US3753992A - Process and intermediates for quinine,quinidine and derivatives thereof - Google Patents

Abstract

QUININE, QUINIDINE, THEIR ANTIPODES OR RACEMATES AND DERIVATIVES THEREOF, ARE PREPARED BY (A) CYCLIZING THE CORRESPONDINGLY SUBSTITUTED 4 - (3-(1-CHLORO-3(R)-ALKYL(OR ALKENYL) - 4(R)-PIPERIDYL)-1-OXOPROPYL)QUINOLINES, ANTIPODES OR RACEMATES THEREOF, TO THE CORRESPONDING 4-(5-(R)ALKYL(OR ALKENYL)-4(S)-QUINUCLIDIN-2(S) OR 2 (R)-YLCARBONYL)QUINOLINES, ANTIPODES OR RACEMATES THEREOF, AND (B) STEREOSELECTIVELY REDUCING THE PRODUCTS OF STEP (A) TO A(S)-(5(R)-ALKYL(OR ALKENYL)-4(S)-QUINUCLIDIN-2(R)-YL)4-QUINOLINEMETHANOLS, ANTIPODES OR RACEMATES THEREOF USING DI ALKYLALUMINUM HYDRIDE, AND A(R)-(5(R)-ALKYL(OR ALKENYL)-4(S)-QUINUCLIDIN-2(S)-YL) - 4 - QUINOLINEMETHANOLS, ANTIPODES OR RACEMATES THEREOF. VARIOUS INTERMEDIATES AND THE END PRODUCTS ARE USEFUL ANTIMALARIAL AND ANTIARRHYTHMIC AGENTS.

Description

United States Patent Oflice 3,753,992 Patented Aug. 21, 1973 3,753,992 PROCESS AND INTERMEDIATES FOR QUININE, QUINTDINE AND DERIVATIVES THEREOF Juerg Albert Walter Gutzwiller, Bettingen, Switzerland, and lVlilan Radoje Uskokovic, Upper Montclair, N.J., assignors to Holfmann-La Roche Inc., Nutley, NJ. No Drawing. Continuation-impart of application Ser. No. 104,785, Jan. 7, 1971, which is a continuation-in-part of application Ser. No. 837,304, June 27, 1969, which is a continuation-in-part of application Ser. No. 741,913, July 2, 1968, all now abandoned. This application Dec. 27, 1971, Ser. No. 212,648

Int. Cl. C07d 43/24 US. Cl. 260-284 55 Claims ABSTRACT OF THE DISCLOSURE Quinine, quinidine, their antipodes or racemates and derivatives thereof, are prepared by (a) cyclizing the correspondingly substituted 4 [3-(1-chloro-3(R)-alkyl(or alkenyl) 4(R)-piperidyl)-1-oxopropyl]quinolines, antipodes or racemates thereof, to the corresponding 4-[5 (R)- alkyl(or alkenyl)-4(S)-quinnclidin-2(S) or 2 (R)-ylcarbonyl]quinolines, antipodes or racemates thereof; and (b) stereoselectively reducing the products of step (a) to u(S)-[5(R)-alkyl(or alkenyl)-4(S)-quinuclidin-2(R)-yl]- 4-qninolinemethanols, antipodes or racemates thereof using di alkylaluminum hydride, and oz(R)-[5(R)-alkyl(or alkenyl)-4(S)-quinuclidin-2(S)-yl] 4 quinolinemethanols, antipodes or racemates thereof. Various intermediates and the end products are useful antimalarial and antiarrhythmic agents.

Cross-reference to related applications This application is a continuation-in-part of application Ser. No. 104,785, filed Jan. 7, 1971, now abandoned, which is a continuation-in-part of application Ser. No. 837,304, filed June 27, 1969, now abandoned, which in turn is a continnation-in-part of application Ser. No. 741,913, filed July 2, 1968, now abandoned.

Summary of the invention The invention relates to a process for preparing quinine, quinidine and derivatives thereof which is exemplified by the following reaction scheme:

Chlorination (R1)m (Rang/j N (In) N /Cyc1lzation I antipodes and racemates thereof;

wherein m is 0, 1 or 2; R is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, trifluoromethyl, or, when m is 2, R taken together with an adjacent R is also methylenedioxy; and R is lower alkyl or lower alkenyl.

In another aspect, the invention relates to compounds of the formulas antipodes and racemates thereof;

wherein n is 1 or 2; R is lower alkyl or lower alkenyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or, when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower al'koxy, lower alkyl, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, 1

0 and pharmaceutically acceptable acid addition salts thereof.

The compounds of Formulas Ic and lIc are useful antimalarial and antiarrhythmic agents.

3 ma fiirtlir aspect, the invention'relates' to compounds of the formulas ide and nLiK /IL N v N/ v antipodes and racemates thereof; 5 wherein R R R and n are as previously described,

and pharmaceutically acceptable acid addition salts there-- of.

The compounds of Formulas Vc and VIc are useful as intermediates and as antimalarial and antiarrhythmic agents. i

In still a further aspect, the invention relates to compounds of the formulas I 1 antipodes and raceinates thereof and antipodes and racemates thereof;

wherein R R R R11 m and n are as previously de scribed, and R is lower alkyl.

4 The compounds of Formiilas IXa, 1110 and IV are useful as intermediates in the process of the invention.

Detailed description of the invention The term lower alkyl as used herein denotes a hydrocarbon group containing 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl and'the like; ethyl is preferred. The term lower alkoxy denotes a lower alkyl ether group in which the lower alkyl moiety is described as above. The term lower alkenyl as used herein denotes a hydrocarbon group containing 2-7 carbon atoms, such as vinyl, propenyl, butenyl and the like; Preferred is vinyl. The term halogen denotes all of the halogens,'i.e., bromine chlorine,fluorine and iodine.

'As is evident from the above R or R or the like are individually selected from the various groupings hereinbefore described. Moreover, when m or n is 2, R or R or the like can additionally form with an adjacent R or R or the like the methylenedioxy radical. Thus, either whenm or nfisl or 2,-R or R or the like can individually also represent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl. Additionally, when m or n is 2, two adjacent groupings of R or R 11 can together represent methylenedioxy.

Chlorination (Rom (Rom fi \N (In) \N (W) Ayelization e R, \/R, H J l H N/ o E 1)m 2 (RQIH N/ N (W) l Reduction 1 Reduction OH I 7 \N/ (I) \N antipodes and racemates thereof wherein m is 0, 1, or 2; R, is hydrogen, hydroxy, halogen, 7

lower alkyl, lower alkoxy or trifiuoromethyl, or when m is 2, R taken together with an adjacent R is also methylenedioxy; and R is lower alkyl or lower alkenyl.

In Reaction Scheme 1', the 4-[3-(3(R)-alkyl(0r alkenyl)-piperid-4 R)-yl-1-ox0propyl]quinolines of Formula III, antipodes or racemates thereof, are converted to the corresponding 4- [3 -'(1-chloro-3 (-R)-alkyl(or alkenyl)- piperid-4(R)-yl)-l-oxopropyl]quinolines of Formula IV, antipodes or racemates thereof, utilizing a chlorinating agent such as sodium hypochloriate, N-chlorosuccinimide or the like. The chlorination is suitably carried out at room temperature or above, preferably at a temperature between 20 and 50 C. Moreover, the chlorination can be suitably carried out in the presence of an inert organic solvent, for example, a hydrocarbon such as benzene, a halogenated hydrocarbon such as dichloromethane or chloroform, or an ether such as ether or dioxane.

The 4 [3 (1-chloro-3(R)-alkyl (or alkenyl)piperid- 4(R)-yl)-1-oxopropyl1quinolines of Formula IV, antipodes or racemates thereof, are converted to the corresponding epimeric 4 [5(R) alkyl(or alkenyl) 4(8)- quinuclidin-2(R)-ylcarbonyl]quinolines of Formula V, antipodes or racemates thereof, and 4-[5( R)-alkyl(or alkenyl) -4 (S) -quinuclidin-2 (S) -ylcarbonyl] quinolines of Formula VI, antipodes or racemates thereof, under acidic conditions, utilizng a cyclizing agent. Exemplary of such agents are inorganic or organic acids such as mineral acids, for example, phosphoric acid and sulfuric acid; strong alkanoic acids, for example, trichloroacetic acid; and mixtures thereof, for example, acetic/sulfuric acid. The reaction is conveniently carried out at room temperature or above, preferably at a temperature between 20 C. and 50 C. Moreover, the cyclization can be suitably carried out in the presence of an inert solvent of the type previously described. As mentioned above, the cyclization yields a mixture of the epimeric compounds of Formulas V and VI, which can be reacted further as such or can be separated into the respective epimers utilizing methods such as crystallization, and the like, and such epimer reacted separately.

The conversion of the 4-[5(R)-alkyl(or alkenyl)-4(8)- quinuclidin-2 R)-ylcarbon'yl]quinolines of Formula V, antipodes or racemates thereof to a(S)-[5(R)-al kyl(or (or alkenyl) -4 (S -quinuclidin-2 R) -yl] -4-quinolinemethanols of Formula I, antipodes or racemates thereof, respectively, is carried out utilizing a stereoselective reducing agent, for example, a dialkylaluminum hydride, such as diisobutylaluminum hydride or the like. The reduction is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. It is preferred to employ a temperature between 20 C. and 50 C. The reduction can be conveniently conducted in the presence of an inert organic solvent, for example, a hydrocarbon such as benzene or toluene, or an ether such as diethylether, tetrahydrofuran or the like.

The conversion of the compounds of Formula V or their racemates to those of Formula I, antipodes or racemates thereof, respectively, when R is lower alkyl, can also be effected utilizing a hydrogenation catalyst such as nickel, palladium, ruthenium, copper or barium chromite in the presence of a solvent, for example, an aqueous or non-aqueous alkanol such as methanol or ethanol, or an ether such as dioxane. When R is lower alkyl or lower alkenyl, the conversion can be effected utilizing a hydrogenation agent such as aluminum in methanol, sodium isopropoxide in toluene, lithium aluminum hydride, aluminum hydride, chloroaluminum hydride, dichloroaluminum hydride, bromoaluminum hydride, dibromoaluminum hydride, lithium tri-tert.-butoxyaluminum hydride in ether, tetrahydrofuran, dioxane or the like.

The conversion of the 4-[5(R) -alkyl(or alkenyl)-4(8)- quinuclidin-ZQR)-ylcarbonyl]quinolines of Formula V1, antipodes or racemates thereof, to the ot(R)-[5(R)-alkyl- (or alkenyl) -4 (S -quinuclidin-2(S -yl] -4-quinolinemethanols of Formula II, antipodes or racemates thereof,

respectively, is carried out according to the procedures described for the conversion of the compounds of Formula V.

The 4- 3- 3 (R -alkyl (or alkenyl) -piperid-4 R) -y1] -1- oxopropyl1quinolines of Formula III, antipodes or racemates thereof can be cyclized to the 4-[5(R)-alkyl(or alkenyl) 4(5) quinuclidin-2(R) (or 2(S))-ylcarbonyl] quinolines of Formula V-VlI, antipodes or racemates thereof, respectively, according to the reaction set forth in Scheme III:

wherein R is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifiuoromethyl, or, when m is 2, R taken together with an adjacent R may be also methylenedioxy; R is alkyl or lower alkenyl; m is 0, 1 or 2; and X is halogen.

In Reaction Scheme III, the N-halogenation of the compounds of Formula III, antipodes or racemates thereof, to the corresponding N-halo compounds of Formula IVc, antipodes or racemates thereof, is effected utilizing a halogenating agent such as hypobromous acid, sodium hypochlorite, N-chlorosuccinimide, N-bromosuccinimide, N- bromoacetamide or the like, in an inert organic solvent, for example, an ether such as tetrahydrofuran, dioxane or the like; a chlorinated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, or the like; or an alkanol such as methanol, ethanol, or the like.

The cyclization of the N-halo compounds of 'Formula IVc, antipodes or racemates thereof, to the corresponding compounds of Formula VVI, antipodes or racemates thereof, is conducted under basic conditions, for example, with sodium ethoxide in ethanol, sodium methoxide in methanol, or the like, or under strongly acidic conditions, for example, with sulfuric acid, phosphoric acid, trichloroacetic acid, trifluoroacetic acid, acetic acid/sulfuric acid mixture or the like.

When R in Formula III is lower alkyl, the cyclization of the compounds of Formula III to the corresponding compound of Formula V-VI can also be conducted according to the reaction set forth in Scheme IV.

B2 H E R2 r1 H 5 U H (v-VI) (XI) R (R wherein R is lower alkyl. In Reaction Scheme V, the halogenation of the compounds of Formula 1112., antipodes or racemates thereof,

to the corresponding compounds of Formula Xa, antipodes or racemates thereof, is effected utilizing a halogenating agent, for example, molecular halogen, such as R2 chlorine or bromine in the presence of a halogen halide,

\ such as hydrogen chloride or hydrogen bromide in Water, ether, acetic acid or other inert organic solvents. The cyclization of the compounds of Formula Xa, antipodes or racemates thereof, to the corresponding compounds of Formula XI, antipodes or racemates thereof, is effected utilizing a sodium allcoxide such as sodium methoxide or I J 0 N sodium ethoxide in an alkanol such as methanol, ethanol (R) or the like. The dehalogenation of the compounds of Formula XI, antipodes or racemates thereof, to the corresponding compounds of Formula V-VI, antipodes or race- (VWI) mates thereof, is effected with, for example, sodium iodide.

In reaction Scheme IV, the C-halogenation of the compounds of Formula III, antipodes or racemates thereof, N H N431 to the corresponding compounds of Formula X, antipodes J or racemates thereof, can be eifected with a halogenating agent, for example, molecular halogen, such as chlorine E or bromine in the presence of a hydrogen halide such as hydrogen chloride or hydrogen bromide in water, ether, 0 O acetic acid or other inert organic solvents. The cyclization of the compounds of 'Formula X, antipodes or racemates thereof, to the corresponding compounds of For- CHQO mula V-VI, antipodes or racemates thereof, is elfected utilizing a sodium alkoxide such as sodium methoxide or sodium ethoxide, for example, in an alkanol such as methanol, ethanol, or the like.

