DE2111938A1 - Process for the preparation of quinoline derivatives - Google Patents

Description

Dr. Ing. Ä, vcn derWerfh

Dr. w
patentanwälti

12. Harz 1971

RAH hloo / lJj

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

Process for the production of quinoline derivatives

The present invention relates to a new process for the preparation of quinoline derivatives of general Formulas

and

II

where m is the number 1 or 2, Rp ethyl or vinyl

1 O 9 8 4 1 / t 9 /> ?

and R _{1 is} hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (R-,) methylenedioxy,

as well as enantiomers, racemates and acid addition salts of this.

The term "lower alkyl" means in the context of the present invention with hydrocarbon groups 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl and the like., Methyl and ethyl being preferred are. The term "lower alkoxy" means lower ones Alkyl ether groups in many ways the lower alkyl radical the above Has meaning. The term "halogen" means all four halogen atoms, i.e. bromine, chlorine, fluorine and iodine, where Chlorine is preferred. The term "aryl" means phenyl or halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and di-lower alkylamino substituted Phenyl. Examples of aryl-lower-alkyl groups are the benzyl, the phenethyl group and the like.

The process for the preparation of the above quinoline derivatives of formula I and II, from enantiomers, racemates and acid addition salts thereof is characterized in that one has a compound of the general formula

Li

Ii

9 «3 ', 1/1947

where R-, and m have the above meaning, with an epimeric compound of the general formula

OHC

VI

or

R 0OC

VIII

where Rp has the above meaning and R_ is lower alkyl, aryl or aryl-lower-alkyl,

or with an enantiomer or a racemate thereof reacts that , when using a compound of the general formula VIII, the resulting compound of the general formula

XI

in which R- ,, R ^ and m have the above meaning, treated with a reducing agent and, if so desired, the bases * thus obtained are converted into acid addition salts.

The reactions mentioned above can be carried out by the 1 Π Π Β U 1/1 9 / ♦ 7

the following reaction schemes I and II are exemplified:

Scheme I.

(RJ

In the

OHC

Li

II

Enantiomers and racemates thereof,

where R ,, Rp and m have the above meaning.

109841/194

Scheme II

VIII

Li

II

1 0 9 β 4 1/1 9 Λ 7

* "
Enantiomers and racemates thereof,

where R ^, Rg, R-, and m have the above meaning.

According to scheme I, a mixture of the epimeric 5 (R) -ethyl (or vinyl) -4 (s) -quinuclidine-2i-carboxaldehydes of the formula VI, enantiomers or racemates thereof, with a 4-quinolyllithiol compound of the formula X to give the corresponding a (S) - [5 (R) -Aethyl (or vinyl) -4 (S) -quinuelidin-2 (R) -yl] -4-quinolinemethanol of the formula I, an enantiomer or the racemate thereof, and the α (R ) - (5 (R) -AethyI (or vinyl) -4 (S) -quinuclidin-2 (S) -yl] -4-quinolinemethanol of the formula II, one enantiomer or the racemate thereof converted. Lithium compounds of the formula X are reacted in at least an equimolar amount with the compounds of the formula VI. Preferably, about 2 moles of the compound of the formula X are used per mole of the compound of the formula VI. The reaction is expediently carried out at room temperature or below room temperature, preferably at one temperature between about 0 ⁰ G and about -70 ° C, in the presence of an inert organic solvent, such as an ether, such as Diethyl ether, tetrahydrofuran, dioxane or diglyme, or a hydrocarbon such as benzene, toluene and the like. Performed. The reaction is also expediently carried out in the presence of a complexing agent, such as in the presence of 1,4-diazabicyclo- [Z, 2, 2] octane or tetra-diethylethylenediamine.

According to scheme II, a mixture of the epimers 5 (R) -Aethyl (or vinyl) -4 (S) -quinuclidine- 2 - ^ - carboxylic acid alkyl esters of the formula VIII, enantiomers or racemates thereof, with a quinolyllithium compound. Of the formula X to the corresponding Mixture of the epimers 4- [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidln-2i-ylcarbonyl] quinolines of the formula XI, enantiomers or racemates thereof reacted. The 'f-Chinoly! Lithium compounds of the formula X In at least äcuimolarer

10 9 8 41/19 4 7

Amount reacted with the compounds of formula VIII. Preference is given to using two moles of the compound of the formula X per mole of the compound of the formula VIII. The reaction is preferably carried out zweekmässig at room temperature or lower at a temperature between about 0 ⁰ C and about -70 ⁰ C. An inert organic solvent, for example an ether such as diethyl ether, tetrahydrofuran, dioxane or diglyme and the like, or a hydrocarbon such as benzene, toluene and the like, is used for two purposes. The reaction is also conveniently carried out in the presence of a complexing agent such as 1,4-diazabicyclo [2.2.2] octane or tetramethylethylenediamine.

The conversion of the mixture of the epimeric 4- [5 (R) -ethyl (or vinyl) -4 (s) -quinuclidine-2l-3 ^r- lcarbonyl] quinolines of the formula XI, enantiomers or racemates thereof, to the α (S) - [5 (R) -Aethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -yl] -4-quinolinemethanol compounds of the formula I, enantiomers! Or racemates thereof, and the cc (R) - [5 ( R) -Aethyl (or vinyl) -4 (s) -quinuclidin-2 (S) -yl] -4-quinolinemethanol compounds of the formula II, enantiomers! or raceinates thereof can be carried out using a stereoselective reducing agent such as a dialkyl aluminum hydride such as diisobutyl aluminum hydride and the like. The reduction is carried out two times at room temperature, but temperatures above or below room temperature can also be used. However, the reduction is preferably carried out at a temperature between approximately 20 ^° C. and approximately 50 ^° C. Furthermore, the reduction is expediently carried out in the presence of an inert organic solvent, for example a hydrocarbon such as benzene or toluene or an ether such as diethyl ether, tetrahydrofuran and the like.

109841/1947

2111933 ~ o

The conversion of the compounds of the formula XI, enantiomers or racemates thereof, to the compounds of the formulas I and II, enantiomers or racemates thereof, can also * if Rp denotes ethyl, using a hydrogenation catalyst such as nickel, palladium, ruthenium, copper or barium chromite in In the presence of a solvent such as an aqueous or non-aqueous alkanol such as methanol or ethanol or an ether such as dioxane. If R _{p is} ethyl or vinyl, the conversion can also be carried out using a reducing agent such as aluminum in ethanol, sodium isopropoxide in toluene, sodium or potassium borohydride in methanol, ethanol, isopropanol or tetrahydrofuran, lithium aluminum hydride, aluminum hydride, chloroaluminum hydride, lithium dichloroaluminum hydride, aluminum bromide hydride -tri-tert-butoxyaluminum hydride in ether, tetrahydrofuran, dioxane and the like.

As a suitable ^ in the inventive method as Compounds of the formula X used as starting material can be named the following:

4-quinolyllithium; 6-methoxy-4-quinolyllithium; 6-methyl-4-quinolyllithiumj 7-methoxy-4-quinolyl lithium; 6,7-3> -imethoxy-4-quinolyllithium; 6,7-methylenedioxy-4-quinolyllithium; 6,8-dimethoxy-4-quinolyllithiumj 6-chloro-4-quinolyllithium; 7-trifluoromethyl-4-quinolyllithium; 7-chloro-4-quinolyllithium; 6,8-dichloro-4-quinolyllithium and the like.

Since the aforementioned 4-quinoly / lithium compounds are extremely unstable, it is advisable to produce them in situ by reacting the appropriate 4-bromoquinolines with, for example, n-butyllithiuin in the presence a solvent such as a hydrocarbon, for example Benzene, toluene, hexane, petroleum ether or an ether such as dioxane, diethyl ether, diglyme, tetrahydrofuran and the like.

1098 4 1/1947

As examples of 4-bromoquinolines, the following can be used to be named:

4-bromoquinoline; 4-bromo-6-methoxyquinoline; 4-bromo-6-methylquinoline; 4-bromo-7-methoxyquinoline, 4-bromo-6,7-dimethoxyquinoline; 4-bromo-6,7-methylenedioxyquinoline; 4-bromo-6,8-dimethoxyquinoline; 4-bromo-6-chloroquinoline; 4-Bromo-7-chloroquinolines 4-Bromo-6,8-dichloroquinolines, 4-Bromo-7-trifluoromethylquinoline and the like

The above-mentioned 4-bromoquinolines can be prepared from the corresponding 4-hydroxyquinolines according to known methods will. Examples of these 4-hydroxyquinolines are:

4-hydroxyquinoline, 4-hydroxy-6-methoxyquinoline; 4-Hydroxy-6-methylquinoline 5 4-hydroxy-7-methoxyquinoline; 4-hydroxy-6,7-dimethoxyquinoline; 4-hydroxy-6,7-methylenedioxyquinoline; 4-hydroxy-7-trifluoromethylquinoline; 4-hydroxy-6,8-dimethoxyehinolini 4-hydroxy-6-chloroquinoline; 4-hydroxy-7-chloroquinoline; 4-hydroxy-6,8-dichloroquinoline and the like.

