NO142134B - SOIL- AND PRESSURE-SAFE WALL. - Google Patents

Description

Process for the preparation of therapeutically valuable araliphatic amines.

Processes for the preparation of diphenylalkane derivatives containing a basic araliphatic have previously been described

substituent, as a cardiac and circulatory agent, cf. Austrian patent 211 827 and the

Belgian patents 578,515 and 578,516.

It has now been found that araliphatic amines of the general formula are obtained

in which R1 means a hydrogen or halogen atom, R2 means one optionally in the phenyl nucleus

by a low molecular weight alkyl or alkoxy group substituted benzyl residue, or a

cyclopentyl resp. cyclohexyl residue. and X

stands for a hydrocarbon residue with 1 or 2

C atoms, when one

(a) reduces phenylacetone in the presence of

amines of the general formula

wherein R 2 and X have the above meaning, or reacts phenylacetone with amines of the formula II and then reduces the condensation products or (b) reacts an amine of the formula II with 1-phenyl-2-halopropane resp. -propene and hydrates any double bond present, or (c) reduces aldehydes with that gene real formula wherein R, and R2 have the aforementioned meaning, and Y means a carbon bond or methylene group, in the presence of 1-phenyl-2-amino-propane or reacting the aldehyde of formula III with 1-phenyl-2-amino-propane and then reducing the condensation product , or (d) reduces carboxylic acid amides by the general formula in which R 1 , R 2 and Y have the aforementioned meaning, in a manner known per se to the corresponding amines, or (e) in a manner known per se hydrogenates compounds of the general formula in which R1, R1, and Y have the aforementioned meaning, and optionally transfer the formed basic compounds to the corresponding salts of inorganic or organic acids. The new method products have valuable therapeutic properties, of which cardiovascular and circulatory properties are in the foreground. The new products are clearly superior to the already known compounds in terms of cardiac and circulatory effects. The reduction of phenylacetone in the presence of amines of formula II is particularly advantageous for the production of the new process products. As amines, for example: 1-phenyl-1-cyclohexyl-3-amino-propane, 1-phenyl-1-cyclohexyl-2-amino-ethane, 1,2-diphenyl-4-amino-butane, 1,2-diphenyl-3-amino-propane, 2-[p-(m,o)chlorophenyl]-l-phenyl-4-amino-butane, 2-[p-(m,o)chlorophenyl]-l -phenyl-3-amino- propane, 2-[p-(m,o)chlorophenyl-1-p-(m,o)tolyl]- 4-amino-butane, 2-[p-(m,o)chlorophenyl-1-p-(m,o)tolyl]- 3-amino-propane, l-phenyl-l-cyclopentyl-3-amino-propane, l-phenyl-l-cyclopentyl-2-amino-ethane, 1 - [p-(m,o)-chlorophenyl]-1 -cyclohexyl-3 - amino-propane, l-[p-(m,o)-chlorophenyl]-l-cyclohexyl-2- aminoethane, 1 - [p-(m,o)-chlorophenyl]-1 -cyclopentyl-3-amino-propane, l-p-(m,o)chlorophenyl-1-cyclopentyl-2- aminoethane, l-[p-(m,o)methoxyphenyl]-2-phenyl-4- amino-butane, 1 - [p-(m,o)-methoxyphenyl]-2-phenyl-3-amino-propane, 1 - [p-(m,o)methoxyphenyl]-2- [p-(m, o) -

chlorophenyl]-4-amino-butane and 1-[p-(m,o)methoxyphenyl]-2-[p-(m,o)-chlorophenyl]-3-amino-propane.

Likewise, the homologous amines can be used in which the aromatic residues are substituted by fluorine or bromine instead of chlorine, and/or by an ethyl-, n-propyl-, isopropyl-, n-butyl-,/isobutyl- or tert. -butyl group instead of the methyl group. These amines can either be obtained by the action of cycloalkyl or benzyl Mg halides on cinnamic nitriles and subsequent hydration (cf. J. Am. Chem. Soc. 33, 338) or by hydration of the condensation products of benzaldehydes with benzyl cyanides.

