CS199633B2 - Method of producing n-cyclohexyl-n-methyl-n-/2-amino-3,5-dibrombenzyl/amine - Google Patents

Abstract

For the preparation of N-cyclohexyl-N-methyl-N-(2-amino-3,5-dibromobenzyl)amine, 3-bromo-2-nitrobenzyl bromide is used as a starting substance and is reacted with N-methylcyclohexylamine in the presence of an acid acceptor. The nitro group of the resultant N-cyclohexyl-N-methyl- 2-nitro-3-bromobenzylamine is then reduced and the resulting N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine is brominated. This process enables the preparation of this compound in a simple manner with a yield of more than 80%. The compound has excellent bronchosecretolytic action and can be used in the therapy of chronic, non-specific disorders of the airways.

Description

The invention relates to a method. Preparation of N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of formula I

and its addition salts with inorganic and organic acids.

The compound of formula I has an excellent bronchosecretolytic effect and is used in chronic therapy. non-specific respiratory diseases.

Of the known processes for preparing N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibroin-benzyl) amine, only a few are suitable for industrial use. In one known industrial process, starting from o-nitrobenzyl bromide, which is reacted with N-methylcyclohexylamine, followed by reduction and substitution with bromine at the 3,5-position of the aromatic ring, the resulting product is obtained. The accumulation yield is only 38.5%, the total synthesis yield 32%; the way is not. thus too economical (DT-PS 1 169 939). A further disadvantage of the described process is that the o-nitrobenzyl bromide used as starting material is harmful to health and severely irritating to the eyes.

According to another known process, 3,5-dibromo-2-aminotoluene is diacetylated, followed by conversion of N-bromosuccinimide to 3,5-dibromo-2-diacetaminobenzylbronide, which is reacted with N-methylcyclohexylamine and finally acid hydrolysis. saline gives the resulting product (DT-PS 1 169 939). N-bromosuccinimide bromination yields a 16% yield, with a total yield of this highly uneconomical process of 7%. Also, 3,5-dibromo-2-diacetaminobenzyl bromide has a strong eye attack and, in addition, is only suitable for producing a sufficiently pure final product after four to six times recrystallization.

According to another known process, the starting material is acid. The acid amide is then prepared via its chloride by reaction with N-methylcyclohexylamine. N-methyl-N-cyclohexyl-o-nitrobenzoic acid, the nitro group of which is converted by reduction according to Bechamp. to an amino group. Subsequently, the aromatic nucleus at the 3,5-position is substituted with bromine and finally the oxo group is reduced with hydride

199133

199833 lithium aluminum (published in the Netherlands patent application 64 03.356). The overall yield of this synthesis was 24%. Another disadvantage is the use of lithium aluminum hydride, which is a constant source of fire and explosion hazards.

Overall, none of the known processes is suitable for the economic industrial production of the compounds of the formula. AND.

It has now been found that N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine is very simple and easy to produce in more than 80% yield by 3-bromo-2. -nitrobenzyl bromide of formula II

CH ^£ Br

NOl (IV

is converted by reaction with N-nethylcyklohexylaminem the presence 'of an acid acceptor N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine of the formula III ^»3 / ~ \ r ^ r ^ ^c <7

8n dm whose nitro group is reduced to give the N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine of formula IV

is brominated.

Reaction of 3-bromo-2-niobenzyl bromide. of the formula II is carried out in the presence of an acid acceptor at 60 to 110 ° C, preferably 70 to 80 ° C. Suitably, aliphatic or aromatic hydrocarbons are used as reaction medium or solvent. chlorinated hydrocarbons or aliphatic alcohols. Like aliphatic alcohols. Suitable bases are all bases which do not enter into side reactions with the starting materials. Preferably, an excess of N-methylcyclohexylamine is used for this purpose, which is recovered from the resulting N-methylcyclohexylamine hydrobromide and recycled to the production process.

The N-Cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine of formula III is reduced in a manner known per se to give the amino compound of formula IV. The reduction is preferably carried out with the hydrosinhydrate in cooperation

Raney nickel as a catalyst in alcohol

C 1 -C 4 as the reaction medium or - but in the hydrochloric acid medium - with tin or zinc chloride as the reducing agent. The reduction is generally carried out at a temperature of 15 to 25 ° C, optionally using cooling, expediently with some delay after the reaction. To accelerate the reaction, in certain cases, it is advantageous to work at elevated temperatures, for example 60 to 100 ° C.

N-Cyclohexyl-N-methyl-2-amino-3-bromobenzylamine is converted to elemental bromine. For example, chlorinated aliphatic hydrocarbons, alcohol ether mixtures or glacial acetic acid can be used as reaction medium or solvents. Sodium acetate or inorganic bases such as sodium or potassium carbonate are suitable as acid acceptors. The bromination is carried out at a temperature of 10 to 25 ° C, optionally under cooling. To accelerate the reaction, it is recommended to complete the reaction at elevated temperature, e.g. 60 ° C.