The compounds of the above formula X are new compounds with the exception of 4-quinolyllithium. These new ones Compounds are also a subject of the present invention.

The compounds of the above formulas VI and VIII, in which Rp is ethyl, can be prepared according to the following reaction scheme III:

1 0984

Scheme III

CCL

III

Vila

villa

1 ο ν β; ι / 19 c 7

- 211-G38

Enantiomers and ratios thereof,

wherein R-, lower alkyl, aryl or aryl-lower-alkyl means.

According to scheme III, the racemic l, l, l-trichloro-; 5- (3-ethyl-4-pyridinyl) propan-2-ol of the formula III [also known as 3-ethyl-4- (2-hydroxy-3i3 , 5-trichloropropyl) pyridine] or one of the Enantionieren thereof, into the corresponding raeemischen, epiraereneis-l _J l-dichloro-3- (3-ethyl-4-piperidinyl) propan-2? -ols of the formulas IVa and Va or converted into the corresponding enantiomers using a hydrogenation catalyst such as a noble metal catalyst such as palladium, platinum or rhodium or Raney nickel and the like. The hydrogenation is expediently carried out at room temperature or above room temperature, preferably at about 60 ° C. and at a hydrogen pressure between about 1 atmosphere and about 100 atmospheres. Furthermore, the hydrogenation is conveniently carried out in the presence of water and an inert organic solvent, for example an alkanol such as ethanol, methanol and the like. And in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Or an organic acid such as acetic acid, Myic acid and the like. Performed.

The individual enantiomers or the radicals of the epirceren cis-l, l-dichloro-3- (3-ethyl-4-piperidinyl) propan-2? -Ols of the formulas IVa and Va are converted into the Mixture of the epimeric 5 (R) -Aethyl-4 (S) -quinuclidin-2 ^ -carboxaldehydes of the formula VIa, enantiomers or Raeemates thereof, converted. Examples of such agents are bases, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as potassium tert-butoxide and basic anion exchange resins such as Amberlit IRA-401 (OH) and the like. The reaction is conveniently carried out at room temperature, although higher

109841/1947

ORiQJNAL

and lower temperatures can be used. Furthermore, the reaction is expediently in the presence of an inert organic solvent, for example an alkanol such as methanol, ethanol and the like, a hydrocarbon, such as benzene, toluene, hexane, petroleum ether and the like., Or an ether such as tetrahydrofuran, diethyl ether, dioxane and diglyme or a mixture of water and an immiscible inert organic solvent such as benzene, dichloromethane and Like. Performed.

The mixture of the epimeric 5 (R) -Aethyl-4 (s) -quinuclidin-2i-earboxaldehydes of the formula VIa, enantiomers or racemates thereof, is obtained by treatment with an oxidizing agent, into the mixture of the epimers 5 (R) -ethyl-4 (S) -quinuclidine-2 ~ carboxylic acids of the formula VIIa, enantiomers or racemates thereof, converted. As an oxidizing agent, in particular Silver oxide, chromic acid, potassium permanganate and the like can be used. The oxidation is conveniently carried out at room temperature or below and, if desired, in the presence a solvent such as an alkanol or water.

The mixture of the epimeric 5 (R) -ethyl-4 (S) -quinuclidine-2J-carboxylic acids of the formula VIIa, enantiomers or racemates thereof, is converted into the mixture of the epimers by esterification 5 (R) -Aethyl-4 (S) -quinuclidine-2 ^ -carboxylic acid alkyl ester of the formula Villa, enantiomers or racemates thereof, converted. The esterification can be carried out using alkanols such as ethanol, methanol and the like. In the presence of an acid such as hydrochloric acid, sulfuric acid and the like. The esterification takes place expediently at a temperature between about room temperature and the reflux temperature of the reaction mixture.

The compounds of the above formulas VI and VIII, wherein 109841/1947

2111 S 3 3

Rp is vinyl or also ethyl, can according to the following reaction slip IV.

Scheme IV

CHO

IX

R ^ OOC - ^ S N ^ H

VII

VIII

109δ41 / 19Α 7

_Λα 2111933 -4J-

Enantiomers and racerates thereof,

where R “and R” have the same meaning as above.

According to scheme IV, the N-benzoyl-; 5 (R) -ethyl (or vinyl) -4 (S) -piperidine acetaldehyde of the formula IX, an enantiomer or the racemate thereof, is converted into the corresponding mixture of epimers by means of a Grignard compound such as, for example, Diehlorniethyllithium l, l-dichloro -> - {; 3 (R) -ethyl (or vinyl) -4 (S) -piperidinylj-propane-2t-ols of the formulas IV and V, enantiomers or racemates thereof, converted. The reaction is preferably carried out conveniently at room temperature or lower at a temperature between about 0 ⁰ C and about -70 ⁰ C. Furthermore, the reaction is expediently carried out in the presence of an inert organic solvent, for example an ether such as tetrahydrofuran, diethyl ether, dioxane or diglyme and the like, or a hydrocarbon such as benzene, toluene, hexane, petroleum ether and the like.

The mixture of the epimeric l, l-Diehlor -> - [; 5 (R) -ethyl (or vinyl) -4 (S) ~ piperidinyl] propan-2f-ols of the formulas IV and V, Enantiomers or racemates thereof will be converted into of the compounds of the formula IVa and Va in an analogous manner, into the mixture of the epimeric 5 (R) -Aethy! (or vinyl) -4 (S) -quinuclidin-2 i-carboxaldehydes of the formula VI, enantiomers or Racemates thereof, transferred.

The mixture of the epimeric 5 (R) -Aethy1 (or vinyl) -4 (s) -quinuclidin-2i-carboxaldehydes of the formula VI, enantiomers or racemates thereof, is described in the foregoing Conversion of the compounds of the formula VIa in an analogous manner into the mixture of the epimeric 5 (R) -Aethy1 (or vinyl) -4 (S) -quinuclidine-2! -Carboxylic acids converted to formula VII.

The mixture of the epimeric 5 (R) -Aetl: yl (or vinyl) -4 (S) -quinuclidin-2 ^ -carboxylic acids of formula VII, enantiomers or

109841/1947

2111338 -

Racemates hereof »is described in the foregoing Overflow of the compounds of the formula VII a is more analogous Way, in the mixture of the epimeric 5 (R) -Aethyl (or Vinyl) -4 (S) -quinuelidin-2 ^ -carboxylic acid alkyl ester of the formula VIII, enantiomers or racemates thereof, converted.

The compounds of the above formulas IV, V, VI, VIIa and the formula Villa in which R-, is lower alkyl, Enantiomers and ratios thereof are new compounds. The present invention also relates to these new compounds.

The compounds of formulas I and H ^ enantiomers and racemates thereof, form acid addition salts and these Salts are also the subject of the present invention. The most suitable salts are, pharmaceutical salts Usable organic and inorganic acids, such as acetic acid * succinic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, Phosphoric acid, sulfuric acid and the like.

The compounds of formulas I and II, enantiomers and racemates and acid addition salts thereof, have antimalarial and antiarrhythmic effects. Your pharmacological valuable antiarrhythmic effect is demonstrated on warm-blooded animals using standard methods, for example, the test substance is administered to prepared hybrid ions. For this purpose, the chest cavity of the previously anesthetized animal was opened and the antiarrhythmic attempt was made carried out according to a modification of the method of Scherf and Chick, Circulation, 3, 764-769 (1951).

The pharmacologically valuable anti-irritant alaric effect of the above-mentioned compounds will be demonstrated in warm-blooded animals using standard methods. Example

1098A1 / 1947

21 <"i λ r \>" ·, <"\ ι ι ι ci jd

-A-

The substance is administered in various amounts to albino mice. The albino mice grow with around 5-10 Millions of red cells infected with P. Berghei were vaccinated.

When radical Y'-methoxy-dihydrocinchonidine-dihydrochloride or racemic T'-methoxy-dihydrocinchonine dihydrochloride can be used as test substance, in doses of about 125 mg / kg to about 250 mg / kg which are microscopic examined blood smears free from P. Berghei (negative).

