DEF0013751MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: January 23, 1954 Obtained on July 12, 1956

GERMAN PATENT OFFICE

It has already been proposed that i-aminoacylamino-2-halo-6-alkylbenzenes, which have excellent local anesthetic properties, thereby producing that i-amino-2-halo-6-alkylbenzenes are acylated with low molecular weight aminocarboxylic acids or that the benzene derivatives mentioned are first reacted with low molecular weight halocarboxylic acids and ammonia, primary or secondary amines act on the haloacylamides formed. As Starting material used for this process in Aminobenzenes substituted in the 2-position by halogen and in the 6-position by a lower alkyl radical are described in the literature, but theirs is Manufacture associated with certain difficulties. While the i-amino-2-chloro-6-methylbenzene through Heating the i-Amino ^ -methyl-ö -chlorobenzenesulfonic acid- (4) with 75% sulfuric acid to a higher temperature according to that described in patent 218,370 Process or as a by-product by fractionation of the chlorination of N-acyltoluidine the resulting chlorination mixture can be obtained after appropriate saponification, the representation of i-amino-2-bromo-6-methylbenzene is designed far more difficult.

To describe z. B. Nevile and Winter (Ber. D. Dtsch. Chem. Ges., Vol. 13, p. 1945) the production of the i-Amino-2-bromo-6-methylbenzene in a multi-stage process from 3-acetylamino-5-bromotoluene. Burton, Hammond and Kenner (Journal of the Chemical Society, [London] 1926, p. 1802)

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obtain the same compound in low yield o-nitrotoluene via a mercuration product. Another multi-stage, to i-acetylamino ^ -bromo-ö-methylbenzene The leading process based on 2-nitro-4-aminotoluene is described by Kondo and Ishiwa (Ber. D. German Chem. Ges., Vol. 70 [1937], p. 2436).

It has now been found that i-aminoacylamino-2-halo-6-alkyl-benzenes can be obtained the general formula

NH-CO —R ₉ -N;

Shark

where R _{1 is} a low molecular weight alkyl radical, R _{2 is} a low molecular weight alkylene group, R ₃ and R _{4 are} hydrogen atoms, low molecular weight alkyl radicals, cycloalkyl radicals or aralkyl radicals or together with the nitrogen atom are members of a saturated heterocyclic ring system and Hal a chlorine or bromine atom, if one i-Amino-4-nitro-6-alkylbenzenes halogenated, the resulting i-amino-2-halogen-4-nitro-6-alkylbenzenes' acylated with low molecular weight halocarboxylic acids, the reaction products to i-haloacylamino ^ -halogen ^ -amino-o -alkylbenzenes reduced, the reduction products diazotized, 'deaminated and the i-haloacylamino-2-halo-6-alkylbenzenes thus formed with ammonia or primary: or secondary amines and optionally the i-aminoacylamino ^ -halo-ö-alkyrbenzenes with alkylating agents treated.

Suitable i-amino-4-nitro-6-alkylbenzenes are those which have lower alkyl radicals, such as, for example Contain methyl, ethyl, propyl, isopropyl. The halogen can be chlorine or bromine. The production the i-amino-2-halogen-4-nitro-6-alkylbenzenes is carried out in a manner known per se (cf.e.g. Beilstein, Handbuch der Organischen Chemie, Hptw., Vol. 12, pp. 849 and 851). , 75

Examples of low molecular weight halogen fatty acids are: chloroacetic acid, α-chloro-propionic acid, / I-chloro-propionic acid, α-, β- or γ-chlorobutyric acid and the corresponding bromine or iodine compounds and similar compounds. It is advantageous to use derivatives of halogenated fatty acids, such as acid chlorides, acid anhydrides, acid esters and similar compounds, for the acylation.

As primary or secondary amines, for. B. in question monomethylamine, monoethylamine, 'monopropylamine, monobutylamine, monoisobutylamine, monohexylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, methylbenzylamine, cyclohexylamine and others. Furthermore, hydrogenated, ^I heterocyclic ring systems, z. B. pyrrolidine, piperidine, morpholine, methylpiperidines, into consideration.

