Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
  • C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/48—Preparation of compounds having groups
  • C07C41/58—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation

Definitions

• the present invention relates to "a process for the preparation of pharmacologically active ⁇ -asarone from toxic ⁇ -asarone rich Acorus calamus oil via intermediate 2,4,5- trimethoxyphenylpropane of the formula I (a dihydro product of toxic ⁇ -asarone) which is obtained via hydrogenation of commercially available Acorus calamus oil rich in ⁇ -asarone containing ⁇ and ⁇ 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 ⁇ -asarone (trans-2,4,5-trimethoxyphenyl-l- propene), a well known pharmacolocally active phenylpropanoid, and trans-2,4,5- trimethoxycinnamaldeh
• the aim of this invention is to utilize internationally banned, but widely available toxic ⁇ -asarone as a simple and economical starting material for the preparation of a potential hypolipidemic and antiplatelet active ⁇ - 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 ⁇ -asarone.
• 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. ⁇ / ⁇ -isomer) propenyls or allyl propenes (i.e. ⁇ -isomer).
• trans-isomers e.g.
• ⁇ -asarone and isoeugenol etc are found safer for human consumption while cis/allyl-isomers (e.g. ⁇ -asarone and saffrole) are found toxic and carcinogenic (Harborne, J. B. and Baxter, H., Phyt ⁇ chemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington DC, 474 (1993)).
• 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.
• 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.
• ⁇ -asarone is experimentally proved to be carcinogenic in animals and has also been found to induce tumors in the duodenal region after oral administration.
• ⁇ -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.
• 2,4,5-trimethoxyphenylpropane also known as l-propyl-2,4,5- trimethoxybenzene
• l-propyl-2,4,5- trimethoxybenzene is invented for the first time as five times less toxic than ⁇ -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.
• 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[(l- 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. Chem., 33, 1 155-1163 (1990) and Sinha, A.K., US Patent No. 09-652376 filed on 31 August (2000)).
• a salicylamide based antipsychotic drug (5,6-dimethoxy-N[(l- ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide) (Thomas, H.; Stefan, B.; Tomas, D.P.; Lars, J.; Peter
• ⁇ -asarone trans-2,4,5-trimethoxyphenyl-l-propene
• hypolipideamic and antiplatelet activity but is generally present in traces with ⁇ and ⁇ -asarone in various plant species including A. calamus (Patra, A. and Mitra, A. K., J. Nat.
• DDQ dehydrogenating agents namely, manganese dioxide, p-chloranil, selenium dioxide, Pd/C, selenium and sulphur
• DDQ dehydrogenating agents
• a solid support such as silica gel, alumina and the like in a mono or biphasic system.
• anhydrous solvent namely, alcohol such as methanol, ethanol and the like; aliphatic and aromatic hydrocarbons such as hexane, benzene, toluene and the like; ether such as tetrahydrofuran, dioxane and the like, the reaction between 2,4,5- trimethoxyphenylpropane and varying amount of DDQ, preferably ranging from 1.0 to 1.1 moles, furnishes the corresponding dehydrogenated product i.e. trans-asarone ( ⁇ -asarone) in 41-44% yield and unreacted starting material (i.e.
• trans-2,4,5-trimethoxycinnamaldehyde prepared by reaction of ⁇ -asarone (tr ⁇ ns-asarone, procured from Sigma Chemical Ltd.) with DDQ in dioxane.
• trans-2,4,5-trimethoxycinnamaldehyde has appeared as a rare phenylpropanoid present in Caesulia axillaries and Alpinia ⁇ abella (0.000015%) in traces (Kulkarni, M.M.; Sohoni, J.; Rojatkar, S. R. and Nagasampagi, B. A., Ind. J. Chem. Sec.
• 2,4,5-trimethoxypropiophenone is realized as an interesting rare phenylpropanoid occurring in well known medicinal plant Acorus calamus, Piper marginatum as well as in Acorus tararinowii but only in traces (Mazza, G., J. of Chromatography, 328,179-206 (1985); Santos, B.N. de O. and Chaves, M.C. de O., Biochem. Systematics Ecology, 25, 539-541 (1999) and Jinfeng, Hu and Xiaozhang, Feng, Planta Medica, 66, 662-664 (2000).
