U.S. patent application number 10/108269 was filed with the patent office on 2003-10-02 for ddq mediated one step dimerisation of beta-asarone or beta-asarone rich acorus calamus oil in the formation of novel neolignan.
This patent application is currently assigned to Council of Scientific & Industrial Research. Invention is credited to Acharya, Ruchi, Joshi, Bhupendra Prasad, Sinha, Arun Kumar.
Application Number | 20030187306 10/108269 |
Document ID | / |
Family ID | 30002057 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030187306 |
Kind Code |
A1 |
Sinha, Arun Kumar ; et
al. |
October 2, 2003 |
DDQ mediated one step dimerisation of beta-asarone or beta-asarone
rich acorus calamus oil in the formation of novel neolignan
Abstract
The present invention relates to a novel neolignan (NEOLASA-I)
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy-phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-(2',4',5'-trimethoxy)phenyl-1-propene and a process for the
preparation of high purity, higher yield neolignan,
.alpha.-asarone, 2,4,5-trimethoxy-phenyl propionone from
.beta.-asarone or .beta.-asarone rich Acorus calamus oil containing
.alpha. and .gamma.-asarone by hydrogenating and dimerizing by
treatment with DDQ in presence of an organic acid.
Inventors: |
Sinha, Arun Kumar; (Himachal
Pradesh, IN) ; Joshi, Bhupendra Prasad; (Himachal
Pradesh, IN) ; Acharya, Ruchi; (Himachal Pradesh,
IN) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Council of Scientific &
Industrial Research
|
Family ID: |
30002057 |
Appl. No.: |
10/108269 |
Filed: |
March 28, 2002 |
Current U.S.
Class: |
568/660 |
Current CPC
Class: |
C07C 43/2055 20130101;
C07C 43/215 20130101 |
Class at
Publication: |
568/660 |
International
Class: |
C07C 043/02; C07C
043/20 |
Claims
1. A novel neolignan
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy-phenyl-1-(2',-
4',5'-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene of
formula (II) 3
2. A neolignan compound as claimed in claim 1 has following
physical characteristics: R.sub.f: 0.45 (solvent:
Ethylacetate-Hexane; 2:8) m.p; 96.degree.-97.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta.6.91 (1H, s, H-6'), 6.84 (1H, s, H-6"),
6.55(1H, s, H-3'), 6.51 (1H, s, H-3"), 6.48 (1H, s, H-1), 3.96 (6H,
s, 2'-OCH.sub.3 and 2"-OCH.sub.3), 3.84 (6H, s, 4'-OCH.sub.3 and
4"-OCH.sub.3), 3.80(3H, s, 5'-OCH.sub.3), 3.78 (3H, s,
5"-OCH.sub.3), 3.59(1H, t, H-3), 1.70-1.97 (2H, m, H-4), 1.66 (3H,
s, H-6), 0.93(3H, t, H-5); .sup.1H NMR (DMSO-d.sub.6) .delta.6.79
(1H, s, H-6'), 6.68 (1H, s, H-6"), 6.67 (1H, s, H-3'), 6.66 (1H, s,
H-3"), 6.34 (1H, s, H-1), 3.84 (9H, s, 2"-OCH.sub.3, 4"-OCH.sub.3
and 5"-OCH.sub.3), 3.68 (3H, s, 2'-OCH.sub.3), 3.66 (3H, s,
4'-OCH.sub.3), 3.62 (3H, s, 5'-OCH.sub.3),3.53 (1H, t, H-3),
1.88-1.67 (2H, m, H-4),1.60(3H,s,H-6), 0.84 (3H, t, H-5);
.sup.13CNMR (CDCl.sub.3) .delta.152.48 (C-2'), 152.02 (C-2"),
148.48 (C-4'), 147.94 (C-4"), 143.57 (C-5'), 142.89 (C-5"), 140.41
(C-2), 124.88 (C-1'), 120.18 (C-1), 119.65 (C-1"), 114.88 (C-6'),
112.14 (C-6"), 99.47 (C-3'), 99.37 (C-3"), 57.37 (5"-OCH.sub.3),
57.09 (5'-OCH.sub.3), 57.07 (4"-OCH.sub.3), 56.94 (4'-OCH.sub.3),
56.55(2"-OCH.sub.3), 56.48 (2'-OCH.sub.3), 47.38 (C-3), 26.74
(C-4), 17.82 (C-6), 12.84 (C-5); .sup.13C NMR (DMSO-d.sub.6)
.delta.152.56 (C-2'), 152.11 (C-2"), 149.07 (C-4'), 148.53 (C-4"),
143.53 (C-5'), 142.84 (C-5"), 139.45(C-2), 123.96 (C-1'), 120.56
(C-1), 119.09 (C-1"), 115.47 (C-6'), 13.02 (C-6"), 99.55 (C-3'),
99.23 (C-3"), 57.39(5"-OCH.sub.3), 57.24 (5'-OCH.sub.3), 57.17
(4"-OCH.sub.3), 57.08 (4'-OCH.sub.3), 56.63 (2"-OCH.sub.3), 56.59
(2'-OCH.sub.3), 47.56 (C-3), 26.46 (C-4), 17.71 (C-6), 13.33 (C-5);
NMR (DEPT-135.degree.) .delta.120.56(C-1), 115.47 (C-6'), 113.02
(C-6"), 99.55 (C-3'), 99.23 (C-3"), 57.39 (5"-OCH.sub.3), 57.24
(5'-OCH.sub.3), 57.17 (4"-OCH.sub.3), 57.08 (4'-OCH.sub.3), 57.08
(4'-OCH.sub.3), 56.63 (2"-OCH.sub.3), 56.59 (2'-OCH.sub.3), 47.56
(C-3, down), 26.46 (C-4), 17.71 (C-6), 13.33 (C-5); EIMS m/z (%):
416 [M]+ (14), 219 (100), 209 (47), 181 (21), 171 (20), 71
(27).
3. A neolignan as claimed in claim 1 is named as NEOLASA-I
4. A neolignan as claimed in claim 1 has one asymmetric center.
5. A neolignan as claimed in claim 1 has aliphatic side chain with
one double bond.
6. A neolignan as claimed in claim 1 is capable of undergoing
conversion into several naturally occurring neolignan and lignan
derivatives.
7. A neolignan as claimed in claim 1 is capable of undergoing
hydrogenation to yield dihydro neolignan
3-ethyl-2-methyl-3-(2",4",5"-tri-
methoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl propane (III) to
further establish the presence of a reducible double bond.
8. A dihydroneolignan as claimed in claim 7 is named as
NEOLASA-II.
9. A dihydroneolignan as claimed in claim 7 has two asymmetric
centers.
10. A process for the preparation of nelignan
3-ethyl-2-methyl-3-(2",4",5"-
-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene of
formual II from toxic .beta.-asarone or .beta.-asarone rich Acorus
calamus oil containing .alpha. and .gamma.-asarone, the said
process comprising the following steps: a) hydrogenating
.beta.-asarone or .beta.-asarone rich calamus oil containing
.alpha. and .gamma.-asarone using 10% Pd/c catalyst, with or
without ammonium formate under pressure between 0-40 psi at room
temperature, b) purifying the product of step (a) over silica gel
column to obtain compound of formula (I), 4c) stirring the compound
of formula (I) of step (b) with DDQ and an organic acid at room
temperature for a period of 16-20 hrs. d) filtering the precipitate
solid (DDQH.sub.2) and washing the residue with an organic acid, e)
evaporating combined organic acid solution of step (d), to obtain a
concentrated solution, f) pouring concentrated solution of step (e)
into water, g) extracting the aqueous solution of step (f) with
aliphatic halogenated hydrocarbon solvent and separating organic
layer, h) washing the organic layer of step (g) with brine, 10%
bicarbonate solution, followed by again brine and drying organic
layer over anhydrous sodium sulphate, filtering and evaporating to
dryness to obtain a residue, and i) purifying residue of step (h)
over silica gel column to obtain three sets of fraction which are
crystallized separately from a mixture of hexane:methanol to obtain
.alpha.-asarone (I, 19% ), 1-(2,4,5-trimethoxy)phenyl-1-propanone
(IIb, 22%) and neolignan
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4-
',5'-trimethoxy)phenyl-1-propene (II, 32%) 5
11) A process as claimed in claim 10 wherein in step (c) the
effective molar ratio of 2,4,5-trimethoxyp propane and DDQ is in
the range of 1:1 to 1:2.1
12) A process as claimed in claim 10, wherein in steps (c) and (d)
the organic acid used is selected form acetic acid or propionic
acid and preferably acetic acid.
