DE890644C - Process for the preparation of derivatives of imidazole - Google Patents

Description

It is known that derivatives of benzimidazoles which are an alkylaminoalkyl radical in the i-position and an alkylaminoalkyl radical in the 2-position contain a hydrocarbon residue (J. Am. Chem. Soc. 71, 2035 [1949]), only such a low spasmolytic Effect (especially on the smooth muscles of the warm-blooded animal that are contracted by histamine) show that they are of no importance for practical therapy. The same applies to benzimidazole derivatives, which contain a basic substituted alkyl radical in the 2-position, those in the i-position but are not substituted, i.e. only carry one hydrogen atom (J. org. Chemistry 6, 25-35, Jan. 1941, Philadelphia).

All the more surprising was the finding that condensed imidazole derivatives, which are in the i-position substituted or unsubstituted aralkyl, aryl or heterocyclic radical or heterocyclic substituted Alkyl radical and in the 2-position one or more basic N atoms, be it primary, secondary or tertiary nature, contained by a straight, branched, non, single or multiple by heteroatoms interrupted carbon chain or by residues of hydroaromatic or heterocyclic nature with linked to the imidazole nucleus, show interesting pharmacological effects, e.g. B. at very low Toxicity have an antispasmodic effect on smooth muscles, some of them ineffective best practically used antiallergic compounds equal or with reference to the Index, d. H. the ratio of the effective dose to Dl 50, even far exceed it. Draw the new connections are also characterized by a particularly strong adhesion, which is advantageous for a protracting effect is. The connections are also via the

Imidazole ring in 4,5-position with an unsubstituted one or substituted aromatic, hydroaromatic or heterocyclic ring system condensed.

For comparison with known compounds it should be mentioned that, for. B. for the hydrochloride of i-benzyl-2- (dimethylaminomethyl) benzimidazole in the white mouse, the Dl 50 is 10 mg per 20 g mouse, while 0.6 mg of the substance is sufficient to induce bronchial asthma in guinea pigs Histamine spray to prevent. In contrast, z. B. the corresponding doses of the hydrochloride of 2- (N-phenyl-N-benzylaminomethyl) -imidazoline 3.36 mg or 1.05 mg, so the index in the first case ι: 17, but in the second case only 1: 3 , 2. The ι - (p - chlorobenzyl) - 2 - (pyrrolidylmethyl) benzimidazole shows an effect in the asthma test that is about 5 times superior to the first mentioned.
Various preparation methods can be used to prepare these imidazole derivatives which are basically substituted in the 2-position and are described in more detail above. You can B. start from aromatic, hydroaromatic or heterocyclic compounds that carry a halogen atom and a nitro group on two adjacent carbon atoms. These o-halonitro compounds can be reacted with aminoaryl (e.g. aniline or toluidine), aminoaralkyl (e.g. benzylamine) or amino-substituted, heterocyclic (e.g. 2-aminomethylthienyl) compounds. Instead of o-nitrohalogen compounds, suitable esters of o-oxynitro compounds, such as. B. the p-toluenesulfonic acid ester, can be used for the reaction with the amino compounds. Of course, this reaction can also be carried out with o-halonitro derivatives, which can contain any other substituents in addition to these two substituents, and the aforementioned aminoaryl, aminoaralkyl or amino-substituted heterocyclic compounds used for the reaction can also contain further substituents, preferably halogen, Alkyl or alkoxyl radicals.

The compounds formed in this way now contain a nitro group in the o-position an aralkylamine, arylamino or heterocyclically substituted amino group, in which one after it Conventional methods convert the nitro group into an amino group. .

For the preparation of the desired imidazal derivatives which are basically substituted in the 2-position, one can now " proceed in such a way that the resulting o-diamino compounds are converted into corresponding imidazole compounds with such basic substituted, aliphatic, hydroaromatic or heterocyclic compounds converts which still contain suitable reactive substituents for ring closure, such as. B. Carboxyl, acid chloride, acid anhydride, acid ester, aldehyde, acid amide or amidine groups.

