HU180440B - New process for producing 2-carbalkoxy-methyl-3-ethyl-9,10-dimethoxy-1,2,3,6,7-hexahydro-11ah-benzo-bracket-a-bracket closed-quinolisine derivatives - Google Patents

Abstract

2-Carbalkoxymethyl-3-ethyl-9,10- dimethoxy 1,2,3,4,6,7-hexahydro-11bH- benzo[a]quinolizines are obtained stereospecifically by reduction of the corresponding 2-carbalkoxymethylene compound with formic acid in the presence of a palladium catalyst, preferably in an aqueous medium.

Description

SUMMARY OF THE INVENTION The present invention relates to a novel process of the known optically active Formula I wherein

R is methyl or ethyl - 2-carbalkoxymethyl-3-ethyl-9,10-dimethoxy-1,2,3,4,

For the preparation of any optical antipode or mixture of optical antipodes of 6,7-hexahydro-11H-benzo (a) -quinolizines of formula II wherein

R is the reduction of any optical antipode of the above compound or mixture of antipodes using formic acid as the reducing agent in the presence of a palladium catalyst.

Since the meaning of R in the general formulas remains unchanged, it will no longer be defined.

The compounds of formula I are intermediates of emetine and its derivatives with amoebic activity. Emetine is a compound containing four asymmetric centers, but only the "natural" (-) emetine of the general formula III is biologically active. Therefore, the basic problem of synthesis is the requirement of stereospecific reactions. One solution for complex emetin synthesis can be found, for example, in J. Chem. Soc. 1461. 25 (1963). The reported yield of the procedure is 68%. One step in the synthesis is the reduction to the compound of formula II. The stereospecific nature of this reaction step is also required. Thus, on the one hand, it is intended that the position of the substituents in the resulting compounds of formula I at positions 2 and 11a is the same as that of the starting material of formula II. On the other hand, the aim is that the newly formed chirality center during the reduction is 2,3-trans-axial, that is, as defined in formula I. The reduction step has already been described in many places. A common feature of these processes is that the compound of general formula II is hydrogenated in the presence of a platinum or palladium catalyst (Swiss Patent Nos. 408,816 and 436,301), with a yield of about 68%. It is well known that hydrogenation is a complex, costly, and inherently quite hazardous operation that requires special equipment.

The present invention is based on the surprising discovery that compounds of formula II can simply be reduced to compounds of formula I by using formic acid in the presence of a palladium catalyst. The essence of the process is that hydrogen released from formic acid decomposed by the catalyst saturates the double bond in situ. The reduction takes place in a stereospecific manner, so that only the 2,3-trans-axial isomer which is advantageous to us is formed.

Compounds of formula II in the form of left and right rotating optical antipodes are 180 440 1

180,440 teas. Thus, in principle, the starting material for the reduction step may be both optical antipodes or a mixture thereof. As a result, the product formed by the reaction may be left and right rotating or a mixture thereof.

The optical purity of the product according to our process is the same as that described in the above Swiss patents.

The significance of the present invention is enhanced by the fact that the product can be obtained in higher yields than 80% by known methods.

In our process, one can naturally start from the optically active antipode of the compound of formula II, either by turning the plane of apolar light to the left, or by a mixture of antipodes.

According to a preferred embodiment of the present invention, it is reduced in an aqueous medium. This makes our process even more economical than previous methods, which eliminate the pyrophoric nature of the catalyst, making the process extremely safe.

The reduction may conveniently be carried out in a dilute aqueous medium using from 2 to 8, preferably 5 molar equivalents of formic acid, relative to the compound of formula II to be reduced.

In addition to the amount of formic acid required for the reduction, a molar equivalent of formic acid is required to form the acid addition salt of the water-insoluble compound of formula II. This salt is soluble in water. In addition to the formic acid required for the reduction, other acids, such as acetic acid, may be used as the salt-forming agents.

The reduction may also be carried out in anhydrous formic acid medium.

The optical antipode of the compound of formula II used as starting material or a mixture of antipodes may be prepared from the corresponding 2-oxo compound, for example, by methoxycarbonylmethylene triphenylphosphorane (J. Chem. Soc. 1963. 1461) or by the phosphonic acetic ester derivative (tetrahedron Letters 1963. page 247).

A further advantage of our process is that it does not lose the activity of the catalyst used during the reaction and can therefore be used several times.

The amount of palladium on the support, as well as the amount of the catalyst as a whole, can be practically varied, and may be economically feasible. Preferably, 10-15% by weight of the catalyst is used, with a palladium content of 1-15% by weight.

