DE1967178C2 - Process for the preparation of quinuclidinyl-4-quinoline methanol derivatives - Google Patents

Description

where Ri is hydrogen, hydroxy, halogen, a lower alkyl group, a lower alkoxy group or methylenedioxy, Ri is a lower alkyl or lower alkenyl group and m is the number 1 or 2, where, when Ri is methylenedioxy, m is the number 1,

their antipodes, racemates and acid addition salts thereof, by reducing the corresponding 4- [quinuclidine-2 (R) -yl-carbonyl] - or 4- [quinuclidine-2 (S) -ylcarbonyl] -quinoline modifiers of the general Formulas

and

in

where Ri, Rj and m have the above meaning,

their antipodes or racemates thereof, characterized in that the reducing agent Dinlederalkylaluminum hydride is used.

2. The method according to claim 1, characterized in that there is Diisobutylalumlnlumhydrld as a reducing agent used.

The present invention relates to a process for the preparation of ar (S) - [quinuclidine-2- (R) -yl] - and a (R) -tchhlnuclidin-2 (S) -yl] -4-chlnolinemethanol derivatives of the general formulas

and

(RJb

where Ri is hydrogen, hydroxy, halogen, a lower alkyl or lower alkoxy group or methylenedioxy, R _{2 is} a lower alkyl or lower alkenyl group and m is the number 1 or 2, where, when Ri is methylenedloxy, m is the number 1,

Their antipodes and racemates and acid addition salts thereof, by reducing the corresponding 4- [Chlnuclldln-2 (R) -yl-carbonyl] - or 4- [Chlnuclldln-2 (S) -ylcarbonyl] -cholnol derivatives of the general formulas

and

IV

where Ri, R ₂ and m are as defined above, their antipodes or racemates thereof.

The term "lower alkyl group" herein means a hydrocarbon group with 1 to 7 carbon atoms, such as the methyl, ethyl, propyl, butyl group; the ethyl group is preferred. The expression "lower Alkoxy ”means lower alkyl ether groups in which the term“ lower alkyl ”has the above meaning. Lower alkenyl means a hydrocarbon group with 2 to 7 carbon atoms, such as the vinyl, propenyl, Buienyl group; the vinyl group is preferred. The term "halogen" means the halogen atoms Bromine, chlorine, fluorine and iodine.

The process for the preparation of the above quinoline derivatives of formulas I and II, their antipodes and racemates and acid addition salts thereof, is characterized in that the reducing agent used is Dl-lower alkylaluminum hydrld used.

The compounds of the above formulas I and II are new compounds with the exception of those in which (Ri) _{m is} hydrogen or a hydroxy or methoxy group in the 6 'position and R _{2 is} the vinyl or ethyl group.

The compounds of the above formulas I and II have an antimalarial and antiarrhythmic activity.

Dlisobutylaluminum hydride is preferably used as the dialkyl aluminum hydride. The reduction can carried out at room temperature, although higher or lower temperatures are also used can be. Temperatures between 20 ° C. and 50 ° C. are preferably used. The reduction can in the presence of an inert organic solvent, for example a hydrocarbon such as benzene, Toluene or xylene, or an ether such as diethyl ether, tetrahydrofuran, Dloxan can be carried out.

The process according to the invention enables the stereoselective reduction of a ketone III or IV to the corresponding alcohol I or II, ie while maintaining the chloruclidine length (no reduction of an unsaturated radical R ₂ in the 5-position, no inversion of the stereoconfiguration in the 2-position), in yields of up to 94%.

On the other hand, according to the In J.A.C.S. 67, 1945, 1428-1429 described method quininone using platinum oxide or Palladlumchlovid with simultaneous reduction of the keto group and the vinyl radical into a mixture converted from hydrochlorine and hydrochloride. When using sodium isopropoxide, page 1429, there is no reduction of the vinyl residue, but quininone wild to a mixture of 60% quinldine and only 30% quinine reduced. In an analogous way, chlorine is produced by means of platinum oxide, palladium chloride or Sodium isopropoxide to a mixture of hydrochlorine and hydrochloride or quinine and quinine reduced. In the reduction of chlnidinone by means of lithium aluminum deuteride described in Tetrahedron 23, 1967, 3261 the yield of quinine is only 49%. The yield of dihydroquinine is analogous in the above article in J.A.C.S. described reduction of Dlhydrochininon using palladium chloride below 50%.