Compounds of the formulas I and II and their pharmaceutically acceptable acid addition salts, Enantiomers and racemates thereof have effects which roughly correspond to the known therapeutics quinine and quinidine. Thus have the according to the invention Processes obtained compounds a range of activities of known efficacy and safety.

The products of the process can be used as remedies in the form Pharmaceutical preparations find use, which these products in mixture with one for the oral or parenteral Administration of suitable, pharmaceutical, organic or inorganic, inert carrier material, such as water, gelatin, Gum arabic, lactose, starch, magnesium stearate, talc, contain vegetable oils, polyalkylene glycol, etc. The pharmaceutical Preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules or in liquid form, e.g. in the form of solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary materials, Preservatives, stabilizers, wetting agents or emulsifiers and salts for changing the osmotic pressure or Buffer. They can also contain other therapeutically valuable substances.

In the examples below, all are temperatures given in ° C.

1 Π Q « U 1/1 9 U 7

2111933

example 1

Production of 6,7-methylenedioxy-4-hydroxyquinoline.

A suspension of 50 g of 4-hydroxy-6,7-methylenedioxyquinoline - ^ - carboxylic acid in 500 ml of distilled quinoline is heated to the end of gas evolution at 200 °, the resulting mixture is cooled to room temperature, diluted with an equal amount of ether and overnight stored in a cool place. The brown precipitate which has separated out is filtered off and dissolved in ethanol under reflux. The insoluble part is removed and the ethanol solution is concentrated to 1 / j of its volume. The solution is then diluted with an equal amount of ether. By cooling "is obtained ^ l t 1 g of 6,7-methylenedioxy-4-hydroxyquinoline with a melting point of 280-282 °. Recrystallization twice from V / ater gives analytically pure 6,7-methylenedioxy-4-hydroxyquinoline in the Form of a pale yellow pest with a melting point of 288-289 ° C.

Example 2

Preparation of 4-bromo-6,7-methylenedioxyquinoline.

A preheated to 60 ° slurry of 10 g of 6,7-methylenedioxy-4-hydroxyquinoline and 10 ml of phosphorus tribromide v / ground 4 ml of phosphorus oxybromide was added and the mixture heated to 15O ^0th After one hour, another 4 ml of phosphorus oxybromide are added and heating is continued for 2 hours with repeated stirring. The mixture is cooled to room temperature and added to one liter of firmly stirred ice. The precipitate is then filtered off, washed with water and suspended in 100 ml v / water. The suspension is made alkaline with solid sodium bicarbonate. The precipitate is filtered off, washed with water and extracted with chloroform. The organic extract is dried over sodium sulfate and evaporated to dryness.

1 09841/1947

21 1 <· ---ο

An almost colorless solid is obtained, which through Sublimation at 100-120 ° and 0.35 mm Hg, 8.3 g of 4-bromo-6,7-methylenedioxyehinoline with a melting point of l47 ~ l49 ° C.

Example 3

Production of 4-bromo-6,8-dichloroquinoline.

Heating a mixture of 33 g of 6,8-Diehlor-4-hydroxyquinoline and 50 ml of phosphorus tribromide at 6o ° and after adding 20 ml (56 g) of phosphorus oxybromide is allowed to stand under repeated stirring the mixture for 3 hours at I50 ^0th The mixture is then cooled and 1.5 liters of vigorously stirred ice are carefully added. The suspension is made alkaline with a 12N sodium hydroxide solution. The precipitate formed is filtered off and dried in vacuo. By sublimation of the dried product at 140 ° under 0.3 mm Hg to obtain 35.7 g of crystalline 4-bromo-6,8-dieinlorchinolin ümkristallisation having a melting point of 163-165 ⁰ C. from ether yields pure 4-bromo-6 , 8-diehlorchinoiin with a melting point of 164-166 ° C.

Example 4

Production of l, l, l-trichloro-3- (3-ethyl-4-pyridinyl) -propane - 2 (R) -ol and of l, l, l-trichloro-3- (3-ethyl-4-pyridinyl) -propane-2 (S) -ol.

A solution of 1O6.6 g of l, l, l-triehlor-3- (3-ethyl-4-pyrldinyl) propan-2-ol in 1.2 liters of hot acetone, a solution of 65.2 g of d-tartaric acid in 1 liter of acetone is added. A crystallized product is obtained by cooling and pure 1,1,1-trichloro-3- {3-ethyl-4-pyridinyl) -propane-2 (R) -ol-d-tatrate is obtained by fractional crystallization from acetone

109 841/1947

with a melting point of 176-177.5 ° C, [α] 2 ⁵ +? 0 / ϊ ^β (c Ο, 96θ, ethanol).

The tartrate is dissolved in water, the solution is made alkaline with a saturated sodium carbonate solution and extracted four times with bichlorine than. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. 1,1,1-Trichloro-5- (5-ethyl-4-pyridinyl) -propane-2 (R) -ol is obtained with a melting point of 150-134 ° C., [<x] £ ⁵ + 45.1 ° (c 1.025, ethanol) after recrystallization from ether.

The mother liquors obtained by the fractional recrystallization are combined, evaporated to dryness and the residue obtained is dissolved in 1 liter of water. After filtering off the insoluble products and making the solution alkaline with 6N sodium hydroxide, the resulting solution is extracted three times with dichlorine than, the combined organic extracts are washed three times with water, dried over sodium sulfate and evaporated to dryness, to give 57 * 2 g of a brown pesticide result. A solution of this product in 8OO ml of acetone is mixed with a solution of 31.8 g of 1-tartaric acid in 700 ml of acetone. Cooling gives 5 ^, 9 δ crystallized tartrate and fractional crystallization from acetone gives pure 1,1,1-trichloro-5- (5-ethyl-4-pyridinyl) -propane-3 (S) -ol-1-tartrate , with a melting point of 177-178 ° C, IaJf ^ -30.3 ° (c 1.065, ethanol).

Pure l, l, l-trichloro-3- (5-ethyl-4-pyridinyl) -propane-2 (S) -ol vfelches, as described above for the preparation of the other enantiomer, from l, l, l-trichloro 3- (3-ethyl-4-pyridinyl) -propane-2 (s) -al.l-tartrate is obtained, has a melting point of 132-1 / '^ ⁰ C after recrintallization from ether,

109841 / 19Λ7

2111338

ία] ^ ⁵ - ^ 5.5 ° (c 1.020, ethanol).

Example 5

Preparation of racemic l, l-diehlor-3- [3 (R) -ethyl-4 (S) -piperidinyl] propane-2 (S) -ol hydrochloride and of racemic 1,1-dichloro-3- [5 (R) -ethyl-4 (S) -piperidinyl] propaii-2 (R) -ol hydrochloride.

4 g of platinum oxide are added to a solution of 26.85 g of racemic 1,1,1-trichloro-3- (3-ethyl-4-pyridinyl) propan-2-ol in 4ΟΟ ml of 5 ^ aqueous hydrochloric acid, and the mixture is added hydrogenated at 60 ° C under 6 atmospheres. After cooling to room temperature, the catalyst is filtered off, the resulting piltrate is evaporated under reduced pressure and the residue is crystallized from 70 ml of absolute ethanol to give 10.5 S racemic 1,1-DiChIOr ^ - [3 (R) -ethyl-4 (5 yield) piperidinyl] propane-2 (S) -ol hydrochloride having a melting point of 205-209 ⁰ C after recrystallization.

After crystallization of the matter liquors from 30 ml of acetone, 9.5 S racemisehes 1,1-dichloro-3- (5 (R) -äthy1-4 (S) -piperidinyl] propane-2 (R) -ol hydrochloride is obtained with a melting point of 123-129 ° C and after two recrystallizations with a melting point of 132-134 ⁰ C.

Example 6 Preparation of l, l-dichloro-3 [3 (S) -ethyl-4 (R) -piperidinyl]

propane-2 (R) -oil hydrochloride and l, l-dichloro-3-ethyl-4 (S) -piperidinyl] -propane-2 (R) -ol hydrochloride.

A solution of 2.7 g of l, l, l-trichloro-3- (3-ethyl-4-

pyridinyl) propane 2 (R) oil in 4θ ml of 5 ^ hydrochloric acid is used in

60-90 ° under 65 atmospheres and in the presence of 0.4 ^ platinum oxide hydrogenated. After cooling to room temperature, the catalyst becomes

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2111338

Filter off and the filtrate obtained is evaporated under reduced pressure. The residue is crystallized from 40 ml of ethanol and 600 mg of l, l-dichloro-3-f3 (S) -ethyl-4 (R) -piperidinylpropane-2 (R) -ol hydrochloride are obtained, which crystallizes out after recrystallization Ethanol has a melting point of [a] ^ ⁵ + 29.63 ° (c 1.0953, methanol) ..

