DE2200496A1 - Quinoline derivatives - Google Patents

Description

PATENT LAWYERS

DR.! NG. A. VAN DER WERTH

21 HAMBURG 9O WlLSTORrER tTR. 32 · TEL. 104 II) 77 08 61

DR. FRANZ '.PDERER

β MONKS 8O

LUCILE-ORAHN-STR. 22 TEL. 100 I Il 47 29 47 * .1

22Ü0A9C

Munich, December 23, 1971 RAN 4103/10 K2

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

"Quinoline derivatives"

The invention relates to new racemic or optically active ohinoline derivatives which are epimeric in «-, 2- and 5-positions, the general formula (I)

HO.

in which R is the vinyl or ethyl group, their acid addition salts and a method for their production.

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22Ü0436

The process for the preparation of the compounds of formula (I) is characterized in that compounds of the general formulas (II) and (Ha)

and

II

in which R has the aforementioned meaning, or its antipodes or racemates are treated with a stereoselective reducing agent _> or a racemate or an optically active compound which is epimeric in the 2- and 5-positions, of the general formula (III)

III

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in which R has the aforementioned meaning, hydroxylated, or a racemate or an optically active compound of the general formula (IV)

■ N — H

IV

in which R has the aforementioned meaning, subject to cyclization, optionally in the compound thus obtained, in which R denotes the vinyl group, the vinyl group is reduced to the ethyl group, optionally the racemate into the optical antipodes cleaves and, if appropriate, the free base into an acid addition salt convicted.

The stereoselective reduction of the compounds of the formulas (II) and (Ha) gives the corresponding compounds of general formulas (Ia) and (Ib)

HO

and

Yes

Ib

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in which R has the aforementioned meaning.

The implementation of the 4- / 5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -ylcarbony! / - quinolines of the formula (II), their antipodes or racemates, to the <x ( S) - / 5 (R) -Ethyl (or vinyl) -4 (S) -quinucjidin-2 (R) -yl7-4-quinolinemethano] s of the formula (Ia), their antipodes or racemates, is carried out using stereoscopic reducing agents, such as dialkyl aluminum hydrides, for example diisobutyl aluminum hydride. The reduction is expediently carried out at room temperature. However, temperatures above or below room temperature can also be used. Preferably, the reduction is carried out at temperatures of about 20 to 5O ⁰ C. The reduction may conveniently be carried out in the presence of inert solvents such as hydrocarbons, for example benzene, toluene or xylene, or ethers, for example Diäthylather, tetrahydrofuran or dioxane, are made.

The implementation of 4- / 5 (R) -ethyl (or vinyl) -4 (S) -quinuclidine-2 ( S) -ylcarbonyl / -quinolines of the formula (Ha), their antipodes or racemates, to the o <(R) - / B (R) -ethyl (or vinyl) -4 (S) -quinuclidine-2 ( S) -yl74-quinolinemethanols of the formula (Ib), their antipodes or racemates, are used in accordance with those for the implementation of the compounds of the formula (II) described process performed.

The compounds of the formulas (II) and (Ha) used as starting compounds, their antipodes or racemates, can accordingly can be prepared according to the following reaction scheme (I), in which R is the vinyl or ethyl group and R. and Rp are lower alkyl radicals mean:

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Scheme I 96

COOIL

COOR.

VI

Hydrolysis and decarboxylation

VII

Ha

Ν — Η

2 0 9 8 3 0/1121

In reaction scheme (I), the cinehoninic acid (lower alkyl) esters of the formula (V), which are analogues of known compounds and are prepared in a simple manner by known processes, in the presence of a base, for example an alkali metal alcoholate, such as sodium methylate, sodium ethylate or Potassium tert-butoxide, with the 1-benzoyl-3 (R) -ethyl (or vinyl) -4 (R) -piperidinpropionic acid esters of the formula (VI), their antipodes or racemates, which are known compounds, to the corresponding o6 -. / T-Benzoyl-3 (R) -ethyl (or vinyl) -4 (R) piperidylmethyl / -vi-oxo-4-quinoline propionic acid esters of the formula (VII), their antipodes or racemates implemented. This reaction is preferably carried out at the reflux temperature. However, lower temperatures can also be used. Inert solvents such as ethers such as tetrahydrofuran or dioxane may be used with advantage.

The implementation of the <X - / i-benzoyl-3 (R) -ethyl (or vinyl) -4 (R) -piperidyl-methyl7 - ^ - oxo-4-quinoline propionic acid esters of the formula (VII), their antipodes or racemates the corresponding 4- / 5- (3 (R) -Ethyl (or vinyl) -4 (R) -piperidyl) -1-oxopropyl / -quinolines of the formula "(VIII), their antipodes or racemates, using a hydrolyzing Compound, such as hydrochloric acid, carried out at reflux temperatures, but temperatures below the reflux temperature can also be advantageous.

The N-halogenation of the compounds of the formula (VIII), their antipodes or Raoemate, to the corresponding N-halogen compounds

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" ⁷ " ^ 200496

fertilize the formula (IX), their antipodes or racemates, is using a halogenating agent such as hypobromous acid, sodium hypochlorite, N-chlorosuccinimide, N-bromosuccinimide or N-bromoacetamide, in inert solvents such as ethers, see B.

Tetrahydrofuran or dioxane, chlorinated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or alkanols such as methanol or ethanol.

The cyclization reaction of the! -Halogen compounds of the formula (IX), their antipodes or racemates, to the corresponding compounds of the formulas (II) and (Ha), their antipodes or racemates, is carried out under basic conditions, for example with sodium ethylate in ethanol or sodium methylate in methanol , or under strongly acidic conditions, for example with sulfuric acid, phosphoric acid, trichloroacetic acid, trifluoroacetic acid or acetic acid / sulfuric acid mixtures, carried out "The reaction is conveniently carried out at room temperature or above, preferably at temperatures of 20 to 5O ⁰ C is performed. In addition, the cyclization can also be carried out with advantage in the presence of inert solvents, such as hydrocarbons, for example benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane or chloroform, or ethers, such as diethyl ether or dioxane.

During the cyclization, mixtures of the epimeric compounds are obtained of the formulas (II) and (Ha), which are prepared by known processes, for example by means of fractional crystallization or chromatography can be separated into the corresponding epimers. The fragrance of the epimeric compounds of the formulas (II) and (IXa) can jjedooh, even without prior separation into the

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speaking epimers ^ are further implemented, being called Reaction products Mixtures of the compounds of the formulas (Ia) and (Ib) obtained by known processes, for example by means of fractional crystallization or chromatography.

The hydroxylation of a compound of the general formula (III) can be carried out by the following reaction schemes (Ia) and (Ib) in which R represents the vinyl or ethyl group:

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9 Scheme Ia

HIa

IHb

Ib

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Scheme Ib

IIIc

IHd

ic

Id

-2 09 830/1121

The hydroxylation of the compounds of the formulas (Ilia), (HIb), (illc) and (HId), their antipodes or racemates, to the compounds of the formulas (Ia), (Ib), (Ic) and (Id), for example, in the presence of molecular oxygen and a reducing agent, such as dimethyl sulfoxide, pyridine, triphenyl phosphine, platinum black or a trialkyl phosphite such as triethyl phosphite in strongly basic solution carried out «,

Suitable bases for the aforementioned reaction are, for example, alkali alcoholates, such as potassium tert-butoxide, sodium tert-butoxide, Sodium amylate or sodium methylate, or alkali amides, such as Lithium diisopropylamide or sodium amide. The reaction can be carried out with advantage in solvents such as dimethyl sulfoxide, dimethylformamide, Hexamethylphosphoramide, pyridine or tert-butanol, hydrocarbons, such as benzene or toluene, ethers such as tetrahydrofuran or dioxane, or mixtures of the aforementioned solvents, be performed. The reaction is preferably carried out in a dimethyl sulfoxide-tert-butanol mixture in the presence made of potassium tert-butoxide.

