Process for the preparation of pharmacologically active...

Details Process for the preparation of pharmacologically active... Process for the preparation of pharmacologically active...

2002-03-28

2003-07-08

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S322000, C568S426000, C568S442000, C568S627000, C568S630000, C568S648000, C568S654000, C568S814000

Reexamination Certificate

active

06590127

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to “a process for the preparation of pharmacologically active &agr;-asarone from toxic &bgr;-asarone rich
Acorus calamus
oil via intermediate 2,4,5-trimethoxyphenylpropane of the formula I (a dihydro product of toxic &bgr;-asarone) which is obtained via hydrogenation of commercially available
Acorus calamus
oil rich in &bgr;-asarone containing &agr; and &ggr; isomer), undergoes dehydrogenation and/or oxidation in a single step by just varying reaction time, temperature, solvent (anhydrous) and amount of dichlorodicyanobenzoquinone (DDQ) with or without a solid support such as silica gel, alumina and the like towards formation of &agr;-asarone (trans-2,4,5-trimethoxyphenyl-1-propene), a well known pharmacolocally active phenylpropanoid, and trans-2,4,5-trimethoxycinnamaldehyde as a side product. However, above dehydrogenation process when conducted in aqueous solvent provides 1-(2,4,5-trimethoxy)phenyl-1-propanone which upon reduction with sodium borohydride into 1-(2,4,5-trimethoxy)phenyl-1-hydroxypropane followed by acidic dehydration affords &agr;-asarone exclusively. Moreover, it is worthwhile to mention that 1-(2,4,5-trimethoxy)phenyl-1-propanone (isoacoramone) and 2,4,5-trimethoxycinnamaldehyde are found as phenylpropanoids present in traces in some of the aromatic and medicinal plants. Overall, the aim of this invention is to utilize internationally banned, but widely available toxic &bgr;-asarone as a simple and economical starting material for the preparation of a potential hypolipidemic and antiplatelet active &agr;-asarone via combination of two simple industrially attractive processes i.e. hydrogenation and dehydrogenation/oxidation in which formation of the unexpected 2,4,5-trimethoxycinnamaldehyde is discovered as a side product during preparation of &agr;-asarone. In the present invention, we have disclosed a simple and economical process that is capable of converting toxic &bgr;-asarone into pharmacological active &agr;-asarone in high yield without contamination of its other isomers i.e. and/or &ggr;-asarone.
BACKGROUND OF THE INVENTION
Although the plant derived products have found widespread applications in the field of essential oils, colours and dyes, cosmetics, pharmaceuticals and in many others, not only because they are easily available and are cheaper but also an important reason has been the notion that they are safer than synthetic products, which may not always be true. There are several phytochemicals which beyond a certain limit, diminishes the market potential of products such as phenylpropanoids rich essential oils which get deteriorated specifically by few isomeric forms of phenylpropenes (Miller, E. C.; Swanson, A. B.; Phillips, D. H.; Fletcher, T. L.; Liem, A. and Miller, J. A., Cancer Research, 43 (3), 1124-1134 (1983); Kim; S. C.; Liem; A.; Stewart; B. C. and Miller, J. A. Carcinogensis, 20 (7), 1303-1307 (1999) and Lazutka, J. R.; Mierauskiene, S. and Dedonyte, V. Food & Chemical Technology, 39, 485-492 (2001)). In fact, phenylpropenes are naturally occurring phenolic compounds wherein an aromatic ring is attached to three-carbon side chain (C
6
-C
3
unit), exist either as pair of cis/trans (i.e. &agr;/&bgr;-isomer) propenyls or allyl propenes (i.e. &ggr;-isomer). Generally, trans-isomers (e.g. &agr;-asarone and isoeugenol etc) are found safer for human consumption while cis/allyl-isomers (e.g. &bgr;-asarone and saffrole) are found toxic and carcinogenic (Harborne, J. B. and Baxter, H., Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington D.C., 474 (1993)). The concentration of phenylpropenes and their isomeric ratio in essential oils is greatly affected by growth stages and habitat of the plant, which in turn affect the demand and application of particular oil. Due to this, the most affected oil is calamus oil obtained by steam distillation of rhizomes of
