SU617011A3 - Method of obtaining imidazole derivatives or salts thereof - Google Patents

Description

(54) METHOD FOR OBTAINING IMIDAZOLE ORDINARY OR SALTS

The invention relates to the field of the preparation of new compounds that can be used as biologically active substances. It is known that aldehydes and ketones are characterized by reactions in which the oxygen atom is replaced by various groups: the action of various amino compounds results in water and forms amino compounds 1. The purpose of the invention is the synthesis of biologically active compounds. This is achieved by a known process for the preparation of imidaeol derivatives, for -OR-C-C-M- (CH2) (l) 1 I I R2 Ap where RI, Rj is lower alkyl; If p is 0.1 or 2, then Ar is phenyl, phenyl substituted by a halogen atom, a lower keel, an alkoxy group, thiekyl or halothienyl; Arphenyl, phenyl substituted with a halogen atom, lower alkyl, lower alkoxy, cyano, nitro, amino, or tetralyl; R is hydrogen, methyl, ethyl; hydrogen, methyl; if n is O, then Ap a-tetralyl or phenyl; or their salts, consisting in that the compound of the formula R, I I 2 Ap where B, R, RI, RJ, Ap have the above values, is subjected to interaction with the compound of the formula HaN - (ab) - Ap (III). where n. Ap have the indicated values. in an inert solvent, in the presence of acid, followed by reduction of the intermediate in C () the answer of the reaction

and isolating the desired product p as a base or coke.

As an inert solvent, aromatic hydrocarbons are preferably used, for example benzene, toluene.

PRI me R 1. A mixture of 11 wt. including N-acetylimidazole and 19 wt. including phenacyl bromide in 40 weight, parts of acetonate are mixed and heated under reflux for two hours. The solvent is evaporated in vacuo, the solid residue is treated with hot water and the solution is cooled and filtered. An aqueous solution of sodium carbonate is added to the aqueous filtrate to pH 9; the product is immediately precipitated. It is filtered and recrystallized twice from water, and then from a mixture of diisopropyl ether and 2-propanol. Get 1- (benzyl-methyl) -imidazole with so pl. 114-117 °

According to the procedure described in Example 1, and replacing phenacyl bromide with an equivalent amount of a corresponding ketone, the following compounds are obtained:

1- (4-megylbenzoylmethyl; hell) -imidazole, m.p. 133-134 ° C, 1- (4-methylbenzoylmethyl) -imidazole hydrochloride, so pl. 210.5-216 ° C, l (4-chlorobenzoylmethyl) -imidazole hydrochloride, m.p. 228229 ° C.

Example 2. To a solution of 20.4 wt. including imidazole in 40 weight, parts of methanol is added 23.3 weight. hours-chlorophenacylbromide, the mixture is stirred for 2 hours at 0 ° C. The solvent was removed in vacuo. The residue is poured into water. The product 2-chloro-2- (1-imidazolyl) -ethetophenone, extracted with chloroform. First recrystallized from a mixture of 2-propanol and diisopropyl ether, and then from a mixture of methanol and diisopropyl ether, to obtain 2-chloro-2- (1-imidazolyl) -acetophenone hydrochloric acid, m.p. 186.5-189 ° C

Example 3. To a solution of 276 wt. h p-fluoroidetophenone 400 weight.h. Dizsana and 640 weight. including absolute ether, dropwise add 320 weight. h. bromine. The mixture is continuously cooled with ice and stirred. The mixture is then brought to room temperature and the solvent is distilled off in a vacuum, until the temperature reaches 110 ° C. The residue is cooled in an ice bath and 640 wt.% Is added to it. including acetone. With stirring at 0 ° C, a solution of 528 wt. Is added. including imidazole in 640 weight. including methanol. The mixture is stirred for 3 hours while cooling, and the solvent is removed at atmospheric pressure until the temperature reaches 125 ° C. After cooling, 750 weight is added to the residue. including chloroform and 500 wt. h of water. The chloroform layer is separated, stirred 30 minutes, rinsed with water, dried, filtered and evaporated. From the residue containing .1- (p-fluorophenacyl) .- imidazole, a hydrochloric salt is prepared by a known method.

The crude salt is recrystallized twice from a mixture of 2-propanol, methanol and diisopropyl ether. The free base is again obtained by treating the salt with an equivalent amount of sodium hydroxide and recrystallized from a mixture of 2-phenyl alcohol and diisopropyl ether. Get 178 weight. including 1- (p-fluorofenacil) -imidazole, so pl. 149-155 ° C.