The quinoline derivatives of the general types used as starting materials in the process of the present invention Formulas III and IV can be prepared by a compound of the general formula

R ₂ H

N-X

where Ri, R ₂ and m have the above meaning and X is halogen, where, if (Ri ) _{m is} hydrogen or the methoxy group in position 6 'and R _{2 is} the vinyl or ethyl group, X is different from bromine,

10

15th

20th

30th 35 40 45 50 55 60

Their antipodes or racemates thereof, or a compound of the general formula

R ₂ 'H

(RO,

N-H

where Ri, X and m have the above meaning and R ' _{2 represents} a lower alkyl group,
Their antipodes or racemates thereof, or a compound of the general formula
X

Ν —Η

where Ri, X and m have the above meaning and R is hydrogen or an alkyl group with 1 to 5 carbons

35 material atoms means

or antipodes or racemates thereof, cyclized by means of a cyclizing agent, that when a compound of the formula VII, antipodes or racemates thereof are used as starting material, the cyclization product is dehalogenated and that the desired bases thus obtained are converted into acid addition salts.
The following reaction schemes Ia and Ib represent preferred embodiments of the process of the present

40 present invention:

Scheme Ia

CH ₃ O

CH ₃ O

IDa

CH =

IVa

CH ₃ O

CH ₃ O

CH ₃

Ia IIa

Scheme la describes the preparation of hydrochlorine Ia and dihydrocholine Ha, antipodes or racemates thereof, starting from hydrochloride of the formula IHa, antipodes or racemates thereof or Hydrochloride dinone of the formula Ha, antipodes or racemates thereof.

Scheme Ib

CH ₃ O

HIb

CH ₃ O

CH ₃ O

CH ₃ O

Ib

15th

20th

Scheme Ib describes the preparation of quinidine Ib and quinine Hb, antipodes and racemates thereof, starting from quininone of the formula IHb, antipodes or racemates thereof or quininone of the formula IVb, Antipodes or racemates thereof.

example 1

Manufacture of dihydrochlorine from dihydroquinidinone.

4.8 ml of a 25% strength solution of diisobutylaluminum hydride in toluene are added with stirring at 20 ° C. in an atmosphere of dry nitrogen to a solution of 2 g of dihydroquinidinone in 150 ml of dry toluene. As soon as all the ketone has been consumed, the reaction is terminated by adding 3 ml of a water / methanol mixture (1: 1). The precipitated aluminum hydroxide is filtered off and washed with benzene and methanol. The combined filtrates are evaporated to dryness. The crystallization of the residue from ethanol gives 1.9 g of dihydrochloride in 3 portions which, after recrystallization from ethanol, have a melting point of 168 to 169 ° C; Ia] ² J + 227.9 ° (c 0.896, ethanol).

Example 2

Production of dihydroquinidine and dihydroquinine from a mixture of dihydroquinidinone and Dihydrochininone.

Contains a solution of 1.25 g Dihydrochinidinon In 50 ml of benzene containing 0.5 ml of methanol is 2 '/ ₂ days under nitrogen at 20 ° C allowed to stand. The solution is then evaporated to dryness in vacuo, the residue is redissolved in benzene and again evaporated to dryness. The oily residue obtained is dissolved in 50 ml of dry benzene and 3 ml of a 25% solution of diisobutylaluminum hydride in toluene are added dropwise and with stirring under an atmosphere of dry nitrogen. The reaction is terminated after about 30 minutes by adding 10 ml of a water / methanol mixture (1: 1) and the mixture is stirred vigorously for a further 30 minutes. The benzene layer is separated. The aqueous aluminum suspension is washed several times with benzene and the combined benzene phases are dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (1.25 g) is a practically pure mixture of dihydroquinidine and dihydroquinine (approx. 1: 1), as can be determined by means of thin-layer chromatography; Ia] Jj- * + 62.2 ° (c 1.64, ethanol). Crystallization from ethanol yields 490 mg of pure dihydroquinidine with a melting point of 167 to 169 ° C.

