DK141700B - Analogous process for the preparation of cinchonin or cinchonidine derivatives. - Google Patents

Description

(11) PUBLICATION MANAGEMENT 141700 in R / DENMARK (61), nt C | 3 c 07 D ^ 53 / oa (21) Application No. 6376/74 (22) Filed on the 6th Dec. 1974 (23) Race day 6 Dec. 1974 (44) The application submitted and _

the writ of publication published on 27 · ffiSj 19 ° G

DIRECTORATE OF THE PATENT AND TRADEMARKET (30) Priority granted from death

Dec 7 1973s 422645, US

(71) F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, Grenzacherstrasse 124 “184, Postfach, CH-4002 Basel, CH.

(72) Inventor: Guenter Grethe, 3 Andover Drive, North Caldwell, N.J., US: Milan Radoje Uikokovlc, 253 Highland Avenue, Upper Montclair, N.J., US.

(74) Plenipotentiary in the proceedings:

Plougmann & Vlngtoft Patentureau.

(64) Analogous process for the preparation of cinchonin or cinchonide * derivatives.

The present invention relates to an analogous process for the preparation of novel cinchonin or cinchonidine derivatives of general formulas I and II

H0 r UO 'f Jr®

hTH I

Wherein R represents halogen or trifluoromethyl, and R represents ethyl or vinyl, or enantiomers or racemates thereof or acid addition salts thereof, which process is characterized in that:

(a) a compound of general formula III

j "H III

OHC + N2

wherein R is as defined above, or an enantiomer or racemate thereof is reacted with a compound of general formula IV

where R · * "has the meaning given above, or

b) a compound of general formula V

R2

I H

IH v

r1OCX

wherein R and R are as defined above, or an enantiomer or racemate thereof is treated with a reducing agent, or

(c) a compound of general formula VI

3 141700 I n "h rr1 ^

in VI

wherein R and R are as defined above, or an enantiomer or racemate thereof is hydroxylated, or

(d) a compound of general formula VII

2 f

R V ^ N-H

where R and R have the meaning given above, or an enantiomer or racemate thereof is cyclized, 2 and, if desired, in a compound thus obtained, where R is vinyl, the vinyl group is reduced to a ethyl group, if desired, a racemate is digested into its optical antipodes, if desired, a won base is converted to an acid addition salt, and, if desired, a won acid addition salt is converted to the free base and this, if desired, is converted to another acid addition salt.

The term "lower alkyl" is used herein to mean a straight or branched hydrocarbon group containing 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl or butyl. The term "lower alkanoyl" refers to groups of 1-6 carbon atoms, e.g. formyl, acetyl, propanoyl and butanoyl. The term, U17D0 4 "halogen" means all the halogens, ie. bromine, chlorine, fluorine and iodine; chlorine is preferred.

Examples of compounds of formulas I and II are: 2.8-bis (trifluoromethyl) -α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [ hereinafter also called 2 ', 8'-bis (trifluoromethyl) -dihydrocinchonidine] and racemate etheraf; 2.8-bis (trifluoromethyl) -α (S) - [5 (S) -ethyl-4 (R) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called the enantiomer of 2'8'- bis (trifluoromethyl) dihydrocinchonidine]; 2.8-bis (trifluoromethyl) -α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 2'8'-bis ( trifluoromethyl) dihydrocinchonine] and the racemate thereof; 2.8-bis (trifluoromethyl) -α (R) - [5 (S) -ethyl-4 (R) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called the enantiomer of 2'81-bis (trifluoromethyl) dihydrocinchonin]; 2,8-bis (trifluoromethyl) -α (R) - [5 (R) -vinyl-4 (S) -quinuclidin-2 (s) -yl] -4-quinoline methanol [hereinafter also called 2'8'-bis ( trifluoromethyl) cinchonidine], its enantiomers and its racemate; 2,8-bis (trifluoromethyl) -α (S) - [5 (R) -vinyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 2'8'-bis ( trifluoromethyl) -cinchonine], its enantiomers and its racemate; 2,8-bis (trifluoromethyl) -α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called 2'8'-bis ( trifluoromethyl) - 9-epi-dihydrocinchonidine], its enantiomers and its racemate; 2,8-bis (trifluoromethyl) -α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 2'8'-bis ( trifluoromethyl) - 9-epi-dihydrocinchonine], its enantiomers and its racemate; 2,7-bis (trifluoromethyl) -α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [also called 2'7'-bis (trifluoromethyl) dihydrocinchonidine], its enantiomers and its racemate; 2,7-bis (trifluoromethyl) -α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 2 ', 7'-bis (trifluoromethyl) dihydrocinchonine], its enantiomers and its racemate; 8-Chloro-2-trifluoromethyl-α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called S'-chloro -trifluoro-methyl-dihydrocinchonidine], its enantiomers and its racemate; 8-Chloro-2-trifluoromethyl-o (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 8, -chloro-2 '-trifluoro-methyl-dihydrocinchonine], its enantiomers and its racemate; 5-Chloro-2-trifluoromethyl-α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called 5'TChloro-2'- trifluoro-methyl-dihydrocinchonidine], its enantiomers and its racemate; 5-Chloro-2-trifluoromethyl-α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 5f-chloro-2 ' -trifluoro-methyl-dihydrocinchonine], its enantiomers and its racemate; 5-Chloro-2-trifluoromethyl-α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called 5 2, -trifluoro-methyl-9-epi-dihydrocindhonidine], its enantiomers and its racemate; 7-Chloro-2-trifluoromethyl-α (R) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol [hereinafter also called 7'-chloro-2 '-trifluoro-methyl-dihydrocinchonidine], its enantiomers and its racemate; 7-Chloro-2-trifluoromethyl-α (S) - [5 (R) -ethyl-4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol [hereinafter also called 7, -chloro-2 , -trifluoro-methyl-dihydrocinchonine], its enantiomers and its racemate;

A preferred compound is racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonine.

The reaction of the epimeric 5 (R) -ethyl (or vinyl) -4- (S) + η1ηησϋΰ1η-2ξ - carboxaldehydes of general formula III or enantiomers or racemates thereof with a 4-quinolyllithium compound of general formula IV to form of the corresponding α (R) - [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol of the general formula I or 6

1Λ17 O O

an enantiomer or racemate thereof and α (S) - [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol of the general formula II or an enantiomer or a racemate thereof may be carried out by methods known per se. Conveniently, the 4- quinolyllithium compound of formula IV is reacted in equimolar or more than equimolar proportions with the compound of formula III. The reaction is conveniently carried out at room temperature or at a temperature below room temperature, preferably at a temperature between 0 and approx. -70 ° C, in the presence of an inert organic solvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxane or diglyme or a hydrocarbon such as benzene or toluene. The compounds of formulas I and II are isolated from the reaction mixture using conventional techniques, e.g. crystallization.

The compounds of the above formulas III and IV are known compounds or are analogous to known compounds and can be prepared by methods known per se.

Examples of compounds of formula IV are: 2,7-bis (trifluoromethyl) -4-quinolyllithium, 2,8-bis (trifluoromethyl) -4-quinolyllithium, 8-chloro-2-trifluoromethyl-4-quinolyllithium, 7-chloro-2-trifluoromethyl 4-quinolyllithium, 2,6-bis (trifluoromethyl) -4-quinolyllithium, 2,5-bis (trifluoromethyl) -4-quinolyllithium, 5-chloro-2-trifluoromethyl-4-quinolyllithium and 6-chloro-2-trifluoromethyl quinolyllithium.

Since the above-mentioned 4-quinolyllithium compound is highly labile, it is preferred to prepare them in situ by reacting the corresponding 4-bromoquinoline with e.g. n-butyllithium in the presence of a solvent, e.g. a hydrocarbon such as benzene, toluene, hexane or petroleum ether or an ether such as dioxane, ether, diglyme or tetrahydrofuran. Examples of the 4-bromoquinoline compounds are: 2.7-bis (trifluoromethyl) -4-bromoquinoline, 2.8-bis (trifluoromethyl) -4-bromoquinoline, 2,4-bis (trifluoromethyl) -4-bromoquinoline, 2.5-bis (trifluoromethyl) - 4-bromo-quinoline, 4-bromo-8-chloro-2-trifluoromethylquinoline, 4-bromo-7-chloro-2-trifluoromethylquinoline 4-bromo-5-chloro-2-trifluoromethylquinoline and 4-bromo-6-chloro-2-trifluoromethylquinoline .

The 4- haloquinolines can be prepared in a manner known per se from the corresponding 4-hydroxyquinolines, and examples of these are: 2.7-bis (trifluoromethyl) -4-quinolinol, 2.8-bis (trifluoromethyl) -4-quinolinol, 2.6- bis (trifluoromethyl) -4-quinolinol, 2,5-bis (trifluoromethyl) -4-quinolinol, 8-chloro-2-trifluoromethyl-4-quinolinol, 7-chloro-2-trifluoromethyl-4-quinolinol, 5-chloro 2-trifluoromethyl-4-quinolinol and 6-chloro-2-trifluoromethyl-4-quinolinol.

The reduction of the epimeric 4- [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-1-ylcarbonyl] quino lines of the formula V or enantiomers or racemates thereof to form a (R) - [5 ( R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (S) -yl] -4-quinoline methanol of formula X or an enantiomer or racemate thereof to give α (S) - [5 ( R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol of formula II or an enantiomer or racemate thereof can be carried out according to methods known per se. It is convenient to carry out the reduction using a stereoselective reducing agent, e.g. a dialkyl aluminum hydride such as diisobutyl aluminum hydride. Reduction is conveniently carried out at room temperature; however, temperatures above or below room temperature may also be used. It is preferred to use a temperature between 20 and 50 ° C. The reduction can conveniently be carried out in the presence of an inert organic solvent, e.g. a hydrocarbon such as benzene or toluene or an ether such as diethyl ether or tetrahydrofuran.

The compounds of the above Formula V and their enantiomers and racemates thereof are novel compounds and may e.g. is prepared by reacting a mixture of epimeric 5 (R) -ethyl (or vinyl) -4 (S) -quinuclidine-2ξ-carboxylic acid alkyl esters of the general formula VIII

8 1A17 O O

R 2 is S VI11 R 3 OOC I N '2 3 where R is as defined above and R is lower alkyl,

or enantiomers or racemates thereof with a 4-quinolyllithium compound of the general formula IV

Li

r1 – µ TI IV

wherein R 3 is as defined above to form a mixture of epimeric 4- [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2C-ylcarbonyl] quinolines of formula V.