According to the procedure described in Example 3, and replacing p-fluoroacetophenone with an equivalent amount of the corresponding methyl aryl ketone or 2-methylpropiophenone, the following compounds can be synthesized:

3-chloro-2- (1-imidazolyl) acetophenone nitrate, m.p. 179.7 ° C;

4-bromo-2- (1-imidazolyl) -ethetophenone, Tchpl. 164 ° C;

2,4-dua10p-2- (1-imidazolyl) acetophenone nitrate, mp. 164.5 ° C;

nitrate 2- (1-imidazolyl) -2-methyladetofenone, so pl. 165.5-167 ° C;

2 .. (1-imidaeolyl) -2-methylacetophenone hydrochloride, t. Pl. 208 ° C;

2- (1-imidazolylmethyl) -2-thienyl ketone nitrate, t. pl. 136 ° C;

2- (1-imidazolyl) -2-methylpropiophenone nitrate, m.p. 167.5 ° C.

Example 4. To a cooled (5-15 ° C sludge 120 parts by weight of imidazole in 125 parts by weight of dimethylformamide, 82 parts by weight of 2- (5-chloro-2-thienyl) acetyl bromide) are added in portions to 125 parts by weight After the introduction of the entire mixture, the mixture is stirred under ice cooling for 2 hours, 1 the mixture is poured into water and 5-chloro-2-shadows L- (1-imiazolylmethyl) -ketone is dispensed. The precipitate is filtered off and dissolved 750 parts by weight of chloroform, washed with water, and then chloroform is evaporated. The residue is triturated in ether and filtered again. The free base is obtained with mp 104-1 06 ° C. 4.4 parts by weight of it is converted into the nitrate salt and, after recrystallization from ethanol, 3.7 parts by weight of 5-zslor-2-thienyl- (1-imidazolylmethyl) -ketone are obtained, tl.161 , 5 ° C.

By the procedure described in example 4, and replacing imidazole with an equivalent amount of the corresponding imidazole derivative and 2- {5-chloro-2-thienyl) acetyl bromide with an equivalent amount of the corresponding acetophenone or propiophenone, the following compounds can be obtained:

4-chloro-2- (1-imidazole)-ieobuyrophenone nitrate, m.p. 178.2 ° C;

41 chloro-2- (2-methyl-1-imidazolyl) -acetophenone, m.p. 209.5 ° C;

4-chloro-2- (2-ethyl-1-imidazolyl) -acetofe} yn, m.p. 160 ° C;