The mother liquors are concentrated and the residue is crystallized from acetone, and 1,1-dichloro-3- [3 (R) -ethyl-4 (s) -piperidinyl] propane-2 (R) -ol hydrochloride is obtained, which after Recrystallization from acetone has a melting point of 168-170 °, [a] ^ ⁵ + 25.25 ° (0 l, 0l40, methanol).

Example 7

Preparation of 1,1-DiChIOr ^ - [3 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol-hydrochloride and of 1,1-dichloro-3- [3 (s) -ethyl-4 (R) -piperidinyl] -propane-2 (S) -ol hydrochloride.

A solution of 2.7 g, l, l ~ trichloro-3- (3-ethyl-4-pyridinyl) propane-2 (S) ~ oil in 40 ml of 5% hydrochloric acid is hydrogenated in the presence of 0.4 g Platinum oxide at 60 ° and below 65 atmospheres. After cooling to room temperature, the catalyst is filtered off and the filtrate obtained is concentrated under reduced pressure. The residue is crystallized from 20 ml of ethanol and 600 mg of l, l-dichloro-3- [3 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol hydrochloride with a melting point are obtained from 227-229 ° C. After repeated recrystallization from ethanol, pure l, l ~ dichloro-3 [3 (R) -ethyl-4 (S) -piperldinyl] -propane-2 (S) -ol hydrochloride with a melting point of 232-233 ^o C is obtained , [a] ^ -28.3 ° (c 1.0237, methanol).

The free base, which is obtained by reacting 1,1-dichloro-3 [5 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol hydrochloride with aqueous potassium carbonate and by extraction with

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2111333

Di chlorine than is obtained, is reacted with ethanolic hydrobromic acid to give l, l-dichloro-j5 [j5 (R) -ethyl-4 (s) -piperidinyl] -propane-2 (s) -ol-hydrobroniicl, which after repeated recrystallization from ethanol has a melting point of 223-22 ^ f ⁰ C, Ia] ^ ⁵ -24.77 ° (c, 0.9 ^ 86, methanol).

The mother liquors obtained by crystallization from 1,1-dichloro-3- [3 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol hydrochloride are combined and concentrated under reduced pressure. The residue is treated with acetone and the crystallized product is umilcristallisiert from acetone, 729 mg of 1,1-dichloro-3- [5 (s) -ethyl-4 (R) -piperidinyl] -propane-2 (S) -ol -hydroehlorid receives. Recrystallization from acetone gives 1,1-dichloro-3i3 (s) -ethyl- ⁱ KR) -piperidinyl] -propane-2 (S) -ol hydrochloride with a melting point of 169 * 5-171 * 5 °, [ α] ψ -25 * 15 ° (co, 93O6, methanol).

Example 8

Production of l, l-dichloro-3- [3 (R) -vinyl-4 (S) -pi-

peridinyl] .- propane-2 (s) -ol-hydrochloride and of 1,1-DIchlor-3- [3 (R) -vinyl-4 (S) -piperidinyl] -propane-2 (R) -ol-hydrochloride .

To a cooled to -70 ⁰ C solution of 3.07 ml of methylene "Chioi ¹ Id in 60 ial anhydrous tetrahydrofuran in an atmosphere of dry nitrogen for one hour 44 Milliraol n-butyllithium in hexane was added 28 ir.l. After stirring the mixture for 20 minutes at the same temperature, 5 * 19 g of 2- [1-benzoyl-3 (R) -vinyl-4 (S) -piperidinyl acetaldehyde in 30 ml of anhydrous tetrahydrofuran are added. The reaction is then interrupted after 30 minutes by adding 30 ml of water and the temperature of the mixture is allowed to rise to room temperature. DariaeL is extracted three times with ether. The combined extracts are washed with water, dried over sodium sulfate and dried to dryness.

1 0 9 B k 1/1 3 4 7

steamed. The residue is dissolved in 80 ml of hydrochloric acid, the acidic solution is washed with ether and neutralized with 3N sodium hydroxide solution. The solution is washed again with ether, made alkaline by adding 3N sodium hydroxide solution and extracted with ether. The extract is then washed with water, dried over sodium sulfate and evaporated to dryness. The residue (3.8 g) is dissolved in ethanol, reacted with an excess of ethanolic hydrochloric acid, the solvent is evaporated under reduced pressure and the solid residue obtained is crystallized from ethanol. 2.0 g of a mixture of epimeric 1,1-dichloro-3-f3 (R) -vinyl-4 (s) -piperidinyl] -propane ^^ - ol-hydrochlorides are obtained. Fractional crystallization from ethanol and recrystallization of the combined fractions from ethanol gives 1,1-dichloro-3 (j5 (R) -vinyl-4 (s) -piperidiiiyl3-propane-2 (s) -ol hydrochloride with a melting point of 225-225.5 ° C, i «] ^ ⁵ ~ 13.3 ° (c 1.02, methanol).

The mother liquors are combined and evaporated to dryness. After crystallization of the residue from acetone, 1,1-dichloro-3 (3 (R) -vinyl-4 (S) -piperidinyl] -propane-2 (R) -ol hydrochloride is obtained, with a melting point of 165 -167 ° C, [a] p ⁵ + 30.7 ° (c 1.00, methanol).

Example 9

Production of epimeric, racemic 4,5-erythro-5 ~ ethylquinuclidine-2 ^l -carboxaldehydes,

a) A solution of 2.77 g of racial 1,1-dichloro-3- [3 (R) ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol-hydrochloride in 20 ml of methanol, a solution of 1.68 g of potassium hydroxide in 15.8 ml of methanol is added. The mixture is during Stirred for 55 hours at room temperature, the resulting precipitate was filtered off and the filtrate was evaporated to dryness.

1098 4 1/1947

2111933

200 ml of ether are added to the residue and the insoluble part is filtered off. Then the filtrate becomes dry evaporated and an oily mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2-t-carboxaldehydes is obtained.

b) The methanolic solution, which as above

5 * 45 g of racemic l, l-dichloro-3- [3 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol hydrochloride is prepared, is evaporated to dryness under reduced pressure at 30 °, the residue dissolved in 300 ml of ether, and insoluble products are filtered off. Obtained by evaporating the filtrate one 4.12 g of an oily residue. A solution of this residue in 100 ml of ether becomes a solution of 2.5 g Sodium bisulfite in 8 ml v / water is added, the solvents are evaporated off under reduced pressure and the The residue is dissolved in 10 ml of water. After adding ethanol and ether, 3.4 g of an addition product precipitate are obtained. This product is added to 50 ml of a saturated sodium carbonate solution and heated to 40 °. The resulting solution is left to stand at 40 ° for a further 5 minutes. Then the mixture is cooled and three times extracted with ether. The combined extracts are dried over potassium carbonate and under reduced pressure evaporated to dryness. 950 mg of liquid aldehyde are obtained and, by distillation at 60-85 ° (oil bath temperature) under a pressure of 0.4 mm Hg in a short path distillation device, 648 rng of a pure mixture of epimers, racemic 4,5-erythro-5-ethyl-quinuclidin-2? -carboxaldehydes.

c) A solution of 1.39 g of racomic 1,1-dichloro-3- [3 (R) -ethyl-4 (S) -piperidinyl) -propane-2 (R) -ol hydrochloride in 25 ml of water is added Given 150 ml of benzene. The mixture is cooled in an ice bath with stirring; 8, ^l j6 ml of a 1.75 η potassium hydroxide solution are added slowly and

1 0 9 8 · '♦ 1/1 iU 7

2111338

stirring is continued at room temperature under a nitrogen atmosphere for 20 hours. The aqueous layer is deposited and extracted with benzene. The organic layer is dried over sodium sulfate and evaporated under reduced pressure at about 30 °. The residue is ^{distilled at 60-85 0} (oil bath temperature) below 0.3 mm Hg in a short-path distillation device, βΟΟ mg of a mixture of epimeric, racemic 4,5-erythro-5-ethyl-quinuclidine-2-carboxaldehydes receives.

d) A solution of 400 mg of racemic, epimeric cis-1, l-dichloro-3- (3-ethyl-4-piperid (hyl) -propan-Si'-ols in 50 ml of methanol become 5 g of IRA-40l (OH) anion exchange resin added, the mixture stirred overnight at room temperature and the resin filtered off. The filtrate is under evaporated almost to dryness under reduced pressure, the residue treated with benzene, the benzene solution obtained over Magnesium sulfate dried and evaporated to dryness under reduced pressure, whereby one epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2 £ -carboxaldehydes receives.

