NO152294B - PROCEDURE FOR THE PREPARATION OF CYCLOALIFATIC KETO- AND HYDROXYAMINES - Google Patents

Abstract

process for the preparation of a compound of the general formula. wherein X represents the group in CO or CH (OH), R represents hydrogen or a C 1 -C 6 alkyl group and R 3 represents hydrogen or a hydroxy group and R represents the adamantyl radical or a saturated or a single unsaturated C may also be substituted by a C 1 -C 4 alkyl group or a halogen atom, as well as their acid addition salts by reacting the corresponding N, N'-methylene-bis-oxazolidines with ketones of formula R subsequent reduction.

Description

From DE-OS 29 19 49 5 various methods are known for the preparation of compounds with the general formula

in which X means the group CO or CH(OH), R 2 means hydrogen or a C 1 -C 8 -alkyl group and R-j means hydrogen or a hydroxy group and R 1 means the adamantyl residue or a saturated or monounsaturated C 1 -C 2 -cycloalkyl residue, in that this C3-C1g-cycloalkyl residue can also be substituted with a C1-C4-alkyl group or a halogen atom, as well as their salts. The most important of these methods consists in reacting an amine of the general formula in which R^ has the indicated meaning with a compound of the general formula

in that X, R- and R2 have the indicated meaning and E means a methylene group or a hydrogen atom and the group -CHj-RRgRtø and R& and R^ are low molecular weight alkyl residues, which can also be joined to a ring or in that E can also mean two hydrogen atoms when X means the CO group and is worked on in the presence of formaldehyde or a formaldehyde-yielding substance and possibly reduced in the compounds formed by an isolated double bond and/or a CO group. The other methods specified in DE-OS 29 19 49 5 are more cumbersome and practically do not come into consideration for the technical

manufacture.

The method according to the invention takes a new path for the production of compounds of formula I, it gives, for example, better yields and is easier to carry out.

In formula I, R 2 preferably means a C 1 -C 4 -alkyl group, especially methyl or ethyl. The saturated or unsaturated C 1 -C 8 cycloalkyl radical preferably consists of 3 to 12 C atoms, especially 3 to 8 C atoms. If this cycloalkyl residue is substituted, then it is preferably one or two identical or different substituents such as methyl, ethyl, chlorine, bromine and/or fluorine.

The method according to the invention takes place, for example, during the reaction of 1 mol of a compound of formula II with 2 - 3 mol, in particular 2.3 - 2.5 mol of a ketone with the formula R^-CO-CR2H2

in the presence of an acid in a solvent at a temperature between 20 to 150°C.

The method is generally carried out in an inert solution or suspending agent at temperatures between 5 and 250°C, preferably 20 and 150°C, especially between 40°C and 90°C. As a solvent, for example: lower aliphatic alcohols (ethanol, methanol, isopropanol, propanol), saturated alicyclic and cyclic ethers (dioxane, tetrahydrofuran, diethyl ether), lower aliphatic ketones (acetone), lower aliphatic hydrocarbons or halohydrocarbons (chloroform, 1 ,2-dichloroethane), aromatic hydrocarbons (benzene, xylene, toluene), glacial acetic acid, water or mixtures of these). The reaction solution must in each case be made acidic, preferably with the help of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. However, organic acids and acidic ion exchangers can also be used for this purpose. Organic acids include, for example: saturated and some unsaturated C^-C^-aliphatic mono- and dicarboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, aromatic carboxylic acids such as benzoic acid, C-^-C^-alkyl -benzoic acids or aliphatic or aromatic sulphonic acids such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid (for example p-toluenesulphonic acid).

Mixtures of these acids can also be used. As acid ion exchangers, for example, those mentioned in the book by K. Dorfner, Ionenaustauscher, Verlag De gruyter, 3rd edition, 1970, volume 1 of the work Ionenaustauscher by E. Helfferich, Verlag Chemie, 1959 or in Rompps Chemie Lexikon volume 3, pages 1616-1618 (1976). In detail, it concerns, for example, organic ion exchangers whose active, i.e. ion-forming group is the carboxyl group or an organic acidic group such as the sulfonic acid group (SO^H) or the phosphoric acid group, while the high molecular structure (matrix) consists of synthetic resin (kcryl resin, polystyrene resin, the acid -divinylbenzene copolymer, styrene-acrylic acid copolymer, divinylbenzene polymer, vinylbenzene polymer, condensation products of phenol and formaldehyde). Furthermore, the following are taken into consideration: acidic cellulose, starch and dextran ion exchangers, carbon ion exchangers (of sulphonated high molecular weight humic coal), as well as acidic inorganic ion exchangers such as zeolites and aluminum silicates.

The pH value of the reaction solution or reaction mixture must be between 1 and 6, preferably 2 and 3.

