NO135707B - - Google Patents

Description

In organic chemistry, it is a generally accepted doctrine that amino-benzaldehydes are very unstable and have a tendency to self-condensate. For further conversions they therefore constitute extremely unfavorable starting compounds (see for example Fieser & Fieser, Organic Chemistry, 3rd edition 1956, page 688, Reinhold Publishing Corporation, New York and Houben-Weyl, Methoden der organischen Chemie, 4th edition, volume VII/ 1, page 408). Therefore, the reductive amination of aminobenzaldehydes and acylamino-benzaldehydes with formic acid and amines has not yet been described in the literature, but at the same time it is known from the literature that in the reductive amination with formic acid, respectively with the corresponding formamide, a lower yield is obtained the greater the degree of substitution of the aromatic aldehyde used (see for example Org. Reactions Vol. 5_, 309 (1949)).

It is therefore very surprising that compounds of the general formula I (which are known from British patents 968,254, 1,098,140 and 1,178,034)

where Hal means a chlorine or bromine atom,

R^ means a hydrogen, chlorine or bromine atom,

R» means a cyclohexyl, hydroxycyclohexyl, morpholinocarbonylmethyl or isopropylaminocarbonylmethyl residue,

R 1 means a hydrogen atom or a methyl group, and

R 4 means a hydrogen atom or, if R 2 means an isopropyl-aminocarbonylmethyl or morpholinocarbonylmethyl residue, a benzoyl residue, can be prepared in good yield by reacting an aldehyde of the general formula II

where Hal, R 1 and R 2 are as above, with an amine of the general formula III

where R 2 and R 1 are as indicated above, in the presence of formic acid or the corresponding formamide, at elevated temperature.

The reductive amination is preferably carried out at temperatures between 150 and 250°C, possibly in a solvent and suitably during simultaneous distillation of the water formed. However, it is particularly advantageous when the amine with the general formula III and/or formic acid used in the reaction simultaneously serves as a solvent. If R3 in a compound of the general formula III is a hydrogen atom, then the reaction mixture obtained, after the reaction with a dilute acid, such as 2n hydrochloric acid, is heated under reflux.

The obtained compounds of the general formula I can, as already described in the literature, be converted to salts thereof with physiologically compatible inorganic or organic acids.

As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid or maleic acid, proved suitable.

They used compounds of the general formula IIa as starting materials

where Hal and R^ are as indicated above, are new and can be prepared by the following methods: a) By benzoylation of a 2-amino-benzaldehyde with the general formula Ilb

where Hal and R^ are as stated above.

The reaction is preferably carried out with a reactive derivative of benzoic acid, e.g. benzoyl chloride or benzoic anhydride, or with benzoic acid in the presence of an acid activating agent, such as N,N-dicyclohexylcarbodiimide, in a solvent, such as ether, dioxane or chloroform, and optionally in the presence of an inorganic or tertiary organic base, suitably at temperatures between 0° C and the boiling point of the solvent used.

b) When oxidizing a compound with the general formula IV

where Hal and R 1 are as indicated above and X means a hydroxyl group or a chlorine, bromine or iodine atom.

If X means a hydroxyl group, then the reaction is carried out with an oxidizing agent, such as manganese dioxide, in a solvent, such as acetone or toluene, and suitably at temperatures between 0 and 50°C.

If X means a halogen atom, then a compound of the general formula IV is reacted with pyridine in a solvent, such as carbon tetrachloride, chloroform or pyridine, at temperatures between 0°C and 100°C, to the corresponding salt, which then with p- Nitroso-dimethylaniline in a solvent, such as ethanol/water, at temperatures between 0 and 100°C, is converted to the corresponding nitrone, which is then hydrolyzed in the presence of an aqueous „ acid at temperatures between 0 - 100°C.

c) By reacting a compound with the general formula V

where Hal and R^ are as indicated above and Y means a halogen atom,

with benzamide at elevated temperature.