4 chloro-2- {2,4-dimethyl-1-imidazolyl) acetophenone, m.p. 185.8 ° C; g6 2,4-dichloro-2- (2-methyl-1-imidazolyl) acetophenone,: 2-methoxy-2- (2-methyl-1-imidazolyl) acetophenone, (5-chloro-2-tinil) - (2-methyl-1-imidaeolylmethyl) -ketone, I 4-bromo-2- (2-ethyl-1-imidazolyl) acetophenone 2- (2-ethyl-1-imidazolyl) 2 methylacetophenone, (2-E1IL-1 -imidazolylmethyl) - {2-thienyl) -ketone, 2- (2-ethyl-1-imidazolyl) -2-methylpropiof-. non, 2- (2,4-dime-shl-1-imidazolyl) acetophenone, 4-methyl-2- (2,4-dimethyl-1-imidazolyl) acetophenone, 2 labels si-2- (2, 4-dimethyl-1-imidazolyl) acetophenone, 2,4-dictor-2- (2,4-dimethyl-1-imidazolyl) acetophenone, 2, 4, 6-trichloro-2- (2,4-dimethyl) 1-imidazolyl) acetophenone. Example 5. To a stirred hot (60-80 ° C) solution of 155 wt. h. p-chlorace tofenone in 250 wt. h. propylene glycol drip 160 ml. h of bromine, the mixture is stirred for 16 hours. After that, the reaction mixture is poured into a dilute sodium hydroxide solution and, according to 11th, the extracted product is extracted with benzene. The extract is dried and scrubbed in an IVB vacuum. The oily residue is distilled; 220 wt. including oily 2- (bromomethyl) -2 - (p-chloromethyl) -4-methyl-13-dioxolane, t. bale. 133 ° (/ 1.25 mm Hg. Distillate is triturated with cooling in 400 parts by weight of 2-propanol, the product becomes solid, it is filtered and recrystallized from 2-propanol. Purified 2- (bromomethyl) -2- ( p-chlorophenyl) -4-methyl-1, 3-dioxolane has a melting point of 71 ° C. According to the procedure described in Example 5, and replacing acetophenone and glycol with an equivalent amount of the corresponding ketone and glycol: the following compounds are obtained: 2- (bromomethyl) 2-0-tolyl-1,3-dioxolium, bp 113-115 ° C / 0.8 mm Hg, 2- (bromomethyl) -2-n-tsyl-1,3- dioxolane, bp 135-137 ° C / 2.5 mmHg, 2- (methyl bromide) -2- (2,5-dichlor phenyl) -1,3-dioxolane, mp 61.5 ° C, 2- (methyl bromide) -2-m-tolyl-1,3-dioxolane, mp 59 ° C, 2- (methyl bromide) - 2- (o-methoxyphenyl) -1,3-dioxolai, mp 99-100 ° C, 2- (methyl bromide) -2- (l-fluorophenyl) -1,3-dioxolane, mp 50 ° C. PRI me R 6. 37.8 parts by weight of methyl 2-thienyl ketone, 48 parts by weight of bromine, 48 parts by weight of dioxane and 96 parts of absolute ether, are stirred and cooled. removed in vacuo. 60 wt. including ethylene glycol in 160 wt. including toluene and several crystals of α-toluene sulfonic acid. The mixture is stirred and heated under reflux for J 5 hours. The mixture is cooled, the toluene layer is separated, washed with potassium carbonate and water, dried, filtered and evaporated in vacuo. The oily residue is distilled under vacuum and in the presence of potassium carbonate. Get 2-bromomethyl-2- (2-thienyl) -1,3-dioxolane, so Kip. 95 ° C / 0.6 mmHg Art. According to the procedure described in Example 6 and replacing acetophenone and glycol with an equivalent amount of the corresponding ketone and glycol, the following compounds are obtained: 2-bromomethyl-2- (o-chlorophenyl) -1,3-dioxolane, m.p. 130 ° C / 0.8 mmHg Art. 2- (bromomethyl) - 2- (l-metoksifenil) -l, 3-diokolane, so pl. 61 ° C. 2- (bromomethyl) -2- (2,3,4-trichlorophenyl) -1,3-dioxolane, m.p. 59.5 ° C. 2-bromomethyl-2- (l-chlorophenyl) -1,3-dioxogl, t. Bale. 149 ° C / 0.2 mmHg Art. Example 7. To a solution of 23 wt. including sodium in 600 wt. including ethanol add 154 wt. including ethyl 5-methylimidazole-4-carboxylate. Then 440 weight. part of ethanol is extruded and 1600 weight% is added to the warm residue. including 2-diieopropyl ether. The mixture is cooled, the sodium salt precipitates out and is filtered off. The sodium salt of ethyl 5-methylimidazole-4-carboxylate is obtained. A mixture of 17.7 wt. including sodium salt of ethyl 5-methylimidazole-4-carboxylate, 35 weight. h: 2-bromomethyl-2- (p-chlorophenyl) -1,3-dioxolane, 22.5 wt. including potassium iodide, 30 wt. including dimethylformamide and 4 wt. h. toluene is stirred and heated under reflux for 12 hours. The mixture is cooled, add 400 weight. h. ether. The organic phase is washed three times with water, dried and an excess of concentrated nitric acid is added. The precipitated nitrate salt is filtered and recrystallized from a mixture of 40 weight. including absolute ethanol and 400 wt. including diisopropyl alcohol. Ethyl-1-2- (l-chlorophenyl) -1,3-dioxolan-2-ylmethyl-5-mothols of gold-4-rbok silachah t-nitramide is obtained. square 130.3 ° C. A mixture of 2 wt. including nitrate ethyl-1- 2- (w-chlorophenol) -l, 3-dioxolan-2-ylmethI-5-methyl fl dazol-4-carboxylate and 7.5 weight. Part 10 and the hydroxide solution is heated and stirred and heated under reflux for 15 minutes. Add 20 wt. including water, then 4.5 wt. including acetic acid. The precipitate is filtered and perekrystalizovany from 80 weight. including ethanol. 1- 2- (and-chlorofequyl) -1,3-dioxol-2-ylmethyl-5-methylimidazole-4-carboxylic acid is obtained, m.p. 258.3 ° Г К 40 wt. at 250 C portions add 25 wt.% of larafinic oil. including I- (2 - (“- chloronyl) -1,3-dioxolan-2-ylmethyl) - 5 distillates; i-4-carboxylic acid. The mixture is heated to 270 ° C until the evolution of carbon monoxide ceases. The mixture is cooled, add 240 weight. h. ether. The solution is filtered and an excess of a concentrated solution of nitric acid is added to the filtrate. The precipitated nitric acid salt is filtered off and recrystallized from a mixture of 120 wt. including ethanol and 340 weight. including diisopropyl ether. 1-2-p-chlorophenyl) -1,3-dioxolane-2-ylmethyl-5-methylimidazole nitrate, m.p. 153.6 ° C. | Q

