SU850006A3 - Method of preparing imidazole derivatives or their salts or optical isomers - Google Patents

Abstract

The present invention relates to a process for preparing an imidazole derivative, having the formula: (SEE FIGURE) wherein: Ar is phenyl, substituted phenyl, thienyl, halothienyl or naphthyl, and wherein the substituted phenyl has the meaning of a phenyl group having in it from 1 to 3 substituents independently consisting of halo, lower alkyl, lower alkyloxy, nitro or cyano, and R is alkyl having from two to 10 carbon atoms, alkyloxymethyl wherein the alkyl group has from 1 to 10 carbon atoms, alkenyl, alkenyloxymethyl, wherein the alkenyl group has from 2 to 10 carbon atoms, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl, aryl-lower alkyl aryloxymethyl, arylthiomethyl or arylmethoxymethyl, wherein the aryl in a member selected from the group consisting of phenyl, substituted phenyl, naphthyl or mono- and di-halonaphthyl, wherein the substituted phenyl has a meaning of a phenyl group it has therein from 1 to 3 substituents independently consisting of halo, lower alkyl, lower alkyloxy, cyano, nitro, phenyl, phenylmethyl, benzoyl, halobenzoyl, lower alkylcarbonyl, lower alkyloxycarbonyl or trifluoromethyl, with the proviso that when more than one substituent is present, only one of them can be selected from the group consisting of phenyl, phenylmethyl, benzoyl and halobenzoyl; characterized by reacting, preferably at reflux temperatures, a compound of the formula (SEE FIGURE) or a metal salt of the compound II, with a compound of the formula (SEE FIGURE) wherein W is a function of this reagent, in an organic solvent preferably in the presence of a metal iodide.

Description

(54) A method for producing derivative of imidazole or their salts, or optical

one

This invention relates to a process for the preparation of new imidaeol derivatives of the formula I

ABOUT

An (i)

sn,

J xM

and

where Ar is phenyl substituted by phenyl, thienyl, chlorothienyl or naphthyl, and in which said substituted phenyl is phenyl having 1 to 3 substituents independently selected from the group consisting of gg shoid, methyl, methoxy-nitro and cyano groups; and R is alkyl having from 2 to 10 carbon atoms, alkoxymethyl in which the alkyl group has from 1 to 10 carbon atoms, ethenyl, 2-propeniloksimetilom, 2-propeniloksimetilom, hydroxymethyl, halomethyl, arylmethyl, ariletilom, ariloksimetilom, ariltiometilom or arilmetoksimetilom wherein said aryl is a substituent selected from the group consisting of feEISOMERS

nyl, substituted phenyl, naphthyl or mono- and di-halo-naphthyl, and in which the specified substituted phenyl

5 is phenyl / having from 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, alkyloxy with C, cyano, Nitro, phenyl, phenylmethyl,

) 0 benzoyl, chlorobenzoyl, alkylcarbonyl with, alkyloxycarbonyl with chlorobenzoyl, alkylcarbonyl with C., Al1-A

kiloxycarbonyl with C. or. trifluoro f-A methyl, provided that when more,

and than one substituent is present, only one of them can be selected from the group consisting of phenyl, benzyl, feiylmethyl or chlorobenzoyl. Possessing biological activity.

 A known method for producing 1- (2-aryl-1, 3-dioxolan-2-ylmethyl) imidazoles by reacting imidazole or its salt with a metal with the corresponding

halogen tl

25

The purpose of the invention is the synthesis of new imidazole derivatives with biological activity.

The goal is achieved by the fact that according to the method for preparing imidazole derivatives of formula I, a compound of the formula or its metal salt is reacted with a compound of the formula CH-LJ R where W is a reactive ester group, in an organic solvent, to release the desired product in the free as salt or optical isomers. The process is carried out by boiling the reaction mass in the presence of iodine metal and in the case when a compound of formula II is used as the starting product, the process is carried out using an excess of azole imide or in the presence of a base such as sodium or potassium carbonate or bicarbonate. Cis and trans diastereomer races can be further divided into their optical isomers, cis {+), CIS (-), trans (+) and trans (-), by applying well-known techniques. The compounds of formula (I) and their salts when added to acids are useful in controlling mold and tank losses. By themselves, they are valuable in the treatment of people, animals and plants suffering from pathogens and in the destruction of microorganisms on materials. Example 1. A mixture of 1.1 parts of imidazole, 1 part of 2- (methyl bromide) -2,4-bis (4-chlorophenyl) -1,3-dioxolane, 0.4 parts of potassium iodide and 20 parts of dimethylformamide stir and boil for 12 hours. Water is added and the product is extracted with diethyl ether. The extract is washed twice with water, dried, filtered and evaporated. The residue, 4-bis (4-chlorophenyl) -1, 3-dioxolan-2-ylmethyl-3-imidazole is converted into the salt of nitric acid. The crude salt is filtered and crystallized from a mixture of isopropanol and diisopropyl ether to give 1- (2,4-bis (4-chlorophenyl) -1,3-dioxolan-2-ylmethyl) -imi; Clazole nitrate, m.p. 192.3 p. Example 2. A mixture of 7h. imidazole, 7.5 parts of 2- (bromomethyl) -2- (4-chlorophenyl) -4-phenyl-1,3-dioxolane, 2 parts of sodium iodide and 100 parts of dimethylformamide are stirred and boiled for 48 hours The reaction mixture is allowed to cool to room temperature and water is added to it. The product is extracted twice with benzene. The extract is washed twice with water and the solvent is removed under vacuum. The residue from (4-chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl3-imidazole is converted to the salt of nitric acid in 4-methyl-2-pentanol and diisopropyl ether. The crude salt is filtered and crystallized from 4-methyl-2-pentanol to give (4-chlorophenyl) -4-phenyl-1,3-dioxolan-2-ylmethyl-3-imidazole nitrate, m.p. 153.20C. Example 3. In Example 2, the following imidazole salts are obtained by adding acids.

