GB2101593A - A process for the production of ketoamines - Google Patents

Abstract

This invention relates to a process for the production of ketoamines corresponding to the formula: <IMAGE> in which R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R1 represents an adamantyl radical or a saturated or mono-unsaturated C3-C16 cycloalkyl radical, which C3-C16 cycloalkyl radical may also be substituted by a C1-C4 alkyl group or a halogen atom, and salts thereof by reducing an unsaturated compound corresponding to the formula: <IMAGE>

Description

SPECIFICATION Process for the production of ketoamines This invention relates to a process for the production of ketoamines.

Compounds corresponding to the formula:

in which X represents the group > CO or > CH(OH), R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R1 represents the adamantyl radical or a saturated or mono-unsaturated C3-C16 cycloalkyl radical, which C3-C16 cycloalkyl radical may also be substituted by a C1-C4 alkyl group or a halogen atom, and salts thereof are known from German Offenlegungsschrift No. 2,919,495. This Offenlegungsschrift also describes various processes for the production of these compounds The present invention provides a further process for the production of these compounds.More particularly the invention provides a process for the production of compounds corresponding to the formula:

in which R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R, represents an adamantyl radical or a saturated or mono-unsaturated C3-C16 cycloalkyl radical, which C3-C16 cycloalkyl radical may also be substituted by a C1-C4 alkyl group or a halogen atom, and for the production of the salts thereof, which comprises reducing one or two non-aromatic double bonds in a compound corresponding to the general formula::

in which R1, R2 and R3 are as defined above, and in the case where R, in the compound produced contains a double bond, optionally reducing this double bond.

The process according to the present invention has the advantage over the known production processes that it produces better yields and/or may be carried out in an easier and improved manner.

The production of the starting materials corresponding to formula Il which are used in the process according to the present invention is also easier and provides a much improved yield in many cases, compared to the production of the corresponding starting materials for the known processes.

The process of the present invention may be carried out in an organic solvent using hydrogen in the presence of metal catalysts or using complex metal hydrides at a temperature of from 20 to 1 500C.

The following are suitable as solvents: water, lower aliphatic saturated alcohols having from 1 to 6 carbon atoms, such as methanol, ethanol, propanol, butanol or hexanol; saturated acyclic ethers having from 2 to 6 carbon atoms, such as diethylether or 1 ,2-dimethoxyethane, or saturated cyclic ethers having 4 carbon atoms, such as tetrahydrofuran, dioxan or mixtures of these solvents.

Conventional metallic hydrogenation catalysts are suitable as metal catalysts, for example: Raney nickel, elementary nickel, palladium catalysts, or platinum containing catalysts, such as platinum, platinum oxide or platinised charcoal. Polar solvents are preferred in this case as solvents, such as alcohols or alcohol-water mixtures, the process preferably being carried out at from 50 to 1 500 C, in particular from 90 to 1200C and at a pressure of from 30 to 150 bars. Hydrogenation is carried out until the quantity of hydrogen necessary for saturating one or two double bonds has been absorbed.

The following, for example, are suitable as complex metal hydrides: lithium aluminium-hydride, sodium-bis(2-methoxy-ethoxy)-aluminium-dihydride, and lithium-tri-tert.-butoxy-aluminium-hydride, acyclic and cyclic ethers preferably being used as solvent, preferably at a temperature of from 20 to 1000C.

When complex metal hydrides or elementary nickel is used, only the exocyclic double bond is reduced in the starting material corresponding to formula II, but not a double bond of the radical R1. In a case of this type, a double bond of the radical R, may then be selectively reduced using Raney nickel, catalysts containing platinum or palladium, in the above-mentioned manner or even under milder conditions (for example, at from 20 to 500C and from 1 to 5 bars).

The starting materials corresponding to formula II may be obtained, for example, by reacting a compound R1-C0-C(R2)H-CH0 or reacting the alkali metal enolate thereof (-C(R2)=CH0-alkali metal) with a compound

in a solvent conventional for this purpose (water, lower alcohols) at from 0 to 500 C. The first reactant R1-C0-C(R2)H-CHO may be obtained by conventional ester condensation of a compound R1-C0-C(R2)H2 with ethyl formate in the presence of sodium. A double bond which is present in R, may then optionally be reduced in conventional manner, for example as described above.