4-Quinolyllithium compounds of formula IV are conveniently reacted in equimolar or more than equimolar proportions with the compound of formula VIII. Preferably, two molar proportions of the quinolylithium compound are used. The reaction is conveniently carried out at room temperature or below room temperature, preferably in the range of between approx. O'C and approx. -70 ° C, conveniently in an inert solvent, for example, an ether such as diethyl ether, tetrahydrofuran, dioxane or diglyme or a hydrocarbon such as benzene or toluene. The reaction may further be conveniently carried out in the presence of complexing agents such as 1-4 diazabicyclo [2.2.2] -efean or tetramethylethylenediamine.

The compounds of formulas IV and VIII listed above are known compounds or are analogous to known compounds and can be prepared by methods known per se.

The hydroxylation of epimeric 4- (α- [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2β-yl] methyl) quinols of formula VI or their enantiomers or feed materials thereof to form a (R) - [5 (R) -ethyl (or vinyl) -9 (400) -quinuclidin-2 (s) -yl] -4-quinoline methanol yielded the formula I or an enantiomer or racemate thereof and to formation of a (S) -I5 (R) - ethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -yl) -4-quinoline methanol of formula II or an enantiomer or racemate thereof can be carried out on in a manner known per se. The hydroxylation is conveniently carried out e.g. in the presence of molecular oxygen and a reducing agent such as dimethylsulfoxide, pyridine, triphenylphosphine or platinum, or a trialkylphosphite such as triethylphosphite in strong basic solution.

A suitable base for the reaction described above is e.g. an alkali metal alkoxide such as potassium tert.butoxide, sodium tert.butoxide, sodium isoamylate or sodium amethoxide or an alkali metal amide such as lithium diisopropylamide or sodium amide. It is convenient to use a solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, pyridine, tert-butanol, a hydrocarbon such as benzene or toluene, an ether such as tetrafuran or dioxane or mixtures thereof. A preferred reaction medium is a mixture of dimethyl sulfoxide and tert-butanol in the presence of potassium tart. butoxide.

Compounds of the above Formula VI and enantiomers and racemates thereof are novel compounds and can be prepared according to Scheme I below: v-pOOR 3 CH 3 p + + fT +

// I

r2j ^ * 4 r2J

Xj / j xi rXI1 B I fe

Ri-øcV ri ~ oc \ ^ ur 3 3 1A1700 10

Reaction Scheme I continued: R2 *

If * (T ^, αΑ vi

R 1 - I

Wherein R and R are as defined above, R represents hydrogen 4 or lower alkyl, and R represents hydrogen or lower alkanoyl.

In Scheme I, compounds of the general formula IX which are known compounds or analogs to the known compounds are readily condensed with compounds of the general formula X or an antipode or racemate thereof in the presence of a base, e.g. .g. an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as sodium methoxide, or a lithium dialkylamide such as lithium diisopropylamide to form a compound of general formula XI or an antipode or racemate thereof. The condensation is conveniently carried out at room temperature; however, temperatures above or below room temperature can be used. The condensation is preferably carried out at a temperature in the range of between about -70 and approx. + 50eC. In addition, the condensation may conveniently be carried out in the presence of an inert organic solvent, e.g. one hydrocarbon such as benzene or hexane, an ether such as diethyl ether, tetrahydrofuran or dioxane, dimethylformamide or hexamethylphosphoramide. A compound of formula XI or an antipode or racemate thereof is converted into a mixture of epimeric compounds of general formula XII, their antipodes or racemates thereof by simultaneous deacylation, if necessary, and reduction. The deacylation and reduction are conveniently carried out using a reducing agent, e.g. diisobutylaluminum hydride or sodium aluminum hydride, in an inert organic solvent, e.g. a hydrocarbon such as benzene or toluene, ether or tetrahydrofuran. The deacylation and reduction are conveniently carried out at room temperature or below, preferably at a temperature in the range of about 10 to about 100 ° C. -70 and approx. + 25 ° C.

11 141700

The epimeric compounds of formula XII or antipodes or racemates thereof are cyclized to form compounds of formula VI or antipodes or racemates thereof. This cyclization can be performed using a cyclizing agent, e.g. an organic acid such as glacial acetic acid. The cyclization is conveniently carried out at room temperature; however, temperatures above or below room temperature may be used. It is preferable to use temperatures in the range of between approx. 25 and approx. In addition, the cyclization can conveniently be 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 or tetrahydrofuran.

The cyclization of epimeric 4- (3- [3 (R) -ethyl (or vinyl) -4 (S) -piperidyl] -1ξ,2C-oxapropyl) quinolines of formula VII or of enantiomers or racemates thereof to form a (R) - [5 (R) -ethyl (or vinyl) -4 (S) - quinuclidin-2 (S) -yl] -4-quinoline methanol of formula I or an enantiomer or racemate thereof to give α (S) - [5 (R) -ethyl (or vinyl) -4 (S) -quinuclidin-2 (R) -yl] -4-quinoline methanol of formula II or an enantiomer or racemate thereof can be carried out on and off say well known way. This cyclization is conveniently carried out by reaction with a weak organic or inorganic protonic acid, e.g. water, ammonium chloride, lower alkanols such as methanol or ethanol or Lewis acids such as aluminum chloride or boron trifluoride. The conversion is conveniently carried out in the presence of an inert organic solvent, e.g. carbon disulfide, hydrocarbons such as benzene or toluene, chlorinated hydrocarbons such as dichloromethane, carbon tetrachloride or chloroform and ethers such as diethyl ether, tetrahydrofuran or dioxane. The reaction temperature is not critical. It can conveniently be in the range between approx. 0 ° C and approximately the reflux temperature of the reaction mixture.

The compounds of the above Formula VII and enantiomeric and racemates thereof are novel compounds and may be prepared according to Scheme II below.

141700 12 J ¥ R2w ^ \. 4

Nj-R'4 N-R '

rH _► rV

/ v * V ^ S, XI11 ø 0 "CXXCTj * OCX",

• 5 H

R 2 R 2 <

In N-R'4 fN-H

wherein R and R have the meaning given above, R 'is lower alkanoyl, and X is halogen.

In Scheme II, the conversion of a compound of general formula Xla or of an antipode or racemate thereof is carried out to form a mixture of epimeric compounds of general formula XIII using a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide or N Bromoacetamido. The halogenation may be carried out in an inert organic solvent, e.g. a hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as carbon tetrachloride or an ether such as diethyl ether, tetrahydrofuran or dioxane. The reaction can conveniently be initiated by a free radical catalyst such as dibenzoyl peroxide or by irradiation with infrared light. The temperature is not critical, but it is preferred, however, to carry out the reaction at a temperature in the range 1Λ1700 13 between approximate room temperature and the reflux temperature of the reaction mixture.

The conversion of epimeric compounds of general formula XIII or enantiomers or racemates thereof to form compounds of general formula XIV or enantiomers or racemates thereof can be carried out using a reducing agent, e.g. alkali metal hydrides such as sodium borohydride, potassium borohydride or lithium tri-tert.butoxyaluminum hydride. The reduction is conveniently carried out in an inert organic solvent, e.g. aliphatic alcohols, such as methanol or ethanol, ethers such as diethyl ether, tetrahydrofuran or dioxane, in a temperature range between about -70 ° C and the approximate reflux temperature of the reaction mixture.

The conversion of a compound of general formula XIV or an enantiomer or racemate thereof to form compounds of general formula VII or enantiomers or racemates thereof can be accomplished using a deacylating agent, e.g. alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, or a reducing deacylating agent, e.g. a dialkyl aluminum hydride such as diisobutyl aluminum hydride or an alkali metal aluminum hydride such as lithium aluminum hydride or sodium aluminum hydride. The deacylation is conveniently carried out in the presence of an inert organic solvent, e.g. lower alkanols such as methanol or ethanol, hydrocarbons such as toluene or ethers such as diethyl ether or tetrahydrofuran. Deacy leaching temperature is not critical. It can conveniently be in the range between approx. -70 ° C and the approximate reflux temperature of the reaction mixture.

When a compound of general formula I or II, 2 wherein R is a vinyl group is formed, this vinyl group can be reduced to an ethyl group. The reduction can be carried out by catalytic hydrogenation using e.g. a precious metal such as palladium or platinum. The hydrogenation is conveniently carried out in an inert solvent, e.g. in water, in an alkanol such as methanol or ethanol or in an organic or inorganic acid such as acetic or hydrochloric acid, or mixtures thereof. The hydrogenation is further conveniently carried out at room temperature; however, temperatures above or below room temperature may be used. Alternatively, the conversion can be accomplished by chemical reduction in the presence of oxygen using hydrazine hydrate 14 and a cupric salt such as cupri sulfate as a catalytic agent. The reduction is conveniently carried out in a polar solvent, e.g. water or a lower alkanol such as methanol or ethanol, preferably at a temperature in the range of room temperature to the boiling temperature of the reaction mixture.

When compounds of general formulas I and IX are formed in their racemic form, this racemate can be digested by known methods such as fractional crystallization of salts with optically active acids.

The compounds of formulas I and II and their enantiomers and racemates form pharmaceutically tolerable acid addition salts, and such salts are included in the invention. Thus, the above compounds form pharmaceutically tolerable addition salts with e.g. both pharmaceutically tolerable organic and inorganic acids such as acetic, succinic, formic, methanesulfonic, p-toluenesulfonic, hydrochloric, nitric, phosphoric and sulfuric.

The compounds of formulas I and II and their pharmaceutically tolerable acid addition salts have antimalarial action and can therefore be used as antimalarial agents.

The pharmacologically useful antimalarial activity of the above compounds is demonstrated on warm-blooded animals using standard techniques. Eg. For example, the test compound can be administered to albino mice in varying amounts. Albinomus inoculated with ca. 10 million red cells infected with P. Berghei. Treatment is started on the first day after inoculation and the drug is administered orally for 4 consecutive days. On the 7th day after the infection, smears are performed, which are stained with giemsa and examined microscopically for P.Berghei.

When racemic 2 ', 8'-bis (trifluoromethyl) -dihydrocinchonidine and racemic 2', 8'-bis (trifluoromethyl) -dihydrocinchonine, which have shown an LD 2 Q value in the range 800 - 900 mg / kg intraperitoneally, test compound at doses in the range of 6 mg / kg to approx. 25 mg / kg, the microscopic examination of the blood smear samples shows that they are free of P.Berghei (negative).

