DK145293B - METHOD FOR PREPARING N-CYCLOHEXYL-N-METHYL-N- (2-AMINO-3,5-DIBROMO-BENZYL) -AMINE - Google Patents

Description

(19) DENMARK (W] f \ J3 /

02) PUBLICATION <n) 11 + 5293 B

DIRECTORATE OF PATENT AND TRADEMARKET

(21) Application No. 32 * 63/76 (51) IntCI. * C 07 C 87/02 (22) Filing date 30 Jul. 1976 (24) Race day 30 Jul. 1976 (41) Aim. available Apr 29 1977 (44) Posted Oct 25 1982 (86) International application no.

(86) International filing day (85) Continuation day _ (62) Stock application number _

(30) Priority Oct 28 1975 * EE 2 ^ 84, HU

(71) Applicant ε0ΥΓ GY0GY5ZERVEGYESZETI GYAR, Budapest X, HU.

(72) Inventor Janos Egri, HU: Tamas Fodor, HU: Jozsef Rakoczi, HU:

Janos Fischer, HU: Pal Vago, HU.

(74) Budde, Sehou & Co. Associate of Engineering (54) Process for Preparation of N-Cyclohexyl-N-methyl-N- (2-a = mlno-5,5-dibromo-benzyl) -amine.

The present invention relates to a novel process for the preparation of N-cyclohexyl-N- (2-amino-3,5-dibromo-benzyl) -amine of the general formula CH-. , - ® Br yv -CH2 - ^ - / \ O \ / (I) T) j N- / O ^ Y ^ \ nh2 “Br ^ as well as acid addition salts formed with inorganic or organic acids thereof. The compound of formula I has an excellent bronchosolecytolytic effect and can be used to treat chronic, non-specific diseases of the respiratory system.

According to a known industrial method for preparing N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromo-benzyl) -amine of the formula I, starting material o-nitrobenzyl bromide reacted with N- methyl cyclohexylamine, followed by reduction and dibromination at the 3.5-position of the aromatic ring. The yield of the bromination is only 38.5% and the total yield of the synthesis is only 32%, ie. the process is not economical (DE Patent No. 1,169,939). A further disadvantage of this process is that the o-nitrobenzyl bromide is harmful and tear-inducing.

According to another known process, 3,5-di-bromo-2-amino-toluene is diacetylated and reacted with N-bromosuccinimide to give 3,5-dibromo-2-diacetaminobenzyl bromide, which is then reacted with N-methyl-cyclohexylamine. followed by hydrolysis with hydrochloric acid (cf. DE patent specification 1,169,939). The yield of the bromination with N-bromine - succinimide is 16% and the total yield of the syntheses is very low, ie. 7%. The 3,5-dibromo-2-diacetamino-benzyl bromide is also tear-inducing and must be recrystallized at least 4-6 times to obtain a final product of appropriate purity.

According to yet another known method, o-ni-trobenzoic acid is used as starting material and via the corresponding acid chloride N-methyl-N-cyclohexyl-o-nitrobenzamide is prepared by reacting said chloride with N-methylcyclohexylamine. Then the nitro group of the latter product is converted to an amino group by Bechamp reduction, the aromatic ring is dibromized to the 3.5 position, and finally the oxo group is reduced with lithium aluminum hydride (cf. DE Patent No. 1,194,418). The total yield of the synthesis is only 24%, and the lithium aluminum hydride used in the final step can cause fire or explosion.

According to DE Publication No. 2,223,193, a corresponding substituted benzaldehyde is reacted with a secondary amine.

DE Publication No. 2,315,310 discloses a process by which one condenses an acetylaminobenzyl alcohol with a secondary amine and then hydrolytically removes the acetyl group or reacts aminobenzyl alcohol with the secondary amine in the presence of a fatty acid.

3 165293

In the method of DE Publication No. 2,456,033, the reaction is carried out according to the second variant of the method according to the aforementioned DE Publication No. 2,315,310, but in the presence of another organic acid.

DE Publication No. 2,411.848 describes as the preparation method the reaction of an ester of benzyl alcohol with N-methylcyclohexylamine.

