Trans-4-piperidine acetic acids and esters and racemic cis-4-piperidine acetic acids and esters
United States Patent [191 Gutzwiller et al.  
 [4 1 Apr. 1, 1975 [75] Inventors: Juerg Albert Walter Gutzwiller,  
 Bettingen, Switzerland; Milan Radoje Uskokovic, Upper Montclair, NJ.  
 [73] Assignee: Hoffman-La Roche, Inc., Nutley,  
 [22] Filed: Aug. 1, 1973 [21] Appl. No.: 384,524  
 Related US. Application Data [60] Division of Ser. No. 212,774, Dec. 27, 1971, Pat. No. 3,772,302, which is a continuation-in-part of Ser. No. 104,784, June 27, 1969, abandoned, which is a continuation-in-part of Ser. No. 741,914, July 2, 1968, abandoned.  
 [52] US. Cl. 260/293.77, 260/293.76 [51] Int. Cl C07d 29/24 [58] Field of Search..... 260/293.77, 293.88, 293.76,  
 [56] References Cited OTHER PUBLICATIONS Rubtsov, Zhur. Obshchei Khim 30:1498-1507 (1960).  
 Suszko et al., C.A. 61:10727g (1964). Lifshits et al., C.A. 40:3761 (1946).  
 Woodward et al., JACS 67:860-874 (1945).  
 Primary Examiner-Henry R. .liles Assistant E.raminerS. D. Winters Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G. Isgro [5 7] ABSTRACT The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methylquinoline and 1-acyl(or l-l-l)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of l-acyl(or l-l-l)-3-vinyl-4-piperidineacetic acids and esters thereof and l-acyl-3-vinyl-4-piperidineacetaldehyde utilizing the corresponding 7-acyldecahydro-2H- pyrido[3,4-d]azepin-2-one, prepared from 2-acyll,3,4,7,8,8a-hexahydro-6(2l-l)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.  
 9 Claims, No Drawings TRANS-4-PIPERIDINE ACETIC ACIDS AND ESTERS AND RACEM IC C IS-4-PIPERIDINE ACETIC ACIDS AND ESTERS This is a division of application Ser. No. 212,774 filed Dec. 27, 1971, now U.S. Pat. No. 3,772,302, issued Nov. 13, 1973, which in turn is a continuation-.in-part of Ser. No. 104,784, filed Jan. 7, 1971, now abandoned, which is a continuation-in-part of Ser. No. 837,354, filed June 27, 1969, now abandoned, which is a continuation-in-part of Ser. No. 741,914, filed July 2, 1968, now abandoned.  
 BRIEF SUMMARY OF THE INVENTION The invention relates to a process for preparing quinine, quinidine, isomers and derivatives thereof which comprises:  
  a. condensing the correspondingly substituted 4- methyl-quinoline with racemic or optically active cis or trans l-acyl (or l-l-l)-3-vinyl(or lower alkyl)-4- piperidineacetic acid ester to yield the corresponding racemic or optically active cis or trans 4-{3-[ l-acyl(or l-H)-3-vinyl(or lower alkyl)-4-piperidyl]-2-oxopropyl}quinoline;  
  b. deacylating, if necessary, and reducing the product of step (a) to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-[3-vinyl(or lower alkyl)-4-piperidyl]-2 -hydroxypropyl}quinolines. If desired, this reaction product can be acylated to yield racemic or optically active epimeric 4-{cis or trans-3-[3- vinyl(or lower alkyl)-4-piperidyl]-2Q-acyloxypropyl} quinolines or dehydrated to yield racemic or optically active cis or trans 4-{cis or trans 3-[3-vinyl(or lower a1kyl)-4-piperidyl] prop-l-enyl}quinolines;  
  c. an alternate process comprises condensing the correspondingly substituted 4-methylquinoline with racemic or optically active cis or trans l-acyl-3-vinyl(or lower alkyl)-4-piperidine-acetaldehyde to yield the corresponding racemic or optically active epimeric 4- {cis or trans-3-[ l-acyl-3-vinyl(or lower alkyl)-4- piperidyl]-2g-hydroxypropyl}quinolines, and deacylating this reaction product to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-[3- vinyl (or lower alkyl)-4-piperidyl]-2-hydroxypropyl quinolines;  
  d. cyclizing the hydroxy, acyloxy or prop-l-enyl quinoline product of step (b) or (c) to yield the corresponding racemic or optically active 4-{a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-methyl}quinoline, epimeric in positions 2 and 5;  
  e. hydroxylating the product of step (d) to yield the corresponding racemic or optically active a-[5-vinyl(or lower alkyl)-2-quinuclidinyll-4-quinolinemethanol, epimeric in positions 01, 2 and 5; and  
 f. recovering the desired reaction product.  
 An alternate process comprises:  
  g. halogenating the product of step (a) above to yield the corresponding racemic or optically active epimeric 4- {cis or trans 3-[ l-acyl-3-vinyl(or lower alkyl)-4- piperidyl]-1lI-halo-Z-oxopropyl}quinolines;  
  h. reducing the product of step (g) with subsequent cyclization to yield a mixture of the corresponding racemic or optically active epimeric 4-{cis or trans-3-[ lacyl-3-vinyl( or lower alkyl )-4-piperidyl]-l Q24 oxapropyl} quinolines;  
  i. deacylating the product of step (g) to yield a mixture of the corresponding racemic or optically active epimeric 4-{cis or trans 3-[3vinyl(or lower alkyl)-4- piperidyl]- l 5,2L-oxapropyl} quinolines;  
  j. cyclizing the product of step (h) to yield the corresponding racemic or optically active a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-4-quinolinemethanol, epimeric in positions a, 2 and 5; and  
 k. recovering the desired reaction product.  
  The end products are useful as antimalarial and antiarrhythmic agents.  
  In another aspect, the invention relates to a process for preparing racemic or optically active cis or trans 1- acyl(or l-l-I)-3-vinyl-4-piperidineacetic acid and esters thereof and racemic or optically active cis or trans .1- acyl-3-viny1-4-piperidine-acetaldehyde by:  
  a. nitrosating a racemic or optically active cis or trans 7-acyl-decahydro-ZH-pyrido[3,4-d]azepin-2-one to yield the corresponding racemic or optically active cis or trans 7-acyll -nitroso-decahydro-2l-l-pyrido[ 3 ,4- d]azepin-2-one;  
  b. pyrrolyzing the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans l-acyl-3-vinyl-4-piperidineacetic acid; and  
  c. hydrolyzing, if desired, and esterifying the reaction product of step (b) to yield the corresponding racemic or optically active cis or trans l-acyl(or l-l-l)-3-vinyl -4-piperidineacetic acid ester; and  
  d. reducing and acylating the reaction product of step (c) to yield racemic or optically active cis or trans lacyl-3-vinyl-4-piperidineacetaidehyde.  
  in a further aspect, the invention relates to an alternate process for preparing racemic or optically active cis and trans l-acyl(or l-H)-3-vinyl-4-piperidineacetic acid and esters thereof by:  
  a. alcoholizing a racemic or optically active cis or trans 7-acyl-decahydro-ZH-pyrido[3,4-d]azepin-2-one to yield the corresponding racemic or optically active cis or trans l-acyl-3-(Z-aminoethyl)-4-piperidineacetic acid esters;  
  b. methylating the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans l-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid esters;  
  c. oxidizing the reaction product of step (b) to yield the corresponding racemic or optically active cis or trans 1-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ester N-oxide; and  
  d. pyrolyzing the reaction product of step (c) to yield the desired acetic acid and esters thereof.  
  In still another aspect, the invention relates to a process for preparing racemic or optically active cis or trans 7-acyl-decahydro-2H-pyrido[3,4-d]azepin-2-one which comprises:  
  a. hydrogenating a racemic or optically active 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone to yield the corresponding racemic or optically active cis or trans 2-acyl-octahydro-6(2H)-isoquinolone; and  
  b. converting the reaction product of step (a), through a Schmidt Rearrangement, to the corresponding racemic or optically active cis or trans 7-acyldecahydro-2H-pyrido[ 3 ,4-d lazepin-Z-one.  
 Alternatively, by a process which comprises:  
  a. converting through a Schmidt Rearrangement, a racemic or optically active 2-acyl-l ,3,4,7,8,8a-hexahydro-6(2l-l)-isoquinolone to the corresponding racemic or optically active 2-acyl-l,2,3,4,7,8,9,9a-octahydro- 6H-pyrido[3,4-d]azepin-6-one; and  
  b. hydrogenating the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans 7-acyl-decahydro-2H-pyrido[3,4-d]azepin- 2-one.  
  In yet another aspect, the invention relates to novel compounds.  
 DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as used herein denotes a hydrocarbon group containing l-7 carbon atoms, such as methyl, ethyl, propyl, butyl and the like; methyl and ethyl are preferred. .The term lower alkoxy denotes a lower alkyl ether group in which the lower alkyl moiety is described as above, such as methoxy, ethoxy, propoxy, butoxy and the like; methoxy and ethoxy are preferred. The term halogen denotes all of the halogens, i.e., bromine, chlorine, fluorine and iodine. Preferred are chlorine and bromine. The term acyl&#34; denotes lower alkanoyl of 1-7 carbon atoms such as formyl, acetyl, propanoyl, butanoyl, heptanoyl, and the like; ar-lower alkanoyl, preferably phenyl-lower alkanoyl wherein phenyl may be substituted by one or more lower alkyl, lower alkoxy or halogen groups such as benzoyl and the like. The term aryl means phenyl which may be substituted by one or more lower alkyl, lower alkoxy or halogen groups. The term aralkyl means a hydrocarbon group of 7-12 carbon atoms such as benzyl, phenethyl, phenylpropyl and the like. The term acyloxy means an acyloxy wherein the acyl moiety is as hereinbefore described, for example, lower alkanoyloxy and ar-lower alkanoyloxy.  
  The process for preparing quinine, quinidine, isomers and derivatives thereof is exemplified by Reaction Scheme la, la, la, lb, lb, lb&#34;.  
 Scheme Ia IIa ( om J wherein m is O, l or 2; R is hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy, or when m is 2, R taken together with an adjacent R is also methylenedioxy; R is vinyl or lower alkyl, preferably ethyl; R is hydrogen or lower alkyl; is hydrogen or acyl, and R is lower alkyl, aryl or ar-lower alkyl. As is evident from the above when m is 2, R or the like is individually selected from the various groupings hereinbefore described.  
  Compounds of the formula Ia and [la above are useful as antimalarial and antiarrhythmic agents.  
  In Reaction Scheme la, 4-methyl-quinolines of formula X, which are known compounds or are analogs of known compounds readily obtained by known procedures, are condensed with l-acyl (or l-H)-3(R)- vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester of formula lXa, antipode or its racemate which are known compounds, are analogs of known compounds readily obtained by known procedures, or are prepared as hereinafter described, in the presence of a base, for  
 example, sodium hydride, an alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide to yield 4-{3-[ l-acyl(or l-H 3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2- oxopropyl}quinoline of formula Villa, antipode or its racemate. The condensation is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. Preferably, the condensation is conducted at a temperature within the range of about and about 50C. Moreover, the condensation can be suitably carried out in the presence of an inert organic solvent, for example, a hydrocarbon, such as benzene, hexane and the like, or an ether such as ether, tetrahydrofuran or dioxane, or dimethylformamide or hexamethylphosphoramide.  
  The 4-{3-[l-acyl(or ll-l)-3(R)-vinyl(or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl} quinoline ture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)- piperidyl]-2-hydroxypropyl} quinolines of formula Vla, their antipodes or racemates by simultaneous deacylation, if necessary, and reduction. The deacyla-.  
  hydrochloric or sulfuric acid as the deacylating agent.- lf desired, the compound of formula Vla can be esterified to the corresponding mixture of epimeric 4-{3- of formula Villa, antipode or its racemate is converted to the mixypropyl}quinolines of formula Vlla, their antipodes or racemates utilizing known procedures, for example, reaction with the corresponding organic acid in the presence of a catalyst, such as boron trifluoride. Alternatively, if desired, the compound of formula Vla can be converted to cis and trans 4-{3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop-l-enyl} quinolines of formula Va, their antipodes or racemates utilizing a dehydrating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in the presence of an organic base, for example, a tertiary amine such as pyridine, triethylamine and the like, at a temperature within the range of about 0 to about room temperature.  
  The cyclization of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-hydroxy(or acyloxy)- propyl}qu inolines of formulas Vla and Vlla, their antipodes or racemates, respectively and cis and trans 4- 3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyl]-propl-enyl} quinolines of formula Va, their antipodes or racemates to 4-{a[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(S) and 2(R)-yl]-methyl} quinolines of formulas llla and Na, their antipodes or its racemate is carried out utilizing a cyclizing agent, for example, an organic acid, such as glacial acetic acid or the like. The cyclization is suitably carried out at room temperature; however, temperatures above or below room temperature may also be employed. It is preferred to employ a temperature within the range of about 25 to about C. Moreover, the cyclization 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 diethyl ether or tetrahydrofuran.  
  The hydroxylation of the compounds of formulas Illa and lVa or their racemates to a(R)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol ofv formula Ia, its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol of formula lIa, its antipode or racemate, respectively, is carried out, for example, in the presence of molecular oxygen 7 and a reducing agent, such as dimethylsulfoxide, pyridine, triphenylphosphine, platinum black, or a trialkylphosphite, such as triethylphosphite, or the like, in a strongly basic solution. I  
 A suitable base for the reaction described above CI&#39; Ia 1) in l &#39;l&#39; Scheme Ia CHO E f l R XXIIIa wherein R R and m are as previously described and R, is acyl.  
  In Reaction Scheme Ia an alternative process for the preparation of compounds of formula VIa is described. 4-Methylquinolines of formula X are condensed with l-acyl-3(R)-vinyl-(or -lower alky)-4(S)- piperidineacetaldehyde of formula XXllla, its antipode or racemate which are new compounds and are prepared as hereinafter described, in the presence of base, for example, sodium hydride, and alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide to yield the mixture of epimeric 4-{3-[l-acyl-3(R)-vinyl-(or lower alkyl)- 4(S)-piperidyll-2c-hydroxypropyl} quinolines of formula XXlVa, their antipodes or racemates. The compounds of formula XXlVa are deacylated to the corresponding mixture ofepimeric 4-{3-3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-hydroxypropyl} quinolines of formula VIa, their antipodes or racemates, utilizing a deacylating agent, for example, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, a reductive deacylating agent such as lithium aluminum hydride, sodium aluminum hydride, diisobutyl aluminum hydride and the like. Preferably, the deacylation is suitably carried out at room temperature; however, temperatures above and below room temperature may be employed. Moreover, the deacylation can be suitably carried out in the presence of an inert organic solvent for example, a lower alkanol, such as methanol or ethanol, or an ether, such as tetrahydrofuran or dioxane.  
 wherein R R R., and m are as previously described and X is halogen.  
  In Reaction Scheme Ia, an alternative process for the conversion of compounds of formula Vllla&#39; to the compounds of formulas la and Ila is described. The conversion of the 4-{3-[ l-acyl-3-(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-oxopropyl}quinoline of formula Vllla, its antipode or racemate to the corresponding mixture of epimeric 4-{3-[ l-acyl-3(R)-vinyl(or lower alkyl)-4(S )-piperidyl]-l -halo-2-oxopropyl}quinolines of formula XXa, their antipodes or racemates, respectively, is effected utilizing a halogenating agent such as N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide and the like. The halogenation can be conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as carbon tetrachloride; an ether such as diethylether, tetrahydrofuran, dioxane and the like. Conveniently, the reaction can be initiated by a free radical catalyst such as dibenzoylperoxide or&#39; by irradiation with infrared. The temperature is not critical, however, it is preferred to conduct the reaction at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture.  
  The conversion of the epimeric compounds of formula XXa, their antipodes or racemates to the corresponding mixture-of diastereomeric 4-{3-[1-acyl-3(R)- vinyl(or lower alkyl)-4(S)-piperidyl]- l 2; ,2g-oxapropyl} quinolines of the formula XXIa, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic solvent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70C. and about the reflux temperature of the reaction mixture.  
  The conversion of the compound of formula XXIa to the corresponding mixture of the diastereomeric 4-{3- [3(R)-vinyl(or lower alkyl)-alkyl-4(S)-piperidyl]- l(,ZQ-oxopropylquinolines of the formula XXlIa, their antipodes or racemates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide, or a reducing deacylating agent, for example, dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkali metal aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride and the like. The deacylation is conveniently conducted in the presence of an I I NRl will a inert organic solvent, for example, lower alkanols such as methanol, ethanol and the like, hydrocarbons such as toluene and the like, others such as diethylether, tetrahydrofuran and the like. The deacylation temperature is not critical. Conveniently, it may be in the range of about 70C. to about the reflux temperature of the reaction mixture.  
  The conversion of the compounds of formula XXlla to the corresponding mixture comprising oz(R)-[5 (R)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula Ia, its antipode or racemate and oz(S)-[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol of formula Ila, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifluoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbon disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane, carbontetrachloride, chloroform and the like, and others such as diethylether, tetrahydrofuran, dioxane and the like. The temperature of the reaction is not critical. Conveniently, it may be in the range of about 0C. and about the reflux temperature of the reaction mixture.  
 Scheme Ib COOR;  
 IXb VIIIb H R2 H R2 H NH M H H z I 1L 0 OH R0 E R3 (R1)? (R1)m VIb V111) R2 R2 I (Tin (gs (R1)m i I (R1) 1% N N IIIb IVb om (R9111 J N N wherein R,, R ,R R R and m are as previously de- Scheme -H)-3(S)-vinyl(or lower alkyl)-4(S )-piperidineacetic scribed.  
