CH622488A5 - Process for the preparation of N-cyclohexyl-N-methyl-N-(2-amino-3,5-dibromobenzyl)amine - Google Patents

Description

The invention relates to a new process for the preparation of the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine corresponding to the formula (I) and its acid addition salts formed with inorganic or organic acids

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Br

<I)

The compound of formula (I) has an excellent bronchosecretolytic effect and is used in the therapy of chronic, non-specific diseases of the airways.

Of the processes known for the preparation of the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine, only a few are suitable for the industrial production of this compound. According to one of the known industrial processes, the starting point is o-nitrobenzyl bromide, which is reacted with N-methylcyclohexalamine and, after subsequent reduction and dibromination of the aromatic ring in the 3,5-position, the end product is obtained. The yield of the 35 bromination is only 38.5%, the total yield of the synthesis 32%; the process is therefore not very economical (DE-PS No. 1 169 939). Another disadvantage of the described method is that the o-nitrobenzyl bromide used as the starting material is harmful to health 40 and is very irritating to the eyes.

According to another known process, 3,5-di-bromo-2-aminotoluene is diacetylated, then reacted with N-bromosuccinimide to give 3,5-dibromo-2-diacetaminobenzylbromide, this is reacted with N-methylcyclohexylamine and 45 finally hydrochloric acid hydrolysis, the end product (DE-PS No. 1 169 939). The bromination with N-bromosuccinimide gives a yield of 16%, the overall yield of this extremely uneconomical process is 7%. The 3,5-dibromo-2-diacetaminobenzyl bromide also strongly attacks the eyes 50 and, moreover, is only suitable for producing a sufficiently pure end product after it has been recrystallized four to six times.

In a further known process, it is assumed that o-nitrobenzoic acid is used, from which the N-methyl-N-cyclohexyl-o-nitrobenzoic acid amide, the nitro group of which is produced by Bechamp, by reaction with N-methylcyclohexylamine Reduction converted into the amino group, then the aromatic ring di-brominated in the 3,5-position and finally the oxo group reduced with lithium aluminum-60 umhydrid (Dutch patent application no.

64 03 356). The overall yield of this synthesis is 24%. Another disadvantage is the use of lithium aluminum hydride, which is a constant source of danger (fire and explosion).

65 In summary, it can be stated that not a single of the known processes for the industrial production of the compound of formula (I) is economically suitable.

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622 488

It has now been found that the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine can be prepared in more than 80% yield in a very simple, easy to carry out manner, by using 3-bromo-2-nitrobenzyl bromide of the formula (II)

ch2 Br

(II)

in the presence of an acid acceptor with N-methylcyclohexylamine, reacting the nitro group of the resulting N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine of the formula (III)

CH-

-ur tili)

reduced and the N-cyclohexyl-N-methyl-2-ami-no-3-bromobenzylamine obtained of the formula (IV)

CH-,

CBL-S -

çc;

(IV)

Br brominated.

The reaction of the 3-bromo-2-nitrobenzyl bromide of the formula (II) with N-methylcyclohexylamine is preferably carried out at 60-110 ° C. in the presence of an acid acceptor. Aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons or aliphatic alcohols are expediently used as the reaction medium or solvent. All bases which do not undergo any side reactions with the starting materials are suitable as acid acceptors. The excess of N-methylcyclohexylamine is preferably used as the acid acceptor. The amine can be recovered from the N-methylcyclohexylamine hydrobromide formed and returned to the process.

The N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine of the formula (III) is reduced in a manner known per se, the amino compound of the formula (IV) being obtained. The reduction is preferably carried out with hydrazine hydrate using Raney nickel as a catalyst in a C 1 -C 4 alcohol as the reaction medium or in a hydrochloric acid medium with tin or tin (II) chloride as the reducing agent. The reduction is generally carried out at 15-25 ° C., optionally using cooling, advantageously with a certain post-reaction time. In some cases, however, to accelerate the reaction, it may also be advantageous to work at a higher temperature, for example at 60-100 ° C.

The N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine is reacted with elemental bromine to the end product. Chlorinated aliphatic hydrocarbons, alcohol-5 ether mixtures or glacial acetic acid, for example, can be used as the reaction medium or solvent. Sodium acetate or inorganic bases, for example sodium carbonate or potassium carbonate, are expediently used as the acid acceptor. The bromination is preferably carried out at 10-25 ° C., if necessary with cooling, and the mixture is expediently allowed to react further, if desired to accelerate the reaction at elevated temperature, for example at 60 ° C.