The compounds of the formulas (Ilia), (HIb), (IHc) and (IHd) used as starting material, their antipodes or racemates, can be prepared according to the following reaction schemes (II) and - (III), in which R has the aforementioned meaning has, R is a hydrogen atom or a lower alkyl radical, R is a hydrogen atom or an acyl radical and Rc is a lower alkyl radical, aryl radical or aryl (lower alkyl) radical.

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Scheme II

XTa

XIVa

2 ng 83 σ / 11 7

"? 2ÖÜ496

XIVb

_2j09830 / 1121

In Reaction Scheme II, the 4-methyl-quinoline derivative of the formula (X), which is an analog of known compounds and is easy to prepare in a known manner, is treated with a 1-acyl (or 1-H) -3 (R) -vinyl (or ethyl) -4 (S) -piperidine acetate of the formula (XIa), its antipode or racemate, which are known compounds, in the presence of bases, such as alkali hydrides, for example sodium hydride, alkali metal alcoholates, such as sodium methylate, or lithium dialkylamides, such as lithium diisopropylamide the 4- {3- / i-acyl (or 1-H) -3 (R) -vinyl (or ethyl) -4 (S) -piperidyl / -2-oxopropylj -quinoline of the formula (XIIa), its antipode or Condensed racemate. The condensation is expediently carried out at room temperature, but temperatures above or below room temperature can also be used. Preferably, the condensation at temperatures of about -70 is performed to about 50 ⁰ C. Additionally, the condensation can also with advantage in the presence of inert organic solvents, such as hydrocarbons., For example benzene or H _e xan, ethers, for example diethyl ether, tetrahydrofuran or dioxane, dimethylformamide or hexamethylphosphoramide, are performed.

The conversion of the 4- £ 3 - / ^ - acyl or (1-H) -3 (R) -vinyl (or ethyl) -4 (S) -piperidyl / ^ - oxopropyl} -quinolines of the formula (XIIa) its antipode or racemate, to the mixture of the epimeric 4- [3- / 3 (R) -vinyl (or ethyl) -4 (S) -piperidyl7-2 ^ -hydroxypropyl} -quinolines of the formula (XIIIa), its antipodes or racemates, is carried out by simultaneous deacylation, if necessary, and reduction. The deacylation and the reduction will be

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expediently using reducing agents such as diisobutyl aluminum hydride or sodium aluminum hydride, in inert organic solvents such as hydrocarbons, e.g. Benzene or toluene, or ethers such as tetrahydrofuran. The deacylation and the reduction are expediently carried out at room temperature or at temperatures below room temperature, preferably at temperatures from about -70 to about 25 C, carried out, ^ he reduction and deacylation can also be carried out in stages be carried out by initially using a compound of the formula (XIIa) in which R. is an acyl radical Sodium borohydride and then reduced using deacylating agents such as aqueous hydrochloric acid or sulfuric acid, deacylated. If necessary, the connection of the formula (XIIIa) to the corresponding mixture of the epimeric 4-J3- / 3 (R) -vinyl (or ethyl) -4 (S) -piperidyl7 ~ 2 ^ -acyloxypropyl5-quinolines of the formula (XIVa), their antipodes or racemates, using known methods, e.g., by reaction with the appropriate organic acids in The presence of a catalyst, such as boron trifluoride, is esterified will.

The cyclization of the epimeric 4- ^ 3- / 3 (R) -vinyl (or lower alkyl) -4 ( S) -piperidyl / -2 ^ -hydroxy (or acyloxy) -propyl] -quinolines of the formulas (XIIIa) and (XIVa), their antipodes or racemates, to 4-4 (- ^ 5lR) -vinyl (or ethyl) -4 (S) -quinuclidine-2 (S) or the 2 (R) -yl7-niethylj-quinolines of the formulas (purple) and (HIb), their antipodes or racemates, is produced using cyclizing agents such as -organic acids, e.g. glacial acetic acid,, carried out. The cyclization takes place expediently

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moderately at room temperature, but temperatures above or below room temperature can also be used. Preferably, the cyclization is carried out at temperatures of about 25 is carried out to about 100 ⁰ C. In addition, the cyclization can also be carried out with advantage in the presence of inert organic solvents, such as hydrocarbons, for example benzene or toluene, ethers, such as diethyl ether or tetrahydrofuran.

In Reaction Scheme IH, the preparation of the compounds of formulas (HIc) and (HId) can be carried out using the in Scheme II for the preparation of the compounds of formulas (HIa) and (IHb) described procedures and conditions take place.

The resulting mixtures of the epimeric compounds of the formulas (HIa) and (HIb) or (IHc) and (IHd) can all be subjected to the further reaction. The resulting reaction product, a mixture of the compounds of the formulas (Ia) and (Ib) or (Ic) and (Id), can be separated using known processes, such as fractional crystallization or chromatography.

The cyclization of a compound of the aforementioned formula (IV) can be represented by the reaction schemes IV and V , in which R represents the vinyl or ethyl group.

'.' it O P -: ρ

^ 200496

Scheme IV

I. I. Γ 1 I. I. H

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Scheme V

IVb

HO

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- ¹⁹ - 220Ü496

The cyclization of the aforementioned compounds of the formula (IVa), their antipodes or racemates, to the corresponding mixture of the o ({Έ.) - / 5 ( R) -vinyl (or ethyl) -4 (S) -quinuclidine-2 ( S) -yl / -4'-quinolinemethanol of the formula (Ia), its antipode or racemate and the d ( S) - / 5 (R) -vinyl (or ethyl) -4 (S) -quinuclidine-2 (R) -y _- l7-4'-quinolinemethanol of the formula (Ib), the antipode or racemate thereof, takes place by reaction with weak organic or inorganic protic acids, such as water, ammonium chloride, lower alkanols, for example methanol or ethanol, or Lewis acids, for example aluminum oxide , Aluminum chloride or boron triiluoride. The reaction is expediently carried out in the presence of inert organic solvents such as carbon disulfide, hydrocarbons such as benzene or toluene, chlorinated hydrocarbons such as methylene chloride, carbon tetrachloride or chloroform, or ethers such as ethyl ether, tetrahydrofuran or dioxane. The reaction temperature does not play a special role. Temperatures of about ⁰ ° C. to the reflux temperature of the reaction mixture are preferably used.

The implementation of the compounds of the formula (IVb), their antipodes or racemates, to the compounds of the formulas (Ic) and (Id), their antipodes or racemates, is according to the for the implementation of the compounds of the formula (IVa) described process carried out.

In the aforementioned cyclization reaction, mixtures of the compounds of the formulas (Ia) and (Ib) and of the formulas are obtained (Ic) and (Id), which are fractionated according to known methods, such as

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Crystallization or chromatography, can be separated.

The compounds of the formulas (IVa) and (IVb) used as starting compounds can be prepared according to the following reaction schemes VI and VII are produced, in which R is the vinyl or ethyl group, R! is an acyl radical and X is a halogen atom:

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^ 200496

Scheme VI

XIIa ¹

XV

XVI

J-H

IVa

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220U496.