gz

si SI,

e)

4-ce

4-ce

2-ce

2,4- (ce) i

2-ce

fc

2-ce

ei)

2,4- (ce) 2

4-B

2,4- (Cfc) 2 4-B

4-ce

4-B

4-B

2,4- (СН),

4-B

2-CE

4-CH5

4-CH

4-F

4-F Example 4. A mixture of 13.6 parts of imidazole, 18.5 parts of 2 (α-bromomethyl) -2- (orthochlorophenyl) -4- (p-chlorophenyl) -1, dioxolane, 4 h, sodium iodide and 150 parts of dimethylformamide are stirred and refluxed for 72 hours. Water is added and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, using chloroform as eluent. The pure fractions are collected and the eluent is evaporated. The residue from (o-chlorophenyl) -4- (p-chlorophenyl) -1, 3-dioxolan-2-ylmethyl 3 -imidazole is converted into the salt of nitric acid in isopropanol and diisopropyl ether. The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether, to give (o-chlorophenyl) -4- (p-chlorophenyl) -1, 3-dioxolan-2-ylmethyl3-imidazol nitrate; m.p. 183.1 ° C. Example 5-. In Example 4 and using an equivalent amount of 2- (methyl bromide) -4- (4-brymphenyl) -2 (2.4-lichlorophenyl) -l, 3-dioxolane used there, you get (4-6pOM phenyl) -2- (3 , 4-dichlorophenyl) -1,3-dihydrogenation table

(soon:

119.9

134.7

183.8

164.2

151

194.7

161.2

156.5

131.1

193.6

144.3

200,8

145.2

210.5

165.4

184.1

207.5

144.3

140.2

163.2

179.3 oxylan-2-ylmethyl-imidazole nitrate; m.p. 141.90 s. Example 6. To a stirred solution of 2.3 parts of sodium in 80 parts of methanol was added 6.8 parts of imidazole, followed by the addition of 100 parts of dimethylformamide, and methanol was removed at atmospheric pressure until the internal temperature will not reach 130 ° C. Then 7 parts of A-2- (bromomethyl) -2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -1, 3-dioxolane are added to the mixture and the mixture is stirred and refluxed. reflux for 3 hours. Water is added to the reaction mixture and the product is extracted with benzene. The extract is dried and evaporated under vacuum. The residue from A-1-G2- (p-chlorophenyl) -4- (4-chloro-o-tolyloxymethyl) -, 3-dioxano-2-yl-methylJ-imidazole is converted to the nitric acid salt in isopropanol. When diisopropyl ether is added, the salt precipitates. It is filtered off and crystallized from a mixture of methanol and diisopropyl ether, to thereby give cis-1-H2 (p-chlorophenyl) -4- (4-chloro-O-tolyloxymethyl) -1, 3-dioxolan-2-ylmethylZimidazole nitrate; m.p. 164 ,.

Example 7. Following the procedure of Example 6 and using equivalent amounts of the corresponding starting materials.

Example 8. To a stirred solution of 4.6 parts of sodium in 160 parts of methanol, 13.6 parts of imidazole, 300 hours, dimethylformamide and 4 parts of sodium iodide were successively added. Methanol is distilled off at atmospheric pressure until the internal temperature reaches 130 ° C. 25.9 parts of A + B-2- (methyl bromide) -2- (parachlorophenyl) -4- (2,6-dichlorophenyloxymethyl) -1,3-dioxolane are then added to the mixture and the contents are stirred at reflux temperature. for 2 hours. The reaction mixture is allowed to cool to room temperature and water is added to it. The product is extracted twice with benzene. The combined extracts are washed twice with water, dried and evaporated under vacuum. The residue, containing the A and B isomers, is chromatographed over silica gel using chloroform as eluent. . The a-isomer is collected as an oily free base and converted

substances, get the following imidazoles and imidazole salts by adding acids

About iwO

psj o-ofe

to the salt of nitric acid in isopropanol. The crude salt is crystallized from isopropanol, thereby obtaining

5 3.8 parts A-1G2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl-imidazole nitrate; m.p. 145.80 p.

