FI77649C - New Process for Preparation of Cycloaliphatic Keto and Hydroxy Amines. - Google Patents

Description

1 77649

A new process for the preparation of cycloaliphatic keto and hydroxyamines DE-A-2 919 495 discloses various processes for the preparation of compounds of the general formula I and their salts 10 in 2 in which X is a> CO or> CH (OH) group, 1 * 2 is hydrogen or a C 1 -C 6 alkyl group and R 3 represents hydrogen or a hydroxy group and is an adamantyl group or a saturated or simply unsaturated C 1 -C 6 cycloalkyl group,

Wherein this C 1 -C 4 cycloalkyl group may be substituted by a C 1 -C 4 alkyl group or a halogen atom. In the most important of these known methods, an amine of formula R is obtained

H2N-CH (CH3) -CH (OH) wherein R3 is as defined above, to react with a compound of general formula

R, -X-C = E 1 I R

Wherein X, R 1 and R 2 are as defined above and E is a methylene group or a hydrogen atom and a group -CH 2 -NR 2 -, wherein R a Rb are lower alkyl groups which may also be ring-closed or E may also represent two hydrogen atoms when X is a CO group and is worked up in the presence of formaldehyde or a substance producing it, and in the compounds obtained optionally the isolated double bond and / or the CO group is reduced. The other methods described in DE application 2 919 495 are more extensive and 35 are not practically possible in industrial manufacture.

77649

The process according to the invention opens up a new possibility for the preparation of the compounds of the formula I, gives better yields and is simpler to carry out than the above-mentioned known processes.

The novel process according to the invention for the preparation of the compounds of the formula I is characterized in that the N, N'-methylene-bis-oxazolidine of the formula (II) is R 3 10 \ CH, ch, \ / W. 1 1> = /

CH-CH CH-CH

| 51 4J ji li

O 1 2 3 N-CH0-N3 2 1 (J

Wherein R 2 is as defined above, is reacted in the presence of an aqueous solution of an inorganic acid in an inert medium with a ketone of formula III.

r1-co- (|: h2 III

R 2 in which R 1 and R 2 are as defined above, to give a compound of formula I in which X represents> CO-, followed by the> CO group of the compound of formula I thus obtained and / or a possible double bond of the cycloalkyl group if desired, is reduced in a known manner.

In formula I, R 2 is preferably a C 1 -C 4 alkyl group, in particular methyl or ethyl. The saturated or unsaturated C 3 -C 16 cycloalkyl group preferably comprises 3 to 12 carbon atoms, especially 3 to 8 carbon atoms. In the case where this cycloalkyl group is substituted, it is preferably one or two substituents, identical or different, such as methyl, ethyl, chlorine, bromine and / or fluorine.

3,77649

In the process according to the invention, e.g. 1 mole of a compound of the formula II reacts with 2-3 moles, in particular 2.3-2.5 moles, of a ketone of the formula R 1 -CO-Cl 2 I 2 in the presence of an acid in a solvent at a temperature which is 20-150 ° C.

The process is generally carried out in an inert solvent or suspending medium, at a temperature of from 5 to 250 ° C, preferably from 20 to 150 ° C, in particular from 40 to 90 ° C. Examples of suitable solvents are lower aliphatic alcohols (ethanol, methanol, isopropanol, propanol), saturated alicyclic and cyclic ethers (dioxane, tetrahydrofuran, diethyl ether), lower aliphatic ketones (acetone), lower aliphatic hydrocarbons (acetone) or lower aliphatic , 1,2-dichloroethane), aromatic hydrocarbons (benzene, xylene, toluene), glacial acetic acid, water or mixtures thereof. In any case, the reaction solution must be acidified, preferably with the aid of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

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

The starting materials of the formula II can be obtained, for example, by reacting phenylethylamine of the general formula IV with R,.