Scheme VII

XVa

XVIa

IVb

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-23- 22ÜU496

According to reaction scheme VI, a compound of the formula (XIIa ')> its antipode or racemate is converted to the corresponding mixture of the epimeric 4- [3- / i-acyl-3 (R) -vinyl (or ethyl) -4 ( S) -piperidylZ-i ^ -halo ^ -oxopropy Ij -quinolines of the formula (XV), their antipodes or racemates, using halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide or N-bromoacetamide. The halogenation can be carried out in inert organic solvents, such as hydrocarbons, for example benzene or toluene, halogenated hydrocarbons, for example carbon tetrachloride, or ethers, for example diethyl ether, tetrahydrofuran or dioxane. The reaction can expediently with free radical catalysts, such as dibenzoyl peroxide _; or initiated by irradiation with IR light. The temperature is not particularly important, but the reaction is preferably carried out at temperatures in the range from about room temperature to the reflux temperature of the reaction mixture.

The conversion of the epimeric compounds of the formula (XV), their antipodes or racemates, to the corresponding mixture of diastereomeric 4- {3- / i-acyl-3 (R) -vinyl (or ethyl) -4 (S) -piperidyl7-1? _f 2 £ -oxapropyl} -quinolines of the formula (XVI), their antipodes or racemates, can be carried out using reducing agents, such as alkali hydrides, for example sodium borohydride, potassium borohydride or lithium tri-tert-butoxyaluminum hydride. The reduction is expediently in inert organic solvents, such as aliphatic alcohols, for example methanol or ethanol, or ethers, such as diethyl ether, tetra

2 0SI830 / 1121

hydrofuran or dioxane, at temperatures in the range of et v / a -70 G to about the reflux temperature of the reaction mixture, carried out.

The conversion of a compound of the formula (XVI) to the corresponding mixture of the diastereomeric 4- {3- / 3 (R) -vinyl (or ethyl) -4 (S) -piperidyl / -i £, 2 ^ -oxapropyl} -quinolines of the formula (IVa), their antipodes or racemates, is carried out using deacylating agents, such as alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, or reducing deacylating agents, such as dialkylaluminum hydrides, for example egg isobutylaluminum hydride, or alkali aluminum hydrides, for example lithium aluminum hydrides, for example lithium aluminum hydrides. The deacylation is expediently carried out in the presence of inert organic solvents, such as lower alkanols, for example methanol or ethanol, hydrocarbons, for example toluene, or ethers, for example diethyl ether or. Tetrahydrofuran. The deacylation temperature does not play a special role. Temperatures in the range from about -70 ° C. to about the reflux temperature of the reaction mixture are expediently used.

In the reaction scheme VII, the reaction is carried out of compounds of formula (XIIb '), their antipodes or racemates, to give the compounds of formula (IVb), its antipodes or racemates, in accordance with the methods described in Reaktionsachema VI.

In the compounds of the general formula (I) in which R is a vinyl group, this vinyl group can be reduced to the ethyl group

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- 25 - ^ 200496

be adorned. This reduction can be carried out by catalytic hydrogenation, for example using noble metals such as palladium or Platinum. The hydrogenation is expedient in inert solvents, such as water, alcohols, e.g. methanol or Ethanol, organic or inorganic acids, e.g. acetic acid or hydrochloric acid, or mixtures thereof. In addition, the hydrogenation is expediently carried out at room temperature. However, temperatures can also be used be used above or below room temperature. The conversion can also be carried out by chemical reduction in Presence of oxygen using hydrazine hydrate and a copper-iHj ^ salt, such as copper (II) sulfate, as a catalyst, be performed. The reduction in polar solvents such as water or lower alkanols, e.g. Methanol or ethanol, preferably at temperatures in the range from room temperature to the boiling point of the reaction mixture, carried out.

If the compounds of the general formula (I) are obtained in the form of the racemates, they can by known methods, such as fractional crystallization or salt formation with optically active acids.

'The compounds of the formula (I), their antipodes or racemates, form acid addition salts with inorganic acids, such as Hydrochloric acid, hydrobromic acid, sulfuric acid or Phosphoric acid, or with organic acids such as acetic acid, tartaric acid, maleic acid, citric acid or p-toluenesulfonic acid.

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The compounds of the formula (I), their antipodes and racemates and the pharmacologically acceptable acid addition salts thereof have a preventive or curative effect in malaria as well as antiarrhythmic properties and are therefore valuable antimalarials and antiarrhythmics. Your therapeutic effect is quantitatively similar to that of quinine and quinidine, but their toxicity is much lower. For example, the toxicity of the preferred compound of the formula (I), namely 7-trifluoromethyl- «(R) - / 5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl7-4-quinolinemethanol, their antipode or racemate, about 7 to 8 times less than that of quinine. The racemic or optically active compounds of the formula (I) which have antipodes and racemates and their acid addition salts thus, with significantly lower toxicity, activity properties similar to those of antimalarial drugs and antiarrhythmic drugs of known effectiveness and safety are the same.

The compounds of formula (I), their antipodes and racemates and pharmacologically acceptable acid addition salts can be packaged into pharmacologically customary forms of administration. They are suitable e.g. for oral or parenteral Application using the usual pharmacological auxiliaries, such as organic or inorganic inert carriers, e.g. water, gelatin, lactose, starch, magnesium stearate, Talc, vegetable gums, vegetable oils or polyalkylene glycols. The pharmaceutical preparations can e.g. in solid form, such as tablets, lozenges, suppositories or capsules, or in liquid form, such as solutions, suspensions or emulsions. Other suitable pharmacological auxiliary

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Substances are e.g. preservatives, stabilizers, wetting or emulsifying agents, or salts that regulate the osmotic Serve pressure or act as a buffer. The preparations can also contain other therapeutic agents.

The amounts of active ingredient contained in the aforementioned dosage forms can vary widely. The frequency, with which these dosage forms are administered depends on the amount of active ingredient contained and on the requirements of the pharmacological situation.

The term "lower alkyl" used here means straight-chain or branched hydrocarbon radicals having 1 to 7 carbon atoms, such as the methyl, ethyl, propyl, isopropyl or butyl group. The methyl and ethyl groups are preferred. The term "halogen atom" includes all halogen atoms, ie, bromine, chlorine, fluorine and iodine atoms. The term “acyl radical” means lower alkanoyl radicals with 1 'to 7 carbon atoms, such as the formyl, acetyl, propanoyl, butanoyl or heptanoyl group. The term "aryl radical ⁵ " denotes phenyl groups which can be substituted by one or more lower alkyl radicals, lower alkoxy radicals or halogen atoms. The term "aryl lower alkyl radical" denotes hydrocarbon radicals with 7 to 12 carbon atoms, such as benzyl, phenethyl ™ or The term "lower alkoxy group" denotes lower alkyl ether groups in which the lower alkyl radical has the aforementioned meaning.

The examples illustrate the invention.