N-Cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine can also be isolated directly in the form of the bromination resulting from bromination.

However, according to the invention it is also possible to release the base of the formula I directly in the reaction mixture of the bromination reaction. The base may optionally be converted into addition salts by reaction with inorganic or organic acids. Further, according to the invention, the compound of formula I can be released from an acid addition salt and converted to another acid addition salt.

According to one preferred embodiment of the process according to the invention, the N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine of formula IV is brominated after reduction without continuous isolation.

In another preferred embodiment of the process of the invention, N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine is converted to an acid addition salt and reacted in this form with elemental bromine.

^3-Bromo-2-ι nilгoben bromide, used as starting material, and · that the intermediates as well as process of the invention is a new compound, is obtained from 3-bromo-2-nitrotoluene by reaction with N-bromosuccinimide.

According to the invention, the 3bromo-2-nitrobenzyl bromide of formula II is converted by reaction with N-methylcyclohexylamine in the presence of an acid acceptor to the N-cyclohexyl-N-methyl-4-methyl-5-bromobenzylamine of formula III which is reduced to the nitro group; the obtained N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine of formula IV is brominated with elemental bromine either directly in the reaction mixture or after isolation in the form of an acid addition salt to the compound of formula I which optionally isolated in the form of its acid addition silage.

According to a particularly preferred embodiment of the process according to the invention, an excess of N-methylcyclohexylamine is used as the acid binder.

According to one advantageous. The process according to the invention is like. · The reducing agent used hydrazine hydrate together with Raney nickel catalyst.

· In another preferred embodiment of the invention is used as a reducing agent tin in hydrochloric acid medium. · - <··· ·, · ^··: '- ··' - ·. ·

The reaction process of the process according to the invention is readily feasible industrially. The process is extremely economical since the yield of the resulting product - based on the 3-bromo-2-nitrobenzyl bromide starting material II - is more than 80%

In contrast to the benzyl bromide derivatives used according to the known methods, the starting compound of the formula II is not harmful to health.

The essence of the invention is apparent from several examples given below.

She said dl

and)

14.5 g (0.049 mol) of 2-nitro-3-bromobenzyl bromide are dissolved in 100 ml of anhydrous benzene and added with stirring to the solution 11.2 g (0.098 mol) of N-methylcyclohexylamine in 50 ml of anhydrous benzene. The reaction mixture was boiled for 5 hours, cooled, and the precipitated mixture was filtered off. The excreted N-methylcyclohexylamine hydrobromide yields N-methylcyclohexylamine with 85% efficiency. The filtrate is extracted with 100 ml of water and then dried over calcined magnesium sulphate. Evaporation gave 16 g of crude product which was recrystallized from benzylamine as yellow crystals (m.p. = 82%) of N-cyclohexyl-N-methyl-2-nitro-3-bromoate from 50 ml of ethanol. This gave 14.7 g (95-61 ° C). The melting point of the hydrobromide is 223-226 ° C. .

Analysis for C 19 H 19 N 2 O 2 Br (mol mass 327.21):

calculated:

. % C, 51.39;% H, 5.85% o / o;

8.56 Oo N, found:

51.61 ° / o C, 6.08 o / o H, 24.75 o / ₀ Br,

8.64% N.

(b)

3.27 g (0.01 mol) of N-cyclohexyl-N'-methyl-2-nitro-3-bromobenzylamine are dissolved in 20 ml of methanol. 0.3 g of Raney nickel suspended in 10 ml of methanol are added to the solution, and then 1.25 g (0.0? 5 mol) of hydrazine hydrate in 10 ml of methanol is added dropwise with stirring. The mixture was boiled for one hour, then cooled, the catalyst was filtered off and the solvent was evaporated. After the reaction, 2.9 g of N-cyclotinyloxy-N, N-methyl-2- (4-methyl-2-amino-3-bromobenzylamine) remained in the form of a greenish oil, corresponding to a yield of 97 to 99%. p-toluenesulfine having a melting point of 187-198 degrees Celsius.

Analysis calculated for C18H18N3O5SBr (mol. Mass 469.43): calcd. -—

% C, 53.73;% H, -6.22; 6.83% S ,.

found::, /

C, 54.45; H, 6.72; N, 5.54; S, 7.13%.

c) ... ·

5.9 g (19.9 mol) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine. and 1.63 g (19.9 mol) of anhydrous sodium acetate are dissolved in 90 ml of glacial acetic acid and, while cooling, 3.18 g (19.9 mol) of bromine in 10 ml of glacial acetic acid are added dropwise. A yellow precipitate is formed. The reaction mixture was then heated in a water bath at 60 ° C for 2 hours, then poured into 150 ml of water and cooled. alkaline - 840 ml of 10% sodium hydroxide solution. The mixture was then extracted twice with chloroform (250 ml each). The combined chloroform phases are dried, clarified and evaporated. The residue (6.9 g, 91.5%) is dissolved in 30 ml of ethanol and N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride is precipitated with ethereal hydrochloric acid. . Yield 7.2 g (87.7%). Melting point: 242 to 250 DEG C. 245 ° C.