In a preferred embodiment of the process, an optically active compound of formula II is suspended in water and 5 molar equivalents of formic acid and 10% palladium on carbon (9% palladium) are added to the substrate. Gas evolution is observed and the reaction can be monitored by thin layer chromatography. After completion of the reaction, the catalyst is filtered off and the optically active compound is liberated from its acid addition salt and the product is isolated by crystallization or precipitation. In this case, the resultant compound of formula I is preferably already optical rotation suitable for emetin synthesis.

However, a mixture of left and right antipodes or a racemate may also be used as starting material. In this case, the reduction of the compound of formula II according to the present invention results in a mixture of the left and right antipodes of the compound of formula I and the racemate. This product will have to be resolved at some point in the subsequent synthesis of emetin.

In summary, according to our process, the compounds of formula I can be prepared more simply, more economically, and extremely safely than previously known methods.

The following examples illustrate the details of our process without limiting the invention to the examples.

Example 1 g (+) - 2-Carbethoxymethylene-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7,7-hexahydro-11b-benzo (a) quinolizine in a 250 ml four-tube flask It is suspended in 50 ml of water. Formic acid (about 6 mL, 5 molar equivalents) was added to the suspension with stirring until a clear solution was obtained, followed by washing with 1.2 g of a 9% palladium on charcoal catalyst in 14% water. Gas evolution is detected. The reaction mixture was stirred at reflux for 2 hours. 110 ° C oil bath. The completion of the reaction was monitored by thin layer chromatography. After cooling, the catalyst is filtered off, 34 ml of isopropanol are added to the aqueous formic acid solution, and the pH is adjusted to 8-8.5 with concentrated ammonium hydroxide and allowed to stand overnight. After decantation, washing with water and drying, the product was 8.5 g (82%) of (-) - 2-carbethoxymethyl-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7- llbH-hexahydro-benzo (a) quinolizine. 99-89 ° C [α] D: -40 ° (c = 1, in ethanol).

Example 2

Dissolve 0.5 g (1.4 mmol) of racemic 2-carbethoxymethylene-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-dibenzo (ia) quinolizine in 5 ml of 98% formic acid. and added dropwise to a suspension of 0.1 g of palladium on carbon (12.7%) in 2 ml of formic acid. The formic acid mixture was heated under reflux for 2 hours in a 110 ° C oil bath. The mixture was then allowed to cool to room temperature. The formic acid solution is filtered off from the catalyst and the formic acid is distilled off in vacuo. The residue was dissolved in water (10 mL) and basified with concentrated ammonium hydroxide (2 mL) and extracted with ether (3 x 20 mL). The combined ester solution was dried over anhydrous magnesium sulfate, filtered and the ether distilled off. The residual oily substance (s.p. 0.45 g) was crystallized from petroleum ether (2 mL).

180,440

The product was 0.4 g (1.12 mmol, 80%) of racemic 2-carbethoxymethylene-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-benzo (a). ) quinolizine.

77-78 ° C.

Example 3 2-carbethoxymethylene-3-ethyl-9,10-dimethoxy-1 containing 80% (+) and 20% (-) of the antipode,

2,3,4,6,7-hexahydro-11 H -benzo (a) quinolizine [α] D: 4-26.4 ° C = 1 in ethanol; In a 250 mL four-tube flask, suspend formic acid (about 6 mL, 5 molar equivalents) in 50 mL of water until a clear solution is obtained, then wash with 1.2 g of palladium on charcoal catalyst in 14 mL of water. Gas evolution is detected. The reaction mixture was stirred for 2 hours under reflux at 110 ° C in an oil bath. The completion of the reaction was monitored by TLC. After cooling, the catalyst is filtered off, 34 ml of isopropanol are added to the aqueous formic acid solution and the pH is adjusted to 8-8.5 with concentrated ammonium hydroxide. The mixture was allowed to stand overnight. After washing, washing with water and drying, the product is a mixture of 2-carbethoxymethyl-3-ethyl-9,10-dimethoxy-1,2-carboxymethyl-8,5 g (80% (-) and 20% (4)). , 3,4,6,7-hexahydro-11 H -benzo (a) 5-quinolizine.

Mp 80-82 ° C, [α] D: -24 ° (c = 1 in ethanol).

Claims (1)

A patent claim The process of formula I is wherein R is a methyl or ethyl group, a quinolizine derivative for the preparation of any optical antipode or mixture of optical antipodes by reducing any optical antipode of the compound of formula II wherein R is as defined above, characterized in that in the presence of palladium catalyst, 2 to 8 molar equivalents of formic acid, relative to the compound of formula II, in aqueous or non-aqueous media.