The N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine can also be isolated directly in the form of the hydrobromide formed in the bromination. According to the invention, however, the base of the formula (I) can also be released directly in the reaction mixture of the bromination reaction. If desired, the base can be reacted with inorganic or organic acids and isolated in the form of its acid addition salt. Furthermore, according to the invention, the compound of formula (I) can be released from one of its acid addition salts and converted to another acid addition salt.

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

According to another preferred embodiment of the process according to the invention, the N-cyclohexyl-N-me-30 thy] -2-amino-3-bromobenzyl] amine is converted to the acid addition salt and is reacted in this form with elemental bromine.

The starting 3-bromo-2-nitrobenzyl bromide - which, like the intermediaries of the process according to the invention, is a new compound - is prepared from 3-bromo-2-nitrotoluene by reaction with N-bromosuccin imide.

Accordingly, the procedure according to the invention is such that 3-bromo-2-nitrobenzyl bromide of the formula (II) is reacted with N-methyl-cyclohexylamine in the presence of an acid binder, the N-cyclohexyl-N-methyl-2-nitro-3-bromo obtained -benzylamine of the formula (III) reduced and the 'N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine obtained expediently without prior isolation and, if desired, after 45 conversion into an acid addition salt with elemental bromine to give the compound of the formula (I ) which, if desired, is isolated in the form of an acid addition salt formed with organic or inorganic acids.

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

In a preferred embodiment of the process according to the invention, hydrazine hydrate 55 is used as the reducing agent together with Raney nickel as the catalyst.

According to another preferred embodiment of the method according to the invention, tin is used as the reducing agent in a hydrochloric acid medium.

The reaction steps of method 60 according to the invention can easily be implemented industrially. The process is extremely economical, its yield of target compound, based on the starting material 3-bromo-2-nitrobenzylbromid of formula (II), is more than 80%.

In contrast to the benzylbro-mid derivatives used in the known processes, the starting compound of the formula (II) is not harmful to health.

The invention is illustrated by the following examples.

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622 488

example 1

a) 14.5 g (0.049 mol) of 2-nitro-3-bromobenzyl bromide are dissolved in 100 ml of anhydrous benzene and, while stirring, 11.2 g (0.098 mol) of N-methylcyclohexylamine in 50 ml of anhydrous benzene are added. The reaction mixture is boiled for 5 hours, then cooled and the salt which has separated out is filtered off. The N-methylcyclohexylamine can be recovered with 85% efficiency from the excreted N-methylcyclohexylamine hydrobromide. The filtrate is extracted with 100 ml of water and then dried over annealed magnesium sulfate. After evaporation, 16 g of crude product are obtained. This is recrystallized from 50 ml of ethanol. 14.7 g (82%) of N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine, which melts at 59-61 ° C., is obtained in the form of a yellow crystalline product. The melting point of the hydrochloride is 223-226 ° C.

Analysis for C14H19N202Br (M = 327.21)

Calc .: C 51.39 H 5.85 Br 24.42 N 8.56% Found: C 51.61 H 6.08 Br 24.75 N 8.64%

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 1.25 g (0.025 mol) of hydrazine hydrate in 10 ml of methanol are then added dropwise with stirring. The mixture is boiled for one hour then cooled, the catalyst removed by filtration and the solvent evaporated. 2.9 g of N-cyclohexyl-N-methyl-2-ami-no-3-bromobenzylamine are obtained as a residue in the form of a greenish oil. This corresponds to a yield of 97-99%. The compound is identified in the form of its p-toluenesulfonic acid salt, the melting point of which is 187-189 ° C.

Analysis for C21H29N203SBr (M = 469.43)

Calc .: C 53.73 H 6.22 N 5.97 S 6.83% 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 mmol) of anhydrous sodium acetate are dissolved in 90 ml of glacial acetic acid and added 3.18 g (19.9 mmol) of bromine in 10 ml of glacial acetic acid were added dropwise to the solution while cooling with ice. A yellow precipitate is eliminated. The reaction mixture is heated on a 60 ° C water bath for two hours, then poured into 150 ml of water and made alkaline with 840 ml of 10% sodium hydroxide solution while cooling. The mixture is extracted twice with 250 ml of chloroform. The combined chloroformic phases are • dried, clarified and evaporated. The remaining 6.9 g (91.5%) oil are dissolved in 30 ml of ethanol and the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride with ethereal hydrochloric acid failed. Yield: 7.2 g (87.7%). Melting point: 242-245 ° C.

