LU84202A1 - NEW METHOD FOR PRODUCING KETOAMINES - Google Patents

Description

- 3 - 81 160 PH

June 10, 1981 1 Degussa Aktiengesellschaft

Weißfrauenstrasse 9, 6000 Frankfurt am Main 5

"I

New process for the production of ketoamines 10

Compounds of the formula R3 15 R1-X-CH-CH2-NH-CH (CH3) -CH (OH) * 2 where X is the group> CO or> CH (OH), R2 is hydrogen 20 or a -Cg-alkyl group and hydrogen or is a hydroxy group and R ^ is the adamantyl radical or a saturated or monounsaturated C ^ -C ^ g cycloalkyl radical, this C ^ -C ^ g cycloalkyl radical also being substituted by a C ^ -C ^ alkyl group or a 25th Halogen atom can be substituted and their salts are known from German Offenlegungssclirift 2 919 495. This publication also describes various processes for the preparation of these compounds.

30

Another way of producing such compounds according to the patent claim has now been found. Compared to the known production processes, the process according to the invention has the advantage that it yields better yields and / or is easier and easier to carry out. In many cases, the preparation of the starting materials of the formula II used in the process according to the invention is easier and in far better yield than the preparation of the corresponding starting materials for the known processes.

The process according to the invention is carried out in an organic solvent using hydrogen in the presence of metal catalysts or using complex metal hydrides at temperatures between 20-150 ° C.

15 Suitable solvents are: water, lower aliphatic saturated alcohols with 1-6 C atoms such as methanol, ethanol, propanol, butanol, hexanol; saturated alicyclic ethers with 2-6 C atoms such as diethyl ether, 1,2-dimethoxyethane 20 or saturated cyclic ethers with 4 C atoms such as tetrahydrofuran, dioxane or mixtures of these agents.

The usual metallic hydrogenation catalysts are suitable as metal catalysts, for example

Raney nickel, elemental nickel, palladium catalysts or platinum-containing catalysts such as platinum, platinum oxide, platinum-carbon. Preferred solvents here are polar solvents such as alcohols or qn

Alcohol-water mixtures into consideration, preferably at 50-150 ° C., in particular at 90-120 ° C. and a pressure between 30 and 150 bar. It is hydrogenated until the amount of water-35 • ’required to saturate one or two double bonds has been absorbed.

«« · Î f ç - 5 - 1 Examples of possible metal hydrides are: lithium aluminum hydride, sodium bis (2-methoxy-ethoxy) aluminum dihydride, lithium tri-tert. -butoxy aluminum hydride, preferably alicyclic and cyclic ethers being used as the solvent at temperatures of preferably 20-100 ° C.

When using complex metal hydrides or elementary nickel, only the exocyclic double bond is reduced in the starting substance of formula II, but not a double bond of the radical R ^. In such a case, a double bond of the radical R ^ can subsequently be selectively reduced with Raney nickel, platinum-containing or palladium-containing catalysts in the manner already specified or under more gentle conditions (for example at 20-50 ° C. and 1-5 bar) .

The starting materials of formula II can, for example, by reacting a compound r1-co-c (r2) h-cho or its alkali metal isolate 25 (-C (R2) = CHO-alkali metal) with a compound _r3 30 H2N-CH (CH3 ) -CH (OH) - ^ in a conventional solvent (water, lower alcohols) between 0 and 50 ° C. The preliminary stage .35 / _ t r - 6 -

R ^ -CO-C (R-2) H-CHO

can be obtained by conventional ester condensation of a compound 5-co-cir2) h2 with ethyl formate in the presence of sodium. Double bond in R ^ can then optionally be reduced in a conventional manner, for example as indicated above.

Starting materials of formula II can also by 15 Friedel-Crafts acylation of acetylene or one

Compound C (R2) = CH with a compound R ^ COHal (Hai = chlorine or bromine).