Acorus calamus
(family: Araceae) which grows wildly and also cultivated in many countries due to its varied medicinal properties and great demand of its essential oil in flavour and perfumery industries (Treben, M., Health Through God's Pharmacy, Wilhelm Ennthaler, Steyer, Austria, 12-14 (1986); Akhtar, H.; Virmani, O. P.; Popli, S. P.; Misra, L. N.; Gupta, M. M.; Srivastava, G. N.; Abraham, Z. and Singh, A. K., Dictionary of Indian Medicinal Plants, CIMAP, RSM Nagar, Lucknow, 10-11 (1992); Motley, T. J., Economic Botany, 48, 397-412 (1994) and Lawrence, B. M. and Reynolds, R. J., Perfumer & Flavorist 22 (2), 59-67 (1997)). However, a lot of discrepancy and variability in quality of
calamus
oil has been observed in which tetraploid and hexaploid varieties (distributed extensively in Asian countries like India, Japan, Pakistan and China) contains a very high percentage of toxic &bgr;-asarone (varying from 70 to 90%) while diploid and triploid varieties contain limited amount of &bgr;-asarone (3 to 8%) which are allowed for use in flavor, perfumery and pharmaceutical industries (Stahl, E. and Keller, K., Planta Medica 43, 128-140 (1981); Waltraud, G. and Schimmer, O., Mutation Research 121, 191-194 (1983); Mazza, G., J. of Chromatography, 328, 179-206 (1985); Nigam, M. C.; Ateeque, A.; Misra, L. N. and Ahmad, A., Indian Perfumer, 34, 282-285 (1990) and Bonaccorsi, I.; Cortroneo, A.; Chowdhury, J. U. and Yusuf, M., Essenze Derv. Agrum., 67(4), 392-402 (1997)).
&bgr;-asarone is experimentally proved to be carcinogenic in animals and has also been found to induce tumors in the duodenal region after oral administration. In addition, &bgr;-asarone has also shown chromosome damaging effect on human lymphocytes in-vitro after metabolic activation (Taylor, J. M.; Jones, W. I.; Hogan, E. C.; Gross, M. A.; David, D. A. and Cook, E. L., Toxicol. Appl. Pharmacol., 10, 405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta Medica 1, 6-9 (1985); Abel, G., Planta Medica, 53(3), 251-253 (1987) and Riaz, M.; Shadab, Q.; Chaudhary, F. M., Hamdard Medicus, 38(2), 50-62 (1995)). As a result, the calamus oil of Asian origin is internationally banned for any kind of use in flavor, perfumery and pharmaceutical industries. To the best of our knowledge, there is no report in which toxic &bgr;-asarone of calamus oil is utilized for its value addition except very recently by our group (Sinha, A. K.; Dogra, R. and Joshi, B. P., Ind. J. Chem., 41B, (2002) (in press); Sinha, A. K.; Joshi, B. P. and Dogra, R., Nat. Prod. Lett., 15(6), 439-444 (2001); Sinha, A. K.; Acharya, R. and Joshi, B. P., J. Nat. Prod. (2002) (in press), Sinha, A. K.; Dogra, R. and Joshi, B. P., Sinha, A. K.; Joshi, B. P., and Dogra, R., JP Patent No. 2001.68716 filed on Mar. 12, 2001; Sinha, A. K.; Joshi, B. P., and Dogra, R., U.S. patent application Ser. No. 09/805,832 filed on Mar. 14, 2001; U.S. patent application Ser. No. 09/823,123 filed on Mar. 31, 2001 and Sinha, A. K.; Joshi, B. P., and Dogra, R., PCT/IN 01/00104 filed on May 21, 2001) wherein ammonium formate/palladium-on-charcoal or H
2
/palladium-on-charcoal assisted reduction of crude
calamus
oil containing high percentage of toxic &bgr;-asarone provides 2,4,5-trimethoxyphenylpropane (dihydro asarone) in 97% purity with yield ranging from 81-87% based on asarones content in
calamus
oil (Example I). Thus, obtained 2,4,5-trimethoxyphenylpropane (also known as 1-propyl-2,4,5-trimethoxybenzene) is invented for the first time as five times less toxic than &bgr;-asarone and thus, this 2,4,5-trimethoxyphenylpropane enables its application in the products such as mouthwashes, tooth pastes, antiseptic soap products, chewing gum flavors and little in spicy products due to its sweet, ylang, slightly spicy and fruity aroma. In addition, 2,4,5-trimethoxyphenylpropane is also discovered as a simple and an economical starting material for synthesis of a salicylamide based antipsychotic drug (5,6-dimethoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide) (Thomas, H.; Stefan, B.; Tomas, D. P.; Lars, J.; Peter, S.; Hakan, H. and Orgen, S. O., J. Med. Che

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