Acid-catalyzed demethylation of echinochrome trimethyl ether

Full text of DOI:10.1007/s10600-008-0026-8

Chemistry of Natural Compounds, Vol. 44, No. 1, 2008
ACID-CATALYZED DEMETHYLATION OF ECHINOCHROME
TRIMETHYL ETHER
S. G. Polonik, N. D. Pokhilo, V. V. Makhan′kov, and V. F. Anufriev
UDC 547.655.6
The final step in the synthesis of the natural bioantioxidant echinochrome (1), the active principle of the drug
HistochromTM [1], is demethylation of its trimethyl ether 2 [2, 3]. This process is known to occur through the action of
anhydrous AlCl in nitrobenzene [2] or with prolonged boiling of 2 in ethanol:HCl (conc.) [4].
3
OH
O
R O
3
OR
OR
1
2
CH OH
O
3
1
- 5
: R = R = R = H; 2: R = R = R = Me
1
3
5
1
2
3
1
2
3
: R = R = Me, R = H; 4: R = Me, R = R = H
1
2
3
1
2
3
: R = R = H, R = Me
1
3
2
We investigated two alternative methods. For the first method, 2 was demethylated through the action of
methanesulfonic acid (MsOH) in AcOH with MsOH from 10 to 50 vol % at 120-170°C. Ether 2 (1 mmol in 12-15 mL) was
converted into 1 after 8-12 h in 35-40% MsOH in AcOH with refluxing at 125-145°C. When the reaction was finished, AcOH
was distilled in vacuo. The solid was dissolved in water and extracted with EtOAc. The extract was washed with water and
dried over Na SO . Solvent was evaporated. Preparative TLC of the solid on SiO2 (0.06-0.20 mm) using
2
4
hexane:toluene:EtOAc:acetone (2:2:1:1, v/v) isolated 1 in 56-72% yield (99% pure according to HPLC). Increasing the
temperature and MsOH content accelerated the reaction but also formed a slightly soluble and difficultly separated gray-black
polymeric solid.
The second method involved demethylating 2 (1 mmol) to echinochrome (1) byrefluxing for 9 h in HBr (conc.):AcOH
(
15 mL, 1:3 v/v). The yield was 77-80% after preparative TLC (99% pure according to HPLC).
In both instances the demethylation occurred successivelythrough formation of the single dimethyl ether 3, which then
was converted into a mixture of monoethers 4 and 5, further hydrolysis of which gave echinochrome. Dimethyl ether 3 and
monomethyl ethers 4 and 5, which are found in sea urchin shell [5] and are the principal products of partial hydrolysis of 2, were
isolated by preparative TLC and characterized by HPLC, PMR, and 13C NMR. Their physical chemical properties agreed with
those reported earlier [4, 5].
Thus, a technicallymore suitable method for demethylating 2 byboiling in HBr:AcOH that not only has a higher yield
but also uses cheap, nontoxic, and highly soluble biodegradable reagents was found. This enables the reaction to be carried out
with lower amounts of reagents and to avoid problems with recycling of synthetic wastes.
Pacific Institute of Bioorganic Chemistry, Far-East Division, Russian Academy of Sciences, 690022, Vladivostok,
prosp. 100-Letiya Vladivostoka, 159, fax: 7(4232) 31 40 50, e-mail: sergpol@piboc.dvo.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 1, p. 73, January-February, 2008. Original article submitted July 13, 2007.
©
0
009-3130/08/4401-0093 2008 Springer Science+Business Media, Inc.
93

ACKNOWLEDGMENT
The work was performed with partial financial support of the Interdisciplinary Integrated Project of the Far-East and
Siberian Divisions of the Russian Academy of Sciences (No. 06-II-CO-05-020).
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