The B-isomer is also collected in the form of an oily free base and converted to a salt of nitric acid in isopropanol and diisopropyl ether. The crude salt is crystallized from isopropanol, yielding 2.2 parts. B-1 2- (p-chlorophenyl) -4- (2,6-dichlorophenoxymethyl) -1,3-dioxolan-2-ylmethyl-imidazole nitrate, V t .pl. 197200, 50c.

Example 9. In Example 8, the following imidazoles and salts of imidazoles are added when acids are added: A-1- 2- (2,4-dichlorophenyl) -4- (o-tolyl-oxymethyl) -1, 3-dioxolan-2-ylmethyl-imidazole nitrate; m.p. 156.2 ° C, 4-dichlorophenyl-4- (o-tolyl5 oxymethyl) -, 3-dioxolan-2-ylmethyl-imidazole sesquioxalate; mp.138, H. (2,4-Dichlorophenyl) -4- (2,6-dimethylphenoxymethyl) 1, 3-dioxolan-2-ylmethyl3-1H-imidaeol nitrate, m.p. 155 bOS, and A + B-1-1: 2- (2,4-dichloro-phenyl) -4- (2,6-dimethylphenoxymethyl) -1, 3-dioxolan-2-ylmethyl} -1H-imidazole nitrate: m.p. 134 ,. Example 10. A mixture of 6.8 parts of imidazole, 7.8 parts of A-2- (methyl bromide) -2- (2, 4-dichlorophenyl) -4- (phenoxymethyl) -1, 3-dioxolane, 4 h. Three times with iodide and 150 parts of dimethylformamide is stirred and refluxed for 3 days. The reaction mixture is allowed to cool to room temperature, water is added to it and the product is extracted twice.

d

diisopropyl ether. The combined extracts containing A-1p- (2,4-dichlorophenyl) -4- {phenoxymethyl) -1, 3-dioxolan-2-ylmethyl-imidazole, washed twice with water and acidified with an excess of concentrated nitric acid solution. The salt is filtered and crystallized from a mixture of ethanol and diisopropyl ether, yielding 5.6 parts (2,4-dichlorophenyl; -4- (phenoxymethyl) -1, 3-dioxolan-2-ylmethyl-imidazole nitrate; m.p. 180.50c. Example 11. Following the procedure of Example 10 and using equivalent amounts of the corresponding starting materials, the following imideol and imidazole salts are added with the addition of acids

Example 12. A mixture of 13.6 hours of imidazole, 22.2 parts of L + B-2- (bromomethyl) -4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane , 4 parts of potassium iodide and 150 parts of dimethylformamide are stirred and refluxed for 3 days. The reaction mixture is allowed to cool to room temperature, water is poured in and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using chloroform as eluent, to give two fractions. The first fraction is evaporated and the residue with A-1-L4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl-imidazole is dissolved in 4-methyl-2-penta "Ol and diisopropyl ether. The solution is acidified with an excess of a concentrated solution of nitric acid. The nitric acid salt is filtered and crystallized from a mixture of 4-methyl-2-pentanol and diisopropyl ether, to give (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3 dioxolan-2-ylmethyl imidazole nitrate, t. square 136.2Pc.

The second fraction is evaporated and the residue with B-1-f4- (o-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl3-imidazole is dissolved in a mixture of 4-methyl-2-pentanol and diisopropyl ether. The solution is acidified with excess oxalic acid. The oxalate salt is filtered off and crystallized from 4-methyl-2-pentanol, yielding 4 h. Bl-f4- (o-chlorophenoxymethyl) -2- (2,4-dichloro-5-phenyl) -, 3-dioxolan-2-ylmethyl - imidazole dioxalate so pl. 103.5С.