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example 1
Making the

A solution, cooled with dry ice, of about 0.206 mol of lithium diisopropylamide (prepared by adding 130 ml of n-butyllithium (about 1.6 M) in hexane with 13 ml of diisopropylamine at -78 C under a dry nitrogen blanket) is added dropwise with stirring (20 min ) mixed with a solution of 43.5 g of 7-trifluoromethyllepidine in 150 ml of tetrahydrofuran. The brownish ^ 7-Trifluormethyllepidyllithium containing mixture is stirred for 30 minutes at -78 ⁰ C and then treated dropwise (60 min) with a solution of 19.0 g of the racemate of cis-3-ethyl-4-piperidineacetic acid added in 140 ml of tetrahydrofuran. Stirring is continued for 1 hour at -78 ⁰ C and 5 hours at -25 C. means 1 η aqueous hydrochloric acid the pH is adjusted to a value of 7, the resultant mixture is thoroughly extracted with ether to remove non-converted 7-Trifluormethyllepidin to remove. The ethereal phases are washed 3 times with water containing 5 percent methanol. The aqueous phases are combined and concentrated ammonium hydroxide, which is saturated with sodium chloride, is added until an alkaline reaction is achieved. The mixture is then extracted thoroughly with chloroform. The usual work-up gives 30 g of a viscous, yellow oil which is converted into the dihydrochloride. Crystallization from ethanol gives 26.4 g of the racemate of cis-7-Trif1 ■ irine thy 1-4- / 3- (3-ethy1-4-piperidyl) -2-oxopropyl / -quinoline dihydrochloride . The "free base" contained in the mother liquor

0 9 8 3 0/1121

is adsorbed on 500 g of silica gel (Merck, 0.05-0.2 mm) and with a chloroform-methanol-ammonia mixture in the ratio 89: 10: 1 eluted. This gives a further 3.2 g of the racemate of cis-7-trifluoromethyl-4 - \ / 3- (3-ethyl-4-piperidyl) -2-O

An ice-cold solution of 14.6 g of the racemate of cis-7-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-oxopropyl7-quinoline in 200 ml of ethanol is mixed with 1.5 g of solid sodium borohydride . After stirring for 15 minutes, 100 ml of water are added; the ethanol is evaporated in vacuo. The aqueous residue is extracted thoroughly with chloroform. Conventional work-up gives 15 g of amorphous, racemic, epimeric cis-7-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-hydroxypropyl / -quinolines. This crude product is dissolved in 500 ml of glacial acetic acid, then 50 ml of boron trifluoride etherate are added. The homogeneous solution is ^{kept at 50 °} C. for 18 hours. The solvent is then removed in vacuo and the residue partitioned between aqueous ammonium hydroxide and chloroform. After working up, 16 g of the amorphous, racemic, epimeric cis-7-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-acetoxypropyl-7-quinolines are obtained. This epimeric mixture is heated under gentle reflux for 17 hours without further purification in 1 liter of benzene containing 50 ml of ennic acid and 150 g of sodium acetate trihydrate. The cold mixture is mixed with 200 ml of ice water, the aqueous phase is mixed with concentrated ammonium hydroxide up to a pH of about 8, then separated from the benzene layer and

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extracted thoroughly with chloroform. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated to dryness. This gives 15 g of crude product. The crude product is adsorbed on 540 g of neutral aluminum oxide (activity II) and eluted with ethyl acetate. About 10 g of a mixture of the racemate of Y'-trifluoromethyldeoxydihydrocinchorddin and the racemate of T'-trifluoromethyldeoxydihydrocirichonine are obtained. When eluting with methanol, about 3 g of a mixture of starting material and end product are obtained, which is subjected to cyclization and work-up under the same conditions. After combining, the reaction products are subjected to further purification by subjecting them to partition extraction using 1 η hydrochloric acid and methylene chloride. The aqueous phase, which has been made alkaline, is then extracted with methylene chloride and worked up in the customary manner. This gives a crystalline mixture of the racemate of 7'-Trifluormethyldeeoxydihydrocinchoni djnund of Ra cemats of 7'-Trifluormethyldesoxydihydrocinchonin which melts after recrystallization from ether / petroleum ether at 85-86 ⁰ C. This crude mixture is used in the process without further purification.

(B) Process of the invention

The reaction is carried out in a 500 ml three- necked flask which is connected to a gas burette and equipped with a gas outlet tube and a magnetic stirrer. Furthermore, the three-necked flask is connected to a goooh rubber with a

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lenmeyer flask connected. A solution of 12.3 g of a mixture of the racemate of 7'-trifluoromethyldeoxydihydrocinehonidine and the racemate of 7'-trifluoromethyldeoxydihydrocinchonine in 300 ml of an anhydrous mixture of dimethyl sulfoxide and tert-butanol (4 ι 1) is first a few minutes at 20 ⁰ g stirred in an atmosphere of dry oxygen
(no O 2 uptake is observed here), 2 g (about 0.5 molar equivalent) of solid potassium tert-butoxide are then added in one go. The resulting reddish solution is stirred while the oxygen uptake is measured. After this
Consumption of 800 ml of oxygen (about 1 molar equivalent; after about 30 minutes) 50 ml of water are added and the pH is adjusted to a value of about 7 by adding acetic acid. The reaction mixture is evaporated to dryness in vacuo. The residue is subjected to partition extraction using methylene chloride and 1 η aqueous hydrochloric acid. After neutralizing with concentrated ammonium hydroxide (pH about 8), the aqueous phase is thoroughly dissolved with chloroform. In the usual work-up, 12.8 g of the crude, crystalline product are obtained, while 5.21 g of predominantly racemic product are obtained on crystallization from methylene chloride / acetone
Gives 7'-trifluoromethyldihydrocinchonine in 2 batches. the
-Mother liquors are converted into the hydrochloride. After this
Crystallization from ethanol gives 3.81 g of predominantly
racemic 7'-trifluoromethyläihydrocinchonidin as monohydrochloride. The free base of the mother liquors is adsorbed on 400 g of silica gel (Merck, 0.05 to O ₉ 2 mm) and treated with chloroform / triethylamine / methanol (89 ι 10 s 1) in the following order

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eluted: 1.3 g of a mixture of the racemic threobases, 0.4 g of the racemate of 7'-trifluoromethyldihydrocinchonine and 1.1 g of the racemate of 7'-trifluoromethyldihyärocinchonidir ;. The racemate of 7'-Trifluormethyldihydrocinchonidin melts after crystallization and recrystallization from acetone at 175-176 ⁰ C, as the monohydrochloride at 265-267 ⁰ G (dec.).

The racemate of 7'-trifluoromethyldihydrocinchonine has a melting point after recrystallization from methylene chloride / acetone from 218 to 219 ° C.

Example 2

(A) Preparation of the starting compounds A dry ice cooled solution of about 0.1 mole of lithium diisopropylamide (prepared by adding 62.5 ml of 1.6 molar n you about-butyllithium in hexane with 11 g of diisopropylamine at -78 ⁰ C under nitrogen) a solution of 21 g of 7-trifluoromethyl] epidine in 250 ml of anhydrous tetrahydrofuran is added dropwise (28 min) with stirring. The resulting red-orange solution of 7-Trifluormethyllepidyllithium 25 minutes at -78 ⁰ C stirred under nitrogen. Is added dropwise (33 min) a solution of 10 g of the racemate of -Cincholoiponäthylester in 250 ml of tetrahydrofuran and stirred for 2.5 hours at -78 ⁰ C and 18.5 Stunder, at -25 ° C Subsequently, 10 ml saturated Sodium sulfate solution added to hydrolyze the lithium enolate obtained. After drying over anhydrous sodium sulfate, the mixture is evaporated. The residue is taken up in 500 ml of chloroform,

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Washed 2 times with 50 ml of water over anhydrous sodium sulfate dried and evaporated. The crude product is purified using a chromatography column loaded with 450 g of silica gel cleaned. 9.70 g of the racemate of trans-7'-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-oxopropyl / -quinoline are obtained in the form of a yellow oil.

An ice-cold solution of 9.75 g of the racemate of trans-7'-trifluoromethyl-4- / 3- ( 3-ethyl-4-piperidyl) -2-OXOPrOPyIZ-ChInOUn in 300 ml of ethanol (95 percent), 1.5 g of sodium borohydride are added in portions while stirring. After 1.5 hours 100 ml of water are added with stirring and the ethanol is removed in vacuo. The aqueous residue is treated with sodium chloride saturated and extracted thoroughly with chloroform. The chloroform extract gives after drying over anhydrous sodium sulfate and evaporating 9.45 g of the crude, racemic, epimeric trans-7'-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-hydroxypropyl / -quinoline.