  The hereinafter described reaction steps of Reaction Scheme lb are effected utilizing the procedures and conditions set forth in Scheme la. The 4-methylquinoline of formula X is condensed with 1-acyl(or 1- acid ester of formula lXb, its antipode or racemate to yield 4-{3-[l-acyl(or lH)-3(S)-vinyl(or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl quinoline of formula VIIlb, its antipode or racemate. The compound of for- X mula VIIlb is deacylated, if necessary, and reduced to 4 the mixture of epimeric 4-{3-[3(S)-vinyl(or lower alky- N/ l)-4(S)-piperidyl]-2-hydroxypropyl}quinolines of for- XXIVb mula Vlb, their antipodes or racemates. If desired, the  
 compounds of formula VIb can be esterified to the mixture of epimeric 4-{3-[3(S)-vinyl(or lower alkyl)-4(S)- piperidyl]-2-acyloxypropyl }quinolines of formula Vllb, their antipodes or racemates or, alternatively, it R2 H can be converted tocis and trans 4-{3-[3(S)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop-l-enyl}quinolines of j formula Vb, their antipodes or racemates. The com pounds of formula Vb, VIb or Vllb are cyclized to 4- 1 /i\ {a-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and 2(R)-yl-] methyl}quinolines of formulas lllb and lVb, their antipodes or racemates. The compounds of 0H formulas lIIb and Nb are hydroxylated to a(R) -[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula lb, its antipode or racemate and 01(8) -[5(S)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol of formula N llc, its antipode or racemate, respectively. VIb  
 The hereinafter described reaction steps of Reaction Scheme Ib are effected utilizing the procedures and G 4;; conditions set forth in Scheme Ia 4-Methyl- 5 H quinolines of formula X are condensed with l-acyI- 3(S)-v inyl(or lower alkyl)-4(S)- piperidineacetaldehyde of formula XXlIlb, its antipode (Rom (B1) J or racemate which are new compounds and are pre- N N pared as hereinafter described, to yield the mixture of 10 IlIa,b-IVa, b Ia, b-IIa, b P y y (f lower Y can also be effected utilizing molecular oxygen and a )-P P l&#34;&#39; yp py h of formula catalyst such as platinum, tris(triphenylphosphine)r- XXWb, antipodes or racemates- The COmPOUPdS hodium chloride or the like or by oxidation utilizing a ofiformula xxlvbflfe deacylated the Correspondmg 15 compound such as selenium dioxide, ruthenium tetrox- P y lower ide, palladium acetate, mercuric acetate, thallium tri- )-P P Y yp py qumolmes of acetate, manganese dioxide, cerium (IV) oxide, or the mula VIb, their antipodes or racemates. |ike Alternate procedures for the conversion of the com- The hydroxylation of the compound of Formulas &#34;la, 20 pounds of Formula Vla,b to the corresponding comb-lVa, b to the end products of Formulas Ia, b-lla, b, pound of formula lIla,b-IVa,b are exemplified in Reaci.e., ti0n Scheme V.  
 R H R H )1 2 2 \/\I|\I-H KT 06H! OH OH om J l)m J N N VIa,b XXXI R H R H i N-H N CaHzi o soc@ecm XXXIII (Ron:  
 XXXII 1119., b-IVa, b  
  The conversion of compounds Vla,b to the corresponding compounds of formula XXXI is effected utilizing a chloroformate such as benzylchloroformate. The compounds of formula XXXI are converted to the compounds of formula XXXlI by tosylation with a compound such as p-toluenesulfonylchloride or p-toluenesulfonic acid anhydride in a solvent such as pyridine. The conversion of the compounds of formula XXXII to the corresponding compound of formula XXXIII is effected by the removal of the N- carbobenzoxy group utilizing, for example, acetic acid/hydrogen bromide mixture. The cyclization of the compounds of formula XXXIII to the corresponding compound of formula llIa,b-lVa,b is effected by heating in an organic solvent such as methanol, ethanol, dimethylformamide, dimethylsulfoxide&#39;and the like.  
 Scheme Ib&#34; wherein R R R&#39;,, m and X are as previously described.  
  In Reaction Scheme lb&#34;, an alternative process for the conversion of compounds of formula VIIIb&#39; to the compounds of formulas Ib and Ilb is described. The  
 conversion of the 4- 3- l-acyl-3(S)-vinyl(or lower alkyl)-4-(S)-piperidyl]-2-oxopropyl }quinoline of formula Vlllb, its antipode or racemate to the corresponding mixture of. epimeric 4{3-[l-acyl-3(S)-vinyl(or lower alkyl )-4( S )-piperidyl]- l fi-halo-Z-oxopropyl}quinolines of formula XXb, their antipodes or racemates. respectively, is effected utilizing a halogenating agent such as N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide and the like. The halogenation can be conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as carbon tetrachloride; an ether such as diethylether, tetrahydrofuran, dioxane and the like. Conveniently, the reaction can be initiated by a free radical catalyst such as dibenzoylperoxide or by irradiation with infrared. The temperature is not critical, however, it is preferred to conduct the reaction at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture.  
  The conversion of the epimeric compounds of formula XXb, their antipodes or racemates to the corresponding mixture of diastereomeric 4- 3-[ l-acyl-3(S)- vinyl(or lower alkyl)-4(S)-piperidyl] -l, 2toxapropyl}quinolines of the formula XXIb, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic solvent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70C. and about the reflux temperature of the reaction mixture.  
  The conversion of the compound of formula XXIb to the corresponding mixture of the diastereomeric 4-{3- [3(S)-vinyl(or lower -alkyl)-4(S)-piperidyl]-lQ24 oxapropyl}quinolines of the formula XXllb, their antipodes or racemates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide, or a reducing deacylating agent, for example, dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkali metal aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride and the like. The deacylation is conveniently conducted in the presence of an inert organic solvent, for example, lower alkanols such as methanol, ethanol and the like, hydrocarbons such as toluene and the like, ethers such as diethylether, tetrahydrofuran and the like. The deacylation temperature is not critical. Conveniently, it may be in the range of about 70C. to about the reflux temperature of the reaction mixture.  
  The conversion of the compounds of formula XXllb to the corresponding mixture comprising a(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula lb, its antipode or racemate and a(S)-[5(S)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yll-4-quinolinemethanol of formulalIb, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifluoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbon disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane, carbontetrachloride, chloroform and the like, and ethers such as diethylether, tetraliydrofuran, dioxane and the like. The temperature of the reaction is&#39; not critical. Conveniently, it may be in the range of about C. and about the reflux temperature of the reaction mixture.  
 The various other process aspects of the invention are exemplified by the following reaction schemes Ila,  
 llb, Illa, lllb and IV.  
 wherein R and R are as previously described, and R is lower alkyl, aryl or ar-lower alkyl.  
  In Reaction Scheme Ila, the conversion of 7-acyldecahydro-2l-l-pyrido[3(R),4(S)-d]axepin-2-one of formula Xla, its antipode or racemate to 7 acyl-1- nitroso-decahydro-Zl-I-pyrido[3(R),4(S)-d]-azepin- 2-one of formula Xlla, its antipode or racemate, respectively, is carried out utilizing a nitroseting agent, such as for example, sodium nitrite or dinitrogen tetroxide. Conveniently, the reaction can be conducted in the presence of a solvent, for example, an organic acid such as acetic acid, or a chlorinated hydrocarbon such as carbon tetrachloride. The nitrozation is conveniently conducted at a temperature within the range of about 0C. to about room temperature, preferably at 0C.  
  The compound of formula Xlla is converted to lacyl-3(R)-vinyl-4(S)-piperidineacetic acid of formula Xllla, its antipode or racemate, respectively, by pyrolysis. Conveniently, the pyrolysis is conducted at a temperature within the range of about room temperature to about 200C, preferably at a temperature within the range of about 100C. to about 130C. Conveniently, a high boiling solvent such as xylene, decaline and the like, can be utilized in the reaction.  
 &#39; The compound of formula Xllla is converted to lacyl(or l-l-I)-3(R)-viny1-4(S)-piperidineacetic acid ester of formula IXc, its antipode or racemate, respectively, utilizing an esterifying agent, for example, a lower alkanol, such as methanol, ethanol, propanol and the like, in the presence, of, for example, an inorganic acid such as hydrochloric acid sulfuric acid and the like. When R is hydrogen, however, the esterification is preceded by hydrolysis in the presence of, for example, an aqueous inorganic acid, such as hydrochloric acid, sulfuric acid and the like.  
  Compounds of formula Xla, wherein R is alkyl, for instance, ethyl, can be prepared as described in Scheme IV.  
 XIIIb wherein R R and R are as previously described.  
  In a like manner, in Reaction Scheme Ilb, the conversion of 7-acyl-decahydro-2l-I-pyrido[3(S),4(S)- d]azepinZ-one of Formula Xlb, its antipode or racemate to 7-acyll -nitroso-decahydro-2 H- pyrido[3(S),4(S)-d]azepin-2-one of Formula Xllb, its antipode or racemate, respectively, is carried out. The compound of Formula Xllb is converted to l-acyl- 3(S)-vinyl-4(S)-piperidineacetic acid of Formula Xlllb, its antipode or racemate, respectively, by pyrolysis. The compound of Formula XllIb is converted to lacyl(or lH)-3(S)-vinyl-4(S)-piperidineacetic acid IXd 5 ester of Formula lXd, its antipode or racemate, respectively.  
 Scheme IIIa COOR; COORa wherein R R and R are as previously described.  