13) A process as claimed in claim 10, wherein in step (g) the
aliphatic halogenated hydrocarbon solvent used is selected from
dichloromethane, carbontetrachloride or chloroform and preferably
dichloromethane.
14) A process of claim 10 provides neolignan and other useful side
products of high purity.
15) A process as claimed in claim 10 wherein in step (I) the
neolignan obtained is termed as NEOLASA-I.
16) A process as claimed in claim 10, wherein the said neolignan
(II) has one asymmetric center.
17) A process as claimed in claim 10, wherein the said neolignan
(II) neolignan obtained provides the opportunity for evaluation of
its biological activity.
18) A process as claimed in claim 10, wherein the said neolignan
(II) has aliphatic side chain with one double bond.
19) A process as claimed in claim 10, wherein the said neolignan
(II) is capable of undergoing conversion into several naturally
occurring neolignans and lignan derivatives.
20) A process as claimed in claim 10, wherein the said neolignan
(II) is capable of undergoing hydrogenation to yield
dihydroneolignan
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethyoxy)ph-
enyl propane (III) to further substantiate the presence of a double
bond in neolignan (II).
21) A dihyroneolignan (II) of claim 17 is named as NEOLASA-II.
22) A dihydrolignan (III) of claim 17 has two asymmetric centers
Description
FIELD OF THE INVENTION
[0001] The present invention relates to "DDQ mediated one step
dimerisation of dihydro product of toxic .beta.-asarone rich Acorus
calamus oil towards formation of novel neolignan:
3-ethyl-2-methyl-3-(2",-
4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene" in
which 2,4,5-trimethoxyphenylpropane (a dihydro product of asarone
obtained via hydrogenation of .beta.-asarone rich Acorus calamus
oil) of the formula (I), undergoes dimerisation in a single step
towards formation of neolignan
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trim-
ethoxy)phenyl-1 propene (named as NEOLASA-I) of the formula II
along with biologically active .alpha.-asarone and
1-(2,4,5-trimethoxy)phenyl-1-prop- anone as side products, thereof.
Further, neolignan (NEOLASA-I) is hydrogenated to obtain its
corresponding dihydro product
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)
phenyl-1-(2',4',5'-trimethoxy)ph- enylpropane (named as
NEONLASA-II) so as to confirm the structure as well as to determine
the position of double bond existing in the above parent neolignan
(NEOLASA-I) which may additionally serve as a simple synthon
towards preparation of naturally occurring rare neolignans (such as
acoradin or magnosalin or heterotropan and phenyl indane
derivative) and their analogues in sufficient quantity to have
opportunity for a wide range of biological activities including
antifungal, antioxidant, antiinflammatory, neuroleptic,
antihepatoxic, anticancer, anti-HIV and anti-PAF activities known
for structurally similar neolignan derivatives (such as aurein or
hexestrol or nordihydroguaiaretic acid derivatives etc.). In the
present invention, the neolignan (NEOLASA-I) formation is the first
example of DDQ assisted one step synthesis of neolignan, a dimer of
phenylpropanoid, in good yield (32%) from
2,4,5-trimethoxyphenylpropane derivative. 1
BACKGROUND OF THE INVENTION
[0002] Neolignans and lignans are known for their wide range of
biological activities including hapatoprotective, harmone blocking,
antibacterial, antifungal, plant growth regulator, anti-HIV,
anticancer and antioxidant activities (Macrae, W. D. and Towers, G.
H. N., Phytochemistry, 23 (6), 1207-1220 (1984); Ward, R. S.,
Tetrahedron, 46 (15), 5029-5041 (1990); Charlton, J. L., J. Nat.
Prod., 61, 1447-1451 (1998); Alves, C. N.; Barroso, L. P.; Santos,
L. S. and Jardim, I. N, J. Braz. Chem. Soc., 9(6), 577-582 (1998);
Juhsz, L.; Dinya, Z.; Antus, S. and Gunda, T. E., Tetrahedron
Letters, 41, 2491-2494 (2000); Tanaka, T.; Konno, Y.; Kuraishi, Y.;
Kimura, I.; Suzuki, T. and Kiniwa, M., Biorg. & Med. Chem.
Letts., 12, 623-627 (2002); U.S. Pat. Nos. 6,294,574; 6,201,016;
5,856,323; 5,639,782; 5,530,141; 4,704,462; 4,619,943 and
4,540,709; JP Patent no. 4082837; WO Patent no. 09215294 and EP
Patent No. 159565)). Neolignans and lignans are a large group of
natural products characterized by the coupling of two
C.sub.6-C.sub.3 units which are derived from cinnamic acid
derivatives, however, both are present in traces in plants (Rao, K.
V. and Rao, N. S. P., J. Nat. Prod., 53(1), 212-215 (1990) and
Filler, F.; Bail, J. C. L.; Duroux, J. L.; Simon, A. and Chulia, A.
J., Planta Medica, 67, 700-704 (2001)). For nomenclature purposes,
the C.sub.6-C.sub.3 unit is treated as propylbenzene and numbered
from 1 to 6 in the benzene ring from 7 to 9 (or .alpha. to .gamma.)
starting from propyl group. With the second C.sub.6-C.sub.3 unit
the numbers are primed. When the two C.sub.6-C.sub.3 units are
linked by a bond between positions 8 and 8' (or .beta. and
.beta.'), the compound is referred as a lignan. In the absence of
the C-8 to C-8' (or .beta. and .beta.') bond, and where the two
C.sub.6-C.sub.3 units are linked by a carbon-carbon bond, compound
is referred to as neolignan. Dimers with linkages other than this
type are known as cycloneolignan, epoxyneolignan and oxyneolignan
etc. Similarly, the presence of a double bond (or triple bond) in
the side chain (i.e. C-7 to C-9 or C-7 to C-9) of the lignan,
neolignan or epoxyneolignan skeleton is indicated by changing the
-ane ending to -ene (or -yne) with a locant to indicate the
position of the double bond (Moss, G. P. Pure Appl. Chem., 72 (8),
1493-1523 (2000)). The basic ring system of these neolignans and
lignans can be deduced by dimerization of allyl and
p-propenylphenols (such as isoeugenol, coniferyl or sinapyl
alcohol). Oxidation of phenols often yields phenoxy radicals, which
couple with little selectivity. Both C--C and C--O bonds are
formed, mainly in ortho- and para-positions to the phenolic
hydroxyl. Synthetically useful reactions are obtained only when the
reactivity is blocked by substituents in the aforementioned
positions. For instance from 2,6- or 2,4-substituted phenols, C--C
bonded biphenyls can be obtained in good yields. In other cases
coupling can be directed by carrying out the reaction
intramolecularly, ring closure being an effective way of inducing
regioselectivity (Whitting, D. A. Oxidative Coupling of Phenols and
Phenol Ethers. In Comprehensive Organic Synthesis, Trost, B. M.;
Fleming, I.; Pattenden, G., Eds.; Pergemon: Oxford, Vol. 3, 659-703
(1991)). Similarly, oxidation of a mixture of two phenols can lead
to a mixture of dimers of the individual phenols and cross-coupling
products between the different phenols. When one phenol reacts much
faster than the other, for instance if it has a lower oxidation
potential, it tends to dimerize without formation of significant
amounts of cross-coupling products (Syrijanen, K. and Brunow, G.,
J. Chem. Soc. Perkin Trans 1, 3425-3429 (1998)). One approach to
this problem is to start with the less reactive phenol in large
excess, and continuously add the more reactive phenol (and the
oxidant) at a rate which is slow enough to keep its concentration
too low for significant dimerisation. But this method is cumbersome
and leads to a large reaction volumes, and is also difficult to
reproduce. A wide range of oxidants such as K.sub.3Fe(CN).sub.6,
H.sub.2O.sub.2, FeCl.sub.3, VOF.sub.3, thallium (III)
tristrifluoacetate, horseradish peroxidase, iodobenzene diacetate
(Frank, B. and Schlingloff, G., Liebig. Ann. Chem., 659, 132
(1962); Taylor, W. I. and Battersby, A. R. In "Oxidative Couplings
of Phenols", Marcel Dekker, New York (1967); Kametani, T. and
Fukumoto, K., Synthesis, 657 (1972); Taylor, E. C.; Andrade, J. G.;
Rall, G. J. H. and McKillop, A., J. Am. Chem. Soc., 93, 4841
(1971); Kaisa, S. and Gosta, B., Tetrahedron, 57, 365-370 (2001);
Juhasz, L.; Kurti, L. and Antus, S., J. Nat. Prod, 63, 866-870
(2000)) and many others have been used for oxidative coupling but
generally these reagents gave poor yield, and often complex
mixtures. Indeed, phenoxy radical or phenoxonium ion intermediate
is most common for synthesis of lignans and neolignans but there
are a few patents and papers where non-phenolic compounds have been
used for the synthesis of lignans and neolignans (Kadota, S.;
Tsubono, K. and Makino, K., Tetrahedron Letters, 28 (25), 2857-2860
(1987) and Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V. and Robin,
J. P., Tetrahedron, 50 (4), 1153-1164 (1994)). For example,
nordihydroguaiaretic acid (one of the most important dimer derived
from resinous exudates of many plants), associated with a wide
range of pharmacological activities, including the inhibition of
the human papillomavirus, herpes simplex, HIV and hyperglycemic
activity, has been synthesized by dimerization of non-phenolic
compounds such as dimethoxypropiophenone (Perry, C. W. U.S. Pat.
