WO1997006131A1

WO1997006131A1 - Method of preparing benzylamine derivatives

Info

Publication number: WO1997006131A1
Application number: PCT/EP1996/003509
Authority: WO
Inventors: Herbert Hansen; Wilhelm-Gustav Schnell
Original assignee: Boehringer Ingelheim Kg; Boehringer Ingelheim International Gmbh
Priority date: 1995-08-10
Filing date: 1996-08-08
Publication date: 1997-02-20
Also published as: DE19529431C1; AU6871396A

Abstract

Described is a method of preparing benzylamine derivatives of general formula (I).

Description

Process for the preparation of benzylamine derivatives

The invention relates to a process for the preparation of benzylamine derivatives of the general formula I.

wherein

X and Y simultaneously or differently from one another are a hydrogen, fluorine, chlorine or bromine atom, but preferably a hydrogen and a chlorine atom and particularly preferably a hydrogen atom;

R-1 is a hydrogen atom or a branched or unbranched C-1-C4-

Alkyl group, for example a methyl, ethyl, n-propyl, n-butyl or iso-propyl, iso-butyl group, but preferably a hydrogen atom and a methyl group and particularly preferably a methyl group;

R2 is an isopropylaminocarbonyimethyl or morpholinocarbonylmethyl radical or a radical of the formula IA

with Z as the hydrogen atom or hydroxy, but preferably a radical of the formula IA with Z as the hydrogen atom or hydroxy and particularly preferably a radical of the formula IA with Z as the hydrogen atom,

and their salts and physiologically tolerable salts of inorganic and / or organic acids, characterized in that the hydrohalide of a compound of general formula II

in the

X and Y and R <| and R2 as defined in the introduction is reduced in the presence or absence of a solvent in the presence of a metal.

Various methods for reduction are described in German patent specification 1169 939. On the one hand, the reaction can be carried out by catalytic reduction, for example with hydrogen in the presence of a noble metal catalyst, such as platinum or palladium, advantageously in a solvent, such as methanol, ethanol, tetrahydrofuran or dioxane, or by reduction with a mixture of hydrazine hydrate and Raney nickel, for example in methanol. Another possibility is the reduction with nascent hydrogen, which is formed, for example, from iron, zinc or tin and a mineral acid. The methods of catalytic reduction are in particular due to the use of hydrogen gas due to its high flammability and the risk of explosion from hydrogen for industrial use Processes in which a high excess of hydrogen generally has to be used are disadvantageous. The processes that use nascent hydrogen are disadvantageous due to the use of mineral acid - generally hydrochloric acid or hydrogen chloride gas - because the pH range from 2 to 0 is very corrosive. In order to make the industrial process safe and manageable despite these corrosive conditions, the use of a particularly corrosion-protected reactor, for example a reactor lined with enamel, is necessary. Furthermore, it is usually unavoidable to use the mineral acid or the mineral acid gas in an excess. Even in the event that the mineral acid or the mineral acid gas only has to be added in stoichiometric amounts, a corrosion-protected metering device is required, just as when using an excess. In the reductions with nascent hydrogen known from the prior art, the metal salts of the metals and mineral acids used are generally obtained. In addition, the reaction solution after the reduction is strongly acidic due to the addition of the mineral acid. It is therefore necessary to add a suitable base, for example sodium hydroxide or the reaction solution Potassium hydroxide to neutralize. In the case of the most frequently used metal-mineral acid combination, in which iron and hydrochloric acid or HCl gas is used, iron hydroxide is obtained in the form of a slimy precipitate when neutralizing with a base, usually sodium hydroxide or potassium hydroxide. It is known to the person skilled in the art that iron hydroxide precipitates can only be separated with difficulty from the solutions containing them by known separation methods, such as, for example, filtration, decanting and centrifuging, and the separation requires a high level of technical and time expenditure.

Furthermore, in the case of such reductions according to the prior art, in particular in the case of catalytic hydrogenation, between 1-5% o-toluidine, a carcinogenic substance according to the safety data sheet, is obtained as a by-product.