  In Reaction Scheme Illa, 7-acyl-decahydro-2H- pyrido[3(R), 4(S)-d]azepin-2-one of formula XIa, its antipode or racemate is converted to l-acyl-3(R)-(2- aminoethyl)-4(S)-piperidineacetic acid ester of formula XIVa, its antipode or racemate, respectively, utilizing an alcoholizing agent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, in the presence of, for example, anhydrous inorganic acid such as hydrochloric acid, sulfuric acid and the like. Conveniently, the alcoholysis is conducted at a temperature within the range of about room temperature to about the boiling point of the alkanol.  
  The compound of formula XIVa is converted to 1- acyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid ester of formula XVa, its antipode or racemate, respectively, utilizing a methylating agent such as, for example, formic acid/formaldehyde mixture or formaldehyde/Raney nickel. The N- methylation is conveniently conducted at a temperature within the range of about room temperature to about the boiling point of the methylating agent.  
  The compound of formula XVa is converted to lacyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid ester N-oxide of formula XVIa, its antipode or racemate, respectively, utilizing an oxidizing agent, for example, hydrogen peroxide or a perorganic acid such as, peracetic acid. The oxidation is conveniently conducted in the presence of a solvent, for example, lower alkanol, such as methanol, ethanol, propanol and the like, or a hydrocarbon such as ben- .zene and the like. The oxidation is conveniently conducted at a temperature within the range of about 0 to about room temperature, preferably at 0C.  
  The compound of formula XVla is converted to lacyl(or l-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula lXc,-its antipode or racemate, respectively, by pyrolysis. Such pyrolysis is conveniently conducted at a temperature in the range of about 80 to about 200C, preferably at a temperature within the range of about 90 to about 125C. When R, is hydrogen, however, the pyrolysis is followed by hydrolysis and reesterification.  
 m Scheme HIb XIVb wherein R R, and R are previously described.  
  In a like manner, in Reaction Scheme IIIb, 7-acyldecahydro-2H-Pyrido[3(S),4(S)-d]azepin-2-one of Formula Xlb, its antipode or racemate is converted to l-acyl-3(S)-(Z-aminoethyl)-4(S)-piperidineacetic acid ester of Formula XIVb, its antipode or racemate, respectively. The compound of Formula XIVb is converted to l-acyl-3(S)-(Z-dimethylaminoethyl)-4(S)- piperidineacetic acid ester N-oxide of Formula XVIb, its antipode or racemate, respectively. The compound of Formula XVlb is converted to l-acyl-3(S)-(2-. dimethylaminoethyl)-4(S)-piperidineacetic acid ester N-oxide of Formula XVIb, its antipode or racemate, respectively. The compound of Formula XVlb is converted to l-acyl(or l-H)-3(S)-vinyl-4(S)- piperidineacetic acid ester of Formula lXd, its antipode or racemate.  
 Scheme IV wherein R is as previously described.  
  In the Reaction Scheme IV, racemic 2-acyll,3,4,7,8,8a-hexahydro-6(2H )-isoquinolone offormula XVII is converted to the racemic cis and trans 2-acyloctahydro-6(2I-I)-isoquinolones of formula XVIIIa and XVlIIb, respectively, utilizing a hydrogenating agent, for example, hydrogen in the presence of palladium or rhodium catalyst. Conveniently, the hydrogenation can be conducted in the presence ofa solvent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, with or without an inorganic acid such as hydrohalic acid, for example, hydrochloric acid and the like. The hydrogenation can be conveniently conducted at a temperature within the range of about room temperature and about 50C.  
  The racemates of the compounds of formula XVIIIa or XVIIIb are resolved to the corresponding optical antipodes by conventional methods which are further illustrated by Examples 3, 4,5.  
  The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2H)-isoquinolone of formula XVIIIa, its antipode or racemate to 7-acyldecahydro-2H-pyrido[3(R),4(S)- dlazepin-Z-one of formula XIa, its antipode or racemate, respectively, is carried out utilizing the known Schmidt rearrangement, i.e., the reaction of the compound of formula XVIIIa with sodium azide in the presence of an inorganic acid such as sulfuric acid or polyphosphoric acid, with or without solvent, at a temperature within the range of from about to about 150C.  
  In a like manner, 2-acyl-4a(S),8a(S)-octahydro- 6(2l-I)-isoquinolone of Formula XVIIIb, its antipode or racemate is converted to 7-acyl-decahydro-2H- pyrido[3(S),4(S)-d]azepin-2-one of Formula XIb, its antipode or racemate, respectively.  
  The racemic compound of Formula XVII is converted to the racemic 2-acyl-l,2,3,4,7,8,9,9aoctahydro-6I-I-pyrido[3,4-d1azepin-6-one of Formula XIX utilizing the Schmidt rearrangement as hereinbefore described. The compound of Formula XIX is converted to the racemic compound of Formula XIa utilizing a hydrogenating agent such as hydrogen in the presence of a catalyst, such as rhodium or palladium, in a solvent, for example, an alkanol, such as ethanol, methianol and the like, in the presence of an inorganic acid, such as hydrochloric acid.  
 and IVe wherein n is O to 2; R is vinyl or lower alkyl; 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 C -C alkoxy, lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is l. R; is lower alkoxy, lower alkyl, hydroxy, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R hydrogen, and their antipodes and racemates.  
  Also included in the purview of the invention are compounds of the formulas CHSO CHaO Ind and  
 wherein R is methyl or C -C lower alkyl, their antipodes and racemates.  
 4() Compounds of formulas lIIc, IIId, IVc and IVd are useful intermediates.  
 In still another aspect, the invention relates to compounds of the formulas 5 wherein n is 0 to 2; R 15 vinyl or lower alkyl; 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 C -C alkoxy, lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is l, R, is lower alkoxy, 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 and their antipodes and racemates.  
  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 referred R or the like can additionally form with an adjacent wherein R is methyl or C -C lower alkyl, their antipodes and racemates. Compounds of formulas Ille, IIlf, We and IVf are useful intermediates.  
  In a further aspect, the invention relates to compounds of the formulas wherein n is to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl or halogen, and when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl or halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and their antipodes and racemates, and pharmaceutically acceptable acid addition salts.  
  Exemplary of the.compounds of formulas lo and [1c are:  
  6,8-dimethoxy-a(R)-[(S)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6, 8-dimethoxy-3-epi-dihydrocinchonidine]its&#39; antipode and racemic analog;  
  7-chloro-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 7- chloro-3-epidihydrocinchonidine]its antipode and racemic analog;  
  6,7-methylenedioxy-a(R)-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter to as 6, 7&#39;-methylenedioxy-3-epidihydrocinchonidine] its antipode and racemic analog;  
  7-trifluoromethyl-a(R)-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethyl-3-epidihydrocinchonidine] its antipode and racemic analog;  
  6,8-dimethoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6,8-dimethoxy-3-epi-dihydrocinchonine] its antipode and racemic analog;  
  7-chloro-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 7- chloro-3-epi-dihydrocinchonine] its antipode and racemic analog;  
  6,7-methylenedioxy-a(S)-[5(S)-ethyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6&#39;,7-methylenedioxy-3-epidihydrocinchonine] its antipode and racemic analog;  
  7-trifluoromethyl-a(S)-[5(S)-ethyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethyl-3-epidihydrocinchonine] its. antipode and racemic analog.  
  Also included in the purview of the invention are compounds of the formulas Ell CH O- 01130 \N/ \NJ IId and  
 wherein R is vinyl, methyl or C -C alkyl, their antipodes and racemates and pharmaceutically acceptable acid addition salts.  
  Also included in the purview of the invention are compounds of the formula:  
  The antipode of 6-methoxy-a(R)&#39;-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6&#39;-methoxy-3-epi-dihydrocinchonidine or 3-epi-dihydroquinine] and its racemic analog (Compound A) and The antipode of 6-methoxy-a(S)-[5(S)-ethyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6-methoxy-3-epi-dihydrocinchonine or 3-epi-dihydroquinidine] and its racemic analog (Compound B). The compounds of formulas 10, Id, IIc and IId, as well? as Compounds A and B, are useful also as antimalarial and antiarrhythmic agents. 7  
  The compounds of the formula IXa have demonstrated cardiovascular activity, such as, hypotensive activity. The pharmacologically useful cardiovascular activity is demonstrated in warm-blooded animals utilizing standard procedures. For example, the test compound is administered to anesthetized (30 mg/kg sodium pentobarbital), artificially respired (Palmer Pump) dogs. Femoral arterial blood pressure and respiratory resistance (measured in terms of pressure) are&#39; recorded on a direct writing oscillographic recorder. A  
 series ofcontrol responses of the blood pressure and d-monotartrate is utilized as the test substance at a dose of 4 mg/kg. intravenously, the following results are obtained:  
 blood pressure 25 for 35 minutes serotonin N E.  
 Central Vagus Stimulation slight inhibition Carotid Occlusion blocking Hypertension N.E. Norepinephrine slight inhibition Histamine slight inhibition The compounds of Formula IXa also exhibit antiestrogenic activity. This useful estrogenic activity is demonstrated in warm-blooded animals. For example, the test compound is administered once daily for three consecutive days to groups of ten immature female rats (40-50 grams). On the first treatment day, all rats are injected subcutaneously with 0.25 meg. estradiol in sesame oil. On the fourth day, uteri are removed at autopsy and weighed on a torsion balance.  