25th

30th

35

40

45

50

55

Example 3

Preparation of racemic dihydroquinine from racemic dihydroquinone.

2.5 ml of a 25% solution of diisobutylaluminum hydride in toluene are added dropwise under tubes and under an atmosphere of dry nitrogen to a solution of 1 g of racemic dihydroquinone in 100 ml of dry benzene. After about 30 minutes, the reaction is terminated by adding 2 ml of methanol / water (1: 1). The precipitated aluminum oxide is filtered off, washed with methanol and the filtrate evaporated to dryness. Crystallization of the crude product (1.003 g) from acetone gives 718 mg of racemic dihydroquinine as monohydrate, which melts at 174 to 177 ° C after recrystallization from acetone.

60

65

Example 4

Production of anhydrous dJ-hydrocholine.

dI-Hydrocholine monohydrate gives after repeated evaporation from a benzene solution d, l-Hydrochine with a melting point of 172 to 174 ° C.

Example p

Preparation of racemic dihydrochlorine sulfate.

ίο A solution of 5.253 g of d, l-Dlhydrochlnln in 20 ml of methanol and 16.1 ml of 1 η aqueous sulfuric acid is cooled to 0 ° C. The crystals which precipitate are filtered off, washed with acetone and stored at 60 ° C./50 mm dried for 20 hours. After additional drying at 80 ° C./0.01 mm, d, l-dihydrocholine sulfate is obtained which contains 0.5 mol of water and melts at 210 to 213 ° C.

Example 6

Preparation of racemic dihydroquinine and racemic dihydroquinine from a mixture of racemic Hydroquinone and racemic dihydroquinone.

The reduction of 5.06 g of a crystalline mixture of racemic dihydroquinone and dihydroquinone (Melting point 76 to 89 ° C.) is used in dry benzene with diisobutylaluminum hydride in Example 1 analog catfish carried out. The methanol extracts (3.87 g) are crystallized from acetone and are obtained 3.14 g of racemic hydrochloride monohydrate in 3 portions. The benzene extracts (1.54 g) are made from a concentrated solution crystallized in ethanol and 579 mg of racemic dihydroquinine in 4 are obtained Servings. Racemic hydrochloride has a melting point of 152 after recrystallization from ethanol

«Up to 154.5 ° C.

Example 7

Preparation of Racemic Hydroquinidine Sulphate.

Gd to 2.02, l-Dlhydrochinldln in 25 ml of absolute ethanol are w 1 η first 6.2 ml aqueous sulfuric acid and then added 5 ml of water. The sulfate (2.03 g) crystallizes out after the total volume has been reduced to 20 ml. After drying at 80 ° C / 0.01 mm for 70 hours, the d, lD! Hydrochloride sulfate with ³ / <mol of water and a melting point of 208 to 21 ° C. is obtained.

Example 8

Manufacture of chlorides from quinidine.

2.4 ml of a 25% strength solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 1 g of quinidone in 40 ml of dry benzene. After stirring at 20 ° C. under an atmosphere of dry nitrogen, 10 ml of water are added. The benzene layer is separated off, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude crystalline product (0.89 g) is recrystallized from ethanol and 0.646 g of crystalline chloride with a melting point of 169 to 171 ° C .; la] ^{2 is obtained} _D ⁵ + 264.3 ° (c 0.98, ethanol).

The following connections can be established in an analogous manner:

7-chloro-ar (S) - [5 (R) -vinyl-4 (: S) -qulnuclidln-2 (R) -yl] -4-quinolinemethanol which crystallizes from ethanol / acetone • »5 and has a melting point from 247 to 250 ° C. [<x]% + 196 °, (c = 0.88, ethanol-methylene chloride 4: 1).

7-chloro-a (R) - [5 (R) -vinyl-4- (S) -qulnuclldln-2 (S) -yl] -4-quinollnmethanol which crystallizes from acetone / ether and has a melting point of 165 to 169 ° C has. [a]% -67 ° (c 0.90, ethanol).