1C 141700 15

The compounds of the present invention containing a trifluoromethylSubstituent 1 2 -setting 1 quinoline moiety are more active and less toxic than the corresponding compounds described in Danish Patent Applications Nos. 1266/71 and 83/72 and which are unsubstituted in 2-position in the quinoline moiety. Thus, it has been found that racemic 2 *, 7'-bis (trifluoromethyl) dihydrocinchonine, one of the products of Example 1, is about twice as active as an antimalarial agent and more than four times less toxic than 7'-trifluoromide thyldihydrocinchonin, one of the products of formula X in Danish Patent Application No. 1266/71 and mentioned in Example 1 of Danish Patent Application No. 83/72, and because of these particularly good pharmacological properties, a preferred embodiment of the process of the present invention is based. p &lt; 21,71-bis (trifluoromethyl) dihydrocinchonine is prepared.

The process according to the invention is further illustrated by the following examples:

Example 1.

Preparation of racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2', 7'-bis (trifluoromethyl) dihydrocinchonine.

To 500 ml of anhydrous ether is added 55 ml of a 1.6M solution of butyllithium in hexane. The resulting solution is cooled to -70 ° C and with stirring 30 g of 2,7-bis (trifluoromethyl) -4-bromoquinoline dissolved in 200 ml of anhydrous ether are added under atmosphere of nitrogen at a rate such that a temperature of Stirring of the solution containing 2,7-bis (trifluoromethyl) -4-quinolyllithium, which is formed, is continued at this temperature for 30 minutes, after which 15.17 g of racemic 4,5-erythro-amine are added. 5-ethylquinuclidine-2C - carboxaldehyde dissolved in 100 ml of anhydrous ether The reaction mixture is stirred at -70 ° C for an additional 3 1/2 hours, then the reaction is quenched with water diluted with 500 ml of ether and the mixture is allowed to warm to room temperature. ethereal solution is washed twice with water, dried over sodium sulfate and evaporated to dryness to give 44.4 g of crude product. Separation and purification are carried out by column chromatography (inner diameter 60 mm) on 2 kg of silica gel with chloroform-acetone. 5: 4: 1 triethylamine as a liquid phase D 150 ml fractions are collected and the progress of the chromatography is shown by thin layer chromatography on silica gel with the same solvent mixture. The combined fractions are evaporated to dryness. After an initially insoluble process of 2550 ml, the next 750 ml give 14.5 g of an oily solid (mainly unreacted starting materials) followed by 6.7 g of a mixture of 9-e-pi derivatives of racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonin (of 2.7 L). After empty fractions of a total of 2.4 liters, continued chromatography gives 4 g of a white solid of the next 4.1 liters. Recrystallization of ethanol yielded purified racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonine, mp 201-203 ° C.

Analysis:

Calcd for C 21 H 22 F 6 N 2 O: C 58.34, H 5.13, N 6.48, F 26.35 Found: C 58.51, H 5.05, N 6.44, F 26.58

After a further 1.2 liters containing a mixture of racemic 2 *, 7 * bis (trifluoromethyl) dihydrocinchonidine and racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonine, the last 7 liters of 6.8 g of an almost white are obtained solid. Recrystallization of ethanol gives 1.4 g of pure racemic 2 ', 7'-bis (trifluoromethyl) dihydrocinchonidine, mp 221 - 222 ° C.

Analysis:

Calcd for C 21 H 22 F 6 N 2 O: C 58.34, H 5.13, N 6.48, F 26.35 Found: C 58.36, H 5.02, N 6.52, F 26.29 2.7-Bis (trifluoromethyl) -4-bromoquinoline is prepared as follows: a) Preparation of 2,7-bis (trifluoromethyl) -4-quinolinol and 2,5-bis (trifluoromethyl) -4-quinolinol.

17 141700

To a solution of 60 g of ethyl ~ 4,4,4-trifluoroacetoacetate in 200 ml of polyphosphoric acid, preheated to 100 ° C, 52.7 g of 3-trifluoromethylaniline are added dropwise. After the addition, the mixture is heated to 140-150 ° C for 2 hours. After standing at room temperature overnight, the reaction mixture is poured into 1 liter of ice water with vigorous stirring. The precipitated substance is isolated by filtration and washed thoroughly with water. The dried substance is taken up in ether. Soluble constituents are removed by filtration and the filtrate is evaporated after drying over sodium sulfate to dryness under reduced pressure to give 62.7 g of a mixture of 2,7-bls (trifluoromethyl) -4-quinolinol and 2.5-bis (trifluotomethyl) - 4-quinolinol. Part of this material is recrystallized several times by ethanol to give 2.5-bis (trifluoromethyl) -4-quinolinol in the form of white needle crystals melting point 314 - 315 ° C.

Analysis:

Calcd for C C HH HFgNOs C 46.99, H 1.79, N 4.98, F 40.55 Found: C 47.19, H 1.70, N 5.05, F 40.66

The mother liquor from the crystallization of 2,5-bis (trifluoromethyl) -4-quinollanol is evaporated to dryness and part of the residue is sublimated at 150-160 ° C and a pressure of 0.1 mm Hg. The sublimate is recrystallized from acetone, whereby pure 2.7-bis (trifluoromethyl) -4-quinolinol is obtained, mp 184 - 185 ° C.

Analysis:

Calculated for C11H5F6N °: C 46.99, H 1.79, N 4.98, F 40.55 Found: C 47.03, H 2.00, N 5.05, F 40.56 b) Preparation of 2 , 7-bis (trifluoromethyl) -4-bromoquinoline and 2.5-bis (trifluoromethyl) -4-bromoquinoline.

To a slurry of 27 g of a mixture of 2,5-bis (trifluoromethyl) -4-quinolinol and 2,7-bis (trifluoromethyl) -4-quinolinol and 40 ml of phosphorus tribromide, preheated to 70 ° C, 27 ml of phosphorus oxy are added. bromide. The mixture is heated to 140 ° C for 4 hours. Then the mixture is cooled to room temperature, gently added to 2 liters of vigorously stirred crushed ice and adjusted to alkaline reaction by the addition of ION sodium hydroxide solution. The precipitate formed is separated from the aqueous phase and decanted. in dichloromethane. Insoluble constituents are removed by filtration. The filtrate is dried over sodium sulfate and evaporated to dryness under reduced pressure. Chromatograph the light brown solid residue (24.6 g) on 1 kg of silica gel with hexane / benzene in an 8: 2 ratio as eluent. Fractions of 200 ml and the progress of chromatography are shown by thin layer chromatography (silica gel, hexane / benzene (8: 2)). Fractions 6-17 are combined and after removal of the solvent 13.5 g of a white solid, 2.7 bis (trifluoromethyl) -4-bromoquinoline, mp 100-101 ° C.

Analysis:

Calcd for C11H4BrF6N: C 38.40 H 1.17 N 4.07 F 33.13

Found: C, 38.37; H, 1.10; N, 4.15; F, 33.05

After collecting 3 fractions containing a mixture of bromides, elution with 4 liters of solvent gives 7.7 g of a clear yellow oil which solidifies on standing. Crystallization of hexane gives pure 2,5-bis (trifluoromethyl) -4-bromoquinoline, mp 48-50 ° C.

Analysis:

Calculated for C C ^^H ^ BrFrFgH: C, 38.40; H, 1.17; N, 4.07; F, 33.13

Found: C, 38.43; H, 1.06; N, 4.11; F, 33.03

The racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehyde used as the starting material is prepared as follows:

Preparation of racemic 4,5-erythro-5-ethylquinuclidine-2-carboxaldehyde.

A solution containing 13.8 g of a mixture of isomeric 1,1-dichloro-3- [3-ethyl-4-piperidinyl] propan-2-ol hydrochlorides in 125 ml of water is poured into 1250 ml of benzene. The stirred mixture is cooled in an ice bath and 81 ml of a 1.85 N potassium hydroxide solution is slowly added. Stirring at room temperature is continued under a nitrogen atmosphere for 20 hours. The aqueous phase is separated and extracted with benzene. The combined organic phases are washed once with water, dried over sodium sulfate and evaporated under reduced pressure at 30 ° C. By distillation of the residue at a bath temperature of 80 ° C and a pressure of 0.1 mm Hg, 5.37 g of liquid racemic are obtained. , epimeric 4,5-erythro-5-ethylquinuclidine-2β-carboxaldehyde.

An analyzer sample of racemic epimeric 4,5-erythro-5-ethylquinoclidin-2C-carbonxaldehyde is prepared as follows: The residue obtained from reaction of 5.45 g of the propanol derivative with potassium hydroxide as above is dissolved in 100 ml of anhydrous ether . The solution is added to 2.5 g of sodium bisulfite in 8 ml of water. The solvents are removed under reduced pressure and the residue is dissolved in 10 ml of water. Upon addition of ethanol followed by addition of ether, 3.4 g of a solid addition product precipitates. This product is added to 50 ml of a saturated aqueous solution of sodium carbonate and heated to 40 ° C. After dissolving all the material, the solution is kept at 40 ° C for an additional 5 minutes. The mixture is cooled and extracted 3 times with ether. The combined ether extracts are dried over potassium carbonate and evaporated to dryness under reduced pressure to give 950 mg of liquid, racemic 4,5-erythro-5-ethylqui-nuclidine-2ξ-carboxaldehyde. By distillation at 60 - 85 ° C (oil bath temperature) under a pressure of 0.4 mm Hg, 648 mg of purified racemic 4,5-erythro-5-quinuclidine-2ξ-carboxaldehyde is obtained.

Analysis:

Calculated for C C ^HH NONO: C 71.81 H 10.25 N 8.38 Found: C 71.91 H 10.02 N 8.58

Example 2.

Preparation of racemic 8, -chloro-2, -trifluoromethyl dihydrocinchonin and racemic 8, -chloro-2'-trifluoromethyl dihydroquinone.