  When meroquinene-t-butylester d-monotartrate is utilized as the test substance at a dosage of 1 mg/kg. p.o., an 1 1 percent antiestrogen inhibition is observed with a l2 percent uterine change.  
  The compounds offormulas Ia, Ila, lb and Ilb, including compounds of the formulas Ic, Id, llc and 11d, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts possess antimalarial and antiarrhythmic properties and are therefore useful as antimalarial and antiarrhythmic agents. Their pharmacologically useful antiarrhythmic 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 barbitol, 300 mg/kg. and pentobarbitol, 15 mg/kg, i.e., is opened up through the third right interspace under artificial respiration and the pericardium is cut and sutured to the wall of the thorax 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, 1951. A dripping of 1 percent solution of acetylcholine is applied to the sinus node and the atrium is irritated by pinching with a pair of forceps. This procedure produces a continuous artiral arrhythmia which mostly consists of atrial fibrillation. Since hypokalemia produces a susceptibility to atrial fibrillation (Leveque, 1964), 2 units/kg. of insulin is administered 30 minutes before the start of the acetylcholine drip. Once atrial fibrillation is established, there is a 10 minute waiting period before the test drug is administered. The test drugs are administered at the rate of l mg/kg/minute until normal sinus rhythm appears or until 30 mg/kg. of drug is administered.  
  When 6-methoxy-0z(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl-4-quinoline methanol is utilized as thetest substance at a dosage of about 4.0 rug/leg, an antifibrillatory effect is observed for more than 60 minutes.  
  Their pharmacological useful antimalarial activity is demonstrated in warm-blooded animals using standard procedures, for example, the test substance is administered to albino mice in variable amounts. Albino mice are inoculated with about 5-10 million red cells infected with P. Bergei. 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. Bergei.  
  When racemic 7&#39;-methoxy-dihydrocinchonidine dihydrochloride or racemic 7-methoxydihydrocinchonine dihydrochloride is utilized as the test substance at dosages in the range of mg/kg. to about 250 mg/kg., the microscopical examination of the blood smears is free of P. Berghei (negative). When 6&#39;-methoxy-a(R) [5(R)-ethyl-4(S)-quinuelidin-2(S)- yl]-4-quinolinemethanol [dihydroquinine] or 6- methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl]- 4-quinolinemethanol is utilized as the test substance at a dose of about 200 mg/kg., the microscopical examination of the blood smears is free of P. Berghei (negative). The compounds of formulas la, Ila, lb and IIb, including the compounds of formulas lc, Id, llc and Ild, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts have effects qualitatively similar, for example, to those of quinine and quinidine, known for their therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with antimalarials and antiarrhythmics of known efficacy and safety.  
  Furthermore, the compounds of the formulas Ia, Ila, lb and Ilb, including the compounds of formulas lc, Id, I10 and 11d, as well as compounds A and B, can be utilized as flavoring agents in beverages in the same manner as quinine is now used for this purpose.  
  The compounds of formulas Ia, Ila, lb and IIb, including the compounds of formulas lc, ld, llc and lld, as well as compounds A and B, form acid addition salts and such salts are also within the scope of this invention. Thus, the compounds of formulas la, Ila, Ib and llb, including the compounds of formulas lc, Id, llc and Ild, as well as compounds A and B, form pharmaceutically acceptable addition salts with, for example, both 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-toluenesulfonic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like.  
 The products of the invention can be incorporated ple, 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, 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 adjuvant 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.  
  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.  
  Due to the possible different spatial arrangements of their atoms, it is to be understood that the compounds of this invention may be obtained in more than one possible 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 EXAMPLE 1 Preparation of racemic cis 2-benzoyl-octahydro-6-2H)- isoquinolone from racemic 2-benzoyl-l,3,4,7,8,8ahexahydro-6(2H)-isoquinolone To a solution containing 151 g. of racemic 2-benzoyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in 3,000 ml. of absolute ethanol were added 300 ml. of 3N aqueous hydrochloric acid and 30 g. of 5% rhodium of alumina catalyst. The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. The catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was partially evaporated in vacuo, diluted with 3,500 ml. of dichloromethane and washed with 3N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to yield a crystalline product. Gas chromatographic analysis indicated that it contained 61.9% of racemic cis 2-benzoy1-octahydro-6(2H)- isoquinolone and 13% of racemic trans 2-benzoyloctahydro-6(2H)-isoquinolone. The product was recrystallized twice from benzene to give racemic cis 2- benzoyloctahydro-6(2H)-isoquinolone having a melting point of 147-148.5.  
 EXAMPLE 2 Preparation of racemic trans 2-benzoyl-octahydro- 6(2H)-isoquinolone from racemic 2-benzoyl- 1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone To a solution containing 25.5 g. of racemic 2- benzoyl- 1 ,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in 1,000 ml. of 95% ethanol were added 2.5 g. of 10% palladium on carbon catalyst and the mixture was hydrogenated at room temperature and 3 atmospheres pressure until the uptake of hydrogen ceased. The catalyst was removed by filtration and washed with 95%ethano] and dichloromethane. The filtrate was evaporated to dryness to yield an oil which crystallized on trituration with ether. The product was recrystallized twice from absolute ethanol to yield racemic trans Z-benzoyloctahydro-6(2H)-isoquinolone, which after two additional recrystallizations from absolute ethanol, had a melting point of l57.5-159.  
 EXAMPLE 3 To a solution containing 23.4 g. of rac. trans-2- benzoyloctahydro-6( lH)-isoquinolone in 2 l. of anhydrous benzene was added 2.24 g. of p-toluenesulfonic acid and 9.83 g. of (-)-butane-2(R),3(R)-diol. The resulting solution was refluxed for 3 hours and the water which formed was collected in a water separator. After the addition of 18 ml. of pyridine, the mixture was diluted to 4 1. with benzene, washed four times with ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The last traces of pyridine were removed by codistillation with toluene in vacuo. The crystalline residue, 29.62 g., was fractionally crystallized by repeating several times the following system:  
 Preparation of 29.62 g. mixture of ketals 6 hours reflux with distilled petroleum ether (b.p. 30-60 C.)  
  I! insoluble part soluble part recrystallization recrystallization from ether from ethanol-water 1:1  
 (5&#39;H)-isoquinoline], 12.45  
 EXAMPLE 4 a(S)-2-benzoyloctahydro-6(2H)-isoquinolone, having a melting point of 151-l53 (from absolute ethanol); [04],, 61.8 (c 1.01, CHC1 4a(S),8a(S)-2-benzoyloctahydroof 2-benzoylv EXAMPLE 5 Preparation of 4a(R),8a(R)-2-benzoyloctahydro- 6(2l-l)-isoquinolone A solution containing 0.329 g. of 2-benzoyl- 4(R),5(R)-dimethyl-1&#39;,2,3,4,4a(R),7&#39;,8&#39;,8a(R)- octahydrospiro[ l,3-dioxolane-2,6 5 &#39;H )-isoquinoline] in 50 ml. of 70% acetic acid was heated at 100-105 for 4 hours and 40 minutes. The reaction mixture was evaporated in vacuo diluted with 500 ml. of benzene, washed with 50 ml. of 2N aqueous sodium carbonate and 3 times with 50 m1. of water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield 0.256 g. of 4a(R),8a(R)-2-benzoyloctahydro-6(2H)- isoquinolone having a melting point of l5ll53 (from absolute ethanol); [th, 62.60 (c 1.005, CHC1 EXAMPLE 6 Preparation of racemic cis 7-benzoyl-decahydro-2l-lpyrido[3,4-d]-azepin-2-one from racemic cis 2- benzoyl-octahydro-6( 2H )-isoquinolone To a suspensioncontaining 20.6 g. of finely ground racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone in 800 g. of polyphosphoric acid were added 10.0 g. of sodium azide, and the mixture was stirred 16 hours at 5560. After cooling at room temperature, the reaction mixture was poured onto crushed ice. The resulting solution was made alkaline with solid sodium carbonate at 0, and was extracted thoroughly with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue crystallized on trituration with acetone. Fractional crystallization of the crystalline product from acetone yielded cis 7-benzoyldecahydro-2l-l-pyrido[3,4-d]azepin-2-one, which after one recrystallization from absolute ethanol and three recrystallizations from acetone had a melting point of 167l68.5.  
 EXAMPLE 7 Preparation of racemic trans 7-benzoyl-decahydro-2l-lpyrido[3,4-d]-azepin-2-one from racemic trans 2- benzoyl-octahydro-6(2H)-isoquino1one To a mixture containing 5.15 g. of trans 2- benzoy1octahydro-6(2H)-isoquinolone and 200 g. of polyphosphoric acid were added 2.5 g. of sodium azide and the reaction mixture was stirred at 5560 for 16 hours. After cooling to room temperature, the polyphosphoric acid was hydrolyzed by addition of ice. The resulting solution was made alkaline with concentrated sodium carbonate solution and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 5.45 g. of crystalline racemic trans 7-benzoyl-decahydro-ZH-pyrido[3,4-d]-azepin- 2-one. After recrystallization from ethanol/ether it had a melting point of l87-l89.  