A solution of 9.45 g of the crude ^ racemic, epimeric trans-7'-trifluoromethyl-4- / 3- (3-ethyl-4-piperidyl) -2-hydroxypropyl / '- quinolines in 290 ml of glacial acetic acid becomes. mixed with 29 ml of freshly distilled boron trifluoride etherate. The mixture obtained is ^{kept at 50 °} C. for 16 hours. The acetic acid is removed by vacuum distillation and after 150 g of ice water have been added, the aqueous solution is adjusted to a pH of 8 with concentrated ammonium hydroxide and extracted thoroughly with methylene chloride. The extract is dried over anhydrous sodium sulfate and then evaporated to dryness. Man

209830/1121

receives 10.63 g of the crude, racemic, epimeric trans-7'-trifluoromethyl-4- / 3- ( 3-ethyl-4-piperidyl) -2-acetoxypropy! / - quinolines as a viscous oil.

A solution of 10.14 g of the. 50 ml of glacial acetic acid and 120 g of sodium acetate trihydrate are added to crude racemic epimeric trans-7'-trifluoromethyl-4- _{1 (} / 3- (3-ethyl-4-piperidyl) -2-acetoxypropyl / -quinoline in 1 liter of benzene The mixture is heated with stirring and reflux for 22 hours, after cooling, 600 g of ice water is added and the pH is adjusted to a value using concentrated ammonium hydroxide
set of about θ. The aqueous phase is thoroughly with
Extracted methylene chloride, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated. 8.53 g of the crude reaction product are obtained. That
Crude product is chromatographed using a column loaded with 450 g of silica gel. When eluting with
Chloroform / triethylamine (9 ί 1) gives 3.48 g of an amorphous mixture of the racemate of 7'-trifluoromethyl-3-epi-deoxydihydrocinchonidine and the racemate of 7'-trifluoromethyl-3-epi-deoxydihydrocinchonine.

(B) Process of the invention

"The reaction is in a 250 ml three-necked flask
carried out, which is connected to a gas burette and equipped with a gas outlet tube and a magnetic stirrer. Furthermore, the three-necked flask is connected to a gooch rubber with a
Erlenmeyer flask connected. A solution of 3.48 g of a mixture of the racemate of 7 ^l -trifluoromethyl-3-epi-deoxydihydro-

209830/1 121

- ⁵⁵ - ^ 200496

cinchonidine and the racerate of 7'-trifluoromethyl-3-epi-deoxydihydrocinchonine in 170 ml of dimethyl sulfoxide / tert-butanol (4: 1) are mixed with 1.69 g of potassium tert-butoxide. The resulting solution is vigorously stirred under an atmosphere of dry oxygen. The oxygen uptake "is 1.2 mol equivalent. The reaction mixture turns light brown * Then it is mixed with water. The resulting solution is neutralized with acetic acid, then the solvents are stripped off in vacuo. The residue is dissolved in 500 ml of methylene chloride, (ml 3 times 25) with a 7-percentage aqueous Natriumhyärogeneartionatlösung and VJasser (1 times 25 ml), dried over anhydrous sodium sulfate and evaporated Upon separation of the crude by column chromatography (silica gel PFp ₁ -., - 0.2 to 0.05 (1: 3); eluent chloroform / triethylamine / methanol, 85 '· 10: 5) one obtains 1.4 g of the racemate of 7'-trifluoromethyl-3-epi-dihydrocinchonidine with a temperature of 192 to 193.5 ° C ( from acetone) and 1.04 g of the racemate of 7'-trifluoromethyl-3-epi-dihydrocinohonine from P. 182 to 184 ⁰ C (from acetone).

Example 3

A solution of 0.229 g (0.63 mlvlol) of a mixture of the racemate of 7'-trifluoromethyl-dihydrocinchonidinone and 7'-trifluoromethyl-dihydrocinchoninone in 20 ml of anhydrous benzene is under a nitrogen atmosphere with 0.5 ml (1.25 mol equivalent) of diisobutylaluminum hydride (25 percent) added to hexane. The reaction mixture is then stirred at room temperature until the absence of the starting ketone on a thin

209830/1121

- 56 - 220Ü496

layer is observed. After the excess hydride has been decomposed with water and 1 η sodium hydroxide has been added to a pH of about 10, the mixture is extracted thoroughly with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and then evaporated to dryness. The crude product is chromatographed using four preparative silica gel plates with the solvent system chloroform / triethylamine / methanol (89: 10: 1). This gives 45 mg of the RacematB of 7'-trifluoromethyl-dihydrocinchonine from P. 215 to 218 ⁰ C (from acetone) and 139 mg of the racemate of 7'-trifluoromethyl-dihydrocinchonidine, melting at 169 to 171 ⁰ C (from acetone).

Example 4

(A) Preparation of the starting compounds 34.1 ml of about 1.6 M (54.6 mmol) of n-butyllithium in hexane are added at -78 · ⁰ C under dry nitrogen with 6.1 g (60.1 mmol) of diisopropylamine . A solution of 10.46 g (49.7 mmol) of 7-trifluoromethyllepidine in 40 ml of tetrahydrofuran is added dropwise to the lithium diisopropylamide thus prepared, while stirring. The brownish, 7-Trifluormethyllepidyllithium containing mixture is stirred for 30 minutes at -78 ⁰ C and then treated dropwise (30 min) with a solution of 5.28 g (28.6 mmol) of 3 (R) -Athyl-4 (S) - methyl piperidine acetate in 40 ml of tetrahydrofuran was added. Stirring is continued for 2 hours at -78 ⁰ C and then for 3 hours at -25 ⁰ C. After the addition of acetic acid to a pH of about 6 5 g of KHCO added. After standing overnight it will

209830/1121

the mixture is filtered, the filter cake is washed with methanol. The filtrate is evaporated, the 'residue is in

300 ml of chloroform taken up, washed with 50 ml of 3 η potassium hydroxide and with 50 ml v / ater. The chlorproform solution is dried, and evaporated. The crude product is passed through a column charged with 420 g of silica gel using chloroform / methanol / ammonium hydroxide (89 s 10: 1). This gives 6.04 g (56 percent) of amorphous 7-trifluoromethyl-4f3- / 3 (R) -ethyl-4 ( S) -piperidyl / -2-oxopropyl} -quinoline.

An ice-cold solution of 16.5 g (45.3 mmol) of 7-trifluoromethyl-4 {3- / 3 (R) -ethyl-4- ( S) -piperidyl / -2-oxopropylj-quinoline in 400 ml of ethanol (95 percent) is 1.87 g (50 mmol) Sodium borohydride added. The reaction mixture is stirred for 2 hours, then with a further 0.45 g (12.5 mmol) of sodium borohydride added and then stirred again for 1 hour. Wake up the decomposition of the excess liatrium borohydride by adding Acetic acid is added to the mixture with 200 ml of water and with concentrated ammonium hydroxide until an alkaline reaction (pH 8) added. After the ethanol has evaporated, the pH is adjusted to a value of about 11 with 3 η potassium hydroxide. The aqueous mixture is extracted with chloroform (3 times 100 ml). The chloroform extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. 15.95 g (97 percent) of the crude epimers are obtained 7-Trifluoromethyl-4 {3- / 3 (R) -ethyl-4 (S) -piperidyl7-2-hydroxypropylj-quinolines.