To 600 ml of anhydrous ether is added 87 ml of a 1.6M solution of butyllithium in hexane. The resulting solution is cooled to -70 ° C, 20 DEG C. and stirred with 39 g of 4-bromo-8-chloro-2-trifluoromethyl-quinoline dissolved in 200 ml of anhydrous ether under nitrogen atmosphere at a rate such that a temperature of -70 ° C is maintained. Stirring of the solution containing 8-chloro-2-trifluoromethyl-4-quinolyl-lithium is continued at this temperature for 30 minutes, after which 23.2 g of racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehyde dissolved in 100 ml are added. ml of anhydrous ether. The reaction mixture is stirred at -70 ° C overnight. The reaction is quenched with water and then diluted with 500 ml of ether and allowed to stand at room temperature. The ethereal solution is washed twice with water, dried over sodium sulfate and evaporated to dryness to give 52.5 g of a brown foamy material. The crude product is purified by column chromatography (inner diameter 60 mm) on silica gel. After the initial 5 liters (solvent: chloroform-acetone-triethylamine 7: 2ri), · the ratio is changed to 4: 5: 1 and 150 ml fractions are collected. The progress of chromatography is shown by thin-layer chromatography on silica gel with the same solvent mixture. The combined fractions are evaporated and the residue is dissolved in dichloromethane. The organic solution is washed with water. The aqueous phase is washed with dichloromethane and the combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure. After 17 no-fractions (2.5 liters), the next 750 ml give 7.9 g of a brown oil (mainly unreacted starting materials) followed by 20.3 g of a mixture of 9-epi derivatives of racemic 8'-chloro 2'-trifluoromethyl dihydrocinchonidine and racemic 8'-chloro-2'-trifluoromethyl dihydrocinchonine (of 2.25 L). After a further interval of contentless fractions totaling 5.5 liters, the next 6 liters of the above solvent and 4.5 liters of acetone-triethylamine in the ratio of 9: 1 elute 15.3 g of a mixture of racemic 8'-chloro 2'-trifluoromethyl-dihydrocinchonidine and racemic 8'-chloro-2'-trifluoromethyl dihydrocinchonine. Crystallization of benzene-petroleum ether gives 6.1 g of racemic 8'-chloro-2'-trifluoromethyl dihydrocinchonidine, mp 234 - 236 ° C after 2 recrystallizations of acetone.

Analysis:

Calcd for C 2 CH 22 Cl 1 F 3 N 2 O: C 60.20 H 5.56 N 7.01 F 14.29

Found: C 60.22 H 5.51 N 7.03 F 14.49 21 141700

Evaporation of the mother liquor gives 4.5 g of racemic 8'-chloro-2'-trifluoromethyl-dihydrocinchonine, mp 194 - 196 ° C after 2 recrystallizations of acetone.

Analysis:

Calcd. For C20.222.33.22: C 60.20 H 5.56 N 7.02 F 14.29 Found: C 60.24 H 5.50 N 7.03 F 14.52 4-Bromo -8-Chloro-2-trifluoromethylquinoline, which is used as starting material, is prepared as follows:

To a slurry of 35 g of 8-chloro-2-trifluoromethyl-4-quinolinol in 70 ml of phosphorus tribromide, which has already been heated to 70 ° C, is added 35 ml of phosphorus oxybromide. The reaction mixture is heated to 140 ° C for 4 hours with occasional manual stirring. The mixture is cooled to room temperature and gently added to 2 liters of vigorously stirred crushed ice. The aqueous suspension is adjusted to alkaline reaction by the addition of 10N sodium hydroxide solution and the temperature is kept down by the addition of more ice when needed. The precipitate is isolated by filtration and washed thoroughly with water. The air-dried filter cake (48 g) is sublimated at 100 ° C and a pressure of 0.5 mm Hg to give 40.2 g of white 4-bromo-8-chloro-2-trifluoromethylquinoline, which upon crystallization of ethanol gives the analyte 4-bromo-8-chloro-2-trifluoromethylquinoline, mp 62-64 ° C.

Analysis:

Calculated for C C ^H4BrClF3N: C 38.68 H 1.30 N 4.51 F 18.35 Found: C 38.53 H 1.23 N 4.60 F 18.06

Example 3

Preparation of racemic 7'-chloro-2'-trifluoromethyl dihydrocinchonidine and racemic 7'-chloro-2'-trifluoromethyl dihydrocinchonine.

141700 22

To 75 ml of anhydrous ether is added 12.5 ml of a 1.6M solution of butyllithium in hexane. The resulting solution is cooled to -70 ° C, and with stirring and under nitrogen atmosphere, 5.3 g of 4-bromo-7-chloro-2-trifluoromethylquinoline dissolved in 50 ml of anhydrous ether is added at a rate such that a temperature of -70 ° C is maintained. Stirring of the solution containing 7-chloro-2-trifluoromethyl-4-quinolyllithium is continued at this temperature for 30 minutes followed by the addition of 3.3 g of racemic 4,5-erythro-5-ethylquinuclidine - 2ξ-carboxaldehyde dissolved in 50 ml of anhydrous ether. The reaction mixture is stirred at -70 ° C for an additional 5 hours, after which it is hydrolyzed with water, diluted with 100 ml of ether and allowed to warm to room temperature.

The ethereal solution is washed twice with water, dried over sodium sulfate and evaporated to dryness to give 6.1 g of a yellow oil. This substance is poured onto a silica gel column (500 g silica gel, column diameter 20 mm) and first eluted with chloroform-acetone-triethylamine in a ratio of 5: 4: 1 (solvent A) (2.5 liters), followed by chloroform 4: 6: 1 acetone triethylamine. Fractions of 50 ml are collected and the progress of the chromatography is shown by thin layer chromatography on silica gel with solvent A as the liquid phase. The combined fractions are evaporated to dryness and the residue is dissolved in dichloromethane. The organic solution is washed with water, the aqueous phase is washed with dichloromethane and the combined organic solvents are dried over sodium sulfate and evaporated under reduced pressure. After a course of 750 ml, the next 300 ml give 1.9 g of a crude mixture of the 9-epi derivatives of racemic 7, -chloro-2 * -trifluoromethyl dihydro-cinchonidine and racemic 7'-chloro-2'-trifluoromethyl dihydrocinchonine. Fractions 29 - 44 give 0.5 g of racemic 1'-chloro-2'-trifluoromethyl dihydrocinchonine. With 2 recrystallisations of acetone, analytical racemic 7'-chloro-2'-trifluoromethyl dihydrocinchonine is obtained, m.p.

Analysis:

Calculated for C 20 H 22 ClF 3 N 3 O: C 60.22 H 5.56 N 7.04 F 14.29

Found: C 60.28 H 5.52 N 7.04 F 14.23 23 141700

With continued chromatography 1.2 g of racemic 7'-chloro-2'-trifluoromethyl dihydrocinchonidine are obtained from fractions 45-70. Crystallization of acetone followed by recrystallization of ether-petroleum * ether gives pure racemic 7-chloro-2-trifluoromethyl dihydrocinchonidine, mp 178-180 ° C.

Analysis:

Calc'd for 2020 2022 ^11 ^3N2O: C 60.22 H 5.56 N 7.02 F 14.29

Found: C 60.22 H 5.60 N 7.03 F 14.49 4- Bromo-7-chloro-2-trifluoromethyl-quinoline used as a starting material is prepared as follows: a) Preparation of 7- chloro-2-trifluoromethyl-4-quinolinol and 5-chloro-2-trifluoromethyl-4-quinolinol.

To a solution of 60 g of ethyl 4,4,4-trifluoroacetoacetate in 200 ml of polyphosphoric acid, which is already heated to 100 ° C, is added dropwise 42 g of 3-chloroaniline. After the addition, the mixture is stirred at 140-150 ° C for 2 hours. After standing at room temperature overnight, the reaction mixture is poured into 500 ml of ice water with vigorous stirring. The precipitate is isolated by filtration and washed thoroughly with water. To ensure dryness, filter cake is repeatedly suspended in ethanol - benzene, followed by removal of the solvent under reduced pressure. The dried crude product is extracted 3 times with 1 liter of hot ether each time. The extracts are combined and, after removal of the solvent, give 76 g of a mixture of 7-chloro-2-trifluoromethyl-4-quinolinol and 5-chloro-2-trifluoromethyl-4-quinolinol. Crystallization of this mixture of ethanol gives a pale yellow solid. Fractional crystallization of ethyl acetate gives 7-chloro-2-trifluoro-methyl-4-quinolinol in bundles of small white crystal needles, mp 310 - 312 ° C.

Analysis:

Calculated for C 10 H 5 ClF 3 NO: C 48.51 H 2.03 N 5.66 F 23.02

Found: C 48.51 H 2.03 N 5.66 F 23.02 24 141700

Evaporation of the mother liquor from the crystallization of 7-chloro-2-trifluoromethyl-4-quinolinol gives 5-chloro-2-trifluoromethyl-4-quinolinol in the form of colorless crystalline cubes, mp 242 - 244 ° C, after several recrystallizations from ethyl acetate.

Analysis:

Calcd for C 10 H 5 ClF 3 NO: C 48.51 H 2.03 N 5.66 F 23.02 Found: C 48.33 H 1.97 N 5.77 F 23.21 b) Preparation of 4-bromo-7-chloro 2-trifluoromethyl-quinoline and 4-b-rom-5-chloro-2-trifluoromethylquinoline.

To a slurry of 50 g of a mixture of 7-chloro-2-trifluoro-methyl-4-quinolinol and 5-chloro-2-trifluoromethyl-4-quinolinol in 100 ml of phosphorous tribromide, which has already been heated to 70 ° C, 50 ml of phosphorus oxybromide is added at once The mixture is heated to 140 ° C for 4 hours. The mixture is cooled to room temperature and gently added to 2 liters of vigorously stirred crushed ice. The aqueous suspension is adjusted to alkaline reaction by the addition of 10N sodium hydroxide solution, and the temperature is kept low by the addition of more ice when needed. The brown precipitate is isolated by filtration, washed thoroughly with water and air dried. By sublimation at 110 ° C and a pressure of 0.1 mm Hg, 50 g of a mixture of 4-bromo-7-chloro-2-trifluoro-methylquinoline and 4-bromo-5-chloro-2-trifluoromethylquinoline are obtained. The separation is carried out by chromatography on silica gel (1 kg, column inner diameter 60 mm) with 8: 2 hexane-benzene as the liquid phase. Fractions of 200 ml are collected and the progress of the chromatography is shown by thin layer chromatography (silica gel, hexane-benzene 8: 2). After a contentless run of 1.2 liters, the fractions 7 - 12 are combined and by removal of the solvent 13.1 g of 4-bromo-7-chloro-2-trifluoromethylquinoline are obtained, mp 68-70 ° C after recrystallization from ethanol.

After collecting 600 ml containing 7 g of a mixture of 4-bromo-7-chloro-2-trifluoromethylquinoline and 4-bromo-5-chloro-2-trifluoromethylquinoline, elution with 4.4 liters of 27.3 g of 4-bromo -5-chloro-2-trifluoromethylquinoline, m.p. 98-100 ° C after recrystallization from ethanol.

By analogy as described above, the compounds listed below can be prepared:

Rac.-5'-chloro-2'-trifluoromethyl-dihydrocinchonidine m.p. 175 DEG-176 DEG C., rac.-51-chloro-2'-trifluoromethyl-dihydrocinchonine; mp 192 - 193 ° C (dec.).