Moreover, the starting materials corresponding to formula II may be obtained by Friedel-Crafts acylation of acetylene or a compound C(R2)~CH with a compound: R,COHal (Hal=chlorine or bromine) into the compound: R,CO--C(R,)=CHHal and by subsequent alkylation with a compound:

Alkylation takes place, for example, in a solvent or dispersing agent (lower aliphatic ethers, cycloaliphatic ethers, such as dioxan, aromatic hydrocarbons, such as xylene, acetonitrile) at from 20 to 1 500 C, optionally in the presence of a base (for example, K2CO3, tertiary amine). A double bond in the radical R, may optionally be hydrogenated in conventional manner in the presence of Raney nickel or catalysts containing palladium or platinum.

Depending on the conditions of the process and on the starting materials, the end products corresponding to formula I are obtained in a free form or in the form of salts thereof. The salts of the end products may be converted again into the free base in known manner, for example using alkali or ion exchangers. Salts may be obtained from the free bases by a reaction with an organic or inorganic acid, in particular those acids which are suitable for the formation of pharmacologically acceptable salts. The following are mentioned as examples of such acids: hydrohalic acids, sulphuric acid, phosphorus acids, nitric acid, perchloric acid, organic mono-, di- or tri-carboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and sulphonic acids. Specific examples of these acids are as follows: formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic or pyruvic acid; phenyl acetic, benzoic, p-amino-benzoic, anthranilic, phydroxy-benzoic, salicylic orp-amino-salicylic acid, embonic acid, methane sulphonic, ethane sulphonic, hydroxy ethane sulphonic, ethylene sulphonic acid, halogen-benzene sulphonic, toluene sulphonic, naphthalene sulphonic acid or sulphanilic acid or 8-chloro-theophylline.

Those compounds which contain asymmetric carbon atoms and are usually produced as racemic compounds may be split into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use optically active or even diastereomeric starting materials from the outset, in which case a corresponding pure, optically active form or a diastereomeric configuration is then obtained as the end product. These compounds are, for example, of the norephedrine and the pseudonorephedrine configuration. Diastereomeric racemic compounds may also occur, because two or more asymmetric carbon atoms are present in the compounds which are produced. Separation may be carried out in a conventional manner, for example by recrystallisation.

The corresponding d-isomers or the racemic compound are obtained if, for example, instead of using the levorotatory norephedrine starting compound, the corresponding dextrorotatory form or the racemic compound is used.

The invention is illustrated by the following Examples: Example 1 Production of 1-[3-hydroxy-3-phenyl-propyl-(2)]-l3-cyclohexyl-3-oXo-propyl]-amine

A) 5.75 g (0.02 mols) of 1-[3-hydroxy-3-phenyl-propyl-(2)]-[3-cyclohexyl-3-oXo-propenyl]amine, dissolved in 50 ml of absolute ether are added dropwise with stirring to a suspension of 2.2 g (0.06 mols) of LiAIH4 in 30 ml of absolute ether. After the addition, the reaction mixture is heated for 2 hours at reflux, then mixed successively with 10 ml of ethyl acetate, 10 ml of methanol and 10 ml of H2O.

The resulting deposit is separated. The ether phase is dried over sodium sulphate and the hydrochloride is produced by adding 3.5 ml of 6N-isopropanolic hydrochloric acid.

M.p. of the hydrochloride 219-2200C; Yield: 75%.

B) 14.37 g (0.05 mols) of l-[3-hydrnxy-3-phenyl-prnpyl-(2)]-[3-cyclohexyl-3-.oxo-prnpenyl- amine are dissolved in 250 ml of ethanol, mixed with 3 g of Pd-C (10%) and hydrogenated at 1000C and 1 25 bars until the end of hydrogen absorption (4 hours). The catalyst is then filtered off and the solvent is distilled off under vacuum. The resulting raw product is converted into the hydrochloride by adding 9 ml of 6N-isopropanolic hydrochloric acid at room temperature.

M.p. of the hydrochloride 129-2200C; Yield: 47%.

