CS221206B1 - A method for producing optical active bases - Google Patents

Abstract

Resolution of racemic vincadififormin bases of formula I, where R represents hydrogen, methyl, ethyl or allyl, into optically active forms by the action of enantiomeric tartaric acids.

Description

The invention relates to a process for the preparation of optical active bases of the formula I

wherein R is ethyl, methyl, hydrogen or allyl.

These bases are new, in addition to the (+) - and (-) - forms of the corresponding ethyl derivative (R in formula I denotes ethyl], which hitherto was only available by isolation from plant material.

The compounds of formula I are important intermediates in the manufacture of medicaments, in particular synthetic analogues of vinca alkaloids, which are widely used. Since only one of the antipodes is usually more effective for optically active substances of natural origin, it is preferable to work with optically active substances from the preparatory and economical point of view from the beginning of the synthesis rather than to carry out fission in the final stages. antipodium.

These disadvantages are overcome by the present invention, which makes it possible to obtain both optically active base forms of the formula I; it is based on the racemic bases of the formula I

in which R is as defined above, are reacted with (+) - or (-) - tartaric acid in ethanol or methanol, and the obtained crystalline substance is treated with a weak inorganic base such as sodium carbonate or sodium hydrogen carbonate or potassium.

According to a preferred embodiment of the process according to the invention, the racemic pulp of formula I is treated successively with both tartaric acid enantiomers, thereby obtaining the (+) - and (-) - base form of formula I.

STEP ¹ may be done also in alternative ways, e.g. by chromatography on optically active support materials. However, the process has the disadvantage of being laborious.

The following examples illustrate but do not limit the generality of the process of the invention.

Examples

Example 1

A mixture of 8.76 g (25 mmol) of 18-methylenvinandifformin (I: R-CH2, CH = CH2) and 3.68 g (24.5 mmol) of (+) - tartaric acid is dissolved in boiling in 35 ml of ethanol. The solution was allowed to stand in the refrigerator the next day and the precipitated crystals were aspirated and boiled with 12 ml of ethanol to give 4.92 g (78.6%) of the salt, m.p. 137-141.5 ° C. This salt was partitioned between 0.7 M aqueous potassium bicarbonate solution and methylene chloride. The organic phase was washed with 0.3 M potassium hydrogen carbonate solution, 2X water and finally with brine. After drying over sodium sulfate, the solution was evaporated to give 3.27 g (96.7%) of a colorless glass with a rotation (a) of + 560.5 ° (ethanol); (+) - 18-methylenevinyldifformin (I:

R = CH 2 CH = CH 2). The bases are released from the original mother liquor as described above. The glass obtained is cleaved with (-) - tartaric acid as described above. (-) -18-methylene-vincadifformin (I: R = CH 2 CH = CH 2) is released from the salt obtained as described above; glass with a specific rotation of (a) —561 ° (ethanol).

Example 2

Using the procedure of Example 1, using methanol instead of ethanol and potassium bicarbonate instead of ethanol, 50.2% of (+) -vincadifformin (I) was obtained from (+) - vincadif formine (I: R = CH 2 CH 3). Mp 92.5-94 ° C, and 54.8% of (-) - vincadifformin (I: R = CH 2 CH 3) mp 92-94.5 ° C.

Claims (1)

A process for the production of optically active bases of the formula I, OF THE INVENTION wherein R is ethyl, methyl, hydrogen or allyl, characterized in that the racemic forms of the base of formula I, wherein R is as defined above, are reacted with (+) - or (vin-tartaric acid) in ethanol or methanol, and treating the obtained crystalline substance with a weak inorganic base, such as sodium or potassium carbonate or hydrogen carbonate.