Example 9

Preparation of 7'-methoxy: y-dlhydrocinchonine and 7'-methoxy-dihydrocinchonidine from a mixture of

Tf ljt ^ U " _n ..JlL..J" _n l. _n L _n ·! 1 T / \ M- * t .JsI 1 t..L _n .lJl _Knn

'-iviGiiiuAjuiiijrunjtiin-nuuiiiuu uiiu / -iviGiiiuAy-umyuiuciui.uuiiiuiiiuii.

3.75 ml of a 25% solution of diisobutylahiminum hydride in toluene are added dropwise with stirring and under an atmosphere of dry nitrogen to a solution of 1.46 g of a mixture of T- methoxy-dihydrocinchoninone and 7'-methoxy-dihydrocinchonidinone in 50 ml given to dry benzene. After all of the ketone has been used up, 5 ml of a 50% strength aqueous methanol solution are added. The precipitated aluminum oxide is filtered off and washed with benzene. The combined filtrates are dried over anhydrous sodium sulfate and then evaporated to dryness. The crude product is treated with acetone and crystallization gives 7'-methoxy-dlhydrocinchontn. After recrystallizations from chloroform / petroleum ether, 7'-Methoxydihydrocinchonln is obtained with a melting point of 231 to 233 ° C; [a]% + 169.5 ° (c 1.00, ethanol). Fractional crystallization of the mother liquor from acetone gives T'-Methoxydlhydrocinchonldln which, after recrystallization, has a melting point of 162 to 165 ° C; [a]% - 80.3 ° (c 0.98, ethanol).

Example 10

Preparation of racemic 7'-methoxy-dihydrocinchonidinone from racemic 7'-methoxy-dihydrocinchonidinone.

6.5 ml of a 25% solution of lgen Dilsobutylalumlnlumhydrld in toluene at 20 ° C and under an atmosphere of dry nitrogen was added dropwise to a solution of 2.32 g of racemic 7'-Methoxydlhydroclnchonldinon (melting point 112 to 116 ⁰ C) In 50 ml given to dry benzene. After stirring for about 30 minutes at 20 ° C., 8 ml of 50% strength aqueous methanol are added. The precipitated aluminum oxide is drained off and washed with benzene. The filtrate is dried over anhydrous sodium sulfate and then evaporated to dryness. The residue is treated with ether and 1.78 g of crystalline racemic 7'-methoxy-dlhydroclnchonldin with a melting point of 155 to 157 ° C. are obtained.

Example 11

Preparation of racemic 7'-methoxy-dlhydroclnchonln and racemic 7'-methoxy-dlhydroclnchonln from a mixture of racemic 7'-methoxydlhydroclnchonlnone and 7'-methoxydlhydroclnchonlnone.

7.2 ml of a 25% solution of dilsobutylaluminum hydride in toluene are added dropwise at 20 ° C. and under an atmosphere of dry nitrogen to a solution of 2.52 g of an amorphous mixture of racemic 7'-methoxide! Hydroc! Nchon! non and racemic 7'-methoxy-d! hydroc! p.chor.! d! r.on in. 50 m! trok- ^ls kenem of benzene. After stirring for about 30 minutes at 20 ° C., 8 ml of 50% strength aqueous methanol are added, the precipitated aluminum oxide is filtered off and then washed with benzene. The filtrates are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is treated with acetone and 1.01 g of racemic 7'-methoxy-dlhydroclnchonln is obtained which, after recrystallization from chloroform / acetone, melts at 217 to 219.degree. 0.63 g of the lower-melting racemic 7'-methoxy-dlhydroclnchonldin are obtained from the mother liquors.

Example 12

Preparation of 6 ', 7'-dimethoxy-dlhydroclnchonin and o'J'-dimethoxy-dlhydroclnchonidin from one Mixture of δ'J'-di-methoxy-dihydroclnchoninone and o'J'-di-methoxy-dihydroclnchonidinone.