The starting material l-[3-hydrnxy-3-phenyl-propyl-(2)-(3-cyclohexyl-3-oxo-prnpenyl)-amine is produced, for example, as follows: 1 5 g (0.1 mol) of l-norephedrine base are added at 550C to a solution of 15 g (0.1 mol) of 3-oxo-3-cyclohexyl-propanal (produced by condensation from 7.4 g (0.1 mol) of ethylformate, 12.6 g (0.1 mol) of acetylcyclohexane and 3 g (0.1 mol) of 80% NaH) in 150 ml of cyclohexane. The mixture is heated for 1 hour at reflux. After cooling, the reaction mixture is mixed with 60 ml of H2O, the phases are separated, the organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The raw product is recrystallised from methylisobutylketone.

M.p.: 980C; Yield: 48%.

Table 1 contains a list of other Examples produced according to the method of Example 1, corresponding to the general formula:

Table 1

M.p. of the hydrochloride Yield Example No. R1 R3 C % Process variant 2 Adamantyl H 241 69 according to Example 1A from 6.8 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3adamantyl-3-oxo-propenyl]-amine 3 Adamantyl p-OH 193 56 according to Example 1A from 7.1 g (0.02 mol) of d, l-[3-hxdroxy-3-(4-hydroxy-phenyl)propyl-(2)]-[3-adamantyl-3-oxo-propenyl]-amine 4 2-Methylcyclohexyl H 200 63 according to Example 1A from 6.0 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3 (2-methyl-cyclohexyl)-3-oxo-propenyl]-amine 5 Cyclopentyl H 194 52 according to Example 1A from 5.5 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3cyclopentyl-3-oxo-propenyl]-amine 6 Cyclohexyl H 160-161 49 according to Example 1A from 6.0 g (0.02 mol) of d, l-[3-hxdroxy-3-(4-hydroxy-phenyl)-propyl (2)]-[3-cyclohexyl-3-oxo-propenyl]-amine 7 Cycloheptyl H 209-211 17 according to Example 1B from 6.0 g (0.02 mol of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3-cycloheptyl-3-oxo-propenyl]-amine 8 Cyclooctyl H 190 59 according to Example 1A from 6.1 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3-cyclooctyl-3-oxo-propenyl]-amine 9 Cyclododecyl H 164 42 according to Example 1A from 7.1 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3-cyclododecyl-3-oxo-propenyl]-amine 10 Cyclohexen-1-yl-(1) H 203-204 56 according to Example 1A from 5.74 g (0.02 mol) of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3-cyclohexen-(1)-yl-(1)-3-oxo-propenyl]-amine Example 11 I[3-Hydrnxy-3-phenyl-prnpyl-( 2)i-(3-cyclohexyl-3-oxo-propyl)-amine

25 g of l-[3-hydroxy-3-phenyl-propyl-(2)]-[3-(1-cyclohexen-1-yl-(1)-3-oxo-propenyl]-amine-HCl are dissolved in 250 ml of methanol/water (2:1), mixed with 2.5 g of Pd-C (10%) and hydrogenated at 500C and at 5 bars until the end of hydrogen absorption. The catalyst is then filtered off, the solvent is distilled off under vacuum and the product is recrystallised from ethanol.

M.p. of the hydrochloride 21 9-2200C; Yield: 85%.

Claims (4)

Claims

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

in which R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R, represents an adamantyl radical or a saturated or mono-unsaturated C3-C16 cycloalkyl radical, which C3-C16 cycloalkyl radical may also be substituted by a C1-C4 alkyl group or a halogen atom, and for the production of the salts thereof, which comprises reducing one or two non-aromatic double bonds in a compound corresponding to the general formula:

in which F1, R2 and R3 are as defined above, and in the case where R, in the compound produced contains a double bond, optionally reducing this double bond.

2. A process as claimed in claim 1, in which the product is converted into an acid addition salt thereof.

3. A process for the production of compounds formula (I) as defined in claim 1 or a salt thereof substantially as described with particular reference to any of the Examples.

4. Compounds of formula (I) as defined in claim 1 and salts thereof when produced by a process as claimed in any of claims 1 to 3.