Synthesis
Currently, the synthesis of (-)-EBURNAMONINE is mainly divided into two methods: semi-synthetic and total synthesis. Semi-synthetic (-)-EBURNAMONINE is mainly synthesized using taponin extracted from potato as the starting material, while the total chemical synthesis method uses the reduction of intermediates. The total chemical synthesis method is more suitable for industrialization. The fully chemical synthesis method is as follows: (+)-15a-ethyl-2,3,6,11,15,15a-hexahydro-1H,5H-indolo[2,3-a]pyran[3,2-i]quinazine-14,14-(13H)-dicarboxylic acid diethyl ester is an intermediate structure in the chemical synthesis of vinblastine. After chiral resolution and reduction, the optically active (+)-15a-ethyl-2,3,6,11,15,15a-hexahydro-1H,5H-indolo[2,3-a]pyran[3,2-i]quinazine-14,14-(13H)-dicarboxylic acid diethyl ester (compound I) is obtained. Subsequent Pd-C reaction yields the effective structure of the vinblastine product (compound II). src="/NewsImg/2017-04-17/201741711512212247.jpg" alt="Synthesis Route" />
Image: Synthesis Route
Manufacturing Process
200 g (0.087 moles) of cis-1-ethyl-1-(2'-hydroxy-2'-carboxyethyl)-
1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine were suspended in 100
ml of xylene. 12 g of supported silver carbonate (a silver carbonate-Celite
reagent, containing 50% of silver carbonate) were added to the suspension,
and the system was boiled for 8 hours under a nitrogen atmosphere, with
constant stirring. Thereafter the hot solution was filtered, washed with 3 x 30
ml to 5% sodium carbonate solution, dried over magnesium sulfate, and
evaporated under reduced pressure. 1.05 g of a solid residue, which was a
mixture of racemic vincamone and racemic vincanol, was obtained. 40 ml of
ethyl ether were added to the mixture, and the insoluble crystals were filtered
off. The crystals were recrystallized from methanol, to yield 0.5 g of (+/-)-
eburnamonine (vincamone). Yield: 29.5%. MP: 201°-202°C. The value was
identical with the literature value (J. Mokry et aI.: CoII. Czech, Chem. Comm.
28, 1309, 1963). The etheral mother liquor was processed by preparative
layer chromatography (adsorbent: Kieselgel PF 254+366 , developing agent: a
14:2 mixture of benzene and methanol). The obtained substance was
recrystallized from ether to yield 0.2 g (16%) of (+/-)-vincanol (eburnamine).
MP: 163-164°C, under decomposition. The IR spectrum of the obtained
substance was identical with that of the authentic sample.
Resolution of (+/-)-vincamone:
10.0 g (0.0342 moles) of (+/-)-vincamone and 12.2 g (0.0342 moles) of (-)-
dibenzoyl tartaric acid were dissolved in 150 ml of dichloromethane, the
solution was seeded with crystalline (-)-vincamone-(-)-dibenzoyl-tartarate,
and the mixture was left to stand. The separated crystals were filtered off,
dissolved in dimethylformamide, and the pH of the solution was adjusted to 9 with aqueous ammonia. The separated substance was filtered off, washed with
water, and dried. This way 4.2 g (84%) of (-)-vincamone were obtained; MP:
-176°C; α D 20 = -96°. The mother liquor of resolution was evaporated and (+)-
vincamone was separeted as described above. The obtained substance had
MP: 173°-176°C.; α D 20 = +96°.