 EXAMPLE 8 Preparation of a(S),9a(S)-7-benzoy1decahydro-2H- pryrido[3,4,-d]azepin-2-one To a mixture of finely ground 2.57 g of 4a(S),8a(S)- 2-benzoyloctahydro-6(2l-l)-isoquinolone and 100 g. of polyphosphoric acid was added 1.3 g. of sodium azide. The reaction mixture was stirred at 5560C. (bath) for 16 hours, cooled to room temperature and poured into ca. 380 g. of crushed ice. After the ice had melted, the resulting solution was made alkaline with 6N aqueous sodium carbonate (370 ml.) and extracted 3 times with 300 ml. of methylene chloride. Methylene chloride extract was washed 3 times with 40 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness. to give 2.72 g. of crystalline 5a(S),9a(S)-7- benzoyldecahydro-ZH-pyrido[ 3 ,4-d]azepin-2-one. From absolute ethanol it crystallized with one mole of ethanol, m.p. 200203C., [(11 37.83 (c. 1.0547, CHCl on drying loses ethanol to give anhydrous form, m.p. 100.  
 EXAMPLE 9 Preparation of racemic 2-benzoyl-l ,2,3,4,7,8,9,9aoctahydro-6l-l-pyrido[3,4-d]azepin-6-one from racemic 2-benzoyll ,3,4,7,8,8a-hexahydro-6( 2H isoquinolone To a suspension containing 1.02 g. of finely ground racemic 2-benzoyll ,3,4,7,8,8a-hexahydro-6( 2H isoquinolone in 40 g. of polyphosphoric acid was added 0.5 g. of sodium azide and the reaction mixture was stirred at 120 for 30 minutes. After cooling to room temperature, ice was added. The resulting solution was made alkaline with saturated aqueous sodium carbonate at 0 and was extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The product was crystallized by trituration with acetone to give racemic 2-benzoy1-1,2,3,4,7,8,9,9aoctahydro-6H-pyrido[3,4-d]azepin-6-one having a melting point of 2l9-221.  
 EXAMPLE 10 Preparation of racemic cis 7-benzoyl-decahydro-2H -pyrido[3,4-d]-azepin-2-one from racemic 2-benzoyl- 1,2,3,4,7,8,9,9a-octahydro-6l-l-pyrido[3,4-d]azepin- 6-one To a solution containing 5.4 g. of racemic 2-benzoyll,2,3,4,7,8,9,9a-octahydro-oH-pyrido[3,4-d]azepin- 6-one in 450 ml. of absolute ethanol were added 10 ml. of 3N aqueous hydrochloric acid and 5.4 g. of 5% rhodium on alumina catalyst. The reaction mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Thereafter, the catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was neutralized with 2N aqueous sodium carbonate and evaporated to a small volume in vacuo. The residue was extracted with 1,000 ml. of dichloromethane. The extract was washed with water, dried with anhydrous sodium sulfate and evaporated to dryness. The non-crystalline product exhibited an lR-spectrum identical to that of the racemic cis 7benzoyl-decahydro-ZH-pyrido[3,4-d]azepin- 2-one of Example 6, and after being recrystallized twice from acetone, had a melting point of 162l65.  
 &#39; EXAMPLE 1 1 Preparation of racemic cis l-benzoyl-3-(2- aminoethyl)-4-piperidineacetic acid ethyl ester from racemic cis 7-benzoyl-decahydro-2l-l-pyrido[3,4- d]azepin-2-one A solution containing 2.8 g. of racemic cis 7-benzoyldecahydro-2H-pyrido[3,4-d]azepin-2-one in 500 ml. of 5% ethanolic hydrochloric acid was refluxed for hours. Thereafter, the solvent was removed by evaporation in vacuo. The residue was taken up in 1,200 ml.  
 of dichloromethane. The resulting solution was shaken with a solution containing 0.53 g. of sodium carbonate in ml. of water, dried over anhydrous sodium sulfate and evaporated to yield oily racemic cis 1benzoyl-3- (2-aminoethyl)-4-piperidineacetic acid ethyl ester.  
 EXAMPLE 12 Preparation of racemic trans l-benzoyl-3-(2- EXAMPLE 13 Preparation of racemic cis l-benzoyl-3-vinyl-4- piperidineacetic acid ethyl ester (racemic N- benzoylmeroquinene ethyl ester) from racemic cis 1- benzoyl-3-( 2-aminoethyl)-4-piperidineacetic acid ethyl ester A mixture containing 1.91 g. of racemic cis lbenzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.38 g. of formic acid and 1.05 g. of 37% formaldehyde was heated for 1 hour at 100. After cooling to room temperature, 3.5 ml. of concentrated hydrochloric acid were added and the mixture thus obtained was evaporated to dryness in vacuo. The residue was dissolved in 50 ml. of water. The solution was washed by shaking with ether, made alkaline to about a pH 8 with 2N sodium carbonate and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give oily racemic cis 1-benzoyl-3- (Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester. To the stirred solution containing this product in 10 ml. of methanol were added 2 ml. of 30% aqueous hydrogen peroxide at 0. The reaction mixture was warmed to room temperature and stirred for 16 hours. The excess of hydrogen peroxide was decomposed by addition of platinum black with stirring for 1 hour at 0. The platinum black was separated by filtration and washed with methanol. The filtrate was evaporated to dryness in vacuo to yield racemic cis l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide as an oil. Heating of this product in vacuo at a temperature from 90 to 125C. over a period of minutes yielded racemic N-benzoylmeroquinene ethyl ester, which. after purification by preparative thin layer chromatography and recrystallization from hexane, had a melting point of 66-68.  
 ester from racemic trans l-benzoy1-3-(2-aminoethyl)- 4-piperidineacetic acid ethyl ester 1-benzoyl-3-(2- A mixture containing 1.4 g. of racemic trans 1- benzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.4 g. of formic acid and 1.1 g. of 37% aqueous formaldehyde was heated at 100. The reaction mixture became a clear solution and a vigorous evolution of gas occurred, which ceased after 1.5 hours. After cooling to room temperature, 1 ml. of concentrated hydrochloric acid was added and the mixture was evaporated in vacuo. The residue was dissolved in ml. of water, washed by shaking with ether, made alkaline with 2N aqueous sodium carbonate and extracted thoroughly with dichloromethane. The extract was dried over anhydrous sodium sulfate and evaporated to yield racemic trans l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidine acetic acid ethyl ester.  
 EXAMPLE 15 Preparation of racemic trans l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide from racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester To a stirred solution containing 0.73 g. of racemic trans l-benzoyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ethyl ester in 10 ml. of methanol was added 1 ml. of 30% hydrogen peroxide at 0. The reation mixture was allowed to warm to room temperature and was then stirred overnight. The excess of hydrogen peroxide was decomposed by stirring with platinum black for 2 hours at 0C. The platinum black was removed by filtration and the filtrate&#39;evaporated to dryness yielding racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide.  
 EXAMPLE 16 Preparation of racemic trans l-benzoyl-3-vinyl-4- piperidineacetic acid ethyl ester from racemic trans 1- benzoyl-3-(Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide A flask containing 0.63 g. of racemic trans l-benzoyl- 3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide was pyrolyzed at 90-120 for 20 minutes. The product was chromatographed on a 400 g. silica gel column with ether to yield racemic trans lbenzoyl-3-vinyl-4-piperidineacetic acid ethyl ester as a glass.  
 EXAMPLE 1? Preparation of racemic cis 7-benzoyl-l-nitrosodecahydro-2H-pyrido[3,4-d]azepin-2-one from racemic cis, 7-benzoyl-decahydro-2H-pyrido[ 3,4-d]azepin- 2-one To a solution containing 5.521 g. of nitrogen tetroxide in 360 ml. of carbon tetrachloride at 70 were added 9.84 g. of anhydrous sodium acetate. The mixture was allowed to warm to 0 and a solution containing 10.88 g. of racemic cis 7-benzoyl-decahydro-2l-lpyrido[3,4-d]azepin-2-one in 40 ml. of dichloromethane was added with stirring. After 30 minutes at 0, the mixture was poured into a slurry of ice and water. The resulting mixture was placed in a separatory funnel and the organic phase was separated. The aqueous phase was extracted thoroughly with ice-cold dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness at C. in vacuo to yield oily racemic cis 7-benzoyl-l-nitroso-decahydro-ZH-pyridol3,4-d]- azepin-Z-one.  
 EXAMPLE 18 Preparation of racemic trans 7-benzoyl-1-nitrosodecahydro-2l-l-pyrido[3,4-d]azepin-2-one from racemic trans 7-benzoyl-decahydro-2H-pyrido[3,4- d]azepin-2-one To 100 ml. of carbontetrachloride solution containing g. of nitrogentetroxide at 70 were added 2.46 g. of anhydrous sodium acetate. The mixture was allowed to warm to 0, and 2.6 g. of racemic trans 7-benzoyldecahydro-2H-pyrido[3,4-d]-azepin-2-one in 50 ml. of dichloromethane were added with stirring. The reaction mixture was maintained at 0 for 30 minutes. Thereafter, it was poured into a slurry of ice and water, transferred to a separatory funnel and the organic phase was removed. The aqueous phase was extracted with three 250 ml. portions of dichloromethane. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield trans 7-benzoyl-l-nitroso-decahydro- 2H-pyrido[ 3,4-d]azepin-2-one, a green yellow powder. All operations were carried out at 0.  