Example 10

Preparation of epimeric, racemic 4,5-erythro-5-ethylquinuelidine-2i '~ carboxylic acid ethyl esters.

a) A solution, cooled to 0 °, of 8.3 g of racemic 1,1-dichloro-3- [3 (R) -ethyl-4 (S) -piperidinyl] -propane-2 (S) -ol hydrochloride in 600 ml of methanol a solution of 5.04 g of potassium hydroxide in 23.4 ml of methanol is added dropwise with stirring. Thereafter, the temperature of the mixture is allowed to rise to room temperature and stirring is continued overnight. After filtering off the insoluble products, the solution is added to a mixture of 11.7 g of Cilbc-raitrat and 4.8 K liatriurnhydroy.yd in 200 ml V / asnor. Dan äremi.sch is after three hours of stirring at room

109841/19 47

2111333

is extracted three times with ether, the combined extracts are washed with water, dried over sodium sulfate and evaporated to dryness. Dissolve the mixture obtained \} \ g) of chemical, epimeric 1,1-dichloro-3- [3 (R) ethyl-4 (s) -piper ± dinyl] -propan- ^ 7-ols in 400 nil methanol. A solution of 1.8 g of potassium hydroxide in 45 ml of methanol is then added and stirring is continued for 50 hours at room temperature. Then the solution is added to a mixture of 2.56 g of sodium hydroxide and ο ^ 'Λ g of silver nitrate in 60 ml of water. After stirring for three hours at room temperature, the reaction mixture is filtered through Celite and the filtrate is evaporated to dryness. Complete dryness is obtained by adding a solvent mixture of ethanol and benzene to the residue and evaporating the solvent under reduced pressure. This procedure v. ^r ird raehriKals repeated and the residue extracted several times with lieissenä ethanol. The combined extracts are evaporated to dryness and the residue, which contains a mixture of epimeric, racemic 4-, 5-erythro-5-ethylquinuclidine-2! ['- carboxylic acids, is esterified iv.with 4% ethanolic hydrochloric acid after the usual work-up and distillation under reduced Dx ¹ UCk 1.8 g of a mixture of epimeric, racemic ⁱ 1.5 ~ erythro-5-ethy ^r lquinuclidine-2-carboxylic acid ethyl esters are obtained.

Example 11

Production of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2 } - carboxylic acid methyl esters.

A mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine ^ s-carboxylic acids, which by the method described in Example 10 (a) from 5j 53 g raeemischem 1,1-Di chi or-3i J-Ol) -ethyl-4 (S) -piperidinyl 3-propane-2 (S) -ol hydrochloride is dissolved in .350 ml of methanol, concentrated sulfuric acid (5 ml) is added and the mixture

1 0 9 8 A 1/1 q h 7

2111933

temperature, filtered through Celite and the filtrate with hydrogen sulfide saturated. The precipitate is filtered off through Celite and the filtrate is evaporated to dryness. Of the The residue is treated with 500 ml of ethanol and the resulting The mixture was refluxed for 3 hours. After filtering through Celite, the resulting filtrate, which is a Mixture of epimeric, racemic 4,5-erythro-5-ethylqu-inuclidine-2t-carboxylic acids contains, saturated with anhydrous hydrogen chloride and refluxed overnight. The resulting precipitate is filtered off and the filtrate is evaporated to dryness. The yellow oil obtained is with Treated 300 ml of a saturated sodium carbonate solution and extracted five times with ether; the combined extracts become dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is distilled off 70-75 ° C (oil bath temperature) under a pressure of 0.3 mm Hg in a short-path distillation device and receives 3.8l g of a liquid mixture of epimeric, racemic 4,5 ~ erythro-5-ethylquinuclidine-2 ? -cai-bcic acid-ethy! esters.

Gas chromatography shows that the product consists of two / one isomers in a 1: 1 ratio. The two isomers have retention times of 8.5 and 9 Λ minutes and can be separated from one another by means of preparative gas chromatography.

b) A solution, cooled to -70 °, of 5 ml of methylene chloride in 70 ml of anhydrous tetrahydrofuran during a Hour in an atmosphere of dry nitrogen, 35 ml a 1.66 molar n-sutyllithiUKklösur, c i-hexane; -u; -esotzt. After stirring the mixture for 20 minutes at the same temperature, 6.8 g of racemic 2- {l-Bc-nzoyl-3 (R) -ethyl-'i (S) -piperidinyl] -acetaldehyde in 30 ml of anhydrous tetrahydrofuran added drop by drop. The implementation is after YO minutes interrupted by the addition of 30% of water and the temperatures the mixture is allowed to rise to room temperature. Thereafter

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333

refluxed overnight. There are still 2 ml concentrated Added sulfuric acid and continued refluxing for 15 hours. The volume will to about 30 ml by evaporation under reduced pressure concentrated, the residue obtained was made alkaline with a saturated sodium carbonate solution and with dichloromethane diluted. The insoluble products are filtered off and dissolved in a minimal amount of water. The aqueous phase is extracted three times with dichloromethane, the combined Extracts and the filtrate. dry the combined organic layers over potassium carbonate and evaporate them under reduced! Pressure a. Then one obtains by distillation ^ of the residue 2.33 g of a liquid mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2r-carboxylic acid methyl esters with a boiling point of 84-85 ° c / O, 35 mm Hg.

Example 12

Production of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2 ^ -carboxylic acid hydrochlorides.

A solution of 2.15 g of a mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2 ^ -carboxylic acid ethyl esters in 100 ml. In hydrochloric acid, W is left to stand for 10 days at room temperature, then washed with ether and. evaporated to dryness under reduced pressure. Complete dryness is achieved by adding toluene to the residue several times and evaporating the solvent under reduced pressure. The residue is crystallized from a mixture of ethane oil and ether and 429 mg of a mixture of epimeric, racernic 4,5-erythro-5-ethylquinuclidine-2 ^{l of} f-carboxylic acid hydrochlorideGn with a melting point of 239-242 ° C. is obtained. The concentrated mother liquor is treated again with 1N hydrochloric acid, whereby 353 mg of a mixture of epiir.cren, racemisehen 4,5-erythro-5-ethy.l quinucli din-2V-cai'bonsiiurolj.vdrocli.l oricien are obtained.

1 0 9 8 4 1/1 9 U 7

2μ1Ξ33

Example 13

Preparation of epimeric 5 (R) -vinyl-4 (S) -quinuclidin-2 ^ -carboxylic acid ethyl esters.

6.48 g of 2- [1-benzoyl-3 (R) -vinyl-4 (S) -piperidinyl] -acetaldehyde are described in a manner similar to that in Example 8, with 3.7 ml of methylene chloride and 55 millimoles of n-butyllithium DichlOiiiiethyllithium produced and the resulting mixture (4.1 g) of epimeric 1,1-dichloro-3- [3 (R) -vinyl-4 (S) ~ piperidinyl] -propan-2f-olen dissolved in 4θΟ ml of methanol. A solution of 1.9 g of potassium hydroxide in 20 ml of methanol is added and stirring is continued for 50 hours at room temperature. The solution, which contains a mixture of epimeric 5 (R) vinyl-4 (S) -quinuclidine-2; j ⁱ -carboxaldehydes, is added to a mixture of 2.56 g of sodium hydroxide and 5.78 g of silver nitrate in 40 ml of water . The reaction mixture obtained is stirred for 3 hours at room temperature, filtered through Celite and the filtrate is evaporated to dryness. Complete dryness is achieved by adding a solvent mixture of ethanol and benzene to the residue and evaporating the solvent under reduced pressure. This process is repeated several times and the residue extracted several times with hot ethanol. The combined extracts are evaporated to dryness and the residue, which contains a mixture of epimeric 5 (R) -Vinyl-4 (S) -quinuclidine ^ '- carboxylic acids, is partially dissolved in 100 ml of 8% ethanolic hydrochloric acid. The reaction mixture is stirred for 3 days at room temperature, then evaporated to dryness and the residue is treated again for 15 hours with 100 ml of 5% ethanolic hydrochloric acid. The solvent is evaporated under reduced pressure, the residue is 100 ml saturated; Potassium carbonate solution added and the mixture extracted three times with ether. The unified; _: -jton extracts wcx'den over sodium sulfate getrookric-t, under vern.indortoni pressure: '. ur ^r JVoc; irenc

1 0 9 δ 4 1/1 9 A 7

2111333

evaporated and the residue is distilled in a short-path distillation device at 77 ° (oil bath temperature) under a pressure of 0.15 ram Hs, v. 1.83 g of liquid, epimeric 5 (R) -Vinyl-4 (s) -quinuclidine ' ? -carboxylic acid ethyl ester; [a] ^ ⁵ + 82.2 ° (c 1.1 95 £ ethanol).

