GB2087397A

GB2087397A - 3-Hydroxy-3-phenyl-2-propylamine derivatives

Info

Publication number: GB2087397A
Application number: GB8134515A
Authority: GB
Original assignee: Degussa GmbH
Current assignee: Evonik Operations GmbH
Priority date: 1980-11-17
Filing date: 1981-11-16
Publication date: 1982-05-26
Also published as: EG15343A; ES8206441A1; MX7032E; AT379379B; YU269081A; YU42253B; ATA493281A; FI813623L; PT73979A; FI77649B; NO152294B; CS227018B2; DK507581A; LU83751A1; IE52081B1; NO152294C; FI77649C; HU185671B; IE812677L; ES507158A0

Abstract

Compounds of the formula:- <IMAGE> in which X represents the group <IMAGE> or <IMAGE> R2 represents hydrogen or a C1-C6-alkyl group and R3 represents hydrogen or a hydroxy group whilst R1 represents the adamantyl radical or a saturated or monounsaturated C3-C16-cycloalkyl radical which may be substituted by a C1-C4-alkyl group or by a halogen atom, and their acid addition salts are prepared by reacting corresponding N,N'-methylene- bis-oxazolidines with ketones of the formula R1-CO-C(R2)H2 in acid medium, optionally followed by reduction.

Description

SPECIFICATION A new process for the production of cycloaliphatic keto- and hydroxy-amines German Offenlegungsschrift No. 29 1 9 495 describes various processes for the production of compounds corresponding to the following general formula

in which X represents the group

R2 represents hydrogen or a C,-C6-alkyl group and R3 represents hydrogen or a hydroxy group whilst R, represents the adamantyl radical or saturated or monounsaturated C3-C,6-cycloalkyl radical which may even be substituted by a C,-C4-alkyl group or by a halogen atom, and their salts.In the most important of these processes, an amine corresponding to the following general formula

in which R3 is as defined above, is reacted with a compound corresponding to the following general formula

in which X, R, and R2 are as defined above and E represents a methylene group or a hydrogen atom and the group H2NR,Rb where R, and Rh are low molecular weight alkyl radicals which may also be closed to form a ring, in addition to which E may represent two hydrogen atoms where X is the CO-group and the reaction is carried out in the presence of formaldehyde or a formaldehyde donor and an isolated double bond and/or a CO-group in the compounds obtained is optionally reduced.The other processes described in German Offenlegungsschrift No. 29 1 9495 are more complicated and are not really suitable for working on a commercial scale.

The process according to the invention represents a new way of producing compounds corresponding to formula I. For example, it gives better yields and is easier to carry out. The present invention provides a process for the production of compounds corresponding to the following general formula

in which X represents the group

R2 represents hydrogen or a C,-C6-alkyl group and R3 represents hydrogen or a hydroxy group whilst R1 represents the adamantyl radical of a saturated or monounsaturated C3-C16-cycloalkyl radical which may even be substituted by a C,-C4-alkyl group or by a halogen atom, and their acid addition salts, characterised in that an N,N'-methylene-bis-oxazolidine corresponding to the following formula

in which R3 is as defined above is reacted with a ketone corresponding to the following formula

in which R, and R2 are as defined above, in the presence of an acid or acid ion exchanger and the double bond and/or

in the resulting compounds of formula I, in which R, contains a double bond and/or X represents the

is/are optionally reduced.

In formula 1, R2 is preferably a C,-C4-alkyl group, particularly a methyl or ethyl group. The saturated or unsaturated C3-C16-cycloalkyl radical preferably consists of 3 to 1 2 carbon atoms and more particularly of 3 to 8 carbon atoms. If this cycloalkyl radical is substituted, the substituents in question are preferably 1 or 2 identical or different substituents, such as methyl, ethyl, chlorine, bromine and/or fluorine.

The process according to the invention is carried out for example by reacting 1 mole of a compound corresponding to formula II with from 2 to 3 moles and, more particularly, with from 2.3 to 2.5 moles of a ketone corresponding to the formula R1CO{:R2H2 in the presence of an acid in a solvent at temperatures in the range from 20 to 1 50 C.