When R in Formula III is lower alkenyl, the cyclization can be effected according to the reaction set forth in Scheme V.

x R n/\ R r rA c1130 Il IH 2L N-H o o X 1)m w om I 01130 01330 (IIIa) (Xe) \N/ (Ia) i antipodes or racemates thereof.

Reaction Scheme Iarepresents a preferred embodiment of Reaction Scheme I, i.e., the preparation of dihydroquinidine and dihydroquinine, and is carried out utilizing the reaction conditions set forth for Reaction Scheme I. In Reaction Scheme Ia, dihydroquinotoxine of Formula IIIa, antipode or racemate thereof, is converted to N-chloro-dihydroquinotoxine of Formula IVa, antipode or racemate thereof. The N-chloro-dihydroquinotoxine of Formula IVa, antipode or racemate thereof, is converted to the epimeric dihydroquinidinone of Formula Va, antipode .or racemate thereof, and dihydroquininone of Formula VIa, antipode or racemate thereof, which are in turn converted to dihydroquim'dine of Formula Ia, antipode or racemate thereof, and dihydroquinine of Formula IIa, antipode or racemate thereof, respectively.

Scheme I(b) CH ll H t rt O i (Ib) \N/ (IIb) Reaction Scheme Ib represents another preferred embodiment of Reaction Scheme I, i.e., the preparation of quinidine and quinine, antipodes or racemates thereof, and is carried out utilizing the reaction conditions set forth in Reaction Scheme I. In Reaction Scheme Ib, quinotoxine of Formula IIIb, antipode or racemate thereof, is converted to N-chloro-quinotoxine of Formula 'IVb, antipode or racemate thereof. The N-chloro-quinotoxine of Formula IVb, antipode or racemate thereof, is converted to quinidinone of Formula Vb, antipode or racemate thereof, and quininone of Formula VIb, antipode or racemate thereof, which are in turn converted to quinidine of Formula Ib, antipode or racemate thereof, and quinine of Formula IIb, antipode or racemate thereof, respectively.

CHQO

SCHEME II (I? O 0 R4 (Rom / O CoHls (VIII) Hydrolysis and x -Y Deearboxylation v o 0 0 R5 0111 w antipodes or racemates thereof In Reaction Scheme II, the cinchoninic acid lower alkyl esters of Formula VII, which are known or are analogs of known compounds readily obtained by known procedures, are reacted in the presence of a base, for example, alkaline metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide and the like, with the 1-benzoyl-3(R)-alkyl(or alkenyl)-4( R)-piperidinepropionic acid esters of Formula VIII, antipodes or racemates thereof, which are known compounds or are analogs of known compounds readily obtained by known procedures, or by the procedure hereinafter described in Scheme III, to yield the corresponding a-[1-benzoyl-3- (R)-alkyl(or alkenyl)-4(R)-piperidylmethyl] fi oXo-4- quinolinepropionic acid esters of Formula IX, antipodes or racemates thereof. The reaction is conveniently con ducted at reflux temperatures; however, lower temperatures may also be employed. An inert solvent, for example, ethers such as tetrahydrofuran, dioxane and the like, may also be conveniently employed.

The conversion of the a-[l-benzoyl 3(R) alkyl(or alkenyl)-4(R)-piperidyl-methyl]-/3-oxo 4 quinolinepropionic acid esters of Formula IX to the corresponding 4-[3 (3(R)-alkyl(or alkenyl) 4( R) -piperidyl)-l-oxopropyl]quinolines of Formula III is effected utilizing a hydrolyzing agent such as hydrochloric acid at reflux temperatures. Conveniently, temperatures below reflux may also be utilized.

The preparation of the 1-benzoyl-3 (R)-alkenyl-4(R)- piperidinepropionic acid esters of Formula VIII, antipodes or racemates thereof, can be carried out as set forth in Reaction Scheme VI.

SCHEME VI G O R 0 O 0 R5 I "1, CE; OH; H H

(XII) (XIII) COORs COORs H H pQ/Cl H. 01

h h i H H 0 CflH5 (XV) l 000R! COORg I; I h

I l I l j (XVI) (VIIIa) wherein R is as previously described, and A is an inorganic acid such as sulfuric acid, phosphoric acid and the like, or organic acids, for example, lower alkanoic acids such as acetic acid, and the like, halogenated lower alkanoic acids such as trifluoroacetic acid, trichloroacetic acid and the like.

In Reaction Scheme VI, the 3 R)-ethy1 4( R) piperidinepropionic acid esters of Formula XII, antipodes or racemates thereof, which are known compounds, are converted to the corresponding 1-chloro-3 (R) ethyl 4(R) piperidine propionic acid esters of Formula XIII, antipodes or racemates thereof, by utilizing a chlorinating agent, for example, N-chlorosuccinimide, N-chloroacetamide, alkali metal hypochlorite such as sodium hypochlorite and the like. The reaction is conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, a halogenated hydrocarbon such as dichloromethane, an alkanol such as methanol, ethanol and the like, an ether such as diethylether, dioxane, tetrahydrofuran and the like. The reaction temperature is not critical; however, preferably, it is in the range of about 0 C. and about room temperature.

The conversion of the compounds of Formula XIII, their antipodes or racemates, to the corresponding 3(R)- (Z-chloroethyl)-4(R)-piperidinepropionic acid ester salts of the Formula XIV, antipodes or racemates thereof, is effected by irridiation with ultraviolet light source such as a 200 w.-I-Iannovia high pressure mercury lamp in an acid such as previously described. The reaction temperature is not critical; however, preferably it is in the range of about 0 C. to about room temperature.

The conversion of the compounds of Formula XIV, antipodes or racemates thereof, to corresponding l-benzoyl 3(R) (2 chloroethyl)-4(R)-piperidinepropionic acid esters of Formula XV, antipodes or racemates thereof, is elfected utilizing a benzoyl halide such as benzoyl chloride, in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as dichloromethane, chloroform and the like, or ethers such as diethyl ethers, tetrahydrofuran, dioxane and the like. The pH of the reaction mixture is maintained between about 6 to about 9 utilizing, for example, alkali metal carbonates such as sodium or potassium carbonate. The reaction temperature is not critical; however, preferably it is in the range of about 0 C. and about room temperature.

The conversion of the compounds of Formula XV, antipodes or racemates thereof, to the corresponding l-bnzoyl- 3 (R) (2 iodoethyl) 4(R)-piperidinepropionic acid esters of the Formula XVI, antipodes or racemates thereof, is elIected utilizing an alkali metal iodide such as potassium iodide, sodium iodide and the like, in an inert organic solvent, for example, dimethylsulfoxide, dimethylformamide, acetonitrile, alkanols such as methanol, ethanol and the like, or ketones such as acetone, methylethylketone and the like. The temperature is not critical; however, preferably it is in the range of about 0 C. and about the reflux of the reaction mixture.

The conversion of the compounds of Formula XVI, antipodes or racemates thereof, to the corresponding 1- benzoyl-3(R)-vinyl-4(R)-piperidinepropionic acid esters of the Formula VIIIa, antipodes or racemates thereof, is effected utilizing an organic base, for example, pyridine, ,B-collidine, dimethylformamide and the like. Advantageously, an inorganic salt, for example, lithium bromide, lithium chloride lithium carbonate, silver fluoride, silver carbonate and the like, may be utilized in the reaction. The reaction temperature is not critical; however, prefer ably it is in the range of about room temperature and about the reflux temperature of the reaction mixture.

The conversion of the compounds of Formula XV, antipodes or racemates thereof, to the corresponding l-benzoy1-3 (R)-vinyl-4(R)-piperidinepropionic acid esters of the Formula VIIIa, antipodes or racemates thereof, is effected by pyrolysis, preferably at a temperature in the range of C. and about 250 C. The reaction can be conducted at atmospheric pressure; however, preferably is conducted at reduced pressure, for example, in the range of about '.1 mm./Hg to .01 mm./Hg.

In still another aspect, the invention comprises the process illustrated by Reaction Scheme VIII:

wherein R and m are as previously described.

In Reaction Scheme VIII the conversion of the a(S)- [5(R) vinyl 4(5) quinuclidin-2(R)-yl]-4-quinolinemethanols of Formula Ie or the OL(R)-[(R)-Vll'ly1-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanols of Formula IIe to the a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)-yl]'4- quinolinemethanols of Formula If or to the a(R)-[5(R)- ethyl 4(S) quinuclidin 2(5) yl]-4-quinolinemetha nols of Formula IIf, respectively, is effected by catalytic hydrogenation utilizing, for example, a noble metal, such as palladium, platinum or the like. Conveniently, the hydrogenation is carried out in an inert solvent, for ex ample, in water, an alkanol, such as methanol, ethanol or the like, or an organic or inorganic acid, such as acetic acid, hydrochloric acid or the like, or mixtures thereof. Further, the hydrogenation is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. Alternatively, the conversion can be effected by a chemical reduction in the presence of oxygen, utilizing hydrazine hydrate and a cupric salt, such as cu-pric sulfate, as the catalytic agent. Conveniently, the reduction is carried out in a polar solvent, for example, Water or a lower alkanol, such as methanol or ethanol, preferably at a temperature in the range of room temperature and the boiling temperature of the reaction mixture.

In another aspect, the invention relates to compounds of the formulas and wherein n is l or 2; R is lower alkyl or lower alkenyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl or halogen, or, when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifiuoromethyl or halogen, or taken together with an adjacent R is also methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen,

and pharmaceutically acceptable acid addition salts thereof.

Exemplary of the compounds of Formulas Ic and 110 are:

7 -methoxy 04s [5(R) ethyl 4 s quinuclidin- 14 7-dimethoxy-dihydrocinchonidine], its antipode and racemic analog;

6,8 dimethoxyrx(R)-[5(R)-ethyl-4(S)-qninuclidin-2 (S)- ylJ-4-quinolinemethanol, its antipode and racemic analog;

6-meth0xy-a (S)-[5(R) propyl 4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol, antipode and racemic analog;

6-rnethoxy-a(R)-[5(R) allyl 4(S) quinuclidin-2(S)- yl]-4-quinolinemethanol, antipode and racemic analog;

6-rnethyl-u(S)-[5 (R) ethyl 4(S)-quinnclidin-2(R)-yl]- 4-quinolinemethanol [hereinafter referred to as 6'- methyldihydrocinchonine]), its antipode and racemic analog;

6-methyl-a(R)-[S(R) ethyl 4(S)-quinuclidin-2(S)-yl]- 4-quinolinemethanol [hereinafter referred to as 6'- methyl'dihydrocinchodine], its antipode and racemic analog;

6chloro-u(S)-[5(R) ethyl 4(S)-quinuclidin-2(R)-yl]- 4-quinolinemethanol [hereinafter referred to as 6'-chloro-dihydrocinchonine], its antipode and racemic analog;

6-Chl0I0-oc(R)-[5(R) ethyl 4(S)-quinuclidin2(S)-yl]- 4-quinolinemethanol [hereinafter referred to as 6-chloro-dihydrocinchonidine], its antipode and racemic analog;

7-chloro-a(S)[5 (R) -'ethyl 4(S)-quinuclidin-2(R)-yl] 4-quinolinemethanol [hereinafter referred to as 7-chloro-dihydrocinchonine], its antipode and racemic analog;

7-chloro-u (R)-[5(R) ethyl 4(S)-quinuclidin-2 (S)-yl]- 4-quinolinernethanol [hereinafter referred to as 7-chloro-dihydrocinchonidine], its antipode and racemic analog;

7-chloro-u(S)-[5 (R) vinyl 4(S)-quinuclidin-2(R)-yl]- 4-quinolinemethanol [hereinafter referred to as 7'-ch1oro-cinchonine], its antipode and racemic analog;

7-Chl0I'O-oc(R)-[5(R) vinyl 4(S)-quinuclidin-2(S)-yl]- 4-quinolinemethanol [hereinafter referred to as 7'-chloro-cinchonidine], its antipode and racemic analog;

6,7 methylenedioxy-u(S)- [5 (R)-vinyl-4 (S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6',7'-methylenedioxy-cinchonine], its antipode and racemic analog;

6,7 methylenedioxy-ot(R)-[5(R)-vinyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7'-methylenedioxy-cinchonidine], its antipode and racemic analog;

6-ChlO1O-oc(S)-[5 (R) vinyl 4(8)-quinuclidin-2(R)-yl]- 4-quinolinemethanol [hereinafter referred to as 6'-chloro-cinchom'ne], its antipode and racemic analog;

6-chloro-a(R)-[5(R) vinyl 4(S)-quinuclidin2(S)-yl]- 4-quin0linemethanol [hereinafter referred to as 6'-chloro-cinchonidine], its antipode and racemic analog;

6,8-dichloro-u(S)-[5(R) vinyl 4(S),-quinuclidin-2(R)- y1]-4-quinolinemethanol [hereinafter referred to as 6',

-dichloro-cinchonine], its antipode and racemic analog;

6,8-dichloroa(R)-[5(R)t vinyl 4(S)-quinnclidin-2(S) y1]-4-quinolinemethanol [hereinafter referred to as 6, 8-dichloro-cinchonidine], its antipode and racemic analog;

6,7 methylenedioxy-a (S)-[5 (R)-ethyl-4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7-methylenedioxy-dihydrocinchonine], its antipode and racemic analog;

6,7 methylenedioxy-ot (R) [5 (R) -ethyl-4 (S -quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6',7'-methylenedioxy-dihydrocinchonidine], its antipode and racemic analog;

7-trifiuoromethyl-a(S)-[5 (R) ethyl 4(S)-quinuclidin- 15 6,-8-dichloro-a(S)-[5(R) ethyl 4(S) quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 6',

8'-dichlorodihydrocinchonine], its antipode and racemic analog;

6,8-dichloro-u(R)[S(R) ethyl 4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 6', 8-dichlorodihydrocinchonidine], its antipode and racemic analog;

7-trifluoromethyl-a(S)-[5 (R) vinyl 4(S)-qninuclidin- 2(R)-yl]-4-quinolinernethanol [hereinafter referred to as 7-trifluoromethylcinchonine], its antipode and'racemic analog;

7-trifluorornethyl-u(R)-[5 (R) vinyl 4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethano1 [hereinafter referred to as 7'-trifluoromethylcinchonidine], its antipode and racemic analog;

-triflu0romethyl-a(S)-[5 (R) vinyl 4(S)-quinuclidin- 2(R)-yl]-4-quinolinernethanol [hereinafter referred to as 5'-triflnoromethylcinchonine], its antipode and racemic analog;

5-trifiuoromethyl-a(R)-[5 (R) vinyl 4(S)-quinuclidin- 2(8)-yl]-4-quinolinemethanol [hereinafter referred to as 5'-trifluoromethylcinchonidine], its antipode and racemic analog;

6-trifluoromethyl-a(S)[5 (R) vinyl 4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6'-trifluoromethylcinchonine], its antipode and racemic analog;

6-trifluoromethyl-a(R)-[5 (R) vinyl 4(S)-q.uinuclidin- 2(8)-yl]-4-quinolinemethanol [hereinafter referred to as 6-trifluoromethylcinchonidine], its antipode and racemic analog;

:In a further aspect, the invention relates to compounds of the formulas and ( uin wherein R ,R R and n are as previously described,

and pharmaceutically acceptable acid addition salts thereof.

