JPS594413B2 - New method for producing 2-amino-benzylamine - Google Patents

Description

Detailed Description of the Invention In the specifications of U.S. Pat. No. 3,336,308, U.S. Pat. No. 3,536,713 and U.S. Pat. 2-amino-benzylamine and inorganic or organic Pharmaceutically acceptable salts thereof with acids, as well as methods for their preparation, are described.

The compound of general formula (1) has useful pharmacological properties, especially secretolytic activity.
) and/or antitussive activity.
activity). Surprisingly, the above 1
A new process has now been found according to the invention, by which compounds of the formula can be prepared in excellent yields.

The method according to the present invention comprises converting a compound of the general formula (wherein Hal and R have the meanings defined above and R4 represents a methyl or phenyl group) into a compound of the general formula (wherein R2
and R3 has the meaning defined above).

The process is suitably carried out at temperatures between 140°C and 220°C in the presence of a solvent such as xylene or tetralin and optionally an acidic catalyst such as ammonium chloride or p-toluenesulfonic acid. However, it is preferably carried out at normal or elevated pressure in the presence of an excess of the amine used.

This reaction can also be carried out in the absence of a solvent. The starting compound of the formula can be obtained, for example, by reacting the corresponding acylated benzyl halide with an alkali salt of phenol or methanol, and then removing the acyl group.

The ester used as this starting compound is also a new compound. If desired, the compound of formula I thus obtained can then be converted into its pharmaceutically acceptable salt with an inorganic or organic acid.

As examples of acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid have proven suitable. The following examples are illustrative of the invention, but not limiting.

Example A illustrates a method for producing phenyl ether used as a starting compound. Example A (2-amino-3.5-dibromo-benzyl)-phenyl ether.

19.77 f of phenol and 12.5 f of potassium hydroxide are dissolved in 0.21 f of absolute ethanol, and this solution is mixed with 85.6 f of 2-diacetylamino-3,5-dibromo-benzyl bromide and 0.5 f of absolute ethanol/? dropwise into the boiling mixture within 20 minutes. This mixture is refluxed for 2 hours. The benzyl bromide thus dissolves and potassium bromide precipitates. After cooling the reaction mixture, the inorganic precipitate is separated off by suction filtration and the filtrate is mixed with 10N sodium monohydroxide solution at 100W LI! and then refluxed for an additional 15 hours. The reaction mixture is then filtered and the filtrate is evaporated. This residue is mixed with 0.51 g of water and then extracted twice with chloroform. The organic phase is dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel with chloroform to give (2amino-3.5-dibromo-benzyl)-phenyl ether in pure form as an oil. Its structure was confirmed by UV-spectrum, IR-spectrum and NMR-spectrum. Uv maximum: 247nm and 310nmR: 3450cm-1 and 3365C!
IL-1...Mbl22Oc! n-1...
・Ether band NMR: 2 to 7.2 and 7.5 ppm
Aromatic protons 6.8 and 7.4 ppm 5 Aromatic protons 4.9 ppm CH2 4 ppm NH2 Example 1 2-Amino-N-cyclohexyl-3,5-dibromo-
N-Methyl-benzylamine (2-amino-3,5-dibromo-benzyl)-phenyl ether 1.07 (0
．． 0028 mol) and 3.2y (0.028 mol) of N-methyl-cyclohexylamine are heated to 200° C. for 15 hours in a closed vessel.

A pressure of approximately 5 atmospheres is created. The reaction solution is then taken up in chloroform, extracted twice with water, dried over sodium sulfate and then evaporated. This residue is dissolved in a small amount of absolute ethanol and acidified with ethanolic hydrochloric acid. Add 2-amino-N-cyclohexyl-3.5 to this solution.
Ether is added until crystallization of -dibromo-N-methyl-benzylamine-hydrochloride begins. Yield: 0.97
7 (84.0% of theory).

Melting point: 233-234.5°C (decomposed). Example 2 2-amino-3,5-dibromo-N-(trans-4-
Hydroxy-cyclohexyl)-benzylamine The title compound was prepared analogously to Example 1 from (2-amino-3.5-dibromo-benzyl)-phenyl ether and trans-4-amino-cyclohexanol.

Melting point of its hydrochloride: 233-234.5°C (decomposed).

Example 3 2-Amino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzinoleamine Example 1
Similarly, (2-amino-6-chlorobenzyl)-
The title compound was prepared from methyl ether and sarcosine morpholide.

Melting point: 116-118°C The present invention is a method as described in the claims, but includes the following embodiments.

(1) A method as claimed in the claims, wherein the reaction is carried out at a temperature of 14°C to 220°C in the presence of a solvent.

(2) The method according to item (1) above, wherein the reaction is carried out using xylene or tetralin as a solvent, or using an excess amount of the amine used.

(3) The method according to the claims and one of the above items (1) to (2), wherein the reaction is carried out in the presence of an acidic catalyst.
(4) The method according to item (3) above, wherein ammonium chloride or p-toluenesulfonic acid is used as the catalyst.

As is clear from the claims, an additional related original patent invention, Japanese Patent No. 1033495 (Japanese Patent Publication No. 55-23820), is based on the formula (wherein Hal represents a chlorine or bromine atom,
Benzylamine or its physiological In the production of an inorganic or organic acid salt acceptable for the formula, [wherein R1 and Hal represent the above-mentioned meanings, or, when R3 represents a hydroxycyclohexyl group, further represents an organic acyloxy group], and a compound represented by the formula (however, R2 and R3 in the formula have the meanings defined above). )
A process characterized in that the product obtained is optionally converted into a physiologically acceptable salt thereof with an inorganic or organic acid.

” is the gist.

Claims (1)

[Claims] 1 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (in the formula, Hal
represents a bromine or chlorine atom, R_1 represents a hydrogen or bromine atom, R_4 represents a methyl or phenyl group)
There are compounds and general formulas represented by ▲mathematical formulas, chemical formulas, tables, etc.▼(III) (in the formula R_
2 represents a cyclohexyl, hydroxycyclohexyl or morpholinocarbonylmethyl group, R_3 represents a hydrogen atom or a methyl group), and if desired, the resulting compound of formula I is then reacted with an inorganic Alternatively, there are general formulas ▲mathematical formulas, chemical formulas, tables, etc. ▼ (I) (wherein Hal, R_1, R_2 and R_3 are as defined above) A novel process for the preparation of 2-amino-benzylamine (with the defined meaning) and its salts with pharmaceutically acceptable inorganic or organic acids.