• our invention discloses a simple and economical process for the preparation of pharmacologically active ⁇ -asarone along with two important naturally occurring phenylpropanoids namely 2,4,5-trimethoxypropiophenone (isoacaromone) and 2,4,5- trimethoxycinnamaldehyde, starting from relatively cheaper and economical material 2,4,5- trimethoxyphenylpropane obtained via hydrogenation of ⁇ -asarone rich Acorus calamus oil as outlined in Scheme-I.
• 2,4,5-trimethoxypropiophenone isoacaromone
• 2,4,5- trimethoxycinnamaldehyde 2,4,5- trimethoxyphenylpropane obtained via hydrogenation of ⁇ -asarone rich Acorus calamus oil as outlined in Scheme-I.
• the main object of the present invention is to prepare pharmacologically active . ⁇ -asarone from 2,4,5-trimethoxyphenylpropane which is, in fact, is a hydrogenated product of toxic ⁇ -asarone isolated from commercially available Acorus calamus oil.
• Another object of the present invention is to explore the possibilities of utilizing toxic calamus oil of tetraploid or hexaploid varieties (distributed extensively in Asian countries), thereby, enhancing the profitable use thereof.
• Still another object of the invention is to develop a simple process for the preparation of ⁇ - asarone exclusively without any contamination of other isomeric forms of asarone (i.e. ⁇ and/or ⁇ -isomer).
• Yet another object of the invention is to characterize the unexpected formation of polar yellow solid, which, in fact, formed as a side product along with ⁇ -asarone. Yet another object of the invention is to establish the structure of yellow solid which finally appeared to be a naturally occurring rare trans-2,4,5-trimethoxycinnamaldehyde. Yet another object of the invention is to develop another route for the preparation of ⁇ - asarone starting from l-(2,4,5-trimethoxy)phenyl-l-propanone.
• Yet another object of the invention is to prepare l-(2,4,5-trimethoxy)phenyl-l-propanone
• Yet another object of the invention is to prepare ⁇ -asarone exclusively via reduction of 1- (2,4,5-trimethoxy)phenyl-l-propanone into corresponding l-(2,4,5-trimethoxy)phenyl-l- propanol followed by the acidic dehydration.
• the present invention provides a process for the preparation of pharmacologically active natural occurring ⁇ -asarone utilizing combination of 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (DDQ) as mild and efficient dehydrogenating agent and 2,4,5- trimethoxyphenylpropane which is, in fact, the hydrogenated product of toxic ⁇ -asarone isolated from commercially available calamus oil.
• DDQ 2,3-dichloro-5,6-dicyano-l,4- benzoquinone
• Figure 1 is ⁇ NMR (300 MHz) spectra of ⁇ -asarone (in CDC1 3 ) of the reaction product of Example II.
• Figure 2 is 13 C NMR (75.4 MHz) spectra of ⁇ -asarone (in CDC1 3 ) of the reaction product of Example H
• Figure 3 is ⁇ NMR (300 MHz) spectra of 2,4,5-trimethoxycinnamaldehyde (in CDC1 3 ) of the reaction product of Example HI.
• Figure 4 is 13 C NMR (75.4 MHz) spectra of 2,4,5-trimethoxycinnamaldehyde (in CDC1 3 ) of the reaction product of Example IH.
• Figure 5 is ⁇ NMR (300 MHz) spectra of l-(2,4,5-trimethxy)phenyl-l-propanone (in
• Figure 7 is ⁇ ⁇ MR (300 MHz) spectra of l-(2,4,5-trimethxy)phenyl-l-hydroxypropane
• the present invention provides "a process for the preparation of pharmacologically active ⁇ -asarone from toxic ⁇ -asarone rich Acorus calamus oil via intermediate 2,4,5-trimethoxyphenylpropane" wherein the said process comprises hydrogenation of toxic ⁇ -asarone or calamus oil containing a mixture of ⁇ , ⁇ and ⁇ -asarone to obtain 2,4,5-trimethoxyphenylpropane of the formula I followed by the dehydrogenation of the above said compound at a temperature in the range of 5- 120°C for a period ranging from 30 minutes to 72 hours using solvent.
