JPS6021590B2 - Method for producing 2-amino- and 2-(disubstituted amino)-4,5-diarylimidazoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (1) [wherein R, R2 represent a hydrogen atom, an alkyl group, an alkoxy group, or a halogen group, and Z represents an amino group, an N/N-dialkylami/group , N-alkyl-N-aralkylamino group, pyrrolidi/group, piperazino group, or N-alkylbiverazino group].

Some of the 2-amino-4.
5-diarylimidazole is produced by the reaction of Q-aminocarbonyl compound with cyanamide (G.C., Lamini a
M E, LaZZari, J, Heter ratio yCIiC
Chem 3, 152 (1966)) and the reduction of 2,2-azoimidazole (A.
Enemy g. Chem 27, Total 6 (1962)), but these methods are difficult to obtain raw materials,
It has the disadvantage of poor yield of the target product.

The present invention provides a novel compound, 4-hydroxy-Misaki-imidazole of the general formula (0) [wherein R, R2, and Z are as described above], which is catalytically reduced to form the following general formula (1) with high yield. 2-amino and 2-(
The present invention was completed by discovering that di-substituted ami/)-415-diarylimidazoles can be obtained.

In general, alcohols are difficult to reduce, and 4-hydroxy-
The ease with which bait-imidazoles undergo catalytic reduction is a completely unexpected result.

Among the compounds of general formula (1), 2-(disubstituted amino)-4,5-diarylimidazoles in particular are new compounds that have not yet been studied in the literature, and their synthesis has become possible for the first time by the method of the present invention. It is something that In carrying out the process of the present invention, the compound of formula (0) or a salt thereof is mixed in a suitable organic solvent, such as alcohols, halogenated hydrocarbons, esters, preferably methanol, with a suitable catalyst, e.g. , platinum oxide, palladium carbon Raney nickel in the presence of 0 to 4020 ℃, preferably 00 to 25℃
It can be produced by hydrogenation for 3 to 4 hours. The catalyst used is suitable for the starting material m) Funashiyasu ~ Tsubasa. After completion of the reduction, the target product can be isolated as free radicals by separating the catalyst and concentrating the reaction solution, but generally, an appropriate amount of mineral acid is added to the reaction solution and left to stand, or the reaction solution is concentrated. Isolate as the corresponding acid salt by cooling, or by concentrating to dryness and recrystallizing from a suitable solvent such as methanol, ethanol, j-propanol, n-butanol, or a mixed solvent of alcohols and ether. hydrochloride and nitrate are particularly suitable for this purpose. 2- obtained by the method of the present invention
Aminoimidazole derivatives are useful as intermediates for the production of nitroimidazoles having antitrichomoniacal activity, and 2-aminoimidazole derivatives and 2-aminoimidazole derivatives themselves have antibacterial activity and other properties. It has biological activity. In the above-mentioned synthesis method by Incini et al., the Q-aminocarbonyl compound as a raw material is generally unstable and elutriated. In particular, the synthesis of Q-aminoaldehyde is difficult and the yield is poor, and this manufacturing method itself is reactive. Various by-products are likely to be produced depending on the pH' of the solution, and therefore the yield is generally low.

Furthermore, in the synthesis method of Kreutz et al., the yield of the target product is good, but it is necessary to use aminoguanidine to prepare the biguanide used as a raw material, and furthermore, the yield is extremely poor.

Therefore, 4H that can be obtained in good yield using guanidines as a raw material
The method of the present invention for reducing -imidazole is superior to known methods, and 2-disubstituted aminoimidazole can only be produced by the method of the present invention. 4-Hydroxy-Misaki-imidazole of the general formula (D) used as a raw material in this method is a new compound having the following general formula (m): - [where RI and R2 have the above-mentioned meanings] For the substituted or unsubstituted penzyl represented by the formula (W), a guanidine derivative represented by the following general formula (W): - [wherein Z has the meaning given above] is dissolved in a suitable organic solvent such as a lower alkanol such as methanol. [Specification of Hakamawaki Sho No. 521 filed on the same day by the present applicant (title of invention: 4-hydroxy-4.5)
-diaryl-'H-imidazole and its production method)
reference〕.

