CS227018B2 - Method of preparing cycloaliphatic ketoamines - Google Patents

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

(54) A method for producing cycloaliphatic keto amines

The present invention relates to a process for the preparation of cycloaliphatic ketoamines of the formula I

1-CO-CW ₃ (CMFNH-CH ₃ CH ₃ ) -CH (OH)

(l) indicating

R 3 is a hydrogen atom;

R, an adamantyl group or a saturated or simply unsaturated cycloalkyl radical of 3 to 16 carbon atoms, the cycloalkyl radical may be substituted by an alkyl group having 1 to 4 carbon atoms or a halogen atom, and their acid addition salts.

DE-OS 29 19 495 discloses various processes for the preparation of compounds of the formula Ia

wherein R ₁ and R 3 are as defined above, wherein

X is = CO or = CH (OH) and!

R ₂ represents hydrogen or alkyl having 1 to 6 carbon atoms.

The most important of these methods is to react the amine of formula

H ₂ N-CH (CH ₅ ) -CH (OΗ) -ζ ^ ³ in which R _{3 is} as defined above, with a compound of the general formula

R 1 -X-C-E r ₂ wherein X, R f and R _{2 are} as defined above and a

E represents a methylene group; is hydrogen or -CH ₂ -NR _a R b, wherein R _a and R _b is a low molecular weight alkyl radicals, which may also be enclosed in a circle; or when X is = CO, it can also be two hydrogen atoms, in the presence of formaldehyde or formaldehyde providing and optionally reducing isolated double bonds and / or carbonyl groups in the compounds obtained. Other methods listed in DOS no.

919 495 are longer and are practically out of the question for technical use.

The process of the present invention represents a novel route for the preparation of compounds of Formula I; for example, it has higher yields and is easier to carry out,

The compounds of formula I cause vascular expansion, especially peripheral blood circulation, and are therefore useful in the manufacture of medicaments.

The principle of the present invention is that N, N,-methylene-bis-oxazolidine II is reacted

wherein R _{3 is} as defined above, with a ketone of formula III

R ₁ -CO-CH ₃ (III), in which R 1 is as defined above, and optionally in the obtained compound of formula I wherein R 1 contains a double bond, the double bond is reduced.

In Formula I R _T saturated or unsaturated cycloalkyl radical having 3 to 16 carbon atoms which preferably contains from 3 to 12 carbon atoms, especially 3-8 carbon atoms. When the cycloalkyl radical is substituted, it is preferably one or two of the same or different substituents, such as methyl or ethyl, chlorine, bromine and / or fluorine.

In the process according to the invention, for example, one mole of a compound of formula II is reacted with two to three moles, in particular 2.3 to 2.5 moles, of a ketone of

R 1 -CO-CH ₃ in the presence of acid at a temperature in the range of 20 to 150 ° C.

The process of the present invention is generally carried out in an inert solvent or suspending agent at temperatures in the range of 5 to 250 ° C, preferably in the range of 20 to 150 ° C, especially at a temperature in the range of 40 to 90 ° C. Suitable solvents are the following:

Lower aliphatic alcohols such as ethyl alcohol, methanol, isopropyl alcohol or propyl alcohol, saturated alicyclic and cyclic ethers such as dioxane, tetrahydrofuran and diethyl ether, lower aliphatic ketones such as acetone, lower aliphatic hydrocarbons, lower aliphatic halocarbons such as chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, glacial acetic acid, water or mixtures thereof.

The reaction solution must in any case be converted to an acidic reaction, preferably with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. However, organic acids and acidic ion exchangers can also be used for this purpose. The following are suitable organic acids:

Saturated and simply unsaturated aliphatic monocarboxylic and dicarboxylic acids having 1 to 4 carbon atoms, such as formic acid, acetic acid, propionic acid, oxalic acid, maleic acid and fumaric acid, aromatic carboxylic acids such as benzoic acid, alkylbenzoic acids Or aliphatic or aromatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid such as p-toluenesulfonic acid.

Mixtures of the acids mentioned may also be used. Possible acidic exchangers are, for example, those mentioned in K. Dorfner's book Ionenaustauscher, De Gruyter, 3rd edition 1970; in Volume 1 of Ionenaustauscher by E. Helfferich, Chemie 1959, or Rompps Chemie Lexikon, Volume 3, pp. 1616—1618 (1976).