Example 14

Preparation of epiineren 5 (R) -Vinyl- '! - (S) -quinuclidin-2! -Carboxylic acids.

A suspension of 510 μg epin.eren 5 (R) -Vinyl-4 (S) -quinuclidine-2t-carboxylic acid ethyl esters in 10 ml V / water is left to stand at room temperature, a clear solution is obtained after 10 days. The V / ater v, ^T IRD evaporated under reduced pressure, the residue at 105 ° sublirniert under a pressure of 0.15 mm Hg and one obtains 210 mg hygroscopic, crystallized, epimeric 5 (R) -vinyl-4 (S) - quinuclidin-2 f-carboxylic acidsi [α} ψ + 78.4 ° (c 0.72, CHCl ₃ ), [α] ^ + 93.2 ° (c 0.87, In NaOH) if measured immediately, and loc] ^ " ³ + 80.8 ° (c 0.87 * In NaOH) after constant heating of the solution at 100 °.

Example 15

Preparation of racemic diir-ydrochiriinon and of

racemic dihydroquinidine.

a) A solution of 488 mg of 4-Brora-c-r: _t ethoxyquinoline in 20 ml of anhydrous ether, under a nitrogen atmosphere to -50 ⁰ C 0, ^h ~ j ir. 1 a solution of 2,? 5 -Moles of butyllithium in hexane added. The o-Kethoxy-A-chinolyllithium suspension containing ^v; ird is stirred at this temperature for a further 15 minutes and then before a solution. - ^! iJ> 3 mg of a. ·; Mixture of epimers, raceii: i. ^f jchr-n ^A , 3-; 2r; / thro -: j-äi-hylquinuclidin-2 y'-carhoiisäureäthylesterii in 20 i :: l v.-water-free ether for 20 minutes added i'ü ,, t. Uach l, ^j hours stirring at -S0 ° dan If Gunn ;; n on on K.:un.r£. Pcrat.u · crliit.-t, with U'aoii

1 0 9? U / 1 9 U 7

hydrolyzed, then the aqueous layer separated and extracted three times with ether. The combined organic solutions are dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed three times with ether as the solvent on preparative silica gel plates. Eluting with methanol obtained ICO to a yellow oil, from which one mg by further treatment of a crystallized mixture of 50 racemischeia Dihydrochininon and raeeiaischem Dihydrochinidinon receives ,, which has a melting point of 86-9-0 ⁰ C-.

b) 0.67 ml of a 1.6 molar solution of butyllithiur- in hexane are added to 5 ml of anhydrous ether, the resulting solution is cooled to -70 ° and while stirring under a nitrogen atmosphere, 119 mg of a solution of 4- Bromo-6-methoxyquinoline was added in 5 ml of ether. The suspension containing 6-methoxy-4-quinolyllithium is reacted with a solution of 56 mg of 1,4-Dia2afoieyclo [2.2.2] oetane in 5 ml of anhydrous ether and the mixture is stirred at -70 ° for 2 hours. Then a solution of 125 rag of a mixture of epinoren, raeeniischen 4.5-erythro-5-ätnylquinuclidin-2t-carbonsäureäthylestern in 5 nil what se r free ether is added and the mixture is stirred J> 0 minutes at -70 ^0th The reaction is stopped by adding water and the mixture is allowed to warm to room temperature. The aqueous layer is separated off, extracted with ether, and the combined organic extracts are then dried over sodium sulfate and evaporated to dryness, giving 184 mg of an oil which contains racend dihydroquininone and racial dihydroquinidinone.

Using the procedure described above, you can you get the following connections, among others:

a) from 7-chloro-4-efainolyllithiurr. a mixture of racetr.ifrohem 7'-Chlordihydrocinehonidinon and of raceiräachom 7'-Chlordihydrocinoiioninon with einc-i ?. Sch: i.el;: r; u: ii: t from 12 -! - 127 ⁰ C,

1 0 9 8 4 1/1 9 U 7

I i. ο O- O

b) from 6-methyl-4-quinoly! lithium, a mixture of racerrri scheu! o'-Methyldihydrocinchonidinone and from raceraisher 6'-Methy1-dihydrocinchonirion with a melting point of 105-108 ° Cj

c) from o-chloro - ^ - quinolyllithium a mixture of racernic 6'-chlorodihydrooinchonidinone and of racemic ö'-chlorodihydrocinchoninone with a melting point of 10 ^J f-107 ^a Cj

d) 7 ~ methoxy-4-chinolyllithium a mixture of racemic 7'-Methoxydihydi "ocinchonidinon and racemic 7 ^-Metho;! sydihydrocinchoninon having a melting point of ⁰ C .111-117.

Example l6

Preparation of racemic dihydroquinine and of racemic dihydroquinidine from a mixture of racemic dihydroquininone and racemic dihydroquinidinone.

A solution of 5 * 06 g of a crystallized

Mixture of racemic dihydroquinone and dihydroohinidinone in 500 ml of dry benzene are 12.5 ml of a 25 / i? -i ^ en solution of diisobutylaluminium hydride in toluene added dropwise with stirring and under a dry nitrogen atmosphere; after about 30 minutes, the reaction with 2 ml of one 1: 1 mixture of methanol and V / ass ^ er interrupted that precipitated aluminum oxide is filtered off and washed with methanol. The residue of the methanol solution (3.87 g) is crystallized from acetone, giving 3.14 g of racial dihydroquinine monohydrate in three servings. The residue of the benzene solution (1.54 g) is made from a concentrated ethanol solution crystallized, giving 579 mg of rkcemisehes dihydroquinidine in four servings. After purification by preparative thin-layer chromatography (chloroforra-triethylamine-methane oil, 85: 10: 5) becomes d, l ~ dihydroquinidine and d, l-dihydroquinine from ethanol or. crystallized from acetone.

109841/1947

2 11 'ε- 3 3 -33-

By using the method described above, the following compounds, among others, can be obtained:

a) from a mixture of racemic 7 ^f -chlorodihydrocinchonidinone and of racemic 7'-chlorodihydrocinchoninone, racemic 7'-chlorodihydroeinchoriidin with a melting point of 192 ~ 193 ° C and racemic 7'-chlorodihydrocinchonine with a melting point of 251-253 ° C;

b) from a mixture of racemic 7'-methoxydihydrocinohonidinone and racemic 7'-methoxydihydrocinchoninone, racemiaches 7'-Methoxydihydrocinchonidln ^ melting point 160 ° C and racemic 7'-methoxydihydroquinchonine melting point 217-219 ° C;

c) from a mixture of racemic 6'-methyldihydrocinchonidinone and of racemic o'-methyldihydrocinchoninone, rachemic ö'-methyldlhydrocinchoninone mp. 26-213 ° and racemic o'-methyldlhydrocinchonine mp '. 153.5 to 155 ⁰ C;

d) from a mixture of racemic 6 '-Chlordihydrocinchoriidi-

non and of racemic 6'-chlorodihydrocinchoninone, racemic o'-chlorodihydroeinchonidine with a melting point of 100-102 ⁰ C and racemic o'-chlorodihydrocinchonine with a melting point of 172.5-173 * 5 ° C.

Example 17

Production of quinine and quinidine.