Next, the method of the present invention will be explained with reference to examples.

Example 1 Preparation of 2-amino-4,5-diphenylimidazole 2.77 g of 2-amino-4-hydroxy-4,5-diphenyl imidazole and 0.60 g of 5% palladium carbon were suspended in 20 g of methanol. Hydrogenate at room temperature.

When absorption of hydrogen gas has stopped, the catalyst is removed in a natural furnace, the furnace liquid is concentrated to dryness, a small amount of ethanol is added to the residue, and the mixture is left at room temperature. The resulting crystals were collected by filtration, washed with a small amount of ethanol, and air-dried to obtain pale yellow columnar crystals. Yield 1.9
7 days (84%), melting point 231-235 days (decomposition). Recrystallization from ethanol gives a product with a melting point of 233-235°C (decomposition) (literature value 2°C-2°C (decomposition)).
Example 2 Production of 2-amino-4,5-diphenylimidazole nitrate After reacting in exactly the same manner as in Example 1, the catalyst was separated from the furnace, a calculated amount of nitric acid was added to the furnace liquid, and the precipitate was removed after standing overnight. Collect by filtration, wash with a small amount of methanol, and air dry to obtain nitrate and colorless needle crystals.

Melting point 163-IM. 0 (decomposition), yield 1. Banyu.

Further nitrates are obtained by concentrating the furnace liquor to about 50% and leaving it in ether for 40 minutes. Melting point 15p to 161p
00 (decomposition), yield 0.64 evening. Total yield 2.58 evenings (total %). Recrystallization from methanol gives colorless needles with a melting point of 1670 (decomposed). Elemental analysis (C, 5 days, 3N
3. Calculated value for HN03: C, 60.39 days,
4.73 N, 18.78% Actual value: C, 60.34,
day, 4.78 N, 19.07% Example 3 Preparation of hydrochloride of 2-amino-4,5-di(p-chlorophenyl)-imidazole 2-amino-4-hydroxy-4,5-di(p-chlorophenyl)-Misaki- Imidazole 1.60 and 5% palladium carbon 0.40
After completion of the reaction, 0.7 g of concentrated hydrochloric acid was added to the reaction solution, the catalyst was removed by filtration, and the furnace liquid was concentrated to dryness. dry.

A white powder was obtained. Yield 1.62 min (95%), melting point 111°C (partial foaming), 2000 total (decomposition). Recrystallization from ethanol and ether gave brown needles. Hakomushi point, 2iso to 26 pi○ (decomposition). Elemental analysis (C, out,
．． Calculated value for N3CI2/HCI: C, 52.8
9 days, 3.55 N, 12.33% Actual value: C, 52
．． 85 days, 3.8fu N, 12.57% Example 42
-Production of amino-4,5-di(p-chlorophenyl)-imidazole nitrate The reaction was carried out in the same manner as in Example 3.

However, after removing the catalyst from the furnace, add the calculated amount of nitric acid instead of concentrated hydrochloric acid. The reaction solution was concentrated to a volume of about 5 ml, and 2 ml of ethanol was added and refrigerated. Obtained as white needles. Yield 1.27
(70%), mp 157-9°C (decomposition). Recrystallization from ethanol gave colorless columnar crystals. Melting point: 160°C (decomposed). Elemental analysis (for C, rainbow, .N3/HN03)
Calculated values: C, 49.00 days, 3.29 N, 15.2
6% actual value: C, 49.0 & day, 3.33 N, 15
．． 25% Example 5 Preparation of 2-amino-4,5-di(p-methylphenyl)-imidazole hydrochloride 2-amino-
4-Hydroxy-4,5-di(p-methylphenyl) 14 days - 3.11 hours of imidazole and 1.20 hours of 5% palladium carbon were suspended in 50' of methanol, hydrogenated at room temperature, and concentrated hydrochloric acid was added to the reaction solution. Add 1.4 and pass through the oven while hot, and concentrate to dryness.