No. 3,769,350 (1975)), substituted benzylmagnesium chloride (Akio,
M.; Kohei, T.; Keizo, S. and Makoto, K. Tetrahedron Letters, 21,
4017-4020 (1980)) and dimethoxyphenylacetone (Mikail, H. G. and
Barbara, N. T. Tetrahedron Letters, 42, 6083-6085 (2001)). However,
above methods have a number of disadvantages including special
handling of reagents, maintaining temperature below zero degree,
expensive reagents and overall low yield, hence, none of the
synthetic methods can be scaled up for industrial exploitation. On
the contrary, the present invention is free from above drawbacks
and discloses one step dimerisation of
2,4,5-trimethoxyphenylpropane (a dihydro product of asarone
obtained via hydrogenation of .beta.-asarone rich Acorus calamus
oil) of the formula I (Example I) into novel neolignan
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)-
phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene (named as NEOLASA-I)
of the formula II (Example II). Further, neolignan (NEOLASA-I) is
hydrogenated to obtain its corresponding dihydro product
(3-ethyl-2-methyl-3-(2",4",5"-
-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenylpropane) (named as
NEONLASA-II) (Example III) so as to confirm the structure as well
as to determine the position of double bond existing in the above
parent neolignan (NEOLASA-I) of the formula (II) which may
additionally serve as a simple synthon towards preparation of
naturally occurring rare neolignans (such as acoradin or magnosalin
or heterotropan and phenyl indane derivative) and their analogues
in sufficient quantity to have opportunity for a wide range of
biological activities (Wenkert, E.; Gottlieb, H. E.; Gottlieb, O.
R.; Pereira, M. O. D. S. and Formiga, M. D., Phytochemistry, 15,
1547-1551 (1976); Kikuchi, T.; Kadota, S.; Yanada, K.; Tanaka, K.;
Watanabe, K.; Yoshozaki, M.; Yokoi, T. and Shingu, T., Chem. Pharm.
Bull. 31, 1112 (1983); Yamamura, S.; Niwa, M.; Nonoyama, M. and
Terada, Y. Tetrahedron Letters, 4891 (1978); Kadota, S.; Tsubono,
K.; Makino, K.; Takeshita, M. and Kikuchi, T., Tetrahedron Letters,
28 (25), 2857-2860 (1987); Shimomura, H.; Sashida, Y and Oohara,
M., Phytochemistry, 26(5), 1513-1515 (1987); Ahn, B. T.; Lee, S.;
Lee, S. B.; Lee, E. S.; Kim, J. G. and Jeong, T. S., J. Nat. Prod.,
64, 1562-1564 (2001) and Filleur, F.; Le Bail, J. C.; Duroux, J.
L.; Simon, A. and Chulia, A. J., Planta Medica, 67, 700-704
(2001)).
[0003] In fact, formation of neolignan was observed accidentally
when we were interested to develop a simple and economical process
for the preparation of .alpha.-asarone, a well known hypolipideamic
and antiplatelet active phenylpropanoid (Hernandez, A.; Lopez, M.
L.; Chamorro, G. and Mendoza, F. T., Planta Medica, 59 (2), 121-124
(1993); Garduno, L.; Salazar, M.; Salazar, S.; Morelos, M. E.;
Labarrios, F.; Tamariz, J. and Chamorro, G. A., J. of
Ethnopharmacology, 55 (2), 161-163, (1997) 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)), via treatment of
2,4,5-trimethoxyphenylpropane of the formula I with DDQ in acetic
acid into 1-(2,4,5-trimethoxy)phenyl-1-acetoxypropane followed by
alkaline hydrolysis and its acidic dehydration to obtain
.alpha.-asarone. This concept was based upon the reported method
wherein treatment of benzylic compound with Hg(OAC).sub.2/AcOH or
DDQ/AcOH provided corresponding acetate derivative (Rao, K. V. and
Chattopadhyay, S. K., Tetrahedron, 43, 669 (1987) and Rao, K. V.
and Rao, N. S. P., J. Nat. Prod. 53(1), 212-215 (1990)). But to our
surprise, the treatment of 2,4,5-trimethoxyphenylprop- ane
(benzylic compound) with DDQ (1.0-1.3 moles) in the presence of
acetic acid, provides mixture of unexpected products namely
neolignan (32% yield), .alpha.-asarone (9% yield) and
1-(2,4,5-trimethoxy)phenyl-1-propa- none (22% yield) (Example II)
without formation of expected 1-phenyl-1-aceoxypropane derivative
(Subodh, K. J. Org. Chem. 50, 3070-3073 (1985) and Ward, R. S.
Tetrahedron Letters, 48 (15), 5029-5041 (1990)). The structure of
neolignan (3-ethyl-2-methyl-3-(2",4",5"-trimeth-
oxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene or
2,2',4,4',5-5'-hexamethoxy-7',8-neolig-7-ene), .alpha.-asarone and
1-(2,4,5-trimethoxy)phenyl-1-propanone (or isoacoramone) are
successfully confirmed on the basis of spectral data (Example II).
The formation of all the three products are postulated only when a
part of 2,4,5-trimethoxyphenylpropane (C.sub.6-C.sub.3) undergoes
dehydrogenation with DDQ towards formation of .alpha.-asarone while
little other part of 2,4,5-trimethoxyphenylpropane undergoes
oxidation with DDQ for isoacoramone formation. However, neolignan
formation is possible only if some part of initially formed
.alpha.-asarone undergoes rearrangements with unreacted
2,4,5-trimethoxyphenylpropane and DDQ towards dimerisation.
Further, detailed mechanistic studies for above products are in
progress. It is worthwhile to mention that increase in the amount
of DDQ (1.4-2.1 moles) in acetic acid gave once again neolignan
(NEOLASA-I) and .alpha.-asarone but
1-(2,4,5-trimethoxyphenyl)-1-propanon- e in little higher yield
(39%) than above (22%) (Example II). Later on, like
.alpha.-asarone, isoacoramone (2,4,5-trimethoxypropiophenone) is
also realized as an interesting rare phenylpropanoid occurring in
well known medicinal plants 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. V. 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).
[0004] In conclusion, our invention discloses a simple and
economical process for preparing novel neolignans
(3-ethyl-2-methyl-3-(2",4",5"-trim-
ethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene of the
formula (II) and
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy-
)phenylpropane of the formula (III) along with .alpha.-asarone of
formula (IIa), and isoacaromone (2,4,5-trimethoxypropiophenone) of
formula (IIb), as side products thereof, starting from relatively
cheaper and economical material 2,4,5-trimethoxyphenylpropane
obtained via hydrogenation of .beta.-asarone rich Acorus calamus
oil as outlined in Scheme-I. Other objectives and advantages of the
present invention will be made apparent as the description
progresses. 2
OBJECTIVES OF THE INVENTION
[0005] The main object of the present invention is to prepare
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nylpropene, a neolignan, from 2,4,5-trimethoxyphenylpropane which
is, in fact, the hydrogenated product of toxic .beta.-asarone
isolated from commercially available Acorus calamus oil.
[0006] Another object of the present invention is to utilize toxic
.beta.-asarone rich calamus oil of tetraploid or hexaploid
varieties (distributed extensively in Asian countries), thereby,
enhancing the profitable use thereof.