The reaction proceeds z. B. according to the following scheme: ■■■■■ '

CH,

O ₉ N

NH ₂

O, N

CH,

CH ₃
H, N -f> -NH-CO-CH ₂ -Cl

NH,

CH, O ₉ N

NH-CO-CH ₂ ■ Cl

-NH-CO-CH, -NH-CH, -CH, -CH, · CH.

2 * V-'Ji-2 ^ ^AJL 2

NH-CO-CH, - Cl

Br

The implementation of the i-amino-2-halogen-4-nitro-6-alkylbenzenes with the haloarboxylic acid derivatives is expedient by heating the components carried out in a solvent or suspending medium.

Aliphatic, for example, can be considered as such or aromatic hydrocarbons such as petroleum ether, benzene, toluene, xylene; chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and others. One can but also without a diluent directly with an excess of, for example, chloroacetic acid chloride work. In these working methods, the hydrogen chloride produced is expelled by heating.

Naturally, in the reduction of the nitro group, those obtained in the first stage of the process are i-Haloacylamino-2-halo-4-nitro-6-alkylbenzenes to choose the conditions so that both the Halogen bonded to the nucleus as well as that of the side chain

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not be reduced with. As a reducing agent come in such a process, for. B. in question Iron + glacial acetic acid, sodium dithionite. Particularly beneficial is the catalytic hydrogenation, which with Raney nickel as a catalyst at room temperature or at slightly elevated temperature, for example at 30 to .35 °, expediently in a solvent, wherein if methanol is advantageously used, is carried out.

The diazotization of the i-haloacylamino-2-halo-4-amino-6-alkylbenzenes obtained can be carried out by the usual methods, for. B. be carried out in an aqueous or alcoholic medium. In the latter case, it is best carried out with isoamyl nitrite, which is added dropwise to a suspension, cooled to 0 °, of the hydrochloride of the corresponding amino compound in a calculated amount in the presence of an excess of alcoholic hydrochloric acid. Deamination can then be carried out by heating the alcoholic solution of the diazonium salt obtained, expediently with the addition of substances which promote deamination, such as formamide and the like. It has proven particularly advantageous to carry out the diazotization in an aqueous solution in the presence of sulfuric acid in the customary manner. It is then followed by the Entaminierung to the i-Halogenacylamino ^ -halo-o-alkyl-benzene smoothly perform when allowed to the cold diazonium salt solution is added dropwise an excess 5o ° / ₀ sodium hypophosphorous acid. The formation of phenolic by-products is kept within narrow limits.

As for the implementation of i-haloacylamino-2-halo-6-alkylbenzenes concerns with primary or secondary amines, it can be both in the presence of even in the absence of diluents at room temperature or at elevated temperature be performed. Examples of diluents which may be mentioned are benzene, toluene and xylene. the Reaction with ammonia is most conveniently carried out in a solvent, advantageously methanol Room temperature or at an elevated temperature. As far as the implementation is still an alkylation should connect, this can be done in a manner known per se, for. B. be carried out with alkyl halides.

It is extremely surprising that the process described in such a smooth reaction and good yield to the i-aminoacylamino-2-haloalkylbenzenes leads, since it is by no means due to the easy mobility of the halogen atoms present it was to be expected that in the reduction of the nitro group and in the diazotization of the diazotized group Compounds the halogen atom is retained.