You can also use compounds of the type marked above for ring closure, which are next to a another substituent suitable for ring closure, primary or secondary to ammonia Amine or diamine exchangeable group, e.g.

Halogen atoms or imido ethers contain, so that one or more amine radicals are thus in this way only secondary with that already in the 2-position on the imidazole compound linked to a seated bridge or creates it.

But you can also proceed in such a way that you start from o-nitroamino compounds. With the amino group are aryl, aralkyl or heterocyclic or a heterocyclic ring by conventional methods containing residues, e.g. B. linked via the corresponding halogen compounds; of course you can Starting material such as linking components, as described above, also here if appropriate Contain substituents of various kinds. The resulting amino-substituted o-nitro compounds are now further converted into the desired end products in accordance with the description given above.

It is of course also possible as a starting material for the synthesis of such imidazole derivatives starting from o-diamino compounds and converting them into such o-diamino compounds, which is aryl, aralkyl or heterocyclic substituted in only one amino group in the manner indicated above are. These can then be converted into the corresponding ring closure methods described above Imidazole derivatives are converted, go

It is also possible to obtain such 1,2-substituted imidazole derivatives to arrive by first following the o-diamino compounds according to the above Methods converted into 2-substituted imidazole derivatives and then subsequently the hydrogen on i-nitrogen by aryl, aralkyl or heterocyclic or a heterocyclic ring containing Rebte substituted.

example 1

23 g of N-benzyl-2-nitroaniline (produced, for example, according to Kehrmann and Tichwinsky [Liebigs Ann. Chem. 290, 293] from o-nitrochlorobenzene and benzylamine) are mixed with 0.315 mol of tin chloride, 95 ecm of concentrated hydrochloric acid is added and the Mixture kept warm on the steam bath for 15 minutes. After cooling, 50% sodium hydroxide solution is added to 390 cc, which is in an amount of from 94 ° / ₀ of theory oily separates o-amino-N-benzyl-aniline is still separated hot, boiled in ligroin addition of some carbon, filtered and brought to crystallization. The base is obtained as white crystals with a melting point of 54 °.

The imidazole ring closure is carried out by boiling in 5N hydrochloric acid with monochloroacetic acid. In a solution of 60 g of monochloroacetic acid in 400 cc of 5 η-hydrochloric acid 80 g of o-aminobenzylaniline entered and 3 ¹ Z boiled for ₂ hours under reflux. Under ice-cooling 66 ° / ₀ of theory of falling out of i-benzyl-2-chloromethyl-benzimidazole hydrochloride crystalline. Another 20 ° / ₀ is obtained from the mother liquor by blunting the free hydrochloric acid contained in it and the rest of monochloroacetic acid. The hydrochloride recrystallized from dioxane sinters at 165 °; it is difficult in water, easily soluble in alcohol, and causes a severe stinging sensation on the skin. The free base

shows an F. of in ⁰ (from ligroin), in alcohol it is difficult, easily soluble in benzene, at 140 ^{0 it} begins to decompose.

26.5 g of 1-benzyl-2-chloromethyl-benzimidazole base are stirred with 25 g of benzene and poured over with 100 g of dimethylamine, dissolved in 200 ecm of benzene, with mild warming occurring. After refluxing for some time, the solution is used to remove the remaining dimethylamine and dimethylamine chlorohydrate formed filtered and extracted with water.

When the benzene solution is drawn out with dilute hydrochloric acid, the hydrochloride of i-benzyl-2-dimethylamino-methyl-benzimidazole is then obtained in the form of rosettes which can be recrystallized from aqueous acetone or from butanol. The melting point is between 210 and 214 ^0, depending on the rate of heating. Slight decomposition occurs with elimination of dimethylamine.

Analogously, the chlorohydrates of i-benzyl-2-diethylaminomethyl-benzimidazole, plates from F. 144 to 146 ⁰ , i-Benzyl-2-pyrrolidylmethyl-benzimidazole, tablets or needles from 192 to 193 °, i-benzyl-2-n-butylaminomethyl-benzimidazole, tablets from 194 to 196 ⁰ , and i-benzyl- 2- (dimethylaminoäthylmethylamino-methyl) -benzimidazole, picrate F. 182 ⁰ , obtained.