[0007] Still another object of the invention is to study the
interaction of 2,4,5-trimethoxyphenylpropane by varying amount of
DDQ, time and temperature.
[0008] Yet another object of the invention is to develop easy
purification process to obtain high purity of neolignan and side
products.
[0009] Yet another object of the invention is to establish the
structure of side products which finally appeared to be a naturally
occurring rare phenylpropanoids namely .alpha.-asarone and
1-(2,4,5-trimethoxy)phenyl-1-- propanone.
[0010] Yet another object of the invention is to further establish
the position of the double bond existing in the above neolignan by
its reduction into corresponding dihydro neolignan i.e.
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nylpropane.
SUMMARY OF THE INVENTION
[0011] The present invention provides a process for the preparation
of neolignan utilizing a mild and efficient reagent
2,3-dichloro-5,6-dicyano- -1,4-benzoquinone (DDQ) and
2,4,5-trimethoxyphenylpropane which is, in fact, the hydrogenated
product of toxic .beta.-asarone isolated from commercially
available calamus oil. It is worthwhile to mention that the above
process not only led to novel neolignan
(3-ethyl-2-methyl-3-(2",4",-
5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene)
(named as NEOLASA-I) but also provided two more products which
later on were characterized as biologically active, rare, naturally
occurring phenylpropanoids namely .alpha.-asarone and
1-(2,4,5-trimethoxyphenyl)-1-- propanone (isoacoramone). Further,
the structure of neolignan (NEOLASA-I) was established by its
catalytic hydrogenation into corresponding dihydro neolignan
(3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-tri-
methoxy)phenylpropane) (named as NEOLASA-II). As per literature
survey, neolignans are found to be interesting dimeric product of
phenylpropanoids having a wide range of activities such as
antioxidant, anti-cancer and anti-HIV but are present only in
traces in the plant kingdom. Keeping in view its wide scope,
several partial and total synthesis of neolignans have been
developed but most of the methods require expensive starting
materials and reagents and also proceed in multisteps with overall
poor yield. Therefore, our finding and disclosure of neolignan
formation during DDQ assisted oxidation of
2,4,5-trimethoxyphenylpropane in one step process, is a cheaper and
economical method than so far reported methods, as well as, our
invention is capable of forming a series of biologically active
neolignan derivatives.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0012] FIG. 1 is .sup.1H NMR (300 MHz) spectra of
3-ethyl-2-methyl-3-(2",4-
",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene (in
CDCl.sub.3) of the reaction product of Example II
[0013] FIG. 2 is .sup.13C NMR (75.4 MHz) spectra of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-propene (in CDCl.sub.3) of the reaction product of Example
II
[0014] FIG. 3 is DEPT-135.sup.0 spectra of
3-ethyl-2-methyl-3-(2",4",5"-tr-
imethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene (in
CDCl.sub.3) of the reaction product of Example II
[0015] FIG. 4 is the electro spray (ES) mass spectrum of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-propene (MW 416) of the reaction product of Example II
[0016] FIG. 5 is .sup.1H NMR (300 MHz) spectra of .alpha.-asarone
(in CDCl.sub.3) of the reaction product of Example II
[0017] FIG. 6 is .sup.13C NMR (75.4 MHz) spectra of .alpha.-asarone
(in CDCl.sub.3) of the reaction product of Example II
[0018] FIG. 7 is .sup.1H NMR (300 MHz) spectra of
1-(2,4,5-trimethoxy)phen- yl-1-propanone (in CDCl.sub.3) of the
reaction product of Example II
[0019] FIG. 8 is .sup.13C NMR (75.4 MHz) spectra of
1-(2,4,5-trimethoxy)phenyl-1-propanone (in CDCl.sub.3) of the
reaction product of Example II
[0020] FIG. 9 is the electro spray (ES) mass spectrum of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-propene (MW 418) of the reaction product of Example III
DETAILED DESCRIPTION OF THE INVENTION
[0021] Accordingly, the present invention provides "DDQ mediated
one step dimerisation of dihydro product of toxic .beta.-asarone
rich Acorus calamus oil in the formation of novel neolignan:
3-ethyl-2-methyl-3-(2",4-
",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene"
wherein the said process comprises hydrogenation of toxic
.beta.-asarone or calamus oil containing mixture of .alpha.,.beta.-
and .gamma.-asarone to obtain 2,4,5-trimethoxyphenylpropane of
formula I followed by reacting the above said compound with DDQ at
a temperature in the range of 5-120.degree. C. for a period ranging
from 30 minutes to 72 hours using acetic acid as solvent to obtain
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)-
phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene and side products
thereof.
[0022] In an embodiment of the present invention, a simple process
is available to prepare neolignan from
2,4,5-trimethoxyphenylpropane, which is, in fact, the hydrogenated
product of toxic .beta.-asarone isolated from commercially
available calamus oil.
[0023] In another embodiment of the present invention, a simple
process is available for the commercial utilization of
internationally banned but widely available toxic .beta.-asarone
from Acorus calamus oil of tetraploid or hexaploid varieties
(distributed extensively in Asian countries), thereby, enhancing
the profitable use thereof.
[0024] In still another embodiment of the present invention, a
simple process involves the conversion of mixture of all the three
isomeric forms of phenylpropene i.e. .alpha.,.beta. and
.gamma.-asarone firstly into 2,4,5-trimethoxyphenylpropane and then
utilizing it as a simple synthon for the preparation of
3-ethyl-2-methyl-1-(2',4',5'-trimethoxy)-p-
henyl)-3-(2",4",5"-trimethoxy)phenyl-1-propene and side products
.alpha.-asarone and 1-(2,4,5-trimethoxy)phenyl-1-propanone
thereof.
[0025] In yet another embodiment of the present invention, a simple
process which discloses the interaction of
2,4,5-trimethoxyphenylpropane with varying amount of DDQ and time,
temperature and solvents.
[0026] In yet another embodiment of the present invention, the
molar ratio of DDQ to 2,4,5-trimethoxyphenylpropane is in the range
of 2.1:1.0 to 1.0:1.0.
[0027] In yet another embodiment of the present invention, provides
an easy purification process to obtain neolignan and side products
in high purity.
[0028] In yet another embodiment of the present invention, provides
novel neolignan in sufficient quantity via simple and economical
route, which further provides the opportunity for the evaluation of
its wide range of biological activities known for structurally
similar neolignans.
[0029] In yet another embodiment of the present invention, provides
novel neolignan as a crystalline solid with melting point ranging
from 96.degree.-97 C.
[0030] In yet another embodiment of the present invention, provides
novel neolignan having one asymmetric center.
[0031] In yet another embodiment of the present invention provides
novel neolignan, this is capable of undergoing conversion into
several naturally occurring neolignan and lignan derivatives.
[0032] In yet another embodiment of the present invention, provides
novel dihydro neolignan i.e.
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(-
2',4',5'-trimethoxy)phenylpropane (NEOLASA-II) obtained by
catalytic hydrogenation of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',-
5'-trimethoxy)phenyl-1-propene (NEOLASA-I).
[0033] In yet another embodiment of the present invention, provides
a novel dihydro (NEOLASA II) which is capable of undergoing
conversion into several naturally occurring neolignan and lignan
derivatives.
[0034] In yet another embodiment of the present invention provides
a novel dihydro neolignan in sufficient quantity via simple and
economical route, thus, providing an opportunity for its biological
evaluation.
[0035] In yet another embodiment of the present invention provides
novel dihydro neolignan having two asymmetric centers.
[0036] Although the plant derived products have found widespread
applications in the field of essential oils, colours and dyes,
cosmetics, pharmaceuticals and in many others, not only because
they are easily available and are cheaper but also an important
reason has been the notion that they are safer than synthetic
products, which may not always be true. There are several
phytochemicals which beyond a certain limit, diminishes the market
potential of products such as phenylpropanoids rich essential oils
which get deteriorated specifically by few isomeric forms of
phenylpropenes (Miller, E. C.; Swanson, A. B.; Phillips, D. H.;
Fletcher, T. L.; Liem, A. and Miller, J. A., Cancer Research, 43
(3), 1124-1134 (1983); Kim; S. C.; Liem; A.; Stewart; B. C. and
Miller, J. A. Carcinogensis, 20 (7), 1303-1307 (1999) and Lazutka,
J. R.; Mierauskien{overscore (e)}, S. and Dedonyt{overscore (e)},
V. Food & Chemical Technology, 39, 485-492 (2001)). Generally,
trans-isomers (e.g. .alpha.-asarone and isoeugenol etc) are found
safer for human consumption while cis/allyl-isomers (e.g.