• a simple process is available to prepare pharmacologically active ⁇ -asarone from 2,4,5-trimethoxyphenylpropane, which is, in fact, the hydrogenated product of toxic ⁇ -asarone isolated from commercially available calamus oil.
• a simple process is available for the commercial utilization of internationally banned but widely available toxic ⁇ -asarone from Acorus calamus oil of tetraploid or hexaploid varieties (distributed extensively in Asian countries), thereby, enhancing the profitable use thereof.
• a simple process involves the conversion of mixture of all the three isomeric forms of phenylpropene i.e. ⁇ , ⁇ and ⁇ -asarone firstly into 2,4,5-trimethoxyphenylpropane and then regenerating 1- (2,4,5-trimethoxy)phenyl-l-propene derivative exclusively in trans form ( ⁇ -asarone).
• a simple process is available for the preparation of ⁇ -asarone exclusively without any contamination of other isomeric forms of asarone (i.e. ⁇ and/or ⁇ -isomer).
• a simple process which discloses the interaction of 2,4,5-trimethoxyphenylpropane with varying amount of dehydrogenating reagent such as DDQ and also varying time, temperature and solvents.
• dehydrogenating reagent such as DDQ
• the molar ratio of dehydrogenating agent (DDQ) to 2,4,5-trimethoxyphenylpropane is used in the ratio of 1.0: 1.0 to 1.3: 1.0 preferably 1.0 to 1.2: 1.0.
• DDQ in organic solvent selected from methanol, dioxane, THF and water in the ratio ranging from 9.9: 0.1 to 9: 1 and at a temperature in the range of 5 - 110°C preferably 8- 60°C; reaction period of time is 1 hour to 54 hours, preferably 6-18 hours.
• ⁇ -asarone provides a process for the preparation of ⁇ -asarone from 2,4,5-trimethoxypropiophenone via its reduction into 1 -(2,4,5- trimethoxy)phenyl-l-hydroxypropane followed by dehydration under acidic condition.
• dehydration of 2,4,5- trimethoxyphenyl-1-hydroxypropane is carried out with p-toulene sulphonic acid and thionyl chloride/pyridine and the like provides ⁇ -asarone.
• Phenylpropanoids (C 6 -C 3 ) are mainly produced in plants in response to pathogen attack.
• This group of secondary metabolites comprises many biologically active compounds like phenylpropanones, cinnamaldehydes, cinnamal alcohols, cinnamic acids and phenylpropenes.
• phenylpropanones cinnamaldehydes
• cinnamal alcohols cinnamic acids
• phenylpropenes Among three isomeric forms of phenylpropene, cis and ⁇ -isomeric forms have proved to be toxic and carcinogenic while trans-isomeric form is reported for its use in flavour, perfumery and pharmaceutical industries but generally trans-isomer is often present in little percentage in plant kingdom (Miller, E.C.; Swanson, A.B.; Phillips, D.H.; Fletcher, T.L.; Liem, A.
• trans-isomer exclusively using cis-isomer i.e. conversion of widely and commercially available toxic ?-asarone (cis-isomer) towards synthesis of ⁇ -asarone (trans- isomer) since rarer ⁇ -asarone has a great potential and scope in the area of pharmaceutical industries as discussed in details below: ⁇ -asarone (trans-2,4,5-trimethoxy-l-propenylbenzene), a constituent of A. calamus and several other plants (Enqiquez, R.G.; Chavez, M.A.
• the available synthetic drugs used for decreasing the levels of cholesterol and triglyceride are Colestipol, Questran, Clofibrate and Neomycin etc which have a certain degree of side effects such as nausea, abdominal and gastrointestinal discomfort, constipation, brittle hair, diarrhea and heartburn.
• neomycin has found to have high toxicity.
• the traditional natural herbs such as Angelica sinesis, Artemisia capillaries, Curcuma longa (Soudamini, K.K.; Unnikrishnan, M.C.; Soni, K.B.
• HDL-cholesterol high density lipoprotein (HDL)-cholesterol was found to be increased.
• HDL high density lipoprotein
• Toxicity of ⁇ — asarone is also investigated in rats and mice and no toxic effect is observed (Salazar, M.; Salaz, S.; Ulloa, V.; Mendoza, T.; Pages, N. and Chamorro, G., J. Toxicol. Clin. Exp., 12, 149-154 (1992); Chamorro, G., Salazar, M.; Salazar, S. and Mendoza, T., Rev. Invest. Clin., 45, 592-604 (1993); Sagimoto, N.; Goto, Y.; Akao, N.; Kiucki, F. and Kondo, K., Biol. Pharm.
