NO773303L - PROCEDURES FOR THE MANUFACTURE OF BENZYLAMINES - Google Patents

Description

In the British patents 968,254 and 1,098,140, among other things, benzylamines of the general formula I are described,

where

Hal means a chlorine or bromine atom,

R^ a hydrogen, chlorine or bromine atom,

R2 a hydrogen atom or a lower alkyl radical with 1 to 3 carbon atoms, a hydroxycyclohexyl radical and

R^a hydrogen atom or

R^an isopropylaminocarbonylmethyl- or morpholinocarbylmethyl radical and R^a hydrogen atom or a -benzoyl radical,

physiologically compatible salts thereof with inorganic or organic acids, and methods for their preparation.

The compounds of the above general formula I exhibit valuable pharmacological properties, in particular secretolytic, antitussive and/or respiratory-stimulating effects.

It has now surprisingly been found that the compounds with the above formula I can also be prepared by the following method with excellent yields and great purity.

According to the invention, a compound with the general formula II is thus reacted

where

R1'R4°^Ha"*" is as indicated above, and ;X means an organic acyloxy acid residue such as an acetoxy-, butyryloxy-, benzoyloxy- or 4-chlorobenzoyloxy group, ;with an amine of the general formula III; ; where ;1*2 and R., are as stated above.

The method according to the present invention can thus be carried out with residues X which intermediately enable the formation of a benzyl cation from a compound with the above general formula II.

The reaction is conveniently carried out in an organic solvent such as ethanol, ether, acetone, tetrahydrofuran, benzene, dioxane, chloroform or carbon tetrachloride, optionally in the presence of an inorganic base such as sodium carbonate or sodium hydroxide, a tertiary organic base such as triethylamine or pyridine, preferably, however, in an excess of the amine of the general formula III used, and depending on the reactivity of the residue X at temperatures between -70 and 200°C, preferably at temperatures between 80 and 170°C. When using a tertiary organic base or an excess of the amine with. the general formula III these can simultaneously serve as a solvent. However, the reaction can also be carried out without a solvent.

The obtained compounds of the general formula I can optionally then be transferred in their physiologically compatible salts with inorganic or organic acids. As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid are suitably used.

The compounds used as starting materials, with the general formula II can be prepared from the corresponding benzyl alcohols, which in turn can be prepared by reducing the corresponding aldehydes with sodium borohydride, by reaction with a corresponding hydrohalic acid, with a corresponding sulphonic acid halide in the presence of sodium hydride, with a corresponding thionyl halide or with a corresponding organic acid halide in the presence of pyridine. The obtained starting substances with the general formula II can, however, also be reacted further without prior isolation.

The new method according to the invention could not be foreseen, as it is known that esters of the general formula II where R. means a hydrogen atom, polymerize in the presence of bases such as amines of the general formula II, and thus are not suitable for further reactions in presence of bases (see, e.g., Ber. Dtsch. chem. Ges. 21_, 3509-3525 (1894)), and moreover, amides and alcohols are normally formed by the reaction of amines with carboxylic acid esters.

The following examples shall serve to further illustrate the invention.

Example 1

2- amino- 3, 5- dibromo- N-( trans- 4- hydroxy- cyclohexyl)- benzylamine

3.5 g (0.01 mol) butyric acid (2-amino-3,5-dibromo-benzyl ester) is boiled with 5.7 g (0.05 mol) transM-aminoq-cyclohexanol for 2.5 hours under reflux, after cooling, the product is dissolved in ether, and the ether solution is shaken three times with water. The organic phase is dried with sodium sulphate, evaporated, the residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and by addition of ether the crystallization of the desired compound is completed.

Yield: 2.92 g (77.8% of the theoretical)

Melting point for the hydrochloride: 233-234.5°C (dec.).

Example 2

2-amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine.

Melting point of the hydrochloride: 233-234.5°C (decomposition).

Prepared from benzoic acid (2-amino-3,5-dibromo-benzyl ester) and trans-4-amino-cyclohexanol analogously to example 1.

Yield: 58.3% of the theoretical.

Example 3

2-amino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine Melting point: 116-118°C.

Prepared from benzoic acid (2-amino-6-chloro-benzyl ester)

and sarcosine morpholide analogously to example 1.

Yield: 67.0% of the theoretical.

Example 4

2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-1-methyl)-benzylamine 2 g (0.0055 mol) N,O-dibenzoyl-2-amino-6-chloro-benzyl alcohol and 5 g ( 0.0316 mol) of sarcosine morpholide is heated for 6 hours to 140°C. After cooling, the reaction mixture is diluted with 50 ml of water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and saturated potassium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue is chromatographed in the system chloroform-methanol (19:1) over a silica gel column.

1.75 g of a crude product is obtained which after crystallization from ether gives 1.68 g (76% of the theoretical) 2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonylmethyl)-benzylamine.

