DE10297696T5 - Process for the preparation of a pharmacologically active alpha-asarone from toxic beta-asarone-rich Acorus calamus oil - Google Patents

Abstract

(c) Dehydrieren unter inerter Atmosphäre der Verbindung von Formel (I) von Schritt (b) durch Behandeln mit DDQ enthaltend optional Silica- oder Aluminiumoxid in anhydridischem organischen Lösungsmittel bei Raumtemperatur für einen Zeitraum von 0,5 bis 72 Stunden.
(d) Filtrieren der Reaktionsmischung von Schritt (c), um das ausgefällte (DDQH₂) zu entfernen, Waschen des Rückstandes mit einem organischen Lösungsmittel und Erhalten eines vereinigten klaren Filtrats,...A process for preparing a pharmacologically active α-asarone (trans isomer) of formula II from the toxic β-asarone (cis isomer) or β-asarone rich Acorus calamus oil containing the α and γ isomers, wherein said process comprises the following steps:
(a) hydrogenating β-asarone or β-asarone rich calamus oil containing α- and γ-asarone using 10% Pd / C catalyst with or without ammonium formate under a pressure of 0-40 psi at room temperature,
(b) purifying the product of step (a) over silica gel by performing a column chromatography to obtain the compound of formula (I)

(c) Dehydrating under inert atmosphere the compound of formula (I) of step (b) by treating with DDQ optionally containing silica or alumina in anhydride organic solvent at room temperature for a period of 0.5 to 72 hours.
(d) filtering the reaction mixture from step (c) to remove the precipitated (DDQH ₂ ), washing the residue with an organic solvent and obtaining a combined clear filtrate, ...

Description

technical area

The The present invention relates to a "process for the preparation of a pharmacological active α-asarone from toxic β-asarone-rich Acorus calamus oil over the Intermediate 2,4,5-Trimethoxyphenylpropan of formula I "(a dihydro product of toxic β-asarone), that will be over the hydrogenation of commercially available Acorus calamus oil rich at β-asarone (containing α- and γ-isomer) is subjected to dehydration and / or oxidation is subjected in a single step only by varying the reaction time, the temperature of the solvent (anhydrous) and the amount of dichlorodicyanobenzoquinone (DDQ) with or without one solid carrier, such as. Silica gel, alumina, and the like until for the training of α-Asaron (trans-2,4,5-trimethoxyphenyl-1-propene), a well-known pharmacological active phenylpropanoid, and trans-2,4,5-trimethoxycinnamaldehyde as a byproduct. However, the above-mentioned dehydration process, when present in an aqueous one Solvent is carried out, 1- (2,4,5-trimethoxy) phenyl-1-propanone, after reduction with sodium borohydride in 1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane followed by acid dehydration exclusive to the α-asarone. Furthermore, it is worth mentioning that 1- (2,4,5-trimethoxy) phenyl-1-propanone (Isoacoramone) and 2,4,5-trimethoxycinnamaldehyde as phenylpropanoids present in traces in some aromatic and medicinal plants being found. First and foremost, it is the goal of the invention internationally banned but widely available toxic β-asarone as a simple and economical Starting material for the production of a potential hypolipidemic and anti-platelet-active α-asarone to use and over the combination of two simple, industrially attractive processes, namely Hydrogenation and dehydrogenation / oxidation, in which the training of the unexpected 2,4,5-trimethoxycinnamaldehyde as a by-product while the production of α-asarone is detected. In the present invention, we have a simple one and economic Pro zess capable of detecting the toxic .beta.-asarone in the pharmacologically active α-asarone to convert in high yield without contamination of the other isomer, i. of the β- and / or γ-Asarons.

background to the state of the art

Plant-derived products have been widely used in the field of essential oils, paints and dyes, cosmetics, pharmaceuticals, and many other fields, not only because they are readily available and cheaper, but also because they are an important cause of insight insisted that they are safer than synthetic products, which may not always be authentic. There are some phytochemical compounds that minimize the market potential of products above a certain threshold, eg phenylpropanoid-rich essential oils that are specifically spoiled by a few isomeric forms of phenylpropenes (Miller, EC, Swanson, AB, Phillips, DH, Fletcher, TL, Liem , A. and Miller, JA, Cancer Research, 43 (3), 1124-1134 (1983); Kim; SC; Liem; A; Stewart; BC and Miller, JA Carcinogensis, 20 (7), 1303-1307 ( 1999) and Lazutka, JR; Mierauskienē, S. and Dedonytē, V. Food & Chemical Technology, 39, 485-492 (2001)). In fact, phenylpropanes are naturally occurring phenolic compounds in which an aromatic ring is attached to three carbon side chains (C ₆ -C ₃ moiety), either as a pair of cis / trans (ie, α / β isomer) propenyls or as allyl propenes (ie γ-isomer) exist. In general, trans isomers (e.g., α-asarone and isoeugenol, etc.) are considered less problematic for human use, whereas cis / allyl isomers (e.g., β-asarone and saffrol) are identified as toxic and carcinogenic (Harborne, JB, and Baxter, H ., Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington DC, 474 (1993)). The concentration of phenylpropenes and their isomer ratio in essential oils is strongly influenced by the growth stages and the appearance of the plant, which in turn affects the need for and use of a particular oil. Due to this fact, the most affected oil is the calamus oil obtained by steam distillation of rhizomes of Acorus calamus (family: Araceae), which is widely grown and cultivated in many countries due to their various medicinal properties and a great need for their essential Oil in flavor and perfume industries (Treben, M., Health Through Gods Pharmacy, Wilhelm Ennthaler, Steyer, Austria, 12-14 (1986); Akhtar, H., Virmani, OP; Popli, SP; Misra, LN; Gupta, MM; Srivastava, GN; Abraham, Z. and Singh, AK, Dictio Indian Medicinal Plants, CIMAP, RSM Nagar, Lucknow, 10-11 (1992); Motley, TJ, Economic Botany, 48, 397-412 (1994) and Lawrence, BM and Reynolds, RJ, Perfumer & Flavorist 22 (2), 59-67 (1997)). However, a large discrepancy and variability in the quality of calamus oil has been observed, with tetraploid and hexaploid species (extensively distributed in Asian countries such as India, Japan, Pakistan, and China) having a very high percentage of toxic β-asarone (varying between 70 and 90%), whereas diploid and triploid species contain limited amounts of β-asarone (3 to 8%) approved for use in the flavor, perfume and pharmaceutical industries, respectively (Stahl, E. and Keller, K Waltraud, G. and Schimmer, O., Mutation Research 121, 191-194 (1983), Mazza, G., J. of Chromatography, 328, 179-206 (1981); Planta Medica 43, 128-140 (1981); Nigam, MC; Ateeque, A. Misra, LN and Ahmad, A., Indian Perfumer, 34, 282-285 (1990) and Bonaccorsi, I., Cortroneo, A., Chowdhury, JU and Yusuf, M , Essenze Derv. Agrum., 67 (4), 392-402 (1997)).

It has been experimentally demonstrated that β-asarone is carcinogenic in animals and it was further found to induce tumors in the duodenal region after oral administration. In addition, β-asarone also demonstrated chromosome damaging effect on human lymphocytes in vitro after metabolic activation (Taylor, JM, Jones, WI, Hogan, EC, Gross, MA, David, DA and Cook, EL, Toxicol, Appl Pharmaco. 10, 405 (19679, Keller, K., Odenthal, KP and Leng, PE, Planta Medica 1, 6-9 (1985), Abel, G., Planta Medica, 53 (3), 251-253 (1987), and Riaz, M., Shadab, Q., Chaudhary, FM, Hamdard Medicus, 38 (2), 50-62 (1995).) As a result, Asian-style calamus oil is internationally recognized for all manner of flavoring, As far as we know, there is no report in which the toxic-β-asarone of calamus oil is used to increase its value, except the actual of our group (Sin ha, AK; Dogra, R. and Joshi, BP, Ind. J. Chem., 41B, (2002) (in press); Sinha, AK; Joshi, BP and Dogra, R., Nat. Prod. Lett., 15 (6), 439 -444 (2001); Sinha, AK; Acharya, R. and Joshi, BP, J. Nat. Prod. (2002) (in press), Sinha, AK; Dogra, R. and Joshi, BP, Sinha, AK; Joshi, BP, and Dogra, R., JP Patent No. 2001, 68716, filed March 12, 2001; Sinha, AK; Joshi, BP, and Dogra, R., US Patent No. 09-805,832, filed March 14, 2001; U.S. Patent No. 09-823,123, filed March 31, 2001, and Sinha, AK; Joshi, AK; Joshi, BP, and Dogra, R., PCT / IN 01/00104 filed May 21, 2001) using ammonium formate / palladium on charcoal or H ₂ / palladium on charcoal assisted reduction of crude calamus oil containing a high percentage of toxic β-asarone 2,4,5-trimethoxyphenylpropane (dihydroasarone) in 97% purity with a yield of 81-87% based on the asarone portion in calamus oil (see Example I). The thus-obtained 2,4,5-trimethoxyphenylpropane (also known as 1-propyl-2,4,5-trimethoxybenzene) was invented for the first time as five times less toxic than β-asarone, and thus 2,4,5-trimethoxyphenylpropane permits For use in products such as mouthwashes, toothpastes, antiseptic soap products, chewing gum flavor and a little bit in aroma products due to its sweet, long-lasting ylang, slightly aromatic and fruity aroma. In addition, it has also been discovered that 2,4,5-trimethoxyphenylpropane is a simple and economical starting material for the synthesis of a salicylamide-based antipsychotic agent (5,6-dimethoxy-N [(1-ethyl-2-pyrrolidinyl) methyl] -3- propyl salicylamide) (Thomas, H .; Stefan, B., Tomas, DP; Lars, J .; Peter, S., Hakan, H. and Orgen, SO, J. Med. Chem., 33, 1155-1163 (1990 ) and Sinha, AK, US Patent No. 09-652376, filed August 31, 2000). In the present invention, we have extended the scope of further studies of 2,4,5-trimethoxyphenylpropane of Formula I as a simple and economical starting material with respect to the formation of the pharmacologically active α-Asarone of Formula II.