.beta.-asarone and saffrole) are found toxic and carcinogenic
(Harborne, J. B. and Baxter, H., Phytochemical Dictionary: A
Handbook of Bioactive Compounds from Plants, Taylor & Francis
Ltd., Washington D.C., 474 (1993)). As a result, the most affected
oil is Acorus calamus (family: Araceae) oil in which tetraploid and
hexaploid varieties (distributed extensively in Asian countries
like India, Japan, Pakistan and China) contain very high percentage
of cis-phenylpropene i.e. .beta.-asarone (varying from 70 to 90%)
while diploid and triploid varieties contain limited amount of
.beta.-asarone (3 to 8%) (Stahl, E. and Keller, K., Planta Medica
43, 128-140 (1981); Waltraud, G. and Schimmer, O., Mutation
Research 121, 191-194 (1983); Mazza, G., J. of Chromatography, 328,
179-206 (1985); Motley, T. J., Economic Botany, 48, 397-412
(1994)).
[0037] .beta.-asarone is experimentally proved to be carcinogenic
in animals and has also been found to induce tumors in the duodenal
region after oral administration. In addition, .beta.-asarone has
also shown chromosome damaging effect on human lymphocytes in-vitro
after metabolic activation (Taylor, J. M.; Jones, W. I.; Hogan, E.
C.; Gross, M. A.; David, D. A. and Cook, E. L., Toxicol. Appl.
Pharmacol., 10, 405 (1967); Keller, K.; Odenthal, K. P. and Leng,
P. E., Planta Medica 1, 6-9 (1985); Abel, G., Planta Medica, 53(3),
251-253 (1987) and Riaz, M.; Shadab, Q.; Chaudhary, F. M., Hamdard
Medicus, 38(2), 50-62 (1995)). As a result, the calamus oil of
Asian origin is internationally banned for any kind of use in
flavor, perfumery and pharmaceutical industries. To the best of our
knowledge, there is no report in which toxic .beta.-asarone of
calamus oil is utilized for its value addition except very recently
by our group (Sinha, A. K.; Dogra, R. and Joshi, B. P., Ind. J.
Chem., 41B, (2002) (in press); Sinha, A. K.; Joshi, B. P. and
Dogra, R., Nat. Prod. Lett., 15(6), 439-444 (2001); Sinha, A. K.;
Acharya, R. and Joshi, B. P., J. Nat. Prod. (2002) (in press),
Sinha, A. K.; Dogra, R. and Joshi, B. P., Sinha, A. K.; Joshi, B.
P., and Dogra, JP Patent No. 2001.68716 filed on Mar. 12, 2001;
Sinha, A. K.; Joshi, B. P., and Dogra, U.S. patent Ser. No.
09-805,832 filed on Mar. 14, 2001 and U.S. patent Ser. No.
09-823,123 filed on Mar. 31, 2001) wherein ammonium
formate/palladium-on-charcoal or H.sub.2/palladium-on-charcoal
assisted reduction of crude calamus oil containing high percentage
of toxic .beta.-asarone provides 2,4,5-trimethoxyphenylpropane
(dihydro asarone) of the formula I in 97% purity with yield ranging
from 81-87% based on asarones content in calamus oil. Thus,
obtained 2,4,5-trimethoxyphenylpropane (or
1-Propyl-2,4,5-trimethoxybenzene) is tested for the first time as
five times less toxic than .beta.-asarone and thus, this
2,4,5-trimethoxyphenylpropane enables its application in the
products such as mouthwashes, tooth pastes, antiseptic soap
products, chewing gum flavors and little in spicy products due to
its sweet, ylang, slightly spicy and fruity aroma. In addition,
2,4,5-trimethoxyphenylpropane is also discovered as a simple and an
economical starting material for synthesis of a salicylamide based
antipsychotic drug
(5,6-dimethoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide)
(Thomas, H.; Stefan, B.; Tomas, D. P.; Lars, J.; Peter, S.; Hakan,
H. and Orgen, S. O., J. Med. Chem., 33, 1155-1163 (1990) and Sinha,
A. K., U.S. patent Ser. No. 09-652,376 filed on Aug. 31, 2000). In
the present invention, we have extended the scope of further
exploitation of 2,4,5-trimethoxyphenylpropane of the formula I as
simple and economical starting material towards the formation of
novel neolignan
(3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)ph-
enyl-1-propene) (named as NEOLASA-I) of the formula II and its
dihydro derivative
(3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-tr-
imethoxy)phenylpropane) (named as NEONLASA-II) of the formula III
and side products .alpha.-asarone of the formula IIa and
1-2,4,5-trimethoxy)phenyl- -1-propanone (isoacoramone) of the
formula IIb thereof which are, in fact, biologically active rarer
phenylpropanoids.
[0038] Keeping in view, the toxicity problem of widely available
.beta.-asarone rich Acorus calamus oil, our initial attempt was to
utilize .beta.-asarone as a simple and cheaper starting material
for the synthesis of pharmacologically active .alpha.-asarone via
dihydro product of .beta.-asarone i.e.
2,4,5-trimethoxyphenylpropane. With this objective,
2,4,5-trimethoxyphenylpropane was treated with mercuric acetate or
DDQ in acetic acid to provide intermediate
1-(2,4,5-trimethoxy)phenyl-1-acetoxypropane followed by alkaline
hydrolysis and acidic dehydration towards formation of
.alpha.-asarone (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)). Treatment of benzylic
compounds such as 8,9,10,11-tetrahydrodibenz(a,h)ac- ridine and
stegane with mercuric acetate/acetic acid or DDQ/acetic acid is
well documented in literature towards formation of corresponding
acetate (Subodh, K., J. Org. Chem., 50, 3070-3073 (1985) and Ward,
R. S., Tetrahedron Letters, 48 (15), 5029-5041 (1990)). However,
2,4,5-trimethoxyphenylpropane (benzylicalkane) failed to produce
any kind of product with mercuric acetate/acetic acid under the
above analogue reaction condition. Interestingly,
2,4,5-trimethoxyphenylpropane/DDQ/AcOH also failed to produce
expected 1-(2,4,5-trimethoxy)phenyl-1-acetoxypropa- ne, but, it
provided a mixture of interesting products which were easily
purified on column chromatography and identified as .alpha.-asarone
of the formula IIa, 1-(2,4,5-trimethoxyphenyl)-1-propanone
(isoacoramone) of the formula IIb and novel neolignan of the
formula II as a crystalline solid having three different mp
44-45.degree. C., 109-110.degree. C. and 96-97.degree. C.
respectively. The structure of .alpha.-asarone (mp 44-45.degree.
C.) was assigned and identified on the basis of spectral data
(Example II). Similarly, structure of crystalline solid having mp
109-110.degree. C. was confirmed on the basis of spectral data in
which IR absorption band appeared at 1658 (conjugated C.dbd.O)
cm.sup.-1 and also gave a positive 2,4-DNP test, thus, confirming
the presence of carbonyl group. .sup.1H NMR showed the 16 number of
protons (Example II) which is less by two number of protons in
comparison to starting material 2,4,5-trimethoxyphenylpropane
(Example I) except for a triplet signal at .delta.1.18 (3H, t,
J=6.9 Hz) and quartet signal at 2.99 (2H, q, J=6.9 Hz) which could
be assigned to a methylene proton coupled with a methyl group
proton which is overall indicative of ethyl group. Further, the
position of two aromatic singlet protons and three singlet for nine
protons from trimethoxy groups are more or less at same .delta.
value as starting material, however, appearance of ethyl protons at
.delta.1.18 (2H, t), 2.99 (3H, q) and carbonyl group (1658
cm.sup.-1) finally supported the possibility of ethylketone
(--CO--CH.sub.2--CH.sub.3) attached to trimethoxy substituted
phenyl ring. Similarly, the .sup.13C NMR and DEPT spectral data
further supported the presence of ethyl group (.delta..sub.c8.4
CH.sub.3; .delta..sub.c36.9 CH.sub.2) and the ketonic carbonyl
(.delta..sub.c200.5) linked directly to the benzene ring (Example
III). The EI mass spectrum showed a clear [M].sup.+ peak at m/z 224
along with base peak at m/z 195 (M.sup.+-29) which was in agreement
with the presence of an ethyl moiety and this together with above
.sup.1H, .sup.13C and IR data, the crystalline solid (mp
109-110.degree. C.) was finally confirmed to be
1-(2,4,5-trimethoxyphenyl)-1-propanone (also known as isoacoramone)
which is later on discovered as a naturally occurring rarer
phenylpropanoid., isolated from Piper marginatum and Acorus
tatarinowii as a light yellowish viscous gum in traces, however,
our method afforded isoacoramone as a crystalline solid (mp
109-110.degree. C.) (Example II) with the similar spectral data as
natural isoacoramone (Jinfeng, Hu and Xiaozhang, Feng, Planta
Medica, 66, 662-664 (2000)). Thus, preparation of
2,4,5-trimethoxypropiophenone (isoacoramone) in sufficient quantity
has allowed to facilitate its more rigorous biological evaluation
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, L. I. B.; Ferri, P. H. and Santos, L. S., Anais Assoc. Bras.