25 ^ -CH - CH - NHj IV

wherein R 1 is as defined above, is reacted with formaldehyde or a conventional formaldehyde-producing agent. This reaction takes place in a solvent or suspending medium, at an elevated temperature such as 80-180 ° C, preferably 100-150 ° C. Suitable solvents or suspending agents are: water, lower saturated aliphatic C1-C6 alcohols, lower aliphatic saturated ethers having alkyl groups having 1 to 5 carbon atoms, aromatic hydrocarbons such as benzene, methylbenzene (toluene) dimethylbenzyldimethylbenzene . In general, the boiling temperature of the solvent used is 4,77649. The water formed in the reaction can be removed, e.g., by adding a desiccant such as sodium sulfate, potassium carbonate or potassium chloride, molecular sieves (e.g., type 4A), or by azeotropic distillation (e.g., using aromatic hydrocarbons as a solvent).

The preparation must be carried out in the absence of acids, because the manufactured products are not resistant to acids.

In general, 1.5 to 5 moles of formaldehyde-10 are used per mole of phenylethylamine of the formula IV. Preferably, 3 moles of formaldehyde or an equivalent amount of formaldehyde-producing agent are used per 2 moles of phenylethylamine of formula IV. Suitable formaldehyde-producing substances are, for example, polyformaldehyde and paraformaldehyde. When formaldehyde-producing agents are used, whereby formaldehyde is released in an acidic medium, the release of formaldehyde must take place before the actual reaction and the excess acid must be carefully neutralized so that the desired dimeric oxazolidines are not exposed to an acidic environment.

For example, N, N'-methylene-bis- (4-methyl-5-phenyl-5-phenyl-oxazolidine can be obtained as follows: 400 g (2.6 moles) of X-norephedrine base are dissolved in 800 ml of water while heating and 330 g of a 35% aqueous solution of formalin are added dropwise.

The reaction mixture is heated for 4 hours in a boiling water bath. It is then extracted several times with methylene chloride, dried over CO2 and the solvent is removed in vacuo. The solid residue is recrystallized from diiso-30-propyl ether.

Yield: 423 g (94.5%)

Melting point: 98-99 ° C.

This compound can also be prepared in the following modified manner: 10 g (0.066 moles) of X-norepinephrine base, 4 g (0.132 moles) of paraformaldehyde, 6.6 g of anhydrous sodium sulfate are slurried in 100 ml of dried xylan-5,77649 and stirred at reflux. for an hour. The inorganic constituents are removed by filtration, the solvent is concentrated in vacuo and the crude solid is recrystallized from diisopropyl ether.

5 Yield: 6.1 g = 55%

Melting point: 98-99 ° C.

10 g (0.066 mol) of 1-norepinephrine base, 4 g (0.132 mol) of paraformaldehyde are slurried in 150 ml of xylene and refluxed in a water separator for 10 hours. The solvent is concentrated in vacuo and the solid residue is recrystallized from diisopropyl ether. Yield: 7.6 g = 68%

Melting point: 100 ° C.

The starting materials of the formula II in which the hydroxy group is labeled may contain a conventional protecting group which cleaves after the reaction. These are groups which are easily cleaved by hydrolysis in a non-acidic medium and possibly cleaved during the reaction. If such protecting groups 20 do not cleave during the process reaction, cleavage occurs after the reaction. The starting compounds · · already contain protecting groups of this kind based on their preparation.

In connection with such protecting groups, it is also possible to question, for example, acyl groups which are easily solvolytically cleavable. The solvolytically cleavable protecting groups are cleaved, for example, by saponification with basic substances (calcium carbonate, soda, aqueous alkali solutions, alcoholic alkaline solutions, aqueous NH 4 solutions) at a temperature of 30 to -150 ° C, in particular at 20 to 100 ° C.

Suitable solvents or suspending agents are, for example, water, lower aliphatic alcohols, cyclic ethers such as dioxane and tetrahydrofuran, aliphatic ethers, dimethylformamide and the like. and 35 mixtures of these substances.