1.5 ml of a 25% solution of diisobutylaluminum hydride in toluene are added dropwise with stirring and under an atmosphere of dry nitrogen at 20 ° C to a solution of 0.745 g of a mixture of 6 ', 7'-di-methoxydihydroclnchoninone and 6'-7' -Dimethoxy-dlhydroclnchonldinon Put in 20 ml of dry benzene. After about 60 minutes, 5 ml of a water / methanol mixture (2: 3) are added. The precipitated aluminum oxide is filtered off and washed with benzene. The combined filtrates are dried over anhydrous sodium sulfate and evaporated to dryness. The crude product is separated into two isomers, namely 6 ', 7'-dimethoxy-dihydrocinchonine and o'I'-dimethoxy-dlhydrocinchonldine, by means of preparative thin-layer chromatography (chloroform / triethylamine / methano! 85: 10: 5). The less polar 6 ', T- dimethoxydilhydroclnchonln is crystallized from ether and, after repeated recrystallization from acetone, has a melting point of 116 to 118 ° C; [ar] ^ + 182.2 ° (c 0.95, ethanol). The more polar 6 ', 7'-Dimethoxydlhydrocinchonldin could not be crystallized; [a]% -87.3 ° (c 0.68, ethanol).

Example 13

Preparation of racemic 6 ', 7'-dimethoxydihydrocinchonidine and racemic 6', 7'-dimethoxydlhydrocinchonine from a mixture of racemic 6 \ 7'-di-methoxydihydrocinchonidinone and racemic 6 ', 7'-di-methoxydihydrocinchoninone.

To a solution of 9.2 g of a mixture of racemic o'J'-Dlmethoxydihydrocinchonldinon and racemic o'J'-Dlmethoxydlhydrocinchoninon in 200 ml of dry benzene with stirring and under an atmosphere of dry nitrogen at 20 ° C dropwise a 25% lge Solution of Isobutylaluminium Hydride Put in toluene. After adding 17.5 ml, the reaction has ended. The reaction is terminated by adding 40 ml of a methanol / water mixture (3: 2). The precipitated aluminum oxide is filtered off and washed with benzene. The filtrates are combined. The benzene layer is separated, dried over anhydrous sodium sulfate and evaporated to dryness. The product is separated off by means of a preparative thin-layer chromatograph (Siicage!; Chloroform-triethylamine-alcohol, 85: 10: 5). The less polar fraction gives 4.4 g of amorphous, racemic o'I'-Dlmethoxydlhydroclnchonin.

For further purification, the base is converted into racemic o'I'-dimethoxydl hydrochloride , which, after recrystallization from methanol, has a melting point of 221 to 225 ° C (decomp.).

The more polar fraction (3.4 g), which contains racemic 6 ', 7'-dimethoxydihydrocinchonide, gives crystals of acetone with a melting point of 155 to 157 ° C. Racemic o'J'-dimethoxydlhydroclnchonldine dihydrochloride is obtained after recrystallization from methanol with a melting point of 208 to 210 ° C (decomp.).

Example 15

Preparation of racemic o'-chlorodlhydrocinchonine and racemic o'-chlorodlhydrocinchonine from a mixture of racemic o'-chlorodlhydrocinchoninone and racemic o'-chlorodlhydrocinchoninone.

To a solution of 6.73 g of a mixture of racemic o'-Chlordlhydrocinchoninon and racemic o'-Chlordihydrocinchoninon (melting point 97.5 to 100 ⁰ C) in 200 ml of dry benzene, is under Stir and drop a 25% solution of under an atmosphere of dry nitrogen at 20 ° C. Given diisobutylaluminum hydride in toluene. After adding 13 ml, the reaction has ended. The reaction, is terminated by adding 20 ml of a methanol / water mixture (2: 3). The unusual aluminum

Umoxide is filtered off and washed with benzene. The filtrates are combined. The benzene layer is separated dried over anhydrous sodium sulfate and evaporated to dryness. The product (6.7 g) could are not crystallized and are therefore analyzed by means of preparative thin-layer chromatography (silica gel; chloroform-triethylamine 9: 1) Separated into three fractions.