Analysis for C14H21N2Br2Cl (M = 412.69):

Calc .: C 40.75 H 5.13 Br 38.73 CI 8.59 N6.69% Found: C 40.39 H 5.27 Br 38.34 Cl 8.63 N6.71% From the base the following salts can also be prepared with the corresponding acids:

Perchlorate mp: 132-134 ° C

Oxalate mp: 181-183 ° C

Hydrobromide mp: 227-228 ° C The 3-bromo-2-nitrobenzyl bromide used as the starting material is produced as follows:

32.4 g (0.15 mol) of 3-bromo-2-nitrotoluoI 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 to the solution. The reaction mixture is then boiled for 16 hours. The succinimide which has separated out is filtered off, the filtrate is evaporated, the residue is taken up in 80 ml of petroleum ether (bp: 40-70 ° C.) and crystallized at 0 ° C. 10.4 g of 3-bromo-2-nitrobenzyl bromide are obtained. The product melts at 91-93 ° C. The mother liquor from the crystallization is evaporated and the remaining 25.0 g of oil are brominated again. The overall yield in this way is 55.0%.

Analysis for C7HsN02Br (M = 294.95):

Calc .: C 28.50 H 1.66 Br 54.20 N 4.74% Found: C 28.91 H 1.90 Br 54.91 N 4.70%

Example 2

3.27 g (0.01 mol) of the N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine prepared according to Example 1, point a) are mixed with 6 g of tin powder (0.05 mol) and 16 ml of water are added and 16 ml of concentrated aqueous hydrochloric acid are added dropwise to the mixture with stirring. The decolorized reaction mixture is boiled on a water bath for 2 hours, then cooled to room temperature, decanted and made alkaline with 20% aqueous sodium hydroxide solution. The alkaline solution is extracted twice with 50 ml of chloroform, the combined organic phases are dried over anhydrous magnesium sulfate and freed from the solvent by evaporation. In this way, 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine are prepared, from the manner described in Example 1, point c), N-cyclohexyl -N-methyl-N- (2-amino-3,5-di-bromobenzyl) amine hydrochloride is obtained.

Example 3

From the N-cyclohexyl-N-methyl-3-bromo-2-aminobenzylamine prepared in the manner described in Example 1, point b), the hydrochloride is prepared in ethanolic medium by introducing dry hydrochloric acid gas. The product is hygroscopic, so its melting point is not sharp. Mp 100-120 ° C (with decomposition).

1 g (3 mmol) of N-cyclohexyl-N-methyl-3-bromo-2-amino-benzylamine hydrochloride and 0.5 g (6 mmol) of anhydrous sodium acetate are dissolved in 20 ml of glacial acetic acid and added to the solution at room temperature 0. 25 ml (4 mmol) of bromine are dropped in 5 ml of glacial acetic acid. The mixture is heated on a 60 ° C water bath with stirring for two hours. After cooling, the mixture is mixed with 50 ml of water and made alkaline with concentrated ammonia. The mixture is then extracted twice with 70 ml of ether each time. The ethereal phase is dried over potassium hydroxide and then evaporated. The remaining oil (1.1 g) is dissolved in 20 ml of ethanol and from the solution the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride is precipitated with ethereal hydrochloric acid. The crude product obtained (1 g) is recrystallized from ethanol, giving 0.95 g (70%). Melting point: 242-244 ° C.

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Claims (5)

622 488 2. The method according to claim 1, characterized in that the excess of N-methylcy-clohexylamine is used as the acid acceptor. 2nd PATENT CLAIMS 1. Process for the preparation of the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of the formula (I) (I) and the acid addition salts of this compound formed with inorganic and organic acids, characterized in that 3-bromo-2-nitrobenzyl bromide having the formula (II) - Br (II) in the presence of an acid acceptor with N-methylcyclohexylamine, reacting the nitro group of the resulting N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine of the formula (III) reduced and the N-cyclohexyl-N-methyl-2-ami-no-3-bromobenzylamine obtained of the formula (IV) (IV) reacted with elemental bromine to give the compound of formula (I) and if appropriate isolating it in the form of its acid addition salts formed with organic or inorganic acids. 3. The method according to any one of claims 1 or 2, characterized in that the reducing agent used is hydrazine hydrate together with Raney nickel. 4. The method according to any one of claims 1 or 2, characterized in that tin is used as the reducing agent in hydrochloric acid solution. 5. The method according to claim 1, characterized in that reacting the compound of formula (IV) without intermediate isolation and after conversion to an acid addition salt with elemental bromine to the compound of formula (I).