Exemplary of the compounds of Formulas Va and VIc are:

6-methyl-4-[5 (R) ethyl 4(S)-quinuclidin-2(R)-ylcarbonylJquinoline [hereinafter referred to as 6-rnethyldihydrocinchoninone], its antipode and racemic ana- 6-methyl-4-[5(R) ethyl 4(S)-quinuclidin-2(S)-ylcarbonyl]quinoline [hereinafter referred to as 6-methyldihydrocinchonidinone], its antipode and racemic analog;

6-chloro4-[5(R) ethyl 4(S)-quinuclidin-2(R)-ylcarbonyl1quinoline [hereinafter referred to as 6'-chlorodihydrocinchoninone], its antipode and racemic analog;

6-chloro-4-[5 (R) ethyl 4(S)-quinuclidin-2(S)-ylcarbonyljquinoline [hereinafter referred to as 6'-chlorodihydrocinchonidinone], its antipode and racemic analog;

7-chloro-4-[5 (R) ethyl 4(S)-quinuclidin-2(R)ylcarbonyl]quinoline [hereinafter referred to as 7-chloro dihydrocinchoninone], its antipode and racemic analog;

7-chloro-4-[5 (R) ethyl 4(S)-quinuelidin-2(S)-ylcarbonylJquinoline [hereinafter referred to as 7'-chlorodih'ydrocinchonidinone], its antipode and racemic ana- 7-chloro-4-[5 (R) vinyl 4(5)-quinuclidin-2(R)-ylcarbonyl]quinoline [hereinafter referred to as 7-chlorodihydrocinchoninone], its antipode and racemic analog;

7-chloro-4-[5(R)- vinyl 4(S)-quinuclidin-2(S)-ylcarbonyl]quinoline [hereinafter referred to as 7'-chlorodihydrocinchonidinone], its antipode and racemic anaand the like;

6,7-methylenedioXy-4[5(R) vinyl 4(8) quinuclidin- 2('R) ylcarbonyl] quinoline [hereinafter referred to as 6',7'-rnethylenedioxy-cinchoninone], its antipode and racemic analog;

6,7-rnethylenedioxy-4 [5(R) vinyl 4(8) quinnclidin- 2(S)-ylcarbonyl]quinoline [hereinafter referred to as 6,7'-rnethylenedioxy-cinchonidinone], its antipode and racemic analog;

6,7-rnethylenedioxy-4-[5(R) ethyl 4(S)quinuclidin- 2('R)-ylcarbony1]qiunoline [hereinafter referred to as 6',7-methylenedioxy-dihydrocinchoninone], its antipode and racemic analog;

6,7-methylenedioXy-4-[5 (R) ethyl 4(S)-quinuclidin- 2(S)-ylcarbonyl]quinoline [hereinafter referred to as 6',7'-methylenedioxy-dihydrocinchoninone], its antipocle 6,7-methylenedioxydihydrocinchonidinone], its antiand racemic analog;

6,8-dichloro-4-[5 (R) ethyl 4(S)-quinuclidin-2(R)-yl carbonylJquinoline [hereinafter referred to as 6',8'-dichloro-dihydrocinchoninone], its antipode and racemic analog;

6,8-dichloro-4 [5 (R) ethyl 4(S)-quinuclidin-2(S)-ylcarbonyl]quinoline [hereinafter referred to as 6',8- dichlorodihydrocinchonidinone], its antipode and racemic analog;

6 chloro- 4 [5(R)-vinyl-4-(S)-quinuclidin-2(R)-ylcarbonyl]-quinoline [hereinafter referred to as 6-chlorocinchoninone], its antipode and racemic analog;

6 chloro 4 [5(R)-vinyl-4(S)-qui11uclidin-2(S)-ylcarbonylj-quinoline [hereinafter referred to as 6'-chlorocinchonidinone], its antipode and racemic analog;

7 trifluoromethyl 4 [5(R) ethyl-4(S)-quinuclidin- 2-(S)-ylcarbonyl]-quinoline [hereinafter referred to as 7'-trifluoromethyl-dihydrocinchonidinone1, its antipode and racemic analog;

7 trifluoromethyl-4-[5(R)-ethyl-4(S)-quinuclidin-2(R)- ylcarbonyl1-quinoline [hereinafter referred to as 7'-trifluoromethyl-dihydrocinchoninone1, its antipode and racemic analog;

6,8 dichloro-4-[S (R)-vinyl-4(S)-quinuclidin-2(R)-ylcarbonyll-quinoline [hereinafter referred to as 6,8-dichlorocinchoninone], its antipode and racemic analog;

6,8-dich1oro 4 [5(R)-vinyl-4(S)-quinuclidin-2(S)-ylcarbonyH-quinoline [hereinafter referred to as 6',8'-dichlorooinchonidinone], its antipode and racemic analog.

17 In a still further aspect, the invention relates to compounds of the formulas i T CaHs 1'1 Matt (IXa) Ra E l E\/ H Ra (RI)D{An l I/ and (R011: A N/ wherein R R R R R m and n are as previously described.

Exemplary of the compounds of Formulas IXa, IIIc and IV are:

a [1 benzoyl-3(R) vinyl-4(R)-piperidyl-methyl] oXo-fl-(6,7 methylenedioxy 4 quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

or [1 benzoyl 3(R) ethyl -4(R) piperidylmethyl]- 8-oxo-B-(7 methoxy 4 quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

or [1 benzoyl 3(R) ethyl 4(R) piperidylmethyllfl-oxo-fi-(6,7 dimethoxy-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a [l-benzoyl 3 (R) -ethyl-4(R)-piperidylmethyl]-B-oxo- ,9-(6,8-dimethoxy 4 quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

oz [1 benzoyl-3(R)-ethyl-4(R)-piperidylmethyl] 9-03(0- 18 B-(6-methyl-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

or [1 benzoyl-S(R)-ethyl-4(R)-piperidylmethyl]-B-oxofi-(6-chloro-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a [1 benzoyl-3(R)-ethyl-4(R)-piperidylmethyl]-/8-oxo- ,8-(7-chloro-4-quinolyl)propionic acid ethyl ester, its antipode ad racemic analog;

0: [1 benzoyl-3(R)-vinyl-4(R)-piperidylmethyl]-,8-oxo- ,6-(7-chloro-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

7 methoxy-4-[3 (3(R)-ethyl-4(R)-piperidyl) 1 oxopropyl]quinoline [hereinafter referred to as 7-methoxy-dihydrocinchotoxine], its antipode and racemic analog;

6,7 dimethoxy 4 [3-(3(R)-ethyl-4(R)piperidyl)-1- oxopropyH-quinoline [hereinafter referred to as 6,7- methoxydihydrocinchotoxine], its antipode and racemic analog;

6,8 dimethoxy 4 [3-(3(R)-ethyl-4(R)-piperidyl)-1- -oxopropyl]-quinoline, its antipode and racemic analog;

6 methyl 4 [3-(3R)-ethyl-4(R)-piperidyl)-1-oxopropy1]-quino1ine [hereinafter referred to as 6'-methyl-dihydrocinchotoxine], its antipode and racemic analog;

6 chloro 4 [3-(3R)-ethyl-4(R)-piperidyl) 1 oxopropy1]quinoline [hereinafter referred to as 6-ch1orodihydrocinchotoxine], its antipode and racemic analog;

7 chloro 4 [3-(3R) ethyl 4(R) piperidyl)-1-oxopropyl]-quinoline [hereinafter referred to as 7'-chlorodihydrocinchotoxine], its antipode and racemic analog;

7 chloro 4 [3-(3R) vinyl 4(R)-piperidyl)-1-oxopropyl]-quinoline [hereinafter referred to as 7-chlorocinchotoxine], its antipode and racemic analog;

6,7 methylenedioxy 4[3-(3R)-vinyl-4(R)-piperidyl-1- oxopropyl]-quinoline [hereinafter referred to as 6',7- methylenedioxycinchotoxine], its antipode and racemic analog;

6 methoxy 4-[3-(1-chloro-3(R)-ethyl-4(R)-piperidyl)- 6,7 dimethoxy 4-[3-(1-chloro-3 (R ethyl-4 (R) -piperidyl)-1-oxopropyl] quinoline [hereinafter referred to as N-chloro 6,7' dimethoxy-dihydrocinchotoxine], its antipode and racemic analog;

6,8 dimethoxy 4-[3-(1-ch1oro-3(R)-ethyl-4(R)-piperidyl)-1-oxopropyl]quinoline, its antipode and racemic analog;

6 methyl 4-[3-(1-chloro-3(R)-ethyl-4(R)-piperidyl)-1- oxopropyl1quin0line [hereinafter referred to as N- chloro-6-methyl-dihydrocinchotoxine], its antipode and racemic analog;

6,7 methylenedioxy 4-[3-(1-chloro-3 (R)-vinyl-4(R)- piperidyl) l-oxo-propyl] quinoline [hereinafter referred to as N-chloro-6.7-methylenedioxyquinotoxine], its antipode and racemic analog;

6 chloro 4-[3(1-chloro-3(R)ethyl-4(R)-piperidyl)-1 oxopropyl1quinoline [hereinafter referred to as N-chloro-6'-chloro-dihydrocinchotoxine], its antipode and racemic analog;

7 chloro 4-[3-(1-chloro-3(R) -vinyl-4(R)-piperidyl)-1- oxopropyl]quin0line [hereinafter referred to as N- chloro-7 -chloro-cinchotoxine], its antipode and racemic analog;

7 chloro 4 [3-(1-chloro-3(R)-ethyl-4(R)-piperidyl)- 1-oXopropyl1-quinoline [hereinafter referred to as N- chloro-7'-chloro-dihydrocinchotoxine], its antipode and racemic analog.

Preferred compounds of Formulas Ic, Ho, 1110, Vc, VIc

and IXa are those wherein the fused benzo ring (hereinafter referred to as ring A) is substituted thusly:

, u u or Also included in the purview of the invention are compounds of Formulas Ic, IIc, Vc, V'Ic, IXa and 1110, where- 'in R is hydrogen; R is methoxy; and R is selected from the group consisting of methyl, C3-C lower alkyl and C C lower alkenyl. Respectively, these compounds have the same utility as the compounds of Formulas Ic, IIc, Vc, Vlc, IXa and IIIc.

to the sinus node and the atrium is irritated by pinching with a pair of forceps. This procedure produces a continuous atrial arrhythmia which mostly consists of atrial fibrillation. Since hypokalemia produces a susceptibility to atrial fibrillation (Leveque, Arch. Int. Pharmacodyn, 149, 297307, 1964), 2 units/kg. of insulin is administered 30 minutesbefore the start of the acetylcholine drip. Once atrial fibrillation is established, there is a tenminute Waiting period before the test drug is adminis- The corresponding compounds of Formulas lie and IE above are characterized by the formulas .wherein R is selected from the group consisting of and pharmaceutically acceptable acid addition salts there- Exemplary of such compounds are 6-methoxy-a(S)- [(R) propyl 4(8) quinuclidin-2(R)-yl]-4-quinolinemethanol and racernic analog; 6-methoxy-u(R)-[5(R)- allyl 4(5)-quinuclidin-2(S)-yl]-4-quinoliuemethanol and racemic analog; and the like.

The compounds of Formulas Ic, IIc, Id, IId, Vc and VIc and their pharmaceutically acceptable acid addition salts possess antimalarial and antiarrhythmic properties and are therefore useful as antimalarial and antiarrhythmic agents. Their pharmacologically useful antiarrhythmtc activity is demonstrated in Warm-blooded animals utilizing standard procedures, for example, the test compound is administered to prepared mongrel dogs. The chest cavity of the experimental animal previously anesthetized using a combination of sodium barbital, 300,mg./kg.and

'pentobarbital, 15 mg./ kg., i.v., is opened up through the tered. The test drugs are administered intravenously at the rate of l mg./kg./minute until normal sinus rhythm appears or until 30 mgjkg. of drug is administered.

When racemic 7'-methoxy-dihydocinchonidinone is utilized as the test substance at a dosage of about 4.4 mg./ 15

kg, i.v., an antifibrillatory effect is observed for more than 60 minutes.

, The pharmacologically useful antimalarial activity of the aforementioned compounds is demonstrated in warmblooded animals using standard procedures, for example, the test substance is administered to albino mice in variable amounts. Albino mice are inoculated with about 10 million red cells infected With P. berghei. Treatment is started on the first day after inoculation, and the drug is administered per os during 4 consecutive days. On the seventh day of infection, smears are made, stained with giemsa and microscopically examined for P. berghei.