The reduction of phenylacetone in the presence of amines is conveniently carried out by catalytic hydrogenation. As catalysts, metals from the 8th group of the periodic system are used, preferably noble metals. It is appropriate to work in the presence of common solvents, e.g. aqueous alcohols, alcohols or water.

Nickel catalysts can also be used, preferably Raney catalysts. The reduction can also be carried out with the aid of sodium borohydride, where it is appropriate to first prepare the condensation product from amine and phenylacetone, optionally at slightly elevated temperatures as well as optionally in the presence of an indifferent organic solvent, for example benzene or toluene, and reduce after dilution with a suitable solvent, for example lower alcohols, optionally in the presence of water, by adding sodium borohydride. Furthermore, one can also reduce with nascent hydrogen, e.g. with aluminum amalgam and alcohol, sodium amalgam or lithium aluminum hydride. The reduction can also be carried out electrolytically.

In another, more advantageous embodiment of the method according to the invention, the above-mentioned amines of formula II can be reacted with 1-phenyl-2-halo-propanes or -propene.

As such l-phenyl-2-halo-propanes resp. -propenes can be used, for example: l-phenyl-2-chloro-propane, l-phenyl-2-bromo-propane or l-phenyl-2-iodo-propane, as well as the corresponding l-phenyl-2-halo-propenes . These compounds can be obtained by halogenation of methylbenzylcarbinol (cf. Beilstein vol. 5, 391 and vol. 5, 1st comp, work 190).

This reaction is conveniently carried out in suitable solvents, for example in aromatic hydrocarbons such as benzene or toluene, with the help of prolonged heating. In order to bind the liberated hydrogen halide, 1 mol of l-phenyl-2-halo-propane or -propene with 2 mol of amine. The hydrogen halide bond can also take place with the help of the usual basic agents such as alkali and earth alkali carbonates or hydroxides, as well as organic bases such as pyridine or quinoline which can possibly serve as a solvent at the same time. The work-up takes place in the usual way by separating the halohydrogen acid salt from the base used, for example by precipitation with ether or shaking with water. The basic process product can be purified by distillation or by transfer into a suitable salt. If propene halides are used, the double bond is then hydrogenated according to the usual methods for this purpose.

A further embodiment of the method according to the invention consists in reducing the aldehyde with formula III in the presence of 1-phenyl-2-amino-propane. As aldehydes can be used, for example: a,[3-diphenylpropionaldehyde, p,y-diphenyl-butyraldehyde, phenyl-cyclohexyl-acetaldehyde, p-phenyl-p-cyclohexyl-propionaldehyde, 0-(o,m,p)-chlorophenyl -(3-phenyl-propionaldehyde, |3- (o,m,p)-chlorophenyl-y-phenyl-butyraldehyde, a-(o,m,p)-chlorophenyl-p-(o,m,p)- tolyl-propionaldehyde, p-(o,m,p)-chlorophenyl-y-(o,m,p)-tolyl-butyraldehyde and p-(o,m,p)-chlorophenyl-y-(o,m ,p)-methoxy enyl-butyraldehyde.

The aldehydes can be produced by rearrangement of the corresponding diphenyl-dihydroxypropanes or -butanes analogously to a regulation set out in "Chem. Zentralblatt", 1932, II, 3704.

Cyclo-alkyl-phenyl-acetaldehydes can be prepared from the corresponding acids according to "Chem. Zentralblatt", 1938, II, 3391.

The reaction of the aldehydes is preferably carried out by hydrogenation in the presence of 1-phenyl-2-amino-propane; It is appropriately reduced catalytically with the help of metals from the 8th group of the periodic table, preferably with noble metals such as palladium or platinum, in the presence of solvents common to this purpose, e.g. aqueous alcohols, alcohols or water. Raney catalysts can also be used. Similarly, one can also reduce with nascent hydrogen, e.g. aluminum amalgam and alcohol, sodium amalgam, lithium aluminum hydride, or particularly advantageously, especially in the case of halogen-substituted aldehydes, with sodium borohydride. The reduction can also be carried out electrolytically.