2 0 9 8 3 0/1121

A solution of 15.5 g (42.3 mmol) of the epimeric 7-trifluoromethyl-4 ^ 3- / 3 (R) -ethyl-4 (S) -piperidyl7-2-hydroxypropyl $ -quinolines in 600 ml of glacial acetic acid is added 60 ml of boron trifluoride etherate are added. The homogeneous reaction mixture is ^{kept at 50 °} C. for 17 hours. The solvent is then evaporated off under reduced pressure and 200 g of ice are added to the residue. After adjusting the pH to about 8 using concentrated ammonium hydroxide, the aqueous mixture is extracted 3 times with 250 ml of methylene chloride. The extract is dried over anhydrous sodium sulfate, filtered and evaporated. 15.7 g (91 #) of the crude epimeric 7-trifluoromethyl-4p- / 3 (R) -ethyl-4 (S) -piperidyl7-2-acetoxypropyl-quinolines are obtained.

A mixture of 15.2 g (37.3 mmol) of the crude epimeric 7-trifluoromethyl-4 {3- ^ 3 (R) -ethyl-4 ( S) -piperidy ^ -2-acetoxypropyIj-quinoline, 1000 ml benzene, 50 ml glacial acetic acid and 150 g sodium acetate trihydrate is refluxed for 16 hours under a nitrogen blanket. The cooled mixture is poured with 600 g of ice added, then the pH is adjusted using concentrated Ammonium hydroxide adjusted to a value of about 8. The aqueous layer is then separated from the benzene and extracted 3 times with 500 ml of methylene chloride. This The extract is combined with the benzene layer, washed with 50 ml of water, dried over anhydrous sodium sulfate and evaporated. 14.12 g of crude product are obtained which, using a column charged with 400 g of silica gel and a chloroform / triethylamine solvent system. 9 J 1) chromatographed. First, 5.63 g of a mixture are made

209830/1121

7'-trifluoromethyl-deoxydihydrocinchonidine and 7'-trifluoromethyl-deoxy'dihydrocinchonine eluted "Then 5.65 g of olefins are eluted as intermediates, which the ' are subjected to the same cyclization and work-up conditions. This gives an additional 1.57 g of the aforementioned Mixture, i.e. a total of 7? 2 g (54 percent).

(B) Process of the invention

The reaction is carried out in a 500 ml three-necked flask, the one connected to a gas burette and with a grass outlet pipe as well as a magnetic stirrer. Furthermore, the three-necked flask is over a Gooch rubber with an Erlenmeyer flask tied together.

A solution of 7.2 g (20.7 mmol) of a mixture of 7'-trifluoromethyl-desoxydihydrocinchonidin and 7'-Trifluormethyldesoxydihydrocinchonin in 250 ml of anhydrous dimethylsulfoxide / tert-butanol (4} 1) is first few minutes at 2O ⁰ C stirred in an atmosphere of dry oxygen. No O ₂ aluminum intake is observed here. Then 3.5 g of solid potassium tert-butoxide are added in one go. The resulting reddish solution is stirred while the oxygen uptake is measured. After 555 ml of oxygen have been consumed (20 min, calc. 465 ml as 1 mol equivalent), the reaction mixture becomes

5 ml of water are added and the pH is adjusted to a value of about 7 by adding acetic acid. After evaporating the reaction mixture to dryness under reduced pressure, the residue is dissolved in 500 ml of methylene chloride

209830/1121

recorded. After washing with 7.5 percent sodium hydrogen carbonate (3 times 50 ml) and water (1 time 50 ml), drying The I.Iethylene chloride is added over anhydrous sodium sulfate and filtration evaporated. The crude product is obtained using a column charged with 600 g of silica gel and hexane / tri-methylamine / isopropanol (85: 10: 5) as eluent chromatographed. The less polar fraction gives 1.9 g

(25 percent) 7'-trifluoromethyl-dihydrocinchonine mp 227 to 23O ⁰ C (from acetone); A ^ ⁵ = + H1 ° (c = 1.00, CH ₃ OH). The dihydrochloride has a melting point of> 174 ⁰ C (dec.) (From ethanol); / cc / ^ ² = + 129.5 ° (c = 1.00, CH ₃ OH).

The more polar fraction gives 1.86 g (24.7 percent) of 7 • -trifluoromethyl-dihydrocinchonidine with a melting point of 163 to 164 ° C. (from methanol / Waaser); / 0 (J ^ = -66.7 ° (c = 0.9, CH ₃ OH). The dihydrochloride has a melting point of> 184 ° C (decomp.) (From ethanol / acetone); / * 7 $ ² = -62.9 ° (c = 1.00, CH ₃ OH).

Example 5

(A) Preparation of the starting compounds 147 ml of about 1.6 M (0.235 mol) n-butyllithium in hexane are mixed with 25 g (0.250 mol) diisopropylamine at -78 C under a dry nitrogen blanket. The ι lithium thus prepared is added dropwise (30 min) added with stirring a solution of 40.3 g (0.192 mol) of 7-Trifluormethyllepidin in 500 ml of tetrahydrofuran. The brownish ^ 7-Trifluormethyllepidyllithium containing mixture is stirred for 30 minutes at -78 C and then dropwise (30 min) with

209830/112 1

- 41 - 2 ^ 00496

a solution of 18.1 g (0.101 mol) of 3 (R) -Vinyl-4 (S) -piperidine acetic acid methyl ester in 500 ml of tetrahydrofuran was added. Stirring is continued for 12 hours at -78 ⁰ C and 3 hours at room temperature. Then the pH is adjusted to a value of about 7 with glacial acetic acid. After adding 250 ml of ether, the organic phase is extracted with 16 times 500 ml of sodium hydrogen carbonate solution (7.5 percent). The aqueous hydrogen carbonate extracts are washed back with 100 ml of ether and then with chloroform. After drying the chloroform extract over anhydrous sodium sulfate, filtering and evaporating, 27.3 g (75 percent) of crude 7-trifluoromethyl-4-p-Z3 (R) -4 (S) -piperidyl7-2-oxopropylj-quinoline are obtained.

An ice-cold solution of 26.3 g (0.0695 mol) 7-trifluoromethyl-4f3- / 3 (R) -vinyl-4 ( S) -piperidyl / -2 ™ oxopropyl ^ -quinoline in 600 ml of ethanol (95 percent) is mixed with 3.5 g (0.945 mol) of sodium borohydride. After stirring the reaction mixture for 2 hours the excess sodium borohydride is decomposed by adding acetic acid. Then 300 ml Water is added and the mixture thus obtained is mixed with concentrated ammonium hydroxide until an alkaline reaction (pH ^ 8) added. After the ethanol has evaporated, the aqueous mixture extracted with chloroform (3 times 100 ml), the The extract is dried and evaporated. 22.5 g are obtained (86 percent) of the crude epimeric 7-trifluoromethyl-4 | 3- / 3 (R) · ™ vinyl-4 (S /) - piperidyl7-2-hydro3 £ ypropylj-quinoline.

A solution of 21 ₉ 5 g (0.0567 moles) of the crude epimers

209830/1121

22Ü0496

propylj-quinoline in 800 ml of glacial acetic acid is mixed with 80 ml of boron trifluoride etherate. The homogeneous Reaktionsgeraisch 17 is held hours 5O ⁰ C. After evaporation of the solvent under reduced pressure, the residue with 200 ι; Ice cream. After the pH has been adjusted to a value of about 8 with concentrated ammonium hydroxide, the aqueous mixture is extracted 3 times with 250 ml of methylene chloride. The extract is dried over anhydrous sodium sulfate, filtered and evaporated. 20 g of crude product are obtained, which is chromatographed using a column charged with 600 g of silica gel and chloroform / triethylamine / methanol (85: 10: 5) as the eluent. 14.0 g (61 percent) of the amorphous epimeric 7-trifluoromethyl-4f3- / 3 (R) -vinyl-4 (S) -piperidyl / -2-acetoxypropyl-quinolines are obtained.