• ⁇ -asarone is also used as a starting material for the synthesis of various biologically active compounds (Mori-K; Komatsu, M; Kido, M and Nakagawa, K, Tetrahedron Letter, 42 (2), 523-528 (1986)) as well as in the formulation of drugs (Harborne, J.B. and Baxter, H. In: Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington DC, 474 (1993)). Conventionally, some synthetic routes have been developed to prepare ⁇ -asarone such as:
• 2,4,5-trimethoxyphenylpropane can be obtained by catalytic reduction of ⁇ -asarone or the like by hydrogenation process in electronic reactor.
• hydrogenation in reactor requires explosive hydrogen gas cylinder and also, monitoring of the progress of reaction by TLC is not possible during the hydrogenation.
• ammonium formate or formic acid/triethylamine as a catalytic hydrogen transfer agent for the first time for the reduction of plant derived ⁇ -asarone or ⁇ -asarone rich calamus oil towards formation of 2,4,5-trimethoxtphenylpropane (Sinha, A.K., US Patent No.
• dehydrogenation reaction Introduction of double bond in a molecule is referred to as a dehydrogenation reaction, which can proceed, by the abstraction of either hydride ion (an ionic mechanism) or hydrogen atom or an electron (free radical mechanism).
• dehydrogenating reagents namely MnO2 , DDQ, DCQ, Hg(OAc) 2 , SeO 2 ,Pd/C, Se and S in which DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) is found effective and facile dehydrogenating reagent for the conversion of 2,4,5-trimethoxyphenylpropane derivatives into trans-asarone.
• DDQ is widely used as a powerful dehydrogenating agent (Sondengam, B.L. and Kimbu, S.F., Tetrahedron Letters, 1, 69-70 (1977) and Guy, A.; Lemaire, M. and Guette, J.P., Chem. Commun., 8 (1980)) which acts as one electron oxidant (Becker, H. D., J. Org Chem. 30, 982 (1965). DDQ was first introduced for the dehydrogenation of tetralin and bibenzyl into naphthalene and stilbene respectively (Braude, E.A. and Waugh, T.D., J. Org. Chem., 30, 3240 (1965)).
• the DDQ-mediated reactions allow to monitor the progress of the reaction as the green-coloured charge transfer (CT)-complex which is formed initially, starts changing into pink or brown colour (as the 2,3-dichloro-5,6- dicyano-l,4-hydrobenzoquinone crystallized out) and thus, indicates the formation of products.
• CT charge transfer
• the precipitated hydrobenzoquinone (DDQH 2 ) can be easily separated by Alteration which allows to obtain 2,3-dichloro-5,6-dicyano-l,4- hydrobenzoquinone (DDQH 2 ) in 91 to 94 % yield.
• the amount of precipitated hydroquinone (DDQH 2 ) is a convenient measure of the extent of hydrogen transfer. DDQH 2 so obtained can be conveniently converted back to DDQ in good yield by standard methods (Walker, D. and Waugh, T.D., J. Org. Chem., 30, 3240 (1965)).
• DDQ dehydrogenating reagents
• dehydrogenating reagents such as chloranil, selenium dioxide, sulphur and selenium
• DDQ dehydrogenating reagent towards formation of the carbon-carbon double bond, exclusively in trans form which has also been found in literature during conversion of 4,4'-dimethoxybibenzyl into trans-4,4'- dimethoxystilbene (Lemaira, M.; Guy, A. and Imbert, D., Chem. Commun., 741 (1986)) and Ireland, R.E. and Brown, G., Org. Synthesis, Coll. Vol.V, 428-431).
• DDQ 2,4,5-trimethoxyphenylpropane
• polar anhydrous solvents namely alcohols such as methanol, ethanol, propanol and the like; ether such as tetrahydrofuran, dioxane and the like; chlorinated solvents such as dichloromethane, chloroform and the like
• DDQ reagent
• ⁇ -asarone is the first example of DDQ assisted one step synthesis of ⁇ -asarone from toxic ⁇ -asarone via 2,4,5-trimethoxyphenylpropane which, in fact, would offer the advantages of simplicity and directness and can be applied for large scale preparations.