When racemic 7'-methoxy-dihydrocinchonidine dihydrochloride and racemic 7'-methoxy-dihydrocinchonine dihydrochloride are utilized as the test substance at dosages in the range of 125 mg./ kg. to about 250 mg./kg., the microscopical examination of the blood smears is free of P. berghez' (negative). The-compounds of Formulas Ic, IIc, Vc and We and the pharmaceutically acceptable acid addition salts have efiects qualitatively similar, for example, to those of quinine and quinidine of known therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with antimalarials and antiarrhythmics of known eflicacy and safety.

The compounds of Formulas Ic, IIc, Id, IId, Vc, and We form acid addition salts and such salts are also Within the scope of this invention. Thus, the aforementioned compounds form pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable organic and inorganic acids, such as acetic acid, succinic acid, formic acid, methanesulfonic acid, p-toluene-sulfonic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like.

The products of the invention can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant materials, e.g., organic or inorganic inert carrier materials such as water, gelatin, lactose,

; starch, magnesium stearate, talc, vegetable oils, gums,

so as to maintain the heart in a pericardial cradle throughout the course of the test procedure. Arterial pressure is monitored by inserting a polyethylene cannula into the aorta via the left carotid artery and is measured with an appropriate Statham pressure transducer. During the course of the experiment, electrical activity of the heart is viewed both on an oscilloscope and recorded on a Sanborn polyviso using standard ECG lead II; The heart is also observed visually. The antiarrhythmic assay of the test drug is undertaken using a modification of the method of Scherf and Chick, Circulation, 3, 764-769 (1951). A dripping of 1 percent solution of acetylcholine is applied polyalkyleneglycols, and the like. The pharmaceutical preparations can be employed in a solid form, e.g., as tablets, troches, suppositories, capsules, or in liquid form, e.g., as solutions, suspensions'or emulsions. The pharmaceutical adjuvaut material can include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. They can also contain other therapeutically active materials.

Furthermore, the compounds of the Formulas Ic, IIc, Id and 11d can be utilized as flavoring agents in beverages in the same manner as quinine is now used for this purpose.-

The quantity of active medicament which is present in any of the above-described dosage forms is variable. The

frequency with which any such dosage form will be administered will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the pharmacological situation.

stereoisomeric form. The novel compounds, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of isomers or single isomers and not as limitations upon the scope of the invention. All temperatures are in degrees ceutigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of dihydroquinidinone To a solution containing 1.5 g. of dihydroquinotoxine in 120 ml. of methylene chloride were added 2.5 ml. of 17% aqueous NaOCl solution and the mixture was stirred 16 hours at 20, under nitrogen. The organic phase was separated, washed once with Water, dried over anhydrous sodium sulfate, and evaporated. The crude N-chloro-dihydroquinotoxine (1.65 g.) was dissolved in 10 ml. of methylene chloride and added dropwise to 80 ml. of 100% phosphoric acid which was stirred vigorously; the viscous mixture was stirred at 20 for 4 hours. The mixture was cooled and made alkaline to a pHzlO with 6 N aqueous sodium hydroxide; the alkaline aqueous phase was extracted thoroughly with chloroform, which was dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product (1.49 g.) was chromatographed on a column of 50 g. of neutral alumina, activity II; elution with methylene chloride yielded 1.1 g. (73%) of an amorphous mixture of dihydroquinidinone and dihydroquininone which was crystallized from ethanol to yield 930 mg. of dihydroquinidinone having a melting point of 102-104 after recrystallization from ether; +71 (c. 1.1, ethanol; after equilibration in ethanolic solution for 18 hours at 20 EXAMPLE 2 Preparation of racemic dihydroquinone and racemic dihydroquinidinone from racemic dihydroquinotoxine To a solution containing 14.8 g. of racemic dihydroquinotoxine in 100 ml. of chloroform were added 26 ml. of 17% aqueous sodium hypochlorite solution, and the mixture was agitated under nitrogen at 20 for 16 hours. The aqueous phase was separated and washed with methylene chloride. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

The crude racemic N-chloro-dihydroquinotoxine (about 15 g.) was dissolved in about 20 ml. of methylene chloride and the concentrated solution was added dropwise to 120 ml. of 100% phosphoric acid which was cooled in an icebath and vigorously stirred for 4 hours; the cooled solution was made alkaline with 6 N aqueous sodium hydroxide and extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate and evaporated to dryness.

The crude product (14 g.) was chromatographed on 500 g. of alumina, activity II. Elution with methylene chloride containing to 1% of methanol yielded 10.1 g. of pure, crystalline mixture of racemic dihydroquininone and racemic dihydroquinidinone (68% yield from dihydroquinotoxine). Crystallization from petroleum ether yielded 8.09 g. of crystals in three crops. The first crop having a melting point of 89-95 Was recrystallized four times from petroleum ether to yield racemic dihydroquininone having a melting point of 100-104.

Recrystallization of the third crop, having a melting point of 80-82, from petroleum ether yielded about a 1:1 mixture of racemic dihydroquinone and racemic dihydroquinidinone having a melting point of 8083.

EXAMPLE 3 Preparation of quinidinone from quinotoxine To a solution containing 1.804 g. of quinotoxine in 35 ml. of methylene chloride were added 6.4 ml. of about a 17% aqueous sodium hypochlorite solution, and the mixture was stirred under nitrogen for 2 /2 hours at 20. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude N-chloroquinotoxine (1.927 g.) was dissolved in about 6 ml. of methylene chloride-acetic acid 4:1 and added dropwise with stirring to 10 ml. of 99.5% phosphoric acid. The resulting viscous mixture was stirred at 0.20 for 2 hours. The reaction mixture was poured into 50 ml. of water. The aqueous phase was made alkaline with 6 N sodium hydroxide and the temperature was allowed to rise to about 40. After 10 minutes, the aqueous alkaline phase was extracted thoroughly with methylene chloride; the organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product (1.714 g.) was chromatographed through 17 g. of neutral alumina, activity II; elution with methylene chloride yielded 1.178 g. (66%) of a mixture of quinidinone and quininone. Crystallization from ether yielded 915 mg. (51%) of quinidinone which after recrystallization from ether had a melting point of 98101; [0:]; +72.6 (c. 0.99, ethanol; after equilibration in ethanolic solution for 18 hours at 20).

EXAMPLE 4 Preparation of racemic 7'-methoxy-dihydrocinchotoxine from cis 1-benzoyl-3-ethyl-4-piperidinepropionic acid ethyl ester and 7-methoxy-4-carbethoxy-quinoline A solution containing 25.4 g. of cis 1-benzoyl-3-ethy1- 4-piperidinepropionic acid ethyl ester in 250 m1. of dry tetrahydrofuran was added dropwise (30 min.) to a gently refluxing mixture of 26.9 g. of potassium t-butoxide and 25.8 g. of 7-methoxy-4-carbethoxyquinoline in 400 ml. of dry tetrahydrofuran, in an atmosphere of dry nitrogen. The mixture was heated under gentle reflux for two hours, and the solvent was removed under reduced pressure. The residue was dissolved in 300 ml. of 0.5 N sodium hydroxide, and was washed with benzene. The alkaline aqueous phase containing 'a-CiS(1-bDZOy1-3- ethyl 4 piperidylmethyl) B oxo-fi-(7-methoxy-4- quinolyl)propionic acid ethyl ester was acidified so that a 6 N aqueous hydrochloric acid solution was obtained, and the solution was heated under reflux for 21 hours. The cooled reaction mixture was made alkaline with 6 N sodium hydroxide, and extracted thoroughly with ether. The ethereal extracts were dried over anhydrous potassium carbonate and concentrated to dryness.

The crude product (21.0 g.) was dissolved in a small volume of acetone and added to a solution containing 14.5 g. of dibenzoyl-d-tartaric acid in acetone. The precipitate was separated by filtration, the free bases of the mother liquors were purified by preparative tlc to yield racemic 7'-methoxy-dihydrocinchotoxine. A sample of the neutral dibenzoyl-d-tartarate was recrystallized from methanol and had a melting point of 174175.5. The free base dl-7'-methoxy-dihydrocinchotoxine was obtained as a yellow oil.

EXAMPLE 5 Preparation of 7-methoxy-dihydrocinchotoxine from N- benzoylhomocincholoipone ethyl ester and 7-meth0xy- 4-carbethoxy quinoline A solution containing 4.14 g. of N-benzoylhomocincholoipone ethyl ester in 40 ml. of dry tetrahydrofuran was added dropwise (20 min.) to a gently refluxing mixture of 4.98 g. of potassium t-butoxide and 4.74 g. of 7-methoxy-4-carbethoxyquinoline in ml. of dry tetrahydrofuran in an atmosphere of dry nitrogen. The mixture was heated under gentle reflux for three hours, then the solvent was removed by distillation under vacuum, and the cooled residue dissolved in 100 ml. of 0.5 N sodium hydroxide. The alkaline .phase was washed with benzene and the benzene phases washed with 0.5 N sodium hydroxide. The combined aqueous phases containing a [1-benzoyl-3 (R)-ethyl-4(R)piperidylmethyl]- r 2 )S-oxo-fi-(7-methoxy-4-quinolyl) propionic acid ethyl ester were acidified so that a 6 N hydrochloric acid solution was obtained, and then heated under gentle reflux for 17 hours. The cooled reaction mixture was made alkaline with 6 N sodium hydroxide and thoroughly extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The crude product (3.30 g.) was dissolved in a small volume of acetone, and 1.7 g. of dibenzoyl-d-tartaric acid as a concentrated solution in acetone was added. Crystallization yielded 4.11 g. (54%) of 7'-methoxy-dihydrocinchotoxine as its neutral dibenzoyl-d-tartarate; having a melting point of 177179 after recrystallization from chloroform-methanol; [M -39.6- [c. 0.5, ethanolchloroform (1:2)].

EXAMPLE 6 Preparation of 7'-methoxy-dihydrocinchoninone and 7- methoxy-dihydrocinchonidinone from 7-methoxy-dihydrocinchotoxine To a solution containing 2.65 g. of 7'-methoxy-dihydrocinchotoxine in 100 ml. of chloroform were added ml. of about a 17% aqueous sodium hypochlorite solution. The resulting mixture was stirred at 20 for 16 hours. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The crude N-chloro-7'-methoxy-dihydrocinchotoxine was dissolved in a minimal amount of chloroform and added dropwise to 15 ml. of 100% phosphoric acid with vigorous stirring. The resulting viscous mixture was stirred at for 4 hours. Thereafter, it was made alkaline with 6 N potassium hydroxide and the temperature of the alkaline phase was allowed to reach about After 10 minutes, the aqueous phase was extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate, and concentrated to dryness. The crude product (2.49 g.) was chromatographed on a column of 75 g. of neutral alumina, activity II; elution with methylene chloride yielded 1.49 g. (56%) of a mixture of 7'-methoxy-dihydrocinchoninone and 7- methoxy-dihydrocinchonidinone having a melting point of 103108 after recrystallization from petroleum ether, and a specific rotation of [M +16 (c. 0.27, ethanol; after equilibration in ethanolic solution for 18 hours at 20).

In the like manner, the following analogs can be prepared:

A mixture of 7-chloro-4-[5(R)-ethyl-4(S)-quinuclidin-2 (R)-ylcarbonyl1-quinoline and 7-chloro-4-[5 (R)-ethyl- 4(S)-quinuclidin-2(S)-ylcarbonyl]quinoline, which is amorphous; its antipode, which is amorphous; and racemate thereof, having a M.P. of 124-127;

A mixture of 7-chloro-4-[5(R)-vinyl-4(S)-quinuclidin-2 (S)-ylcarbonyl]-quinoline and 7-chloro-4-[5(R) -vinyl- 4(S)-quinuclidin-2(S)-ylcarbonyl1-quino1ine, which is amorphous;

A mixture of racemic 7-trifiuoromethyl-4-[5(R)-ethy1-4 (S)-quinuclidin 2(R) ylcarbonyll-quinoline and racemic 7 -trifluoromethyl-4- [5 (R) -ethyl-4(S) quinuclidin-2(5)-ylcarbonyl]-quinoline; M.P. l06-11l.

EXAMPLE 7 Prepartion of racemic 7'-methoxy-dihydrocinchonidinone and racemic 7-methoxy-dihyldrocinchoninone from racemic 7-methoxydihydrocinchotoxine To a solution containing 20.6 g. of racemic 7-methoxydihydrocinchotoxine in 150 ml. of chloroform were added ml. of about a 17% aqueous sodium hypochlorite solution, and the mixture was agitated for 16 hours at 20. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude racemic N-chloro-7methoxydihydrocinchotoxine was dissolved in a minimum volume of chloroform and added dropwise to 150 ml. of concentrated V r 24 phosphoric acid at 20 with vigorous stirring. The resulting viscous mixture was stirred for 2 hours. The solution was cooled with ice, diluted wit water, and made alkaline with 6 N sodium hydroxide. During neutralization, the temperature was allowed to reach about 40. After about 10 minutes, the alkaline aqueous phase was extracted thoroughly with ether and the ethereal phase was dried over anhydrous potassium carbonate and evaporated to dryness. The crude, crystalline product (20.4 g.) was dissolved in petroleum ether, leaving an insoluble, tarry residue of 3.4 g. Crystallization from the same solvent yielded 9.49 g. of racemic 7'-methoxy-dihydrocinchonidinone and 7.52 g. of an amorphous mixture of racemic 7'-methoxy-dihydrocinchoninone and racemic 7'-methoxydihydrocinchonidinone (total yield 82%). After 2 recrystallizations from petroleum ether, racemic 7-methoxy-dihydrocinchonidinone had a melting point of 1l5118.