Example 13. Following the procedure of Example 12 and using equivalent amounts of the corresponding starting materials, the following imidazoles and salts of imidazoles are obtained by adding acids. Only one isomer is present here, the second fraction is not obtained by chromatography. Example 14, a Mixture of 9.7 hours 1H-imidazole, 12.5 parts A + B-2- (bromomethyl (-4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1, 3-dioxolane, 3 parts of potassium and 135 hours , the dimethyl form of the amide is stirred and boiled under q at reflux for 72 hours Water is poured into the reaction mixture and the product is extracted twice with diethyl ether. The extract containing (4-bromophenoxymethyl) -2- (4-methylphenyl) -, 3-dioxolane -2-Ylmethyl-1H-imidazole, washed twice with water and an excess of a solution of concentrated nitric acid and di-isopropyl ether were added. The resulting mixture was filtered and crystallized from ethanol. anola and diisopropyl efr to obtain 5.6 parts of (4-bromophenoxymethyl) -2- (4-methylphenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; mp 175 ,. Example 15. Following the procedure of Example 14, but replacing the A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-methylphenyl) -1,3-dioxolane used there with equivalent amounts of A + B-2 - (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4-chlorophenyl) -1,3-dioxol on and A + B-2- (bromomethyl) -4- (4-bromophenoxymethyl) -2- (4 -bromophenyl) -1,3 dioxolane, (4-bromo-phenoxymethyl) -2- (4-chlorophenyl) -1; 3-dioxolan-2-ylmethyl} -1H-imide azole and its nitric acid salt are obtained (m.p. . 158 ° C) and (4-bromophenoxymethyl) -2- (4-bromophenyl) -1,3-dioxolan-2-ylmethyl -1H-imidazole and its nitric acid salt (mp. 170.3 ° C). Example 16. A mixture of 7.9 parts of 1H-imidazole, 11.5 hours, A + B-2 -. (Bromomethyl) -2- (2,4-dichlorophenyl) -4- (4-phenyl phenoxymethyl) - 1,3-dioxolane, 4 h. potassium iodide and 135 parts of dimethylformamide are stirred and refluxed for 3 days. Water is added to the reaction mixture and the product is extracted twice with diethyl ether. The combined extracts are melted with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel, using chloroform as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in 4-methyl-2-pentanol and diisopropyl ether. The salt is filtered off and crystallized from a mixture of ethanol and diisopropyl ether, thus obtaining A + 5-1- 2- (2,4-dichlorophenyl) -4- (4-phenylphenoxy methyl) -, 3-dioxolan-2-ylmethyl -1H- imidazole nitrate; m.p. 187.9C. The second fraction is collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanol to give trans-1-C2-U 4-dichlorophenyl) -4- (4-phenylphenoxymethyl) -1,3-dioxol-2-ylmethyl -1H-imidazole; t. square 155, Example 17. A mixture of 6.8 h imidazole, 8.5 h. B-2- (bromomethyl) -4-p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxolane, 2 h. sodium iodide and 100 parts of dimethylformamide are stirred and refluxed for 36 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted twice with benzene. The combined organic salts are washed twice with water, dried and the solvent is removed under vacuum. The residue was purified by column chromatography over silica gel using chloroform as eluent. Pure fractions are collected and the eluent is evaporated. The residue with (p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl-imidazole is converted to the oxalate salt in 4-methyl-2-pentanol; adding diisopropyl ether salt precipitates. It is filtered off and crystallized from 4-methyl-2-pentanol, thus obtaining 3.1 parts of trans-1-4-p-chlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxolane-2- Ilmethyl-imidazole sesquioxalate; mt pl. Example 18. In Example 17, (2, 4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl-imidazole sesquioxalate is obtained; m.p. 121.2 ° C, by reacting B-2- (bromomethyl) -4- (2, 4-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxolane with imidazole. Example .19, Mixture of 8.6 parts of 1H-imidazole, 11.3 parts. A-2- (brog methyl) -2- (2, 4-dichlorophenyl) -4- (3, -5-dimethylphenoxymethyl) - 1,3-dioxolane, 4 parts of potassium iodide and 135 parts of dimethylacetamide are stirred and refluxed for 3 days. Water is added to the reaction mixture and the product is extracted twice with diisopropyl ether. The combined extracts are washed twice with water and an excess of a concentrated solution of nitric acid is added. The resulting nitric acid salt is filtered and crystallized from a mixture of isopropanol and diisopropyl ether. The product is again filtered and recrystallized from 4-methyl-2-pentanol, to thereby obtain the hydrate (2,4-dichlorophenyl) -4- (3,5-dimethylphenoxymethyl) -1,3-dioxolan-2-ylmethyl -1H-imidazole nitrate ; m.p. 122.6 ° C. Example 20. Following the procedure of rimer 19 and using equivalent amounts of the corresponding starting materials, the following imidzols and imidazoles salts are added with the addition of acids. Example 21. Mixture of 42 parts. 