α-Asarone (trans-2,4,5-trimethoxyphenyl-1-propene) is well known for its various pharmacological activities including hypolipidemic and Antibody platelet activity, however, is generally in traces with β- and γ-asarone in various plant species including A. calamus (Patra, A. and Mitra, A.K., J. Nat., Prod., 44, 668-669 (1981); Dung, N.X .; Moi, L.D .; Nam, V.V .; Cu, L.D. and Leclercq, P.A., J. of Ess. Oil Res., 7 (1), 111-112 (1995) and Parmar, V. S .; Jain, S. C .; Bisht, K.

S .; Jain, R .; Taneja, P .; Jha, A .; Tyagi, OD; Prasad, AK; Wengel, J .; Olsen, CE; Boll, PM, Phytochemistry, 46 (4), 597-673 (1997)). Separation of little excess α-asarone is particularly difficult via column chromatography of asarone-rich essential oil. Although some methods can be found in the literature for the synthesis of α-asarone, including the alkaline isomerization of γ-asarone (2,4,5-trimethoxyallylbenzene), however, there is always a small amount of toxic β-asarone along with α-asarone during alkaline isomerization (Devgan, ON and Bokadia, MM, Aust. J. Chem., 21, 3001-3003 (1968)). Consequently, the reported synthetic methods are not free of disadvantages such as a multi-step approach, expensive reagents and especially a poor yield with contamination by its isomers. Because of these problems, two factors are crucial for the synthesis of α-asarone, first achieving the highest possible selectivity for the formation of the α-isomer, without secondly, that there is somehow another isomer, and secondly, the search for economical and efficient methods to obtain α-asarone, which can be readily accomplished by the dehydrogenation of 2,4,5-trimethoxyphenylpropane with the aid of dehydrating reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Among the dehydrating agents, namely, manganese dioxide, p-chloranil, selenium dioxide, Pd / C, selenium, and sulfur, DDQ is invented as a single reagent of choice with respect to the formation of α-asarone in a single step, just by varying the reaction time , the temperature, the solvent and the amount of reagent (DDQ) with or without a solid support, such as silica gel, alumina and the like, in a one or two phase system. In the anhydrous solvent, that is, alcohols such as methanol, ethanol and the like; aliphatic and aromatic hydrocarbons such as hexane, benzene, toluene and the like; Ethers such as tetrahydrofuran, dioxane and the like, the reaction between 2,4,5-trimethoxyphenylpropane and varying amount of DDQ, preferably in a range of 1.0 to 1.1 moles, results in the corresponding dehydrogenated product, ie trans -asarone (cf. α-asarone) in a yield of 41-44% and an unreacted starting material (ie, 2,4,5-trimethoxyphenylpropane) together with a yellow colored compound as a by-product (4-6%), whereas 2,4,5-trimethoxyphenylpropane and varying amount of DDQ, preferably in the range of 1.1 to 1.3 mol, to α-asarone (48-51%) as well as the above yellow colored compound (9-11%), but without remaining starting material (Example II ). It is interesting to note that the addition of a catalytic amount of a solid carrier such as pulp, silica gel, alumina, resin and the like to the above mixtures of 2,4,5-trimethoxyphenylpropane and DDQ (1.1 to 1.3 mol) dramatically accelerated the rate of dehydration as well as improved the yield of α-asarone (67-72%) (Example III). Based on IR, NMR and mass spectral data, the yellow solid has been found to be trans-2,4,5-trimethoxycinnamaldehyde, further by comparison of the mixed mp (139-140 ° C) of standard trans-2 , 4,5-trimethoxycinnamaldehyde prepared by reacting α-asarone (trans-asarone, manufactured by Sigma Chemical Ltd.) with DDQ in dioxane. In addition, trans-2,4,5-trimethoxycinnamaldehyde has emerged as a rare phenylpropanoid found in trace amounts in Caesulia axillaries and Alpinia flabella (0.000015%) (Kulkarni, MM; Sohoni, J .; Rojatkar, SR and Nagasampagi, BA, Ind. J. Chem. Sec B 25B, 981-982 (1986) and Kikuzaki, H .; Tesaki, S. Yonemori S. and Nakatani, N. Phytochemistry, 56 (1), 109-114 (2001) and, consequently, the production of trans-2,4,5-trimethoxycinnamaldehyde opens up new prospects for assessing its various applications, as are known for structurally similar cinnamic aldehyde derivatives (Tomoshi, K. and Makoto, F., Am. JP Pat No. 58055414 A2; Saotome, K., JP Pat. No. 58201703 A2; Watanabe, T., Komeno, T. and Hatanaka, M., JP Pat. No. 6312916 A2 and Castelijns, AMCF, Hogeweg, JM and Van Nispen, SPJM, US Pat. No. 5,811,588)). When we confirmed the structure of α-asarone and trans-2,4,5-trimethoxycinnamaldehyde, our attention was focused on the exclusive formation of α-asarone in a high yield without any starting material and yellow by-product (ie 2,4, 5-Trimethoxyzimtaldeyhd).

When an alternative way for the synthesis of α-asarone has a way over 1- (2,4,5-trimethoxy) phenyl-1-propanone exposed what can easily be made by treatment of 2,4,5-trimethoxyphenylpropane with varying amounts of DDQ (1.0 to 3 mol), preferably in the range of 1.6 to 2.1 mol and while in a watery organic solvents selected from methanol, ethanol, tetrahydrofuran, dioxane and the like. Later let himself go 2,4,5-trimethoxypropiophenone (isoacoramone) as an interesting to realize rare phenylpropanoid, that in the well-known medical Plant Acorus calamus, in Piper marginatum as well as in Acorus tararinowii, but only in trace amounts (Mazza, G., J. of Chromatography, 328, 179-206 (1985); Santos, Bk.V. de O. and Chaves, M.C. de O., Biochem. Systematics Ecology, 25, 539-541 (1999) and Jinfeng, Hu and Xiaozhang, Planta Medica, 66, 662-664 (2000). Consequently, the formation of 2,4,5-trimethoxypropiohenone (Isoacoramone) not just as a synthon for the production of α-asarone, but allows also a broader biological assessment, as they are structurally similar Propiophenone derivatives (Stauffer, S.R .; Coletta, C.J .; Tedesco, R .; Nishiguchi, G .; Carlson, K .; Sun, J .; Katzenellenbogen, B.S. and Katzenellenbogen, J.A., J. Med. Chem., 43, 4934-4947 (2000) and Jaimol, T .; Moreau, P .; Finiels, A .; Ramaswamy, A.V. and Singh, A.P., Applied Catalysis A: General, 214, 1-10 (2001)). To get α-Asarone, becomes 1- (2,4,5-trimethoxy) phenyl-1-propanone with sodium borohydride reduced to give (1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane) from acidic dehydration using p-toluenesulfonic acid or Thionyl chloride / pyridine and the like (Example IV-VI).

Summa sumarum reveals our invention a simple and economical Process for the production of pharmacologically active α-asarone together with two important ones, of course occurring phenylpropanoids, namely 2,4,5-trimethoxypropiophenone (Isoacaromon) and 2,4,5-Trimethoxyzimtaldeyd, starting from the relative cheaper and more economical Material 2,4,5-trimethoxyphenylpropane obtained by hydrogenation of β-asarone rich Acorus calamus oil as shown in Scheme I. Other tasks and advantages of the present The invention will become apparent in the course of this description.

Scheme I

Objects of the invention

The primary The object of the present invention is pharmacologically active α-asarone from 2,4,5-trimethoxyphenylpropane to produce that, in fact is a hydrogenated product of toxic β-asarone isolated from commercial available Acorus calamus oil.

A Another object of the present invention is the possibilities the use of toxic Kalmus oil from tetraploid or hexaploid Species (extensively distributed in Asian countries), and while improving their profitable use.

Furthermore Another object of the invention is a simple process for the production of α-asarone exclusive without any impurity of another isomer Form of Asaron (i.e. and / or γ-isomer) to develop.

Yet Another object of the invention is to provide a process for manufacturing a non-toxic compound, i. α-Asarone from a toxic Compound, i. β-Asarone, to develop.

Yet Another object of the invention is the interaction of 2,4,5-trimethoxyphenylpropane investigate by varying time, temperature, solvents and amounts of dehydrating reagent DDQ.

Yet Another object of the invention is the first use from DDQ as a dehydrating reagent for exclusive production of α-Asarone 2,4,5-trimethoxyphenylpropane.

Yet Another object of the invention is to provide a simple purification process develop to α-asarone to obtain in high purity as well as in good yield.

A Another object of the invention is the unexpected training of the polar yellow solid, which is actually considered to be a by-product together with α-asarone occurs.

Yet another object of the invention is to establish the structure of the yellow solid, which ultimately turns out to be a naturally occurring, less common trans-2,4,5-trimethoxycinnamaldehyde Has.

Yet Another object of the invention is to provide another route for the manufacture starting from α-Asaron of 1- (2,4,5-trimethoxy) phenyl-1-propanone.

Yet a further object of the invention is 1- (2,4,5-trimethoxy) phenyl) -1-propanone (isoacoramone) by treating 2,4,5-trimethoxyphenylpropane with DDQ in one aqueous organic solvents manufacture.

Yet Another object of the invention is α-Asarone exclusively over the Reduction of 1- (2,4,5-trimethoxy) phenyl-1-propanone in the corresponding 1- (2,4,5-trimethoxy) phenyl-1-propanol, followed by acid dehydration.

Summary the invention

The The present invention provides a process for the preparation of pharmacological active naturally occurring α-asarone ready, using a combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as a mild and efficient dehydrogenating agent and 2,4,5-trimethoxyphenylpropane, the indeed the hydrogenated product of toxic β-asarone isolated from commercial available Kalmus oil represents. It's worth mentioning that the above DDQ assisted dehydration process is not only to α-asarone led, but also delivered two more products, which later than Naturally occurring rarer phenylpropanoids were characterized, namely 2,4,5-Trimethoxyphenylpropanon (Isoacoramone) and 2,4,5-trimethoxycinnamaldehyde. Consequently, the formation of α-Asarone, Isoacoramone and 2,4,5-trimethoxycinnamaldehyde in a one-step Procedure over DDQ assisted dehydrogenation / oxidation of 2,4,5-trimethoxyphenylpropane a cheaper and more economical Procedures as the previously reported methods, and further our invention is capable of producing a range of biologically active Phenylpropanoidderivate form.

