DE1166787B - Process for the production of new garnetanol (3ª ‰) esters and their hydrohalides - Google Patents

Description

Process for the preparation of new garnetanol (31β) esters and their hydrohalides The invention relates to a process for the preparation of new garnetanol (3β) esters of the formula in which X denotes a hydroxyl group, Y denotes phenyl or cycloalkyl radicals and R1 denotes lower alkyl or aralkyl radicals, and its hydrohalides, which is characterized in that, in a manner known per se, garnets (34) of the formula with substituted phenylacetic acids of the formula or their lower alkyl esters and, if appropriate, the esters obtained with halogenated water a: trans form According to the information in the aforementioned Austrian patent, the esters there are mainly treated with chemical acids. When using lower alkyl esters is expediently in the presence of basic catalysts, for. B. sodium or. Sodium methylate, worked.

From the Austrian patent specification 198 771 there is already a method for the preparation of the esters of Granatanolen- (3) become known (Examples 14 to 23). However, these are garnetanol (3a) esters, as can be seen from physical Data results.

The existing cis-trans isomerism regarding the position of the nitrogen bridge and the acid residue is illustrated by the following formulas: B: cis-form a strong local anesthetic effect, but also spasmolytic activity and antihistamine effect.

Surprisingly, those produced according to the process now show Granatanol (3β) esters in animal experiments (mouse, rat) in comparison with the known 3a compounds have particularly pronounced central anticholinergic properties at the same time a more favorable therapeutic index.

The central action of anticholinergics is used to treat the Parkinson's disease and when used as a tranquilizer, e.g. B. when using exploited by scopolamine to induce anesthesia. The therapeutic application the central effects are often caused by peripheral phenomena, such as dry mouth and accommodation disorders, disabled. The development of centrally highly effective anticholinergics (high central specificity), which have the lowest possible peripheral effects, is therefore of great importance.

The garnet alcohols (3ß) used as starting materials are through Reduction of the corresponding garnet cannon (3) obtained. Here, however, is on it care should be taken that, depending on the type of reduction method used, the positional isomers Garnetanols (3a) or - (3ß) can be formed.

Catalytic hydrogenation with Raney nickel works almost exclusively to the 3 a isomers (trans form), while the reduction with sodium in a primary Alcohol predominantly gives the 3β isomers (cis form). The reduction of grenade cannon- (3) by means of lithium aluminum hydride, according to K. A 1 d e r and co-workers (cf. Liebigs Annalen der Chemie, Vol. 620 [1959], pp. 73 to 87) also give the 3ß-isomer (cf. also the LiA1H4 reduction of tropinone according to M i n z a, Nature, Vol. 170 [1952], P. 630, which leads exclusively to the 3β isomer pseudotropin). In contrast it has been found that reducing garnetanone- (3) with lithium aluminum hydride almost exclusively contains the 3a isomer (R1 CIIi). The manufacture of the raw material Serving garnet alcohol (3ß) is not the subject of the invention.

The new garnetanol (3) esters can be converted into theirs in the usual way Transfer hydrohalides.

Example 1 N-Benzyl-norgranatanol- (3β) - (a-phenyl-a-cyclohexylglycolic acid) ester 23.1 g of N-benzylnorgranatanol- (3β) (boiling point 0.4168 to 194 "C) and 24.8 g of methyl α-phenyl-α-cyclohexylglycolate (Kp.o, 94 to 980 C, prepared according to S. B. Coan, B. Jaffe and D. Papa, Journal of the American Chemical Society, Vol. 78 [1956], pp. 3701-3703) are under Addition of 1 g of sodium hydride in 1.5 l of heptane for 6 hours with stirring under reflux heated; about 200 ml of a mixture are added to a descending cooler distilled off from heptane and methanol. Another 1 g of sodium hydride is added and the mixture was heated for a further 7 hours, again taking about 200 ml of solvent are distilled off.

After cooling, the reaction mixture is extracted by shaking with 200 ml of water; the heptane layer is separated, dried and concentrated. This gives 34.8 g N-benzyl-norgranatanol- (3fl) - (a-phenyl-a-cyclohexylglycolic acid) ester; the The yield is 730%. The substance melts after recrystallization from petroleum ether at 141 to 142 "C.

From an ethereal solution of the base one obtains by precipitation with ethereal hydrochloric acid, the hydrochloride, which after recrystallization from isopropanol melts at 225 "C.

Example 2 Granatanol- (3β) -benzilic acid ester 46.6 g Granatanol- (3ft), 76 g of methyl benzilate and 0.5 g of sodium are at a pressure of 30 mm 3 Hours to 90 ° C., then heated to 130 ° C. for 7 hours. The mixture is removed from the melt any remaining unreacted sodium.

After cooling, 200 ml of 2N hydrochloric acid are added and the mixture is heated briefly Time to simmer. It is allowed to cool and then 250 ml of ether are added while stirring. The previously greasy residue becomes crystalline. Receives by suction 65.5 g of garnetanol (3β) benzilic acid ester hydrochloride (53.30 / 0 yield).

After recrystallizing twice from isopropanol, the substance melts with decomposition at 227 "C.

Example 3 N-Benzyl-norgranatanol- (3β) -benzilic acid ester According to the The procedure described in Example 2 is 23.1 g of N-benzyl-norgranatanol- (3β) (Boiling point, 4,168 to 194 ° C) (0.1 mol) with 24.2 g of methyl benzilate in the presence implemented by 0.3 g of sodium. 18.2 g (= 38% of theory) of N-benzyl are obtained - norgranatanol - (3ß) - benzilic acid ester in the form of the hydrochloride; F. 226 bis 227 ° C (from isopropanol).

Claims (1)

Claim: Process for the preparation of new garnetanol (3β) esters of the general formula in which X denotes a hydroxyl group, Y denotes phenyl or cycloalkyl radicals and R1 denotes lower alkyl or aralkyl radicals, and their hydrohalides, characterized in that garnetanols (3β) of the general formula with substituted phenylacetic acids of the general formula or their lower alkyl esters and optionally treated the esters obtained with hydrohalic acids. Publications considered: Austrian patent specification No. 198 771.