Example 4

Preparation of racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2', 8'-bis (trifluoromethyl) dihydrocinchonin.

To 200 ml of anhydrous ether is added 20 ml of a 1.6M solution of butyllithium in hexane. The resulting solution is cooled to -70 ° C and with stirring and under nitrogen atmosphere 11.0 g of 2,8-bis (trifluoromethyl) -4-bromoquinoline dissolved in 200 ml of anhydrous ether are added at a rate to maintain a low reaction temperature. Stirring is continued at -70 ° C for a further 15 minutes 1 followed by the addition of 5.35 g of racemic 4,5-erythro-5-ethyl-quinuclidine-2ξ-carboxaldehyde dissolved in 100 ml of anhydrous ether. The reaction mixture is stirred for an additional 1 1/2 hours, then quenched with 10 ml of water, diluted with 500 ml of ether and allowed to warm to room temperature. The ethereal solution is washed with 100 ml of water, dried over sodium sulfate and evaporated under reduced pressure to give 14.2 of an oil. The same reaction is carried out under identical conditions with 9.35 2,8-bis (trifluoromethyl) -4-bromoquinoline and 4.53 g of racemic 4,5-θΓγ ^ Γθ-5-β · ϋψ ^ ηίηησ1ΐάϊη-2ξ-03Λοχ3 ^ βϊ ^ to give 13 g of crude product. Both products are combined and chromatographed on 2 kg (column of 60 mm inner diameter) silica gel with chloroform-acetone-triethylamine in the ratio 5: 4: 1 as solvent. 125 ml fractions are collected. The progress of the chromatography is shown by thin layer chromatography on silica gel with the same solvent. The combined fractions are evaporated and the residue is dissolved in dichloromethane. The organic solution is washed with water, the aqueous phase is washed with dichloromethane and the combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure.

After an initially insoluble process of 1125 ml, the next 1250 ml gives 5.9 g of an orange oil (mainly unreacted starting materials) followed by 10.1 g of a yellow oil from 26 U1700 4.25 liters. Crystallization of this substance from ether gives 3 g of white powdery racemic 2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonine, m.p. 166-168 ° C.

Analysis:

Calcd. For C 21 H 22 F 6 N 2 O: C 58.34 H 5.13 N 6.48 F 26.35 Found: C 58.16 H 5.11 N 6.43 F 26.40

The mother liquor from the crystallization of racemic 2 *, 8'-bis (trifluoromethyl) - 9-epi-dihydrocinchonin is evaporated and the oily residue is dissolved in ethanolic hydrochloric acid and the solution is diluted with ether.

The precipitated oil crystallizes on standing to give 2.4 g of a white solid, mp 249 - 252 ° C. 0.2 g of this material is treated with 1 N sodium hydroxide solution and the free base is extracted into dichloromethane. The extract is dried over sodium sulfate and, by removing the solvent under reduced pressure, a yellow oil is obtained. Crystallization of benzene-petroleum ether (boiling range 30 - 60 ° C) gives 78 mg of racemic 2 ', 8'-bis (trifluoromethyl) - 9-epi-dihydrocinchonidine, mp 149-150 ° C.

Analysis:

Calculated for C 21 H 22 F 6 N 2 O: C 58.34 H 5.13 N 6.48 F 26.35

Found: C 58.30 H 5.03 N 6.49 F 26.30

Continuing the chromatography, a total of 6.2 liters of 4.3 g of a yellow oil from the next 11.9 liters is obtained after no-fraction fractions. The crude product, upon crystallization of chloroform, gives 2.2 g of a white solid, m.p. 208 - 210 ° C, which upon recrystallization of chloroform ether gives pure racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonine, m.p. after drying at 100 ° C for 20 hours in high vacuum.

Analysis:

Calcd for C21 ** 22F6 ^ 20: C 58.34 H 5.13 N 6.48 F 26.35

Found: C 58.21 H 5.13 N 6.34 F 26.41 27 141700

After a further 15.6 liters containing 1.2 g of a mixture of racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2', 8'-bis (trifluoromethyl) dihydrocinchonine give the last 12.5 liters 2.6 g of crude product. Crystallization of ether gives 1.9 g of a white solid, m.p. 217 - 219 ° C, which upon recrystallization of methanol gives pure racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine, m.p. 225-222 ° C.

Analysis:

Calc'd for 1 C 58.34 H 5.13 N 6.48 F 26.35 Found: C 58.09 H 5.06 N 6.45 F 26.22 2,8-Bis (trifluoromethyl) -4-bromoquinoline, used as a starting material are prepared as follows:

A suspension of 25.5 g of 2,8-bis (trifluoromethyl) -4-hydroxyquinoline in 50 ml of phosphorus tribromide is heated to 70 ° C. At once 70 g (25 ml) of phosphorus oxybromide is added. The temperature is raised to 140 ° C and the mixture is kept at this temperature for 4 hours. After cooling the mixture to room temperature, 1 liter of crushed ice is gently added with vigorous stirring. Additional ice is added when needed until the exothermic reaction has ceased. The solution is adjusted to an alkaline reaction by the addition of 12N sodium hydroxide solution and ice is added again to cool. The yellow solid precipitate is isolated by filtration and air dried overnight.

By sublimation at 50 ° C and a pressure of 0.2 mm Hg, 28.6 g (92% of theory) of 2,8-bis (trifluoromethyl) -4-bromoquinoline, m.p. 57-58 ° C, are obtained. 1 g of the sublimated material of 95% ethanol to give 0.7 g of analytical 2,8-bis (trifluoromethyl) -4-bromoquinoline, mp 59-60 ° C.

Analysis:

Calcd for C CH HBrFgN: C 38.40 H 1.17 N 4.07 F 33.13

Found: C 38.45 H 1.05 N 4.15 F 33.34 141700 28

Example 5

Preparation of the enantiomer of 2 ', 8'-bis (trifluoromethyl) di-hydrocinchonidine and the enantiomer of 2', 8'-bis (trifluoromethyl) dihydrocinchonine.

To 150 ml of anhydrous ether is added 27.5 ml of a 1.6M solution of butyllithium in hexane. This solution is poured at -70 ° C under a nitrogen atmosphere together with a solution of 15.5 g of 2,8-bis (trifluoromethyl) -4-bromoquinoline in 150 ml of anhydrous ether at such a rate that the low temperature is maintained. After the addition is complete, the mixture containing 2,8-bis (trifluoromethyl) -4-quinolyllithium is stirred for an additional 30 minutes. Then 7.1 g of epimeric 5 (S) -ethyl-4 (R) -quinuclidine-2? -Carboxaldehyde dissolved in 100 ml of anhydrous ether are added. After stirring overnight at -70 ° C, the reaction is quenched with water and diluted with 300 ml of ether. The ethereal solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue (19.6 g) is chromatographed on 2 kg of silica gel (column of 60 mm internal diameter) with chloroform-acetone-triethylamine in the ratio 5: 4: 1 as solvent. 150 ml fractions are collected. The progress of chromatography is shown by thin layer chromatography on silica gel with the same solvent.

ISLAND

The combined fractions are evaporated and the residue dissolved in dichloromethane. The organic solution is washed with water, the aqueous solution is washed with dichloromethane and the combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure. After a course of 4 liters containing substantially unreacted starting materials, fractions 27 - 45 give 8.4 g of a mixture of the enantiomers of 2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonidine and 2', 8'- bis (trifluoromethyl) -9-epi-dihydrocinchonin. Fractions 133 - 205, after working up, give 4.2 g of an oil which crystallizes on standing and after 2 recrystallisations of ether, the analyzed enantiomers of 2 ', 8'-bis (trifluoromethyl) dihydrocinchonine are obtained, m.p. 205-206 ° C. drying at 100 ° C overnight under reduced pressure; [α] D = -122.17 ° (c = 1.1757 in methanol).

Analysis:

Calcd for C 21 H 22 F 6 N 2 ° (3wt. 432.36): C 58.34 H 5.13 N 6.48 F 26.35

Found: C 58.32 H 5.06 N 6.53 F 26.24 141700 29

By continuing the chromatography with the solvent system changed to 7: 2: 1 chloroform-methanol-triethylamine, 2.8 g of a yellow solid can be isolated from fractions 216-260.

Upon 2 recrystallizations of this material of ether, the analyzed enantiomers of 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine are obtained, m.p. 229 - 230 ° C after drying at 100 ° C overnight under reduced pressure # [ct] + = +57.06 "(c = 1.020 in methanol).

Analysis:

Calcd for C 21 H 22 F 6 N 2 ° (sewer guard 432.36): C 58.34 H 5.13 N 6.48 F 26.35 Found: C 58.03 H 4.89 N 6.39 F 26.49

The epimers 5 (5) -θϋ ^ 1-4 (Η) -φΐ1ηηο11 {ϊ1η-2ξ-θ3Γΐ3θΧ3 ^ β1 ^ άβ som, which are used as starting material, are prepared as follows:

A solution containing 1.34 gl, 1-dichloro-3- [3 (S) -ethyl-4 (R) -piperidinyl] propan-2 (S) -ol hydrochloride in 10 ml of water is poured into 150 ml of benzene . The stirred mixture is cooled in an ice bath and slowly added 8.7 ml of 1.68N potassium hydroxide solution. Stirring at room temperature is continued under a nitrogen atmosphere for 20 hours.

The aqueous phase is isolated and extracted with benzene. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure at 30 ° C. By distillation of the residue, 500 mg of liquid epimers 5 (S) -ethyl-4 (R) ^ υ1ηησϋά1η-2ξ-ο3Λοχ3 90 ° C at 0.1 mm Hg; [α] 20 D -85.56 "(c = 1.0682 in methanol).

Analysis:

Calculated for C C ^H ^^ NONO: C 71.81 H 10.25 N 8.38 Found: C 71.55 H 10.29 N 8.65

Example 6

Preparation of 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and 2', 8'-bis (trifluoromethyl) dihydrocinchonin.