DE Publication No. 2,345,443 discloses the conversion of a benzyl ether with the amine, DE Publication No. 2,338,408 discloses the conversion of a benzyl ester with an amine, DE Publication No. 2,337,931 discloses the conversion of benzyl alcohol with a phosphoric acid triamide, DE publication 2,337,455 discloses the reaction of a benzyl alcohol with the amine in the presence of a base, and DE Publication No. 2,311,637 discloses the reaction of a benzyl ester with an amine.

A common feature of the aforementioned known methods is that in their implementation, 2-amino-3,5-dibromobenzyl aldehyde or 2-amino-3,5-dibromobenzyl alcohol or a derivative of the latter compound is reacted with N-methyl-cyclohexylamine. The yield of these known methods is on average approx. 80%, in some cases even more. These known methods can be carried out in one or two steps and thus appear to be advantageous. However, all these known processes have the crucial common disadvantage that the preparation of the starting compounds is markedly difficult.

The preparation of 2-amino-3,5-dibromo-benzaldehyde is known from Berichte, £ 3, 1338 (1901). According to this literature site, o-aminobenzaldehyde is prepared by diazotizing a diazonium salt, after which this salt is brominated in acidic medium and the separated solid diazonium salt is separated and finally treated with concentrated ammonia. According to this literature site, a total yield of 36% is obtained when the components are reacted in an amount of 0.025 mol. However, this process is not suitable for industrial production of 2-amino-3,5-dibromobenzaldehyde.

When the size of the charge simply increases moderately, the yield decreases very quickly. Eg. a total yield of 8% is found when the synthesis is carried out with an amount of 0.19 mol. It is a disadvantage that, in carrying out the process, a solid diazonium salt must be treated and the separation of 2-amino-3,5-dibromo-benzaldehyde is possible only by several days steam distillation.

According to the site of literature Monats., 36. ' 113-141, 2-amino-3,5-dibromobenzaldehyde is produced in a single step, namely by direct bromination of o-aminobenzaldehyde. The melting point of the product thus produced is only 110 ° C (according to the previous literature site, the melting point is 137-138 ° C and the latter melting point is actually reproducible), which clearly indicates that this product contains larger amounts of impurities or also consists of various isomers. . It has been found that this product can be purified chromatographically and thus a product having a melting point of 137-138 ° C can be prepared in a yield of approx. 5%. This process is also obviously not suitable for industrial production of 2-amino-3,5-dibromobenzaldehyde.

Another starting compound, namely 2-amino-3,5-di-bromobenzyl alcohol, can be prepared by reducing 2-amino-3,5-dibromobenzaldehyde (which, as explained above, is difficult to prepare itself) with sodium borohydride. Also, the use of sodium borohydride in industrial sized batches is uneconomical, so the preparation of this compound is absolutely uneconomical.

The 2-amino-3,5-dibromobenzyl alcohol esters useful as additional alternative starting compounds require a further process step and consequently the use of these compounds causes the disadvantages already mentioned.

On the basis of the above, it can be concluded that the known processes using 2-amino-3,5-dibromobenzaldehyde or 2-amino-3,5-dibromobenzyl alcohol or a derivative of the latter compound, at best, laboratory methods for the preparation of N-cyclohexyl - N-methyl-N- (2-amino-3,5-dibromobenzyl) -amine, but are not usable on an industrial scale, since the preparation of the starting compounds is already uneconomical under laboratory conditions .

A further disadvantage of the process disclosed in DE Publication No. 2,337,931 is that the N, N1, N ', - tricyclohexyl-N, N', N, N, N ', used for the reaction of 2-amino-3,5-dibromobenzaldehyde are used. Trimethylphosphoric acid triamide itself must be prepared in a separate step and according to the literature site J. Am. Chem. Soc., 64, 1553 (1942) can only be prepared with a 72% yield.

145293 5

In the process of DE Publication No. 2,345,443 (2-amino-3,5-dibromobenzyl) phenyl ether is reacted with N-methyl-cyclohexylamine at a temperature of 200 ° C. The reaction time is very long, being approx. 15 hours, and the yield of 84% at an applied amount of 0.0028 mol decreases very rapidly as the charge size increases. At a charge size of just 0.05 moles, only 72% yield can be obtained. The starting compound (2-amino-3,5-dibromobenzyl) phenyl ether is prepared by reacting 2-diacetamino-3,5-dibromobenzyl bromide with phenol. 2-Diacetamino-3,5-dibromobenzyl bromide can be obtained by diacetylation of 3,5-dibromo-2-aminotoluene and subsequent bromination with N-bromosuccinimide. The yield on the latter turnover is only 16%. This known method is thus extremely uneconomical.