The least polar fraction (1.34 g) is crystallized and recrystallization from acetone gives racemic 6'-Chlordlhydroclnchonln with a melting point of 172.5 to 173.5 ° C. Racemic 6'-Chlordlhydroclnchonln-dlhydrochlorld has a melting point of 218 to 221 ° C (decomp.).

The middle fraction (2.83 g) is crystallized from acetone and obtained o'-Chlordlhydrocinchonidin having a melting point of 100-102 ⁰ C.

Racemic o'-Chlordlhydroclnchonldln dihydrochloride has a melting point of 219 to 220 ° C (decomp.) after recrystallization from methanol / ether.

The most polar fraction (1.42 g) is crystallized from ethanol and obtained a mixture of chlorine-free racemic Dihydroclnchonln and racemic Dlhydrocinchonidin having a melting point of 190-192 ⁰ C.

Example! 6

Preparation of racemic δ'-methyl-dihydrochlorine and racemic 6'-methyl-dihydrochlorine from a mixture of racemic o'-methyl-dihydroclnchoninone and racemic 6'-methyl-dihydroclnchoninone.

12.3 g of a mixture of racemic o'-methyl-dihydrochloride dinone and racemic 6'-methyl-dihydrochlorine-dinone is reduced in several parts. According to one embodiment, 4 g becomes crystalline The mixture was dissolved in 125 ml of dry benzene and treated with 9 ml of a 2596 lgen solution of diisobutylaluminum hydride added dropwise at 20 ° C and with stirring under an atmosphere of dry nitrogen.

After about 30 minutes, the reaction is terminated by adding 15 ml of aqueous methanol (2: 3). That precipitated aluminum oxide is filtered off and washed with benzene. The filtrates are combined that Separated benzene layer, dried over anhydrous sodium sulfate and evaporated to dryness. By Treatment with acetone gives crystalline o'-methyl-hydrochloride with a melting point of 216 up to 218 ° C after recrystallization from tetrahydrofuran.

Racemic o'-methyl-dihydrochloride-dihydrochloride is crystallized from methanol / ether and has a melting point of 213 to 216 ° C (dec.).

The mother liquors are converted into the hydrochloride, whereupon 2.8 g of racemic 6'-methyl hydrochlorine-hydrochloride are added obtained by crystallization from methanol with a melting point of 219 bis 220 ° C (dec.).

A portion is converted into the free base and crystallized from acetone and racemic is obtained o'-Methyldihydroclnchonln with a melting point of 153.5 to 155 ° C.

Verglelchsbelsplel

Preparation of a mixture of racemic 6'-methyldihydroepiclnchonldine and racemic 6'-methyldlhydroepiclnchonln, racemic o'-methyl-dihydrocinchonine and racemic 6'-methyl-dihydrocinchonine from a mixture of racemic o'-methyl-dihydroclnchonldinone and ö'-methyl-dthydroclnchonlnone.

To an ice-cold solution of 0.308 g of a mixture of racemic o'-methyl-dihydrocinchonidinone and racemic o'-met'nyl-dlhydroclnchoninon 0.3 g of solid sodium borohydride are added to 20 ml of methanol and the resulting solution was stirred at 0 ° C. for 60 minutes. 10 ml of water are added and that Methanol evaporated in vacuo. The aqueous residue is extracted with dichloromethane. The organic Extracts are dried over anhydrous sodium sulfate and evaporated to dryness. 0.291 g is obtained of a product which by means of preparatlver thin-layer chromatography (silica gel; chloroform-triethylamine-methanol 89: 10: 1) in 0.157 g of an amorphous, inseparable mixture of racemic 6'-methyl-hydrochloride and racemic o'-methyl-dihydroepicinchonine, 0.020 g of racemic o'-methyl-dihydrocinchonine and separating 0.023 g of racemic 6'-methyl-dlhydrocinchonldine.

Claims (1)

Patent claims: 1. Process for the preparation of a (S) - [ChlnuclJdln-2- (R) -yl] - and ar (R) - [Chlnucldln-2 (S) -yl] -4-chlnolnmethanol derivatives of the general formulas (RJb HO and (RJb