In many cases it can be advantageous to first isolate the condensation product obtained from aldehyde and 1-phenyl-2-amino-propane and then to reduce it in another reaction step. The condensation that takes place in the first stage is usually already successful at room temperature or a slightly elevated temperature (steam bath). It is appropriate to work in the presence of indifferent organic solvents such as benzene or toluene. For the reduction, one advantageously uses one of the already mentioned solvents and proceeds as indicated above. For example, you can reduce with sodium borohydride.

According to a further embodiment of the method according to the invention, carboxylic acid amides with the general formula IV can also be reduced according to methods known per se, the reduction with lithium aluminum hydride being particularly advantageous. The production of the carboxylic acid amides used as starting materials can, for example, be carried out by reacting acid chlorides with the general formula

where Y, R, and R 2 have the aforementioned meaning, with 1-phenyl-2-amino-propane.

The reaction of these acid chlorides with 1-phenyl-2-amino-propane is mostly carried out in indifferent solvents such as ether, benzene or chloroform. It is advantageous to use 2 mol of 1-phenyl-2-amino-propane to 1 mol of acid chloride to bind the liberated hydrogen chloride.

As such carboxylic acid chlorides, the following can be used, for example: a-phenyl-p-phenylpropionyl chloride, p-phenyl-y-phenylbutyryl chloride,

a-phenyl-p-(o,m,p)-tolyl-propionyl chloride, p-phenyl-y-(o,m,p)-tolyl-butyryl chloride, «-phenyl-p-(o,m,p)-methoxyphenyl -propionyl chloride.

p-phenyl-γ-(o,m,p)-methoxy enylbutyryl chloride,

α-chlorophenyl-p-(o,m,p)-tolyl-propionyl chloride,

p-chlorophenyl-γ-(o,m,p)-tolyl-butyryl chloride, phenyl-cyclohexyl-acetyl chloride and p-phenyl-p-cyclohexyl-propionyl chloride.

The acids corresponding to the aforementioned acid chlorides can be prepared by reduction of the corresponding cinnamic acids. (Cf. Chem. Ber. 70, 1886 or Beilstein 9, 678).

The reduction of the carboxylic acid amides using lithium aluminum hydride is carried out according to methods known per se, suitably in the presence of indifferent organic solvents such as ether, dioxane or tetrahydrofuran. It is advantageous to work in such a way that one puts the amide of the lithium aluminum hydride suspension in one of the mentioned solvents, then allows the reaction mixture to boil for some time under reflux and then carefully mixes with water, and works up in the usual way by separating the organics from the inorganic constituents. The reduction of the described carboxylic acid amides to the amines can also be carried out electrolytically.

Finally, the process products can also be prepared by hydrogenating compounds with the general formula

in which Rj, R2 and Y have the aforementioned meaning, for example take place by dehydration by methods known per se. Preparation of compounds with the general formula of such unsaturated compounds can

(wherein R 1 , R 2 and Y have the aforementioned meaning). Dehydration is usually already successful by brief heating with acids, for example halogen-hydrogen acid, sulfuric acid, phosphoric acids etc. It can also be carried out using phosphorus pentoxide, phosphorus halides or thionyl chloride. The transfer of these unsaturated compounds of formula V into the process products takes place advantageously by means of catalytic hydrogenation. Metals from the 8th group of the periodic system such as palladium, platinum or nickel are preferably used as catalysts. Raney catalysts can also be used.

The process products can be transferred as basic compounds by means of inorganic or organic acids in the corresponding salts. Examples of inorganic acids that come into consideration are: hydrohalic acids, such as hydrochloric acid and hydrobromic acid as well as sulfuric acid, phosphoric acid and amidosulfonic acid. Examples of organic acids include: Formic acid, acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aceturic acid, oxyethanesulphonic acid and ethylene diamine triacetic acid. The process products have an extremely good cardiac and circulatory effect. Thus, e.g. administration of 1-phenyl-2-[1'-phenyl-1'-cyclohexyl-propyl-(3')]-aminopropane in experiments on isolated rabbit hearts according to Langendorff by a single injection of only 2.5 v to a strong coronary artery dilation, which compared to the normal untreated heart corresponds to an increase in the coronary flow of approx. 50 percent

The process products are considerably superior to the already known compounds of similar structure, thus for example the already known 1-phenyl-2-[1',r-diphenyl-propyl-(3')]-amino-propane is the application of the double dose (5 y) necessary, when an equally strong coronary dilating effect is to be achieved.