EXAMPLE 8 Preparation of dihydroquinidine from dihydroquinidinone To a solution containing 2.0 g. of dihydroquinidinone in 150 ml. of dry toluene, stirred at 20 in an atmosphere of dry nitrogen, were added dropwise 4.8 ml. of a 25% solution of diisobutyl aluminum hydride in toluene. As soon as all the ketone was consumed, the reaction was quenched by the addition of 3 ml. of water-methanol (1:1). The aluminum hydroxide which precipitated was separated by filtration and was washed thoroughly with benzene and methanol. The combined filtrates were evaporated to dryness. Crystallization of the residue from ethanol yielded 1.90 g. of dihydroquinidine (94% yield) in three crops which after recrystallization from ethanol had a melting point of l68169; [a] +2Z7.9 (c. 0.896, ethanol).

- EXAMPLE 9 Preparation of dihydroquinidine and dihydroquinine from a mixture of dihydroquinidinone and dihydroquininone A solution containing 1.25 g. of dihydroquinidinone in 50 ml. of benzene containing 0.5 ml. of methanol was maintained at 20 for 2 /2 days under nitrogen. The solution was evaporated to complete dryness under vacuum, and the residue redissolved in benzene and again evap orated to dryness. The resulting oily residue was dissolved in 50 ml. of dry benzene, and 3 ml. of a 25 solution of di-isobutyl aluminum hydride in toluene were added dropwise with stirring under an atmosphere of dry nitrogen. The reaction was quenched after about 30 minutes by adding 10 ml. of water-methanol (1:1), and the mixture was stirred vigorously for 30 minutes. The benzene layer was decanted. The aqueous aluminum suspension was washed several times with benzene and the combined benzene phases were dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (1.25 g. of colorless foam) was a practically pure mixture of dihydroquinidine and dihydroquinine (about 1:1) as determined by thin layer chromatography; and a specific rotation [a] +62.2 (c. 1.64, ethanol). Crystallization from ethanol yielded 490 mg. of pure dihydroquinidine having a melting point of 167-169". Chromatographic separation from mother liquors gave 550 M.P. of dihydroquinine, M.P. 168-170", [M -137.5.

EXAMPLE 10 Preparation of racemic dihydroquinine from racemic '7 dihydroquininone To a solution containing 1.0 g. of racemic dihydroquininone in ml. of dry benzene were added 2.5 ml. of a 25 solution of di-isobutyl aluminum hydride in toluene with stirring under an atmosphere of dry nitrogen. After about 30 minutes, the reaction was quenched by the addition of 2 ml. of methanol-water (1:1). The alumina which precipitated was separated by filtration, washed thoroughly with methanol, and the filtrate was evaporated to dryness. Crystallization of the crudeproduct (1.003 g.)

from acetone yielded 718 mg. of racemic dihydroquinine as its monohydrate, which after recrystallization from acetone had a melting point of l74-177.

EXAMPLE 11 Preparation of anhydrous d,l-dihydroquinine d,l-Dihydroquinine monohydrate after repeated evaporation from a benzene solution yielded d,l-dihydroquinine having a melting point of 172-174.

EXAMPLE 12 Preparation of racemic dihydroquinine sulfate A solution containing 5.253 g. of d,l-dihydroquinine in 20 ml. of methanol and 16.1 ml. of 1 N aqueous sulfuric acid was cooled at The precipitated crystals were separated by filtration, washed with acetone and dried at 60/50 mm. for 20 hours. After additional drying at 80/ 0.01 mm., d,l-dihydroquinine sulfate was obtained, which contained 0.5 mole of water and had a melting point of 210-213".

EXAMPLE 13 Preparation of racemic dihydroquinine and racemic dihydroquinidine from a mixture of racemic dihydroquininone and racemic dihydroquinidinone The reduction of 5.06 g. of a crystalline mixture of racemic dihydroquininone and dihydroquinidinone (melt ing point of 76-89) was carried out in dry benzene with di-isobutyl aluminum hydride according to the procedure described in Example 8. The methanol extracts (3.87 g.) were crystallized from acetone to yield 3.14 g. (61%) of racemic dihydroquinine monohydrate in three crops. The benzene extracts (1.54 g.) were crystallized from a concentrated solution in ethanol to yield 579 mg. (11%) of racemic dihydroquinidine in four crops. Racemic dihydroquinidine: after recrystallization from ethanol had a melting point of 152-1545".

EXAMPLE 14 I Preparation of racemic dihydroquinidine sulfate To 2.02 g. of d,l-dihydroquinidine in 25 ml. of absolute ethanol were first added 6.2 ml. of 1 N aqueous sulfuric acid, followed by ml. of water. The sulfate (2.03 g.) crystallized after the volume was evaporated to 20 ml. After drying at 80/0.01 mm. for 70 hours, the d,l-dihydroquinidine 50.; contained mole of water and had a melting point of 208-211".

EXAMPLE 15 Preparation of quinidine from quinidinone To a solution containing 1.00 g. of quinidine in 40 ml. of dry benzene were added dropwise 2.4 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene. After stirring at under an atmosphere of dry nitrogen, 10 ml. of water was added. The benzene layer was separated, dried over anhydrous magnesium sulfate, and evaporated to dryness. The crude, crystalline product (0.890 g.) was recrystallized from ethanol to yield 0.646 g. of crystalline quinidine having a melting point of 169-171; [M +264.3 (c. 0.98, ethanol).

In the like manner, the following can be prepared:

6-chloro-a(S)-[5(R)-ethyl 4(S) quinuclidin-2 R)-yl]- 4-quinolinemethanol, M.P. 98l00.

6-chloro-a(R)-[5(R)-ethyl 4(S) quinuclidin-2(S)-yl]- 4-quinolinemethanol, M.P. 196-198.

Antipodes of 7-ChlOIO-oc (S)-[5 (R)-ethyl-4(S)-quinuclidin- 2(R)-yl] 4 quinolinemethanol, M.P. 278-280, and racemic analog, M.P. 251253.

7-chlor0-a(R)-[5(R)-ethyl 4(S) quinuclidin-2(S)-yl]- 4-quinolinemethanol, M.P. 218-220", antipode, M.P. 224-225, and racemic analog, M.P. 192-193.

6-chloro-a(S)-[5(R)-vinyl 4(S) quinuclidin-2(R)-yl]- 4-quinolinemethanol, M.P. 154-155.

6-chloro-a(R)-[5(R)-vinyl 4(S) quinuclidin-2 (S)-yl]- 4-quinolinernethanol, M.P. 193-194.

6,8-diChlOIOot(S)-['5 (R)-vinyl 4(S) quinuclidin-2(R)- yl]-4-quinolinemethanol (dihydrochloride, M.P. 250 dec.).

6,8-dichloro-a(R)-[5(R)-vinyl 4(S) quinuclidin-2(S)- yl]-4-quinolinemethanol, M.P. -108".

Racemic 7-trifluoromethyl a(S) [5 (R) ethyl 4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol, M.P. 218- 219.5

Racemic 7-trifiuoromethyl a(R) [5 (R) ethyl 4(S)- quinuclidin-Z (S)-yl]-4-quinolinemethanol, M.P. 176.

7-trifluoromethyl-a(S)-[5(R) vinyl 4(S) quinuclidin- 2(iR)-yl]-4-quinolinemethanol, M.P. 228-229".

7-trifluoromethyl-u('R)-[5(R)-vinyl 4(S) quinuclidin- 2(S)-yl]-4-quinolinemethanol (dihydrochloride, M.P. 211-215 7-trifluoromethyl-a(S)-[5(R)-ethyl 4(S) quinuclidin- 2 (R) -yl] -4-quinolinemethanol, M.P. 227-230 7-trifiuoromethyl-a(R)-[5(R)ethyl 4(S) quinuclidin- 2(S)-yl]-4-quinolinemethanol, M.P. 163-164".

5-trifluoromethyl-a-(S)-[5(R)-vinyl 4(S) quinuclidin- 2 R) yl] -4-quinolinemethanol.

5-trifiuoromethyl-a(R)-[5(R)-vinyl 4(S) quinuclidin- 2 (S) -yl] -4-quinolinemethanol.

6-trifluoromethyl-a(S)-[5(R)-vinyl 4(S) quinuclidin- 2 (R) yl] -4- quinolinemethanol.

6-tlifiu0I'OII16thYl-a (R)-[5(R)-vinyl 4(S) quinuclidin- 2 (S) -yl] -4-quinolinemethanol.

EXAMPLE 16 thoxy-dihydrocinchoninone and 7'-methoxy-dihydrocinchonidinone To a solution containing 1.46 g. of a mixture of 7'-methoxy dihydrocinchoninone and 7-methoxy-dihydrocinchonidinone in 50 ml. of dry benzene, stirred under an atmosphere of dry nitrogen at 20, were added dropwise 3.75 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene. When all the ketone was consumed, 5 ml. of 50% aqueous methanol were added. The alumina which precipitated was separated by filtration, and washed thoroughly with benzene. The combined filtrates were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was triturated with acetone, and crystallization yielded 7'-methoxy-dihydrocinchonine. After recrystallizations from chloroform-petroleum ether, 7'-methoxy-dihydrocinconine had a melting point of 231- 233; +l69.5 (c. 1.00, ethanol). From the mother liquors, 7'-methoxy-dihydrocinchonidine was obtained by fractional crystallization from acetone. After recrystallization, '-methoxy-dihydrocinchonidine had a melting point of 162-165"; -80.3 (c. 0.98, ethanol).

EXLAMPLE 17 Preparation of racemic 7'-methoxy-dihydrocinchonidine racemic 7'-methoxy-dihydrocinchonidinone To a solution containing 2.32 g. of racemic 7'-methoxydihydrocinchonidinone (melting point 112-116) in 50 ml. of dry benzene were added dropwise 6.5 ml. of a 25 solution of di-isobutyl aluminum hydride in toluene 27 I at 20 under an atmosphere of dry nitrogen. After stirring for about 30 minutes at 20, 8 m1. of 50% aqueous methanol were added. The alumina which precipitated was separated by filtration and washed thoroughly with benzene.

The filtrate was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was triturated with ether and 1.78 g. of crystalline racemic 7'-methoxydihydrocinchonidine having a melting point of 155-157 were collected. 1

EXAMPLE 18 Preparation of racemic 7'-methoxy-dihydrocinchonine and racemic 7-methoxy-dihydrocinchonidinefrom a mixture of racemic 7'-methoxy-dihydrocinchoninone and 7'-methoxy-dihydrocinchonidinone To a solution containing 2.52 g. of an amorphous mixture of racemic 7 -methoxy-dihydrocinchoninone and racemic 7-methoxy-dihydrocinchonidinone in 50 ml. of

solution of di-isobutyl aluminum hydride in toluene at 20 under an atmosphere of dry nitrogen. After stirring for about 30 minutes at 20, 8 ml. of 50% aqueous methanol were added, the alumina which precipitated was sepdry benzene, were added dropwise 7.2 ml. of a 25% I arated by filtration and washed thoroughly with benzene.

Preparation of 6',7' dimethoxy-dihydrocinchotoxine from 6,7-dimethoxy-4-carbethoxy quinoline and N-benzoylhomocinchloipon'ethyl ester A solution containing 3.28 g. of N-benzoyl-homocincholoipon ethyl ester in 30 ml. of dry tetrahydrofuran .was added dropwise (30 min.) to a gently refluxing mixture of 3.13 g. of 6,7-dimethoxy-4-carbethoxyquinoline and 3.40 g. of potassium S-butoxide in 50 ml. of dry tetrahydrofuran in an atmosphere of dry nitrogen. The

mixture was heated under reflux for an'additional two hours and then the solvent was removed by distillation under reduced pressure. The cooled residue was dissolved in 75 ml. of 0.5 N sodium hydroxide. The alkaline phase was washed with benzene and the benzene extracts were washed with 0.5 N sodium hydroxide. The combined aqueous phase was acidified with concentrated hydrochloric acid, so that about a 6 N hydrochloric acid solution was obtained, and heated under gentle reflux for 24 hours. The cold reaction mixture was made alkaline with 6 N sodium hydroxide and was thoroughly extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The crude product was dissolved in a small volume of acetone, and 0.805 g. of dibenzoyl-d-tartaric acid was added as a concentrated solution in acetone. Crystallization yielded 1.63 I

g. of 6,7'-dimethoxy-dihydrocinchotoxine neutral dibenzoyl-d-tartarate, having a melting point of 16l.5163.5,

.after three recrystallizations from methylene chloride/ acetone; [04],; 37.7 (2: 1 1.

[0. 1.02, chloroform-ethanol EXAMPLE 20 Mixture of 6',7-dimethoxy-dihydrocinchoninone and 6,7'-dimethoxy-dihydrocinchnidinone from 6,7'-dimethoxy-dihydrocinchotoxine To a solution containing 1.42 g. of 6',7'-dimethoxydihydrocinchotoxine in 50 ml. of chloroform was added 3.5 ml. of about 17% aqueous sodium hypochlorite, and the mixture was stirred at 20 for 90 minutes. The organic phase was separated, washedwith water, dried over anhydrous sodium sulfate and concentrated to a volume 28 of 10 ml. The solution containing 6,7-dimethoxy-4[3-(1- chloro-3(R)-ethyl-4(R)-piperidyl) 1 oxopropylJ-quinoline was added dropwise to 10 ml. of 100% phosphoric acid, and the viscous mixture was stirred at 20 for 5 hours. The mixture was diluted with water, made alkaline with 6 N potassium hydroxide while allowing the alkaline phase to reach about 40, and extracted thoroughly with ether. The ethereal phase was dried over anhydrous po tassium carbonate and concentrated to dryness. The crude product was purified on preparative talc plates [chloroform-triethylamine (9:1)], to yield .794 g. of a pure, amorphous mixture (about 1:1) of 6',7'-dimethoxy-dihydrocinchoninone and 6',7-dimethoxy-dihydrocinchonidinone.