6 77649

Examples of hydrolytically cleavable groups include: trifluoroacetylphthalyl, trityl, p-toluenesulfonyl and the like, and lower alkanoyl groups such as acetyl, formyl, tert-butyl-5-oxycarbonyl and the like. Carboalkoxy groups (e.g. small molecules) are also possible.

The reduction of the keto groups following the reactions in question in the compounds in which X represents a> CO group to the compounds in which X is a> CHOH group, as well as the reduction of the double bond of the group, is generally carried out by catalytic hydrogenation. Suitable catalysts are, for example, conventional, finely divided metal catalysts, such as precious metal catalysts, e.g.

15 Raney nickel, platinum or especially palladium. The preparation can be carried out at normal or elevated temperatures. It is expedient to work in the temperature range 40-200 ° C, possibly at elevated pressure (1-100, in particular 1-50 bar). If the phenolic hydroxyl-20 li group contains a benzyl protecting group, then this is cleaved simultaneously during the catalytic hydrogenation when e.g. a palladium catalyst is used.

However, reduction of the keto group is also equally possible in another way, for example by means of complex metal hydrides (e.g. lithium aluminum hydride, sodium borohydride, cyanoborohydride, lithium tri-tert-butoxyaluminum hydride) or aluminum alcoholates according to Monnwein and Ponn. ° C, especially 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 of these substances.

Selective reduction of the double bond of the residue R 1 by hydrogenation under careful conditions in the presence of noble metal catalysts (Pd, Pt) or Raney nickel is possible.

7 77649

The starting amine of formula IV used may belong to the diastereomeric series of ephedrine (erythro series) or pseudoephedrine. Both pure enantiomers as well as the corresponding racemates can be used. Accordingly, bis-oxazolidines of the formula II belonging to either the erythro series or the threo series are obtained. The bis-oxazolidines of both series differ in the position of the CH 2 group and the phenyl ring. The location of both substituents is shown in the stereo formulas below; 10

(Cjl H CH- |] H

j 0UH V?> CH 3, _ O \ / \ 15 \ N-CH »- O N-CH - CH- '2 Sch2 2 erythro threo (pseudo) 20 Depending on the starting material IV from the corresponding pure enantiomers or racemates, bis-oxazolidine of formula II in the form of pure enantiomers or racemates with saunas. When the bis-oxazolidine is cleaved under acidic conditions, the centers of asymmetry are not touched, so that these follow in each case while maintaining the existing configuration.

The products of the formula I as well as the crude bis-oxazolidine of the formula II, which are prepared as racemates, can be decomposed into optically active isomers, for example, by means of a optically active acid under careful conditions at low temperatures.

It is, of course, also possible to use optically active or diastereomeric starting materials from the outset, the corresponding end product of the formula I being obtained in a correspondingly pure optically active form or diastereomeric configuration. For example, these are compounds having the norepinephrine s 77649 configuration (erythro-series and) and the pseudonorephedrine configuration (threo-series).

Diastereomeric racemates may also be present because the compounds prepared have two or more asymmetric carbon atoms. Separation is possible in a conventional manner, e.g. by recrystallization.

Depending on the preparation conditions and starting materials, the final products of formula I are obtained in free form.

10 or in the form of its salts. The salts of the final products can be converted back to bases in a manner known per se, for example by means of an alkali or an ion exchanger. The latter provide salts with organic or inorganic acids, especially those suitable for the formation of therapeutically useful salts. Examples of such acids are: hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of aliphatic, alicyclic, aromatic or heterocyclic series, and sulfonic acids.

Examples are: formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic and benzoic acid; phenylacetic, benzoic, p-amino-benzo-25-soo, anthranilic, p-hydroxy-benzoic, salicylic and p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; , halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid and sulfanilic acid and also 8-chloro-theophyl-30.

Example 1

Reaction mixture of 16.92 g (0.05 mol) of 1-N, N'-methylene-bis- (4-methyl-5-phenyl-oxazolidine) (prepared from 1-norepinephrine), 15.14 g (0.12 mol) of acetylcyclohexane, 35 ml of isopropanol and 19 ml of 5.1 N isopropanol hydrochloric acid are refluxed for 6 hours with stirring.

