IE48396B1 - 6(oxo-or hydroxy-)decahydroquinolines - Google Patents

Description

The compounds of this invention are prepared according to a procedure illustrated generally in reaction Scheme II. The procedure is exemplified with only (referring to the stereochemistry of the bridge-head) one of the possible stereoisomers, the 4afS, 8aa isomer.

Reaction Scheme II CO I z\ • CH,=C~COOZ’ ' 2 I ♦ ' 9 ί 1 \z CH2Hal \;z ..—COOZ' o-co-z acid M/ BH4~ HO—COOZ' z EtOH z CH~ HCl \—cooz XII \zl·/ H | R XI pyridine HCl CrO, -COOZ' XIII 4839 6 - 4 In the above reaction scheme, Z-CO is an acyl protecting group in which Z is (C^-Cg) alkyl, (Cg-Cg)-alkenyl, (C^-Cfalkynyl, (Cg—Cg)cyeloalkyl, phenyl or substituted phenyl wherein the substituting group can be methyl, methoxy, chloro and the like at any position of the phenyl ring. Illustratively, Z-CO can be acetyl, propionyl, butyryl, propiolyl, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, mmethoxybenzoyl, and so on. Hal is chloro or bromo and Z' is part of a readily hydrolyzable group Z'O-CO such as (C^-C2)alkyl, phenyl substituted-(C^-Cg)alkyl, illustratively benzyl, phenethyl, p-methoxybenzyl, methyl, or ethyl.

In accordance with the Reaction Scheme II, a 4acyloxycyclohexanone is reacted with an a-halo-methylacrylate ester, for illustrative purposes, the ethyl ester and an amine, RNH2, wherein R is C^-Cg alkyl, allyl or benzyl. The product of this reaction is a mixture of dl-l-substituted-3-ethoxycarbonyl-6-acyloxy-l,2,3,4,5,6,7,8-octahydroquinoline and dl-l-substituted-3-ethoxycarbonyl-6-acyloxy1,2,3,4,4a,5,6,7-octahydroquinoline represented by X in which the dotted line indicates the alternate positions of the double bonds. The hydrochloride salts of these isomers were prepared and the resulting mixture reduced with sodium cyanoborohydride to yield trans-dl-l-substituted-3-ethoxycarbonyl-6-acyloxydecahydroquinoline (XI). Hydrolysis of this diester to yield a 6-hydroxy-3-carboxylic acid followed by reesterification of the carboxylic acid group with ethanol or other suitable alcohol in the presence of acid yields trans-dl-l-substituted-3-ethoxycarbonyl-6-hydroxydecahydroquinoline (XII) of the invention. Oxidation of the hydroxy group with Sarett's Reagent (pyridine hydrochloride and chromium trioxide) produces the corresponding 6-oxo compound (XIII) of the invention.

The compounds of this invention are useful as intermediates in the preparation of octahydro pyrazolo /5,4-g7 quinolines having pharmaceutical activity, which form the subject of Patent Specification No. /^7/7^ . - 5 This Invention is further illustrated by the following specific example.

EXAMPLE 1 A mixture of 10 ml. of n-propyl amine and 400 ml. of toluene were cooled in an ice-water bath. A solution of 16.5 g, of ethyl a-(bromomethyl)acrylate in 50 ml. of toluene was added thereto in dropwise fashion. The resulting mixture was stirred with cooling for about 25 minutes. Next, a solution of 11 g. of 4-benzoyloxycyclohexanone in 75 ml. of toluene was added in dropwise fashion. This new mixture was heated under a nitrogen atmosphere to refluxing temperature for about 23 hours. The reflux condenser was equipped with a Soxhlet extractor containing a 5A sieve to remove water. Next the reaction mixture was cooled and the cooled mixture filtered. Evaporation of the filtrate yielded a residue comprising a mixture of l-n-propyl-3ethoxycarbonyl-6-benzoyloxy-l,2,3,4,5,6,7,8-octahydroquinoline and l-n-propyl-3-ethoxycarbonyl-6-benzoyloxy-l,2,3,4,4a, 5,6,7-octahydroquinoline, The residue was dissolved in an ether-chloroform solvent mixture and the resulting solution saturated with gaseous hydrogen chloride while maintaining the temperature In the range 0-5°C. The solvent was decanted from the crystalline hydrochloride salts thus formed. The salts were dissolved in 100 ml. of methanol. 300 ml. of THF were added and the resulting solution cooled in an ice-water bath. 15 g. of sodium cyanoborohydride were added In portions to the stirred and cooled reaction mixture. After the addition had been completed, the reaction mixture was stirred for another 1.25 hours after which time it was diluted with aqueous sodium bicarbonate. The aqueous alkaline mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined extracts washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent yielded trans-dl-l-n-propyl-3-ethoxycarbonyl6-benzoyloxydecahydroquinollne. The compound was dissolved 8 3 9 6 - 6 in a mixture of 400 ml. of methanol and 100 ml, of 2N aqueous sodium hydroxide. This mixture was stirred at ambient temperature under a nitrogen atmosphere for 64 hours after which time the volatile constituents were removed by evaporation in vacuo. The resulting residue was suspended in 800 ml. of ethanol and 15 ml. of 12N aqueous hydrochloric acid. The esterification mixture was heated to refluxing temperature and about 300 ml. of solvent removed by distillation. 300 ml. of additional etha10 nol were added and the reaction mixture heated to refluxing temperature for 26 hours in an apparatus equipped with a Soxhlet trap containing a 3A sieve. The reaction mixture was cooled, diluted with aqueous sodium bicarbonate and the alkaline mixture extracted several times with chloroform.

The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium cloride and then dried. Evaporation of the chloroform yielded 10.3 g. of a residue comprising trans-dl-l-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline formed in the above hydrolysis after chromatography over 150 g. of Florisil (Registered Trade Mark) using chloroform containing increasing amounts (2-10S) of methanol as the eluant.

A solution was prepared from 8.8 g. of trans-dll-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline and 400 ml. of methylene dichloride. 4.1 g. of sodium acetate were added. Next, 10.8 g. of pyridine hydrochloride:chromium trioxide were added and the resulting mixture stirred for about 22 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resulting concent30 rate was dissolved in chloroform and the chloroform solution chromatographed over 150 g. of Florisil using chloroform containing increasing amounts (1-2%) of methanol as the eluant. Fractions shown by thin-layer chromatography contained trans-dl-l-n-propyl-3-ethoxycarbonyl-6-oxodeca35 hydroquinoline formed in the above reaction were combined and the solvent removed from combined extracts to yield 3.48 g. of the 6-oxo-compound as a residue.

Claims (3)

1. A trans-dl racemate of the formula wherein R is (C-^-Cj) alkyl, allyl or benzyl and R 1 is 5 COOZ' wherein Z' is (C^-Cj)alkyl or phenyl-substituted (Cj-C 2 )alkyl.

2. A trans-dl racemate of the formula N ' I (XIII) wherein R is (C^-C 3 )alkyl, allyl or benzyl and R 1 is 10 COOZ' wherein Z' is (C^-C-j)alkyl or phenyl-substituted (Cj-C 2 )alkyl.

3. A compound bed, with reference of claim 1 or claim 2 as herein descri-