Title of Invention

A MICROWAVE INDUCED PROCESS FOR THE PREPARATION OF SUBSTITUTED 4-VINYLPHENOLS

Abstract The present invention relates to "a microwave induced process for the preparation oi 4-vinylphenols or its derivatives" in which commercially important FEMA GRAS approved perfumery and flavouring vinylphenols (i.e. hydroxystyrenes) namely 4 vinylguaiacol (FEMA GRAS No. 2675) and 4-vinylphenol (FEMA GRAS No. 37391 as well as other useful vinylphenols such as 2,6-dimethoxy-4-vinylphenol. 2-hydroxyd 4-vinylphenol, 3-hydroxy-4-vinylphenol etc. by condensation of malonic acid and 4-hydroxyphenylaldehydes or its derivatives.
Full Text A MICROWAVE INDUCED PROCESS FOR THE PREPARATION OF
SUBSTITUTED 4-VINYLPHENOLS
Technical Field
The present invention relates to "A microwave induced process for the preparation of
substituted 4-vinylphenols' in which commercially important FEMA GRAS approved
perfumery and flavouring vinylphenols (i.e. hydroxystyrenes) namely 4-vinylguaiacol
(FEMA GRAS No. 2675) and 4-vinylphenol (FEMA GRAS No. 3739) as well as
other useful vinylphenols such as 2,6-dimethoxy-4-vinylphenol, 2-hydroxy-4-
vinylphenol, 3-hydroxy-4-vinylphenol etc. are obtained in a one pot during
condensation of malonic acid and corresponding substituted 4-hydroxy
phenylaldehydes (4-hydroxy benzaldehydes) under microwave irradiation.
In the present invention, the formation of substituted vinylphenols is the first example
from 4-hydroxy phenylaldehydes in one step under microwave irradiation otherwise
literature till today reveals the formation of vinylphenols only by decarboxylation of
cinnamic acid either by microorganisms or conventional methods.
Background Art
Aroma compounds of natural origin are of major interest to flavour and fragrance
industries, however, nature alone cannot meet the ever-increasing world demand on its
own due to limited percentage of such compounds in plant kingdom. Therefore, there
is a growing interest in developing alternative sources for natural aroma compounds
and in particular, substituted 4-vinylphenols such as 4-vinylguaiacol (p-vinylguaiacol
or 2-methoxy-4-vinylphenol or 4-hydroxy-3-methoxystyrene or 4-ethenyl-2-
methoxyphenol), 4-hydroxystyrene (p-vinylphenol or 4-ethenylphenol), 3,5-
dimethoxy-4-hydroxy styrene and others have been the most extensively investigated
ones due to their widespread applications in food and alcoholic beverages, flavouring
substances and as intermediates in the preparation of polymers and copolymers useful
in coatings, electronic applications, ion exchange resins and photo resists etc.
(Perfume and Flavor Chemicals, Aroma Chemicals, ed. Steffen, A., Allured
Publishing Corporation, Vol I-IV (1994) and Encyclopedia of Food and Color
Additives, ed. George, A.B., CRC Press, Inc., Vol I-II (1996)). The preparation of
these substituted 4-vinylphenols such as 4-vinylguaiacol (FEMA GRAS No. 2675), 4-
vinylphenol (FEMA GRAS No. 3739) and others are well known in the art,
however, a more efficient process for preparing substituted 4-vinylphenols is
desired and needed. The present invention provides a process wherein microwave
assisted (Bose, A.K., Banik, B.K., Lavlinskaia, N., Jayaraman, M. and Manhas, M.S.,
Chemtech, 27, 18-24, (1997) and Larhed, M. and Hallberg, Drug Discovery Today,
6(8), 406-416, (2001)) condensation of substituted 4-hydroxy phenylaldehydes and
malonic acid in the presence of organic base and organic acid provides only
substituted 4-vinylphenols in one pot within 20 minutes and not cinnamic acid as
generally obtained in conventional Knoevenagel-Doebner condensation reaction
(Furniss, B.S., Hannaford, A.J., Rogers, V., Smith, P.W.G. and Tatchell, A.R: In:
Vogel's Textbook of Practical Organic Chemistry, fourth Edn., ELBS, UK, 802
(1978); Susanne, R.H., Kerry, C.A., Dae, D.M., Ducan, J.N., Christopher, H.L.,
Rita, H.M., Mary, L. E., Nanette, N. F., Martin, S.W., Kjell, S. A., Matt, Z. J.,
Arvid, C. and Chiu-Hong, L., J. Med. Chem., 44, 4716-4732 (2001) and James, M.,
Jennifer, A. S. and Sonja, W., Tetrahedron Letters, 39, 8013-8016 (1998)). It is
worthwhile to mention that microwave-assisted chemical transformation is a new
emerging technique which is generally known for ecofriendly, rapid and high yielding
process, however, such a surprising effect of microwave is observed for the first time
in the above invention where both condensation and decarboxylation have occurred
simultaneously without addition of decarboxylating agent.