The remaining bamboo was dissolved in 6 parts hot methanol and allowed to cool to room temperature overnight. The resulting crystals were collected in a furnace, washed once with 3 parts of methanol, and then air-dried. Pale yellow columnar crystals were obtained. Melting point 24t
to 2560 (decomposition), yield 2.40 (78%). Recrystallization from methanol gave pale yellow columnar crystals. melting point,
255-259oo (decomposition). Elemental analysis (C, 7 days,
Calculated value for 7N3HCI 20: C, 6612
, day, 6.20N, 13.60% actual value: C, 6023
Day, 61&N, 1371% Example 62-amino-4
- Production of 5-di(p-methylphenyl)-imidazole nitrate The reaction was carried out in the same manner as in Example 5.

However, after separating the catalyst, add the calculated amount of nitric acid instead of concentrated hydrochloric acid. The reaction solution was heated in a hot oven, and the solution was concentrated to about 500ml and then refrigerated. Pale yellow-green granular crystals were obtained. Melting point: 20-0 (decomposition)
, yield 3.04 evenings (93%). Recrystallization from ethanol gave pale yellow needles. Melting point: 18 whistle (decomposition). Elemental analysis (C, 7 days, for 7N3/HN03) Calculated values:
C, 62.50 days, 5.50 N, 17.17% Actual value: C, 62.62 days, 56 N, 17.19% Example 72-dimethylamidium/-4.5-diphenylimidazole hydrochloric acid Preparation of salt 2-dimethylamino-4-hydroxy-4,5-diphenyl-4H-imidazole 1.4
Hydrogenate 150 g of platinum oxide and 0.15 g of platinum oxide at room temperature under 150 g of methanol. After the reaction is complete, 0.7 g of concentrated hydrochloric acid is added to the reaction solution, the catalyst is separated from the furnace, and the furnace liquid is concentrated to dryness.

The residual liquid was dissolved in hot ethanol for 27 hours, and after passing through a hot furnace, the furnace liquid was allowed to cool to room temperature. The precipitated crystals are collected by filtration and air-dried to yield colorless columnar crystals with a melting point of 261 to 271°C (decomposed). Yield: 0.76 yen. Colorless columnar crystals, melting point 278 to 200 (decomposition) were obtained in the same manner from the mother liquor with the crystals removed.
, with a yield of 0.32 min. Total yield1. Meyu (72%)
. Recrystallization from ethanol gave colorless columnar crystals. Melting point: 283 ○ (decomposed). Elemental analysis (C, 7 days, 7N3・H
Calculated value for CI: C, plaque. 11, Sun, 6.05
N, 14.02% Actual value: C, Road. 00 days, 620
N, 14.07% Example 82-dimethylamino-4.
Preparation of 5-di(p-methoxyphenyl)-imidazole hydrochloride 2-dimethylamino-4-hydroxy-4,5-
Di(p-methoxyphenyl)-Misaki-imidazole 1.6
9 yen and platinum oxide 0.17 yen in methanol 150 yen underground,
The reaction was carried out in the same manner as in Example 7, and the same treatment was carried out.

Yield 1.46°C (82%), melting point 2°C to 241°C (decomposition). Recrystallization from ethanol gave colorless needles.