A mixture of 13 wt. including ("-chlorophenyl) -1,3-D} okslanan-2-ylmethyl-S-methyl razolol, 100 weight.h. acetic acid and 50 wt. including diluted hydrochloric acid is stirred and heated under reflux for 18 hours. The solvent is evaporated, 100 weight is successively added to the residue. including water and excess sodium hydroxide. This precipitates 4-chloro-2- (5-methyl-1-imidazole) adetophenone. The product is filtered off and recrystallized from 50% by weight. including 10% dimethylformamide. Get 6.5 weight. including 4-chloro-2- (L-methyl-1-imidazole) -acetophenone, so pl. 123 ° C.

Example According to the procedure described in Example 7, except that the equivalent amount of each dioxolane derivative is replaced by 2-bromomethyl-2- (l-chlorophenyl) -, 3-dioxolane, the following ketones are obtained:

(1-imidazolylmethyl) -2-thieni.sh eton; 2 chloro-2- (5-methyl-1-imidazolyl) acetophenone; 2-methyl-2- (5-methyl-1-imidazolyl) acetophenone; 4-methyl-2- (5-methyl-1-imidazolyl) -acetophenone; 3-methoxy-2- (5-methyl-1-imidazolyl) acetophenone; 35 2,5-dichloro-2- (5-mechyl-1-imidazolyl) -acetophenone; 3-methyl-2- (5-methyl-1-imidazoyl) adetophenone; 2,3, 4-trichloro-2- (5-methyl-1-imidaeolyl) adetophenone; 2-methoxy-2- (5-methyl-1-imidazolyl) -l-acetophenone; 3-chloro-2- (5-methyl-1-imide- o azolyl) - acetophenone; 4-fluoro-2- (5-methyl-1-imidazo / shl) - acetophenone.

PRI me R 9. According to the procedure described, and in Example 7, the substitutions equivalent to the number 5 in each of the following dioxolane derivatives:

2-bromomethyl-2-phenyl-1,3-dioxolane; 2-bromomethyl-2- ("-bromophenyl) ..1,3-dioxolane; 2-bromomethyl-2- ("-methoxyphenyl) -1,3-dioxolane and 2-50

- (2-bromisopropyl) -2-phenyl-1,3-dioxolane at 2-b5X) Mmethyl-2- (p-chlorophenyl) -1,3-dioxolane; 5-methyl-imidzolyl ketones of general formula II are obtained:

2- (5-methyl-1-imidazolyl) -Adetophenone; 4-55 rum-2 (5-methyl-1-imidazolyl) acetophenone; 4-methoxy-2- (5-methyl-1-imidazo-gsl) -adetofenone and 2- (5-methyl-1-imidazolyl) -2-meGi; tropiophenone.

Example 10. A solution of 18.6 wt. including 1- (benzoylmethyl) -imidazole and 14.5 wt. hours / 3-phenethylamine in 160 weight. including absolute benzene containing a small amount of i-toluenesulfonic acid, stirred and heated under reflux. After 24 hours, the theoretical amount of water is recovered. The solvent is removed in vacuo. The residue is dissolved in 120 wt. including ethanol and the solution is subjected to hydrogenation at an initial hydrogen pressure of 4.5 kg / cm and room temperature in the presence of 3 weight. including palladium catalyst deposited on activated carbon in the amount of 5%. After the introduction of the calculated amount of hydrogen, the hydrogenation is completed. The solution is filtered and the solvent is removed in vacuo. The residue is dissolved in acetone, an excess of a solution of concentrated nitric acid in di-eopropyl ether is added to the resulting solution, and the nitric acid salt is separated in the form of an oil. The solvent is decanted and a new portion of acetone is added to the residue along with a small amount of diisopropyl ether, from which cristamine solid salt is added. The product is filtered, washed with acetone and recrystallized from a mixture of methanol, acetone and schisopropyl ether. A 1- | 3-phenethylamino-phenethyl) -imidazole dinigrate is obtained, m.p. 164.5-168 ° C.