65 ml of a 1.6M solution of n-butyllithium in hexane dissolved in 250 ml of anhydrous ether and 35.7 g of 2,8-bis (trifluoromethyl) -4-bromo guinoline dissolved in 150 ml of anhydrous ether are combined under stirring under a nitrogen atmosphere. at such a rate that a temperature of -70 ° C is maintained. After completion of the addition, stirring of the mixture containing 2,8-bis (trifluoromethyl) -4-quinolyllithium is continued for an additional 30 minutes, after which 17 g of epimer 5 (R) -ethyl-4 (S) -quinuclidine-2ξ-carboxaldehydes dissolved are added. in 150 ml of anhydrous ether. The reaction mixture is stirred overnight at -70 ° C, quenched with water and diluted with 500 ml of ether. After warming to room temperature, the ethereal solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue (52.3 g) is chromatographed on 2 kg of silica gel (Merck 60, inner diameter of the column 60 mm) with chloroform-acetone-triethylamine in the ratio 5: 4: 1 as the solvent. 150 ml fractions are collected. The progress of chromatography is shown by thin layer chromatography on silica gel with the same solvent. The combined fractions are evaporated and the residue is dissolved in dichloromethane. The organic solution is washed with water, the aqueous phase is washed with dichloromethane and the combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure.

After a contentless run of 2.1 liters, the next 7 fractions give 8.3 g of unreacted quinoline followed by the next 17 fractions of 22.3 g of an oil consisting mainly of unreacted aldehyde, 2 ', 8'-bis (trifluoromethyl). -9-epi-dihydrocinchonidine and 2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonin. Fractions 128 - 202 give 14.3 g of a white solid which, after two recrystallizations of ether-petroelum ether (boiling range 30 - 60 ° C), yields pure 2 ', 8'-bis (trifluoromethyl) dihydrocinchonine, mp 205-206 ° C after 25 drying at 100r-C overnight under reduced pressure; aD = +124.38 "(c = 1.008 in methanol).

Analysis:

Calc'd for C 21 H 22 F 6 N 2 O (m = 432.36) C 58.34 H 5.13 N 6.48 F 26.35 Found: C 58.15 H 5.21 N 6.47 F 26.43 31 U1700 1, 1 g of a mixture of 2 ', 8' bis (trifluoromethyl) dihydrocinchonin and 2 ', 8' bis (trifluoromethyl) dihydrocinchonidine are obtained. from Fractions 203 - 219.

After changing the solvent system after fraction 210 to chloroform-methanol-triethylamine in a ratio of 7: 2: 1, fractions 220-280 give 5.3 g of a white solid. Two recrystallisations of ether-petroleum ether (boiling range 30 - 60 ° C) give 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine in the form of white crystals, mp 229 - 230 ° C, drying at 100 ° C overnight. reduced pressure; [α] D = -57.06 ° (c = 1.076 in methanol).

Analysis:

Calcd. For C 21 H 22 F 6 N 2 ° imolv® 9t 432.36): C 58.34 H 5.13 N 6.48 F 26.35 Found: C 58.16 H 5.20 N 6.46 F 26.27

The epimers 5 (R) -ethyl-4 (S) -quinuclidine-2g-carboxaldehydes, used together as starting material, are prepared as follows: a) A solution containing 1.14 g / l, 1-dichloro-3- [3 (R) ) -ethyl- -4 (S) -piperidinyl] propan-2 (S) -ol hydrochloride in 20 ml of water is added to 450 ml of benzene. The stirred mixture is cooled in an ice bath and 7.4 ml of a 1.68N potassium hydroxide solution is slowly added. Stirring at room temperature is continued under a nitrogen atmosphere for 20 hours. The aqueous phase is separated and extracted with benzene. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure at 30 ° C. The residue gives by distillation at 80 ° C and a pressure of 0.1 mm Hg 283 mg of liquid epimer 5 (R) -ethyl-4 (S) -quinuclidine-2--carboxaldehyde.

Analysis:

Calculated for C C ^H ^^ NONO: C 71.81 H 10.25 N 8.38 Found: C 71.75 H 9.97 N 8.44 b) Using the procedure described above, 32 1 * 1700 gives a mixture of 1.94 g of 1,1-dichloro-3- [3 (R ) -ethyl-4 (S) -piperidinyl] propan-2 (R) -ol hydrochloride after distillation at 80 C and a pressure of 0.3 mm Hg 538 mg of epimer 5 (R) -ethyl-4 (S ) -quinuclidine - 2C-carboxaldehydes: [α] 25 D +102.61 (c = 1.168 in methanol).

Example 7

Preparation of 2 *, 8'-bis (trifluoromethyl) cinchonidine and 2 ', 8'-bis (trifluoromethyl) cinchonin.

To 150 ml of anhydrous ether, 17.6 ml of a 2.04M solution of n-butyllithium in hexane is added. The resulting solution is cooled to -70 ° C and with stirring and under nitrogen atmosphere 12.7 g of 2,8-bis (trifluoromethyl) -4-bromoquinoline dissolved in 150 ml of anhydrous ether are added at a rate such that a temperature of -70 ° C is maintained. Stirring of the solution containing 2,8-bis (trifluoromethyl) -4-quinolinyl lithium is continued at this temperature for 30 minutes, after which 5.6 g of epimer 5 (R) -vinyl-4 (S) -qui-nuclidine is added dropwise. -2 L -carboxaldehydes dissolved in 50 ml of anhydrous ether. The reaction mixture is stirred at -70 ° C overnight, hydrolyzed with water and allowed to warm to room temperature. The ethereal solution is washed twice with water, dried over sodium sulfate and evaporated to dryness to give 17.6 g of crude material. This residue is chromatographed on 2 kg of silica gel (Merck 60) with chloroform-acetone-triethylamine in the ratio of 5: 4: 1 as solvent. 150 ml fractions are collected. The progress of chromatography is shown by thin-layer chromatography on silica gel with the same solvent. The combined fractions are evaporated and the residue is dissolved in dichloromethane. The organic solution is washed with water, the aqueous phase is washed with dichloromethane and the combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure. After a course of 2.7 liters containing substantially unreacted starting materials, the next 1.8 liters elute 6.8 g of a crude mixture of 2 ', 8'-bis (trifluoromethyl) -9-epicinchonin and 2', 8'-bis (trifluoromethyl) -9-epi-cinchonidine. Fractions 73 - 120 give, after working up, 1.7 g of a yellow solid. With two recrystallizations of ether-petroleum ether (boiling range 30 - 60 ° C), the crude 2 ', 8'-bis (trifluoromethyl) cinchonin is obtained, m.p. 199-200 ° C, after drying at 100 ° C overnight under reduced pressure; [α] p 5 = + 136.19 ° (c = 1.1308 in methanol).

141700 33

Analysis:

Calcd for C 21 H 20 F 6 N 2 ° (mol. Weight 430.39): C 58.61 H 4.68 N 6.51 F 26.48 Found: C 58.73 H 4.87 N 6.55 F 26.41

Continued chromatography with the solvent system change to chloroform-methanol-triethylamine in a ratio of 7: 2: 1 results in the isolation of 2.1 g of a white solid from fractions 121 - 175. After two recrystallisations of ether, analyte 2 ', 8 is obtained. bis (trifluoromethyl) cinchonidine, mp 225-222 ° C after drying for 20 hours, is at 100 ° C under reduced pressure; [α] β * -67.79 * (c * 1.1137 in methanol).

Analysis:

Calc'd for C 21 H 20 F 6 N 2 ° 430/39) C 58.61 H 4.68 N 6.51 F 26.48 Found: C 58.73 H 4.84 N 6.44 F 26.61.

The epimers 5 (Κ) -ν1ηγ1-4 (3) -ςρι1ηησϋΰ1η-2ξ-α0 £ Γΐ3θχη3 £ βΙιγύθΓ used as starting material are prepared as follows:

A solution containing 2.36 g of a mixture of 1,1-dichloro-3 - [3 (R) -vinyl-4 (S) -piperidinyl] propane-2 (S) -ol hydrochloride and 1.1- dichloro-3- [3 (R) -vinyl-4 (S) -piperidinyl] propan-2 (R) -ol hydrochloride in 35 ml of water is added to 850 ml of benzene. The stirred mixture is cooled in an ice bath and 15.4 g of 1.6βΝ potassium hydroxide solution are slowly added under a nitrogen atmosphere. Stirring at room temperature is continued for 16 hours. The aqueous phase is separated and extracted with benzene. The combined organic phases are washed with water, dried over sodium sulfate and evaporated under reduced pressure at 30 ° C. Distillation of the residue gives 767 mg of liquid epimeric 5 (R) -vinyl-4 (S) -quinuclidine-2β-carboxaldehydes at boiling point 60 ° C at 0.05 rom Hg; = + 154.85 * (c = 0.8957 in chloroform).

141700 34

Example 8.

Preparation of racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2', 8'-bis (trifluoromethyl) dihydrocinchonin.

A mixture of racemic 2 ', 8'-bis (trifluoromethyl) -dihydrocin-chonidinone and racemic 2', 8'-bis (trifluoromethyl) -dihydrocin-quininone is dissolved in 100 ml of anhydrous toluene and added to the ice-cold solution. over 1 hour 16.5 ml of a 1.5M solution of diisobutylaluminum hydride in toluene under a dry nitrogen atmosphere. The reaction mixture is stirred for 1 hour at room temperature, then quenched by the addition of 10 ml of water-methanol in a 1: 1 ratio. The precipitate is isolated by filtration through Celite as a filter aid.

The clear solution is washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product (11 g) is purified by column chromatography ring on silica gel (300 g.- Merck 60). After an initially insoluble process of 1.4 liters (solvent: benzene), the solvent is changed to benzene-methanol in a ratio of 1: 1 and fractions of 200 ml are collected. Fractions 5-13 are combined and by evaporation 2.2 g of an oil is obtained. Crystallization of ether-benzene gives 1.8 g of a mixture of racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and racemic 2', 8'-bis (trifluoromethyl) dihydrocinchonine. Chromatography on silica gel with chloroform-acetone-triethylamine in the ratio of 5: 4: 1 as a solvent gives racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine, mp 225-2260C after recrystallization from methanol and racemic 2', 8 ' - bis (trifluoromethyl) dihydrocinchonin, mp 113 - 115 ° C after recrystallization from cholroform ether.

The racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidinone and the racemic 2', 8'-bis (trifluoromethyl) dihydrocinchoninone used as starting material are prepared as follows: a) Preparation of racemic ethyl 4,5-erythro -5-ethyl-quinuclidine - 2C-carboxylate.

