentane,

starting with 5.1 g (0.02 mol) of 4-hydroxy-4-methoxybenzyl and 1.72 g (0.02 mol) of pivalaldehyde; .-butyl-4 (5) - (l-hydroxyphenyl) 5 (4) - (g-tolyl) -imidazole; m.p. 227-228 ° C from toluene-cyclohexane; from 4.8 g

(0.02 mol) 4-hydroxy-3-methylbenzyl and 1.72 g (0.02 mol) of pivalaldehyde; 2-t / Seg.but4 (5) - (l-hydroxyphenyl) -5 (4) - (w - chlorfepyl) imidazole; m.p. 238-240 ° C from toluene-cyclohexane; starting from 5.2 g (0.02 mol) of 4-hydroxy-3-chlorobenzyl and 1.72 g (0.02 mol) of pivalaldehyde.

Example 8. A mixture, 0 g of 4-methylsulfonyl-4-me-10-benzyl, 0.3 g of pivalaldehyde, 2.0 g of ammonium acetate and 30 ml of ice vinegar are boiled for 14 hours with reverse

refrigerator and then with vigorous stirring poured on 100 g of ice. The yellow solution is mildly alkaline with the HELP of ammonia and extracted with ethyl acetate. The organic phase is separated, dried over yp1 sulphate and evaporated. The residue is recrystallized from cyclohexane and dried under high vacuum at 110 ° C, yielding 2-tert. (5) - (l-methylsulfonyl) phenyl-5 (4) - ("- methoxyphenyl) -imidazole; m.p. 205-207С.

Subject invention

The method of obtaining imidazole derivatives of the general formula

at.-/

RS

where RI is an alkyl group with 2-6 carbon atoms or a cycloalkyl group with 3-6 carbon atoms;

Rj is a methyl, methoxy, hydroxy or methylsulfonyl group;

Ra-methyl or methoxy, hydrogen or chlorine.

or salts thereof, characterized in that the compound of the general formula

where R2 and Rs have the indicated meanings, are reacted with an excess of ammonia or with an excess of formamide and an aldehyde of the general formula

N.

C-RI

(Iii)

ABOUT

where RI has the indicated meanings

or with their mixture with the subsequent isolation of the target product in free form or in the form of a salt by known methods.

Priorities by featured:

31.H11.1969G. at

RI is an alkyl group with 2-6 carbon atoms or a cycloalkyl group with 3-6 carbon atoms,

Rs-methyl or methoxy,

Rs is methyl or methoxy or hydrogen;

04.XII.I970, with

Ra is a hydroxy or methylsulfonyl group,

Rs is chlorine.