The reaction is preferably carried out at an elevated temperature, e.g. temperatures between 100-200°C, suitably in a solvent, such as nitrobenzene, and optionally in the presence of a base, such as potassium carbonate, and in the presence of a reaction accelerator, such as copper powder and/or copper (I) bromide.

The aldehydes with the general formula IIb used as starting materials can be prepared according to methods known in the literature, e.g. by oxidation of the corresponding benzyl alcohols with lignite.

The compounds with the general formula IV used as starting materials are obtained according to methods known per se from the corresponding toluidines by side chain halogenation, and optionally then reaction with potassium acetate and hydrolysis.

The compounds with the general formula V used as starting materials are obtained by methods known per se, for example by oxidation of the corresponding benzyl alcohols.

The object of the present application is consequently a new process for the preparation of the compounds of the general formula I, which possess valuable pharmacological properties, in particular secretolytic, antitussive and/or respiratory-analeptic properties.

The following examples shall further illustrate the invention.

Example 1

N-(2-amino-3,5-dibromo-benzyl)-N-methyl-trans-4-amino-cyclohexanol hydrochloride 5 g 2-amino-3,5-dibromo-benzaldehyde, 5.75 g trans-4 -methyl-amino-cyclohexanol and 2 ml of formic acid are heated for 30 minutes to 200°C, whereby the water formed is distilled off. The same amount of amine and formic acid is then added and further heated for 1 1/2 hours. The reaction product is dissolved by shaking with 0.5 1 of diluted ammonia and 50 ml of chloroform. The chloroform phase is separated and the aqueous phase is shaken out with 50 ml of chloroform. The combined chloroform phases are evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. After adding some ether, the hydrochloride crystallizes out.

Yield: 6.3 g (82% of the theoretical).

Melting point: 216.5 - 217.5°C (dec.).

Example 2

N-(2-amino-3,5-dibromo-benzyl)-trans-4-amino-cyclohexanol hydrochloride

5 g of 2-amino-3,5-dibromo-benzaldehyde, 5.75 g of trans-4-amino-cyclohexanol and 2 ml of formic acid are heated for 30 minutes at 200°C, whereby the water formed is distilled off. The same amounts of amine and formic acid are then added and heated further for 1 1/2 hours. The reaction product is dissolved by

shake with 0.5 1 of diluted ammonia and 50 ml of chloroform.

The chloroform phase is separated and the aqueous phase is shaken out with 50 ml of chloroform. The combined chloroform phases are evaporated to dryness. Dissolve the residue in 200 ml of 2N hydrochloric acid, boil for some time with reflux, decolorize with activated charcoal, make alkaline with concentrated ammonia and decant twice with 50 ml of chloroform each time. The combined chloroform phases are evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. After adding some ether, the hydrochloride crystallizes out. Yield: 4.5 g (60.6% of the theoretical).

Melting point: 233-234°C (dec.).

Example 3

N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclohexylamine

Prepared from 2-amino-3,5-dibromobenzaldehyde and N-methyl-cyclohexylamine in the same manner as in Example 1.

Melting point of the hydrochloride: 232-235°C (dec.).

Example 4

N-(2-amino-3, 5- dibromo- benzyl)- N- methyl- cis- 3- amino- cyclohexanol

Prepared from 2-amino-3,5-dibromobenzaldehyde and cis-3-methylaminocyclohexanol in the same manner as in Example 1.

Melting point of the hydrochloride: 207-208°C (dec.).

Example 5

N-(2- benzoylamino- 4- chloro- benzyl)- N- methyl- qlycine- isopropylamide

10.4 g (0.04 mol) of 2-benzoylamino-4-chloro-benzaldehyde and

26.0 g (0.2 mol) sarcosine-isopropylamide is added dropwise to 7.64 ml (0.2 mol) 98% formic acid, whereby heating to approx.