In the process described in DE Publication No. 2,311,637, N-methylcyclohexylamine is reacted with a halide prepared by halogenation of 2-amino-3,5-dibenzyl alcohol or with the tosyl ester obtained by reaction of 2-amino-3,5 -dibromobenzyl alcohol with p-toluenesulfonyl chloride. The disadvantages associated with the use of 2-amino-3,5-dibromobenzyl alcohol are only exacerbated by the losses at the necessary additional conversion step, whereby the yield determined by the reaction with two-ester 27.2% and the yield determined by the halide reaction of 65.8 -85.7% is greatly reduced.

In summary, it can thus be stated that none of the known processes is suitable for the industrial preparation of the compound of formula I in an economical manner.

It has now been found that N-cyclohexyl-N-methyl-N- (2-ami-no-3,5-dibromobenzyl) amine can be readily prepared with a yield of more than 80% by reacting 3-bromine. 2-nitrobenzyl bromide of the formula ^^^^ CH2-Br T (ii) Y ^ NO2

Br with N-methyl-cyclohexylamine in the presence of an acid-binding agent, reduce the nitro group of the N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine thus formed of the formula CH3 6 145293 .CH - N - / \ (III ) O ^

Br and bromine the thus-obtained N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of the formula ^ .CH2 - N - / (IV)

br

The reaction of the 3-bromo-2-nitrobenzyl bromide of formula II with N-methyl-cyclohexylamine is carried out in the presence of an acid-binding agent at a temperature of 60-110 ° C, preferably 70-80 ° C. As a medium or solvent, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons or aliphatic alcohols are used in particular. As an acid binding agent, any base which does not react with the starting material in a side reaction can be used. In particular, as an acid binding agent, an excess of N-methyl-cyclohexylamine is used. The amine can be recovered from the N-methyl-cyclohexylamine hydrobromide formed during the reaction and can. used again in the method, i.e. it can be recycled.

The amino compound of formula IV can be prepared by reducing N-cyclohexyl-N-methyl-2-nitro-2-bromobenzamine of formula III by itself known reducing agents. In particular, as the reducing agent, hydrazine hydrate and Raney nickel are used in a C ^ alkohol alcoholic solution, or alternatively tin or tin (II) chloride can be used in an acidic medium. The reduction is carried out at a temperature of 15-25 ° C with eventual cooling of the reaction mixture, followed by a short post-reaction. However, in some cases, an elevated temperature, preferably a temperature of 60-100 ° C, can be used to reduce the reaction time.

The N-Cyclohexyl-N-methyl-2-amino-3-bromobenzamine of formula IV is converted to the final product with elemental bromine. Chlorinated aliphatic hydrocarbons, a mixture of alcohol and ether or glacial acetic acid may be used as reaction medium 7 145293 or as a solvent. As an acid binding agent, sodium acetate or inorganic bases such as e.g. sodium carbonate or potassium carbonate. The bromination is preferably carried out at a temperature of 10-25 ° C, optionally during cooling and a post-reaction, if desired at elevated temperature, preferably at 60 ° C.

The N-Cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of formula I can be separated in the form of the hydrobromide salt formed during the bromination. According to yet another embodiment of the process of the present invention, the free base of formula I can be released into the brominating reaction mixture itself, whereupon the free base can optionally be reacted with an organic or inorganic acid and isolated in the form of an acid addition salt. Furthermore, the free base of formula I can be released from one acid addition salt thereof and converted to another acid addition salt.

According to an advantageous embodiment of the present invention, the N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of formula IV is brominated after the reduction without isolation.

According to a further advantageous embodiment of the present invention, the N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of formula IV is reacted with elemental bromine after conversion to an acid addition salt.

The starting material of formula II, 3-bromo-2-nitrobenzyl bromide (a novel compound, like other intermediates of the invention), is prepared from 3-bromo-2-nitro-toluene by bromination with N-bromosuccinimide.