Short description the attached drawings

1 is a ¹ H NMR (300 MHz) spectrum of the α-asarone (in CDCl ₃ ) of the reaction product of Example II.

2 is a ¹³ C NMR (75.4 MHz) spectrum of the α-asarone (in CDCl ₃ ) of the reaction product of Example II.

3 is a ¹ H NMR (300 MHz) spectrum of 2,4,5-trimethoxycinnamaldehyde (in CDCl ₃ ) of the reaction product of Example III.

4 is a ¹³ C NMR (75.4 MHz) spectrum of the 2,4,5-trimethoxycinnamaldehyde (in CDCl ₃ ) of the reaction product of Example III.

5 is a ¹ H NMR (300 MHz) spectrum of the 1- (2,4,5-trimethoxy) phenyl-1-propanone (in CDCl ₃ ) of the reaction product of Example IV.

6 is a ¹³ C (75.4 MHz) spectrum of the 1- (2,4,5-trimethoxy) phenyl-1-propanone (in CDCl ₃ ) of the reaction product of Example IV.

7 is a ¹ H NMR (300 MHz) spectrum of the 1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane (in CDCl ₃ ) of the reaction product of Example V.

8th is a ¹³ C (75.4 MHz) spectrum of the 1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane (in CDCl ₃ ) of the reaction product of Example V.

detailed Description of the invention

Accordingly, the present invention provides a "process for the production of a pharmacologically active α-asarone from toxic β-asarone-rich Acorus calamus oil via the intermediate 2,4,5-trimethoxyphenylpropane", said process involving the hydrogenation of toxic β-asarone or Kalmus oil comprising a mixture of α-, β- and γ-asarone to 2,4,5-trimethoxyphenylpropane of Formula I, followed by dehydration of the above compound at a temperature in the range of 5-120 ° C over a period of 30 minutes to 72 hours using a solvent.

In an embodiment In accordance with the present invention, a simple process is available to pharmacologically active α-asarone from 2,4,5-Trimethoxyphenylpropan, which is actually the hydrogenated product of toxic β-asarone isolated from commercially available Kalmus oil represents.

In a further embodiment In the present invention, a simpler process is available for the commercial Use of internationally prohibited, but widely used toxic β-asarone from Acorus calamus oil of tetraploid or hexaploid species (which is extensively found in Asiatic Countries expelled ), which improves its profitable use.

In yet another embodiment In the present invention, a simple method includes Conversion of the mixture of all of the three isomeric forms of phenylpropene, i.e. α- , β- and γ-asarone initially in 2,4,5-Trimethoxyphenylpropan, as well as the subsequent Wiedererzeugen of 1- (2,4,5-trimethoxy) phenyl-1-propene derivative and was exclusively in trans form (α-Asaron). In a further embodiment of the Present invention is a simple process available for the production of α-Asarone exclusively without any contamination by others isomeric forms of asarone (i.e. and / or γ-isomer).

In yet another embodiment In the present invention, a simple process is available for manufacture a less toxic compound (i.e., α-asarone) from a known toxic Compound (β-Asarone).

In yet another embodiment According to the present invention, a simple process is available which the interaction of 2,4,5-trimethoxyphenylpropane with variable Amounts of dehydrating reagent disclosed, e.g. from DDQ and this also under variation of time, temperature and solvents.

In yet another embodiment The present invention is α-asarone from 2,4,5-trimethoxyphenylpropane first using the mild dehydrating reagent DDQ provided.

In yet another embodiment In the present invention, the molar ratio of the dehydrating agent (DDQ) to 2,4,5-trimethoxyphenylpropane in a ratio of 1.0: 1.0 to 1.3: 1.0, preferably 1.0 to 1.2: 1.0.

In yet another embodiment The present invention provides a simple purification process provided to α-asarone to get in good yield.

In yet another embodiment The present invention is the unexpected formation of a characterized by polar yellow solid, which ultimately as natural occurring rare trans-2,4,5-trimethoxycinnamaldehyde exposed Has.

In yet another embodiment The present invention provides a semisynthetic route for α-asarone in provided a high yield, which is suitable for industrial production scale be able to.

In a still further embodiment The present invention provides 2,4,5-trimethoxyphenylpropanone exclusively by treating 2,4,5-trimethoxyphenylpropane with DDQ in an organic solvent selected from methanol, dioxane, THF and water in the ratio ranges of 9.9: 0.1 to 9: 1 and at a temperature in the range of 5-110 ° C, preferably 8-60 ° C; in which the reaction time is 1 hour to 54 hours, preferably 6-18 hours is.

In yet another embodiment According to the present invention, 2,4,5-trimethoxypropiophenone is used as a solid Provided, whereas natural 2,4,5-trimethoxypropiophenone (isolated from Acorus tatarinowii and Piper marginatum) as more viscous Rubber is described.

In yet another embodiment The present invention will be natural 2,4,5-trimethoxypropiophenone provided in sufficient quantity, which further the possibility providing for one biological evaluation on the whole Scale.

In yet another embodiment The present invention is a process for the preparation of α-asarone 2,4,5-trimethoxypropiophenone over its reduction followed by 1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane provided by dehydration under acidic conditions.

In yet another embodiment The present invention relates to the dehydration of 2,4,5-trimethoxyphenyl-1-hydroxypropane carried out with p-toluenesulfonic acid and thionyl chloride / pyridine and the like, and provides α-asarone.

• (a) ein Verfahren unter Verwendung von Trimethoxybenzen als Ausgangsmaterial (Francisco, D.; Leticia, C.; Rosa, F.; Joaquin, T.; Fernando, L.; German, C.; Heber, M. Org. Prep. Proced. Int. 23 (2), 133–138 (1991)).
• (b) ein Verfahren, in welchem 2,4,5-Trimethoxybenzaldehyd mit Ethylmagnesiumbromid (einem Grignard-Reagens) behandelt wurde, um den korrespondierenden Alkohol zu erzeugen und mit anschließender Dehydratation des Alkohols zu α-Asaron (Wang, Z.; Jiang, L. and Xingxiang, X., Youji Huaxue, 10 (4), 350–352 (1990); Shirokova, E.A.; Segal, G.M. and Torgov, I.V., Bioorg. Khim., 11 (2), 270–275 (1985) and Janusz, P.; Bozena, L.; Alina, T.D.; Barbara, L.; Stanislaw, W.; Danuta, S.; Jacek, P.; Roman, K.; Jacek, C.; Malgorzata, S. and Zdzislaw, C., J. Med. Chem., 43, 3671–3676 (2000)).
• (c) ein Verfahren, unter Verwendung von Vanillin als Ausgangsmaterial (Nenokichi, N. and Shibamoto, N., Kinki Daigaku Rikogakubu Kenkyu Hokoku, 12,63–66 (1977)).
• (d) ein Verfahren umfassend die fotochemische Isomerisierung von beta-Asaron (Saxena, D.B. and Mukerjee, S.K., Indian J. of Chem, 24B, 683–684 (1985)).

Phenylpropanoids (C ₆ -C ₃ ) are mainly produced in plants in response to pathogenic infestation. This group of secondary metabolites includes many biologically active compounds such as phenylpropanones, cinnamaldehydes, cinnamic alcohols, cinnamic acids and phenylpropenes. Among three isomeric forms of phenylpropene, cis and gamma isomeric forms have been shown to be toxic and carcinogenic, whereas trans isomeric forms have been reported to be used in flavor, perfume and pharmaceutical industries, but generally the trans isomer often in low percentage in the plant kingdom (Miller, EC, Swanson, AB; Phillips, DH; Fletcher, TL; Liem, A. and Miller, JA, Cancer Research, 43 (3), 1124-1134 (1983); Kim; Liem; A; Stewart; BC and Miller, JA Carcinogensis, 20 (7), 1303-1307 (1999) and Lazutka, JR; Mierauskienē, S. and Dedonytē, V. Food & Chemical Technology, 39, 485- 492 (2001)). Despite several synthetic procedures, the alkaline isomerization of the γ isomer results in the significant trans isomer, but always along with a small percentage of the toxic cis isomer. Consequently, it appears to be very interesting and challenging to develop a simple exclusive method for producing the trans isomer using the cis isomer, ie, a conversion of the widely and commercially available toxic β-asarone (cis isomer) for the synthesis of α-Asarone (trans isomer), as the rare α-asarone has great potential and a wide range of application in the pharmaceutical industry, as discussed in detail below: α-Asarone (trans-2,4,5-trimethoxy) 1-propenylbenzene), a component of A. calamus and some other plants (Engiquez, RG; Chavez, MA ande Jauregui, F., Phytochemistry, 19 (9), 2024-2025 (1980) and Dung, NX; Moi, LD Nam, VV; Cu, LD and Leclercq, PA, J. of Ess Oil Res., 7 (1), 111-112 (1995)) is well known for its pharmacological effects, such as sedative neuroleptic, spasmolytic, antiulcerogenic, antiatherogens (Menon, MK, and Dandiya, PC, J. Pharm. Pharmacol., 9 (3), 170-175 (1967 ) and Belova, LF; Alibekov, SD; Baginskaya, AI; Sokolov, SY and Pokrovskava, GV, Farmakol. Toksikol., 48, 17-20 (1985)), including hypolipidemic and antiplatelet activities (Janusz, P., Bozena, L., Alina, TD; Barbara, L. Stanislaw, W .; Danuta, S., Jacek, P.; Roman, K., Jacek, C. Malgorzata, S. and Zdzislaw, C., J. Med. Chem., 43, 3671-3676 (2000)). Inasmuch as hypolipidemic activity is concerned, the available synthetic agents are used to lower levels of cholesterol and triglyceride, 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 palpitations. In particular, neomycin has been found to be highly toxic. Consequently, to date, there are no effective and safe drugs that can lower high levels of cholesterol and triglycerides in patients without side effects. On the other hand, natural herbs such as Angelica sinesis, Artemisia capillaries and Curcuma longa, (Soudamini, KK; Unnikrishnan, MC; Soni, KB and Kuttan, R., Ind. J. Physiol. Pharmacol., 36, 239- 243 (1992) and Deters, M., Siegers, C., Hansel, W. Schneider, KP and Hennighausen, G., Planta Medica, 66, 429-434 (2000)) used in clinics for lowering levels of hyperlipidemia , Similarly, the bark of Guatteria gaumeri, a traditional Mexican medicine, is also used to treat hypercholesterolemia and cholelithiasis, and the active ingredient is α-asarone (Gomez, C., Chamorro, G., Chav'ez, Martinez, G. Salazar, M., Pages, N., Plant Med Med Phytother., 21, 279-284 (1987)). Cholesterol and triglyceride lowering activity was observed for α-asarone in an oral dose of 80 mg / kg in mice fed a high cholesterol diet, showing a reduction of 49.6% and 83.7%, respectively. However, high density lipoprotein (HDL) cholesterol was found to increase (Hernandez, A., Lopez, ML, Chamorro, G. and Mendoza, FT, Planta Medica, 59 (2), 121-124 (1993); Salamar, Salazar, S. and Mendoza, FT, Revista-de-Investigacion Clinica, 45 (6), 597-604 (1993) and Garduno, L .; Salazar, M .; Salazar, S. Morelos, ME; Labarrios, F., Tamariz, J. and Chamorro, GA, J. of Ethnopharmacology, 55 (2), 161-163, (1997). The toxicity of α-asarone is also demonstrated in rats and rats 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. Bull., 18, 605-609 (1995); Lopez, ML; Hernandez, A., Chamorro, G. and Mendoza, FT, Planta Medica, 59 (2), 115-120 (1993) and Chamorr o, GA; Salazar, M .; Tamariz, J .; Diaz, F. and Labarrios. F., Phytotheraphy Research, 13 (4), 308-311 (1999)). In addition, α-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 US Pat also the formulation of active ingredients (Harborne, JB and Baxter, In. In: Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington DC, 474 (1993)). Conventionally, some synthetic pathways have been developed to produce α-asarone, e.g. B .:

• (a) a method using trimethoxybenzene as a starting material (Francisco, D .; Leticia, C .; Rosa, F. Joaquin, T., Fernando, L .; German, C. Heber, M. Org., Prep. Proced. Int., 23 (2), 133-138 (1991)).
• (b) a process in which 2,4,5-trimethoxybenzaldehyde was treated with ethylmagnesium bromide (a Grignard reagent) to produce the corresponding alcohol, followed by dehydration of the alcohol to α-asarone (Wang, Z. Jiang, L. and Xingxiang, X., Youji Huaxue, 10 (4), 350-352 (1990); Shirokova, EA; Segal, GM and Torgov, IV, Bioorg. Khim., 11 (2), 270-275 (1985 ) and Janusz, P., Bozena, L .; Alina, TD; Barbara, L. Stanislaw, W., Danuta, S., Jacek, P., Roman, K., Jacek, C., Malgorzata, S. and Zdzislaw, C., J. Med. Chem., 43, 3671-3676 (2000)).
• (c) a method using vanillin as a starting material (Nenokichi, N. and Shibamoto, N., Kinki Daigaku Rikogakubu Kenkyu Hokoku, 12, 63-66 (1977)).
• (d) a method comprising the photochemical isomerization of beta-asarone (Saxena, DB and Mukerjee, SK, Indian J. of Chem, 24B, 683-684 (1985)).

All However, the above methods are impractical since they are need several steps, expensive Reagents and starting materials and especially poor yields demonstrate. The ongoing efforts to synthesize α-asarone with the highest selectivity appear a two-step process that makes the hydrogenation of far and commercial available β-Asarone (as discussed above) in 2,4,5-trimethoxyphenylpropane (Dihydroasarone), followed by dehydration, none of have the disadvantages mentioned above.

2,4,5-trimethoxyphenylpropane can be obtained by catalytic reduction of β-asarone or the like become through a hydrogenation process in a pair of reactor. however needed the hydrogenation in a pair of reactors an explosive hydrogen gas cylinder and further, the monitoring the progress of the reaction by TLC not possible during the Hydrogenation. Consequently, we have recently the effectiveness of ammonium formate or formic acid / triethylamine as catalytic Hydrogen transferring agent first time for the reduction of plant derived β-asarone or β-asarone rich calamus oil for training 2,4,5-trimethoxyphenylpropane (Sinha, A.K., US Patent No. 09-652376, filed on Aug. 31 (2000), with good reviews Yields, giving details in the examples (Example I). The resulting 2,4,5-trimethoxyphenylpropane serves as a simple one and economic Starting material for forming the double bond in trans form (i.e., α-asarone) using a dehydrating agent, e.g. DDQ.

The introduction of a double bond into a molecule is called a dehydrogenation reaction, which can proceed either by abstraction of a hydride ion (an ionic mechanism) or a hydrogen atom or an electron (free radical mechanism). There are several known dehydrating reagents, namely MnO ₂ , DDQ, DCQ, Hg (OAc) ₂ , SeO ₂ , Pd / C, Se and S, among which DDQ (2,3-dichloro-5,6-dicyano-1, 4-benzoquinone) was identified as an effective and useful dehydrogenating reagent for the conversion of 2,4,5-trimethoxyphenylpropane derivatives to trans -asarone. DDQ is widely used as a significant dehydrogenating agent (Sondengam, BL and Kimbu, SF, Tetrahedron Letters, 1.69-70 (1977) and Guy, A.) Lemaire, M. and Guette, JP, Chem. Commun., 8 (1980 ), which acts as an egg-electron oxidant (Becker, HD, J. Org Chem., 30, 982 (1965).) DDQ was first used for the dehydrogenation of tetralin and bibenzyl to naphthalene or stilbene (Braude, EA and Waugh Chem., 30, 3240 (1965).) The highly important quinone has also found wide application (Walker, D. and Hiebert, J.D., Chem. Rev., 67, 153 (1967)), in particular In the field of steroids and its scope has been extended to the dehydrogenation of ketones, alcohols and lactones A variety of allyl and benzyl alcohols react rapidly with DDQ at room temperature (Findlay, JWA and Turner, AB, J. Chem. Soc ), 23 (1971)), which undergo either coupling reactions or dehydrations, depending on their structure in compounds which have active tertiary hydrogen atoms (Brown, W. and Turner, AB, J. Chem. Soc. (C), 2057 (1971)). In addition, the DDQ-mediated reactions allow the progress of the reaction to be monitored, since the green color Charge Transfer (CT) complex, which initially forms the fer (CT) complex, begins in pink or a brown hue (with the crystallization of 2,3-dichloro-5,6-dicyano-1,4-hydrobenzoquinone) and thus indicates the formation of the product. At the end of the reaction, the precipitated hydrobenzoquinone (DDQH ₂ ) can be easily separated by filtration, allowing 2,3-dichloro-5,6-dicyano-1,4-hydrobenzoquinone (DDQH ₂ ) in 91 to 94% yield to obtain. The yield of precipitated hydroquinone (DDQH ₂ ) is a suitable measure of the extent of the water material transfers. DDQH ₂ thus obtained can be conventionally converted back to DDQ in good yield by standard methods (Walker, D. and Waugh, TD, J. Org. Chem., 30, 3240 (1965)). It is worth noting that with respect to all dehydrogenation reagents (such as chloranil, selenium dioxide, sulfur and selenium) DDQ has been found to be the effective dehydrogenating reagent for the formation of carbon-carbon bond exclusively in the trans-form, which also in the literature during the conversion of 4,4'-dimethoxybibenzyl to trans-4,4'-dimethoxystilbene (Lemaira, M., Guy, A. and Imbert, D., Chem. Commun., 741 (1986)) and Ireland, RE and Brown, G., Org. Synthesis, Coll. Vo. V, 428-431).