Starting substances with formula II can, for example, be obtained by

a phenylethylamine of the general formula

is reacted with formaldehyde, which can also be used in the form of a normal formaldehyde-producing substance. This transaction takes place

in a solvent or suspending agent at temperatures between 20 and 180°C, especially between 30°C and 150°C. As a solvent or suspending agent, the following come into consideration: water, lower saturated aliphatic C-^-C^ alcohols, lower aliphatic saturated ethers with acrylic residues of 1 - 5 C atoms, aromatic hydrocarbons such as benzene, methylbenzenes (toluene), dimethylbenzenes (xylene). Usually one works at the boiling temperature of the solvent used. The water formed during the reaction can for example be removed by adding drying agents such as sodium sulphate, potassium carbonate, potassium chloride, molecular sieves (for example type 4A), or by azeotropic distillation (for example when using aromatic hydrocarbons as a solvent). The process must be carried out under the exclusion of acids, as the process products are acid-labile.

Usually, one uses per 1 mol of phenylethylamine with formula

IV 1.5 - 5 moles of formaldehyde. Preferably, you use 3 mol of formaldehyde or the equivalent of a formaldehyde-producing substance per 2 mol of phenylethylamine of formula IV. Examples of formaldehyde-producing substances found on roofs are: polyformaldehyde, paraformaldehyde. When using formaldehyde-delivering substances, where the formaldehyde is released in an acidic medium, the formaldehyde release should be preceded by the actual reaction and excess acid carefully neutralized so that the desired dimeric oxazolidines are not exposed to an acidic environment.

For example, N,N<1->methylene-bis(4-methyl-5-phenylroxazolidine) can be obtained as follows: 400 g (2.6 mol) £-norephedrine base is dissolved in 800 ml water, hot, and added dropwise 330 g 35% aqueous formalin solution. The reaction mixture is heated for 4 hours in a boiling water bath. It is then extracted several times with methylene chloride, dried with I^CO^ and the solvent is removed in water. The solid residue is recrystallized from diisopropyl ether.

Yield 423 g (94.5%), melting point 98 - 99°C.

Preparation of this compound can also take place in the following modified way: 10 g (0.066 mol) £-norephedrine base, 4 g (0.132 mol) paraformaldehyde, 6.6 g anhydrous sodium sulphate are suspended in 100 ml dry xylene and heated with stirring for 5 hours during reflux. The inorganic components are filtered off, the solvent is evaporated in vacuo and the solid crude product is recrystallized from isopropyl ether.

Yield 6.1 g = 55%, melting point 98 - 99°C.

10 g (0.066 mol)<£->norephedrine base, 4 g (0.132^01) of paraformaldehyde are suspended in 150 ml of xylene and heated in a water separator for 5 hours under reflux. The solvent is evaporated in vacuo and the solid residue is recrystallized from diisopropyl ether.

Yield 7.6 g = 68%, melting point 100°C.

The starting material of formula II, in which R means a hydroxy group, may contain a common protective group which is cleaved off after the reaction. This refers in particular to residues which are easily split off by hydrolysis in a non-acidic medium and possibly already split off during the reaction.

If such protecting groups are not cleaved off during the method reaction, cleaving takes place after the reaction. Often the output connections contain due to their production already such protection groups. These protective groups are, for example, easily solvolytically cleavable acyl groups. The solvolytic cleavable protective groups are removed, for example, by saponification using basic substances (pot ash, soda ash, aqueous alkali solutions, alcoholic alkali solutions, aqueous NH 4 ) at temperatures between 10 and 150°C, especially 20 - 100°C. For example, water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide and so on, as well as mixtures of these agents, are taken into consideration as solvents or suspending agents. Examples of hydrolytically cleavable residues are: trifluoroacetyl residue, pthalyl residue, trityl residue, p-toluene-sulfonyl residue and the like as well as lower alkanoyl residues such as acetyl residue, formyl residue, tert-butyloxycarbonyl residue and the like. The carbaloxy group (for example, low molecular weight) is also mentioned.

The eventuality reaction associated reduction of the keto group of the compound in which X means the group )CO to compound in which X is the group ^CHOH, as well as reduction of a double bond of the residue R, is usually carried out by means of catalytic hydrogenation. Catalysts include, for example, the usual finely divided metal catalysts such as noble metal catalysts, for example Raney nickel, platinum or especially palladium. The procedure can be carried out at normal temperatures or elevated temperatures. Ideally, you work in a temperature range of approx. 40 to 200°C, possibly under elevated pressure (1 - 100, especially 1-50 bar). If the phenolic hydroxyl group contains the benzyl protecting group, this is split off at the same time during the catalytic hydrogenation when, for example, a palladium catalyst is used.