By replacing- | 3-phenethylamine with an equivalent amount of the corresponding amine, the following imidazole amines are synthesized:

1- {| 3-anilinophenyl} -imidazole dihydrochloride, so pl. 217.5-230 ° C (with decomp.), (-Tetraalinylamino) -phenethyl-i, midazol dknitrat, t. Pl. 139-143 ° C.

Claims (2)

Example 11. A solution of 18.6 wt. including 1- (benzoylmethyl) -imidazole and 12.9 weight. including benzylamine in 80 wt. including benzene containing 0.5 weight. including l-toluensulfonate, stirred and heated under reflux. within 4 hours The solvent is removed in vacuo and the residue is dissolved in 120 wt. including ethanol. At room temperature, add the first portion of 3.8 weight. including sodium borohydri: yes, the mixture is stirred and heated with a reflux cooler for 30 minutes. Then add a second portion of 3.8 weight. including sodium borohydride, the mixture is again stirred and heated under reflux for one hour, and the solvent is removed in vacuo. 100 wt. including water and 70 wt. including concentrated hydrochloric acid to pH 2-3. The solution is stirred and heated under reflux for one hour. After cooling with ice, the solution is filtered and the filtrate is made alkaline with 10 N Stree hydroxide. The resulting free base is extracted with methylene chloride. The extract is flushed with water, dried, filtered and shredded in a vacuum. The liberated free base was dissolved in acetone and an excess of 2-propanol, previously saturated with gaseous hydrogen chloride, was added to this solution. Upon addition to the resulting solution, the dinospropyl ether precipitates the hydrochloride salt. It is filtered and recrystallized twice: the first time from a mixture of methanol and diisopropyl ether and the second time from a mixture of ethanol and diisopropyl ether. Get 1- (benzylaminophenet1) -im. azole 1 dagidrokhlorid, so pl. 263.5-266.5 ° C. Claim 1. The method of obtaining the imidazole derivatives of the general orormula,. N —O — I, - with —C — SH - (CH2) (I) Ig Ar where RI, R2 is hydrogen, lower alkyl; if n is 0.1 or 2, then Ar is phenyl, phenyl, substituted by halogen atom, lower alkyl, lower and coygroup, hyenyl or halothieni. Arphenyl, phenyl, displaced by halo atom, lower alkyl, lower alkoxy, cyan nitro , amino or tetralyl. R is hydrogen, methyl, ethyl, R is hydrogen, methyl; EU; wn - O, Ap - as tetralyl or phenyl; or a salt thereof, characterized in that the compound of the general formula 6 to .--- - "ILR & I K2 Ap where R, R, R (, Rj, Ap have the above meanings, is reacted with a compound of the general formula H2N- (CH2 ) j-Ap (III), where l, Ap have the above values, in an inert solvent, acid is present, followed by reduction of the industrial compound) in the corresponding form and distribution of the desired product as a base or corai. 2. The method according to claim 1, wherein the use of a hydrolytic hydrogen, such as benzene, toluene, is used as an inert solvent. Priority signs: 19.08.68. R, Rj is hydrogen, lower alkyl; if n is 0.1 or 2, then Ap is phenyl, which is substituted by a halogen atom by alkyl, lower alkoxy group, and .anyl or halothienyl. Ar is phenyl, substituted by a halogen atom, sh {evil alkyl, tskkey lksoks-, cyano- (shtro-, am1-shogr ppoy or seteralll, R - hydrogen, methyl, ethyl, R - hydrogen; if n - O, then Ar - a-tetrazh l or phenyl; IL.I. their SOL1 {.A.08.08.69. R - meth. Ap -, substituted by a circle o. Istoshshki t {form taken 5), I. Temnikova T. And The course of theoretical foundations of orgasmic .and, L, Ed. Chemie, 1968, p. 4GL