These are, for example, organic ion exchangers whose active, i.e. ion-forming, groups are carboxylic or organic acid groups, such as the sulfonic acid (SO ₃ H) or phosphoric acid residue, while the high-molecular-weight matrix consists of an artificial resin such as is, for example, acrylic resin, polystyrene resin, styrene-divinylbenzene copolymer, styrene-acrylic acid copolymerisate, divinylbenzene polymerisate, vinylbenzene polymerisate, and phenol-formaldehyde condensation products. Possible ion exchangers based on acidic cellulose, starch and dextrin, coal exchangers (high-molecular-weight humus coal) and acid inorganic ion exchangers such as zeolites and alumosilicates are also suitable.

The pH of the reaction solution or reaction mixture should be in the range of 1 to 6, preferably 2 to 3.

For example, the starting materials of formula (II) can be obtained by reacting the phenylethylamine of formula (IV)

R f ³ ch-ch-nh ₂ (IV) in which R _{3 is} as defined above, with formaldehyde, which may also be used in the form of a conventional formaldehyde-providing substance. This reaction is carried out in a solvent or suspending agent at temperatures in the range of 20 to 180 ° C, in particular at temperatures in the range of 30 to 150 ° C. Suitable solvents and suspending agents are:

Water, lower saturated aliphatic alcohols having 1 to 6 carbon atoms, lower saturated aliphatic ethers having alkyl radicals having 1 to 5 carbon atoms, aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzenes. In general, the reaction is carried out at the boiling point of the solvent used. The water produced in the reaction can be removed, for example, by the addition of desiccants such as sodium sulfate, potassium carbonate, potassium chloride, molecular sieves (e.g. type 4A) or by azeotropic distillation (e.g. using aromatic hydrocarbons as solvents).

This process must be carried out with the exclusion of acids, since the products of the process are acid labile.

Generally, 1.5 to 5 moles of formaldehyde are used per mole of phenylethylamine of formula IV. Preferably, moles of formaldehyde, or equivalent of formaldehyde-providing substance, are used per 2 moles of phenylethylamine of formula IV. Examples of suitable formaldehyde donors are: polyformaldehyde, paraformaldehyde.

When using formaldehyde-providing substances in which formaldehyde is released in an acidic environment, the formaldehyde release must be carried out prior to the reaction and the excess acid must be completely neutralized so as not to impair the desired formation of dimeric oxazolidines by the acidic environment.

For example, N, N‘-methylene-bis- (4-methyl-5-phenyl-oxazolidine) can be obtained as follows:

400 g (2.6 mol) of 1-norephedrine base are dissolved in 800 ml of water while hot and 330 g of a 35% aqueous formaldehyde solution are added dropwise. The reaction mixture was then heated on a boiling water bath for 4 hours. The reaction mixture was extracted several times with methylene chloride, the extract was dried over anhydrous potassium carbonate and the solvent was evaporated in vacuo. The solid residue is recrystallized from diisopropyl ether.

Yield: 423 g (94.5% of theory);

mp 98-99 ° C.

Said compound can also be produced as follows:

g (0.066 mol) of 1-norephedrine base, g (0.132 mol) of paraformaldehyde and 6.6 g of anhydrous sodium sulfate were suspended in 100 ml of anhydrous xylene and the mixture was heated under reflux for 5 hours with stirring. The inorganic components are then filtered off, the solvent is removed in vacuo and the solid crude product is recrystallized from diisopropyl ether.

Yield: 6.1 g (55%): mp 98-99 ° C.

It is also possible to proceed as follows:

g (0.066 mol) of 1-norephedrine base and 4 g (0.132 mol) of paraformaldehyde are suspended in 150 ml of xylene and the reaction mixture is heated under reflux in a water trap for 5 hours. The solvent was then evaporated in vacuo and the solid residue was recrystallized from diisopropyl ether.

Yield 7.6 g (68%); mp 100 ° C.