EXAMPLE 21 6',7'-dimethoxy-dihydrocinchonine and 6',7'-dimethoxydihydrocinchonidine from a mixture of 6',7'-dimethoxydihydrocinchoninone and 6',7'-dimethoxy-dihydrocinchonidinone To a solution containing .745 g. of a mixture of 6',7- dimethoxy dihydrocinchoninone and 6',7-dimethoxy-dihydrocinchonidinone in 20 ml. of dry benzene, which was stirred in an atmosphere of dry nitrogen at 20, were added dropwise, 1.5 ml. of 25% di-isobutyl aluminum hydride in toluene. After about 60 minutes, 5 ml. of watermethanol (2:3) mixture was added. The precipitated alumina was separated by filtration and washed thoroughly with benzene. The combined filtrates were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was separated by preparative talc (chloroform-triethylamine-methanol=z10:5) into the two isomers 6,7'-dimethoxydihydrocinchonine and 6',7'-dirnethoxy-dihydrocinchonidine. The less polar 6,7'-dimethoxy-dihydrocinchonine was crystallized from ether; and had a melting point of 116-118. after several recrystallizations from acetone; [111 +l82.2 (c. 0.95, ethanol). The more polar 6',7' dimethoxy dihydrocinchonidine could not be crystallized; [M 87.3 (c. 0.68, ethanol).

EXAMPLE 22 Preparation of racemic 6',7'-dimethoxydihydrocinchotoxine from cis 1-benzoyl-3-ethyl-4-piperidinepropionic acid ethyl ester and 6,7-dimethoxy-4-carbethoxyquino line A solution containing 31.7 g. of cis (1-benzoyl-3-ethyl- Lpiperidinepropionic acid ethyl ester in 250 ml. of dry tetrahydrofuran was added dropwise (40 min.) to a refluxing mixture of 36.5 g. of 6,7-dimethoxy-4-carbethoxyquinoline and 33.6 g. of potassium t-butoxide in 500 ml. of dry tetrahydrofuran under an atmosphere of dry nitrogen. The mixture was heated under reflux for two hours and the solvent was removed under reduced pressure. The cold residue was dissolved in 300 ml. of 0.5 N sodium hydroxide and washed with four '60 ml. portions of benzene. The combined aqueous phases containing the fl-ketoester were acidified with cone. HCl, whereby a 6 N hydrochloric acid solution was obtained, and then heated under reflux for 24 hours. The reaction mixture was allowed to cool, made alkaline with 6 N sodium hydroxide and extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness to give 14.5 g. (40%) of amorphous racemic 6,7'-dimethoxydihydrocinchotoxine. 1

EXAMPLE 23 Preparation of racemic 6,7'-dimethoxydihydrocinchonidinone and racemic 6',7'-dimethoxydihydrocinchoninone from racemic 6',7-dimethoxydihydrocinchotoxine To a solution containing 14.5 g. of racemic 6,7'-dimethoxydihydrocinchotoxine in 200 ml. of dichloromethane was added 25 ml. of about a 17% aqueous sodium hypochlorite, and the mixture was stirred vigorously for 60 min. The organic phase was separated, washed with water,

29 dried over anhydrous sodium sulfate, and evaporated to a volume of about 20 ml. This solution containing the chloramine was added dropwise to 60 ml. of 99.5% phosphoric acid. The cosolvent was evaporated and the viscous mixture stirred at 20 for 4 hours. The mixture was diluted with water and made alkaline with 6 N sodium hydroxide. The alkaline phase was allowed to reach about 40, and was extracted with ether. The ethereal phase was dried over anhydrous potassium carbonate and concentrated to dryness. The product (12.8 g.) was absorbed on 100 g. of neutral alumina, activity II. =Elution with benzene and dichloromethane yielded 9.2 g. (65%) of an amorphous mixture comprising racemic 6',7'-dimethoxydihy drocinchonidinone and racemic 6',7'-dimethoxydihydrocinchoninone.

EXAMPLE 24 Preparation of racemic 6',7' dimethoxydihydrocinchonidine and racemic 6',7' dimethoxydihydrocinchonine from a mixture of racemic 6',7 dimethoxydihydrocinchonidinone and racemic 6,7' dimethoxydihydrocincinchoninone.

To a solution containing 9.2 g. of a mixture of the racemic 6,7'-dimethoxydihydrocinchonidinone and racemic 6,7' dimethoxydihydrocinchoninone in 200 ml. of dry benzene, which was stirred under an atmosphere of dry nitrogen at 20, was added dropwise a 25% solution of di-isobutyl aluminum hydride in toluene. After the addition of 17.5 ml., the reaction was completed. The reaction was quenched by addition of 40 m1. of methanolwater (3:2). The precipitated alumina was separated by filtration and washed thoroughly with benzene. The filtrates were combined. The benzene layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The product was separated by preparative thin layer chromatography (silica gel GF chloroform-triethylamine-methanol, 85 :10:5). The less polar fraction yielded 4.4 g. of amorphous, racemic 6', 7-dimethoxydihydrocinchonine.

For final purification, the base was converted to the racemic 6,7' dimethoxydihydrocinchonine dihydrochloride, which had a melting point of 221225 (dec.) after recrystallization from methanol.

The more polar fraction (3.4 g.) containing racemic 6',7' dimethoxydihydrocinchonidine gave crystals from acetone having a melting point of 155-157. Racemic 6',7' dimethoxydihydrocinchonidine dihydrochloride was obtained after recrystallization from methanol and had a melting point of 208-210 (dec.).

EXAMPLE 25 Rac. cis 1-chloro-3-ethyl-4piperidinepropionic acid ethyl ester (A) To a solution of 1.064 g. of racemic cis 3-ethyl- 4-piperidinepropionic acid ethyl ester in 30 ml. of ether was added 30 ml. of a 16.9 percent aqueous solution of sodium hypochlorite. The mixture was shaken at room temperature. In intervals of 1 hour the aqueous layer was separated and fresh sodium hypochlorite solution (30 ml.) was added. After 4.5 hours, 100 ml. of benzene was added to the mixture. The organic layer was separated and washed successively with water (2X 3 N aqueous hydrochloric acid (3X) and water (3x). After drying over sodium sulfate and evaporating under reduced pressure 0.90 g. of liquid racemic cis 1-chloro-3-ethyl-4- piperidinepropionic acid ethyl ester was obtained.

(B) To a stirred suspension of 11 g. of N-chlorosuccinimide in 200 ml. of anhydrous ether was added in a nitrogen atmosphere a solution of 15 g. of racemic cis 3-ethyl-4-piperidinepropionic acid ethyl ester in 100 ml. of anhydrous ether. After continued stirring for 1 hour at room temperature the mixture was successively washed with water (3X), 2.5 N aqueous sulfuric acid (2X) and water. The ethereal solution was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 18 g. of liquid racemic cis 1- chloro-3-ethyl-4-piperidinepropionic acid ethyl ester.

EXAMPLE 26 Rac. cis 1-benzoyl-3-(2-chloroethyl)-4-piperidinepropionic acid ethyl ester Eighteen grams of racemic cis l-chloro 3 ethyl-4- piperidinepropionic acid ethyl ester was dissolved in 150 ml. of trifluoroacetic acid at 0. The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 10 with 200 w.-Hanovia high-pressure mercury lamp. At intervals, samples were removed and the reaction was continued until a negative starch-iodide test was obtained. After 5 hours, the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This procedure was repeated several times. To a stirred solution of 40 g. of the cude racemic cis 3-(2-chloroethyl) 4 piperidinepropionic acid ethyl ester trifluoroacetate and 26 g. of benzoyl chloride in 400 ml. of benzene was added over a period of 2 hours a saturated aqueous solution of potassium carbonate until the pH reached 9. Stirring was continued for 1 hour. After the addition of 200 ml. of benzene, the mixture was washed successively with 6 N aqueous sodium hydroxide (3X) water, 3 N aqueous hydrochloric acid and water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 30 g. of oily material, which was chromatographed on 650 g. of silica gel with benzeneethyl acetate (9:1) as the liquid phase to give 22.3 g. of 96.3 percent pure of racemic cis 1-benzoyl-3-(2-chloroethyl) 4 piperidinepropionic acid ethyl ester. Yield 87 percent.

EXAMPLE 27 Rac. cis 1-benzoyl-3-vinyl-4-piperidinepropionic acid ethyl ester (A) A solution of 3.5 g. of race-mic cis 1-benzoyl-3- (2-chloroethyl) 4 piperidinepropionic acid ethyl ester and 2.3 g. of sodium iodide in 120 ml. of methyl ethyl ketone was kept at reflux temperature for 44 hours. The mixture in which a precipitate had formed was diluted with 50 ml. of water and ml. of ether. The organic layer was separated, washed with water, diluted with benzene (100 1111.), dried over anhydrous sodium sulfate, and evaporated to dryness to give 4 g. of liquid racemic cis l-benzoyl 3 (2 iodoethyl) 4 piperidinepropionic acid ethyl ester. This was dissolved in ml. of anhydrous pyridine, and after the addition of 2.5 g. of silved fluoride, the mixture was stirred at room temperature for 24 hours. Ether (800 .ml.) was added, and the black precipitate was removed by filtration. The filtrate was washed with 3 N aqueous hydrochloric acid (3X) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was distilled under a pressure of 0.015 mm. Hg togive two fractions: at 120 C. 0.615 g. of 82 percent pure and at C. 0.990 g. of 71 percent pure of liquid racemic cis 1-benzoy1-3- vinyl 4 piperidinepropionic acid ethyl ester: yield 38 percent.

(B) The mixture of 0.5 g. of racemic cis 1-benzoyl-3- (2-chloroethyl)-4-piperidinepropionic acid ethyl ester and glass powder was heated at under a pressure of 0.025 mm. for 5 hours. The black reaction mixture was dissolved in dichloromethane, the glass powder was .removed by filtration, and the filtrate was evaporated to dryness. The residue (350 mg.) was distilled at 0.015 mm. Hg and 150 C., to give 99 mg. of liquid 78% pure rac. cis 1-benzoyl-3-vinyl-4-piperidinepropionic acid ethyl ester.

31 EXAMPLE 2s 2-benzoyl-3 (S) -(2-chloroethyl) 4 (S) -piperidinepropionic acid ethyl ester The mono-l-tartrate of 3 (S)3-ethy1-4(S)-piperidinepropionic acid ethyl ester (8.9 g.) was treated with excess 2 N aqueous potassium carbonate. The liberated free base was extracted into dichloromethane. The combined organic extract was dried over potassium carbonate and evaporated to dryness under reduced pressure to give/ g. of 3(S)-ethyl-4 (S)-piperidinepropionic acid ethyl ester. A solution of the free base in 35 m1. of anhydrous ether was added in 'a nitrogen atmosphere to a stirred suspension of 3.4 g. of N-chloro-succinimide in 70 ml. of an hydrous ether. After continued stirring for 1 hour at room temperature, the mixture was successively washed with water (3X 2.5 N aqueous sulfuric acid (2X) and water. The ethereal solution was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 5.1 g. of liquid 1-chloro-3 (S)-ethyl-4(S)- piperidinepropionic acid ethyl ester. This N-chloroamine was dissolved in 150 ml. of trifluoroacetic acid at 0. The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 14 with a 200 W-Hanovia high-pressure mercury lamp. At intervals, samples were removed and the reaction was continued as long as positive starchiodine test was obtained. After 3 hours the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This proceure was repeated several times. To a stirred solution of thus obtained 3(S)-(2-chloroethyl)- 4(S)-piperidinepropionic acid ethyl ester trifluoroacetate (11.9 g.) and 8 g. of benzoylchloride in 100 ml. of benzene was added slowly a saturated aqueous solution of potassium carbonate until the mixture reached pH 9. Stirring was continued for 90 minutes. After the addition of 100 ml. of benzene, the mixture was washed successively with 6 N aqueous sodium hydroxide (3X), water, 3 N aqueous hydrochloric acid and Water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 8.4 g. of oily material which was chromatographed on 250 g. of silica gel. Elution with 95:5, 9:1 and 9:2 mixtures of henzene and ethylacetate gave 5.95 g. of liquid 87 percent pure 1-benz0yl-3 (S)- (2 chloroethyl) -4(S)-piperidinepropi0nic acid ethyl ester. Yield 60 percent. This product was distilled twice at 0.015 mm. Hg and 160 C., to give 2 g. of 98.9 percent pure 1-benz0yl-3 (S)-(2-chloroethyl)- 4(S)piperidinepropionic acid ethyl ester [01 20.0 '(c.=0.99, methanol).

EXAMPLE 29 l-benzoyl-3 (S) -vinyl-4( S -piperidinepropionic acid ethyl ester A solution of 1.9 g. of 1-benzoyl-3(S)-(2-chloroethyl)- 4(S)-piperidinepropionic acid ethyl ester and 1.22 g. of sodium iodide in 60 ml. of methyl ethyl ketone was kept at reflux temperature for 50 hours. The mixture in which a precipitate had formed was diluted with 30 ml. of water and 50 ml. of ether. The organic layer was separated, washed with water, diluted with benzene (50 ml.), dried over anhydrous sodium sulfate, and evaporated to dryness to give 2.2 g. of liquid crude 1-benzoyl-3(S)-(2- iodoethyl)-4(S)-piperidinepropionic acid ethyl ester. This was dissolved in 60 ml. of anhydrous pyridine, and after the addition of 1.3 g. of silver fluoride, the mixture was stirred at room temperature for 20 hours. Ether (400 ml.) was added and the black precipitate was removed by filtration. The filtrate was washed with 3 N aqueous hydrochloric acid (3X) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The

liquid residue (0.82 g.) was distilled at 0.015 mm. Hg

and 118 C. to give 540 mg. of 75 percent pure l-benzoyl- 3(S)-vinyl-4( )-p peridinepropionic acid ethyl ester.