Quim., 44(3), 22-27 (1995); 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). Additionally, 2,4,5-trimethoxypropiophenone
(isoacoramone) can be utilized as a simple synthon for the
preparation of diarylbutane type lignan as an analogue of
nordihydroguaiaretic acid (NDGA acid) which is prepared by
dimerization of 4,5-dimethoxypropiophenone (Perry, C. W. U.S. Pat.
No. 3,769,350 (1975)).
[0039] In order to establish the structure of third crystalline
solid having mp 96-97.degree. C., a comprehensive investigation of
NMR spectral data recorded in two solvents (CDCl.sub.3 and
DMSO-d.sub.6) for better clarity and separation of each peaks was
undertaken. The electrospray (ES)-mass spectrum of crystalline
solid gave molecular ion at m/e 418 (M.sup.+). The .sup.1H NMR
spectra of solid (mp 96-97.degree. C.) showed the presence of six
methoxyls indicating it to be a possible dimer of asarone like
phenylindane (a unsymmetrical dimer reported from Acorus calamus)
(Saxena, D. B. Phytochemistry 25 (2), 553-555 (1986)) but with
change in side chain structure. It is interesting to note from the
aromatic region integrated for the four protons indicating that
none of aromatic proton participates in dimerisation, however, one
of the aromatic proton of phenylindane
(2,3-dihydro-4,5,7-trimethoxy-1-ethyl-2-m-
ethyl-3-(2,4,5-trimethoxyphenyl)indene) has taken part in
dimerisation. The other groups found to be an ethyl group appeared
at .delta.0.93 (3H, t, H-5), 1.70-1.97 (2H, m, H-4), 3.59 (1H, t,
H-3), a tertiary methyl group 1.66 (3H, s, H-6) and a alkene proton
on a carbon atom attached to the phenyl ring 6.48 (1H, s, H-1). The
above skeleton is further supported by .sup.13C (DEPT-135.degree.)
spectra data and mass fragmentation pattern m/z: 418 (M.sup.+)
(Example II). On the basis of above spectral data and further, its
comparison with some known neolignans such as Magnoshinin,
Magnosalin and Heterotropan (Kikuchi, T.; Kadota, S.; Yanada, K.;
Tanaka, K.; Watanabe, K.; Yoshozaki, M.; Yokoi, T. and Shingu, T.,
Chem. Pharm. Bull. 31, 1112 (1983); Yamamura, S.; Niwa, M.;
Nonoyama, M. and Terada, Y. Tetrahedron Letters, 4891 (1978) and
Kadota, S.; Tsubono, K.; Makino, K.; Takeshita, M. and Kikuchi, T.,
Tetrahedron Letters, 28 (25), 2857-2860 (1987)) having some degree
of similarity in their structure (Wenkert, E.; Gottlieb, H. E.;
Gottlieb, O. R.; Pereira, M. O. D. S. and Formiga, M. D.,
Phytochemistry, 15, 1547-1551 (1976), the crystalline solid is
identified as neolignan i.e.
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-propene) (named as NEOLASA-I) (Example II). Further,
neolignan (NEOLASA-I) is hydrogenated (Example III) to obtain its
corresponding dihydro product i.e.
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2'-
,4',5'-trimethoxy)phenylpropane (named as NEONLASA-II) so as to
confirm the structure as well as to determine the position of
double bond existing in the above parent neolignan (NEOLASA-I)
which may additionally serve as a simple synthon towards
preparation of neolignans derivatives in sufficient quantity to
have opportunity for a wide range of biological activities
including antifungal, antioxidant, anti-inflammatory, neuroleptic,
anti-hepatotoxic, anticancer, anti-HIV and anti-PAF activities
known for structurally similar neolignan derivatives. Neolignans
and lignans comprise a class of natural plant products and they are
found in the roots, stems, bark, fruit and seeds of many plant
species. More than 200 compounds in this general class have been
identified and a great diversity in the chemical assembly of the
two characteristic phenylpropanoid units, as well as degree of
oxidation and types of substituents is apparent. In addition, some
natural lignans/neolignans are used as starting materials for the
semi-synthesis of biological active compounds such as
podophyllotoxin, isolated from Podophyllum species, is used for the
semi-synthesis of the anticancer compounds etoposide and teniposide
(Sthelin, H. F. and Wartburg, A. V., Cancer Research, 51, 5-15
(1991)). A number of chemical reviews on natural as well as
synthetic neolignans and lignans are available including their
biological activities. However, neolignas/lignans are found in
traces in plant kingdom and for these reasons, several methods of
preparation of neolignas/lignans have been developed by several
chemists and some of the reported conventional methods include the
following:
[0040] Typical prior art refrences include Iguchi, M., Nishiyama,
A., Terada, Y. and Yamamura, S., Tetrahedron, 51, 4511-4514 (1977);
McKillop, A.; Turrell, A. G. and Taylor, E. C., J. Org. Chem., 765
(1977); Minato, A.; Tamao, K.; Suzuki, K. and Kumada, M.,
Tetrahedron Letters, 21, 4017-4020 (1980); Cambie, R. C.; Clark, G.
R.; Craw, P. A.; Rutledge, P. S. and Woodgate, P. D., Aust. J.
Chem., 1775 (1984); Kadota, S., Tsubono, K., Makino, K., Takeshita,
M and Kikuchi, T., Tetrahedron Letters, 28 (25), 2857-2860 (1987);
Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V. and Robin, J. P.,
Tetrahedron, 50(4), 1153-1164 (1994); Meyers, M. J.; Sun, J.;
Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S. and
Katzenellenbogen, J. A., J. Med. Chem., 44, 4230-4251 (2001):
Gezginci, M. H. and Timmermann, B. N., Tetrahedron Letters, 42,
6083-6085 (2001); Robin, J. P. and Yannick, L., Tetrahedron, 48
(5), 819-830 (1992) and U.S. Pat. Nos. 3,769,350; 4,873,349 and
6,136,992.
[0041] All the above methods including patents have various
limitations and none of them have been found suitable for the
economical production of neolignan derivative. In seeking a simple
synthesis of neolignan derivatives from a cheaper material and
reagents, 2,4,5-trimethoxyphenylp- ropane (isolated from
hydrogenation of commercially available Acorus calamus oil rich in
asarones content) appears as a simple and economical starting
material in which 2,4,5-trimethoxyphenylpropane undergoes
dehydrogenation, oxidation and demerisation to afford
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nyl-1-propene (NEOLASA-I) as well as rarer phenylpropanoids namely
.alpha.-asarone and isoacoramone. In the present invention, the
formation of neolignan (NEOLASA-I) and its dihydro product
(NEOLASA-II) are the first example of DDQ assisted one step
synthesis of dimer from phenylpropane derivatives which, in fact,
would offer the advantages of simplicity and directness and can be
applied for large scale preparations.
EXAMPLES
[0042] 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
[0043] Preparation 2,4,5-trimethoxyphenylpropane (dihydro asarone):
The starting material 2,4,5-trimethoxyphenylpropane is prepared by
hydrogenation of either .beta.-asarone (isolated from Acorus
calamus oil) or commercially available calamus oil rich in asarones
(i.e. .beta. and/or .alpha.,.gamma.-asarone) content.