To 100 ml of anhydrous ether are 14.5 ml of a 1.45 molar solution of n-butyllithium in hexane added, the resulting solution cooled to -70 ⁰ C and a solution of 4.76 g of 4-Brorn ~ 6-methoxychinoliri in 100 ml of anhydrous Aotho.r was added with stirring and under an atmosphere of dry nitrogen, whereupon the resulting yellow suspension of 6-methoxy-4-quinolyllithiurN in ether is stirred for 2 hours at -70 °. A solution of 2.1 g epirncror 5 (R) -Vinyl - 4 (S) -qu.i.nuc.lidin-2 ^< f-carboxylic acid ethyl liter in 100 ml vianscr-

1 0 9 δ A 1/1 9 U 7

2111933 -31-

Free ether is added, the reaction is interrupted after 30 minutes by adding water and the reaction mixture is allowed to warm to room temperature. The ethereal solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure, giving 5.03 g of an oil which contains a mixture of quininone and quinidinone. A cooled solution of ^, 7 ¹ S- ε of this mixture in 100 ml w ater dry benzene 13 isl a-25 ^ solution of diisobutylaluminum hydride in toluene under an atmosphere of dry nitrogen was added and after one hour the reaction is iriit 20 ml of a 1: 1 mixture of water / water and methanol interrupted with stirring. The resulting precipitate is filtered off, washed with methanol, the piltrate is dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in chloroform is washed successively with sodium hydroxide and water, dried over sodium sulfate and evaporated to dryness. The product obtained (4.1 g) is chromatographed on 150 g of neutral aluminum oxide (activity T) with a 1: 1 mixture of ethyl acetate and E & nzol (500 ml), ethyl acetate (800 ml) and methanol (400 ml) as eluent oil . The methanol portion is evaporated and the product obtained (2.5 g) is graphed over preparative silica gel plates (20 × 20 × 0.2 cm) with an 85: 10: 5 mixture of chloroform, triethylamine and methanol. By elation the lower of the three main stripes with a, ';; A 1: 1 mixture of chloroform and methanol gives 289% of a yellow oil, which is dissolved in ethanol and reacted with 44% d-V-tartaric acid in ethanol, neutral quinine tartrate crystallized as a result being obtained with a :; Sehn.elzp ".kt from 2-1 ^ -215 ⁰ I [a] ^ ⁵ -149 ° (c 0.985, MeOH); the IR spectrum that of an original sample and the melting point is not reduced by adding the original sample. By eluting the middle strip with a 1: 1 mixture of Met ^ Liiol-Chlorcf ... "one 311 mg quinidine, v? eLch"? s λ «.λ! j ^ tt'issallisatian from ethanol

1098-1 / 1947

2 1 i; S 3 8

and drying for 15 hours at 80 ° under reduced pressure, has a melting point of 170 ° -172 ° C, [or] ^ ² + 2.61 ° (c 0.9913, ethanol). The IR spectrum and the thin-layer chromatography R, value agree with that of the pure product. Addition of this does not result in a reduction in the melting point. By eluting the top strip with a; 1: 1 mixture of methanol-chloroform gives 95 mg of an oily residue, consisting of a mixture of epichinine and epichinidine

Using the reaction conditions described above the following connections can be obtained:

a) from 7-chloro-4-quinolyllitb.iuin, 7'-chlorcinchonidine with a melting point of 177-179 ° and 7 ^f -chlorinchonine with a melting point of 245-246 ° }

b) 4-ehinoly from o, 8-dichloro ~! lithium, 6 ^l, 8'-Dichlorcinchonldin having a melting point of 103-108 ° and 6 ^1-ß 'Dichlorcinchonindiliydrochlorid-ißonohydrafc having a melting point of 2150 ° (Sign-s .) i

c) from ö-chlorine - ^ - quinolyllithium, G'-chlorocinchcnidine, melting point 193-194 ° and o'-chlorocinchonine, melting point 15 ^J ^ -

d) from 4-cliinolyllithium, cinchonidine and cinchonine.

Example 18

Preparation of racemic ^{δ 1} , S'-dichlorodihydrocinchonidii dihydrochloride and of racemic 6 ', 8'-dichlorodihydrocinchonindiliydi'ochloride.

a) To 500 ml of water-free ether, add 38 ml of a 1. ^ molar solution of butylithium in Kexsü: the solution is cooled to -68 ° and a solution of IJ;, 8 g of 4-bromo-6,8-dichloroquinoline in 175 n \ viasser fr eggs tetrahydrofuran for half an hour with stirring and under a

109841/1947

Nitrogen atmosphere added. A solution of 5.3 g of a mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2r-carboxylic acid ethyl esters in 250 ml of anhydrous ether is then added to the so prepared öjS-dichloro - ^ - quinolyllithium, stirring for one hour -70 ° continued, then interrupted the reaction with water and allowed the mixture to warm to room temperature. The organic solution is washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to give 19j0 g of an oily residue which is a mixture of racemic 6 ', S'-dichlorodihydrocinchonidinone and of racemic 6 ¹ , e'-dichlorodihydrocinchoninone contains. This product is dissolved in 250 ml of anhydrous benzene, cooled and 17 ml of a 25% solution of diisobutylaluminum hydride in toluene are added over 15 minutes under an atmosphere of dry nitrogen. The mixture is stirred for one hour at room temperature, the reaction is interrupted by adding 20 ml of a 1: 1 water-methanol mixture and the resulting precipitate is filtered off, washed with methanol and a solution of the residue 3η chloroform is washed with 1N sodium hydroxide and water. The combined organic solutions are dried over sodium sulfate, evaporated to dryness and the resulting product (14.1 g) on 500 g of neutral aluminum oxide (Aktivj tat 1) with ethyl acetate (1.8 liters) and later with methanol ('.?,? Liters) chromatographed as the eluent. Evaporation of the methanol fractions gives 5 * 27 g of a product which is chromatographed on 700 g of silica gel together with 6.9 g of the material previously prepared. Fractions of 250 ml each are collected. After 25 fractions with a 97: 2 Chloroforir.-Träthylamin-Ge: nlsch the composition of the eluent κ is changed to 96: 4. Fractions 29 to 40 are combined, evaporated to dryness, the residue is dissolved in dichloromethane, the organic solution obtained is washed twice with water and dried over sodium sulfate

1 0 9 8 Λ 1/1 9 Λ 7

211: 338

and evaporated to dryness under reduced pressure. By crystallization of the residue (1.79 g) from a 1: 2 Benz oil Hexangemiscn obtained 1.3 g of crystalline, racemic 6 ^T, 8'-Dichlordihydrocinchonin and by recrystallization from benzene-hexane (1: 1) and drying of the product at 80 ° under reduced pressure up to constant weight, racemic 6 ', 8'-dichlorodihydrocinchonine, which contains 1/3 mol of benzene and has a melting point of 172-173 °. Dissolve 1.05% of the free base with sufficient ethanol Hydrochloric acid, added ether and obtained 1.0 g of a crystallized precipitate of racemic 6 ', 8'-dichlorodihydrocinchonine dihydrochloride with a melting point of 210-212 ° and after two recrystallizations from ethanol-ether, 100 minutes drying at 80 ° under reduced pressure the melting point is 214-216 °.

The fractions 42 to 57 are combined, evaporated to dryness, the residue dissolved in dichlorine than, the solution washed twice with water and dried over sodium sulfate and evaporated to dryness under reduced pressure. Then the residue (1.56 g) in sufficient ethanolic hydrochloric acid dissolved and by adding ether, 1.15 g of a crystallized precipitate of racemischeni is obtained 6 ', 8'-dichlorodihydrochloride dihydrochloride which after Urnkr i s t al 1 i s a t i on au s Me t h anol · - Λ ο the r has a melting point of 226-227 °.

b) 38 ml of a 1.5 molar solution of butyllithium in hexane are added to 500 ml of anhydrous ether, the solution is cooled to -70 ° and, with stirring, a solution of 13.8 g of ^ -Bromo-Ö ^ -dichloroquinoline in 200 ml of anhydrous tetrahydrofuran was added under a nitrogen atmosphere. The stirring of the 6,8-diehlor »> l ~ ohlnolyllithiumlöi; ur ,, j; continued at -70 ° for 10 minutes, then a solution of 5.6 g was; .-or free em Tetraniethylündlainin in ? .'- jO ml iVsX.lv:·ν YAn-

1 0 9 8 I * 1/1 Π Α 7

2111 Ξ-33

-st-

after a quarter of an hour of stirring, 5.8 g of a mixture of epirneren, racenic 4j5-erythro-5-ethylquinuclidin-2fcarboxylic acid ethyl ester dissolved in 250 ml of anhydrous ether are added: -; tj da ". The mixture is stirred for one hour at 70 °, then the reaction interrupted ir.it VJasser and the mixture to room temperature err.ävi-.en left. the organic solution is gevwasehen IAIT water ü.V> ^r? r Watriunsulfat evaporated and dried under reduced pressure for :: dryness to 17j5 S of an oil residue is obtained which contains a mixture of raceiaischeim 6 ¹ , 8 '-dichloro dihydro cinchonidinone and of racemisehera 6 ^s , 8 ^f -dichlorodihydroeinchoninone. Racemic dies 6', e'-JDIchlordiir / arocinchonidindihydrochlorid and 6 ¹ , 8 * -Dichlorodifcydrocinchonine are prepared as described under (a).