32 EXAMPLE 30 1-benzoyl-3 (R) (Z-chloroethyl) -4 (R )-piperidinepropionic acid ethyl ester The mono-d-tartrate of 3(R)-ethyl-4(R)-piperidinepropionic acid ethyl ester (15 g.) was treated with excess 2 N aqueous potassium carbonate. The liberated free base was extracted into dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 8.8 g. of 3(R)-ethyl-4(R)-piperidinepropionic acid ethyl ester. A solution of the free base in 60 m1. of anhydrous ether was added in a nitrogen atmosphere to a stirred suspension of 6.0 g. of N-chlorosuccinimide in 120 ml. of anhydrous ether. After continued stirring for 1 hour at room temperature, the mixture was successively washed with water (3X 2.5 N aqueous sulfuric acid (2X) and water. The ethereal solution was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9 g. of liquid 1-chloro-3(R)-ethyl-4(R)- piperidinepropionic acid ethyl ester. This N-chloroamine was dissolved in 150 ml. of trifluoroacetic acid at 0". The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 10 with 200 W-Hanovia high pressure mercury lamp. At intervals, samples were removed and the reaction was continued as long as a positive starchiodine test was obtained. After 5 hours, the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This procedure was repeated several times. To a stirred solution of 3(R)-(2-chloroethyl)-4(R)-piperidinepropionic acid ethyl ester trifiuoroacetate (22 g.) thus obtained and 15 g. of benzoylchloride in 150 ml. of henzene was added slowly a saturated aqueous solution of potassium carbonate until the mixture reached pH 9. Stirring was continued for 1 hour. After the addition of 200 ml. of benzene, the mixture was washed successively with 6 N aqueous sodium hydroxide (3X), water, 3 N aqueous hydrochloride acid and water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 18 g. of oily material which was chromatographed on 650 g. of silica gel. Elution with 9:1 mixture of benzene and ethyl acetate gave 11.1 g. of liquid 97.5 percent pure 1-benzoyl-3(R)-(2-chloroethyl)-4(R)-piperidinepropionic acid ethyl ester. Yield 74 percent. Analytical sample of 98.6 percent purity was obtained by distillation at 0.018 mm. Hg and 150 C [a] =+20.2 (c. 1.09, methanol).

EXAMPLE 31 1-benzoyl-3 (R) -viny1-4(R)piperidinepropionic acid ethyl ester A solution of 1.8 g of 1-benzoyl-3 (R)-(2-chloroethyl)- 4-(R)-piperidinepropionic acid ethyl ester and 1.2 g. of sodium iodide in 60 ml. of methyl ethyl ketone was kept at reflux temperature for 44 hours. The mixture in which a precipitate had formed was diluted with 30 ml. of water and 50 ml. of ether. The organic layer was separated. washed with water, diluted with benzene (50 ml.), dried over anhydrous sodium sulfate and evaporoated to dryness to give 2.3 g. of liquid crude 1-benzoyl-3 (R)-(2-iodoethyl)-4(R)-piperidinepropionic acid ethyl ester. This was dissolved in 60 ml. of anhydrous pyridine, and after the addition of 1.29 g. of silver fluoride the mixture was stirred at room temperature for 15 hours. Ether (400 ml.) was added and the black precipitate was removed by filtration. The filtrate was washed with 3 N aqueous hydrochloric acid (3X) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The liquid residue (1.23 g.) was distilled under a pressure of 0.015 mm. Hg. A fraction (560 mg.) distilling at (oil bath temperature) contained 94 percent pure 1-benzoyl-3(R)-vinyl-4(R)-piperidinepropionic acid ethyl ester. By raising the oil bath temperature to 320 mg. of

33 a second fraction containing 87 percent pure l-benzoyl- 3(R)-vinyl-4(R)-piperidinepropionic acid ethyl ester was obtained. Total yield 50 percent.

EXAMPLE 32 Preparation of 7-chlorodihydrocinchonine from 7'- chlorocinchonine EXAMPLE 32a 6'-chlorodihydrocinconidine from 6'-chlorocinchonidine To a solution of 2.39 g. of 6'-chlorocinchonidine in 100 ml. of absolute methanol was added 1.5 g. of 99 percent hydrazine hydrate (4 molar equivalents) and about 20 mg. of cupric acetate. The mixture was stirred in an open flask at 20 for 3 days, filtered through celite, the filtrate evaporated and the crude product was crystallized from acetonitrile to give 1.9 g. of crystalline 6'-chlorodihydrocinchonidine; after recrystallization from acetonitrile: M.P. 196-197; [M -111.9 (c. 0.94, methanol). Dihydrochloride, crystallized from ethanolacetone: M.P. 215-2l6 (dec.); 115 (0.

1.02, methanol).

EXAMPLE 32b 6'-chlorodihydrocinchonine from 6'-chlorocinchonine To a solution of 1.3 g. of 6-chlorocinchonine in 50 ml. of absolute methanol was added 0.8 g. of 99 percent hydrazine hydrate (4 molar equivalents) and about 10 mg. of cupric acetate. The mixture was stirred in an open flask for 3 days at 20, filtered through celite, the filtrate was evaporated, and the crude product crystallized from acetone. The first crop (0.4 g.) was combined with mother liquors purified by prep. layer chromatography and recrystallized from acetone to give 0.94'g. (about 72 percent yield) of 6'-chlorodihydrocinchonine; M.P. 98-100"; +185.2 (c. 1.0, methanol); dihydrochloride, crystallized from ethanol-acetone as three quarter hydrate: M.P. 172-174"; +171 (c. 0.94, methanol).

EXAMPLE 33 Preparation of racemic 6'-chlorodihydrocinchotoxine from cis 1-benzoyl-3-ethyl-4-piperidinepropionic acid ethyl ester and 6-chloro-4-carbethoxyquinoline A solution containing 25.4 g. of cis l-benzoyl 3-ethyl- 4-piperidinepropionic acid ethyl ester in 250 ml. of dry tetrahydrofuran was added dropwise (30 min.) to a refluxing mixture of 26.9 g. of potassium t-butoxide and 19.0 g. of 6-chloro-4-carbethoxyquinoline under an atmosphere of dry nitrogen. The mixture was heated under reflux for two hours, and the solvent was removed under reduced pressure. The cold residue was dissolved in 300 ml. of 0.5 N sodium hydroxide, and washed with four 50 ml. portions of benzene. The combined aqueous phases containing the S-ketoester were acidified (cone. HCl) whereby a 6 N hydrochloric acid solution was obtained, and then heated under reflux for 20 hours. The cooled reaction mixture was made alkaline with 6 N sodium hydroxide, and extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The product (17.3 g.) was absorbed on 500 g. of neutral alumina, activity II. Elution with benzene and with dichloromethane removed some less polar impurities. Elution with methanol yielded 13.6 g. (51%) of amorphous racemic 6'-chlorodihydrocinchotoxine.

EXAMPLE 34 Preparation of a mixture of racemic 6'-chlorodihydrocinchonidinone and racemic 6-chlorodihydrocinchoninone from racemic 6'-chlorodihydrocinchotoxine To a solution containing 13.6 g. of racemic 6'-chlorodihydrocinchotoxine in 200 ml. of dichloromethane was added 18 ml. of about a 17% aqueous sodium hypochlorite and the mixture was stirred for 60 min. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to a volume of about 20 ml. This solution, containing the chloramine, was added dropwise to 60 ml. of 99.5% phosphoric acid. The solvent was evaporated, and the viscous mixture was stirred at 20 for 17 hours. The mixture was diluted with water, and made alkaline with 6 N potassium hydroxide. The alkaline aqueous phase Was kept at about 70 for 30 min., and, thereafter, it was extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate and concentrated to dryness. The product (11.7 g.) was absorbed on g. of neutral alumina, activity II. Elution with benzene and dichloromethane yielded 9.3 g. (69%) of racemic 6-chlorodihydrocinchonidinone and racemic 6- chlorodihydrocinchoninone which was crystallized from hexane to give 7.56 g. of a product having a melting point of 97.5-100.5 containing some chlorine free impurity. A crystalline mixture of racemic 6'-chlorod1hydrocinchonidinone and racemic 6'-chlorodihydrocinchoninone was prepared also by reoxidizing a mixture of racemic 6-chlorodihydrocinchonine and racemic 6'- chlorodihydrocinchonidine.

EXAMPLE 3 5 Preparation of racemic 6' chlorodihydrocinchonidine and racemic 6'-chlorodihydrocinchonine from a mixture of racemic 6-chlorodihydrocinchonidinone and racemic 6-chlorodihydrocinchoninone To a solution of 6.73 g. of a mixture of the racemic 6-chlorodihydrocinchonidinone and racemic 6'-chlorodihydrocinchoninone (material melting at 97.5-100") in 200 ml. of dry benzene, stirred under an atmosphere of dry nitrogen at 20 was added dropwise a 25 percent solution of di-isobutyl alumina hydride in toluene. After addition of 13 ml., the reaction was completed. The reaction was quenched by addition of 20 ml. of methanol-water (2:3). The precipitated alumina was separated by filtration and washed thoroughly with benzene. The filtrates were combined. The benzene layer was separated and dried over anhydrous sodium sulfate and evaporated to dryness. The product (6.7 g.) could not be crystallized; therefore, it was separated by preparative thin layer chromatography (silica gel GF chloroform-triethylamine :911) into three fractions.

The least polar fraction (1.34 g.) was crystallized and recrystallized from acetone to give racemic 6'-chlorodihydrocinchonine having a melting point of 1725-1735. Racemic 6'-chlorodihydrocinchonine dihydrochloride had a melting point of 218-221 (dec.).

The middle fraction (2.83 g.) was crystallized from acetone to give racemic 6'-chlorodihydrocinchonidine having a melting point of 100-102.

Racemic 6-chlorodihydrocinchonidine dihydrochloride had a melting point of 219-222 (dec.) (recrystallize from methanolether).

A solution containing 19.6 g. of cis (l-benZoyl-3-ethyl- 4-piperidinepropionic acid ethyl ester in 600 ml. of dry benzene was added dropwise (3 /2 hours) to a refluxing mixture comprising 20.3 g. of 6-methyl- 4- carbethoxyquinoline and 20.8 g. of potassium t-butoxide in 300 ml. of dry benzene under an atmosphere of dry nitrogen. The mixture was heated under reflux for an additional hour and maintained at 20 overnight. The crude mixture was extracted once with 200 ml. and three times with 20 ml. of cold 0.5 N aqueous potassium hydroxide. Thereafter, the aqueous phases were washed with 4 portions of 50 ml. of benzene. The combined alkaline aqueous phases containing the crude fi-ketoester were acidified 'with cone. HCl whereby a 6 N hydrochloric acid solution was obtained, and then heated under reflux for 24 hours. The cooled mixture was made alkaline with 6 N potassium hydroxide, and extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness to give 13.1 g.

(68%) of racemic 6-methyl-dihydrocinchotoxhie.

EXAMPLE 37 Preparation of a mixture of racemic 6'-methyl-dihydrocinchonidinone and racemic 6' methyl dihydrocinchoninone from racemic 6' methyl dihydrocinchotoxine To a solution containing 13.1 g. of racemic 6 -rnethyldihydrocinchotoxine in 150 ml. of dichloromethane was added an excess of about 17% aqueous sodium hypochlorite solution, and the'mixture was stirred at 20 for 1 hour. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to 20 ml. This solution, containing the chloramine, was added dropwise to 50 ml. of 99.5 phosphoric acid. The dichloromethane was evaporated, and the viscous mixture was stirred at 20 for 17 hours. Thereafter, the mixture was diluted with 20 ml. of water and made alkaline with 6 N potassium hydroxide. The alkaline aqueous phase was maintained at 40 for 30 min., and subsequently extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness to give 13.2 g. of a crystalline product. A portion was recrystallized twice from hexane to give about a 1:1 mixture of 6'-methyl-dihydrocinchonidinone and racemic 6'- methyl-dihydrocinehoninone having a melting point of 105-108.

EXAMPLE 38 Preparation of racemic 6 methyl dihydrocinchonidine and racemic 6'-methyl-dihydrocinchonine from a mixture of racemic 6-methyl-dihydrocinchorddinone and racemic 6'-methyl-dihydrocinchoninone 12.3 g. of a mixture Eomprising racemic 6'-methyl-dihydrocinchonidinone and racemic 6'-methyldihydrocinchoninone was reduced in several batches. In a typical run 4.0 g. of crystalline mixture was dissolved in 125 ml.

of dry benzene, and 9 ml. of a 25% solution of di-isobutyl aluminum hydride was added dropwise at 20 to the stirred solution under an atmosphere of dry nitrogen. After about 30 min, the reaction was quenched by addition of 15 ml. of aqueous methanol (2:3). The precipitated alumina was separated by filtration and washed thoroughly with benzene. The filtrates were combined, and the benzene layer separated, dried over anhydrous 36 sodium sulfate and evaporated to dryness. Trituration with acetone yielded crystalline 6' methyldihydrocinchonidine having a melting point of 2162 18 after recrystallization from tetrahydrofuran.

Racemic 6' -methyldihydrocinchonidine dihydrochloride was crystallized from methanol-ethyl, M.P. 213- 216 (dec.).

The mother liquors were converted to the dihydrochloride, whereupon 2.8 g. of racemic 6-methyldihydrocinchonine dihydrochloride was crystallized from methanol and had a melting point of 219-220 '(dec.).

A portion was converted to the free base and crystallized from acetone to give racemic 6'-methyldihydrocinchonine having a melting point of 153.5-155".

EXAMPLE 40 Preparation of racemic N-benzoyl6-7'-methylenedioxycinchotoxine A solution of 15.8 g. of racemic N-benzoyl-homomeroquinene ethyl ester in 200 ml. of anhydrous tetrahydrofuran was added during minutes to a gently refluxing mixture of 14.7 g. of 6,7-methylenedioxy-4-carbethoxyquinoline ethyl ester and 16.8 g. of potassium-t-butoxide in 250 ml. of anhydrous tetrahydrofuran under an atmosphere of dry nitrogen. After completed addition refluxing was continued for an additional 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in 200 ml. of 0.5 N sodium hydroxide. The solution was washed with benzene twice and rendered acidic by the addition of 3 N hydrochloric acid. The acidic solution was extracted three times with a benzene-ether mixture. The combined organic extract was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to give 20 g. of crude racemic a-[l-benzoyl- 3-vinyl 4 piperidylmethyl] B oxo-fl-(6,7-methy1enedioxy-4-quinolyl)-propionie acid ethyl ester.