 EXAMPLE 19 Preparation of racemic N-benzoyl-meroquinene [racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid] from racemic cis 7-benzoyl-l-nitroso-decahydro-2H- pyridol3,4-d]azepin-2-one The racemic cis 7-benzoyl-l-nitroso-decahydro-ZH- pyrido[3,4-d]azepin-2-one from Example 17 was placed in a flask fitted with a reflux condenser and heated under nitrogen on an oil bath maintained at 125 for about 1 hour. The residue was taken up in 50 ml. of 1N potassium hydroxide, diluted with 50 ml. of water and washed by shaking with ether. The aqueous phase was neutralized with 50 ml. of 1N hydrochloric acid and extracted with ether. The ether phase was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to yield racemic N- benzoyl-meroquinene, as an oil.  
 EXAMPLE 20 Preparation of racemic trans l-benzoy1-3-vinyl-4- piperidineacetic acid from racemic trans 7-benzoyl-1- nitroso-decahydro-2l-l-pyrido-[3,4-d]azepin-2-one The product of Example 18, i.e., racemic trans 7- benzoyll -nitroso-decahydro-2l-l-pyrido[ 3,4-d]azepin- 2-one-was heated at 125 under nitrogen for 1 hour. The product was taken up in 13 ml. of 1N aqueous potassium hydroxide and 30 ml. of water, washed with four 100 ml. portions of ether, neutralized with 13 ml. of 1N aqueous hydrochloric acid and extracted with four 200 &#39;ml. portions of ether. The ethereal extract was washed with 70 ml. of water, which was combined with aqueous phase, dried over anhydrous magnesium sulfate and evaporated to yield oily racemic trans lbenzoyl-3-vinyl-4-piperidineacetic acid.  
 EXAMPLE 21 Preparation of 1-benzoyl-3(S)-vinyl-4(S)- piperidineacetic acid To 143 ml. of 0.15M solution of dinitrogen tetroxide in carbontetrachloride immersed in a dry ice-acetone bath were added 3.51 g. of anhydrous sodium acetate,  
 and the mixture was allowed to warm to 0C. A solution containing 3.86 g. of 5a(S),9a(S)-7-benzoyldecahydro- 2H-pyrido[3,4-d]azepin-2-one in 50 ml. of methylene chloride was added with stirring, and after standing for 30 minutes at 0C. the mixture was poured into a slurry of ice and water (280ml.). The resulting mixture was placed in a separatory funnel and the organic phase was removed. The aqueous phase was extracted 3 times with 430 ml. of methylene chloride. The combined organic phases were washed with ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. All these operations were carried out at 0C. It gave quantitative yield of pale yellow powder, 1- nitroso-5a(S),9a(S)-7-benzoyldecahydro-2H- pyrido[3,4-d]azepin-2-one, which was processed immediately further.  
  The nitroso product was heated at C. (bath) under nitrogen. Initially violent reaction ceased slowly after 30 minutes. The residue (3.92 g.) was taken up in 19 ml. of 1N aqueous potassium hydroxide, diluted with water (60 ml.) and washed 4 times with ml. of ether. It was then neutralized with 19 ml. of 1N aqueous hydrochloric acid and extracted 4 times with 300 ml. of ether. The ethereal extract was washed with 60 ml. of water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 2.34 g. of oily lbenzoyl-3(S)-vinyl-4(S)-piperidineacetic acid which contained minor impurities (tlc).  
 EXAMPLE 22 Preparation of racemic N-benzoylmeroquinene methyl ester [racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester] from racemic N- benzoylmeroquinene [racemic cis l-benzoyl-3-vinyl-4- piperidineacetic acid] To a stirred solution containing 5.29 g. of racemic N- benzoylmeroquinene in 500 ml. of ether was added 1 g. of diazomethane in 50 ml. of ether. Stirring was continued for 15 minutes. The excess diazomethane was decomposed by a dropwise addition of glacial acetic acid until the yellow color disappeared. The reaction mixture was diluted to 1,000 ml. with ether, washed with 2N sodium carbonate and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield oily N-benzoylmeroquinene methyl ester.  
 EXAMPLE 23 Preparation of l-benzoyl-3(R)-vinyl-4(S)- piperidineacetaldehyde from l-benzoyl-3(R)-vinyl- 4(S)-piperidineacetic acid methyl ester To a dry ice cooled solution of 1.48 g. (0.005 mole) of l-benzoyl-3(R)-vinyl-4(S)-piperidineacetic acid methyl ester in 100 ml. of toluene was added dropwise (5 min.) with stirring 8 ml. (ca. 0.012 mole) of a 25% solution of diisobutyl aluminum hydride in toluene. Stirring was continued for 30 min. at 78, then 5 ml. of methanol-water (1:1) was added, and stirring at --78 was continued. After 90 min., 0.6 ml. (0.005 mole) of benzoylchloride and 4 g. of solid sodium carbonate was added, the dry ice bath was removed, and the mixture was stirred for 60 min. The inorganic solids were removed by filtration, washed with methanol, and the combined organic phases evaporated to dryness. The crude product was dissolved in 100 ml. of dichloromethane, washed (l X 1N sodium carbonate, 1 X water), dried (sodium sulfate) and evaporated. The crude product (1.7 g.) was separated by preparative layer chromatography to give 0.235 g. 17.5%) of l-benzoyl- 3(R)-vinyl-4(S)-piperidineacetaldehyde as a colorless oil.  
 EXAMPLE 24 Preparation of rac. trans piperidineacetic acid methyl ester To the solution of 0.476 g. of rac. trans l-benzoyl-3- vinyl-4-piperidineacetic acid in 4 ml. of methanol was added 9 ml. of diazomethane solution in ether (concentration ca. 3 g./130 ml.). After few minutes an additional 9 ml. of diazomethane solution was added, and then stirred at room temperature for 1 hour. The excess of diazomethane was destroyed by addition of several drops glacial acetic acid, and thus resulted mixture was evaporated to dryness in vacuo, leaving 0.5 g. of oily residue. The crude product was chromatographed on 7 Brinkman silica gel preparative plates with benzeneether 1:1 mixture. Elution with 95% ethanol gave 0.201  
 1-benzoyl-3-viny1-4- g. of oily rac. trans l-benzoyl-3-vinyl-4- piperidineacetic acid methyl ester.  
 EXAMPLE 25 Preparation of 1-benzoyl-3(S)-vinyl-4(S)- piperidineacetic acid methyl ester To a cooled solution containing 2.34 g. of l-benzoyl- -3(S)-vinyl-4(S)-piperidineacetic acid in 20 ml. of methanol was added 20 ml. of diazomethane solution in ether (concentration ca 3 g./130 ml.). After few minutes an additional 20 ml. of diazomethane solution was added and then stirred at room temperature for minutes. The excess of diazomethane was destroyed by addition of several drops of glacial acetic acid, and thus resulted mixture was evaporated to dryness in vacuo, leaving 2.9 g. of oil residue. The crude product was chromatographed on 26 Brinkman silica gel preparative plates with benzene-ether 1:1 mixture. Elution with 95% ethanol gave 1.059 g. ofoily 1-benzoyl-3(S)-vinyl- 4(S)-piperidineacetic acid methyl ester, [01],, l.6l (c 1.1193, CHCl EXAMPLE 26 Preparation of racemic 3-(a-benzyloxycarbonylcyanomethyl) glutaric acid diethyl ester To the boiling solution of 37.24 g. of glutaconic acid diethyl ester and 70.08 g. of benzylcyanoacetate in 100 ml. of anhydrous tetrahydrofuran was added dropwise 22.4 g. (0.20 mole) of potassium t-butoxide in 300 ml. of anhydrous tetrahydrofuran over a hour-hour period. The reaction mixture was stirred and refluxed for 12 hours. The solvent was removed by distillation in vacuo. To the residue was added 100 ml. of water and extracted with 3 l. of benzene. The benzene extract was washed four times with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was fractionally distilled to give 42.55 g. of racemic 3-(a-benzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, b.p. 167-174 at 0.15 mml-lg. Large scale runs average to 61% yield.  
 EXAMPLE 27 Preparation of racemic 3-(l-benzyloxycarbonyl-lcyanopropyl) glutaric acid diethyl ester The mixture of 18 g. of racemic 3-(abenzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, 15.6 g. of ethyliodide and 6.72 g. of potassium t-butoxide in 200 m1. of anhydrous tetrahydrofuran was stirred and refluxed for 3 hours, which it became neutral. The precipitate formed during the reaction was separated by filtration and washed with tetrahydrofuran. The combined filtrates were evaporated to dryness, and after addition of 20 ml. of water, extracted with l l. of benzene. The&#39;benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was fractionally distilled to give 11.35 g. of racemic 3-(1- benzyloxycarbonyl- 1 -cyanopropy1)glutaric acid diethyl ester, b.p. 154-l59 at 25 microns. Large scale runs average to yield.  
