DD202425A5 - NEW METHOD FOR THE PRODUCTION OF KETOAMINES - Google Patents

Abstract

The invention relates to a process for the preparation of ketoamines of the formula I by reduction of an unsaturated compound of the formula II.

Description

The invention relates to a novel process for the preparation of Eetoaminen.

Characteristic of the known technical solutions Compounds of the formula

_a ₃

E ₁ -S-CH-CH ₂ -SH-CH (CH,) - CH (OH) P * \ I

= 2

wherein Σ is the group COCO or >CH (OH), E _{2 is} hydrogen or a C 1 -C 6 -alkyl group and E 1 is hydrogen or a hydroxy group and IL is the adamantyl radical or a saturated or monounsaturated C 1 -C -cycloalkyl radical, wherein this C 1 -C 7 -cycloalkyl radical may also be substituted by a C 1 -C 4 -alkyl group or a halogen atom and the salts thereof are known from DE-OS 2 919 495. In this publication, various methods are also disclosed Preparation of these compounds described.

Object of the invention

The object of the invention is to provide an improved process for the preparation of eoamines which is simpler and more feasible and gives better yields.

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Explanation of the essence of the invention

The invention has for its object to find readily available starting compounds for the production of ketoamines.

According to the invention, compounds of the formula E ₁ -O-OH-CH ₂ -NH-OH (CHO) -OB (OE) -C * J

prepared in such a way that the compounds of general formula

E ₁ -CO-C = OE -HH-CH (CHj) -CH (OE) - $ s ~ *> II

wherein E _x .., Rp and E have the meanings indicated, one or two non-aromatic double bonds reduced and optionally in the resulting compounds of formula I, orin R _x , a double bond optionally contains this double bond reduced.

The recovered process products can then be converted into their acid addition salts.

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The process according to the invention is easy to carry out and gives very good yield of ketoamines. The preparation of the starting materials of the formula II used in the erfindungsgemäBen process is in many cases compared to the preparation of the corresponding starting materials for the known methods easier and in much better yield possible.

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

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

Suitable metal catalysts are the customary metallic hydrogenation catalysts, for example Raney-Eickel, elemental nickel, palladium catalysts or platinum-containing catalysts such as platinum, platinum oxide. Platinum-carbon. As a solvent here are preferably polar solvents such as alcohols or alcohol-laß mixtures into consideration, it is preferably at 50 to 150 ⁰ C, in particular at 90 to 120 ⁰ C and a pressure 'between 30 and 150 bar works. It is hydrogenated until the amount of hydrogen required to saturate one or two double bonds is taken up. ,

24 0 72 3

Suitable complex metal hydrides are for example: lithium aluminum hydride, sodium bis (2-methoxy-ethoxy) aluminum dihydride, lithium tri-tert-butoxy-aluminum hydride, wherein preferably alicyclic and cyclic ethers are used as the solvent Temperatures of preferably 20-100 ° C.

, When using complex metal hydrides or elemental nickel is in the starting material of the

TO formula II reduces only the exocyclic double bond, but not a double bond of the radical R ₁ . In such a case, a double bond of the radical R _{1 can} then be selectively reduced with Raney nickel, platinum-containing or palladium-containing catalysts in the manner already indicated or under gentler conditions (for example at 20-50 ° C and 1-5 bar).

The starting materials of the formula II can be prepared, for example, by reacting a compound

R ₁ -CO-C (R ₂ ) H-CHO

or their alkali alcolate 25

(-C (R ₂ ) = CHO-alkali metal;

with a connection

30 H ₂ N-CH (CH ₃ ) -CH (OH)

be obtained in a customary solvent (water, lower alcohols) between 0 and 50 ° C. The preliminary stage

2407

R ₁ -CO-C (R ₂ ) H-CHO

can by conventional ester condensation of a compound

R ₁ -CO-C (R ₂ ) H ₂

with ethyl formate in the presence of sodium. An existing double bond in R can then optionally be reduced in a customary manner, for example as indicated above.

Starting materials of formula II can also be prepared by 5 Friedel-Crafts acylation of acetylene or a compound C (R _) = CH with a compound

R ₁ COHaI (Hai = chlorine or bromine)

^ ^u to the connection

R ₁ CO-C (R ₂ ) s

and subsequent alkylation with a compound

H ₂ N-CH (CH ₃ ) -CH (OH)

to be obtained. The alkylation is carried out, for example, in a solvent or suspending agent (lower aliphatic ethers, cycloaliphatic ethers such as dioxane, aromatic hydrocarbons such as xylene, acetonitrile) between 20 and 150 ° C, optionally in the presence of a basic substance (for example K ₂ CO ₃ , tertiary amine). A double bond in the radical R ₁ can optionally be hydrogenated in the customary manner in the presence of Raney nickel, palladium- or platinum-containing catalysts.

