CH644119A5 - METHOD FOR PRODUCING 2-CARBALKOXY-METHYL-3-AETHYL-9.10-DIMETHOXY-1,2,3,4,6,7-HEXAHYDRO-11BH-BENZO (A) CHINOLIZINES. - Google Patents

Description

The present invention relates to a process for the preparation of 2-carbalkoxy-methyl-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-1 lbH-benzo [a] quinolizines of the general formula I,

CK ^ O

CH3 °

CHjCOOR

ss is biologically active. The fundamental problem of the synthesis is therefore that the reaction should be carried out stereospecifically.

A method for total emetine synthesis is described by J. Chem. Soc. P. 1461 (1963). In one of the procedural steps of the synthesis, compounds of the general formula II are reduced to compounds of the general formula I. The stereo specificity is also a prerequisite here, i.e. the substituents should have positions corresponding to formula I. This reduction step was mentioned in 65 different references. All process variants are characterized in that the hydrogenation of the compounds of the general formula II in the presence of platinum or palladium catalyst is carried out

leads. (CH Patent No. 408 816 and No. 437 301).

It is well known that hydrogenation is a complex, costly and very dangerous operation that requires special facilities.

It has now been found that the compounds of the general formula II can be reduced very easily to compounds of the general formula I if formic acid is used as the reducing agent in the presence of palladium catalyst. The hydrogen atoms arising from the catalytically decomposed formic acid saturate the double bond in situ.

Surprisingly, we have found that the reduction according to the invention is stereospecific and practically only the 2,3-trans-axial isomer is formed. The optical purity of the product thus produced is identical to that stated in the two Swiss patents mentioned above.

Another advantage of the method according to the invention is that the yield is higher (80%) than in the previously known methods. The catalyst used does not lose its activity and can therefore be used several times.

According to the invention, the optical antipodes of the compounds of the general formula II or their mixture can be used: the product can be resolved in this case.

The reduction according to the invention is expediently carried out in an aqueous medium. The process is on the one hand more economical than the known methods which carry out the hydrogenation in an alcoholic medium and on the other hand the catalyst in the water is not pyrophoric and so it is no longer dangerous.

The reduction is expediently carried out in a dilute aqueous medium, 2-8 molar equivalents, advantageously 5 molar equivalents, of formic acid being calculated per mol of the compound of the formula II.

In order to convert the otherwise water-insoluble compound of the general formula II into a water-soluble salt, one mole of formic acid is required per mole of the compound of the general formula II in addition to the amount of formic acid required for the reduction. For this purpose, other acids such as e.g. Use acetic acid. However, the reduction can also be carried out without a solvent, i.e. only be carried out in formic acid.

The preparation of the starting materials of the general formula II or their optically active antipodes or the mixture of the antipodes is described in J. Chem. Soc. P. 1461 '(1963) or in Tetrahedron Letters (1963) 247.

The amount of catalyst used can be varied as desired, but of course economic factors have to be taken into account. According to an advantageous embodiment of the method according to the invention, 10-15% catalyst is used, calculated on the substrate, the catalyst containing 1-15% palladium.

644119

The process according to the invention is explained in detail below: the optically active compounds of the general formula II or their antipodes or the racemic form are suspended in water and the molar solution obtained is 5 molar equivalents of formic acid - calculated on one mol of the substrate - and 10% palladium catalyst (Pd content: 9%).

After the reaction has ended, the catalyst is filtered and then the optically active compounds of the general formula I or their antipodes or the racemates are isolated in a known manner.

The process according to the invention enables the compounds of the general formula I or the corresponding racemates to be prepared more simply, more economically and under safer conditions than the previous ones.

example 1

10 g of the (-) - 2-carbäthoxymethylene-3-ethyl-9,10-di-methoxy-1,2,3,4,6,7-hexahidro-11 bH-benzo [a] quinolizine are dissolved in 50 ml of water suspended. Formic acid is metered into this suspension with constant stirring until a clear solution is obtained (about 6 ml, i.e. 5 molar equivalents of formic acid are used); soon 1.2 g of the wet, filtered Pd / C catalyst of 9% palladium content are rinsed into the solution with the help of 14 ml of water. The reaction mixture is heated under reflux condenser with constant stirring through an oil bath (110 ° C). The completeness of the reaction is checked by thin layer chromatography. The catalyst is then filtered; 34 ml of isopropanol are added to the solution and the pH of the solution is then adjusted to 8-8.5 with concentrated ammonium hydroxide. The solution remains overnight. The resulting precipitate is filtered and washed with water; after drying, 8.5 g (82%) of the end product are obtained. Melting point: 88-89 °, [ci] d: —40 ° (c = 1 in ethanol)

Example 2

0.5 g of (1.4 mmol) racemic (-) - 2-carb-ethoxy-methylene-3-ethyl-9,10-dimethoxy-l, 2,3,4,6,7-hexa- hydro-1 lbH-benzo [a] quinolizine is dissolved in 5 ml of 98% formic acid and this solution is added dropwise to a suspension of 0.1 g dry Pd / C (12.7%) in 2 ml formic acid. The mixture is heated in a 110 ° C oil bath under reflux for 2 hours. The solution, cooled to room temperature, is freed from the catalyst by filtering. The formic acid is distilled off in vacuo. The residue is dissolved in 10 ml of water, with 2 ml of cc. Ammonium hydroxide solution made alkaline, and then extracted 3 times with 20 ml of diethyl ether. The combined ethereal phase is dried with magnesium sulfate and, after filtration, freed from the ether by distillation. The oily residue weighing 0.45 g is crystallized from 2 ml of petroleum ether. 0.4 g of the (1.12 mol, 80%) racemic end product are obtained. Melting point: 77-78 ° C.

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Claims (3)

644119 2. The method according to claim 1, characterized in that the reduction is carried out in an aqueous medium. 2nd PATENT CLAIMS 1. Process for the preparation of compounds of general formula I in which R represents a methyl or ethyl group, from compounds of the general formula II, (II) CHjO C, H ir s CWjCOOR ROOC where R is methyl or ethyl group, by reducing the compounds of general formula II CH30 (II) C, H LnS wherein R has the meaning given above, by reduction, characterized in that formic acid is used as reducing agent in the presence of palladium catalyst. Since R always has the same meaning in the general formulas, its definition is not repeated below. 25 Formulas I and II encompass all optical antipodes and their mixtures. The compounds of formula I are valuable intermediates for the production of emetine and their derivatives, which have an antiamoebal effect. Emetin is a compound with four centers of asymmetry, but only the so-called "natural" (-) - emetin with the general formula III ROOC —C H where R has the meaning given above, characterized in that formic acid is used as the reducing agent in the presence of a palladium catalyst. 3. Process according to claims 1 and 2, characterized in that 2-8 molar equivalents, advantageously 5 molar equivalents of formic acid to one mole of the compound of formula II - in which R has the above meaning - are used.