A solution of the crude tx-[1-benzoyl-3-vinyl-4-piperidylmethyl]-fi-oxo-;3-(6,7 methylenedioxy 4 quinolyl) propionic acid ethyl ester (20 g.) in 200 ml. of 6 N hydrochloric acid was heated under reflux for 1 hour. The cooled reaction mixture was Washed with ether, made alkaline with 6 N sodium hydroxide and extracted thoroughly with an ether-benzene mixture. The organic extract was dried over sodium sulfate and concentrated to dryness to give 9.5 g. of residue. Chromatography of this material (7.9 g.) on silica gel with ethyl acetate as eluant afforded 6.17 g. (28%) of racemic N-benzoyl-6,7 methylenedioxy-cinchotoxine. The free base (630 mg.) was dissolved in an excess of ethanolic hydrogen chloride. Addition of ether to the solution precipitated 560 mg. of crystalline racemic N benzoyl 6',7-methylenedioxycinchotoxine hydrochloride (4-HCl), M.P. 142-144". Recrystallization from ethanol-ether afforded analytically pure hydrochloride of racemic N-benzoyl-6',7'-methylenedioxy-cinchotoxine, M.P. 145-147.

EXAMPLE 41 I Preparation of racemic 6',7-methylenedioxy-cinchotoxine A solution of 5.3 g. of racemic N-benzoyl-6,7'-methylenedioxy-cinchotoxine in 350 ml. of a methanol-water mixture (3: 1) was heated under reflux for 48 hours. After the addition of ml. of water the solution was concentrated under reduced pressure and extracted repeatedly with a benzene-ether mixture. The combined organic extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 3.2 g. of oily residue. Trituration with acetone afforded 1.65 g. (41%) of crystalline racemic 6,7'-methylenedioxy-cinchotoxine, M.P. l30l3 1 Analysis.Calcd. for C20H22N203 (338.39) percent): C, 70.98; H, 6.55; N, 8.28. Found (percent): C, 70.72; H, 6.63; N, 8.09.

EXAMPLE 42 Preparation of racemic 6',7'-methylenedioxy-cinchonidinone and racemic 6',7'-methylenedioxy-cinchoninone To a solution of 1.4 g. of racemic 6,7'-methylenedioxycinchotoxine in 80 ml. of dichloromethane was added 50 ml. of a 17% aqueous sodium hypochlorite solution. The resulting mixture was stirred at 2025 .for 2.5 hours. The organic phase was separated and the aqueous layer was Washed with dichloromethane. The combined organic solution was washed with water, dried over anhydrous sodium sulfate and concentrated to a volume of ml. This solution was added dropwise to 20 ml. of 99.7% phosphoric acid with vigorous stirring. The viscous mixture was stirred at 20-25" for 17 hours, poured onto ice and rendered alkaline by the addition of ammonium hydroxide. The mixture was kept at 5560 for 40 minutes and then extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue (1.4 g.) was chromatographed on 14 g. of neutral alumina (Woelm), activity II; elution with 350 ml. of benzene aflorded 1.17 g. (84%) of a mixture of racemic 6,7'- methylenedioxy-cinchonidinone and racemic 6,7'-methylenedioxycinchoninone.

EXAMPLE 43 Preparation of racemic 6',7'-methylenedioxy-cinchonidine and racemic 6',7'-methylenedioxy-cinchonine To a solution of 1.455 g. of a mixture of racemic 6',7'- methylenedioxy-cinchonidinone and racemic 6',7'-methylenedioxy-cinchoninone in 20 ml. of anhydrous benzene was added dropwise 2.87 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene under an atmosphere of dry nitrogen. The reaction was quenched after 90 minutes by adding ml. of water-methanol (1:1) with vigorous 40 stirring. The precipitate was collected by filtration and Washed thoroughly with methanol. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in chloroform was washed successively with 1 N sodium hydroxide and water, dried 45 over anhydrous sodium sulfate, and evaporated to dryness. The crude produce (1.4 g.) was chromatographed on Merck F254 silica gel preparative plates (20 x 20 x 0.2 cm.) with chloroform-triethylamine (85:10) as the solvent mixture. Elution of the lower of two major bands with methanol-chloroform and crystallization of the eluate from acetone gave 422 mg. (30%) of racemic 6',7'-methylenedioxy-cinchonidine, M.P. 224-225 Analysis.Calcd. for C H N O (338.39) (percent): C, 70.98; H, 6.55; N, 8.28. Found (percent): C, 70.76; H, 6.60; N, 8.13.

Upon addition of excess ethanolic hydrogen chloride to a solution of the free base (367 mg.) in a mixture of chloroform-ethanol 445 mg. of crystalline racemic 6',7'- methylenedioxy-cinchonidine dihydrochloride (7.2 HCl) was obtained, M.P. 284 285". After recrystallization from methanol a sample had M.P. 285.

Analysis.-Calcd. for C H N O -2HCI (411.33) (percent): C, 58.40; H, 5.88; N, 6.81. Found (percent): C, 58.63; H, 5.94; N, 6.79.

Elution of the other major band with methanol-chloroform and crystallization of the eluate from acetone afforded 488 mg. (35%) of racemic 6 ,7-methylenedioxycinchonine, M.P. 228-229.

Analysis.Calcd. for C H N O (338.30) (percent): C, 70.98; H, 6.55; N, 8.28. Found (percent): C, 70.87; H, 6.47; N, 8.43.

Upon addition of excess ethanolic hydrogen chloride to a solution of the free base (429 mg.) in a mixture of chloroform-ethanol 516 mg. of crystalline racemic 6',7'-

(percent): C, 58.40; H, 5.88; N, 6.81. Found (percent): 5 c, 58.45; H, 5.93; N, 6.84.

EXAMPLE 44 Preparation of racemic 6,7'-methylenedioxy-dihydrocinchonidine and racemic 6',7-methylenedioxy-dihydrocinchonine A solution of 4.9 g. of racemic N-benzoyl-6',7'-methylenedioxy-dihydrocinchotoxine in 200 ml. of 6 N hydrochloric acid was kept at reflux temperature for hours.

15 The cooled reaction mixture was rendered alkaline by addition of 6 N sodium hydroxide and extracted with three 200 ml.-portions of dichloromethane. The combined organic extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 3.61 g. of solid racemic 6',7'-methylenedioxy-dihydrocinchotoxine.

A solution of the crude compound in 250 ml. of dichloromethane was added to 200 ml.-of a 17 aqueous sodium hypochlorite solution. The resulting mixture was stirred at 20-25 for 2.5 hours. The organic phase was separated and the aqueous layer was washed with dichloromethane. The combined organic solution was washed with water, dried over anhydrous sodium sulfate and concentrated to avolume of 15 ml. This solution was added dropwise to 60 ml. of 99.7% phosphoric acid with vigorous stirring. The viscous mixture was stirred at 20- 25" for 17 hours, poured onto 300 g. of ice and rendered alkaline by the addition of ammonium hydroxide. The mixture was kept at 5560 for minutes and extracted with three 100 mL-portions of benzene. The combined extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2.58 g. of a crude mixture of racemic 6,7'-methylenedioxy-dihydrocinchonidinone and racemic '6',7'-methylenedioxy-dihydrocinchoninone.

To a solution of 2.5 8 g. of the crude mixture of racemic 6',7-methylenedioxy-dihydrocinchonidinone and racemic 6',7' methylenedioxy-dihydrocinchoninone in ml. of anyh'drous benzene was added dropwise with ice cooling 10 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene under an atmosphere of dry nitrogen. The reaction was quenched after 1 hour by adding 10 ml. of water-methanol (1:1) with vigorous stirring. The precipitate was collected by filtration and washed thoroughly 50 with methanol. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in chloroform was washed successively with 1 N sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product (2.64 g. of yellow solid material) was chromatographed on Merck F-254 silica gel preparative plates (20 x 20 x 0.2 cm.) with chloroform-triethylamine (85:10) as the solvent mixture. The plates were developed six times. Elution of the lower of two major bands with methanol-chloroform and crystallization of the eluate from acetone gave racemic 6,7'-methylenedioxy-dihydrocinchonidine, M.P. 232233 with dec. 226".

Elution of the other major band with methanol-chloroform and crystallization of the eluate from acetone afforded 6',7' methylenedioxy-dihydrocinchonine, M.P.

EXAMPLE 45 Preparation of racemic 6',8'-dichloro-dihydrocinchonidine and racemic 6',8'-dichloro-dihydrocinohonine To a solution of 15.4 g. of a crude mixture of racemic 6,8'-dichloro-dihydrocinchonidinone and racemic 6',8'dichloro-dihydrocinchoninone in 250 ml. of anhydrous benzene was added dropwise with ice-cooling 17 ml. of a 25% solution of di-isohutyl aluminum hydride in toluene under an atmosphere of dry nitrogen. The reaction was quenched after 1 hour by adding 20 ml. of water-methanol (1:1) with vigorous stirring. The precipitate was collected by filtration and washed thoroughly with methanol. The residue was suspended in chloroform and the suspension was washed successively with 1 N sodium hydroxide and water. The organic solutions were combined, dried over sodium sulfate and evaporated to dryness to give 13.4 g. of viscous oil which was chromatographed on aluminum oxide (Woelm, neutral) with ethyl acetate followed by methanol as the solvent. The methanol-eluate was concentrated and the residue (5.87 g.) was chromatographed on silica gel (Merck, 0.05-0.2 mm.) with chloroform-triethylamine (97:3 and 96:4) as the solvent. Fractions 29-40 (250- ml. each) were combined, evaporated and the residue was dissolved in dichloromethane. The solution Was washed twice with water, dried over sodium sulfate and evaporated to dryness. The solid residue after recrystallization from benzene-hexane (1:2) yielded racemic 6',8'dichloro-dihydrocinchonine, M.P. 172-173.

The free base racemic 6',8'-dichloro-dihydrocinchonine was dissolved in ethanolic hydrogen chloride and upon addition of ether the crystalline dihydrochloride of racemic 6,8'-dichloro-dihydrocinchonine was obtained, M.P. 214-215 from ethanol-ether.

Fractions 42-57 were combined, the solvent was evaporated to dryness and the residue was dissolved in ethanolic hydrogen chloride. Upon treatment with ether the crystalline dihydrochloride of racemic -6',8'-dichloro-dihydrocinchonidine was obtained, M.P. 226-227 from methanol-ether.

EXAMPLE 46 Preparation of racemic 7'-trifluoromethyl-dihydrocinchonidine and 7-trifluoromethyl-dihydrocinchonine from the mixture of racemic 7'-trifluoromethyl-dihydrocinchonidinone and 7-trifiuoromethyl-dihydrocinchoninone To the solution of 0.229 g. of a mixture of racemic 7- trifluorometh'yl-dihydrocinchonidinone and 7-trifiuoromethyl-dihydrocinchoninone in 20 ml. of anhydrous ben zene under a nitrogen atmosphere was added 0.5 ml. of

.25 percent diisobutylaluminum hydride in hexane. The

reaction mixture was then stirred at room temperature until the absence of starting ketone was observed on thin layer chromatography. The excess of hydride was decomposed with water. Thereafter, the pH was adjusted to 10 with 1 N sodium hydroxide, and the mixture was extracted'thoroughly with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was chromatographed on four preparative silica gel plates with 89:10:! chloroform-triethylamine-methanol solvent system to give 45 mg. of racemic 7'-trifiuoromethyl-dihydrocinchonine, M.P. 215-218 (from acetone), and 139 mg. of racemic 7'-trifluoromethyl-dihydrocinchonidine, M.P. 169-171 (from acetone).

Procedure: 25 parts of racemic 7-methoxy-dihydrocinchonidinone and 24 parts of corn starch were mixed together and passed through a N0. screen in Model I Fitzmill with hammers forward. This premix was then mixed with 175 parts of dicalcium phosphate and onehalf part of magnesium stearate, passed through a No. 1A screen in Model J Fitzrnill with knives forward, and slugged. The slugs were passed through a No. 2A plate in a Model D Fitzmill at slow speed with knives forward, and the remaining magnesium stearate was added. The mixture was mixed and compressed.

EXAMPLE 48 Capsule formulation Per capsule, mg. Racemic 7'-methoxy-dihydrocinchonidinone Corn starch, U.S.-P. Talc, U.S.P. 10

Total weight 210 Procedure: Fifty parts of racemic 7-methoxy-dihydrocinchonidinone were mixed with 150 parts of corn starch in a suitable mixer. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward. The blended powder was returned to the mixer and 10 parts of talc were added and blended thoroughly. The mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.

EXAMPLE 49 Suppository formulation Per 1.3 gm. suppository, gm.

Racemic dihydroquinone 0.025 Hydrogenated coconut oil 1.230 Carnauba Wax 0.045

Procedure: 123 parts of hydrogenated coconut oil (Wecobee M-E. F. Drew Co., New York, NY.) and 4.5 parts of carnauba wax were melted in a suitable size glass lined container (stainless steel may also be used), mixed well and cooled to 45 C. 2.5 parts of racemic dihydroquinone, which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed. The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 gms. The suppositories were cooled and removed from molds and individually wrapped in wax paper for packaging.

We claim:

1. A process for preparing compounds of the formulas (Ii-Du;

antipodes and racemates thereof,

wherein m is 0 to 2; R is hydrogen, hydroxy, halogen,

methyl, ethyl, propyl, butyl, methoxy, or trifluoromethyl, or when m is 2, R taken together with an adjacent R is also methylenedioxy; and R is ethyl or vinyl; which comprises the steps of