Interestingly, the interaction between DDQ and 2,4,5-trimethoxyphenylpropane strongly depends on the time, temperature, solvent and amount of reagent (DDQ). In the polar aqueous solvent, namely, alcohols such as methanol, ethanol, propanol and the like; Ethers such as tetrahydrofuran, dioxane and the like; chlorinated solvents such as dichloromethane, chloroform, and the like, the reaction between 2,4,5-trimethoxyphenylpropane and vary the amount of DDQ preferably in the range of 1.0 to 1.1 mol to the corresponding dehydrated product, ie α-asarone and unreacted starting material together with a yellow polar compound as a byproduct, whereas 2,4,5-trimethoxyphenylpropane and varying amounts of DDQ, preferably in the range of 1.1 to 1.3 mol in the same solvent to α-asarone, as well as the above mentioned yellow colored compound, but without any starting material (Example II). The addition of catalytic amounts of solid matrix, such as pulp, silica gel, alumina, resin and the like, dramatically accelerates the rate of dehydrogenation and increases the yield of α-asarone (Example III), as does the concept of using reagents adsorbed on inert matrices for organic synthesis has recently been used by some chemists (Posner, GH and Rogers, DZ, J. Am. Chem. Soc. 99, 8208 (1997); J Filippo, JS and Chem, CI, J. Org. Chem. 42, 2182 (1979)). The formation of by-products are not surprising for oxidants such as DDQ and many others such as PCC, MnO ₂ , KMnO ₄ , Cr (VI), etc. (Muzart, J. Tetrahedron Letters 28 (40) 4665-4668 (1987)). Initially, the by-product (ie, the yellow band) remained within the column a few times (during column chromatography), being considered unreacted DDQ, since DDQ per se is a yellow-colored reagent. An unsatisfactory yield of trans-Asaron, however, led us to separate each band and then to characterize it in detail. Finally, the melting point of the yellow solid (139-140 ° C) allowed the exclusion of the possibility of DDQ (209-214 ° C) and then we successfully characterized the substance as 2,4,5-trimethoxycinnamaldehyde based on spectroscopic data. The yellow solid showed an IR absorption band at 1648 (conjugate C = O) cm ^-1 and showed a positive 2,4-DNP assay, confirming the presence of a carbonyl group. The aldehydic nature of the carbonyl function was indicated by the Tollen's test. The ¹ H NMR of the yellow solid showed 14 different protons (Example II), which is two less than the number of protons compared to β-asarone (Patra, A. and Mitra, AK, Phytochemistry, 44, 668-669, (1981)), with the exception of the doublet at δ 9.65 (1H, d, J = 7.8 Hz), which could be assigned to an aldehyde proton, and an olefinic proton, which was used as a doublet at δ 6.64 (1H , dd, J = 15.8 Hz,). This second proton formed its typical large coupling constant with the other olefinic proton δ 7.81 (1H, d, J = 15.8 Hz), and further, part of the large value of J is an indication of the trans stereo- chemistry. Furthermore, the position of the two aromatic singlet protons and the three singlets for nine proteones of the trimethoxy groups is more or less the same δ value as in the starting material, but the appearance of three protons at δ 9.65 (1H, d), Finally, 7.81 (1H, d) and 6.64 (1H, dd,) supported the possibility of an unsaturated aldehyde group (-CH = CH-CHO) attached to the trimethoxy-substituted phenyl ring. Similarly, ¹³ C NMR of the yellow solid (occurred at δ 194.1, 154.1, 153.2, 147.6, 143.3, 126.4, 114.5, 110.5, 96) , 5, 56.4, 56.2, 56.0) clearly indicate the presence of 12 carbon atoms, which is similar to the 12 carbon atoms of β-asarone, except that the position of the side propyl group, which has appeared at δ 194.1 (C-3 ') 154.1 (C-1') and 126.4 (C-2 '), due to the (-CH = CH-CHO) group. The EI mass spectrum of the yellow solid showed a clear [M] ⁺ peak at m / z 222. This together with the above-mentioned ¹ H, ¹³ C and IR data finally resulted in the yellow solid as 2, 4,5-trimethoxycinnamaldehyde was confirmed to be a trans isomer, which was later identified as a naturally occurring rarer phenylpropanoid (Kulkarni, MM; Sohoni, J .; Rojatkar, SR and Nagasampagi, BA, Indian J Chem, 25B, 981 ( It is also worth mentioning that the formation of trans-2,4,5-trimethoxycinnamaldehyde in the single step of the phenylalkane, ie, 2,4,5-trimethoxypropane, opens a new pathway for the synthesis of cinnamic aldehyde derivatives, and we have recently extended this discovery towards the development of a series of substituted cinnamic aldehyde derivatives (Sinha, AK, Joshi, BP and Dogra, R. US Patent No. 09-805832 filed March 14, 2001 and Sinha, AK, Joshi, BP and Dogra, R. PCT Patent No. 01/00104 filed May 21 2001), which is actually mild and simpler than previously reported synthetic methods (US Patent, 2,529,186, Nov. 7, (1950); Friedrich and Hartmann, Chem. Ber., 94, 838 (1961); Ger. Pat. 1,114,798, Oct. 12, (1961); U.S. Pat. 3,028,419, April 3, (1962); Deuchert, SK, Hertenstein, U. and Hunig, S., Synthesis, 777 (1973); EI-Feraly, FS and Hoffstetter, MD, J. Nat. Prod. 43, 407 (1980); Rajasekhar, D. and Subbaraju, GV, Indian. J. Chem, 38, 837-838 (1999)). To the best of our knowledge, such a two-step hydrogenation of a widely available allyl and / or propenylphenyl to phenylpropane and the subsequent dehydrogenation of phenylpropane to a trans-phenyl-propane derivative (α-asarone) has not been previously reported, although the alkaline isomerization of allylphenyl is always well-transposed. Isomer, but always with a varying amount of toxic cis isomer (β-Asarone). Although the above procedure provides an α-asarone in 72% yield (Example II), our main focus was still on increasing the percentage of α-asarone and the yield of the abnormal formation of 2,4,5-trimethoxycinnamic aldehyde during the dehydrogenation / oxidation of 2,4,5-Trimethoxyphenylpropane decrease or reduce.

• (a) Die Friedel Craft-Reaktion von Aryl oder substituierter Arylgruppe mit AlCl₃ und Acylchlorid führen zu Arylketon, jedoch kann das methoxysubstituierte Aryl in gewissem Grad zur Methoxylierung mit AlCl₃ während der Friedel-Craft-Reaktion führen (Horie, T., Tominaga, H., Kawamura, Y., Hada, T., Ueda, N., Amano, Y. and Yamamoto, S., J. Med. Chem., 34, 2169–2176 (1991) and Shaun, R.S.; Christopher, J.C.; Rosanna, T.; Gisele, N.; Kathryn, C; Jun, S.; Benita, S.K. and J, A.K., J. Med. Chem., 43, 4934–4947 (2000)). d
• (b) Herstellung durch die Acylierung von substituierten Benzenderivaten unter Verwendung eines sauren Katalysators, wie z.B. TiCl₄, FeCl₃, SnCl₄, CF₃SO₃H, Nafion-H und Metalloxiden etc. (Brown, H.C. and Marino, G., J. Am. Chem. Soc, 81, 3308 (1959); Olah, G.A.; Malhotra, R.; Narang, S.C. and Olah, J.A., Synthesis, 672 (1978) and Yamaguchi, T., Appl. Catal., 61,1 (1990)).
• (c) Herstellung durch Oxidation von benzylischem Kohlenwasserstoff in ein Keton mit kalziniertem ZnCrCO₃, NiAlCO₃, CuZnAlCO₃ und MgAlCo₃ (Hydrotalcit) (Choudhary, B.M.; Bhuma, V. and Narender, N., Indian J. Chem, 36B, 278–280 (1997)).
• (d) Die Herstellung in einigen Schritten durch Reaktion von Vanillinacetat mit Propyliodid/Magnesiumband, gefolgt von Dehydrierung des Carbinolderivats in ein Phenyl propanon (Suri, O.P., Bindra, R.S., Satti, N.K. and Khajuria, R.K., Indian J. Chemistry, 26B, 587–588 (1987)).
• (e) Die Herstellung durch Phenyllithium-Verbindungen und Grignard-Reagenzien mit Lithiumcarboxylaten (Levine, R.; Karten, M.J. and Kaudunce W.M., J. Org. Chem., 40,1770–1773 (1975)).
• (f) Die Herstellung durch Reaktion von Ameisensäure und Eisen(II)salz mit Benzoesäure (Granito, C. and Schultz, H.P., J. Org. Chem., 879–881 (1963)).
• (g) Die Herstellung der Reaktion von methoxyliertem Benzol mit Propylchlorid unter Verwendung von Zeolit H-beta-Katalysatoren (Jaimol, T.; Moreau, P.; Finiels, A.; Ramaswamy, A.V. and Singh, A.P., Applied Catalysis A: General, 214,1–10 (2001)).

To further increase the yield of α-asarone, an alternative pathway for the preparation of the intermediate 1- (2,4,5-trimethoxy) phenyl-1-propanone (isoacroramon) by treating 2,4,5-trimethoxyphenylpropane arises DDQ in aqueous organic solvent leading to treatment with sodium borohydride leading to 1- (2,4,5-trimethoxy) phenyl-1-hydroxypropane, followed by acid dehydration for the formation of α-asarone. The structure of 1- (2,4,5-trimethoxy) phenyl-1-propanone, a crystalline solid (mp 109-110 ° C), was confirmed on the basis of spectroscopic data (Example IV), which later turned out to be a natural one the more prominent phenylpropanoid isolated by Acorus tatarinowii as a pale yellow viscous gum; however, our method isoacoramone provided a crystalline solid with similar spectroscopic data to natural isoacoramone (Jinfeng, Hu and Xiaozhang, Feng, Planta Medica, 66, 662-664 (2000)). It is also worth mentioning that the formation of 1- (2,4,5-trimethoxyphenyl) -1-propanone in one step from phenylalkane, ie 2,4,5-trimethoxypropane, opens a new route for the synthesis of phenylpropanone derivatives which in fact generally exists as a mild, simple and disadvantageous process, generally in comparison to reported synthetic processes, some of the reported processes being the following:

• (a) The Friedel Craft reaction of aryl or substituted aryl group with AlCl ₃ and acyl chloride lead to aryl ketone, however, the methoxy substituted aryl may to some extent result in methoxylation with AlCl ₃ during the Friedel-Craft reaction (Horie, T., Tominaga , H., Kawamura, Y., Hada, T., Ueda, N., Amano, Y. and Yamamoto, S., J. Med. Chem., 34, 2169-2176 (1991) and Shaun, RS; Christopher Rosanna, T., Gisele, N., Kathryn, C., Jun, S., Benita, SK and J, AK, J. Med. Chem., 43, 4934-4947 (2000)). d
• (b) Preparation by the acylation of substituted benzene derivatives using an acidic catalyst such as TiCl ₄ , FeCl ₃ , SnCl ₄ , CF ₃ SO ₃ H, Nafion-H and metal oxides, etc. (Brown, HC and Marino, G. J. Am. Chem Soc, 81, 3308 (1959); Olah, GA; Malhotra, R. Narang, SC and Olah, JA, Synthesis, 672 (1978) and Yamaguchi, T., Appl. Catal., 61 , 1 (1990)).
• (c) Preparation by oxidation of benzylic hydrocarbon to a ketone with calcined ZnCrCO ₃ , NiAlCO ₃ , CuZnAlCO ₃ and MgAlCo ₃ (hydrotalcite) (Choudhary, BM; Bhuma, V. and Narender, N., Indian J. Chem, 36B, 278-280 (1997)).
• (d) The preparation in some steps by reaction of vanillin acetate with propyl iodide / magnesium band, followed by dehydrogenation of the carbinol derivative into a phenylpropanone (Suri, OP, Bindra, RS, Satti, NK and Khajuria, RK, Indian J. Chemistry, 26B, 587-588 (1987)).
• (e) Preparation by Phenyllithium Compounds and Grignard Reagents with Lithium Carboxylates (Levine, R .; Karten, MJ and Kaudunce WM, J. Org. Chem., 40, 1770-1773 (1975)).
• (f) The preparation by reaction of formic acid and iron (II) salt with benzoic acid (Granito, C. and Schultz, HP, J. Org. Chem., 879-881 (1963)).
• (g) The preparation of the reaction of methoxylated benzene with propyl chloride using zeolite H-beta catalysts (Jaimol, T. Moreau, P., Finiels, A., Ramaswamy, AV and Singh, AP, Applied Catalysis A: General , 214, 1-10 (2001)).