35 U17D0

To a solution of 8.3 g of isomeric erythro-1,1-dichloro-3- (3-ethyl-4-piperidinyl) propane / o-hydrochloride in 600 ml of methanol, cooled to 0 ° C, is added dropwise under stirring a solution of 5.04 g of potassium hydroxide in 23.4 ml of methanol. Upon completion of addition, the mixture temperature is allowed to rise to room temperature and stirring is continued overnight. Insoluble material is removed by filtration and the solution is added to a mixture of 11.7 g of silver nitrate and 4.8 g of sodium hydroxide in 200 ml of water. The reaction mixture is filtered after stirring for 3 hours at room temperature through Celite filter aid and the filtrate is saturated with hydrogen sulfide. The precipitate is removed by filtration through Celite filter aid and the filtrate is evaporated to dryness. Complete dryness is obtained by adding an ethanol-benzene-solvent mixture to the residue, followed by removal of the solvents under reduced pressure. This procedure is repeated three times. The residue is treated with 500 ml of ethanol and the mixture is refluxed for 3 hours. After filtration through Celite filter aid, the filtrate is saturated with anhydrous hydrogen chloride and boiled to reflux overnight. The precipitate is removed by filtration and the filtrate is evaporated to dryness. The obtained yellow oil is treated with 300 ml of a saturated aqueous solution of sodium carbonate and extracted five times with ether. The combined ether extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is distilled at 70-75 ° C (oil bath) under a pressure of 0.3 mm Hg to give 3.81 g (60% of theory) of liquid racemic β ^ γ1-4,5-βΓγ ^ Γθ-5 -β! Ιιγ1 <| α1ηιΚϊ11ά1η-2ξ-03Γΐχ ^ -lat. For analysis purposes, a sample is redistributed at 101 ° C and 0.5 mm Hg.

Analysis:

Calcd for C12 H21 NO2: C 68.21 H 10.02 N 6.63 Found: C 68.19 H 9.84 N 6.88

Gas phase chromatography shows that the material consists of two isomers in a ratio of 1: 1. Separation of the two isomers is obtained by preparative gas phase chromatography.

b) A solution of 18.1 ml of n-butyllithium (1.6M in hexane) in 150 ml of anhydrous ether is cooled to -70 ° C. With stirring and under a nitrogen atmosphere, 10 g of 2,8-bis (trifluoro-methyl) -4-bromoquinoline dissolved in 100 ml of anhydrous ether are added over 30 minutes. Then a solution of 6.15 g of racemic ethyl 4,5-erythro-5-ethylquinuclidine-2ξ-carboxylate in 100 ml of anhydrous ether is slowly added to the mixture containing 2,8-bis (trifluoromethyl) -4-quinolyllithium. After the addition is complete, stirring is continued for 3 hours at -70 ° C. The reaction is quenched by the addition of water and the mixture is allowed 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 16.1 g of a mixture containing racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidinone and racemic 2', 8 'bis (trifluoromethyl) di-hydrocinchoninon. This material is purified by chromatography on silica gel with benzene-ethyl acetate in a 1: 1 ratio as solvent. The progress of the chromatography is shown by thin layer chromatography on silica gel with the same solvent mixture. Fractions containing the desired material are combined and evaporated to dryness. The residue is treated with ethanolic hydrogen chloride and the resulting solid is recrystallized first by benzene ether and then by acetone ether to give an epimeric mixture of racemic 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidinone hydrocholide and racemic 2', 8 -bis (trifluoromethyl) dihydrocinchoninone hydrocholide in the form of white crystals, mp 245 - 247 ° C after drying at 100 ° C for 20 hours under reduced pressure.

Analysis:

Calcd for C2-LH2gFgN2O.5H2O.HCl C 53.01 H 4.66 N 5.89 F 23.95 Found: C 53.03 H 4.41 N 5.92 F 23.42.

Example 9

By analogy as described in Example 8, the compounds listed below can be prepared: rac-2 ', 7'-bis (trifluoromethyl) dihydrocinchonidine; m.p. 221 - 222 ° C, rac-2 ', 7'-bis (trifluoromethyl) dihydrocinchonine; mp 201-203 ° C, rac-81-chloro-21-trifluoromethyl-dihydrocinchonidine; mp 234 - 236 ° C, rac-81-chloro-21-trifluoromethyl-dihydrocinchonine; mp 194 - 196 ° C, 37 141700 rac.-7'-chloro-2'-trifluoromethyl-dihydrocinchonidine; m.p. 178-180 ° C, rac-7'chloro-21-trifluoromethyl-dihydrocinchonin; m.p. 203-205 ° C, rac.-5'-chloro-2'-trifluoromethyl-dihydrocinchonidine; mp 175-176 ° C 5-Chloro-2'-trifluoromethyl-dihydrocinchonine; m.p. 193 ° C, rac-2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonidine; mp 149-150 ° C, rac-2 ', 8'-b is (trifluoromethyl) -9-epi-dihydrocinchonin; mp 166 - 168 "C, the enantiomer of 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine; mp 229 - 230" C, the enentiomer of 2', 8'-bis (trifluoromethyl) dihydrocinchonin; m.p. 205 - 206aC, 2 ", 81-bis (trifluoromethyl) dihydrocinchonidine; m.p. ) Cinchonidine; m.p. 225 DEG-226 DEG C., and 2 ', 8'-bis (trifluoromethyl) cinchonine;

Example 10.

Preparation of 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine and 2', 8'-bis (trifluoromethyl) dihydrocinchonin.

The reaction is carried out in a 3-neck flask connected to a glass burette and provided with a gas discharge tube, an Erlenmeyer flask connected by a piece of rubber hose and a magnetic stirrer.

A solution of a mixture of 2 ', 8'-bis (trifluoromethyl) oxydihydrocinchonidine and 2', 8'-bis (trifluoromethyl) -desoxydihydrocinchonine in forty parts of anhydrous dimethylsulfoxide-tert.butanol in a ratio of 4: 1 is first stirred under an atmosphere of dry oxygen at 20 ° C for several minutes, then at once add a 50% excess of solid 1417αθ 38 potassium tert.butoxide. The resulting reddish solution is stirred and the uptake of oxygen is ground. After consumption of 1.1 1.2 equivalents of oxygen are quenched by the addition of a small amount of water and the pH is adjusted to about 7 by the addition of acetic acid, the reaction mixture is evaporated to dryness under reduced pressure and the residue is taken up in ten parts of dichloromethane. three times with each one part 7.5% sodium bicarbonate solution and water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product is chromatographed on silica gel with chloroform-acetone-triethylamine. in the ratio 5: 4: 1 as the solvent to give 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine, m.p. 229-230 ° C after recrystallization of ether and 2', 8'-bis (trifluoromethyl) dihydrocinchonine, m.p. - 206 ° C after ether recrystallization.

The 2 ', 8'-Bis (trifluoromethyl) desoxydihydrocinchonidine and the 2', 8'-bis (trifluoromethyldesoxydihydrocinchonin used as starting materials are prepared as follows: a) Preparation of 2,8-bis (trifluoromethyl) lepidine.

To a mixture of 51 g of 1,1,1-trifluoro-2,4-pentanedione in 200 ml of polyphosphoric acid, previously heated to 80 ° C, is added dropwise 54 g of 2-trifluoromethylaniline. After completion of the addition, the reaction mixture is stirred at 120 ° C for 10 hours, then left at room temperature for a further 10 hours. The mixture is then poured into 1 liter of water with vigorous stirring. The aqueous mixture is extracted with dichloromethane, the combined organic extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 54.6 g of a dark oil. This substance is purified by two successive column chromatographs on silica gel (2 kg silica gel each time; Merck 60) with benzene as the solvent in the first and hexane-benzene in the ratio of 8: 2 in the second. During the last chromatography, fractions of 500 ml are collected. After a contentless run of 6 liters, the next 6 liters after evaporation give 24 g of a light yellow solid. By recrystallization of absolute ethanol and then of petroleum ether (boiling range 30 - 60 ° C), analytical 2.8-bis (trifluoromethyl) lepidine with melting point 94 - 96 ° C is obtained after drying at room temperature for 20 hours under reduced pressure.

b) Preparation of 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl] -2-oxopropyl) quinoline.

141700 39

To twenty equivalents of n-butyllithium in hexane (about 1.6M), at -70 ° C, under a nitrogen atmosphere, a 20% excess of dilsopropylamine is added.

To the lithium diisopropylamide thus prepared, a solution of eighteen equivalents of 2 ', 8,8-bis (trifluoromethyl) lepidine in anhydrous tetrahydrofuran (1: 4) is added over 30 minutes with stirring.

The brownish mixture containing 2 ', 8'-bis (trifluoromethyl) lepidyl-lithium is stirred at -70 ° C for an additional 30 minutes, after which ten equivalents of methyl-3 (R) -ethyl 1-4 are added dropwise over 30 minutes. S) -piperidine acetate dissolved in an eight-fold volume of anhydrous tetrahydrofuran. Stirring is continued for 2 hours at -70 ° C and then at -25 ° C for 3 hours. Acetic acid is added to adjust the pH of the solution to 6, followed by the addition of 5 g of potassium hydrogen carbonate. After standing overnight, the mixture is filtered and the solid washed thoroughly with methanol. The filtrate is evaporated and the chloroform solution of the residue is washed successively with equal amounts of 3N potassium hydroxide solution and water. The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product can be purified by chromatography on silica gel with chloroform-methanol-ammonium hydroxide in the ratio of 89: 10: 1 as solvent mixture to give 2.8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl) 4 (S) -piperidyl] -2 - oxopropyl) quinoline.

c) Preparation of an Epimer Mix of 2,8-Bis (Trifluoromethyl) -4- (3-- [3 (R) -ethyl-4 (S) -piperidyl] -2ξ-1β ΓθχγρΓοργ1) ςριίηό11ηθΓ.

To an ice-cold solution of 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl] -2-oxopropyl) quinoline in 30 parts of 95% ethanol is added. a 10% excess sodium borohydride. After stirring for 2 hours at room temperature, an additional 0.3 equivalents of sodium borohydride is added and stirring is continued for 1 hour. Excess amount of reducing agent is decomposed by the addition of acetic acid. The mixture is diluted with 15 parts of water and adjusted to basic reaction by adding concentrated ammonia water. The ethanol is removed by distillation under reduced pressure and the pH of the solution is adjusted to 11 by the addition of 3N potassium hydroxide solution. The aqueous mixture is then extracted three times with chloroform. The combined organic extract is washed with water, dried over sodium sulfate and evaporated to give an epimeric mixture of 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl]) 2C-hydroxypropyl) quinolines.

d) Preparation of an epimeric mixture of 2,8-bis (trifluoromethyl) -4- (3 - [3 (R) -ethyl-4 (S) -piperidyl] -2C-acetoxypropyl) quinolines.