1-phenyl-2-[1'-(p-4olyl)-2'-(p-chlorophenyl)-propyl-(3')]-amino-propane acts on isolated rabbit hearts according to Langendorff in a dosage of 25 y en increase in coronary flow by 47 percent. This

substance is tolerable in a dose three times higher than that from Belgian patent no. 578 515 known 1-phenyl-2-[1'-1'-diphenyl-propyl-(3')J-aminopropane and than that from Austrian patent no. 211,827 known 2-[1,1-diphenyl-propyl-(3)-diethylamino-acetylamino]-3-phenylpropane. Furthermore, with this test device, 1-phenyl-2-[1', 2'-diphenyl-butyl-(4')]-amino-propane increases the coronary circulation by 87 percent in a dosage of 5 y. l-phenyl-2-[l'-phenyl-l'-cyclohexyl-

ethyl-(2')]-amino-propane increases the coronary circulation by 39 percent at a dosage of 5 Y-

Example 1.

13 g of 1-p-tolyl-2-p-chlorophenyl-3-amino-propane are heated with 6.7 g of phenylacetone for 30 min. in a steam bath. The reaction mixture is then diluted with 100 cm<8> of methanol and mixed in portions with 1 g of sodium borohydride. After standing for 1 hour at 80° C, the solvent is distilled off under reduced pressure. The residue is mixed with approx. 20 cm<3 >water. You get an oil that is extracted. The ethereal solution is dried and the ether is distilled off, obtaining 17 g of an oily residue. The calculated amount of maleic acid dissolved in alcohol is added and 1-phenyl-2-[1'-(p-tolyl)-2'-(p-chlorophenyl)-propyl-(3')]-aminopropane maleate is obtained with a melting point of 138 -140°C.

Example 2.

Corresponding to the regulation given in example 1, 11.3 g of 1,2-diphenyl-4-amino-butane and 6.7 g of phenylacetone yield 17.5 g of 1-phenyl-2-[l\2'-diphenyl-bu> tyl-(4')]-amino-propane in the form of an oil-like residue. After adding the calculated amount of 2n-hydrochloric acid, the solution is evaporated under reduced pressure to dryness. When the residue is expelled with acetone, the hydrochloride of the base crystallizes with a melting point of 162-164° C (from ethanol).

Example 3.

Corresponding to the regulation given in example 1, 10.8 g of 1-phenyl-1-cyclohexyl-3-amino-propane and 6.2 g of phenylacetone yield 17 g of 1-phenyl-2-[l'-phenyl-1'- cyclohexyl-propyl-(3')]-amino-propane as an oil-like residue. After the mixture with alcoholic hydrochloric acid and ether, the crystalline hydrochloride is obtained. Melting point 182-184°C (from ethanol/ether).

Example 4.

Corresponding to the regulation stated in example 1, 10.1 g of 1-phenyl-1-cyclohexyl-2-amino-ethane and 6.7 g of phenylacetone yield 16 g of 1-phenyl-2-[l'-phenyl-1'- cyclohexyl-ethyl-(2')]-amino-propane in the form of an oil. The maleinate of the compound melts at 167-168° C (from ethanol).

Example 5.

22.5 g of 1,2-diphenyl-4-aminobutane is boiled for 6 hours under reflux with 10 g of 1,2-phenyl-2-bromo-propane in 150 cm<3> toluene. After cooling, it is mixed with 100 cm<3> of water, the layers are separated and, after drying with sodium sulphate, the solvent is distilled from the toluene solution under reduced pressure. The oil-like residue is transferred with 2n-hydrochloric acid to the hydrochloride of 1-phenyl-2-[1',2'-diphenyl-butyl-(4')]-amino-propane with melting point 162-163° C (ethanol).