20 to the compound R1CO-C (R2) = CHHal and subsequent alkylation with a compound 25 R3

H2N-CH (CH3) -CH (OH} W

j can be obtained .. The alkylation is carried out! · ·. · 2o play in a solvent or suspension medium I '(lower aliphatic ether, cycloaliphatic ether such as dioxane, aromatic hydrocarbons such as xylene, acetonitrile) between 20 and 150 ° C, optionally in the presence of a basic substance (for example | 35 K2C03 , tertiary amine). A double bond in that; The rest of R. can optionally be in the usual manner

Are hydrogenated in the presence of Raney nickel, palladium or platinum-containing catalysts. - 7 - 1 Depending on the process conditions and the starting materials, the end products of the formula I1 are obtained in free form or in the form of their salts The salts of the end products can be converted back into the bases in a manner known per se, for example with 5 alkali or ion exchangers From the latter, TO salts can be obtained by reaction with organic or inorganic acids, in particular those which are suitable for the formation of therapeutically usable salts. Examples of such acids are: hydrogen halide acids, sulfuric acid, phosphoric acids, nitric acid, Perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and sulfonic acids, examples of which are: formic acid, acetic acid, propionic acid, amber acid, glycolic acid, lactic acid , Malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic or çreaz grape acid; ' Phenylacetic, benzoic, p-amino-benzoic, '20 anthranil, p-hydroxy-benzoic, salicyl- or p-amino-salicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesulfonic acid, Toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid or 8-chloro-theophylline.

25th

Those compounds that have asymmetrical coal. Containing atoms of matter and generally occurring as racemates can be split into the 30 optically active isomers in a manner known per se, for example by means of an optically active acid. However, it is also possible to use optically active or diasteromeric starting materials from the outset, the end product then being a correspondingly pure optically active form or diastereomeric configuration.

For example, they are compounds of the norephedrine and pseudonorephedrine configurations. Diastereomeric racemates can also occur because two or more asymmetric carbon atoms are present in the compounds produced. Separation is possible in the usual way, for example by recrystallization.

The corresponding d-isomers or the racemate are obtained if, for example, instead of the left-handed norephedrine starting compound, the corresponding right-handed form or the racemate is used.

15, u 20 25 30 35 - 9 - 1 Example 1

Preparation of - £ - / 3-hydroxy-3-phenyl-propyl- (2 ^ 7 ** £ 3-cy clohexy 1 - 3-oxo-pr opy l7-amine 5

0 CH, OH

/ ~ X_ Il I I _jF \ (H V-— C - CH2CH2 - NH - CH - CH -V y 10 A) To a suspension of 2.2 g (0.06 mol)

LiAlH ^ in 30 ml of absolute ether 5.75 g (0.02 mol) £ - / 3-hydroxy-3-phenyl-propyl- (2J \ J - / 3-cyclohexyl-3-oxo-propenyl7amine, dissolved in U 50 ml of absolute ether was added dropwise with stirring.

When the dropwise addition has ended, the reaction mixture is refluxed for 2 hours, 10 ml of ethyl acetate, 10 ml of methanol and 10 ml of H20 are added in succession. It is separated from the resulting precipitation. The ether phase is over

Dried sodium sulfate and the hydrochloride was prepared by adding 3.5 ml of 6N isopropanolic hydrochloric acid.

F. hydrochloride 219-220 ° C; 25 Yield: 75%.

B) 14.37 g (0.05 mol) - / 3-hydroxy-3-phenyl-propyl- (2l7- / 3-cyclohexyl-3-ox ° -propenyl7-amine are dissolved in 30 250 ml of ethanol, with 3 g of Pd-C (10% strength) are added and the mixture is hydrogenated at 100 ° C. and 125 bar until the hydrogen uptake has ended (4 hours), after which the catalyst is filtered off and the solvent is distilled off in vacuo. The resulting crude product is converted into the hydrochloride by adding ~ -9 * ml of 6N-isopro.panolischer._salz -____ acid at room temperature.

5 F. of hydrochloride 219 - 220 ° C;

Yield: 47%.