40 U, 70 °

For the solution of an epimeric mixture of 2,8-bis (trifluoromethyl) -4- (3-- [3 (Ε) -β ^ γ1-4 (3) -ρχρβΓΪάγ1] -2ξ-1ιγ <1:!: Οχγρ: ι : οργ1 ^ ηΐηο1χηβΓ (in part) in 40 parts of glacial acetic acid are added 4 parts of boron trifluoride etherate, the homogeneous reaction mixture is kept at 50 ° C for 17 hours, the solvent is evaporated under reduced pressure and 15 parts of ice are added to the residue. in the mixture is adjusted to 8 by the addition of concentrated ammonia water and the mixture is extracted three times with dichloromethane.

The combined extract is dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude epimeric mixture of 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl]) -2? -acetoxypro-PY1) quinolines.

e) Preparation of 2 ', 8'-bis (trifluoromethyl) desoxydihydrocinchonidine and 2', 8'-bis (trifluoromethyl) desoxydihydrocinchonin.

The mixture of 1 part crude epimer 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl] -25-acetoxypropyl) quinolines, 3 parts glacial acetic acid and 10 parts sodium acetate -Trihydrate in 65 parts of benzene is refluxed under nitrogen atmosphere for 16 hours. Add 40 parts of ice to the cooled mixture. After adjusting the pH to 8 by adding concentrated ammonia water, the aqueous phase is separated and extracted three times with methylene chloride. The extracts are combined with the benzene phase and washed with water, dried and evaporated to dryness under reduced pressure. The residue is then purified by column chromatography on silica gel (1:40) with chloroform-triethylamine in 9: 1 as solvent mixture to give a mixture of 2 ', 8'-bis (trifluoromethyl) desoxydihydrocinchonidine and 2', 8 ' bis (trifluoromethyl) deoxide ihydrocinchonin.

Example 11.

By analogy as described in Example 10, the compounds listed below can be prepared: 2 ', 8'-bis (trifluoromethyl) cinchonidine; mp 225 - 226 ° C, 2 ', 8'-bis (trifluoromethyl) cinchonine; mp 199 - 200 ° C, rac. 2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine; 4i 141700 Melting point 225 - 226 * 0 / rac. 2 ', 8'-bis (trifluoromethyl) dihydrocinchoninj melting point 213 - 215'C, rac. 2', 7 * -bis (trifluoromethyl) dihydrocinchonidine * mp 221 - 222 * 0 / rac.-2 ', 7'-bis (trifluoromethyl) dihydrocinchonine melting point 201-203 * 0, rac.-8'-chloro-2'-trifluoromethyl-dihydrochonchonidine melting point 234-236 ° C chloro-2'-trifluoromethyl-dihydrocinchonine melting point 194 - 196 * 0, rac.-7'-chloro-2 * -trifluoromethyl-dihydrocinchonidine m.p. 203 - 205 * C / the enantiomer of 2 '»e'-bis trifluoromethyl dihydrocinchonidia» mp 229 - 230 * 0, the enantiomer of 2', 8'-bis (trifluoromethyl) dihydrocinchoninj melting point 205 - 206 * 0, rac. , 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonidine melting point 149-150 ° C, and rac-2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinohoninj melting point 166-168 ° C.

Example 12.

Preparation of 2 ', 8'-bis (trifluoromethyl) dihydrooinchonldine and 2', 8 'bis (trifluoromethyl dihydrooinchonine).

A solution of 1 part diastereomeric 2,8-bis (triffluoromethyl) -4- (3 - [3 (R) -ethyl-4 (S5-piperidyl) -U, 2C-oxapropyl) quinolines in ISO parts toluene and 6 parts Ethanol is heated under gentle reflux for 24 hours. The solvent is evaporated and the residue is absorbed in silica gel. By elution with chloroform-acetone-triethylamine in the ratio 51411, first a mixture of 2'-e'-bieitrifluoromethyl-S-epi-dihydro- drocinchonine and 21,8'-bis (trifluoromethyl) -9-epi-dihydreeinohonidine and then 2 '/ e'-blsitrifluoromethyl dihydroolnohonine, m.p. 205-206'c after recrystallization of ether-petroleum ether (boiling range 30 - 60 * 0 with ehloroform-methanel-triethylamine in the ratio of 7122 ffis 2 '# 8'-bis (trifluoromethyl) dihydrocinchonidine, m.p.

42 1417 00

The diastereomeric 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (s) -piperidyl] -1ξ, 2ξ-οΓηρΓοργ1) quinolines used as starting materials are prepared as follows. : a) Preparation of epimeric 2,8-bis (trifluoromethyl) -4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -2-oxopropyl) quinolines.

To an equivalent of lithium diisopropylamide (prepared in a dry nitrogen atmosphere by adding a 10% excess diisopropylamine in 1 part toluene to a solution of an equivalent of a 2.4M solution of n-butyllithium in hexane at -70 "C) is added dropwise over 10 minutes with stirring a solution of a 10% excess of 2,8-bis (trifluoromethyl) lepidine in 12 parts of tetrahydrofuran. The mixture is stirred at -70 ° C for 30 minutes, after which a solution of 0.5 equivalents of N-benzoylcincholoipon ethyl ester in 15 parts of tetrahydrofuran is added dropwise over 10 minutes.

After further stirring for 30 minutes at -70 ° C, the cooling bath is removed and stirring is continued for another 30 minutes. Water is added and the aqueous phase is neutralized by the addition of acetic acid and exhaustively extracted with ether. The organic solution is washed with water, dried and evaporated under reduced pressure. After purification by chromatography on neutral alumina with activity step II, the residue gives 2,8-bis (trifluoromethyl) -4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -2 oxopropyl) quinoline.

b) Preparation of epimeric 2,8-bis (trifluoromethyl) -4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -1-bromo-2-oxopropyl) quinolines.

To a solution of 1 part 2,8-bis (trifluoromethyl) -4- (3- [i-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -2-oxopropyl) quinoline in 100 parts dry carbon tetrachloride in a Pyrex flask is added a 50% excess of solid N-bromosuccinimide and a catalytic amount of dibenzoyl peroxide. The mixture is then irradiated by means of a 250-watt iR heat lamp with stirring. After irradiation for 90 minutes, the refluxing mixture is cooled and filtered, the filter cake is washed with carbon tetrachloride and the combined filtrates are evaporated to dryness to give a crude mixture of 2,8-bis (trifluoromethyl) epimers - 4 (3- [1-Benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -Ιξ-bromo-2-oxopropyl) quinolines.

c) Preparation of diastereomeric 2,8-bis (trifluoromethyl) -4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -1ξ, 2ξ-oxapropyl) quinolines.

141700 43

To a solution of 1 part of the crude epimers 2,8-bis (trifluoromethyl) - 4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -15-bromo-2 (oxopropyl) quinolines in 100 parts of methanol are added an excess of sodium borohydride. The solution is stirred at room temperature for 30 minutes, 15 parts of water are added and stirring is continued for an additional 12 hours. The methanol is evaporated and the aqueous residue is extracted exhaustively with dichloromethane. The combined organic extract is washed with water, dried and evaporated under reduced pressure. After purification by chromatography on neutral alumina, activity step II, the residue gives a mixture of the diastereomeric 2,8-bis (trifluoromethyl) -4- (3- [1-benzoyl-3 (R) -ethyl-4 (S) - piperidyl] -1ξ, 2ξ-oxapropyl) quinolines.

d) Preparation of diastereomeric 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -ethyl-4 (S) -piperidyl] -1ξ, 2C-oxapropyl) quinolines.

To a stirred solution of 1 part diastereomeric 2,8-bis (trifluoromethyl) -4- (3 - [1-benzoyl-3 (R) -ethyl-4 (S) -piperidyl] -1ξ, 2ξ-χβ-propylquinolines in 100 parts of dry toluene under nitrogen atmosphere at -70 ° C is added a 50% excess of an approximately 1.5M solution of diisobutylaluminum hydride in toluene, stirring is continued at this low temperature for 45 minutes, then 5 parts are added. 1: 1 methanol-water and the mixture is stirred at 20 ° C for 90 minutes. The precipitate is isolated by filtration and washed with methanol, and the combined filtrates are concentrated under reduced pressure. The crude product is purified by chromatography on silica gel to give a mixture of the diastereomeric 2,8-bis (trifluoromethyl) -4- (3- [3 (R) -4 (S) -piperidyl] -1,2,25-oxapropyl) quinolines.

Example 13

By analogy as described in Example 12, the following compounds are prepared: 2 ', 8'-bis (trifluoromethyl) cinchonidine; mp 225 - 226 ° C, 2 ', 8'-bis (trifluoromethyl) cinchonine? m.p. 199 - 200 ° C, rac-2 ', 8'-bis (trifluoromethyl) dihydrocinchonidine * mp 225 - 226eC, rac-2', 8'-bis (trifluoromethyl) dihydrocinchonin

Claims (2)

44 141700 mp 213 - 215 ° C, rac. - 2 ', 8'-bis (trifluoromethyl) -9-epi-dihydrocinchonidine; mp 149-150 ° C, rac-2 ', 8 * -bis (trifluoromethyl) -9-epi-dihydrocinchonine; m.p. 166 - 168 ° C, rac-2 ', 71-bis (trifluoromethyl) dihydrocinchonidine; m.p. 221 - 222 ° C, rac-2 ', 1'-bis (trifluoromethyl) dihydrocinchonin; mp 201-220 ° C, rac-7r-chloro-2'-trifluoromethyl dihydrocinchonidine; m.p. 178-180 ° C, rac-7'-chloro-21-trifluoromethyl dihydrocinchonine; m.p. 203-205 ° C, rac.-8'-chloro-2'-trifluoromethyl dihydrocinchonidine; -chloro-2'-trifluoromethyl dihydrocinchonine; m.p. 194 - 196 ° C, the enantiomer of 2 ', 81-bis (trifluoromethyl) dihydrocinchonidine; m.p. m.p. 205 - 206 ° C, rac-5'-chloro-2'-trifluoromethyl dihydrocinchonidine; m.p. 175 - 176 ° C; claims. An analogous process for the preparation of cinchonin or cinchonidine derivatives of the general formulas I and II, wherein R 2 represents halogen or trifluoromethyl and R 2 represents ethyl or vinyl, or enantiomers or racemates thereof or acid addition salts thereof, characterized in that a) a compound of the general formula III 2 y OHC H2 where R has the meaning given above, or an enantiomer or racemate thereof is reacted with a compound of the general formula IV wherein R has the meaning given above, or b) a compound of the general formula V-1 I H H tJ ^ CF3 wherein R 1 and R 2 have the meaning given above, or an enantiomer or racemate thereof is treated with reducing agent, or c) a compound having the general formula VI