It is also worth mentioning that 1- (2,4,5-trimethoxy) phenyl-1-propanone (also known as 2,4,5-trimethoxypropiophenone) has hitherto been isolated from two well-known medicinal plants (Acorus tatarinowii and Piper marginatum), but only in trace amounts. Thus, the preparation of 2,4,5-trimethoxypropiophenone (isoacoramone) has not only made it possible to allow its more weighty biological evaluation as is known for structurally similar propiophenone derivatives (Kuchar, M. Brunova, B .; Rejholec, V, Roubal, Z. and Nemecek, O., Collection Czechoslov Chem, 41, 633-646 (1976); Lariucci, C; Homar, LIB; Ferri, PH and Santos, LS, Anais Assoc. Bras. Quim , 44 (3), 22-27 (1995); Stauffer, SR; Coletta, CJ; Tedesco, R .; Nishiguchi, G .; Carlson, K .; Sun, J.; Katzenellenbogen, BS and Katzenellenbogen, JA, J. Med. Chem., 43, 4934-4947 (2000) and Jaimol, T. Moreau, P., Finiels, A., Ramaswamy, AV and Singh, AP, Applied Catalysis A: General, 214, 1-10 (2001)), but also their provision as a synthon for the production of α-asarone via the reduction of 2,4,5-trimethoxypropiophenone with sodium bo Rehydride and the like leading to 1- (2,4,5-trimethoxyphenyl) -1-hydroxypropane followed by its acid dehydration with p-toluenesulfonic acid (Examples VI and VII).

Alles the procedures that have been used for the synthesis of α-asarone Francisco, D .; Leticia, C; Rosa, F. Joaquin, T .; Femando, L .; German, C; Heber, M. Org. Prep. Proced. Int. 23 (2), 133-138 (1991); Wang, Z .; Jiang, L. and Xingxiang, X., Youji Huaxue, 10 (4), 350-352 (1990); Shirokova, E.A .; Segal, G.M. and Torgov, I.V., Bioorg. Khim., 11 (2), 270-275 (1985) and Janusz, P .; Bozena, L; Alina, T.D .; Barbara, L .; Sta nislaw, W .; Danuta, S .; Jacek, P .; Roman, K .; Jacek, C; Malgorzata, S. and Zdzislaw, C, J. Med. Chem., 43, 3671-3676 (2000)); Nenokichi, H. and Shibamoto, N., Kinki Daigaku Rikogakubu Kenkyu Hokoku, 12, 63-66 (1977); Saxena, D.B. and Mukerjee, S. K., Indian J. of Chem., 24B, 683-684 (1985)) have different limitations and none of the procedures has proved to be suitable for the economical production of α-asarone. In the search for a simple synthesis of α-asarone as a cheaper one Material and reagents are 2,4,5-trimethoxyphenylpropane (isolated by hydrogenation of commercially available Acorus calamus oil rich at Asaronanteiten) as a simple and economical source material in which 2,4,5-trimethoxyphenylpropane undergoes dehydrogenation and oxidation, and not only to α-asarone, but also to rarer ones Phenylpropanoiden of biological importance, namely isoacoramone and 2,4,5-trimethoxycinnamaldehyde. In the present invention, the discovery of α-asarone is the first example of a DDQ-assisted one-step synthesis of α-asarone from toxic β-asarone via 2,4,5-trimethoxyphenylpropane, what actually to reveal the advantages of simplicity and direct access would and can be used for Preparations in the big one Scale.

Examples

The Invention will now be described by way of example with reference on the attached Examples provided for the purpose of explanation and should not be construed as containing the present Limit invention.

example 1

Preparation of 2,4,5-trimethoxyphenylpropane (Dihydroasaron)

The Starting material 2,4,5-trimethoxyphenylpropane is prepared by Hydrogenation of β-asarone (isolated of Acorus calamus oil) or a commercially available one calamus, which is rich in asarone moiety (i.e., β- and / or α, γ-asarone).

(a) Hydrogenation of β-asarone leading to 2,4,5-Trimethoxyphenylpropane (dihydroasarone):

β-Asarone was isolated by loading the crude calamus oil (17.00 g) onto a silica gel column followed by elution of the column with hexane to remove unwanted non-polar compounds. Subsequent elution with a hexane-ethyl acetate mixture increasing in the proportion of ethyl acetate up to 10% results in 13.94 g (82%, w / w) of pure liquid; Rf 0.63 (hexanes: toluene: ethyl acetate = 1: 1: 0.1); ¹ H NMR _(CDCl3, 300 MHz) δ 6.84 (1H, s, H-6), 6.53 (1H, s, H-3), 6.50 (1H, dd, J = 15.8 Hz and 1.5 Hz, HI), 5.78 (1H, dq, j = 6.5 Hz and 15.8 Hz, H-2 '), 3.88, 3.83 and 3.79 (s, 3H, each 3-OCH ₃ ) and 1.85 (3H, dd, j = 6.5 Hz and 1.5 Hz, H-3 '); ³ C NMR (CDCl ₃ , 75.4 MHz) δ 15.4 (C-2), 148.5 (C-4), 142.3 (C-5), 125.5 (C-1), 124 , 7 (C-2), 118.0 (C-1), 114.1 (C-6), 97.6 (C-3), 56.5, 56.2 & 55.9 (3 x OCH ₃ ) and 14.5 (C-3 '); EIMS m / z 208 (M ⁺ , 100), 193 (M ⁺ -Me, 46), 165 (M ⁺ -C ₃ H ₇ , 24). On the basis of the above-mentioned spectral types and in comparison with the literature reported (Gonzalez, MC, Sentandrew, MA, Rao, KS, Zafra, MC and Cortes, D., Phytochemistry 43, 1366-1364 (1996) 5, the fluid became identified as β-asarone of 94% purity (by GC performed on a Shimadzu GC-14B gas chromatograph under the following conditions: SE-30 column, 30 m × 0.25 mm, injector 250 ° / C, FID detector 230 ° / C, temp. Programs 40 (held for 2 min) to 220 ° C (held for 10 min), 10 ° C min ^-1 , vol 1 μl, N ₂ flow 30 ml / min, H ₂ flow 40 ml / min. air flow 300 ml / min, split injection ratio: 1:30).

The β-asarone (6.00 g, 0.029 mol) in 160 mL of ethanol is stirred with 10% palladium on charcoal (0.80 g) and ammonium formate (17.00 g, 0.27 mol) at room temperature under a nitrogen atmosphere until the starting material has disappeared. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with water, dried (Na ₂ SO ₄ ) and filtered. Removal of the filtrate left a liquid which was chromatographed on silica gel using a mixture of hexane-ethyl acetate with an increasing amount of ethyl acetate up to 10% as the Eluent. The eluate was stripped, resulting in 5.87 g (97%) of clear, sweet and pleasant liquid; R _f 0.69 on silica gel plate (hexane: toluene: ethyl acetate - 1: 1: 0.1) which solidified below 0 ° C; ¹ H NMR (DMSO-d6) δ 6.72 (1H, s, H-6), 6.62 (1H, s, H-3), 3.76 to 3.68 (9H, s, 3-OCH ₃ ), 2.5 (2H, t, C-1 '), 1.6 (2H, m, C-2') and 0.9 (3H, t, C-3 '); ¹³ C NMR (CDCl ₃ ) δ 151.4 (C-2), 147.4 (C-4), 142.7 (C-5), 122.7 (C-1), 114.3 (C) 6), 98.0 (C-3) and 56.5, 56.2 & 56.0 (3 × OCH ₃ ), 31.6 (C-1 '), 23.3 (C-2') and 13.79 (C-3 '); EIMS m / z 210 (M ⁺ , 39), 181 (M ⁺ -C ₂ H ₅ , 100), 167 (M ⁺ -C ₃ H ₇ , 5), 151 (M ⁺ -OCH ₃ + CO, 29) , 136 (M ⁺ -C ₃ H ₇ + OCH ₃ , 10). On the basis of ¹ H NMR, ¹³ C NMR and mass spectral data, the above liquid was identified as 2,4,5-trimethoxyphenylpropane in 99% purity (by GC).

(b) hydrogenation of crude Acorus calamus oil for too Dihydroasaron:

In this procedure, 42.00 g of crude calamulus oil (rich in β and / or α, γ-asarone) was hydrogenated in 300 mL of methanol in a 10% Pd / C (4.80 g) paired reactor at 10-40 psi at room temperature until the starting material disappeared. The catalyst was filtered and the solvent removed under reduced pressure resulting in 39.9 g (95 w / w) of reduced oil. Purification by column chromatography of reduced oil on a silica gel column using the above eluent system (hexane-ethyl acetate mixture) gave 2,4,5-trimethoxyphenylpropane (35.76 g) as a liquid in an 85% yield (w / w). ; R _f 0.69 (hexane: toluene: ethyl acetate = 1: 1: 0.1); ¹ H NMR (CDCl ₃ ) of the liquid appeared at δ 6.81 (1H, s, H-6), 6.32 (1H, s, H-3), 3.84 to 3.78 (9H, s, 3-OCH ₃ ), 2,4 (2H, t, C-1 '), 1,6 (2H, m, C-2'), 0,9 (3H, t, C-3). Based on the spectral data, the liquid was identified as 2,4,5-trimethoxyphenylpropane.