[0044] (a) Hydrogenation of .beta.-asarone into
2,4,5-trimethoxyphenylprop- ane (dihydro asarone): .beta.-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. Subsequent elution with
hexane-ethylacetate mixture with increasing proportion of
ethylacetate upto 10% gave 13.94 g (82%, w/w) of pure liquid;
R.sub.f 0.63 (hexane:toluene: ethylacetate=1:1:0.1); .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.6.84 (1H, s, H-6), 6.53 (1H, s, H-3),
6.50 (1H, dd, J=15.8 Hz and 1.5 Hz, H-1'), 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.sub.3)
and 1.85 (3H, dd, J=6.5 Hz and 1.5 Hz, H-3'); .sup.13C NMR
(CDCl.sub.3, 75.4 MHz) .delta.151.4 (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.times.OCH.sub.3) and 14.5 (C-3');
EIMS m/z 208 (M.sup.+, 100), 193 (M.sup.+-Me, 46), 165
(M.sup.+-C.sub.3H.sub.7- , 24). On the basis of above spectral data
and comparing with reported literature (Gonzalez, M. C.;
Sentandrew, M. A.; Rao, K. S.; Zafra, M. C. and Cortes, D.,
Phytochemistry 43,1361-1364 (1996)), the liquid was identified as
.beta.-asarone in 94% purity (by GC, performed on a Shimadzu-GC-14B
gas chromatograph with the following conditions: SE-30 column; 30
m.times.0.25 mm; injector 250.degree./C.; FID detector
230.degree./c; temp. programme 40 (hold for 2 min.) to 220.degree.
C. (hold for 10 min.), 10.degree. c min.sup.-1; vol. 1 .mu.l;
N.sub.2 flow 30 ml/min; H.sub.2 flow 40 ml/min.; airflow 300
ml/min.; split injection ratio 1:30)
[0045] The .beta.-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.sub.2SO.sub.4) and filtered. Evaporation of
filtrate left a liquid, which was chromatographed, on silica gel
using hexane-ethyl acetate mixture with increasing proportion of
ethyl acetate upto 10% as the eluent. The eluate was evaporated to
give 5.87 g (97%) of a clear sweet and pleasant liquid; R.sub.f
0.69 on silica gel plate (hexane:toluene:ethylacetate=1:1:0.1)
which solidified below 0.degree. C.; .sup.1H NMR (DMSO-d6)
.delta.6.72 (1H, s, H-6), 6.62 (1H, s, H-3), 3.76 to 3.68 (9H, s,
3-OCH.sub.3), 2.5 (2H, t, C-1'), 1.6 (2H, m, C-2') and 0.9 (3H, t,
C-3'); .sup.13C NMR (CDCl.sub.3) .delta.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.times.OCH.sub.3), 31.6 (C-1'), 23.3 (C-2') and 13.79
(C-3'); EIMS m/z 210 (M.sup.+, 39), 181(M.sup.+-C.sub.2H.sub.5,
100), 167 (M.sup.+-C.sub.3H.sub.7, 5), 151 (M.sup.+-OCH.sub.3+CO,
29), 136 (M.sup.+-C.sub.3H.sub.7+OCH.sub.3, 10). On the basis of
.sup.1H NMR, .sup.13C NMR and Mass spectral data, the above liquid
was identified as 2,4,5-trimethoxyphenylpropane in 99% purity (by
GC).
[0046] (b) Hydrogenation of crude Acorus calamus oil into dihydro
asarone: In this method 42.00 g of crude calamus oil (rich in
.beta. and/or .alpha.,.gamma.-asarone) in 300 ml methanol was
hydrogenated in the parr reactor with 10% Pd/C (4.80 g) at 10-40
psi at room temperature till the disappearance of starting
material. The catalyst was filtered and the solvent was removed
under reduced pressure, which afforded 39.9 g (95 w/w) of reduced
oil. Column purification of reduced oil on silica gel column using
above eluent system (hexane-ethyl acetate mixture) gave
2,4,5-trimethoxyphenylpropane (35.76 g) as a liquid in 85% yield
(w/w); R.sub.f 0.69 (hexane:toluene:ethylacetate=1:1:0.1); .sup.1H
NMR (CDCl.sub.3) of liquid appeared at .delta.6.81 (1H, s, H-6),
6.32 (1H, s, H-3), 3.84 to 3.78 (9H, s, 3-OCH.sub.3), 2.4 (2H, t,
C-1'), 1.6 (2H, m, C-2'), 0.9 (3H, t, C-3'). On the basis of
spectral data, the liquid was identified as
2,4,5-trimethoxyphenylpropane.
Example II
[0047] Preparation of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2'-
,4',5'-trimethoxy)phenyl-1-propene: DDQ (6.13-7.97 g) was added
over a period of 10-15 min to a ice cold and well stirred solution
of 2,4,5-trimethoxyphenylpropane (5.67 g, 0.027 mol) in acetic acid
(55 mL) and stirring was continued at room temperature for over
night. The precipitated solid of DDQH.sub.2 was filtered and the
filter cake washed twice with acetic acid. The combined acetic acid
layer was evaporated and mixture was poured into water and
extracted with dichloromethane (3.times.70 mL). The combined
organic layer were washed with brine (3.times.15 mL), 10% sodium
bicarbonate (2.times.10 mL), brine (3.times.15 mL) and dried over
sodium sulphate. The residue obtained on evaporation of the
solvents was chromatographed on silica gel using hexane-ethyl
acetate mixture with increasing proportion of ethyl acetate upto
40% and the fractions having similar R.sub.f were mixed which after
evaporation of solvents provided three viscous liquids which were
further crystallized from mixture of hexane and methanol to afford
three white solids having mp 44-45.degree. C., 109-110.degree. C.
and 96-97.degree. C. with 9%, 22% and 32% yield respectively.
[0048] White solid having mp 44-45.degree. C. was identified as
.alpha.-asarone (9%); R.sub.f 0.63
(hexane:toluene:ethylacetate::1:1:0.1)- ; .sup.1H NMR (CDCl.sub.3):
.delta.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.sub.3), 1.87 (3H, dd, J=6.2 Hz
and 1.5 Hz, H-3.sup.1); .sup.13H NMR (CDCl.sub.3): .delta.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.sub.3), 18.7 (C-3'); EIMS m/z 208 (M.sup.+, 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 above spectral data and comparing
with reported literature (Patra, A. and Mitra, A. K., J. Nat. Prod.
44, 668-669 (1981) and Gonzalez, M. C.; Sentandrew, M. A.; Rao, K.
S.; Zafra, M. C. and Cortes, D., Phytochemistry 43:1361-1364
(1996)), the structure of white solid (mp 44-45.degree. C.) was
finally confirmed as .alpha.-asarone.
[0049] Another white solid (22%) having mp 109-110.degree. C. was
identified as 1-(2,4,5-trimethoxy)phenyl-1-propanone; R.sub.f 0.78
(28% ethylacetate in hexane); .sup.1H NMR (CDCl.sub.3) at
.delta.7.45 (1H, s, H-6), 6.77 (1H, s, H-3), 3.96, 3.93 and 3.89
(each 3H, s, three-OCH.sub.3), 2.99 (2H, q, J=6.9 Hz, H-2'), 1.18
(3H, J=6.9 Hz, H-3'); .sup.13C NMR (CDCl.sub.3, 75.4 MHz)
.delta.200.5 (C-1'), 155.0 (C-2), 153.4 (C-4), 142.8 (C-5), 118.9
(C-1), 112.6 (C-6), 96.3 (C-3), 56.1 (4-OCH.sub.3 and 5-OCH.sub.3),
55.9 (2-OCH.sub.3), 36.9 (C-2'), 8.4 (C-3'); EIMS m/z 224 [M].sup.+
(16), 195 (100), 179 (14), 171 (10), 151 (7), 69 (15); IR (KBr)
1658 cm-1 (C.dbd.O). On the basis of above spectral data and
comparing with reported literature ((Jinfeng, Hu and Xiaozhang,
Feng, Planta Medica, 66, 662-664 (2000)), the structure of another
white solid (mp 109-110.degree. C.) was confirmed as
1-(2,4,5-trimethoxy)phenyl-1-propanone (or isoacoramone).