1H-imidazole, 63 hours. A + B-4- (1.1 -diphenyl) -4-yloxymethyl -2- (brog dalethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane, 20 hours, potassium iodide and 675 parts of dimethylformamide are stirred and boiled under reflux in for 3 days. Water is added to the reaction mixture and the product is extracted with diisopropyl ether. The extract is dried, filtered and evaporated. The residue is converted to a salt of nitric acid in 4-methyl-2-pentanol and diisopropyl ether. The product is isolated as an oil. The liquid phase is decanted, and the residual oil solidifies upon trituration in 4-methyl-2-pentanol. The nitric acid salt is filtered and crystallized from ethanol to obtain 5 parts of CYN-1-G4-1,1-diphenyl (-4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-2 -apmethyl -1H-imidazole nitrate, so pl. 186.5. Example 22. Following the procedure of Example 21 and using equivalent amounts of the corresponding starting materials, cis-1- 2- (2,4-dichlorophenyl) -4- (2-methoxyphenoxymethyl) -1, 3-dioxolan-2-ylmethyl -1H- imidazole oxalate hemihydrate; m.p. 123 ,, and cis-1 2- (2,4-dichlorophenyl) -4- (4-fluorophenoxymethylH, 3-dioxolan-2-ylmethyl -1H-imidazole; mp 106; Example 23. A mixture of 6, 4 parts of 1H-imidazole, 10 parts of A + B-2- (bromomethyl) -4-3-chloro (1,1-diphenyl) -4-yloxymethyl -2- (2,4-dichlorophenyl) -1,3 dioxolane and 135 parts of dimethylacetamide are stirred and boiled under reflux for 5 days. The reaction mixture is cooled to room temperature and water is poured in. The product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is recrystallized from 4% m tyl-2-pentanol, thus obtaining 2.2 parts (22%) of trans-1-1 4-3-chloro- (1,1-diphenyl) -4-yloxymethyl -2- (2,4-dichloro phenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole, mp 140. Example 24 A mixture of 10.2 h of 1H-imidazole and 26.8 parts of a 30% sodium methoxide solution stir and boil under reflux for 15 minutes Then 90 parts of dimethylformamide are added to the mixture.Metanol is distilled off until the internal temperature reaches approximately 130 ° C. After adding an additional amount of 90 parts of dimethyl formamide, 50 h are added in portions at approximately 100 ° C, A + B-4- (1,1-diphenyl) -4-yloxymethyl -2- (methyl bromide-2- 2, 4-dichlorophenyl) -1,3-dioxole on. Upon completion of the addition, stirring is continued for 5 hours at reflux temperature. A mixture of water and toluene is added to the reaction mixture. The organic phase is separated and mixed with activated charcoal. The latter is filtered off and the filter is evaporated. The residue is purified twice by column chromatography over silica gel using a mixture of chloroform and 1% methanol as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from isopropanol to obtain 9.3 parts of cis-1-4- (1,1-diphenyl) -4-yloxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-2- ilmethyl-1H-imidazole; m.p. 150 ,. Example 25. A mixture of 17 h 1H-imidazole, 27.4 hours. And + B-4- (1,1-diphenyl) -4-yloxymethyl} -2- (bromomethyl) -2- (3,4,5- t & chlorophenyl) -1,3-dioxole and 135 parts of dimethyl acetamide are stirred and refluxed for 5 days. The reaction mixture is cooled and water is added to it. The product is extracted twice with diethyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using chloroform as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in 4-methyl-2-pentanol and diisopropyl ether. The salt is filtered off and crystallized from a mixture of acetonitrile and diisopropyl ether, yielding 3 parts of cis-1-4- (1,1-diphenyl-4-yloxymethyl) -2- (3,4, 5-trichlorophenyl) -1, 3 dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 212.20 p. The second fraction is collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in 4-methyl-2-pentanol and diisopropyl ether. The salt is filtered off and crystallized from a mixture of acetonitrile and diisopropyl ether to obtain 1.9 parts of trans-1-4-4 (1,1-diphenyl) -4-yloxymethyl -2- (3,4,5-trichlorophenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 1580C. Example 26. Following the procedure of Example 25 and using equivalent amounts of the appropriate starting materials, the following imidazoles and salts of imidazoles are added by adding acids: cis-1-4- (1,4-diphenyl) -4-yloxymethyl -2- (4-bromo- 2-chlorophenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole, so pl. 161.8 ° C; Trans-1- 4- (1,1-diphenyl-) -4-yloxymethyl -2- (4-bromo-2-chlorophenyl) -1,3-dioxolan-2-ylmethyl3-1H-imidazole; mp 164 , 6 ° С; cis-1- (1,1-diphenyl) -4-yloxymethyl) -2- (2-naphthalenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole; mp. 15 2.60 С; trans-1- (1,1-diphenyl) -4-yloxymethyl) -2- (2-naphthalenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 230.6 ° C; cis-1-4- (1,1-diphenyl) -4-yloxymethyl -2- (2,4,5-trichlorophenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; mp.199, and trans-1- 4- (1,1-diphenyl) -4-yloxymethyl-2- (2,4,5-trichlorophenyl) -1,3-dioxolan-2-ylmethyl - H-imidazole ; m.p. 139.20 p. Example 27. A mixture of 11.5 parts of 1H-imidazole, 17.5 parts of L + B-2- (bromomethyl) -2- (2,4-dichlorophenyl) -4- (3,4,5 trichlorophenoxymethyl) -1 , 3-dioxolane, 3 h. potassium iodide and 180 parts of dimethylacetamide are stirred and refluxed for 3 days. Water is added to the K-reaction mixture and the product is extracted 4 times with diethyl ether. The combined extracts are washed 5 times with water, dried, filtered and evaporated. The acidic residue is purified to encourage column chromatography over silica gel using chloroform as the eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The oily residue converts the nitric acid salt to 4-methyl-2-pentanol. The salt is filtered off and distilled from a mixture of 4-methyl-2pentanol and diisopropyl ether, to give, after drying, 7.5 parts (40%) of ishydrate -1-2- (2,4-dichlorophenyl) 4- (3,4,5 -trichlorophenoxymethyl) -1,3 dioxolan-2-ylmethyl -1H-imidazole itrate; m.p. 149, The second fraction (B-isomer) is collected and the eluent is evaporated. The oily stat is converted to the salt of nitric acid in 4-methyl-2-pentanol. The salt is filtered and crystallized from a mixture of 4-methyl-2-pentanol. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanol and diisoropyl ether, obtaining after drying 6.2 hours (27%) trans-1-1.2- (2, 4-dichlorophenyl) -4- (3.4, 5-trichlorophenoxymethyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 169 ,. Example 28. Following the procedure of Example 25 and using equivalent amounts of the corresponding starting materials, the following imidazoles and imidazoles salts are added with the addition of acids. When only one isomer is present, this means that the second fraction is not obtained from chromatography. Cys-1-G4- (2-chloro-5-methylphenoxymethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-2-ylmethyl -1H-imidazole; m.p. 131, 7 ° C, trans-1-C4- (2-HLOR-5-methylphenoxymethyl) -2- (2,4-dichpophenyl) -1,3-dioxolan-2-ylmethylZ-1H-imidazole sesquy-oxssat, m.p. . 