It is an object of the invention to solve the aforementioned problems.

Surprisingly, a process for the preparation of the compounds having the general formula I

wherein

X and Y simultaneously or differently from each other are a hydrogen, fluorine, chlorine, bromine atom;

R-1 is a hydrogen atom or a branched or unbranched C1-C4 alkyl group;

IA with Z as hydrogen atom or hydroxy,

and their salts and physiologically acceptable salts of inorganic and / or organic acids, characterized in that the hydrohalide of a compound of general formula II

in the

X and Y and R-j and R2 as defined in the introduction are reduced in the presence or absence of a solvent in the presence of a metal

In the process according to the invention, it is no longer necessary to work in appropriately corrosion-protected reactors, for example coated with enamel, since the pH range of the reaction is between 5 and 2, preferably between 4 and 2, particularly preferably between 3 and 2. Furthermore, due to the use of the hydrohalide - this can be the hydrofluoride, bromide and iodide, but preferably the hydrochloride of the general formula II - the problem of metering the mineral acid or mineral acid gas, for example hydrochloric acid or HCl gas Hydrohalide of the general formula II can be added in the course of the reaction or be introduced at the start of the reaction. It is also possible to add the metal in excess, but preferably in stoichiometric amounts. It is advantageous if the metal has a large surface area. These requirements are met in particular by metal wools, metal sponges, metal granules, metal foams and metal powder. However, it is also possible to use the metal in a modification with a small surface area in relation to the amount of metal used. Suitable metals for the process according to the invention are metals which, in the presence of the hydrohalide, preferably the hydrochloride of the compound of the general formula II, reduce the same compound to the compound of the general formula I and are present in the form of their oxides after the reaction. Suitable metals for the process according to the invention are iron , Zinc or tin, with iron being particularly preferred. The metal or the metals can be added in the course of the reaction or be introduced at the beginning of the reaction. Since the metals are present in the form of their oxides, preferably their powdery oxides, at the end of the reaction, they can be very easily by conventional Separation processes, such as decanting, filtering and centrifuging, are separated from the reaction solution. If, for example, iron is used for the process according to the invention, the iron oxide which accumulates, which preferably accumulates as a solid powder, can be compared to the iron hydroxide which forms a slimy precipitate and which is characterized by the state of the art Technically described reduction by means of iron and mineral acid and subsequent basic work-up occurs, can be separated off by generally known, inexpensive separation processes, such as filtration, decanting and preferably by centrifugation. The process according to the invention can be carried out in protic solvents and solvent mixtures, preferably solvent mixtures consisting of alcohols and water. Suitable alcohols are alcohols with a branched or unbranched C 1 -C 5 -alkyl chain, methanol, ethanol and isopropanol being particularly preferred. The solvent or solvent mixture can contain water and the abovementioned alcohols alone or in any mixing ratio. A solvent mixture of water, methanol, ethanol is preferred. A mixing ratio of water, methanol, ethanol of (water / alcohol) 1 / 5-1 / 50, preferably 1 / 10-1 / 20, particularly preferably 1/15 - is particularly preferred. 1/25

The reaction according to the invention can be in a concentration range from 0 25 to 2.5 mol / l, preferably 0.5 to 1.5 mol / l, particularly preferably 0.6 to 0.8 mol / liter, based on one mol of the compound of general formula II per I solvent

The reaction according to the invention can be carried out in a temperature range from 10 to 150 ° C., preferably from 20 to 100 ° C., particularly preferably from 30 to 70 ° C. and at the boiling point of the solvent

The reaction time for reacting 1 mole of the compound with the general formula II is generally 30 to 240, preferably 60 to 120, particularly preferably 70 to 90 minutes

The process according to the invention can be carried out as a continuous or discontinuous process under reduced pressure and elevated pressure, preferably under normal pressure It is also surprising that no carcinogenic o-toluidine is obtained as a by-product in the process according to the invention

The compounds of general formula I obtained can be converted into their acid salts in a known manner using physiologically acceptable inorganic or organic acids, for example by reacting an alcoholic solution of the acid in question with the corresponding base, preferably in equimolar proportions , Hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid or maleic acid have been found to be suitable. The acid addition salts are water-soluble; the salts with one equivalent of the acid in question are used in particular.