Melting point: 122.5-123°C.

Example 5

2- benzoylamino- 6- chloro- N- methyl1- N-( morpholino- carbonylmethyl)- benzylamine

Dissolve 2.62 g (0.01 mol) of 2-benzoylamino-6-chloro-benzyl alcohol in 50 ml of absolute ether and 10 ml of absolute tetrahydrofuran and add 0.32 g (0.01 mol) of 75% sodium hydride in oil at room temperature with stirring during 5 minutes. After 1/2 hour of stirring, the sodium salt begins to precipitate as a gel-like precipitate. It is stirred for a further 1 hour, the whole is allowed to stand overnight at room temperature, the resulting mixture is diluted with 150 ml of absolute ether and cooled to -50°C. While stirring, a solution of 1.91 g (0.01 mol) of p-toluenesulfonic acid chloride in 50 ml of absolute ether is added dropwise over the course of 15 minutes, and stirring is continued for 2 hours at -50 to -40°C to obtain the p-toluenesulfonic acid ester of 2-benzoylamino-6-chloro-benzyl alcohol. A solution of 7.9 g (0.05 mol) of sarcosine morpholide in 50 ml of absolute ether is then added dropwise over the course of 5 minutes at -50°C. Stirring is continued for 3 hours and the temperature is allowed to rise to 10°C. The reaction mixture is then evaporated in vacuo, the residue is absorbed

100 ml of ethyl acetate, washed with water and 5% sodium bicarbonate solution and extracted twice with 2N hydrochloric acid. The acidic extract is washed with ethyl acetate, made alkaline with concentrated ammonia and extracted 3 times with ethyl acetate. The organic phase is washed with water, dried with magnesium sulphate and evaporated in vacuo. The oily 2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine crystallizes from ether. Yield: 1.3 g (32.4% of the theoretical).

Melting point: 122.5-123°C.

Example 6

2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine

Melting point of the hydrochloride: 206-208°C (decomposition). Prepared from butyric acid—(2-benzoylamino-6-chloro-benzyl ester) and sarcosine morpholide analogously to example 4.

Yield: 24.0% of the theoretical..

Example 7

2-Benzoylamino-6-chloro-N-isopropyl-N-(morpholino-carbonylmethyl)-benzylamine

Melting point: 125-127°C.

Prepared from benzoic acid (2-benzoylamino-6-chloro-benzyl ester) and N-isopropylglycine morpholide analogously to example 4. Yield: 63.0% of the theoretical.

Example 8

2-benzoylamino-4-chloro-N-methyl-N-(isopropylamino-carbonyl-methyl)-benzylamine

Melting point: 140-142°C.

Prepared from p-chloro-benzoic acid (2-benzoylamino-4-chloro-benzyl ester) and sarcosine-isopropylamide analogously to example 4. Yield: 68.0% of the theoretical).

Example 9

, 2-benzoylamino-6-bromo-N-methyl-N-(morpholino-carbonylmethyl)-benzylamine Melting point: 159-161°C.

Prepared from N,0-dibenzoyl-2-amino-6-bromo-benzyl alcohol and sarcosine morpholide analogously to example 4. yield: 72.0% of the theoretical.

Claims (5)

I. Process according to patent (application 3063/73) for the preparation of benzylamines of the general formula I where Hal means a chlorine or bromine atom, a hydrogen, chlorine or bromine atom, R2 a hydrogen atom or a lower alkyl residue with 1-3 carbon atoms, R^ a hydroxycyclohexyl residue and R^ a hydrogen atom or R^ an isopropylaminocarbonylmethyl or morpholinocarbonylmethyl residue and R^ a hydrogen atom or a benzoyl residue, and their physiologically compatible salts with inorganic or organic acids, characterized by the compound of formula II where R1'R4 °^ Ha^" is as indicated above, and X means an organic acyloxy acid residue, is reacted with an amine of the general formula III, where R 2 and R 3 are as indicated above, and optionally an obtained compound of the general formula I is transferred to its physiologically compatible salt with an inorganic or organic acid. 2. Procedure as stated in claim 1, characterized in that the turnover is carried out at temperatures between -70 and 200°C. 3. Procedure as stated in claims 1 and 2, characterized in that the reaction is carried out in a solvent, e.g. ethanol, ether, acetone, tetrahydrofuran, benzene, dioxane, chloroform, carbon tetrachloride or in an excess of the amine of the general formula III used. 4. Procedure as stated in claims 1, 2 and 3, characterized in that an acetyloxy, butyryloxy, benzoyloxy or 4-chlorobenzoyloxy residue is used as the organic acyloxy residue in a compound of the general formula II. 5. Method as set forth in claims 1, 2, 3 and 4, characterized in that a compound of the general formula II is used in the reaction without prior isolation thereof.