60°C occurs. The reaction mixture is then heated to 150°C for 5 hours. After cooling, a further 0.2 mol of formic acid and 0.2 mol of sarcosine-isopropylamide are added. After a further 5 hours at 150°C, it is cooled, occasionally 0.02 mol of formic acid and sarcosine-isopropylamide are added and heated once more for 8 hours at 150°C. Add the cold mixture approx. 200 ml of 2N caustic soda and extract with chloroform. The organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo. A brown oil is obtained, which is chromatographically purified over a column (silica gel, chloroform/methanol = 19:1). The oily evaporation residue of the substance-containing fractions is crystallized by pulverization with approx. 10 ml isopropanol. Cool strongly (ice/methanol), filter and recrystallize from 10 ml of isopropanol.

Yield: 6.1 g (40.8% of the theoretical).

Melting point: 140-142°C.

Example 6

N-(2- benzoylamino- 6- bromo- benzyl)- N- methyl- glycine- morpholide

Prepared from 2-benzoylamino-6-bromobenzaldehyde and sarcosine morpholide in the same manner as in Example 5.

Melting point: 159-161°C.

Example 7

N-(2- benzoylamino- 6- chloro- benzyl)- N- methyl- glycine- morpholide

2.6 g of 2-benzoylamino-6-chloro-benzaldehyde, 15.8 g of sarcosine morpholide and 4.6 ml of formic acid are heated to 150°C for 2 1/2 hours. The cooled reaction product is taken up in 20 ml of dilute hydrochloric acid, filtered and the filtrate is made alkaline with dilute ammonia. The desired benzylamine is deposited in an oily form. By decanting and adding some ether, the crystalline base is obtained.

Yield: 1.3 g (32.4% of the theoretical).

Melting point: 122°C.

Example 8

N-(2- benzoylamino- 3;5- dibromo- benzyl)- N- methyl- glycine- morpholide

Prepared from 2-benzoylamino-3,5-dibromobenzaldehyde and sarcosine morpholide in the same manner as in Example 7.

Melting point of the base: 164°C.

Example 9

2- benzoylamino- 4- chloro-benzaldehyde

a) 824 g (2.53 mol) of 2-benzoylamino-4-chloro-benzyl bromide are added in portions to 1100 ml of pyridine while stirring, whereby a slight heating occurs. After the addition is complete, the mixture is heated for 1 hour on a steam bath to complete the reaction, cooled and the crystallized N-(2-benzoylamino-4-chloro-benzyl)-pyridinium bromide is filtered off with suction, which is washed with ether. Melting point: 190-193°C. b) 250 g (0.87 mol) of N-(2-benzoylamino-4-chloro-benzyl)-pyridinium bromide are dissolved in 4.5 1 of water while heating.

It is cooled to room temperature, and a solution of

130 g (0.87 mol) of p-nitroso-N,N-dimethylaniline in 1000 ml of ethanol and also 34.6 g (0.87 mol) of sodium hydroxide in 350 ml of water. You let this stand overnight at room temperature and then vacuum it off

crystallized, yellow C-(2-benzoylamino-4-chloro-phenyl)-N-(4-dimethylamino-phenyl)-nitrone, which is washed with water. The crude product obtained decomposes between 190 and 196°c.

c) 150 g (0.38 mol) of C-(2-benzoylamino-4-chloro-phenyl)-N-(4-dimethylamino-phenyl)-nitron are suspended in 900 ml of water and

stirred mechanically. During external cooling with ice, 300 ml of conc. hydrochloric acid. After a further 45 minutes at room temperature, 3 1 of water are emptied, the crystallized 2-benzoyl-amino-4-chloro-benzaldehyde is filtered off with suction and washed until neutral with water. To clean, it is boiled with 1.5 1 ethanol and sucked off after cooling. The obtained substance turns brown little by little above 140°C, and decomposes between 154 and 158°C.

