CS227014B2 - Method of preparing decahydroquinoline - Google Patents

Description

The present invention relates to a process for the preparation of decahydroquinoline derivatives of the general formula XIII

ix ///;

where

R is alkyl of 1 to 3 carbon atoms, allyl or benzyl and R ¹ is COOZ ', wherein Z' is alkyl of 1 to 2 carbon atoms or phenyl substituted alkyl of 1 to 2 carbon atoms, characterized in that reacting a compound of formula XII wherein

R and Z ‘are as defined above, with pyridine hydrochloride and chromium oxide.

In the above formulas, the term C 1 -C 2 alkyl includes methyl and ethyl, and the term C 1 -C 3 alkyl also includes n-propyl and isopropyl.

The compounds of the invention are prepared according to the general scheme depicted in the reaction scheme. The procedure is shown only (due to the stereochemistry at the j-junction of one stereoisomer, i.e., the 4a (3,8aa-isomer).

Reaction scheme of

l

where

Z is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 3 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, phenyl or substituted phenyl, wherein the substituent is methyl, methoxy or chlorine in any of the position of the phenyl ring, hal is chlorine or bromine and Z 'is part of an easily hydrolyzable group Z'-O-CO, such as C 1 -C 2 alkyl, phenyl substituted C 1 -C 2 alkyl, for example benzyl, phenethyl, p-methoxybenzyl, methyl or ethyl.

In accordance with the reaction scheme, 4-acyloxycyclohexanone is reacted with an α-halomethylacrylic acid ester, for example, ethyl ester and amine, RNHz, where R is C 1 -C 3 alkyl, allyl or benzyl. The product of this reaction is a mixture of dl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and dl-1-substituted-3-ethoxycarbonyl-6-acyloxy 2,3,4,4a, 5,6,7-octahydroquinoline of formula X, wherein the dotted line represents alternative positions of double bonds. The hydrochlorides of these isomers were prepared and the resulting mixture was reduced with sodium cyanoborohydride to give trans-dl-1-substituted-3-ethoxycarbonyl-6-acyloxydecahydroquinoline (XI). Hydrolysis of this diester affords 6-hydroxy-3-carboxylic acid and subsequent reesterification of the carboxylic acid with ethanol or another suitable alcohol in the presence of the acid affords a novel intermediate, trans-dl-1-substituted 3-ethoxycarbonyl-6-hydroxydecahydroquinoline (XII). Oxidation of the hydroxyl group with Sarett's reagent (pyridine hydrochloride and chromium trioxide) affords the corresponding desired 6-oxo compound (XIII).

The compounds of the present invention are useful as starting compounds for the preparation of octahydropyrazolo [3,4-g] quinolines of Formula Ia and Ib

ϋζ)

R 1 is alkyl of 1 to 3 carbon atoms or allyl and

R 1 is hydrogen or CH 2 X, wherein X is OCH 3, SCH 3, CN, SO 2 CH 3 or CONH 2, and pharmaceutically acceptable salts thereof.

The compounds of formulas Ia and 1b together with their pharmaceutically acceptable salts are useful as dopamine agonists.

The present invention is illustrated by the following example.

Example 1

A mixture of n-propylamine (10 ml) and toluene (400 ml) was cooled in an ice bath. A solution of 16.5 g of α- (bromomethyl) acrylic acid ethyl ester in 50 ml of toluene is then added dropwise. The resulting mixture was stirred under cooling for 25 minutes. A solution of 11 g of 4-benzoyloxycyclohexanone in 75 ml of toluene is then added dropwise. The new mixture was heated to reflux for 23 hours under a nitrogen atmosphere. The reflux condenser was equipped with a Soxlet extractor containing 5A water removal sieves. Then the reaction mixture was cooled and the cooled mixture was filtered. Evaporation of the filtrate gave a residue consisting of a mixture of 1-n-propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-n-propyl-3-ethoxycarbonyl-6- benzoyloxy-1,2,3,44a, 5,6,7-octahydroquinoline. The residue was dissolved in an ether-chloroform solvent mixture and the resulting solution was saturated with hydrogen chloride gas, maintaining the temperature between 0-5 ° C. The solvent is removed by decantation from the crystalline hydrochloride thus formed. The salts are dissolved in 100 ml of methanol, 300 ml of tetrahydrofuran are added and the solution is cooled in an ice bath. To the stirred cooled reaction mixture was added portionwise 15 g of sodium cyanoborohydride. After the addition was complete, the reaction mixture was stirred for an additional 1.25 hours and then 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 were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave trans-dl-1-n-propyl-3-ethoxycarbonyl-6-benzoyloxydecahydroquinoline. The compound was dissolved in a mixture of 400 mL of methanol and 100 mL of 2N aqueous sodium hydroxide. The mixture was stirred at room temperature for 64 hours under nitrogen, then the volatiles 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 is heated to boiling and about 300 ml of solvent is then distilled off. An additional 300 mL of ethanol was added and the reaction mixture was heated to boiling in a Soxhlet trap containing 3A sieves for 26 hours. The reaction mixture was cooled, diluted with aqueous sodium bicarbonate solution and extracted with chloroform several times. The chloroform extracts were combined and the combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of chloroform gave 10.3 g of a residue containing trans-dl-ln-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline resulting from the hydrolysis described above, which was purified by chromatography on 150 g of florisil using chloroform containing increasing amounts (2-10%). o) methanol as eluent.

A solution was prepared from 8.8 g of trans-dl-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline in 400 ml of methylene chloride, to which 4.1 g of sodium acetate was added. 10.8 g of a mixture of pyridine hydrochloride and chromium trioxide are then added and the mixture is stirred for 22 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting concentrate was dissolved in chloroform and the chloroform solution was chromatographed on 150 ml grams of florisil using chloroform with increasing amounts (1-2% methanol). Thin layer fraction containing trans-dl-l-propyl-3-ethoxycarbonyl- 6-Oxodecahydroquinoline.

IR (CHCl3)

1715 cm ^-1 ketone> C = O

1725 cm ^-1 ester> C = O

NMR (CDCl 3 J (60 MHz) cps, (triplet,> N - CH 2 - CH 2 - CH 3 cps, triplet, - O - CH 2 - CH 3

250 cps, quartet, —O — CH2CH3.

Claims (1)

I will invent PftEDMfiT A process for the preparation of a decahydroquinoline derivative of the formula (XIII) with a (C1-C2) alkyl group, characterized in that a compound of the formula (XII) is reacted wherein: R is alkyl of 1 to 3 carbon atoms, allyl or benzyl, and R ¹ is COOZ ', wherein Z' is alkyl of 1 to 2 carbon atoms or phenyl substituted with R and Z ‘are as defined above, with pyridine hydrochloride and chromium oxide. Severography, n. P., Plant 7, Most