The process is generally carried out in an inert solvent or suspending agent at temperatures in the range from 5 to 250 C, preferably at temperatures in the range from 20 to 1 50 C and, more particularly, at temperatures in the range from 40"C to 90"C. Suitable solvents, are, 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 halogenated hydrocarbons (chloroform, 1 ,2-dichloroethane), aromatic hydrocarbons (benzene, xylene, toluene), glacial acetic acid, water or mixturcs of these solvents.At all events, the reaction solution has to be acidified, preferably by mineral acids.

such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. However. organic acids and acid ion ex changers may also be used for this purpose. Suitable organic acids are for example, saturated and monounsaturated C1-C4-aliphatic monocarboxylic 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,-C4-alkyl benzoic acids or aliphatic or aromatic sulfonic acids, such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid (for example p-toluene sulfonic acid). Mixtures of these acids may also be used.

Suitable acid ion exchangers are, for example those described in the book by K. Dorfner, entitled "lonenaustauscher (lon Exchangers)", Verlag De Gruyter, 3rd Edition, 1970; in Vol. 1 of the book by E. Helfferich entitled "lonenaustauscher (lon Exchangers)", Verlag Chemie, 1959 or in Römpps Chemie Lexikon, Vol. 3, pages 1616-1618 (1976). More particularly, the acid ion exchangers used are, for example, organic ion exchangers of which the active, i.e. ionforming, group is the carboxyl group or an organic acid group, such as for example the sulfonic acid group (SO3H) or phosphoric acid group, whilst the high molecular weight matrix consists of a synthetic resin (acrylic resin, polystyrene resin, styrene-divinyl benzene copolymer, styreneacrylic acid copolymer, divinyl benzene polymer, vinyl benzene polymer, condensation products of phenol and formaldehyde).It is also possible to use acid cellulose, starch and dextran ion exchangers, carbon ion exchangers (from sulfonated high molecular weight humus carbons) and also acid inorganic ion exchangers, such as zeolites and aluminium silicates.

The pH-value of the reaction solution or reaction mixture should be in the range from 1 to 6 and preferably in the range from 2 to 3.

The starting materials of formula II may be obtained for example by reacting a phenyl ethyl amine corresponding to the following general formula

with formaldehyde which may also be used in the form of a standard formaldehyde donor. The reaction is carried out in a solvent or suspending agent at temperatures in the range from 20 to 180"C and, more particularly, at temperatures in the range from 30"C to 150 C. Suitable solvents or suspending agents are water, lower saturated aliphatic C1-C6-alcohols, lower aliphatic saturated ethers containing C1-C5-alkyl radicals, aromatic hydrocarbons, such as benzene, methyl benzenes (toluene), dimethyl benzenes (xylene). In general, the reaction is carried out at the boiling temperature of the solvent used.The water formed during the reaction may be removed for example by the addition of drying agents, such as sodium sulfate, potassium carbonate, potassium chloride, molecular sieves (for example type 4A), or by azeotropic distillation (for example where aromatic hydrocarbons are used as the solvent).

The process has to be carried out in the absence of acids because the end products of the process are labile in acids.

In general, from 1 5 to 5 moles of formaldehyde are used per mole of phenylethyl amine corresponding to formula IV. It is preferred to use 3 moles of formaldehyde or the equivalent of a formaldehyde donor for every 2 moles of phenylethylamine corresponding to formula IV.

Suitable formaldehyde donors are, for example, polyformaldehyde and paraformaldehyde.

Where the formaldehyde donors used release formaldehyde in the acid medium, liberation of the formaldehyde should precede the actual reaction and excess acid should be carefully neutralised so that the dimeric oxazolidines required are not exposed to the acid medium.

For example, N,N'-methylene-bis-(4-methyl-5-phenyl-oxazolidine) may be obtained as follows: 400 g (2.6 moles) of l-norephedrine base are dissolved with heating in 800 ml of water, followed by the dropwise addition of 330 g of a 35% aqueous formalin solution. The reaction mixture is heated for 4 hours in a boiling water bath. After repeated extraction with methylene chloride, the product is dried with K2CO3 and the solvent removed in vacuo. The solid residue is recrystallised from diisopropyl ether. Yield: 423 g (94.5%), M.p.:98-99"C.