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Depending on the process conditions and starting materials, the end products of the formula I 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 alkali or ion exchangers. Of the latter, salts can be obtained by reaction with organic or inorganic satins, in particular those which are suitable for the formation of therapeutically useful salts. Examples of such acids are: hydrogen halides, sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and also sulfonic acids. Examples of these are: formic, acetic, propionic, succinic, glycolic, lactic, apple, veinic, citric, ascorbic, maleic, fumaric, hyaluric, pyruvic, pyruvic, phenylacetic, Benzoic, p-aminobenzoic, anthranil, p-Eydrozy-benzoic, salicylic or p-Aminosalicylsäure, Etnbonsäure, Methansulf on, Ithansulfon-, Hydroxyäthansulfon-, Äthylensulfonsäure · halobenzenesulfonyl, toluenesulfone -, naphthalenesulfonic acid or subilanilic acid or even 8-chloro-theophylline ..

Those compounds which contain asymmetric carbon atoms and are generally obtained as racemates can be cleaved in a manner known per se, for example by means of an optically active acid, into the optically active isomers. But it is also possible to use from the outset optically active or even diastesßDmere starting materials, in which case the corresponding end product

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pure optically active form or diastereomeric configuration is obtained, for example, are compounds of the norephedrine and the pseudonorephedrine Eonfiguration. It is also possible for di-isomeric racemates to have two or more asymmetric carbon atoms present in the compounds prepared; separation is possible on a regular basis, for example by recrystallization.

The corresponding d-isomers or the hematite are obtained, for example, if the corresponding dextrorotatory form or the racemate is used instead of the levorotatory Iiorephedrin starting compound.

embodiment

The invention is explained in more detail below with reference to some examples.

O / Π Γ?

1 4 O 7

example 1

Preparation of ^ - / _ 3-hydroxy-3-phenylpropyl- (2j_ / - / _ "3-cyclohexyl-3-oxo-propyl-7-amine

O CH, OH

Il I ³ I

C - CH ₂ CH ₂ --NH - CH - CH

10 15 20 25

A) To a suspension of 2,2'g (0.06 mol) of LiAlH ₄ in 30 ml of absolute ether, 5.75 g (0.02 mol) of Tf - / _ "3-hydroxy-3-phenyl-propyl (2) 7-C / S-cycroleuxyl-S-oxo-propenylamine / amine, dissolved in 50 ml of absolute ether, are added dropwise with stirring. After the dropwise addition is complete, the reaction mixture is heated at reflux for 2 hours, successively with 10 ml of ethyl acetate, 10 ml Methanol and 10 ml of H 2 O. The precipitate is separated off, the ethereal phase is dried over sodium sulphate and the hydrochloride is prepared by adding 3.5 ml of 6N-isopropanolic hydrochloric acid

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

B) 14.37 g (0.05 mol) of β- / 3-hydroxy-3-phenyl-propyl- (2-4-7 / 3-CyClOhBXy1-3-oxo-propenyl-amine are dissolved in 250 ml of ethanol, with 3 g of Pd-C (10% strength) and hydrogenated at 100 ° C. and 125 bar until hydrogen uptake ceases (4 hours), after which the catalyst is filtered off, the solvent is removed in vacuo.

distilled. The resulting crude product is converted by addition of 9 ml of isopropanolic hydrochloric acid at room temperature in the hydrochloride.

5 F. of the hydrochloride 219-220 ° C; Yield: 4 7%.

The starting material - £ - / _ 3-hydroxy-3-phenyl-propyl - (2j_7-P-cyclohexyl-S-oxo-propenyl ·) -amine becomes

10 is made, for example, as follows:

To a solution of 15 g (0.1 mol) of 3-oxo-3-ecyclohexyl-propanal (prepared by condensation from 7.4 g (0.1 mol) of ethyl formate, 12.6 g (0.1 mol) of acetylcyclohexane and 3 g (0.1 mol) of 80% NaH) in 150 ml of cyclohexane, 15 g (0.1 mol) of ^ -norephedrine base are added at 55 ° C. The mixture is heated at reflux for 1 hour. After cooling, the reaction mixture is treated with 60 ml of H ₂ Q, the phases are separated, the organic phase over Na_SO. dried, filtered off and concentrated in vacuo. The crude product is recrystallized from methyl isobutyl ketone. F. 98 ° C; Yield: 48%.