The starting compound of formula (II) in which R3 is a hydroxyl group may contain a conventional protecting group which is cleaved off after the reaction. This is particularly the case - residues which are readily cleavable by hydrolysis in a non-acid medium and, if appropriate, already cleaved during the reaction. If such protecting groups do not cleave in the reaction in the process, cleavage is carried out after the reaction. Often the starting compounds already contain such protective groups because of their production.

Such protecting groups are, for example, easily solvolytically cleavable acyl groups. For example, the solvolytically cleavable protecting groups are cleaved by saponification with basic substances (potassium carbonate, sodium carbonate, aqueous alkali solutions, alkaline alcoholic solutions or aqueous ammonia) at temperatures in the range of -10 ° C to 150 ° C, especially in the range of 20 ° C to 100 ° C. Suitable solvents or suspending agents are, for example, the following:

Water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran aliphatic ethers, dimethylformmiamide and the like, as well as mixtures thereof.

Examples of hydrolytically cleavable residues are as follows:

Trifluoroacetyl, phthalyl, trityl, p-toluenesulfonyl and the like, as well as lower alkanoyl radicals such as acetyl, formyl, nyl and the like. Carbalkoxy (e.g., low molecular weight) is also contemplated.

The optional reduction of the double bond of the radical R @ 6 is generally carried out by catalytic hydrogenation. Suitable catalysts are, for example, conventional finely divided metal catalysts, such as noble metal catalysts, for example platinum. Raney nickel or especially palladium. The process can be operated at normal temperatures or at elevated temperatures;

It is expedient to operate at a temperature in the range of about 40 to 200 [deg.] C., optionally under elevated pressure, in the range of 0.1 to 10 MPa, in particular in the range of 0.1 to 5.0 MPa. If it contains a phenolic hydroxyl group - a benzyl protecting group - then it is also cleaved off during catalytic hydrogenation when, for example, a palladium catalyst is used.

For example, selective reduction of the double bond of the Rt -se- residue is carried out under gentle conditions by hydrogenation in the presence of noble metal catalysts (palladium or platinum) or Raney nickel.

The starting compounds of formula IV used may belong to the diastereoisomeric series of ephedrine (erythro series) or pseudoephedrine. Both pure enantiomers and the corresponding racemates can be used. Accordingly, the bis-oxazolidines of formula (II) are obtained which belong either to the erythro series or to the threo series. ^r

The bis-oxazoles of both series differ in the position of the methyl group and the phenyl ring. The position of both substituents results from the following formulas:

threo

Depending on whether starting from the corresponding pure enantiomers or the racemate of formula IV, the bis-oxazoline of formula II is also obtained in the form of pure enantiomers or of the racemate. In the digestion of bis-cycazo-hines in an acidic environment, the alpha-centers are not abolished, so that the original configuration is always obtained.

The products of the formula I as well as the starting bis-oxazohdes of the formula II which fall out as racemates can be separated into the optically active isomers in a known manner under low temperature conditions, for example using an optically active acid.

Naturally, it is also possible to start from optically active or possibly diastereoisomeric starting compounds, whereby the corresponding pure optically active form or diastereoisomeric configuration is obtained as the final product of formula (I). For example, they are compounds of the Norefedrin (erythro-series) -configuration or -pseudoephedrine (threo-series) configuration. Diastreoisomeric racemates may also occur as two or more asymmetric carbon atoms may exist in the compounds produced. Separation is possible by conventional means, for example by crystallization.

Depending on the process conditions and the starting materials, the end products of the formula I are obtained in free form or in the form of their salts. Salts of the compounds of formula (I) can again be converted into the free bases by methods known per se, for example by treatment with alkali or ion exchangers. Salts can be obtained from the - free bases by reaction with - organic or inorganic acids, in particular with - those which are suitable for forming the salt. physiologically acceptable salts. Such acids include, for example:

hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, organic monocarboxylic, dicarboxylic or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series, as well as sulfonic acids. Examples include 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 benzemic acid; phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethansuffonic acid, ethylenesulfonic acid:. halobenzenesulfonic acids, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or 8-chlorotheophyllin.