This compound may also be produced by the following modified method: 10 g (0.066 mole) of I-norephredrine base, 4 g (0.132 mole) of paraformaldehyde and 6.6 g of anhydrous sodium sulfate are suspended in 100 ml of dried xylene and the resulting suspension heated under reflux for 5 hours with stirring. The inorganic constituents are filtered off, the solvent is concentrated in vacuo and the solid crude product is recrystallised from diisopropyl ether. Yield: 6.1 g = 55%, M.p.: 98-99"C.

10 g (0.066 mole) of I norephedrine base and 4 g (0.132 mole) of paraformaldehyde are suspended in 1 50 ml of xylene and heated under reflux for 5 hours in a water separator. The solvent is concentrated in vacuo and the solid residue is recrystallised from diisopropyl ether.

Yield: 7.6 g = 68%. M.p.: 1 00'C.

Starting compounds corresponding to formula II in which R3 is a hydroxy group may contain one of the usual protective groups which is split off after the reaction. The protective group in question is in particular a radical of the type which may readily be split off by hydrolysis in nonacid medium and which may even be split off during the actual reaction. If protective groups of the type in question are not split off during the reaction on which the process is based, they are split off after the reaction. In many cases, the starting compound contain protective groups of the type in question from their production.

The protective groups in question here are, for example, acyl groups which may readily be split off by solvolysis. The protective groups removable by solvolysis are split off for example by hydrolysis with basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, aqueous NH3) at temperatures in the range from 10 to 150 C and, more particularly, at temperatures in the range from 20 to 100"C. Suitable solvents and suspending agents are, for example, water, lower aliphatic alcohols, cyclic ethers, such as dioxane or tetrahydrofuran, aliphatic ethers, dimethyl formamide and so on and also mixtures thereof.

Examples of radicals which may be split off by hydrolysis are the trifluoroacetyl radical, the phthalyl radical, the trityl radical, the p-toluene sulfonyl radical and the like, as well as lower alkanoyl radicals, such as the acetyi radical, the formyl radical, the tert.-butyloxycarbonyl radical and the like. The carbalkoxy group (for example of low molecular weight) may also be used for the protective function.

The subsequent reduction of the keto group carried out as an optional reaction on compounds in which X represents the group

to form compounds in which X represents the group

and also the reduction of a double bond in the radical R, are generally carried out by catalytic hydrogenation. The catalysts used are, for example the usual finely divided metal catalysts, such as noble metal catalysts, for example Raney nickel, platinum or, in particular, palladium. The process may be carried out at normal or elevated temperature.It is best to work at temperatures in the range from about 40 to 200"C, optionally under elevated pressure (1 to 100 and, more particularly 1 to 50 bars). If the phenolic hydroxyl group contains the protective benzyl group, this protective benzyl group is split off during the catalytic hydrogenation reaction in cases where for example a palladium catalyst is used.

However, the keto group may also be otherwise reduced, for example using complex metal hydrides (for example lithium aluminium hydride, sodium borohydride, cyanoborohydride, lithium tri-tert.-butoxy aluminium hydride) or aluminium alcoholates, for example aluminium isopropylate (Meerwein and Ponndorf's method) at temperatures in the range from 0 to 150"C and, more particularly, at temperatures in the range from 20 to 100"C. Suitable solvents or suspending agents for this reaction are, for example, lower aliphatic alcohols, dioxane, tetrahydrofuran, water or aromatic hydrocarbons, such as benzene, toluene, and mixtures thereof.

Selective reduction of a double bond in the radical R, is possible for example under mild conditions by hydrogenation in the presence of noble metal catalysts (pd, Pt) or Raney nickel.