9 77649

The reaction mixture is allowed to stand overnight at room temperature. The crystallized product is separated off and washed with 5 ml of isopropanol and 20 ml of acetone. 32.58 g (67% of theory) of 1- [3-hydroxy-3-phenyl-propyl- (2) -7- [3-cyclo-5-hexyl-3-oxo-propyl] -amine hydrochloride are obtained.

Melting point: 219-221 ° C.

Example 2 1- [3-Hydroxy-3-phenyl-propyl- (2) -N- ([3- (1-cyclohexen-1-yl) -3-oxo-propyl] -amine] 16.92 g (0.05 mol) of 1-N, N'-methylene-bis- (4-methyl-5-phenyl-oxazolidine), 14.9 g (0.12 mol) of 1-acetyl-1 -cyclohexene, 35 ml of isopropanol and 19 ml of 5.1 N isopropanol hydrochloric acid are refluxed with stirring for 6 hours 15 The reaction mixture is allowed to stand overnight at room temperature, the crystallized hydrochloride is filtered off with suction and washed with 5 ml of isopropanol and 20 ml of acetone. Yield 23.3 g.

Melting point of the hydrochloride 203-204 ° C.

Example 3 1- [3-Hydroxy-3-phenyl-propyl- (2) -N- (3-cyclopropyl-3-oxo-propyl] -7-amine

Reaction mixture of 16.92 g (0.05 moles) of 1-N, N'-methylene-bis- (4-methyl-5-phenyl-oxazolidine): 10.10 g (0.12 moles) of acetylcyclopropane , 35 ml of isopropanol 25 and 19 ml of 5.1 N isopropanol hydrochloric acid, reflux for 6 hours with stirring. The reaction mixture is allowed to stand overnight at room temperature. The crystallized hydrochloride is filtered off with suction and washed with 5 ml of isopropanol and 20 ml of acetone. Yield 10.2 g. Melting point of hydrochloride-308 ° C.

Example 4 1- [3-Hydroxy-3-phenyl-propyl- (2) -N- [3- (1-adamantyl) -3-oxo-propyl] -amine

Reaction mixture of 16.92 g (0.05 moles) of 1-N, N'-35 methylene-bis- (4-methyl-5-phenyl-oxazolidine) 21.40 g of 1-acetyladamantane, 40 ml of isopropanol and 20 ml of 5.1 10 7764 9 N isopropanol hydrochloric acid, reflux for 6 hours. The reaction mixture is allowed to stand overnight at room temperature. The crystallized hydrochloride is filtered off with suction and washed with 10 ml of isopropanol and 20 ml of acetone.

5 Yield 12.7 g.

Melting point of the hydrochloride 241 ° C.

Example 5 1- [3-Hydroxy-3-phenyl-propyl- (2) -N- [3- (2-methyl-1-cyclohexen-1-yl) -3-oxopropyl] -7-amine. .92 g (0.05 mol) of 1-N, N'-methylene-bis- (4-methyl-5-phenyloxazolidine), 16.56 g of 2-methyl-1-acetyl-1-cyclohexene, 35 ml isopropanol and 19 ml of 5.1 N hydrochloric acid containing isopropanol are refluxed for 6 hours with stirring.

The reaction mixture is allowed to stand at room temperature overnight. The crystallized hydrochloride is filtered off with suction and washed with 5 ml of isopropanol and 20 ml of acetone. Yield 13.7 g. Melting point of the hydrochloride 197 ° C.