A mixture of 14 g (0.0345 mol) of the epimeric 7-trifluoromethyl-473- / 3 (R) -vinyl-4 ( S) -piperidyl / -2-acetoxypropylj-quinoline, 900 ml benzene, 45 ml glacial acetic acid and 138 g sodium acetate trihydrate is refluxed for 16 hours under a nitrogen blanket. The cooled mixture is mixed with 200 g of ice, then the pH is adjusted to a value of about 8 with concentrated ammonium hydroxide. The aqueous layer becomes after separating the benzene with methylene chloride (3 times 500 ml) extracted The organic phases are combined, washed with 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is passed through a column charged with 400 g of silica gel using chloroform / triethylamine (9 ί 1) chromatographed as the eluent. 4.8 g of the cyclized product and 7.8 g of inter-

209830/112 1

with the olefins formed * The olefins are subjected to the same cyclization and work-up conditions. This gives an additional 1.3 g of the cyclized product. The overall yield is 6.1 g (51 percent) of a mixture of 7'-trifluoromethyl-deoxycinchonidine and 7'-trifluoromethyl-deoxycinchonine _; ßU ² ^ = + 73.3 ° (o = 1.3, CH, OH).

(B) Process of the invention

The reaction is carried out in a 500 ml three-necked flask connected to a gas burette and with a. Gas outlet and a magnetic stirrer is equipped. The three-necked flask is over a gooch gum with an Erlenmeyer flask tied together.

A solution of 5-7 g (0.0164 mol) of a mixture of 7'-trifluoromethyl-deoxycinchonidine and 7'-trifluoromethyl-eesoxycinchonine in 200 ml of anhydrous dimethylsulfoxide / tert-butanol (4: 1) is first heated for a few minutes at 2O ^{Stirred at 0} C in an atmosphere of dry oxygen. No surgical recording is observed here. Then 2.96 g (0.0264 mol) of solid potassium tert-butoxide are added in one pour. The resulting reddish solution is stirred while the oxygen uptake is measured. After 400 ml of oxygen have been consumed (20 min _c . 368 ml as 1 mol equivalent), the reaction mixture becomes

mixed with 5 ml of water, the pH is adjusted with Acetic acid adjusted to a value of about 7. After evaporation under reduced pressure, the residue is dissolved in 500 ml Methylene chloride suspended and then with 7.5 percent sodium hydrogen carbonate solution (3 times 50 ml) and water (50 ml)

209830/1121

- 44 - ^ 20OA96

washed. The aqueous layer is back-extracted with 100 ml of methylene chloride, the organic phases are combined, dried over anhydrous sodium sulfate, filtered and evaporated. 7.1 g of the crude crystalline product are chromatographed using a column charged with 600 g of silica gel and chloroform / triethylamine (9 J 1) as the eluent. The less polar 7'-trifluoromethylcinchonine (1 »4 g; 23.6 percent) is crystallized from acetone, P. 223 to 229 ° C, / ~ σ $ ψ = + 154 ° (c = 0.95, CH, 0H). The more polar 7'-trifluoromethylcinchonidine (1.7 g, 28.7 ^c />) is crystallized in the form of the dihydrochloride from ethanol, mp 211 to 215 ° C, βg ^ = -84.3 ° (c = 1, 1, CH ₅ OH).

Using the same procedure, the following compounds are made: 5'-trifluoromethyl-cinchonidine, 5'-trifluoromethyl-cinchonine, 6 • -trifluoromethyl-cinchonidine, 6'-trifluoromethyl-cinchonine.

Example 6

(A) Preparation of the starting compounds A solution of 3.0 g of 7-trifluoromethyl-4-f3- / i-'benzoyl-3 (R) -vinyl-4 (S) -piperidyl7-2-oxopropyl | -quinoline in 300 ml 1.72 g of solid N-bromosuccinimide and a few crystals of dibenzoyl peroxide are added to anhydrous carbon tetrachloride in a 500 ml Pyrex flask. The mixture is irradiated with a 250 V / att IR heating lamp while stirring. After 90 minutes of irradiation, the refluxing mixture is cooled and filtered. Of the

209830/1 1 21

Filter cake is washed with carbon tetrachloride which Filtrates are combined and evaporated to dryness. You get a crude amorphous mixture of the epimeric 7-trifluoromethyl-4-f; 5- / i-benzoyl-3 ( R) -vinyl-4 (S) -piperidyl7-i £ -bromo-2-oxopropylj quinolines.

A solution of 3> 9 g of the crude epimeric 7-trifluoromethyl-4-f3- / i-benzoyl-3 (R) -vinyl-4 ( S) -piperidyl7-1 ^ -bromo-2-oxopropylj quinolines in 300 ml of methanol is nut an excess of solid Sodium borohydride added. The solution is 30 minutes at room temperature stirred, then mixed with 50 ml v / water and stirred again for 12 hours. After the methanol has evaporated the aqueous residue extracted thoroughly with methylene chloride, the organic extracts are washed with water over Dried sodium sulfate and evaporated. A crude product is obtained which is adsorbed on 90 g of neutral aluminum oxide, activity II. When eluting with benzene, that's 10 to 50 percent Contains ethyl acetate, an amorphous, inseparable one is obtained Mixture of the diastereomeric 7-trifluoromethyl-4-f3- / i -benzoyl-3 (R) -vinyl-4 ( S) -piperidyl / -i |, 2 ^ -oxapropylj »quinolines.

A solution, cooled with dry ice, of 1.2 g of the diastereomeric 7-trifluoromethyl-4-i-3- / i-benzoyl-3 (R) -vinyl ~ 4 (S) -piperidyl / -16,2ξ-oxapropyIy-quinolines in 100 ml of anhydrous toluene are mixed with 2 ml of an approximately 1.5 molar solution of diisobutylaluminum hydride in toluene while stirring and under a dry nitrogen blanket. Stirring is continued for 45 minutes at -78 ⁰ O, add 5 ml of methanol / water (1 s 1) and stir the mixture for 90 minutes at 20 ⁰ C. The precipitate is filtered off and washed with methanol. The filtrates are combined and evaporated to dryness.

509830/1121

22ÜU496

steams. The crude product is separated by means of preparative layer chromatography (silica gel GPp ₁ -; chloroform / triethylamine / methanol 85: 10: 5). An amorphous, inseparable mixture of the diastereomeric 7-trifluoromethyl-J3- / 3 (R) -vinyl-4 (S) -piperidyl / -1ξ, 2 ^ -oxapropyl (-quinolines) is obtained.

(B) Process of the invention

A solution of 0.356 g of the diastereomeric 7-trifluoromethyl-4-j3- / 3 ( R) -vinyl-4 (S) -piperidyl / -1 |, 2 ^ -oxapropyll-quinolines in 50 ml of toluene and 2 ml of ethanol is heated under gentle reflux for 24 hours. After evaporation of the solvents the residue is separated by means of preparative thin layer chromatography. The 7'-trifluoromethylcinchonidine is obtained 7'-trifluoromethylcinchonine.

Example 7

A solution of 2.638 g (0.0075 mol) of 7'-trifluoromethylcinchonidine in 100 ml of anhydrous methanol is mixed with 1.5 g of hydrazine hydrate (99 percent) and about 20 mg of copper (II) acetate. The reaction mixture is stirred for 3 days at room temperature, then filtered through "Gelite" and evaporated. The 7'-trifluoromethyl-dihydrocinchonidine is obtained with a ^{temperature of 163 to 164 °} C. (from methanol / water).

209830/1 121

22UÜ496

- 47 Example 8

According to the recipe given, "known methods Capsules made.

7'-trifluoromethyl-dihydrocinchonidine

Cornstarch
talc

Total weight 210 mg

Per capsule 50 mg 150 mg 10 mg

Example 9

According to the given recipe, suppositories are produced using known methods.