The starting compound of formula IV used may belong to the diastereomeric series of ephedrine (erythro series) or pseudo ephedrine. It is possible to use both the pure enantiomers and also the corresponding racemates. Accordingly, bis-oxazolidines corresponding to formula ll belonging either to the erythro series or to the threo series are obtained. The bis-oxazolidines of the two series differ from one another in the position of the CH3-group and the phenyl ring. The position of the two substituents is apparent from the following two stereo formulae:

erythro

threo (pseudo) Depending on whether corresponding pure enantiomers or racemates of the starting compounds of formula IV are used, the bis-oxazolidines of formula II are also obtained in the form of the pure enantiomers or the racemates.Splitting of the bis-oxazolidines under acid conditions does not affect the asymmetry centres so that splitting takes place with the particular configuration present intact.

Those products of formula I and also the starting bisoxazolidines of formula II which are obtained as racemates may be split into the optically active isomers by methods known per se for example using an optically active acid under mild conditions and at low temperatures.

It is of course also possible to use optically active or even diastereomeric starting compounds from the outset, in which case a corresponding pure optically active form or diastereomeric configuration is obtained as the end product of formula I. For example, the compounds in question are compounds of the norephedrine configuration (erythro series) and of the pseudo norephedrine configuration (threo series). Diastereomeric racemates may also be obtained because there are two or more asymmetrical carbon atoms in the compounds produced.

Separation is possible by standard methods, for example by recrystallisation.

The end products corresponding to formula I are obtained either in free form or in the form of their salts, depending on the process conditions and starting materials used. The salts of the end products may be converted back into the bases by methods known per se, for example using alkali or ion exchangers. Salts may be obtained from the bases by reaction with organic or inorganic acids, particularly acids of the type suitable for forming therapeutically acceptable salts. Acids such as these are, for example, hydrohalic acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic monocarboxylic, dicarboxylic or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and also sulfonic acids.Examples of acids such as these 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, hydroxy maleic acid or pyruvic acid; phenyl acetic acid, benzoic acid, p-amino-benzoic acid, anthranilic acid, phydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methane sulfonic acid, ethane sulfonic acid, hydroxy ethane sulfonic acid, ethylene sulfonic acid; halogen benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid or sulfanilic acid or even 8chlorotheophylline.

EXAMPLE 1 A reaction mixture of 16.92 g (0.05 mole) of l-N,N'-methylene-bis-(4-methyl-5-phenyloxazolidine) (produced from Inorephedrine), 15.14 g (0.12 mole) of acetyl cyclohexane, 35 ml of isopropanol and 19 ml of 5.1 n isopropanolic hydrochloric acid is heated under reflux for 6 hours with stirring. The reaction mixture is left standing overnight at room temperature. The product which has crystallised out is filtered off under suction and washed with 5 ml of isopropanol and 20 ml of acetone. I-[3-hydroxy-3-phenyl-(2)-prnpyl]-[3-cyclohexyl-3-oxo-prnpyl]- amine hydrochloride is obtained in a yield of for example 32.58 g, corresponding to 67% of the theoretical. M.p.: 219-221"C.

Claims

1. A process for the production of compounds corresponding to the following general formula

in which X represents the group

R2 represents hydrogen or a C,-C6-alkyl group and R3 represents hydrogen or a hydroxy group whilst R1 represents the adamantyl radical or a saturated or monounsaturated C3-C16-cycloalkyl radical which may even be substituted by a C1-C4-alkyl group or by a halogen atom, and their acid addition salts, characterised in that an N,N'-methylene-bis-oxazolidine corresponding to the following formula

in which R1 and R2 are as defined above, in the presence of an acid or acid ion exchanger and the double bond and/or

in the resulting compounds of formula I, in which R1 contains a double bond and/or X represents the

is/are optionally reduced.

2. A process as claimed in Claim 1, characterised in that compounds of formula I, in which R2 and R3 represent hydrogen and R1 is a saturated or monounsaturated C6-C8-cycloalkyl radical, are produced.

3. A process as claimed in one or more of the preceding Claims, characterised in that the products obtained by the process are converted into the salts.

4. A process as claimed in one or more of the preceding Claims, characterised in that the starting compounds contain protective groups which are split off during or after the reaction on which the process is based.