The compounds of the general formula I which can be prepared according to the invention have valuable pharmacological properties, in particular they have excellent secretolytic activity with extremely low toxicity.

The following examples are intended to explain the invention in more detail.

example 1

a) N- [2-Amιnobenzy] -N-methyl-cyclohexylamιn-hydrochloride

64.6 g of iron powder are placed in a 1 liter reactor, 175 ml of methanol are added and the mixture is refluxed with vigorous stirring. Over a period of 30 to 45 minutes, a solution of 100 g of N- [2-nitrobenzyl] -N-methylcyclohexylamine hydrochloride, 25 ml of demineralized water and 375 ml of methanol was mixed beforehand at 40 to 50 ° C. with stirring were added with vigorous stirring and refluxing. The reaction is continued for 30 minutes while boiling under reflux and finally cooled to 20 to 25 ° C. For working up, the resulting suspension is filtered and washed with 2 x 50 ml of methanol. The methanol is drawn off from the solution in vacuo (50 to 100 mbar) at 50 to 60 ° C. The residue is taken up in 350 ml of isopropanol at 50 to 60 ° C, mixed with 34.5 to 35 ml of 37% hydrochloric acid, stirred vigorously, cooled to 0 to 5 ° C and further stirred for one hour. The resulting suspension was filtered and washed with 50 ml of isopropanol b) N- [2-aminobenzy] -N-methyl-cyclohexylamine

450 ml of water are added to the N- [2-aminobenzy] -N-methyl-cyclohexylamine hydrochloride thus obtained in the residue and then alkalized with 85 to 95 g of 45% sodium hydroxide solution at 25 to 30 ° C. Then 300 ml are tert. Butyl methyl ether is added, the mixture is stirred vigorously for 10 minutes and the phases are separated. The phases are separated from one another, the aqueous phase is discarded and the solvent of the organic phase is removed in vacuo (50 to 100 mbar) at 40 to 50 ° C., with N- [2-aminobenzy] -N-methyl-cyclohexylamine as pale yellow to colorless viscous oil was obtained, which crystallized to a crystal block on storage (40 - 45 ° C). Yield: 70.8 g, 92.3% of theory

Example 2

N- [2-aminobenzy] -N-methylcyclohexylamine

The entire example 1 was repeated, except that instead of 350 ml of isoproanol, 350 ml of ethanol were used as solvent and washed with 50 ml of ethanol. The yield was 80% of theory.

Example 3

N- [2-aminobenzy] -N-methylcyclohexylamine

The entire example 1 was repeated, except that instead of 350 ml of isoproanol, 350 ml of methanol were used as the solvent and washed with 50 ml of methanol. The yield was 73% of theory.

Example 4

a) N- [2-Aminobenzy] -N-methylcyclohexylamine hydrochloride

64.6 kg of iron powder are placed in a 1000 liter reactor, 175 l of methanol are added and the mixture is heated to reflux with vigorous stirring. Over a period of 30 to 45 minutes, a solution of 100 kg of N- [2-nitrobenzyl] -N- methyl-cyclohexylamine hydrochloride, 25 l of demineralized water and 375 l of methanol, which had previously been mixed at 40 to 50 ° C. with stirring, added with vigorous stirring and refluxing. The reaction is continued for 30 minutes while refluxing and finally on Cooled 20 to 25 ° C. For working up, the resulting suspension is filtered and washed with 2 × 50 l of methanol. The methanol is removed from the solution in vacuo (50 to 100 mbar) at 50 to 60 ° C. The residue is dissolved in 350 l of isopropanol Recorded 50 to 60 ° C, mixed with 34.5 to 35 I 37% hydrochloric acid, stirred vigorously, cooled to 0 to 5 ° C and continued stirring for one hour. The resulting suspension was filtered and washed with 50 l of isopropanol.