Analysis for C 14 H 21 N 2 Br 2 Cl (mol. Mass 412.619):

calculated:

40.75 ° C, 5.13% H, 38.73% Br, <

8.59% Cl, 6.69% N, found:

40.39 ° C, 5.27% H, 38.34% Br, 8.63 ° C, 6.71% N.

from the base can be. prepare the following salts using the appropriate acids:

perchlorate melting point 132-134 ° C oxalate melting point 181-183 ° C hydrobromide melting point 227-228 ° C

The 3-bromo-2-nitrobenzyl bromide used as starting material is prepared as follows:.

32.4 g (0.15 mol) of 3-bromo-4-aminotoluene are dissolved in 200 ml of anhydrous carbon tetrachloride and 25.5 g (0.143 mol) of N-bromosuccinimide and 1 g of dibenzoyl peroxide are added. The reaction mixture was then boiled for 16 hours. The precipitated succinimide is filtered off, the filtrate is evaporated, the residue is saturated with 80 ml of petroleum ether (b.p. 40-70 ° C) and left to crystallize at 0 ° C. The product melts at 91-93 ° C. The mother liquor from the crystallization was evaporated and the remaining 25.0 g of oil was brominated again. Thus a total yield of 55.0 / _0th

Analysis for C 7 H 8 NO 2 Br (MW 294.95):

calculated:

28.50 o / o C, 1.66% H, 54.20% Br, 4.74 θ / ο N, found:

28.91% C, 1.90 θ / ο H, 54.91% Br, 4.70% N.

Example 2

3.27 g (0.01 mol) of N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine,. prepared according to Example 1a), 6 g of tin powder (0.05 mol) and 16 ml of water are mixed and 16 ml of concentrated aqueous hydrochloric acid are added dropwise with stirring. The bleached reaction mixture was boiled in a water bath for 2 hours, then cooled to room temperature, decanted and basified with 20% aqueous sodium hydroxide. Alkaline solution. The mixture is extracted twice with chloroform (50 ml each) of the combined organic phase, dried over anhydrous magnesium sulphate and the solvent is evaporated off. 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine are obtained, from which, according to the method of Example 1c), N-cyclohexyl-N-methyl-N- ( 2-amino-3,5-dibromobenzyl) amine.

Example 3

From N-cyclohexyl-N-methyl-3-bromo-2-aminobenzylamine prepared according to the method of Example 1b), the hydrochloride is prepared in an ethanol medium by introducing dry hydrochloric acid gas. The product is hygroscopic so that its melting point varies between 100 and 120 ° C (with simultaneous decomposition).

g. (3 millimoles) of (N -cyclohexyl-NH-methyl-3-bromo-2-aminobenzylamine hydrochloride) and 0.5 g (6 millimoles) of anhydrous sodium acetate are dissolved in 20 ml of glacial acetic acid and 0.25 ml ( 4 millimoles of bromine in 5 ml of glacial acetic acid The mixture was heated with stirring in a water bath at 60 DEG C. for 2 hours, after cooling, treated with 50 ml of water and basified with concentrated ammonia, then extracted twice with concentrated ammonia (70 ml each). The ethereal phase is dried over potassium hydroxide and finally evaporated, the residual oil (1.1 g) is dissolved in 20 ml of ethanol and N-cyclohexyl-N-methyl-N1 (2-amino-1,3,5-dibromobenzyl) hydrochloride is precipitated from the solution. The crude product obtained was crystallized from ethanol to give 0.95 g (70%), mp 242-244 ° C.

Claims (4)

the subject of the invention A process for the preparation of an N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of formula I, converted by reaction with N-methylcyclohexylamine, in the presence of an acid acceptor, to Ncyclohexyl-N-methyl-2-nitro- 3-Bromobenzyl amine (III) and its addition salts with inorganic and organic acids, characterized in that 3-bromo-2-nitrobenzyl bromide (II) CH 2 Br NO ^ Ulη (U1 whose nitro group is reduced and the resulting N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine of formula IV is brominated with elemental bromine either directly in the reaction mixture or after isolation in the form of an acid addition salt to the compound of formula I, which is optionally isolated in the form of its acid addition salt. 2. Process according to claim 1, characterized in that an excess of N-methylcyclohexylamine is used as acid acceptor. O Process according to either of Claims 1 and 2, characterized in that hydrazine hydrate is used as reducing agent together with Raney nickel. 4. The process according to claim 1, wherein the reducing agent is tin in hydrochloric acid solution.