Example 6.

20.2 g of phenyl-cyclohexyl-acetaldehyde are dissolved with 13.5 g of 1-phenyl-2-amino-propane in 50 cm<3> toluene and heated on a steam bath. After separation of the calculated amount of water, 100 cm<3> of methanol and 1 g of NaBH4 are added in portions. After 1 hour's rest, the solvent is removed under reduced pressure. The oil-like residue is dissolved in a little alcohol, and mixed with the calculated amount of alcoholic maleic acid solution. After the addition of ether, the hydrochloride of 1-phenyl-2-[1'-phenyl-1'-cyclohexyl-ethyl-(2')]-amino-propane crystallizes out, which melts at 167-168° C. (from alcohol).

Example 7.

23.2 g of (3-phenyl-(3-cyclohexyl-propionic acid) is transferred with 20 g of thionyl chloride in acid chloride. After distilling off excess thionyl chloride under reduced pressure, the residue is taken up in ether and mixed dropwise with stirring with 1-phenyl-2- amino-propane in 50 cm<3> ether until the reaction solution reacts weakly alkaline. For this, 20-25 g of 1-phenyl-2-amino-propane is necessary. After stirring for 2 hours, it is filtered, the ethereal solution is washed with water, and the solvent is removed after drying. The oily residue is dissolved in about 50 cm<3> of ether and added dropwise with stirring to a suspension of 5 g of Li A1H, in 300 cm<3> of ether. After 8 hours of boiling under reflux, the with water, the precipitate is sucked off and washed with ether. The combined ether solutions are dried with sodium sulfate, and the solvent is evaporated. The oily residue is transferred with alcoholic hydrochloric acid into the hydrochloride of l-phenyl-2-[r-phenyl-l '-cyclohexyl-propyl-(3') ]-amino-propane which melts at 182-184° C ( from alcohol).

Example 8.

l-phenyl-2-[r-phenyl-1'-cyclohexyl-propane-(V)-yl-(3')]-amino-propane prepared by water splitting from l-phenyl-2-[l'-phenyl- 1'-cyclohexyl-1'-hydroxy-propyl-

(3')]-amino-propane by means of toluene-sulfonic acid in toluene, catalytically hydrogenates in the presence of palladium black. After filtration and evaporation of the solvent, 1-phenyl-2-[1'-phenyl-1'-cyclohexyl-

propyl-(3')]-amino-propane as an oil-like residue. The base's hydrochloride melts at 182-184° C (from alcohol).

The starting material l-phenyl-2-[l'-phenyl-1'-cyclohexyl-r-hydroxy-propyl-(3')]-amino-propane can be prepared in the following way: 1-phenyl-l-cyclohexyl-1-hy droxy-3-amino-propane produced according to German patent no. 1,051,281 is condensed in the manner indicated in example 1 with phenylacetone, and the condensation product is then reduced with NaBH4.

Patent claim: Process for the preparation of therapeutically valuable araliphatic amines of the general formula in which R, means a hydrogen or halogen atom, R 2 means a benzyl radical optionally substituted in the phenyl nucleus with a lower molecular weight alkyl or alkoxy group, or a cyclopentyl resp. cyclohexyl residue, and X stands for a hydrocarbon residue with 1 or 2 C atoms, as well as acid addition salts of these compounds, characterized by a) reducing phenylacetone in the presence of amines with the general formula in which R1, R2 and X have the aforementioned meaning, or reacts phenylacetone with amines of the formula II and then reduces the condensation products, or b) reacts an amine of the formula II with 1-phenyl-2-halo-propane resp. -propene and hydrates a possibly present double bond, or c) reduces the aldehyde with that gene real formula wherein R, and R2 have the aforementioned meaning and Y represents a carbon-carbon bond or methylene group, in the presence of l-phenyl-2-amino-propane, or reacting the aldehyde with l-phenyl-2-amino-propane and then reducing the condensation products, or d) reduces carbonic acid amides with it general formula in which R1, R2 and Y have the aforementioned meaning, in a manner known per se to the corresponding amines, or e) in a manner known per se hydrogenates compounds of the general formula

in which Rj, R2 and Y have the aforementioned meaning, and optionally transfer the prepared basic compound into the corresponding salts of inorganic or organic acids.