Example 2

22.5 g of o-nitrochlorobenzene be 49.3 g p-anisidine and 11.7 g of sodium acetate by heating to 210 I4stündiges converted to 215 ^0th Crystallize from ethanol 24.4 g of o-nitro-N- (p-methoxyphenyl) -aniline, mp 86-87 ⁰ in the form of red crystals.
22 g of o-nitro-N- (p-methoxyphenyl) -aniline are reduced in 100 ecm of methanol, 100 ecm of ethyl acetate and 5 ecm of water with Raney nickel and hydrogen at room temperature. It will arise 19.1 g of o-amino-N- (p-methoxyphenyl) -aniline, either equal to or after recrystallisation from ligroin, from which they precipitate is dyed in the form of pale pink flakes, mp 56-57 ^0, processed can.

15 g of o-amino-N- (p-methoxyphenyl) aniline are refluxed for 4 hours with 10 g of monochloroacetic acid and 70 ecm of 5N hydrochloric acid. After cooling, the oily chlorohydrate of i- (p-methoxyphenyl) -2-chloromethyl-benzimidazole is converted with bicarbonate into the base (17.2 g) and this is converted into the base (17.2 g) from methanol with the addition of a little carbon in the form of a light purple powder from 130 to 135 ° C.

2 g of i- (p-methuxyphenyl) -2-chloromethyl-benzimidazole are stirred with 2 ecm of benzene and heated with 1.3 g of pyrrolidine on a water bath for 2 hours. After diluting with benzene and shaking with water, the benzene is evaporated off; the residue recrystallized from ligroin gives 0.7 g of i- (p-methoxyphenyl) -2-pyrrolidylmethylbenzimidazole needles with a melting point of 110 to 112 ⁰ , easily soluble in ether, alcohol and benzene.

Claims (1)

PATENT CLAIM: Process for the preparation of derivatives of imidazole which are unsubstituted in the 1-position or substituted aryl, aralkyl or heterocyclic radical or a heterocyclic radical substituted alkyl radical and in the 2-position one or more basic N atoms, be it primary, secondary, dary or tertiary nature, contained by a straight, branched, not, single or multiple by Heteroatoms interrupted carbon chain or by residues of hydroaromatic or heterocyclic Nature are linked to the imidazole nucleus and at the same time via the imidazole ring in 4,5-position with an unsubstituted or substituted aromatic, hydroaromatic or heterocyclic Ring system are condensed, characterized in that one a) aromatic, hydroaromatic or heterocyclic compounds which _{carry a halogen atom and an NO 2} group on two adjacent carbon atoms or converts suitable esters of corresponding o-oxynitro compounds with primary aromatic or araliphatic amines or amino-substituted heterocyclic compounds, the nitro group and the resulting monosubstituted o-diamines with basic substituted compounds which still contain substituents suitable for ring closure are condensed to imidazoles or the monosubstituted o-diamines are condensed with such compounds to form imidazoles which, in addition to the substituents suitable for ring closure, have further, e.g. . B. halogen atoms or imido ethers, which you then with ammonia, primary or secondary amines , or allows diamines to react with the formation of imidazoles which are basically substituted in the 2-position; or that one b) substituted the amino group of o-nitroaminoverbindungen, then the nitro group for Amino group is reduced and the resulting o-diamino compounds are treated further according to a); or that one c) starts from o-diamino compounds, one of the two amino groups through an aryl, aralkylode'r substituted and substituted heterocyclic radical or a heterocyclic radical containing alkyl radical then makes the ring closure; or that one d) o-diamino compounds initially in imidazole derivatives transferred and then the hydrogen on the nitrogen in the i-position of the imidazole ring by an aryl, aralkyl or heterocyclic radical or containing a heterocyclic radical Substituted alkyl. 1 9526 6.54