Example 10

2- benz oylamino- 6- bromo- benz aldehyde

Prepared from 2-benzoylamino-6-bromo-benzyl bromide (prepared by bromination of 3-bromo-o-benzotoluidide) in the same manner as in Example 9.

Melting point: 140-142°C.

Example 11

2- benzoylamino- 6- chloro- benzaldehyde

In 80 ml of nitrobenzene, 30.0 g (0.175 mol) of 2,6-dichlorobenzaldehyde, 21.2 g (0.175 mol) of benzamide, 2 g of potassium carbonate, 1 g of copper powder and 1 g of copper (I) bromide are heated for two hours to 160°c. During this time, a further 23 g of potassium carbonate is introduced in portions. Then heat for 3 hours to 180°C.

After cooling, 300 ml of hot water is added and steam is blown over the nitrobenzene. The aqueous solution is extracted with chloroform, the organic extracts are washed with water and evaporated in vacuo. The evaporation residue is chromatographically purified over silica gel with benzene as solvent. After working up the fractions containing the substance, 2-benzoylamino-6-chloro-benzaldehyde with a melting point of 110-111°C (from cyclohexane) is recovered.

Example 12

2- benzoylamino- 3, 5- dibromobenzaldehyde

7 g of 2-amino-3,5-dibromobenzaldehyde, 175 g of benzoyl chloride and 21.0 g of finely powdered, anhydrous soda are boiled under reflux for 4 hours in 70 ml of toluene. After cooling the reaction mixture, the crystal mush is sucked to dryness with ether, and

the nut contents are stirred with water, suctioned off and dried.

Melting point: 18 4°C.

Example 13

2- benzovlamino- 6- chlorobenzaldehyde

15.6 g of 2-amino-6-chlorobenzaldehyde, 98.5 g of benzoyl chloride

and 42.3 g of anhydrous soda is heated in 750 ml of toluene for 2 1/2 hours under reflux. After filtering the cooled reaction solution, the filtrate is added approx. 400 ml of dilute ammonia (200 ml of conc. ammonia and 200 ml of water), stirred for 15 minutes, and separated the toluene phase in a separatory funnel. When the organic phase dried with sodium sulphate is evaporated to dryness, a crystalline product is obtained.

Melting point: 110-111°C.

Example 14

2- benzoylamino- 6- chloro- benzaldehyde

10 g of 2-benzoylamino-6-chloro-benzyl alcohol, 16.5 g of lignite and 100 ml of toluene are heated to 90°C for 1 hour under stirring

stirring. After filtering the hot solution, the filtrate is evaporated to dryness in vacuo, the residue is dissolved in 100 ml of hot ethanol and filtered." On cooling, the aldehyde is deposited in crystalline form.

Melting point: 110-111°C (from ethanol).

Claims (4)

1. Process for the preparation of 2-amino-benzylamines of the general formula I where Hal means a chlorine or bromine atom, means a hydrogen, chlorine or bromine atom, R2 means a cyclohexyl, hydroxycyclohexyl, morpholinocarbonyl methyl or isopropylaminocarbonylmethyl radical, R3 means a hydrogen atom or a methyl group, and R. means a hydrogen atom or, if R^ means an isopropylaminocarbonylmethyl or morpholinocarbonylmethyl radical, a benzoyl radical, characterized in that an aldehyde with the general formula II where Hal, R^ and R^ are as indicated above, is reacted with an amine of the general formula III where R2 and R^ are as indicated above, in the presence of formic acid or the corresponding formamide at elevated temperature, and if R3 in a compound of the general formula III means a hydrogen atom, the reaction mixture obtained is then heated with a dilute acid under reflux. 2. Procedure as stated in claim 1, characterized in that the reaction is carried out at temperatures between 150 and 250°C. 3. Method as stated in claims 1 and 2, characterized in that the water formed is distilled off during the turnover. 4. Process as stated in claims 1, 2 and 3, characterized in that the reaction is carried out in an excess of the used anine of the general formula III and formic acid.