The starting material / 3-hydroxy-3-phenyl-propyl - (227- <3-cyclohexyl-3-oxo-propenyl) .TaiQiH-Will. _.

10, for example, produced as follows:

To a solution of 15 g (0.1 mol) of 3-oxo-3-cyclohexyl-propanal (prepared by condensation from 7 g of 4 g. (0.1 mol) of ethyl formate, 12.6 g (0.1 mol)

Acetylcyclohexane and 3 g (0.1 mol) 80% NaH) 1 ^ in. 150 ml cyclohexane, 15 g (0.1 mol) ^ -norephedrine base are added at 55 ° C. The mixture is refluxed for 1 hour. After cooling, the reaction mixture is mixed with 60 ml of B2O: the phases are separated, the organic phase is dried over 7Ω w Na ^ SO ^, filtered and km vacuum is concentrated. The crude product is recrystallized from methyl isobutyl * ketone. F. 98 ° C? Yield: 48%.

. I.

25th

Table 1 contains a list of further examples of the general formula on CH- prepared according to Example 1. OH Ro. 30 II / rx R1 - CO - CH2CH2 - NH - CB - CH— ('' y 35 / * · · / - 11 - k, fr: V μ- kl · ·: SI X ^ 5. Vi VA V £ i | Il if II; £} ^ N g NI Np 0> i ° ο o tN os, ° g ο α π o, io, i 1 - “il --¾ .. -¾ ίο", f “§bi ° -à'l -1 «'

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d i e & £ m 51 -¾> ι ο ©! J & o 's s 2 S I § 3 35 I «& & & & & £ -¾ ------- I ^ 3, £ S K ë” - ^ ® en - o> - - 13 - j »! 1 example 11 € - / 3 ^ hydroxy-3-phenyl-propyl- (2 \ J- (3-cyclohexyl-3-oxo-propyl) -amine 5 __ tv

^ y-CO-CH2-CH2-NH-CH (CH3) -CH (OH) -O

»25 g ~ € - / 3-hydroxy-3-pheny 1-propy 1 - {2 \ J- / 3- {1 -cycl-o —.....—] 0 hexen- (1) -y l - (1) -3-oxo-propyl7-arain-HCl are dissolved in 250 ml methanol / water (2: 1), · mixed with 2.5 g Pd-C (10%) and at 50 ° C and 5 bar up to · m

Hydrogen cessation stopped hydrogenated. Then the catalyst is filtered off, the solvent 15 is distilled off in vacuo and the product is recrystallized from ethanol.

F. of hydrochloride 219-220 ° C Yield: 85%.

20 * · ♦ 25 30 35

Claims (2)

1. Process for the preparation of compounds of the formula R3 R1-CO-CH-CH2-NH-CH (CH3) -CH (OH) -er · * r9 · 20 2 1. i * i ί wherein R2 is hydrogen or a -Cg -Alkylgruppe j * and R, hydrogen or a hydroxyl group is i 25 and Rj clen adamantyl radical or a saturated \ or monounsaturated C ^ -C ^ g cycloalkyl radical I means, whereby this C ^ -C ^ g cycloalkyl radical is also [by a C ^ -C ^ alkyl group or a halogen | can be atom-substituted and their salts, characterized in that in compounds of the general formula BI R.-CO-C = CH-NH-CH (CH -) - CH (OH) —II i 35 I 3 \ = /: r2 i Ir 5 - 2 - 1 in which R ^, R2 and the meanings given reduce one or two non-aromatic double bonds and, if appropriate, in the compounds of the formula I obtained, in which R ^ 5 contains a double bond, if appropriate Double bond reduced. * 1 Degussa Aktiengesellschaft Weißfrauenstrasse 9, 6000 Frankfurt am Fein 5 New process for the production of ketoamines »io 2. The method according to claim 1, 10 characterized in that the process products are converted into their acid addition salts. Λ S \ f r 15 \ \ \ \ \ \ ... "’ v '\% * V \' 'V 20' A 25 '' 30 35