b) N- [2-aminobenzy] -N-methyl-cyclohexylamine

The N- [2-aminobenzy] -N-methyl-cyclohexylamine hydrochloride thus obtained in the residue is mixed with 450 ml of water and then alkalized at 25 to 30 ° C. with 85 to 95 kg of 45% sodium hydroxide solution. Then 300 ml are tert. Butyl methyl ether is added, the mixture is stirred vigorously for 10 minutes and the phases are separated. The phases are separated from one another, the aqueous phase is discarded and the solvent of the organic phase is removed in vacuo (50 to 100 mbar) at 40 to 50 ° C., N- [2- Aminobenzy] -N-methyl-cyclohexylamine was obtained as a pale yellow to colorless viscous oil which crystallized to a crystal block on storage (40-45 ° C.). Yield 71.3 kg, 93% of theory

Analytics

JR ^* . against comparison UV ": 237 nm 320-340 287 nm 88-98 against comparison DC ^*** : Dragendorff's reagent against comparison toluidine - undetectable yields with methanol as solvent 71-75% as hydrochloride

^* Infrared spectroscopy

^** UV-vis spectroscopy

^*** Thin layer chromatography Yields with ethanol as solvent 78 - 81%

TLC ^* "Rf value N- [2-aminobenzy] -N-methyl-cyclohexylamine 0.45

Superplasticizer CHCI3 60 ml

OCH3OH 20 ml HCOOH 2 ml

H ₂ O 1 ml

Mp 42-47 ° C [base], 220-222 ° C [x HCl]

HPLC cartridge 125 x 4 mm, Superspher RP select B 4 μm

Mobile phase: 700 ml H2O

250 ml acetonitrile

2 g heptanesulfonic acid 4 ml 0.05 M o-phosphoric acid Gross retention times: N- [2-aminobenzy] -N-methyl-cyclohexylamine 5.8 min.

1 H-NMR of N- [2-aminobenzy] -N-methyl-cyclohexylamine [chemical shift in ppm]: m 0.7 - 1.95 10 H, s 211 3H; m 2.42 1 H, s 3.59 2 H, s 4.57 2H (- NH ₂ ), m 6.57 - 7.03 4 H aromatics

^* "Thin layer chromatography

Claims

claims

1. Process for the preparation of benzylamine derivatives of the general formula I,

wherein

R- | a hydrogen atom or a branched or unbranched CjC. _} - alkyl group;

R2 is an isopropyl aminocarbonyl methyl or morpholinocarbonyl methyl group or a radical of the formula IA

with Z as hydrogen atom or hydroxy,

and their salts and physiologically tolerable salts of inorganic and / or organic acids, characterized in that a hydrohalide of a compound of general formula II

in the

X and Y and R- and R2 are as defined in the introduction, is reduced in the presence or absence of a solvent in the presence of a metal.

2. Benzylamine derivative of the general formula I

in the

X and Y and R- | and R2 are as defined in the introduction, and their salts and physiologically tolerable salts of inorganic and / or organic acids, characterized in that it was produced by a process according to claim 1.

3. Medicament containing a benzylamine derivative according to claim 2.

4. The method according to claim 1, characterized in that in a temperature range from 20 to 150 ° C, preferably from 40 - 90 ° C, in a solvent, preferably in a protic solvent mixture, in the presence of reducing metals, preferably reduced with a large surface area becomes.

5. The method according to claims 1 and 4, characterized in that is reduced to form metal oxide and metal oxide mixtures.

6. The method according to claims 1, 4 and 5, characterized in that the hydrochloride of the compound of general formula II is reduced in the presence of iron powder in a solvent mixture of methanol, ethanol and water.

7. Process according to claims 1, 4, 5 and 6, characterized in that N- [2-aminobenzyl] -N-methyl-cyclohexylamine or its hydrochloride is prepared.