Using the reaction conditions described above you can still get the following connections

a) from 6,7-Dinietho: Q '- ^ - quinolyllitlriiu] ru, racemic 6,7-Diinethoxydihydrocinchor.idindihydroefilorid (Schnislzpunkt 208-210 °) and racemisehes 6', 7 ^l -DiEaetiio :: ydih7drocinehonindihydropunkt 221-21,25 °) and

b) from 6,7-methylenedio: iy- ^J l-quinolyllithiurr _t , 6 ^f , 7 * -methylenedioxy-dihydrocinchonidine (melting point 2j; -2-23j; - ⁰ ) and racer.-iino. 6 ^! , 7 '-MethylenedioxydihyirocincLoi.in (Sehrrielzpankt 2 ^ 4-2 ^^ °)

Example 19

Manufacture of race ^ iGeheim Dihy. i'Oühiniti or: d of racemic in dihydioquinidine.

To ^ O ml of anhydrous asther i ^ rden 2.22 ::.! a 2

molar Löoung of DutyIIithiuir, i ^ !! -:;: ■: γ.π - ^: ;;: ■.: 'j ^ ^r \, oils Lc "U: _i -08 ° chilled, 1.19 g ^ - Brom- o- ^ etiiio ^ - ^ i ^ ioli ^ "-ίΐτ-- 'stirring under a nitrogenate:;"i; sjr. £ r ^ - ninzuirefü ^ t, viobei

1 0 9 B U 1/1 9 L1

BATH

2111933

immediately a yellow suspension of o-methoxy - ^ - quinolyllithiuni forms. This suspension is a solution of 1.42 g of a crude mixture of epirneren, racemischexi ■ '«, ^ - Erythro - ^ - s-thyl-quinuclidin- ^ l-carboxal dehy den in 30 ml of anhydrous ether is added, then a Stirred for an hour at -6p ° and the mixture in ice water poured out and extracted with dichlorine than. D? R Dichloromethane extract is washed with water over sodium sulfate dried, evaporated to dryness and the residue dissolved in dichloromethane. The solution is extracted twice with 2N hydrochloric acid, the extract is prepared with dichloromethane and makes it alkaline with 6N sodium hydroxide. The released Bases are extracted with dichloride than, the Extract washed with water over anhydrous sodium sulfate dried and evaporated to dryness, whereby one a crude oily product is obtained, which is then placed on preparable Silleagel plates with a ratio of: 85: 10: 5 "Chlorofora-TriäthylaminHtäethanol-Geni sch chromatographed. Two different strips are eluted and racemic is obtained Dihydroc! Iiiiidiii (Sehmel point 15J'-15 ^ °) and racemic Dihydroehinine (melting point 171-172 °).

Example gQ

Preparation of racemic 6 ', 7' -Methylcndioxydihydrocinchonidin and of racemic 6 ¹ , 7 '-. I-thyle;: aio; v'-diV.;, Αίνο inch onin.

To 250 ml of water-free ether add 19 * 7 "e" 1 of a 1.5 molar solution. before. Added n-butyllithium in hexane, the solution cooled to -68 ° and then 6.55 g of a solution of i-bror; ·.-6,7-MetlijleiidIo>: yquinoline in 2CO ml of anhydrous tetrahydrofuran with stirring for 50 minutes under a Stickst of fatrno.'jphäre suitssotzt, v.'obei one gets o ^ -Methyler.ciioxy - ^ - chirj.olyllithium. Stirring is continued for half an hour - \; · '- sets, GtJTMi ei no solution "of 2.15 g' xir.es Gv-ir.irchc.-r; ·: ■ y.iy.yynx.,

109841/19 ^ 7

2111933

racemic 4,5-erythro-5-ethy! quinuclidine? -carboxaldehydes added in 250 ml of ether for one hour. The mixture is left overnight at -70 ° under a nitrogen atmosphere touched. The reaction is then terminated by adding water and the appliance is allowed to warm to room temperature and concentrated under reduced pressure. The residue is dissolved in ether, the solution is washed with water, dried over sodium sulfate and evaporated to dryness 6.54 g of an oil being obtained. Man chromato ~ graphed on neutral aluminum oxide (activity I) with ethyl acetate and obtained 2.97 ΰ of a yellow solid, its elution with methanol gives 3.37 g of a brown oil. The latter is done on preparative silica gel plates with a 97O ethyl acetate-triethylamine solvent mixture chromatographed and the plates are developed three times. The lower major strip is eluted with methanol-chloroform and the eluate (510 mg) crystallizes from acetone, whereby racemic 6 ', 7'-methylenedioxy-dihydroo.inchonidin (Melting point 232-235 °) receives. By eluting the next higher strip with methanol-chloroform and crystallizing the eluate (597 mg) from acetone gives racemic 6 ', 7'-methylene " dioxy-dihydrocinchonine (melting point 2.34-235 °)

Using the method described above, one can obtain the following compounds, among others:

a) from 6-methyl-4-quinolyllithium, racemic o'-methyldihydrocinchonidine (Melting point 216-218 °) and racemic 6'-methyldihydrocinchonine (melting point 153 »5-155 ° C) i

b) from 6-chloro-4-quinolyllithiuin, racemic 6 ^f -chlorodihydrocinchonidine (melting point 100-102 °) and racemic δ'-chlorodihydrocindonine (melting point 172.5-173.5 °) j

c) from 6,7-dimethoxy-4-quinolyllithium, racemic δ ', 7'-dimethoxydiliydrocinchonidine dihydrochloride (melting point 208-210 °, ' / Ww ..) and raernnisoh ^ s 6 ',' ( '-diinethoxydihydrociDchonindihydroclilorid (melting point ? 21-2? 5 °);

-HI-

d) from Y-methoxy ^ -quinolyllithlum, - racemic 7'-methcocy-dihydrocinehonidine (Melting point 1δθ °) and racemic 7'-methoxydihydrocinchonine (Melting point 217-219 °);

e) from 7-chloro-4-quinolyllithium, racemic 7'-chlorodihydrocinchonidine (melting point 192-193 °) and racemic 7 ^! -Chlordihydrocinchonine (melting point 251-253 °, dec.) I

f) from 6,8-dichloro-4-quinolyllithium, racemic 6 ^! , 8'-dichlorodihydrocinchonidine dihydrochloride (melting point 226-227 °) and racemic 6 ', e'-dichlorodihydrocinchonine dihydrochloride (melting point 214-215 °).

109841/1947

Claims (9)

Claims Process for the preparation of quinoline derivative general formulas and II where m is the number 1 or 2, R _{2 is} vinyl or AethyI, and R-, hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (R,) Kethyleridioxy, of enantiomers, racemates and acid reaction salts thereof, characterized by having a verb charge of general formula where R and m have the above meaning, 1 0 9 8 4 1/1?. 4 7 -13- 211133 with an epimeric compound of the general formula or PL 0OC 5 VI VIII where Rp has the above meaning and R., lower alkyl, aryl or aryl-lower-alkyl means, or reacts with an enantiomer or a racemate thereof, that when using a compound of the general formula VJlII the resulting compound of the general formula R, where R,, R and m have the above meaning: n, treated with a reducing agent and »that ir.an thus obtained Build, if desired, converted into acid caadiciorus salts. 1098Λ1 / 1Ρ / + 7 ■ ΜΗ- 2 . The method of claim l _t characterized in that at least 1 mole, preferably about 2 moles of the compound of formula X per mole of the compounds of the formulas VI or VIII used. 3. The method of claim 1. or 2, characterized in that one carries out the reaction in the presence of an inert organic solvent and at a temperature between about room temperature and about -70 ⁰ C, preferably between about ⁰ ° C and about -70 ⁰ C. 4th Method according to one of Claims 1-3, characterized characterized in that the reaction is carried out in the presence of a complexing agent. 5. The method according to claim 4, characterized in that 1,4-diazabicyclo [ 2.2.2] octane or tetramethyethylene diamine is used as the complexing agent. 109841/1947, 6th Method according to one of Claims 1-5, characterized characterized in that a dialkyl aluminum hydride is used as a reducing agent. 7th Method according to Claim 6, characterized in that that diisobutylaluminum hydride is used as a reducing agent. 8th . A method according to any one of claims ^l-7, characterized in that there is used as starting material of formula X a compound _'t wherein R, is hydrogen, chlorine, methyl, methoxy, methylenedioxy or trifluoromethyl. 9. The method according to claims, characterized in that 4 — quinolyllithium ^{i-methoxy 1} ! -Quinolyllithium; S- methyl-4-quinolyllithium; 7-methoxy-4-quinolyllithium; 6,7-dirnethoxy-4-quinolyllithium; 6,8-dinrethoxy-4-quinolyllithiumj 6, V-methylenedioxyM-quinolylli-6-chloro-4-quinolyllithium; 7-trifluoromethyl-4-quinolyllithiumJ] thiui 7-chloro-4-quinolyl lithium or 6,8-dichloro-4-quinolyllithium used as the starting material of the formula X. 109841/1947