Example 6 20 d, 1- [3-Hydroxy-3- (4-hydroxyphenyl) -propyl- (2) -N- [3-cyclohexyl-3-oxo-propyl] -7-amine A reaction mixture containing 18.5 g (O .05 moles) d, 1N, N'-methylene-bis- (4-methyl-5- (4-hydroxyphenyl) -oxazolidine), 15.14 g (0.12 moles) acetylcyclohexane, 45 25 ml isopropanol and 19 ml of 5.1 N hydrochloric acid containing isopropanol are refluxed for 6 hours with stirring. The reaction mixture is allowed to stand at room temperature overnight. The crystallized hydrochloride is filtered off with suction and washed with 15 ml of isopropanol and 25 ml of acetone.

30 Yield 8 g.

Melting point of the hydrochloride 160-161 ° C.

Example 7 1- [3-Hydroxy-3-phenyl-propyl- (2) (3-cyclohexyl-3-oxo-propyl) -amine] [3] γλ S. y CO-CH2-CH2-NH-CH (CH3 ) -CH (OH) - Λ 11 77649 25 g of 1- [3-hydroxy-3-phenyl-propyl- (2) -N- [3- (cyclohexen-1-yl) -3-oxo-propyl] -7- The amine HCl is dissolved in 250 ml of a methanol / water (2: 1) mixture, 2.5 g of Pd-C (10%) are added and the mixture is hydrogenated at 50 [deg.] C. and 5 bar.

The catalyst is filtered off, the solvent is distilled off in vacuo and the product is crystallized from ethanol.

Yield 85%.

Melting point of the hydrochloride 219-221 ° C.

Examples 8-20 10 The execution of the examples is shown in Table 2.

12 77649

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Example 21 1- [3-Hydroxy-3-phenyl-propyl- (2) -N- (3-adamantyl-3-oxo-propyl) -amine 3 g of 1- [3-hydroxy-3-phenyl-propyl- ( 2) (3-adaman-5-style-3-oxo-propyl) -amine hydrochloride is suspended in dilute ammonia. The suspension is shaken a few times with chloroform. Drying is performed, after which the solvent is removed in vacuo. Recrystallization from isopropanol is performed.

10 Yield 82%.

Melting point 119-121 ° C.

Example 22 (Comparative Example) Preparation of 1- [3-hydroxy-3-phenyl-propyl- (2) .7- [3-cyclohexyl-3-oxo-propyl] -amine hydrochloride by the method of DE-Hake-15 mus 2,919,495 0.12 mol (15.14 g) of acetylcyclohexane and 0.10 mol (16.32 g) of the monomeric oxazolidine (prepared from 1-norephedrine and formaldehyde or paraformaldehyde) are dissolved in 35 ml of isopropanol and then mixed with 19 ml of 5.1. isopropanol solution of HCl. The reaction mixture is heated to reflux for 6 hours. After cooling, the crystallized title product is collected by filtration and washed with 5 ml of isopropanol and 20 ml of acetone. Yield 11.5 g (35.3% of theory). Melting point 207-211 ° C.

Claims (2)

A process for the preparation of compounds of the general formula I 5 / n ** 2 R-, -X-CH-CH - NH-CH (CH-,) -CH (OH) - / R 2 is X is the group> CO or> CH (OH), R 2 is hydrogen or a C 1 -C 6 alkyl group and is hydrogen or a hydroxy group and R 2 is an adamantyl group or a saturated or simply unsaturated C -cycloalkyl group, wherein this C ^-C ^ cycloalkyl group may be substituted with a C ^-C ^ alkyl group or with a halogen atom, and their acid addition salts, characterized by reacting an N, N'-methylene -bis-oxazolidine of formula II? 3 R3 / a ch3 ch3 \ \ 2o \ = y II CH-CH CH-CH 5. i | 4 5 I 11 bl 9 3 N-CHO-n3 9 id ^ 2 where R represents the same as above, with a ketone of formula III R, -CO-CH-, III 1 I R 2 and R 2 are the same as above, in the presence of an aqueous solution of an inorganic acid in an inert medium, whereby a compound of formula I is obtained, where X represents the group> CO, and then, if desired, reduces in the thus obtained compound of formula I in a manner known per se, the CO group and / or the double bond optionally present in the cycloalkyl group.