148; T. (1,6-dibromo-2-naphtalenyloxy-methyl -2-U, 4-dichlorophenyl; -1,3-dioxolan-2-ylmethyl-1H-imidazole nitrate; mp. 179.4 ° C; (( 2,3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl -1, 3-dioxolan-2-ylmethyl -1H-IMIDazole oxalate; mp 151.1 ° C and B-1-4- (2, 3-dichlorophenoxymethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxo / 1-2-ylmethyl -1H-imidazole sesquioxalate, mp 156, Example 29. Following the procedure of Example 10 using equivalent amounts the corresponding starting materials, the following compounds are obtained: A + B-1- 4- (4-bromophenylthiomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl -1H-imidazole nitrate, A + B -1- 2- (2,4-d iichlorophenyl) -4- (phenylthiomethyl) -, 3-dioxolan-2-ylmetl -1 H-imidazole nitrate; mp 122, Example 30. Mixture of 4.5 parts of 1H-imidazole, 6.5 hours. A -2- (bromomethyl -4- {4-bromophenoxymethyl) -2- (2,3-dichlorophenyl) -1,3-dioxolane and 125 parts of dimethylacetamide are stirred and refluxed for two days. The reaction mixture allowed to cool to room temperature, water is added and the product is extracted twice with diethyl ether. The combined extracts were washed with water and an excess of concentrated nitric acid solution was added. The resulting nitric acid salt is filtered off and crystallized from 4-methyl-2-pentanol, to thereby obtain 5 parts (68%) of cis-1-4- (4-bro-phenoxymethyl) -2- (2,3-dichlorophenyl) - 1, 3-dioxolan-2-ylmethyl -1H-imidaeol nitrate; m.p. 138.9 ° C. Example 31 Following the procedure of Example 25 and using equivalent amounts of the corresponding starting materials, the following imidazole salts are obtained by adding acids: cis-1-4-S3-chloro- (1,1-diphenyl-4-yloxymethyl) -2- (2, 4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 171, cis-1-G - (1, - (ifenyl) -4-yloxymethyl) -2- (2-chloro-4-methoxyphenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 172.9C, A + B-1-p- (2,4-dichlorophenyl) -4- (phenylmethyl) -1,3-dioxolan-2-ylmethyl -1H-imidazo oxalate; m.p. 117, A + B-1- 2- (2,4-dichlorophenyl) -4- (4-fluorophenyl) thiomethyl -1, 3-dioxolan-2-ylmethyl3-1H-imidaeol oxalate; m.p. 129, BOC; A + B-l-4f- (4-chlorobenzyl) -2- (2,4-dichles rphenyl) -1, 3-dioxolan-2-ylmethyl -1H-imidazole sesquioxalate, m.p. 141.6 ° C; A + B-1-H2- (2; 4-dichlorophenyl) -4- (4-methoxybenzyl) -, 3-dioxolan-2-ylmethyl1 -1H-imidazole dioxalate / so pl. 94 ,, cis-2-2- (2, 4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxybenzonitrile nitrate; m.p. 162.1C and cis-butyl (2,4-dichlrrphenyl) -2- (1H-imidazol-1-ylmethyl) -, 3-dioxolan-4-ylgmethoxy 3-benzoate nitrate; mp. 90 ,. Example 32. A mixture of 14.4 parts of 1H-imidazole, 18.5 parts A + B-2- (bromomethyl) -2- (2,4-diclorophenyl) (4-methoxyphenyl) ethyl -1,3- dioxolane, 5 parts of potassium iodide and 135 parts of dimethylacetamide are stirred and refluxed for two days. The reaction mixture is allowed to cool to room temperature and water is added to it. The product is extracted twice with diisopropyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is converted to the salt of oxalic acid in 4-methyl-2-pentanol and diisopropyl ether. The salt is filtered off and crystallized FROM a mixture of diisopropyl ether and ethanol, thus obtaining A + B-1- 2- (2, 4-dichlorophenyl) -4- 2- (4-methoxyphenyl) -ethyl} -1, 3-dioxolane-2 -methyl -1H-imidazole sesquioxalate; m.p. 130.70s -. Example 33 Following the procedure of Example 25 and using equivalent amounts of the corresponding starting materials, the following imidazoles and salts of imidazoles are added with the addition of acids: (4-chlorophenyl) ethyl) -2- (2,4-dichlorophenyl -1, 3-dioxolane 2-nmethyl -1H-imidaeol dioxalate / melting point 131.90, (2,4-dichlorophenyl) -4- (2-phenylethyl) -1,3-dioxolan-2-nmethyl -1H-imidazole sesquioxalate; mp 117.8 s and A + B-1-C2- (2.4 Dichlorophenyl) -4- (2- (4-methylphenyl) -ethyl) -1,3-dioxolan-2-ylmethyl -1H-imide az ol sesquioxalate and hydrate; mp. 123,. (2-chlorophenyl) ethyl -2- / ((2,4-dichlOrphenyl) -1, 3-dioxolan-2-ylmethyl} -1H-im dazol nitrate; mp. 98.8 ° C, (2,4-lichlorophenyl-1- (2- (2,4-dichlorophenyl) -ethyl -1, 3-dioxolan-2-ylmethylJ-1H-imidazole nitrate; mp 158.1 ° C and A + B-1-C2- (2,4-dichlorophenyl) -4- (2-12,4-dichlorophenyl) ethyl -1, 3-dioxolane -2-ylmethyl - 1H-imidazole nitrate, t.p. 140.1 ° C. Example 34. To a stirred solution of sodium methylate, prepared from 3.8 hours of sodium in 40i hours of methanol, 11 parts of 1H-imidazole and 225 parts of dimethylformamide are added. The methanol is distilled until the internal temperature reaches. Then 19 hours are added to the mixture. A + B-2- (methyl bromide) -2- (2,4-dichlorophenyl) -4-ethyl-1, 3-dioxolane and the contents are stirred and refluxed for 1 h. The reaction mixture is allowed to cool to room temperature and water is added to the mixture. The product is extracted three times with diethyl ether. The combined extracts of pr01 “| 1 with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of chloroform and 1% methanol as eluench. The first fraction is collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in diisopropyl ether. The salt is filtered off and crystallized from a mixture of isopropanol and diisopropyl ether, yielding 12 hours (56%) A + B-1- 2, 4-dichlorophenyl 1-4-ETHYL-1,3-dioxo l-2-yl methyl - Dn-imidazole nitrate; m.p. 149,100. Example 35. To a stirred solution of sodium methoxide, obtained 2-ce-C (n,