7'-trifluoromethyl-dihydrocinchonidine

hydrogenated coconut oil
Carnauba wax

per 1.3 g of suppository

0.025 g 1.230 g 0.045 g

Example 10

According to the given recipe, tablets are produced by known processes.

per tablet

7'-trifluoromethyl-dihydrocinchonidine dicalcium phosphate dihydrate, unground corn starch
Magnesium stearate - ^

Total weight 225 mg

25th mg 175 mg 24 mg 1 mg

209830/1121

Claims (31)

2 2 UU Λ 9 - 48 claims ΛΪ Process for the preparation of racemic or optically active quinoline derivatives, which are epirner in ° t-, 2- and 5-position, of the general formula (I) in which R denotes the vinyl or ethyl group, its antipodes and racemates and acid addition salts here of, characterized in that compounds of the general formulas (II) and (Ha) and II in which R has the aforementioned meaning, 209830/1121 or their antipodes, or racemates, with a stereoselective Treated reducing agent, or a racemic or optically active compound which is epimeric in the 2- and 5-positions, the general formula (III) III in which R has the aforementioned meaning, hydroxylated, or a racemic or optically active compound of the general formula (IV) N-H IV in which R has the aforementioned meaning, 2 0 9 8 3 0/1121 2 / ÜÜ496 subject to cyclization, optionally in those compounds in which R is the vinyl group, this vinyl group reduced to the ethyl group, optionally the racemates splits into their optical antipodes and optionally converts the free bases into the acid addition salts. 2. Process for the preparation of quinoline derivatives of the general Formulas (Ia) and (Ib) in which R denotes the vinyl or ethyl group, their antipodes and racemates and acid addition salts thereof, characterized in that compounds of the general formulas (II) and (Ha) N ^: II Ha in which R has the aforementioned meaning, 209830/112 1 22ÜÜ496 Treated with a stereoselective reducing agent, ^ e ^ even if those compounds in which R is the vinyl group, this vinyl group is reduced to the ethyl group, if necessary the racemates in their optical antipodes so / ie _% splits the free bases in the Acid addition salts transferred. 3. Process for the preparation of quinoline derivatives of the general Formula (I) HO (D in which R denotes the vinyl or ethyl group, its antipodes and racemates and acid addition salts thereof, characterized in that a racemic or optically active compound which is epimeric in the 2- and 5-positions, of the general formula (III) CP. in which R has the aforementioned meaning, 209830/1121 220ÜA36 hydroxylated, or a locally or optically active compound of the general formula (IV) N-H IV in which R has the aforementioned meaning, subjects to the cyclization, optionally splitting the racenates into the optical antipodes and optionally the free bases converted into the acid addition salts. 4. The method according to claim 1 or 2, characterized in that a Li (lower alkyl) aluminum hydride is used as the stereoselective reducing agent used. 5. The method according to claim 1, 2 or 4, characterized in that there is diisobutylaluminum hydride as the stereoselective reducing agent used. 6. A method according to any one of claims 1,2, 4 or 5, characterized in that one carries out the stereoselective reduction at temperatures of from about 20 to about 5O ⁰ C. 209830/112 1 7. The method according to any one of claims 1, 2 or 4 to 6, characterized in that compounds of the formulas (II) and (Ha), in which the trifluoromethyl group is in the 5- or 7-3 position whose antipodes or racemates are used as starting compounds. ^ - 8. The method according to any one of claims 1, 2 or 4 bii; 7, thereby characterized in that 7 ~ T-rifluoromethyl-4/5 (R) -vinyl (or ethyl) -4 (S) -quinuclidin-2 (S) -ylcarbonyl / -quinoline, its Antipode or racemate, used as the starting compound. 9. The method according to claim 1 or 3, characterized in that the hydroxylation is carried out in the presence of molecular oxygen. 10. The method according to claim 1 _? 3 or 9 "characterized in that the hydroxylation is carried out in a strongly basic solution. 11. The method according to any one of claims 1 _p 5s? 9 or 10, characterized in that an alkali hydroxide or an alkali alkoxide is used as the strong base ₀ 12. The method naoh one of claims 1 ₉ 3 or 9 to 11 "characterized ρ that one carries out the Ejaroiijli & rimg at about room temperature ο 13 "" ancestors zmofa © © m in the? Äasprüoli © 1 "3 or 9 to 12 ₉ gekennseiGhnet ₅ characterized in that a compound of formula (111 In the ö.er Tr if luoras thy! Group in 5 or 7 ~ = position stands ₉ whose antipode or Raeematp used as the starting compound «. 2 0 9 8 3 0/1121 14. The method according to any one of claims 1, 3 or 9 to 13, characterized in that 7-trifluoromethyl-4-f «'- / 5 (R) -vinyl (or ethyl) -4 (S) -quinuclidin-2 (S) -ylj-quinoline, its Antipode or racemate, used as the starting compound. 15. The method according to claim 1 or 3, characterized in that that the cyclization of a compound of general formula (IV) by means of a weak organic or inorganic protic acid is carried out. 16. The method according to claim 15, characterized in that the weak Protonensäure.Wasser, ammonium chloride, one lower alkanol or a Lewis acid is used. 17. The method according to any one of claims 1, 3, 15 or 16, characterized in that the cyclization is carried out at temperatures from about O ⁰ C to about the reflux temperature of the reaction mixture. 18. The method according to any one of claims 1, 3 or 15 to 17, characterized in that a compound of the formula (IV) in which the trifluoromethyl group is in the 5- or 7-position, its antipode or racemate, used as the starting compound. 19. The method according to any one of claims 1, 3 or 15 to 18, characterized in that 7-Trif.l uormethyl-4- j3- / 3 (R) -vinyl (or ethyl) -4 (i)) - piperidyi / ~ 1. _f 2-oxapropylr -quinoline, the antipode or Raeemat _{f used} as the starting compound. 2 U 9 8 3 0/1121 20. Process for the manufacture of pharmaceutical preparations, characterized in that a compound of the general Formula (I) HO (D in which R is the vinyl or ethy group, its antipode or racemate, or an acid addition salt thereof mixed as an active ingredient with non-toxic, therapeutically acceptable solid or liquid carriers that are usually used in pharmaceutical preparations. 21. Pharmaceutical preparations containing a compound of the general formula (I) HO in which R is the vinyl or ethyl group, antipode or racemate or an acid addition salt read: 209830/112 1 " ^5β " of, as well as a pharmacologically acceptable carrier. 22. Quinoline derivatives of the general formula (I) HO in which R is the vinyl or ethyl group, their antipodes and racemates and acid addition salts thereof. 23. Ohinoline derivatives according to claim 22, in which the trifluoromethyl group is in the 5- or 7-position, their antipodes and racemates and acid addition salts thereof. 24. T'-trifluoromethyl-dihydro-cinchonidine, its antipode and racemate and acid addition salts thereof. 25. 7 ^l -trifluoromethyl-dihydro-cir) chonine, its antipode and Racemate and acid addition salts thereof. T 26. 7'-Trifluoromethyl-cinchonine, its antipode and racemate and acid addition salts thereof. 27. 7'-Trifluoroethyl-cinchonidine, its antipode and racemate and acid addition salts thereof. 209 830/1121 28. 7'-Trifluoromethyl-3-epi-dihydrocinchonidine, its antipode and racemate and acid addition salts thereof .. 29. 7'-Trifluoromethyl-3-epi-dihydrocinchonine, its antipode and racemate and acid addition salts thereof. 30. S'-trifluoromethyl-cinchonine, its antipode and racemate and acid addition salts thereof. 31. S'-trifluoroethyl-cinchonidine, its antipode and racemate and acid addition salts thereof. 209830/1121