Example 1

16.92 g (0.05 mol) of N, N'-methylene-bis- (4-methyl-5-phenyl-oxazoline) (made from Inooephedrine), 15.14 g (0.12 mol) were mixed. acetylcyclohexane, 35 ml of isopropyl alcohol and 19 ml of 5.1 n isopropanolic hydrochloric acid, and the reaction mixture is heated under reflux for 6 hours. The reaction is then obtained. mixture. . After standing overnight at room temperature, the crystalline product formed is filtered off with suction and washed with 5 ml of isopropanol and 20 ml of acetone.

32.58 g of 1- [3-hydroxy-3-phenylpropyl- (2)) - (3-cyclohexyl-3-oxo-propyl) -amine hydrochloride are obtained, corresponding to 67% of theory.

Melting point 219-221 ° C.

Example 2

1- (4-Hydroxy-4-phenyl-propyl) -4- (3- (1-cyclohexen-1-yl) -3-oxo-propyl) -amine

Reaction mixture from 16.92 g (0.05 mol) of 1-N, N'-methylene-bis- (4-methyl-5-phenyl-oxazolidine), 14.90 g (0.12 mol) of 1-acetyl 1-cyclohexene, 35 ml isopropyl alcohol and 19 ml

5.1 N isopropanolic hydrochloric acid was heated to reflux with stirring for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. Crystallized hydrochloride. sucks off. and washed with 5 ml of isopropyl alcohol and 20 ml of acetone.

Yield: 23.3 g.

Melting point of hydrochloride: 203-204 ° C.

Example 3

1- (3-Hydroxy-3-enyl-2-propyl) - (3-cyclopropyl-3-oxo-propyl) -amine

Reaction mixture from 16.92 g (0.05 mol) of 1-N-methylene-bis- (4-methyl-5-phenylcoxazolidine), 10.10 g (0.12 mol) of acetyl cyclopropane, 35 ml of isopropyl alcohol and 19 ml

5.1 N isopropanolic hydrochloric acid was heated to reflux with stirring for 6 hours. The reaction mixture was then 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;

Temperature. m.p. hydrochloride: 188 ° C.

Example 1 a d 4

1 - ((γ-γοχυ--ιπυ ----- γορυΙ) - 3-1-adamantyl) -3-oxo-propy 1j-amine

Reaction mixture from 16.92 g (0.05 mol) of 1-N, N-t-methylene-bis- (4-methyl-5-phenyl-o-xazolidine), 21.40 g of 1-acetyl-adamantane, 40 ml of isopropanol and 20 ml of 5.1N isopropanolic hydrochloric acid are heated at reflux for 6 hours. The reaction mixture is then allowed to stand. over. night at room temperature. The crystallized hydrochloride is filtered off with suction and washed with 10 ml of isopropanol and 20 ml of acetone.

Yield: 12.7 g; Melting point hydrochloride: 241 ° C.

Example 5

1 - [(- y-droxy-3-enynyl-2-ylamino) -3- (2-methyl-1-cyclohexen-1-yl) -3-oxo-propyl] -amine

Reaction mixture of 16.92 g (0.05 mol) of 1-N, N'-methylene-bis- (1-methyl-phenylphenyl-oxazolidine), 16.56 g of 2-methyl-acetyl-1-cyclohexene, 35 ml of isopropanol and 19 ml

5.1 n isopropanolic hydrochloric acid was heated under reflux for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. The crystallized hydrochloride is filtered off with suction and washed with 5 ml of iso-alcohol and 20 ml of acetone.

Yield: 13.7 g;

Melting point hydrochloride: 197 ° C.

Example 6 d, 1- [3-hydroxy-3c (4-hydroxy-phenyl) -2-propyl] - (3-cyclohexyl-3-oxo-propyl) -amine

Reaction mixture from 18.5 g (0.05 mol) of d, 1 N, N'-methylene-bis- [4-methyl-5- (4-hydroxy-ifenyl) -oxazolinone], 15.14 g (0.12) mole) of acetylcyclohexane, 45 ml of isopropanol and 19 ml of 5.1 n isopropanolic hydrochloric acid are heated under reflux for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. The crystallized hydrochloride is filtered off with suction and washed with 15 ml of isopropanol and 25 ml of acetone.