2-CH, -CN

4-sn, -s, n

2,3,4- (ce), 2-B,

2,3- (ce), j, s-sg-s n

4-OCH, -CgH

2-CH2 -4-Ce-C Hj

2-Се-4-ОСН, -СЫН

h, 4.5- (cr) ,, 2-naphthyl

gz

Ni5

MB

147.6 117.5 172.7 176.4 135.3 140.3 151.6 157.1 126.8 117.7 195.8 195.1 mu, based on 2.7 parts of sodium in 40 hours methanol, 8 parts of 1H-imidazole and 225 parts of dimethylformamide are added. The methanol is distilled until the internal temperature reaches. Then 30 hours are added to the mixture. A + B-2- (4-bromo-2-chlorophenyl) -2- (bromomethyl) -4-ethyl-1, 3-dioxolane and stirring is continued for 1 hour at boiling point with reflux. Cool the reaction mixture and pour in water. The product is extracted twice with diisopropyl ether. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of chloroform and 2% methanol as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in diisopropyl ether. The salt is filtered off and crystallized from a mixture of 4-methyl-2-pentanol and diisopropyl ether, to give 8.5 hours (26%) A + B-1-2- (4-bromo-2-chlorophenyl) -4-ethyl -1,3-dioxolan-2-ylmethyl -1H-imidazole nitrate; m.p. 162,2-С. Example 36. Following the procedure of Example 25 and using equivalent amounts of the corresponding starting materials, the following imidazbl salts are obtained by adding acids.

23

Example 37. A mixture of 7.7 parts of 1H-imidazole, 8 parts of cis-2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolane-4-methanol, 1 part of potassium iodide and 180 h, dimethylacetamide is stirred and boiled under reflux for 3 days. The reaction mixture is cooled and evaporated. Then 50 parts of water and 300 parts of chloroform are added to the residue. The contents are washed three times with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of chloroform and 2% methanol as eluent. Pure fractions are collected in an eluent evaporated to give 9.2 parts of dis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1, 3-dioxolane-4-methanol; m.p. 140C.