Table 1 contains a list of further examples prepared according to Example 1 of the general formula

CH, OH R 1 R ₁ -CO-CH ₂ CH ₂ -NH-CH-CH- ''

Table 1

Play R. # * R ₃ F. of the hydro-chloride 0 ⁰ O Yield % process variant 2 adamantyl H 241 69 according to Example 1 A from 6.8 g (0.02 mol) of € - ^ 3-hydroxy-3-phenyl-propyl (2) 7 ~ ^ 5 ~ adamant yl-3-oxo-propenyl / amine 3 adamantyl p-OH 193 56 Example 1 A from 7i1 g (0.02 mol) d, £ - / 3 ~ hydroxy-3- (4-hydroxy-phenyl) -propyl- (2) / - (3-adamantyl-3-oxo-propenyl) amine -ti- 2-methylcyclohexyl H " 200 63 of Example 1 A from 6.0 g (0.02 mol) of Q - ^ - hydroxy-3-phenyl-propyl - (2) ^ - / 3- (2-methyl-cyclohexyl) -3-oxo-propenyl7-smin 5 cyclopentyl H 194 52 according to Example 1 A from ^ _t 3 g (0.02 mol) of t - / 3-hydroxy-3-phenyl-propyl- (2) 7- ^ 3- cyclopentyl ~ 3-oxo-propenyl / -amine

Continuation Table 1

At game no. R ^ 4-OH F. of the hydro-chloride O ⁰ O Yield % process variant 6 cyclohexyl H 160-161 49 Example 1 A from 6.0 g (0.02 mol) of d, - - / ^ - hydroxy ^ - (4-hydroxy-phenyl) -propyl - (2) / ^ - oyolone xyl-3-oxo-pr-openyl 7-amine 7 cycloheptyl H 209-211 17 according to Example 1 B from 6.0 g (0.02 mol ^ V5-hydroxy-3-phenyl-propyl- (2) 7- ₍ / 3 ~ cycloheptyl-3-oxo-propenyl-7-amine 8th cyclooctyl H 190 59 according to Example 1 A from 6.1 g (0.02 mol) of C - ^ 3 ~ hydroxy ~ 3 ~ phenyl ~ pOT) pyl- (2) 7- ₍ / 3 ~ cyclooctyl-3-osro ~ propenyl7-aniin 9 Gyclododecy] H 164 42 according to Example 1 A from 7.1 S (0.02 mol) ζ - ^ 3-Hpbx) ^ - 3-phenyl-propyl- (2) 7- ^ 3-cyclododecyl-3-oxo-propenyl7 ~ amine 10 Cyclohexene (DyI- (D 203-204 56 from Example 1 A from 5.74 (0.02 mol) of C 3-3 -hydroxy-3-phenyl-propyl-2-methylcyclohexene-1-yl-1-yl-oxo propenyl-7-amine

24

] Example 11

£ - / 3-hydroxy-3-phenyl-propyl- (2) J- { S-cyclohexyl-S-oxopropyl) -amine

/ \ CO-CH ₀ -CH ₀ -NH-CH (CH,) - CH (OH) - // V

25 30

25 g of - / 3-hydroxy-3-phenylpropyl- (2J_7- / 3- (1-cyclohexene- (1) -yl- (1) -3-oxo-propyl.-amine-HCl are prepared in Dissolved 250 ml of methanol / water (2: 1), with 2,5 -'g Pd-C (10%) and hydrogenated at 50 ° C and 5 bar until the completion of the hydrogen absorption Then the catalyst is filtered off, the Distilled solvent in vacuo and the product recrystallized from ethanol

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

20

Claims (1)

invention claim wherein Ep is hydrogen or one and E _{0 is} hydrogen "or a hydroxy group and E _x , the adamantyl radical or a saturated or monounsaturated C ₀ -Cg -cycloalkyl radical, where this Co-Cg-Oycloalkylrest also by a C ^ -C ^ - Alkylgrüppe or a halogen atom be substituted] and their salts, characterized in that. In compounds of the general Fornel ^R 3 E-CO-C =CH-HH-CH (CH ₃ ) -CH (OH) ζ ^ wherein E., S ^ and E _{0 have} the meanings indicated, reduced one or two non-aromatic double bonds and optionally in the resulting compounds of formula I wherein R ₁ * contains a double bond optionally reduces this double bond. AP C 07 C / 24-0 723/2 60 657 11 Process according to point 1 », characterized in that one converts the Verfahrenspiodukte in their acid addition salts.