Melting point 239-241°C (decomposition). Elemental analysis (C, illusion 2
, N302/HCI) Calculated value: C, mother 342,
Sun, 610 N, 11. Actual measured value of spot percentage: C, streaks. 4th day,
6.42, N, 11. Rudder% Example 9 Preparation of 2-dimethylamino-4,5-di(p-chlorophenyl)-imidazole hydrochloride 2-dimethylamino-4-hydroxy-4
・5-di(p-chlorophenyl)-yama-imidazole 1
．． 39 mol and platinum oxide 0.14 mol were hydrogenated in methanol 150 ml at room temperature, and after the reaction was completed, concentrated hydrochloric acid was added to the reaction solution.
．． Separate the catalyst in a furnace and concentrate the furnace liquid to dryness.

Zenizumi is dissolved in hot methanol 26%, and after passing through a hot furnace, the furnace liquid is allowed to cool. The resulting crystals were filtered, collected and air-dried. Colorless granular crystals, melting point over 303 qo, yield 0.57 qo. When two ethers are left in the lachrymal fluid, colorless granular crystals with a melting point of 30 to 0 or higher are obtained in a yield of 0.41 mm. Total yield 0.98
Evening (66%). Mass spectrum: m/e331 (M+,
100%).

Example 102-(N-penzyl-N-methylamino)
-Production of 4,5-diphenylimidazole hydrochloride 2-(
The same machine as in Example 7 was treated with 0.35 hours of imidazole and 0.04 hours of platinum oxide per day.

The yield was 100%, and colorless needle crystals were obtained by recrystallization from ethanol. Melting point: 228-23〆○ (decomposed). Mass spectrum: m/e 339 (M+, 91%).

Example 11 Production of hydrochloride of 2-pyrrolidino-4,5-di(p-methoxyphenyl)-imidazole 2-pyrrolidino-4-hydroxy-4,5-di(p-methoxyphenyl)-Yamaichi imidazole 1.48% and platinum oxide 0 .15
The mixture was suspended in 40 methanol and treated in the same manner as in Example 7.

White granular crystals were obtained. Melting point 268-271°C (foaming),
Yield 1.21 evenings (79%). Recrystallization from ethanol and ether gives a melting point of 269-271°C (foaming).
Elemental analysis (C2, day 33N302/HCI) Calculated values: C, 65.30 days, 6.27, N, 10.89
% Actual value: C, 65.49 days, 6.27, N, 10.
90% Example 12 Preparation of 2-(N-benzyl-N-methylamino)-4,5-di(p-methoxyphenyl)-imidazole hydrochloride 2-(N-penzyl-N-methylamino)-4-hydroxy-4・Hydrogenate 0.45 g of 5-di(p-methoxyphenyl)-4H-imidazole hydrochloride and 0.05 g of platinum oxide in 10 g of methanol at room temperature, and after the reaction is complete, the catalyst is carved in an oven. The furnace solution was concentrated to dryness and dried in vacuum.

Yield 100%. Recrystallization from ethanol and ether gave pale green platelets. Melting point: 234-2°C (decomposed).
Mass spectrum: m/e 399 (M+, 100%).

Example 13 Preparation of 2-(N-methylpiverazi/)-4,5-diphenylimidazole hydrochloride 2-(N-methylpiberazino)-4-hydroxy-4,5-diphenyl-
4 days - 3.34 hours of imidazole and 0.33 hours of platinum oxide were treated in the same manner as in Example 7 with 100 doses of methanol to obtain a white powder.

The melting point was 28 mm (decomposition), the yield was 3.43 mm (97%), and recrystallization from ethanol gave pale pink needles. Melting point 2
81°C (decomposition). Mass spectrum, m/e 319 (M+, 100%).

Claims (1)

[Claims] 1 General formula (II) ▲ Includes mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 represent a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom, and Z is an amino group and N・
N-dialkylamino group, N-alkyl-N-aralkylamino group, pyrrolidino group, piperazino group or N-alkylpiperazino group] is characterized by catalytic reduction of 4-hydroxy-4H-imidazoles represented by 2-amino- and 2-(disubstituted amino)-4 represented by the following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc.・5
-Production method of diarylimidazoles.