Example II

Preparation of α-asarone (trans-2,4,5-trimethoxyphenylpropene) via the dehydrogenation of 2,4,5-trimethoxyphenylpropane with DDQ: A solution of DDQ (2.04-2.65 g) in anhydrous dioxane (40 ml ) was added dropwise over 10 to 15 minutes to an ice-cooled and well-stirred solution of 2,4,5-trimethoxyphenylpropane (1.89 g, 0.009 mol) in anhydrous dioxane (55 ml), and the stirring became at room temperature continued overnight under inert atmosphere. The precipitated solid (DDQH ₂ ) was filtered and washed twice with dioxane. The combined dioxane was stripped off and the concentrate was poured onto 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 sulfate. The residue obtained, after stripping off the solvent, was chromatographed on a silica gel column using a hexane-ethyl acetate mixture with an increasing amount of ethyl acetate of up to 40%, and the fractions showing similar R _f values were mixed, which, after stripping off the solvent afforded two viscous liquids which were further crystallized from the mixture of hexane and ethanol resulting in 0.09 g of a white solid (48%, mp 44-45 ° C) and 0.18 g of a yellow solid (9%, mp 139-140 ° C) as a by-product.

The white solid (mp 44-45 ° C) as obtained above had an R _f value of 0.63 (hexane: toluene: ethyl acetate = 1: 1: 0.1); ¹ H NMR _(CDCl3): δ 6.91 (1H, s, H-6), 6.64 (1H, dd, J = 1.5 Hz and 16 Hz, H-1 '), 6.45 ( 1H, s, H-3), 6.02 (1H, dq, j = 6.2 Hz and 16.0 Hz, H-2 '), 3.84, 3.81 and 3.77 (each 3H, s, three OCH ₃ ), 1.87 (3H, dd, j = 6.2 Hz and 1.5 Hz, H-3); ¹³ C NMR (CDCl ₃ ): δ 149.9 (C-2), 148.0 (C-4), 142.6 (C-5), 124.4 (C-1 '), 123.4 ( C-2 '), 118.3 (C-1), 109.2 (C-6), 97.3 (C-3), 56.1, 55.7 & 55.1 (3-OCH ₃ ) , 18.7 (C-3 '); EIMS m / z 208 ( ^M +, 100), 193 (74), 177 (24), 165 (26), 137 (12), 105 (8), 91 (26), 77 (24), 69 (34 ), 65 (8), 53 (16). On the basis of the above-mentioned spectroscopic data and in comparison with the literature reported (Patra, A. and Mitra, AK, J. Nat., Prod. 44, 668-669 (1981) and Gonzalez, MC; Sentandrew, MA; Rao, KS, Zafra, MC and Cortes, D., Phytochemistry 43: 1361-1364 (1996)), the white solid (mp 44-45 ° C) was identified as α-asarone.

The yellow solid (melting point 139-140 ° C) obtained as a by-product was identified as trans-2,4,5-trimethoxycinnamaldehyde with an R _f value of 0.45 (hexane: ethyl acetate = 4: 1); ¹ H NMR δ 9.65 (1H, d, j = 7.8 Hz, H-3 '), 7.81 (1H, d, j = 15.8 Hz, H-1'), 7.03 (1H, s, H-6), 6.64 (1H, dd, j = 15.8 Hz, j = 7.8 Hz, H-2 '), 6.51 (1H, s, H-3), 3, 95th 3.91 and 3.87 (each 3H, s, three OCH ₃ ); ¹³ C NMR δ 194.1 (C-3 '), 154.1 (C-1'), 153.2 (C-2), 147.6 (C-4), 143.3 (C-5) , 126.4 (C-2 '), 114.5 (C-1), 110.5 (C-6), 96.5 (C-3), 56.4 (5-OCH ₃ ), 56, 2 (2-OCH ₃ ), 56.0 (4-OCH ₃ ); EMS m / z 222 [M] ⁺ (44), 207 (18), 191 (100), 179 (14), 171 (27), 151 (14), 147 (7), 69 (58), 58 ( 80); IR (film) vmax 1648 (conjugated carbonyl), 1602, 1504, 1466, 1448, 1350, 125, 1120, 1024, 856 cm ^-1 ; UV (MeOH) λax 244, 298, 366 nm. On the basis of the above spectroscopic data and in comparison with the reported literature, the yellow solid (mp 139-140 ° C) was reported as trans-2,4,5-trimethoxycinnamaldehyde identified.

Example III

manufacturing of α-asarone via dehydration of 2,4,5-trimethoxyphenylpropane with DDQ containing a minor Amount of Silica Gel: Addition of Catalytic Amounts of Silica Gel (0.2-0.6 g) dramatically accelerated the rate of reaction and improved also the yield of α-asarone, when the above-mentioned dehydrogenation process (Example II-a) under the same conditions were performed, resulting in α-asarone in a 72% Yield and trans-2,4,5-trimethoxycinnamaldehyde in a yield of 18% resulted.

Example IV:

manufacturing of isoacoramone (1- (2,4,5-trimethoxyphenyl) -1-propanone): A solution of DDQ (3.06 - 4.09 g) in dioxane (40 ml) was added dropwise over a period of 10 minutes to an iced and well stirred solution of 2,4,5-trimethoxyphenylpropane (1.89 g, 0.009 mol) in wet dioxane or ethanol (55 ml), and the resulting mixture became at room temperature overnight touched. The precipitate was filtered off and further with twice Dioxane washed. The combined dioxane layer was stripped off and the mixture was poured into water and extracted with dichloromethane (3 x 70 ml). The combined organic layer was washed with brine (3 x 15 ml) washed and over Dried sodium sulfate. The residue obtained after removal of the solvent was subjected to chromatography on a silica gel column using a hexane-ethyl acetate mixture with increasing proportion of ethyl acetate of up to 40%, resulting in a viscous liquid led, which was crystallized from ethyl acetate / hexane and to 1.19 g (59%) of a white one Crystal leads to isoacoramone. The spectroscopic data are similar to those mentioned above in the Example III highlighted.

Example V

Preparation of 1- (2,4,5-trimethoxyphenyl) -1-propanol: A solution of isoacoramone (1.12 g, 0.005 mol) in 40 mL of THF was stirred at below -5 ° C. A precooled solution of NaBH ₄ (0.24-0.39 g) in water (1.2-1.8 ml) was added dropwise, with the temperature being added below the reaction, with the temperature of the reaction mixture below 0 ° C was held. After complete addition of NaBH ₄ , a few drops of 10% NaOH were added and the reaction mixture allowed to stand overnight with stirring. Finally, the reaction mixture was diluted with a saturated ammonium chloride solution (20 ml) and further stirred at room temperature for 20 minutes. The THF was removed under reduced pressure and the mixture was extracted twice with EtOAc. The EtOAc solution was washed twice with H ₂ O (twice), twice with brine, and then filtered. The filtrate was dried over sodium sulfate and evaporated to dryness. The residue obtained after evaporation was found to be pure enough for the next step, but was chromatographed on a neutral alumina column using a hexane-ethyl acetate mixture with increasing ethyl acetate up to 25% resulting in 1- (2 , 4,5-trimethoxy) phenyl-1-propanol (1.01 g, 89%) as a liquid which upon crystallization gave a white solid; R _f 0.78 (28% ethyl acetate in hexane); mp 98-99 ° C; ¹ H NMR (CDCl ₃ ) at δ 7.06 (1H, s, H-6), 6.50 (1H, s, H-3), 4.45 (1H, t, J = 6.6 Hz, H-1 '), 3.91, 3.89 and 3.68 (each 3H, s, three - OCH ₃ ), 1.81-1.54 (2H, m, H-2), 0.85 ( 3H, J = 7.4 Hz, H-3); ¹³ C NMR (CDCl ₃ ) δ 152.0 (C-2), 148.5 (C-4), 143.7 (C-5), 123.77 (C-1), 110.9 (C) 6), 97.9 (C-3), 73.4 (C-1 '), 57.0 (4-OCH ₃ ), 56.7 (5-OCH ₃ ), 56.43 (2-OCH ₃ ), 31.9 (C-2), 11.0 (C-3); IR (KBr) 3300 cm ^-1 (OH).

Example VI

manufacturing of α-Asarone (trans-2,4-5-trmethoxyphenyl-1-propene): The catalytic amount of p-toluenesulfonic acid (0.4-0.6 g) became a solution of 1- (2,4,5-trimethoxy) phenyl-1-propanol (0.90 g, 0.004 mol) in toluene (80 ml). The mixture was left under backflow for 12-14 hours under a Dean Stark apparatus. Subsequently, the mixture was on Poured ice water and extracted with toluene (3 x 70 ml). The united organic Layer was washed with saline (3 x 15 ml), with saturated Sodium bicarbonate (2 × 10 ml), with saline (3 x 15 ml) and was over Dried sodium sulfate. The residue obtained after removal of the solvent was subjected to chromatography on a silica gel column using a hexane-ethyl acetate mixture with an increasing proportion of Ethyl acetate of up to 10%, yielding pure α-asarone (0.72 g, 87%) as one white solid with a melting point of 44-45 ° C led. The spectroscopic data turned out to be the same as mentioned above (Example II).