• Example 1 The invention will now be described by way of example with refrence to the accompanying examples which are provided for the purpose of illustration and are not to be constructed as being limiting on the present invention.
• Example 1
• 2,4,5-trimethoxyphenylpropane (dihydro asarone):
• the starting material 2,4,5-trimethoxyphenylpropane is prepared by hydrogenation of ⁇ -asarone (isolated from Acorus calamus oil) or of commercially available calamus oil rich in asarones (i.e. ⁇ and/or ⁇ , ⁇ -asarone ) content.
• ⁇ -asarone Hydrogenation of ⁇ -asarone into 2,4,5-trimethoxyphenylpropane (dihydro asarone): ⁇ -asarone was isolated by loading the crude calamus oil (17.00 g) on silica gel column and then eluted the column with hexane to remove unwanted non-polar compounds.
• the ⁇ -asarone (6.00 g, 0.029 mol) in 160 ml of ethanol is stirred with 10% palladium on activated charcoal (0.80 g) and ammonium formate (17.00 g, 0.27 mol) at room temperature under nitrogen atmosphere till the disappearance of starting material.
• the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the ethyl acetate layer washed with water, dried (Na 2 SO 4 ) and filtered.
• the combined dioxane was evaporated and concentrate was poured into water and then extracted with dichloromethane (3 x 70 mL). The combined organic layers were washed with brine (3 x 15 mL), 10% sodium bicarbonate (2 x 10 mL), brine (3 x 15 mL) and dried over anhydrous sodium sulphate.
• Isoacoramone (l-(2,4,5-trimethoxyphenyl)-l-propanone): A solution of DDQ (3.06-4.09 g) in dioxane (40 mL) was added dropwise over a period of 10 min to a ice cold and well stirred solution of 2,4,5-trimethoxyphenylpropane (1.89g, 0.009 mol) in wet dioxane or ethanol (55 mL) and the resulting mixture was stirred at room temperature for over night. The precipitate was filtered and further washed twice with dioxane.
• a process discloses DDQ as a versatile reagent to provide a wide range of rarer phenylpropanoids namely ⁇ -asarone, 2,4,5-trimethoxtcinnamaldehyde and 1 -(2,4,5- trimethoxy)phenyl-l-propanone (isoacoramone) in one step with varying solvents, time, temperature and amount of dehydrogenating DDQ reagent.
• the process enables us to convert mixture of all the three isomeric forms of phenylpropenes (i.e. ⁇ , ⁇ and ⁇ -asarone) firstly into 2,4,5-trimethoxyphenylpropane (via hydrogenation) and then regenerating phenylpropene (via. dehydrogenation) but exclusively in trans form (i.e. ⁇ -asarone) whereas previously reported method always provide ⁇ -asarone with varying amount of toxic ⁇ -asarone, during alkaline isomerization of ⁇ -asarone and the like.
• 7. A process to prepare . ⁇ -asarone from 2,4,5-trimethoxyphenylpropane using mild dehydrogenating DDQ reagent for the first time.
• a process provides alternative route for the preparation ⁇ -asarone starting from 2,4,5- trimethoxypropiophenone obtained by treating 2,4,5-trimethoxyphenylpropane with DDQ in aqueous solvent.
• a process provides 2,4,5-trimethoxypropiophenone as solid whereas natural 2,4,5- trimethoxypropiophenone (isolated from Acorus tatarinowii and Piper marginatum) is reported as viscous gum.
• a process wherein formation of 2,4,5-trimethoxypropiophenone opens a new synthetic route for the preparation of a series of propiophenone derivatives in single step from phenylpropane derivatives i.e. 2,4,5-trimethoxyphenylpropane.
• a process forms naturally occurring 2,4,5-trimethoxypropiophenone in sufficient quantity provides the opportunity for the its wide range of biological evaluation.
• a process provides ⁇ -asarone exclusively via reduction of 2,4,5- trimethoxypropiophenone into 2,4,5-trimethoxyphenyl-l-hydroxypropane in high yield followed by acidic dehydration using p-toluenesulphonic acid and thionyl chloride/pyridine and the like.

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