Example 38 Following the procedure of Example 37 and using an equivalent amount of trans-2- (methylmethyl) -2- (2,4-dichlorophenyl) -1, 3-dioxolane-4-methanol as starting material, trans-2- ( 2,4-dichlorophenyl) -2- (1H-imidazol-1-nlmethyl) -1, 3-dioxan-4-methanol; mp, 129c,

Example 39. A mixture of 13.8 parts of 1- (2-chloro-4-fluorophenyl) -2- (1H-imidazol-1-yl) -ethanol hydrochloride, 14.6 hours of 3- (1,1-diphenyl) -4-yloxy -1,2-propanediol, 16 parts of p-toluenesulfonic acid, 40 parts of butanol and 225 parts of xylene are stirred and boiled with a separator for 1 week with a water separator. After cooling, diethyl ether is added and the contents are washed sequentially with a dilute sodium hydroxide solution and water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using chloroform as eluent. The first fraction (A-isomer) is collected and the eluent is evaporated. The residue is converted to the salt of nitric acid in 4-met-285000624

Table continuation

-pentanol and diisopropyl ether. The product is filtered off and crystallized from a mixture of acetonitrile and diiso0 propyl ether, thus obtaining 5 parts of cis-1- | 4- (1,1-diphenyl) -4-yloxymethyl -2- (2-chloro-4-fluorophenyl) -1, 3-dioxolan-2-ylmethylT {-1H-imide-. azole nitrate; m.p. 185,

The second fraction (B-isomar) is collected and the eluent is evaporated. The residue is converted to a salt of nitric acid in 4-methyl-2-pentanol and di-eopropyl ether, thus obtaining 5.9 parts of trans-1- {4- (1,1-diphenyl) -4-yloxy-D-methyl} -2- ( 2-chloro-4-fluorophenyl) -1,3-dioxolyl-2-ylmethyl -1H-imidapaze nitrate, m.p. 156 ,.

Example 40. Following the procedure of Example 39 and using equivalent

5 of the amount of the corresponding starting materials, the following imidazoles and imidazole salts are added by the addition of acids. When only one isomer is represented / then no second fraction is obtained from the chromatography.

0

Cys-1-54- (1,1-diphenyl) -4-yloxy, methylX-2- (2-thienyl) -1,3-dioxolan-2-ylmethyl1-1H-imidazole; mp. 149.5C, trans-1-4-C (1 D-Diphenyl) -4-yloxymethyl -2- (2-thienyl) -1, 3-dioxolan-25-methylmethyl -1H-imidazole; m.p. cis-1- (4- (1,1-diphenyl) -4-yloxymethyl -2- (2,4-libromophenyl) -1,3-dioxolan-2-ylmethyl} -1H-imidazole nitrate, mp 174 , 40c, TpaHc-lU- (l, l-di0 phenyl) -4-yloxymethyl-2- (2,4-dibromophenyl-1, 3-dioxolan-2-ylmethyl 5-1H-imidazole nitrate, mp. 141.850 and cis-1-i4-G (1,1-diphenyl),) -4-yloxymech1} -2-G5-chloro-2-thienyl) -1,3-dioxolane-2-ylmethyl} -1H-imidazole nitrate, t .pl. 1700s

Claims (4)

1. The method of obtaining imidase derivatives of formula G ABOUT x S where A is phenyl, 3ah4emeHHbin phenyl, thienyl, chlorothienyl or naphthyl, and in which said substituted, phenyl has the meaning of a phenyl group having from 1 to 3 substituents independently consisting of halogen, methyl, methoxy, nitro or cyano; R is an apyl having from 2 to 10 carbon atoms, alkoxymethyl, in which the alkyl group 1 has from 1 to 10 carbon atoms, ethenyl, 2-propenyloxymethyl, 2-propynyloxymethyl, hydroxymethyl, halomethyl, aryl methyl, aryl ethyl, aryloxymethyl, arylthiomethyl or arylmethoxymethyl wherein said aryl is phenyl, substituted phenyl / naphthyl, or mono- and di-halo-naphthyl, and wherein said substituted phenyl means a phenyl group having from 1 to 3 substituents, independently consisting of halo, lower Csh, lower ashkyloxy C, la S. cyano, nitr -groups, phenyl, phenylmethyl, benzoyl, chlorobenzoyl, lower alkylcarbonyl with C, lower yoshkyloxycarbonyl with C. or trifluoromethyl, provided that when more than one substituent is present, only one substituent can be selected from the group consisting phenyl, benzyl, frnyl methyl or chlorobenzoyl, characterized in that the compounds of formula II or its metal salt are reacted with a compound of formula II I. In which W represents a reactive ester group in an organic solvent, with the desired product in free form, in the form of a salt or optical isomers. 2. The method according to claim 1, distinguishes with the fact that the process is carried out at boiling of the reaction mass. 3. Method according to paragraphs. 1-2, characterized in that the process is carried out in the presence of a metal iodide. 4. Method according to paragraphs. 1-3, characterized in that when a compound of formula II is used as the starting product, the process is carried out using an excess of imidazole or in the presence of a base such as sodium or potassium carbonate or bicarbonate. Prior on the grounds: 01/27/75 Ar - phenyl, mono-di- or tri-shosphenyl, lower alkylphenyl, lower alkoxyphenyl; R is phenyl, substituted phenyl, naphthyl or halo-naphthyl, where substituted phenyl means phenyl having from 1 to 3 substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, cyano, phenyl or benzyl. 10/6/75 A ,, - has all other meanings; R - has all other values. Sources of information taken into account in the examination, 1. US Patent 3575999, cl. 260-309, published. 1971.