The compounds prepared by the process of the present invention are excellent Anesthetics. They are characterized by a rapid onset of insensitivity to pain, due to the depth of the anesthesia and its low toxicity.

example

a) To a suspension of 152 g of i-amino-4-nitro-6-methylbenzene in 3 l of water, 168 g of bromine are added dropwise over 45 minutes with vigorous stirring. Stirring is continued for some time, left to stand overnight, filtered off with suction and washed with water. The crude i-amino-2-bromo-4-nitro-6-methyl-benzene obtained is recrystallized from ethanol. It is obtained in long golden needles which melt at 179 ^0th Yield 160g. ■

b) 145 g of chloroacetyl chloride are added to a suspension of 145 g of finely powdered i-amino-a-bromo ^ -nitro-ö-methylbenzene in 2I benzene, and the mixture is heated to boiling under reflux. With the evolution of hydrogen chloride, a clear solution is initially formed, from which crystals separate out after a while. After 1½ hours of boiling, the mixture is cooled and the crystals which have separated out are filtered off with suction. The obtained i- (co-Chloro-acetylamino) -2-bromo-4-nitro-6-methyl-benzene melts at 207 ^0th Yield 183g.

c) 30.6 g of i- (co-chloro-acetylamino) -2-bromo-4-nitro-6-methyl-benzene are dissolved in 1.7 l of methanol and in the presence of Raney nickel at room temperature hydrogenated. After the calculated amount (6.721) of hydrogen has been absorbed, it is filtered from the catalyst and concentrated in vacuo. 18 g of i- (ft> -chloro-acetylamino) -2-bromo-4-amino-6-methyl-benzene are obtained, that melts at 163 to 164 °. By dissolving in methanol and adding to the solution alcoholic hydrochloric acid gives the hydrochloride of the base.

d) 12.6 g of finely ground ι- (ω- chloro-acetylamino-2-bromo-4-amino-6-methylbenzene hydrochloride are suspended in 75 ecm of water to which 5 ecm of concentrated sulfuric acid has been added, while cooling with ice and stirring is allowed to slowly added a solution of 3 g of sodium nitrite in 15 cc of water are added dropwise. the hydrochloride gradually goes into solution. After diazotization is complete, is added dropwise with further stirring, 70 cc 5o ° / ₀ hypophosphorous acid. separates under evolution of nitrogen, a crystalline Precipitate of i- (α> -chloroacetylamino) -2-bromo-6-methyl-benzene, which is filtered off with suction after standing overnight in the refrigerator and washed with water. Yield 10 g, melting point 136 to 137 ^0. After recrystallization of a sample from isopropyl alcohol this melts at 143 °.

e) 10 g of the crude i- (ca-chloroacetylamino) -2-bromo-6-methyl-benzene are dissolved in 100 ecm of n-butylamine. Mild warming occurs. The mixture is left to stand overnight, the excess butylamine is distilled off in vacuo and the residue is shaken with a mixture of. Ether and caustic soda. The ether solution is dried with potassium carbonate and concentrated. The residue of i- (butylaminoacetylamino) -2-bromo-6-methylbenzene obtained is triturated with 2N hydrochloric acid. The crystals obtained are recrystallized from a little water using animal charcoal. 12 g of i- (butylamino-acetylamino) -2-bromo -6-methylbenzene hydrochloride are obtained. The melting point of the pure substance is 221 ⁰ .

Claims (1)

PATENT CLAIM: Process for the preparation of basic substituted carboxamides of the general 609 549/498 formula NH-CO-R ₂ -N; Hal F 13751 IVb / 12q , R, R ₄ ίο where R _{1 is} a low molecular weight alkyl radical, R _{2 is} a low molecular weight alkylene group, R ₃ and R _{4 are} hydrogen atoms, low molecular weight alkyl radicals, cycloalkyl radicals or aralkyl radicals or, together with the nitrogen atom, are members of a saturated heterocyclic ring system and Hai are a chlorine or bromine atom, characterized in that that i-amino-4-nitro-6-alkylbenzenes are halogenated, the i-amino-2-halogen-4-nitro-6-alkylbenzenes obtained are acylated with low molecular weight halocarboxylic acids, the reaction products are converted to i- (haloacylamino) -2-halogen- 4-amino-6-alkylbenzenes reduced, the reduction products diazotized, deaminated and the i- (haloacylamino) -2-halo-6-alkylbenzenes thus formed are reacted with ammonia or primary or secondary amines and the i- (amino-acylamino) - 2-halo-6-alkylbenzenes optionally treated with alkylating agents. © 609 549 / Φ98 7.56