Yield: 8 g;

Melting point of hydrochloride: 160-161 ° C.

Example 7

1- (З-Ьуйгоху-ЗЛ’епуЬг-ргоруП - (3-Cyclohexyl-3-oxo-propyl) -amine)

CO-CH 2 CH 2 NH-CH (CH 3 -CH (OH J

g of 1- [C-hydroxy-3-enyl-1-rooyl- (2)] - [C- (1-cyclohexen-yl) -3-oxo-1-propyl] -amine hydrochloride is dissolved in 250 ml of a mixture of methanol and water (2). 1), this solution is mixed with 2.5 g of palladium on carbon (10%) and hydrogenated at 50 psi at 50 psi until hydrogen uptake is complete. The catalyst is then filtered off, the solvent is distilled off in vacuo and the product is recrystallized from methanol.

Yield: 85%;

Melting point of hydrochloride: 219-221 cq.

Further examples of reduction are given in Table 2.

Example 8

1- (C-hydroxy-C-phenyl-2-propyl) - [3- (2-chloro

-1-cyclopenten-yl) -C-oxo-propyl] -amine Reaction mixture from 16.92 g (0.05 mol) of 1-N, N'-methylene-bis- (4-methyl-5- 1-acetyl-2-chloro-1-cyclopentene, 35 ml of isopropanol and 19 ml of 5.1 n isopropanolic hydrochloric acid are heated at reflux for 6 hours. stirring. The reaction mixture was then allowed to stand overnight at room temperature. The crystallized product (hydrochloride) is filtered off and washed with 5 ml of isopropanol and 20 ml of acetone.

Yield: 9 g

M.p. 204-205 ° C.

Table 2

example Rl Rc Temperature yield starting quantity comment melting (hyd- compounds ob. vz. AND rochlorid) (hydrochloride); Yippee

given only a residue that has a different meaning else than in col. 1

9 2-methyl- H 200 ° C 67% R: 2-Ethyl-cycl- analogous -cyclohexyl lohexenyl; 4 g as in 7 10 cyclo- H 194 ° C 62 R: 1; analogous pentyil 59 6,5 g as in 7 11 cyclo- 4-OH 160— R: 1-cyclohexenyl; analogous hexyl - 161 ° C 15 g as in Example 7 from DL-p-OH-nore ¹ : edrin ⁺⁾ 12 cyclo- H 209— 85% R _f: 1-cycloheptenyl; analogous heptyl —21 ° C 81% 24,8 g as in 7 13 cyjklo- H 190 ° C R: 1-cyclooctecyl; analogous oiktyl 6 g as in 7 14 cyclo- H Mp 164 ° C 42% R: ljcyklododece- analogous dodecyl nyl; 5 g as in 7

+) The starting material is dissolved in 100 ml of methanol and mixed with a solution of 8 g of sodium borohydride in 100 ml of methanol. The reaction mixture was heated at reflux for 8 hours, then treated with 50 ml of acetone and the solvent evaporated in vacuo. After addition of 100 ml of water, it is extracted several times with chloroform. The residue obtained after drying over sodium sulfate and evaporation of the solvent in vacuo was recrystallized from isopropyl alcohol.

Claims (2)

OBJECT OF INVENTION A process for the preparation of cycloaliphatic ketoamines of the general formula I wherein: R ₃ represents hydrogen or hydroxyl and R _{1 is an} adamantyl radical or a saturated or simply unsaturated cycloalkyl radical having 3 to 16 carbon atoms, which cycloalkyl radical may be substituted by an alkyl group having 1 to 4 carbon atoms or a halogen atom, and their acid addition salts, characterized in that reacting an N, N'-methylene-bis-o-xazolindine of formula II wherein R 3 is as defined above with a ketone of formula III R 1 - S - R 2 (III), in which R 1 is as defined above, in the presence of an acid or acidic ion exchanger and - optionally in a compound of formula I wherein R 1 contains a double bond, the compound of formula I is converted to. their physiologically acceptable salts. 2. A process according to claim 1, wherein a compound of formula II in which R3 is hydrogen is reacted with a compound of formula III in which R1 is. saturated or simply unsaturated cycloalkyl radical having 6 to 8 carbon atoms.