Thus, the present invention relates to a process for the preparation of N-cyclohexyl-N-methyl-N- (2-amino - 3,5-dibromobenzyl) -amine of formula I and acid addition salts thereof prepared with inorganic or organic acids, which process is peculiarly by reacting 3-bromo-2-ni-trobenzyl bromide of formula II in the presence of an acid-binding agent with N-methyl-cyclohexylamine, treating the N-cyclohexyl-N-methyl-2-nitro-3 thus obtained -bromobenzamine of formula III with a reducing agent and converting the thus obtained N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of formula IV, preferably without isolation, and if desired after conversion to an acid addition salt, to said compound of formula By reaction with elemental bromine, the compound of formula I is isolated, optionally, in the form of an acid addition salt formed with an organic or inorganic acid.

According to a particularly advantageous embodiment of the present process, as acid-binding agent N-methyl-cyclohexylamine is used in excess.

According to another particularly advantageous embodiment of the present process, hydrazine hydrate and Raney nickel are used as reducing agents.

According to a further, particularly advantageous embodiment of the present process, as the reducing agent, tin is used in hydrochloric acid.

The process of the invention encompasses reaction steps that are readily accomplished in practice and are very economical. The reaction product can be prepared with a yield of approx. 80% attributed to the 3-bromo-2-nitrobenzyl bromide of formula II.

The starting material of formula II is not harmful to humans in comparison with the benzyl bromide derivatives as well as analogues used in the known methods.

The process according to the invention is further illustrated in the following examples:

Example 1 a) Dissolve 14.5 g (0.049 mol) of 2-nitro-3-bromobenzyl bromide in 100 ml of anhydrous benzene and add 11.2 g (0.098 mol) of N-methyl-cyclohexylamine in 50 ml of anhydrous benzene with stirring. The reaction mixture is refluxed for five hours and cooled, and the separated salt is filtered. N-Methyl-cyclohexylamine can be recovered from the separated N-methyl-cyclohexylamine hydrobromide in a yield of 85%. The filtrate is extracted with 100 ml of water and dried over anhydrous magnesium sulfate. The benzene is distilled off and the prepared 16 g of crude product is recrystallized from 50 ml of ethanol. 14.7 g (92%) of yellow crystalline N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine are obtained, m.p. 59-61 ° C. The melting point of the hydrochloride salt is 223-226 ° C.

Analysis for C ]4HH9BrN₂ · 2 (molecular weight: 327.21) C% H% Br% N

Calculated: 51.39 5.85 24.42 8.56

Found: 51.61 6.08 24.75 8.64 b) 3.27 g (0.01 mole) of N-cyclohexyl-N-methyl-2-nitro-3-bromo-benzamine are dissolved in 20 ml of methanol, and a suspension of 0.3 g of Raney nickel catalyst in 10 ml of methanol is added. The reaction mixture is heated for one hour, the catalyst removed by filtration after cooling, and the solvent removed by evaporation. The residue 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine is obtained in the form of a green oil. The p-toluenesulfonic acid salt is identified and has a melting point of 187-189 ° C.

Analysis for C 21 H 29 BrN 2 ° 3® (molecular weight: 469.43) C% H% N% S%

Calculated: 53.73 6.22 5.97 6.83

Found: 54.45 6.72 5.54 7.13 c) 5.9 g (19.9 mmol) N-cyclohexyl-N-methyl-2-amino-3-bromo-benzamine and 1.63 g (19 Dissolve (9 mmol) anhydrous sodium acetate in 90 ml glacial acetic acid and, under cooling with ice, add 3.18 g (19.9 mmol) of bromine in 30 ml glacial acetic acid. One yellow substance is excreted. The reaction mixture is heated for two hours over a water bath at 60 ° C, after which the reaction mixture is poured into 150 ml of water and made alkaline with cooling with 840 ml of 10% sodium hydroxide solution. The reaction mixture is extracted twice with 250 ml of chloroform, the combined organic layers are dried, filtered on charcoal and evaporated. The remaining 6.9 g (91.5%) of oil is dissolved in 30 ml of ethanol and the N-cyclohexyl-N-methyl - N- (2-amino-3,5-dibromobeiizyi) amine hydrochloride is separated with a mixture of hydrochloric acid and ether. Yield: 7.2 g (87.7%), m.p. 242-245 ° C. Analysis for C ^H₂ ^ Br₂N₂Cl (molecular weight: 412.69) C% H% Br% Cl% N%

Calculated: 40.75 5.13 38.73 8.59 6.79

Found: 40.39 5.27 38.34 8.63 6.71

Examples of other salts prepared from the free base with a suitable acid in alcohol include the following:

perchlorate: m.p. 132-134 ° C

oxalate: m.p. 181-183 ° C.