[0050] Third white solid (32%) having mp 96-97.degree. C. was
identified as
(3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy-
)phenyl-1-propene); R.sub.f 0.45 (20% ethylacetate in hexane);
.sup.1H NMR (CDCl.sub.3) .delta.6.91 (1H, s, H-6'), 6.84 (1H, s,
H-6"), 6.55 (1H, s, H-3'), 6.51(1H, s, H-3"), 6.48 (1H, s, H-1),
3.96 (6H,s, 2'-OCH.sub.3 and 2"-OCH.sub.3), 3.84 (6H, s,
4'-OCH.sub.3 and 4"-OCH.sub.3), 3.80 (3H, s, 5'-OCH.sub.3), 3.78
(3H, s, 5"-OCH.sub.3), 3.59 (1H, t, H-3), 1.70-1.97 (2H, m, H-4),
1.66 (3H, s, H-6), 0.93 (3H, t, H-5); .sup.1H NMR ((DMSO-d.sub.6)
.delta.6.79 (1H, s, H-6'), 6.68 (1H, s, H-6"), 6.67 (1H, s, H-3'),
6.66(1H, s, H-3"), 6.34 (1H, s, H-1), 3.84 (9H,s, 2"-OCH.sub.3,
4"-OCH.sub.3 and 5"-OCH.sub.3), 3.68(3H, s, 2'-OCH.sub.3), 3.66
(3H, s, 4'-OCH.sub.3), 3.62 (3H, s, 5'-OCH.sub.3), 3.53 (1H, t,
H-3), 1.88-1.67 (2H, m, H-4), 1.60 (3H, s, H-6), 0.84 (3H, t, H-5);
.sup.13C NMR (CDCl.sub.3) .delta.152.48 (C-2'), 152.02 (C-2"),
148.48 (C-4'), 147.94 (C4"), 143.57 (C-5'), 142.89 (C-5"), 140.41
(C-2), 124.88 (C-1'), 120.18 (C-1), 119.65 (C-1"), 114.88 (C-6'),
112.14 (C-6"), 99.47 (C-3'), 99.37 (C-3"), 57.37 (5"-OCH.sub.3),
57.09 (5'-OCH.sub.3), 57.07 (4"-OCH.sub.3), 56.94 (4'-OCH.sub.3),
56.55 (2"-OCH.sub.3), 56.48 (2'-OCH.sub.3), 47.38 (C-3), 26.74
(C-4), 17.82 (C-6), 12.84 (C-5); .sup.13C NMR (DMSO-d.sub.6)
.delta.152.56 (C-2'), 152.11 (C-2"), 149.07 (C-4'), 148.53 (C-4"),
143.53 (C-5'), 142.84 (C-5"), 139.45 (C-2), 123.96 (C-1'), 120.56
(C-1), 119.09 (C-1"), 115.47 (C-6'), 113.02 (C-6"), 99.55 (C-3'),
99.23 (C-3"), 57.39 (5"-OCH.sub.3), 57.24 (5'-OCH.sub.3), 57.17
(4"-OCH.sub.3), 57.08 (4'-OCH.sub.3), 56.63 (2"-OCH.sub.3), 56.59
(2'-OCH.sub.3), 47.56 (C-3), 26.46 (C-4), 17.71 (C-6), 13.33 (C-5);
NMR (DEPT-135.sup.0) .delta.120.56 (C-1), 115.47 (C-6'), 113.02
(C-6"), 99.55 (C-3'), 99.23 (C-3"), 57.39 (5"-OCH.sub.3), 57.24
(5'-OCH.sub.3), 57.17 (4"-OCH.sub.3), 57.08 (4'-OCH.sub.3), 56.63
(2"-OCH.sub.3), 56.59 (2'-OCH.sub.3), 47.56 (C-3, down), 26.46
(C-4), 17.71 (C-6), 13.33 (C-5); EIMS m/z 416 [M].sup.+ (14), 219
(100), 209 (47), 181(21), 171 (20), 71 (27).
[0051] Addition of a large excess of DDQ (8.58-12.87 g) in above
said process using 5.67 g, of 2,4,5-trimethoxyphenylpropane in
acetic acid (55 mL), improved the yield of
1-(2,4,5-trimethoxy)phenyl-1-propanone upto 39%, however, reduction
in the yield of 3-ethyl-2-methyl-3-(2",4",5"-trim-
ethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene (16%)
.alpha.-asarone (10%) was observed.
Example III
[0052] Preparation of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2'-
,4',5'-trimethoxy)phenylpropane: 0.20 mg of 5% Pd/C was added to a
solution of
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-tr-
imethoxy)phenyl-1-propene (0.35 g, 0.84 mmole) in ethyl acetate (40
mL) and methanol (25 mL) and was shaken under atmosphere of
hydrogen in paar reactor (5-20 psi) at room temperature till the
disappearance of starting material. The catalyst was filtered and
the solvent was removed under reduced pressure, which afforded a
liquid. The liquid was purified on silica gel using above eluent
system (hexane-ethyl acetate mixture) gave
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nylpropane (0.32 g) as a liquid in 91% yield; R.sub.f 0.47 (20%
ethylacetate in hexane); .sup.1H NMR (CDCl.sub.3) .delta.6.77 (1H,
s, H-3"), 6.68 (1H, d, H-6"), 6.54 (1H, d, H-6'), 6.51(1H, s,
H-3'), 3.96 (6H,s, 2'-OCH.sub.3 and 2"-OCH.sub.3), 3.84 (6H, s,
4'-OCH.sub.3 and 4"-OCH.sub.3), 3.80 (3H, s, 5'-OCH.sub.3), 3.78
(3H, s, 5"-OCH.sub.3), 2.60 (2H, d, H-1), 2.08 (1H, t, H-3), 1.95
(1H, m, H-2), 1.92-1.57 (2H, m, H-4), 0.88 (3H, d, H-6), 0.82(3H,
t, H-5); EIMS m/z 418 [M].sup.+ (14), 209 (100), 179 (14), 181
(29), 151 (9), 69 (6).
[0053] The Main Advantages of the Present Invention Are:
[0054] 1. The process to prepare
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)p-
henyl-1-(2',4',5'-trimethoxy)phenyl-1-propene, a novel neolignan,
along with side products in single step from
2,4,5-trimethoxyphenylpropane using DDQ as a mild and efficient
reagent for the first time.
[0055] 2. The process for the commercial utilization of
internationally banned but widely available toxic .beta.-asarone
from Acorus calamus oil of tetraploid or hexaploid varieties
(distributed extensively in Asian countries), thereby, enhancing
the profitable use thereof.
[0056] 3. The simple process which discloses the formation of new
kind of products by the interaction of
2,4,5-trimethoxyphenylpropane with varying amount of DDQ and time,
temperature and solvents.
[0057] 4. The simple process which involves the conversion of
mixture of all the three isomeric forms of phenylpropene i.e.
.alpha.,.beta. and .gamma.-asarone firstly into
2,4,5-trimethoxyphenylpropane and then utilizing it as a simple
synthon for the preparation of
3-ethyl-2-methyl-1-(2',4',5'-trimethoxy)-phenyl)-3-(2",4",5"-trimethoxy)p-
henyl-1-propene and side products .alpha.-asarone and
1-(2,4,5-trimethoxy)phenyl-1-propanone thereof.
[0058] 5. The process provides neolignan and side products
.alpha.-asarone and 1-(2,4,5-trimethoxy)phenyl-1-propanone in high
purity.
[0059] 6. The process provides 2,4,5-trimethoxypropiophenone as a
solid compound whereas, natural 2,4,5-trimethoxypropiophenone
(isolated from Acorus tatarinowii and Piper marginatum) is reported
as viscous gum.
[0060] 7. The process provides
1-(2,4,5-trimethoxy)phenyl-1-propanone in sufficient quantity and
thus provides the opportunity for the evaluation of its wide range
of biological activities known for structurally similar
phenylpropanone derivatives.
[0061] 8. The process provides novel neolignan in sufficient
quantity and thus provides the opportunity for the evaluation of
its wide range of biological activities known for structurally
similar neolignans.
[0062] 9. The process provides novel neolignan as a crystalline
solid with m.p. ranging from 96.degree.-97 C.
[0063] 10. The process provides novel neolignan (NEOLASA-I) having
one asymmetric center and one double bond in aliphatic side chain
which is further capable of undergoing conversion into several
naturally occurring neolignan and lignan derivatives.
[0064] 11. The process provides novel dihydro neolignan i.e.
3-ethyl-2-methyl-3-(2",4",5"-trimethoxy)phenyl-1-(2',4',5'-trimethoxy)phe-
nylpropane (NEOLASA-II) by hydrogenation of
3-ethyl-2-methyl-3-(2",4",5"-t-
rimethoxy)phenyl-1-(2',4',5'-trimethoxy)phenyl-1-propene
(NEOLASA-I).
[0065] 12. The process provides a novel dihydro neolignan in
sufficient quantity via simple and economical route, thus,
providing an opportunity for its biological evaluation.
[0066] 13. The process provides a novel dihydro (NEOLASA II) which
is capable of undergoing conversion into several naturally
occurring neolignan and lignan derivatives.
* * * * *