Publications cited: • Austrian Patent No. 211,827.

Belgian Patent No. 578,515, 578,516.

Claims (7)

1. Fire- and pressure-proof wall which is built up from a number of sections (4), each of which has a largely rectangular, plate-shaped part (5) and an insulation (25), characterized in that it comprises flange-like parts (6) which are connected by two parallel edges of the plate-shaped part (5) and are located on the same side of the plane of the plate-shaped part (5), the joint (8) between two sections (4) being formed between a flange ( 6) on one section (4) and a flange (6) for the other section (4), first fastening means (7) connecting the flanges (6) at the joints (8) whereby the sections (4) are thereby connected to each other, first sealing means (9) which are arranged between the flange-like parts (6) in the joints (8) to the fastening means (7) along the entire length of the joints (8), reinforcement profiles (10) which have a thickness that is independent of the thickness of the flange-shaped parts (6) and are arranged at the flanges (6) on the inside of the sections (4), an end profile (11; 18; 32) which is arranged along each of the two end edges of the wall which extends across the joints, which end profiles (11; 18; 32) exhibit a branch (16; 22) which overlaps the end portions of the plate-shaped parts (5) up to said end edges on the side of the plate-shaped parts (5) which is opposite the flanges (6), other fastening means (17; 24; 37) which connect the branches (16; 22) and the plate-shaped parts (5), whereby the sections (4) and the end profiles (11; 18; 32) are connected to each other, second sealing means (15; 23; 39) which are arranged between the branches (16; 22) and the plate-shaped parts (5) along the entire length of the branches; means (13, 14 f 20, 21; 36, 35) for connecting the end profile (11; 18; 32) in a pressure-tight manner to an adjacent structure (3; 2; 34), and a cover plate (26) covering the insulation (25). 2. Wall according to claim 1, characterized in that said end edges of the plate-shaped parts (5) exhibit a reinforcement seam (29; 31) which extends largely perpendicular to the plane of the plate-shaped part and is located on the same side of the plate-shaped part (5 ) as the flanges (6). 3. Wall according to one of the preceding claims, characterized in that the branch (16; 22) at its free end exhibits a reinforcement fold (28; 30) which is largely perpendicular to the branch (16; 22) and which is directed away from it adjacent plate-shaped part (5). 4. Wall according to a preceding claim, characterized in that the end profile (11; 18; 32) has a cross-section like a U, the end edge of the sections (4) being inserted between the legs of the U-shaped end profile (11; 18; 32) and one (16; 22) of the legs constitutes said branch. 5. Wall according to claim 4 which is connected to a floor (3) or a roof (2), characterized in that the middle part (12; 19) of the U-profile (11; 18) is attached to the floor or the roof by means of fastening means (14; 21), sealing means (13; 20) being arranged between the middle part (12; 19) and the floor (3) or the ceiling (2). 6. Wall according to claim 4 which is connected to a roof (34) which rests on the wall, characterized in that the roof (34) rests on an element (33) which projects from the free end of said branch and which is directed away from the adjacent plate-shaped part (5), sealing means being arranged between said element (33) and the roof (34) and fastening means (35) being arranged for fastening the roof (34) to the element (33). 7. Wall as specified in any of the preceding claims, characterized by a supporting part (42) arranged for every second flange (6) counted in the direction across the joints (8) between the sections (4), and extending largely parallel to the plane of the plate-shaped part (5), and a largely rectangular cover plate (26) showing a largely non-buoyed edge (43) and parallel to it a double-buoyed edge (44), the cover plate (26) being intended to rest with its non-boyded edge (43) against said supporting part (42), and an adjacent cover plate (26) is designed to be pushed over the non-boyded edge (43) and the supporting part (42) with its double width edge (44) thereby partially locking itself and partially the non-boyded edge of the first-mentioned cover plate (26) to said supporting part (42).