The melting point of the corresponding hydrogen bromide is 227-228 ° C.

The starting material 3-bromo-2-nitrobenzyl bromide is prepared as follows: 32.4 g (0.15 mol) of 3-bromo-2-nitrotoluene are dissolved in 200 ml of anhydrous carbon tetrachloride, after which 25.5 g (0.143 mol) of N bromosuccinimide and 1 g of dibenzoyl peroxide. The reaction mixture is then heated for 16 hours. The separated succinimide is filtered, the filtrate is evaporated and 80 ml of petroleum ether with a boiling point of 40-70 ° C are added to the residue, after which the 3-bromo-2-nitrobenzyl bromide is crystallized at 0 ° C. The product is 10.4 g and melts at 91-93 ° C. The mother liquor is evaporated and the remaining 25.0 g of oil is repeatedly subjected to bromination. Thus, a total yield of 55.0% is obtained.

Analysis for CyH₂-B ^ NC ^ (molecular weight: 294.95) C% H% Br% N%

Calculated: 28.50 1.66 54.20 4.74

Found: 28.91 1.90 54.91 4.70

Example 2

To 3.27 g (0.01 mole) of N-cyclohexyl-N-methyl-2-nitro-3-bromo-benzamine prepared according to Example 1 a) are added 6 g (0.05 mole) of powdered tin and 16 ml of water. and, while stirring, 16 ml of a concentrated aqueous hydrochloric acid solution is added dropwise. The faded reaction mixture is heated for two hours on a water bath and the mixture is cooled to room temperature and decanted, then made alkaline with a 20% aqueous sodium hydroxide solution. The alkaline solution is extracted with 2 x 50 ml of chloroform, the combined organic layers are dried over anhydrous magnesium sulfate and the solvent is distilled off. 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine are obtained from which N-cyclohexyl-N-methyl-N- (2-amino-3,5 -dibromobenzyl) amine hydrochloride is prepared according to the method described in Example 1 (c).

Example 3

From N-cyclohexyl-N-methyl-3-bromo-2-aminobenzamine prepared according to the method described in Example 1 (b), the corresponding hydrochloride salt is prepared with dry hydrogen chloride gas in an ethanolic medium. The melting point is not clear due to its hygroscopic nature and is at 100-120 ° C (decomposition).

1 g (3 mmol) of N-cyclohexyl-N-methyl-3-bromo-2-aminobenzamine hydrochloride and 0.5 g (6 mmol) of anhydrous sodium acetate are dissolved in 20 ml glacial acetic acid and 0.25 ml (4 mmpl) bromine add dropwise at room temperature in 5 ml of glacial acetic acid. The reaction mixture is heated for two hours on a water bath at 60 ° C with stirring. After cooling, 50 ml of water is added, then the mixture is made alkaline with a concentrated ammonium hydroxide solution and extracted twice with 70 ml of ether.

145293 11

The combined extracts are dried over potassium hydroxide and evaporated. 1.1 g of the residue is obtained, dissolved in 20 ml of ethanol, and the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride is separated off with ether containing hydrochloric acid. 1 g of product is obtained which weighs 0.95 g after recrystallization from ethanol (70%) and has m.p. 242-244 ° C.

Claims (2)

145293 12 Patent Claims. A process for the preparation of N-cyclohexyl-N-methyl - N- (2-amino-3,5-dibromobenzyl) -amine of the formula ch3 - A- / N- - (i) y and acid addition salts thereof prepared with inorganic or organic acids, characterized by reacting 3-bromo-2-nitrobenzyl bromide of formula I (II) γ ^ Η02 Br in the presence of an acid-binding agent with N-methyl-cyclohexylamine the N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine thus prepared of the formula CH 2 λ.γ \ I (III) Y ^ h ° 2 Br with a reducing agent and converting the N-cyclohexyl thus obtained -N-methyl-2-amino-3-bromobenzamine of the formula CH 2 X / CH 2 -