 EXAMPLE 28 Preparation of racemic 3-(1-cyanopropyl)glutaric acid diethyl ester To the solution of 23.4 g. (0.06 mole) of 3-(1- benzyloxycarbonyl-1-cyanopropyl)glutaric acid diethyl ester in 600 ml. of ethanol was added 3 g. of 10% palladium on carbon, and hydrogenated at room temperature and atmospheric pressure. After uptake of 0.06 mole of hydrogen, the reaction ceased. Catalyst was removed by filtration through celite, and the filtrate was evaporated to dryness. The residue, 2032 g., was heated at l70l80 in vacuo for 1 hour. After cooling to room temperature, it was dissolved in 1 l. of ether. The ethereal solution was washed three times with 50 ml. of concentrated aqeous solution of sodium bicarbonate, and water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 14.17 g. of racemic 3-(l-cyanopropyl)glutaric acid diethyl ester, b.p. 8486 at 20 microns.  
 EXAMPLE 29 Preparation of racemic cis 4-ethoxycarbonylmethyl-5- ethyl-2-piperidone and racemic trans 4- ethoxycarbonylmethyl-Sethyl-2-piperidone To a solution of 101.23 g. (0.395 mole) of 3-(1- cyanopropyl) glutaric acid diethyl ester in 1200 ml. of absolute ethanol was added 31.8 g. of Raney nickel, and hydrogenated at 1 10 atm and temperature, which in the course of 3 hours rose slowly from room to 152C. After cooling to room temperature, the catalyst was separated by filtration through celite and the filtrate evaporated to dryness in vacuo. On trituration with ether, 57.6 g. of racemic trans ethoxycarbonylmethyl-SethyLZ-piperidone,  
 8688 was obtained. After one recrystallization from.  
 methylene chloride-ether, m.p. was 89-9l.  
 The mother liquors were evaporated to give 23.5 g.  
 of oily residue, which was chromatographed on a 2 kg. silica gel column. The elution with ethanol-chloroform mixture gave 16 g. of racemic cis 4- ethoxycarbonylmethyl-Sethyl-2-piperidone.  
 &#39; EXAMPLE 30 of racemic trans 4 temperature, then diluted with 50 ml. of water and extracted with 1 l. of methylene chloride. Methylene chloride extract was washed with water (3 X 50 m1.), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 7 ml. of ice-cold 1N hydrochloric acid, the resulting solution diluted with 100 ml. of water and washed 5 times by shaking with 50 ml. of ether. It was then made alkaline with 8 ml. of 1N sodium hydroxide and extracted with 1 1. of methylene chloride. Methylene chloride extract was washed three times with 50 ml. of water, dried over an-. hydrous sodium sulfate and evaporated to dryness, to give 0.591 g. (99%) of racemic trans 3-ethyl-4- piperidineacetic acid ethyl ester b.p. 91-92 (bath) at 0.5 mmHg.  
 EXAMPLE 31 Preparation of racemic cis 6-methoxy-4-{3-[ l-benzoyl- 3-vinyl-4-piperidyll-2-oxopropyl }quinoline from 6- methoxylepidine and racemic N-benzoylmeroquinene methyl ester [cis lbenzoyl-3-vinyl-4-piperidineacetic acid methyl ester] To a solution containing about 0.032 mole of lithium diisopropyl amide [prepared at 20 in an atmosphere of dry nitrogent by the addition of 6 ml. of dry diisopropylamine to 15.5 ml. of phenyllithium in benzene-ether (7:3)] were added dropwise a solution containing 5.6 g. of 6-methoxylepidine in 60 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred for 20 minutes. To the practically homogeneous, dark-brown solution of 6-methoxylepidyl lithium thus obtained was added dropwise over a period of 20 minutes a solution containing 4.6 g. of racemic N-benzoylmeroquinene methyl ester in 60 ml. of anhydrous tetrahydrofuran. After the addition was completed, stirring was continued for 60 minutes. During the whole operation the reaction temperature was maintained at 20. Thereafter, ice and water were added and the reaction mixture was neutralized to a pH 8 with acetic acid and 10% sodium bicarbonate. The aqueous phase was extracted thoroughly with ether. The ethereal extract was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue was adsorbed on a 550 g. neutral alumina column (activity ll). After elution of unreacted 6-methoxylepidine with benzene, the amorphous racemic cis 6-methoxy-4-{3-[ l-benzoyl-3-vinyl- 4-piperidyl]-2-oxopropyl }quinoline was eluted with benzene containing 20-50% of ethyl acetate.  
 EXAMPLE 32 Preparation of 6-&#39;methoxy-4{3-[l-benzoyl-3(R)-vinyl- 4(S)-piperidyl]-2-oxopropyl quinoline from 6 methoxy-lepidine and N-benzoyl meroquinene ethyl ester 1 To a solution of ca. 0.07 mole of lithium diisopropyl amide [prepared by addition of ml. of dry diisopropyl amine in 10 ml. of toluene to 35 ml. of ca. 2 molar n-butyl lithium in hexane, at -78 under nitrogen] was added dropwise 10 min.) with stirring a solution of 13 g. (0.075 mole) of -methoxy-lepidine in 120 m1. of tetrahydrofuran. The mixture was stirred at 78 for 30 min., and there was added dropwise (10 min.) a solution of 10.5 g. (0.0345 mole) of N- benzoylmeroquinene ethyl ester in 150 m1. of tetrahydrofuran. Stirring was continued at 78 for 30 min. The cooling bath was removed and the stirring was continued for another 30 min. Water was added, the aqueous layer was neutralized (pl-l ca. 8) with acetic acid and extracted thoroughly with ether. The ethereal phase was washed (water), dried (magnesium sulfate) and evaporated in vacuo. The residue was absorbed on 600 g. of neutral alumina, activity 11; after elution of excess 6-methoxy-lepidine with benzene, elution with benzene-ethyl acetate (1:1) afforded amorphous 6- methoxy-4 {3-[ l-benzoyl-3(R)-vinyl-4(S)-piperidy1]-2- oxopropyl}-quinoline; [01] 27.3 (c 1.205; chloroform).  
 EXAMPLE 33 Preparation of 6-methoxy-4 {-3-[ l-benzoyl-3(R)-vinyl- 4(S)-piperidyl]-2-oxopropyl quinoline from 6- methoxylepidine and N-benzoyl-meroquinene methyl ester A condensation reaction carried out in analogous way as in Example 30a with 1.8 g. (0.0104 mole) of 6- methoxylepidine and 1.49 g. (0.0052 mole) of N- benzoyl-meroquinene methyl ester (phenyl lithium was used instead of n-butyl lithium) yielded after a similar technique and separation by column chromatography 6-methoxy-4{3-[1-benzoy1-3(R)-vinyl-4(S)- piperidyl]-2-oxopropyl}-quinoline.  
 EXAMPLE 34 Preparation of 7-chloro-4-{3-[l-benzoyl-3(R)-vinyl- 4(S)-piperidyl]-2-oxopropyl quinoline from 7- chlorolepidine and N-benzoyl-meroquinene ethyl ester To a dry ice cooled solution of ca. 0.061 mole of lithium diisopropyl amide [prepared in an atmosphere of dry nitrogen by addition of 10 ml. (ca. 0.07 mole) of diisopropylamine in 30 ml. of tetrahydrofuran to 30 ml. of ca. 2M n-butyllithium in hexane] was added dropwise (20 min.) a solution of 11 g. (0.061 mole) of 7- chlorolepidine in ml. of tetrahydrofuran. The resulting brown suspension was stirred at 78 for 30 min., then there was added a solution of 9.2 g. (0.0305 mole) of N-benzoyl-meroquinene ethyl ester in 60 ml. of tetrahydrofuran. Stirring was continued at 78 for 40 min. After removing the cooling bath, stirring was continued for another 40 min. After addition of 50 ml. of water, the mixture was neutralized with acetic acid and the pH was adjusted to ca. 8 by addition of 10% sodium bicarbonate. The aqueous phase was extracted thoroughly with ether, the ethereal phases were washed (2 X 10% sodium bicarbonate), dried (magnesium sulfate) and evaporated to dryness. Crystallization from acetone-ether afforded crystalline 7-chloro-4-{3-[1- benzoyl-3(R)-viny1-4(S)-piperidyl]-2- oxopropyl}quinoline; the mother liquor was absorbed on 300 g. of neutral alumina, activity 11, and elution with ethyl acetate afforded additional amounts of 7- chloro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline; m.p. l47-l48 (acetone); [(11 38.7 (c 1.00, chloroform).  
 EXAMPLE 35 Preparation of epimeric 7-chloro-4-{3-[3(R)-vinyl- 4(S) -piperidy1]-2-hydroxypropyl }-quinolines from 7- ch1oro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline To an ice cold solution of 7.84 g. (0.018 mole) of 7- chloro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline in 200 ml. of methanol was added excess solid sodium borohydride, and the solution was stirred for 60 min. at 0. Fifty ml. of water was added,