The main ones Advantages of the present invention are:

• 1. A procedure that calls DDQ a versatile one Reagent revealed to a wide range of seltneren phenylpropanoids to provide, notably α-Asaron, 2,4,5-trimethoxycinnamaldehyde and 1- (2,4,5-trimethoxy) phenyl-1-propanone (isoacoramone) in one step with variation of solvents, time, temperature and the amount of dehydrating DDQ reagent.
• 2. A simple process for the preparation of pharmacological active α-asarone from 2,4,5-trimethoxyphenylpropane, which is actually the hydrogenated product toxic β-asarone isolated from commercially available calamus represents.
• 3. A simple process for using internationally prohibited, but still available, of toxic β-asarone rich calamus oil over a two-stage process, i. Hydrogenation and dehydration, in well-known pharmacologically active α-asarone, causing the profitable use of Acorus calamus by tetraploid or hexaploid Species (extensively in Asian countries sold).
• 4. A simple process for the production of α-asarone exclusive, without any pollution from corresponding ones isomeric forms of asarones (i.e., β and / or γ isomers).
• 5. A process for producing a non-toxic or less toxic Compound (i.e., α-asarone) from a toxic compound (i.e., β-asarone).
• 6. The procedure allows Us mixtures of all of the three isomeric forms of Phyenylpropenen (i.e., α-, β-, and γ-asarone) first to convert to 2,4,5-trimethoxyphenylpropane (via hydrogenation) and then the regeneration of phenylpropene (via dehydration), but exclusively into the transform (i.e., α-Asaron), whereas earlier reported Always method α-Asarone with varying amounts of toxic β-asarone during alkaline isomerization from γ-Asaron and the like.
• 7. A process for producing α-asarone from 2,4,5-trimethoxyphenylpropane using first-time dehydrating DDQ reagent.
• 8. A method of producing naturally occurring rare trans-2,4,5-trimethoxycinnamaldehyde, the indeed while the production of α-asarone from 2,4,5-trimethoxyphenylpropane was discovered in a single Step from the phenylpropane derivative.
• 9. A procedure that provides an alternative path for manufacturing of α-Asarone obtained starting from 2,4,5-trimethoxypropiophenone by treating 2,4,5-trimethoxyphenylpropane with DDQ in aqueous Solution.
• 10. A process using 2,4,5-trimethoxypropiophenone as a solid whereas the natural 2,4,5-trimethoxypropiophenone (isolated from Acorus tatarinowii and Piper marginatum) as more viscous Gum is reported.
• 12. A process wherein the formation of 2,4,5-trimethoxypropiophenone opened a new synthesis route for the Preparation of a series of propiophenone derivatives in one step from phenylpropane derivatives, i. 2,4,5-trimethoxyphenylpropane.
• 14. A procedure that, of course occurring 2,4,5-Trimethoxypropiophenon forms in sufficient quantity and the possibility provides for its biological assessment on a broad scale.
• 15. A procedure called α-asarone exclusively over the reduction of 2,4,5-trimethoxypropiophenone leading to 2,4,5-Trimethoxyphenyl-1-hydroxypropane in high yield followed acid dehydration using p-toluenesulfonic acid and thionyl chloride / pyridine and the like.

Summary

The The present invention relates to a process for the production of α-asarone in high purity and yield, of trans-2,4,5-trimethoxycinnamaldehyde, 2,4,5-Trimethoxyphenylpropion from β-Asarone or β-Asarone-rich Acorus calamus oil containing α- and γ-asarone by hydrogenation followed by treatment with DDQ with or without a solid matrix of silica gel or alumina in one dry organic solvent. About that In addition, -sarone can also be obtained by treating the hydrogenated product of β-Asarone or β-Asarone-rich Acorus calamus with DDQ in an aqueous organic solvent, to obtain 2,4,5-trimethoxyphenylpropion as an intermediate, which in turn is reduced with sodium borohydride to the corresponding one 2,4,5-Trimethoxyphenylpropanol and then a final treatment with a dehydrating agent.

Claims (20)

A process for preparing a pharmacologically active α-asarone (trans isomer) of formula II from the toxic β-asarone (cis isomer) or β-asarone rich Acorus calamus oil containing the α and γ isomers, wherein said process comprising the steps of: (a) hydrogenating β-asarone or β-asarone rich calamus oil containing α- and γ-asarone using of 10% Pd / C catalyst with or without ammonium formate under a pressure of 0-40 psi at room temperature, (b) purifying the product of step (a) over silica gel by performing a column chromatography to obtain the compound of formula (I) to obtain,

(c) Dehydrating under inert atmosphere the compound of formula (I) of step (b) by treating with DDQ optionally containing silica or alumina in anhydride organic solvent at room temperature for a period of 0.5 to 72 hours. (d) filtering the reaction mixture from step (c) to remove the precipitated (DDQH ₂ ), washing the residue with an organic solvent and obtaining a combined clear filtrate, (e) concentrating the combined filtrate from step (d) and pouring the concentrate on water, extracting with a water immiscible organic solvent, (f) combining the organic solvent extract of step (e), washing with brine, 10% aqueous bicarbonate, followed by rinsing with brine, drying over anhydrous sodium sulfate, filtering and evaporating to dryness to obtain a residue, (g) purifying the residue of step (f) over a silica gel column, eluting with a mixture of hexane: ethyl acetate to afford α-asarone as a viscous liquid and a yellow solid, characterized as trans-2,4,5-trimethoxycinnamaldehyde of the formula (IIa)

(h) crystallizing the viscous liquid containing α-asarone using a hexane to methanol mixture to obtain a white solid of α-asarone (II).

(i) obtaining α-asarone also from a compound and formula (I) of step (a) by treating with DDQ in an aqueous organic solvent at room temperature for a period of 16-20 hours, (j) filtering the reaction mixture of the step (i) to remove the precipitated solid in (DDQH ₂ ), washing the residue with the organic solvent and obtaining a clear solution, (k) evaporating the clear solution of step (j) and pouring the residue on water, extracting with an organic solvent, washing the organic solvent extract with brine, drying over anhydrous sodium sulfate, filtering and evaporating to obtain a residue, (l) purifying the residue of step (k) over a silica gel column eluting with a mixture of hexane: ethyl acetate to obtain a viscous liquid fraction containing isoacoramone which crystallizes from ethyl acetate: hexane to give white crystals of isoacoramone of the formula (II) III),

(m) treating the compound of formula (III) of step (1) with sodium borohydride in an organic solvent in the presence of an aqueous alkali hydroxide solution in a temperature range of -5 ° C to room temperature over a period of 16-20 hours, (n) Diluting the reaction mixture of step (n) with a saturated ammonium chloride solution, stirring for 20-30 minutes, (o) removing the organic solvent of the solution of step (n) under reduced pressure and extracting the aqueous layer with ethyl acetate, (p) washing the Ethyl acetate layer of step (o) with water, drying the ethyl acetate layer over anhydrous sodium sulfate, filtering and evaporating the organic solvent to dryness to obtain a residue, (q) purifying the residue from step (p) over a neutral alumina column using an eluent from hexane: ethyl acetate to give 1- (2,4,5-trimethoxy) -phenyl-1-propanol of the formula (IIIa ) to get,

(d) dehydrating the formula of the compound (IIIa) by treating with p-touluenesulfonic acid in an aromatic hydrocarbon solvent at a reflux temperature using a Dean stack apparatus for continuously removing water, (s) pouring the reaction mixture from the step (r) cold water, extracting with an aromatic hydrocarbon solvent and separating an organic layer, (t) washing the organic layer of step (s) with brine, saturated bicarbonate solution, followed by rinsing in brine, drying in anhydrous sodium sulfate, Filtering and evaporating the organic solvent to obtain a residue, (u) purifying the residue of step (t) over a silica gel column, eluting with a hexane: ethyl acetate mixture to obtain a white solid of α-asarone of formula (II) , A process as claimed in claim 1, wherein in steps (c) and (d) the anhydrous organic used solvent selected is selected from the group consisting of methanol, ethanol, hexane, benzene, Toluene, tetrahydrofuran or dioxane, and most preferably anhydrous dioxane. A process as claimed in claim 1, wherein (c) the molar ratio from DDQ to 2,4,5-trimethoxyphenylpropane used in a range is from 1.1 to 1.3: 1. A process as claimed in claim 1, wherein in step (i) the molar ratio from DDQ to 2,4,5-trimethoxypropane of the formula (I) used is in the range of 1.6: 1 to 2.1: 1. A process as claimed in claim 1 wherein the dehydrogenation of 2,4,5-trimethoxypropane is Formula (I) provides α-asarone of the formula (II) in a 51% yield and a yellow solid and 2,4,5-trimethoxycinnamaldehyde of the formula (II) with an 11% yield. A process as claimed in claim 1, wherein in step (c), adding a catalytic amount of silica gel or of alumina, the yield of α-asarone increased up to 72% and from trans-2,4,5-trimethoxybenzaldehyde up to 18%. A process as claimed in claim 1, wherein in step (e) the water immiscible organic solvent, which is used, selected is from the group of carbon tetrachloride, dichloromethane or Chloroform, and preferably dichloromethane. A process as claimed in claim 1, wherein in step (i) and (j) the organic solvent used will be chosen is selected from the group consisting of methanol, ethanol, hexane, benzene, Toluene, tetrahydrofuran or dioxane and more preferably ethanol, and most preferably tetrahydrofuran. A process as claimed in claim 1, wherein in step (i) the ratio from water to the organic solvent, which is in the range of 0.1: 9.9 to 1: 9. A process as claimed in claim 1, wherein in step (k) the organic solvent, which is used selected is selected from the group consisting of methanol, ethanol, tetrahydrofuran or dioxane, and most preferably dioxane. A process as claimed in claim 1, wherein in step (m) the organic solvent, that was used is tetrahydrofuran. A process as claimed in claim 1, wherein in step (r) the dehydrating agent used is selected is from the group of p-toluenesulfonic acid or thionyl chloride / pyridine and preferably p-toluenesulfonic acid is. A process as claimed in claim 1, wherein in step (r) the aromatic hydrocarbon solvent, which is used, selected is selected from the group consisting of benzene, toluene and xylene and am most preferred is toluene. A process as claimed in claim 1, wherein in step (u) the yield of α-asarone is up to 87%. A process as claimed in claim 1, which is preferably at a temperature in the range of 20 ° -70 ° C over a period of 4-12 hours carried out becomes. A process of claim 1 providing a method varying with reagent, solvent, temperature and time to increase the yield of the required product. A process as claimed in claim 1, wherein in step (I) the isoacoramone (2,4,5-trimethoxypropiophenone) of Formula (III) is obtained as a crystalline solid containing a Having melting point of 107-110 ° C. A process as claimed in claim 1 which comprises α-asarone in provides a high purity which is completely free of β- and γ-asarone. A process as claimed in claim 1, comprising Proceedings opened, to obtain synthetic trans-cinnamaldehyde and phenylpropanone derivatives. A process of claim 1 that is economically and commercially applicable is.