However, the reduction of the keto group is also possible in another way, for example by means of complex metal hydrides (for example lithium aluminum hydride, sodium borohydride, carboborohydride, lithium tri-tert.-butoxy-aluminium hydride) or by means of aluminum alcoholates according to Meerwein and Ponndorf (for example by using aluminum isopropylate) at temperatures between 0 and 150°C, especially 20 and 100°C. For example, lower aliphatic alcohols, dioxane, tetrahydrofuran, water or aromatic hydrocarbons such as benzene, toluene and mixtures of these come into consideration as a solvent or suspending agent for this reaction.

A selective reduction of a double bond of the resin R^ is for example possible under gentle conditions by the hydrogenation in the presence of noble metal catalysts (Pd, Pt) or Raney nickel.

The starting amine of formula IV used can belong to the diastereomeric series of ephedrine (erythro series) or pseudoephedrine. It can use the pure enantiomers as well as the corresponding racemates. Consequently, the bis-oxazolidine of formula II is obtained which either belongs to the erythro series or the threo series. Bis-oxazolidines of the two series differ in the position of the CH^ group and the phenyl ring. The position of the two substituents appears from the two stereo formulas below:

Depending on whether one starts from corresponding pure enantiomers or racemates of the starting substances IV, the bis-oxazolidines of formula II are likewise obtained in the form of pure enantiomers or racemates. During the cleavage of the bis-oxazolidines under acidic conditions, the centers of symmetry are not touched so that this takes place while maintaining the possibly present configuration.

The process products of formula I as well as the starting bis-oxazolidines of formula II which appear as racemates can be cleaved in a manner known per se, for example by means of an optically active acid under gentle conditions at low temperatures into the optically active isomers. It is of course also possible from the beginning to use optically active or diastereomeric starting substances, as the final product I is then obtained in a correspondingly pure optically active form, respectively diastereomeric configuration. For example, these are compounds of the norephedrine configuration (erythro series) and the pseudonorephedrine configuration (threo series).

Diastereomeric racemates can also occur, as two or more asymmetric carbon atoms are present in the compounds produced. The separation is possible in the usual way, for example as crystallization.

Depending on the process conditions and starting materials get

one the end substances of formula I in free form or in the form of their salts. The salts of the end substances can be transferred back into the bases in a manner known per se, for example with alkali or ion exchangers. Of the latter, it is possible by reaction with organic or inorganic acids, especially those that are calculated to form therapeutic uses

only salts, salts are produced. Examples of such acids should be mentioned: hydrohalic acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or di-carboxylic acids from the aliphatic, alicyclic, aromatic or heterocyclic series as well as sulphonic acids. Examples here are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid or grape acid, phenyl-acetic acid, benzoic acid, p-amino-benzoic acid, anthranic acid, p-hydroxy -benzoic acid, salicylic acid or p-amino-salicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid or also 8-chloro-theophylline.

Example 1

The reaction mixture of 16.92 g (0.05 mol) £- N,N<1->methylene-bis-(4-methyl-5-phenyl-oxazolidine) (prepared from £-norephedrine), 15.14 g (0 .12 mol) acetylcyclohexane, 35 ml of isopropanol and 19 ml of 5.ln isopropanolic hydrochloric acid are heated for 6 hours with stirring and reflux. The reaction mixture is allowed to stand overnight at room temperature. The crystallized product is suctioned off and washed with 5 ml of isopropanol and 20 ml of acetone. One obtains, for example, 32.58 g (67% of the theoretical) £-[3-hydroxy-3-phenyl-propyl-(2)] [3-cyclohexyl-3-oxo-propyl]-amine hydrochloride with a melting point of 219 - 221°C

Claims (2)

1. Process for the preparation of compounds of the general formula in which X means the group CO or CH (OH) , R,, means hydrogen or a C-^-Cg alkyl group and R^ means hydrogen or a hydroxy group and R^ means the adamantyl residue or a saturated or monounsaturated C^-C^g -cycloalkyl radical, as this C₁-C₁₂ cycloalkyl radical can also be substituted with a C₁-C₁-alkyl group or a halogen atom, as well as their acid addition salts, characterized in that an N,N'-methylene-bis-oxazolidine with formula II in which R^ has the indicated meaning, is reacted with a ketone of formula III wherein R^ and R^ have the above meaning in the presence of an acid or acidic ion exchanger and optionally reduce the formed compounds of formula I, wherein R, contains a double bond and/or X represents the CO group, optionally this double bond and/or this CO -group. 2. Method according to claim 1 for the preparation of a compound of the general formula I, in which X has the meaning stated in claim 1, and R2 and R^ mean hydrogen, and R^ means a saturated or monounsaturated Cg-Cg cycloalkyl residue, characterized by using an N,N'-methylene-bis-oxazolidine of formula II and a ketone of formula III, where R^ R 2 and R^ have the meaning indicated above.