The following prior art references are disclosed as below:
U.S. Patent No. 6,468,566 discloses a method for the preparation of 4-vinylguaiacol
from ferulic acid decarboxylase enzyme.
U.S. patent No.6, 235,507 disclose a method for the preparation of 4-vinylguaiacol
from microbial conversion of ferulic acid at a pH more than 9.
U.S. patent No.5,493,062 disclose a method for the preparation of 4-vinylphenol from
p-alpha-aminoethylphenol (AEP) at high temperature.
U.S. patent No. 5,087,772 discloses a method for the preparation of 4-vinylphenol
from 4-acetoxystyrene with a suitable alcohol in the presence of a suitable base.
U.S. patent No. 5,256,809 discloses a method for the preparation of 4-vinylphenol
from 4-acetoxystyrene.
Journal of Biotechnology, (2000), 80, 195-202, discloses a method for the preparation
of 4-vinylguaiacol from decarboxylation of ferulic acid by Bacillus coagulans.
Enzyme and Microbial Technology, (1998), 23, 261-266, discloses a method for the
preparation of 4-vinylguaiacol from decarboxylation of ferulic acid by Bacillus
pumilus.
Archives of Biochemistry and Biophysics, (1998), 359(2), 225-230, discloses a
method for the preparation of 4-vinylphenol from decarboxylation of
hydroxycinnamic acid by Klebsiella oxytoca.
J. Fermentation and Bioengineering, (1996), 82(1), 46-50, discloses a method for the
isolation of 4-vinylguaiacol from distilled and stored model solutions of "shochu" (a
name of alcoholic beverage in Japan).
Encyclopedia of Food and Color Additives, ed. George, A.B., CRC Press, Inc., Vol II,
1705 (1996) discloses a method for the preparation of styrene by reaction of
phenylaldehydes with acetic anhydride in the presence of sodium acetate to give
cinnamic acid followed by decarboxylation of cinnamic acid.
Perfume and Flavor Chemicals (Aroma Chemicals), ed. Steffen, A., Allured"
Publishing Corporation, Vol II, 1891 (1994) discloses a method for the preparation of
vinylphenol (4-hydroxy-3-methoxystyrene) by catalytic oxidation of 1,1-
diphenylethane (1,1 -di-(4-hydroxy-3-methoxy)phenyiethane).
Journal of Biol. Chem., (1993), 268, 23954-23958, discloses a method for the
preparation of 4-vinylguaiacol from decarboxylation of ferulic acid by Rhodotorula
rubra.
Appl. Environ. Microbial., (1993), 59, 2244-2250, discloses a method for the
preparation of 4-vinylguaiacol from decarboxylation of ferulic acid by
Saccharomyces cerevisiae and Pseudomonasfluorescens.
Journal of Biol. Chem., (1962), 237, 2926-2931, discloses a method for the
preparation of 4-vinylphenol from decarboxylation of 4-hydroxy-cinnamic acid by
Aerobacter.
Journal of Biol. Chem., (1961), 236, 2302, discloses a method for the decarboxylation
of trans-cinnamic acids into styrene derivatives by using pyruvate decarboxylase
enzyme.
Journal of Biol. Chem., (1957), 227, 151, discloses a method for the decarboxylation
of trans-cinnamic acids into styrene derivatives by using oxalate decarboxylase
1
enzyme.
Journal of Biol. Chem., (1960), 235, 1649, discloses a method for the decarboxylation
of trans-cinnamic acids into styrene derivatives by using glutamate decarboxylase
enzyme.
Journal of Biol. Chem., (1957), 226, 703, discloses a method for the decarboxylation
of trans-cinnamic acids into styrene derivatives by using aconitate decarboxylase
enzyme.
Journal of Biol. Chem., (1964), 239, 879, discloses a method for the decarboxylation
of trans-cinnamic acids into styrene derivatives by using aspartate 4-decarboxylase
enzyme.
Tetrahedron Letters, (1999), 40, 6595-6598, discloses a method for the
decarboxylation of trans-cinnamic acids into styrene derivatives by using plant cell
cultures.
Journal of Biol. Chem., (1962), 237, 2926-2931, discloses a method for the
decarboxylation of trans-4-hydroxycinnamic acid into 4-hydroxystyrene.
Applied Catalyst A: General, (1995), 133, 219-239, discloses a method for the
preparation of styrene from dehydrogenation of ethylbenzene.
Organic Synthesis Collective Volume I, 441-442 (1941) as well as Volume TV, 731-
734 (1963), discloses a method for the preparation of styrenes by decarboxylation of
cinnamic acids with quinoline in the presence of copper powder at 200-300°C
Some of other typical prior art refrences include U.S. Pat. Nos. 4,316,995; 4,868,256;
4,868,257; 4,933,495; 5,072,025; 5,128,253; 5,247,124; 5,344,963; 5,563,289;
6,111,133; European Pat. Nos. 0-128-984; 0-108-624; Dutch Pat. Nos. 72.09426;
72.13842; 75.04532; Japan Pat. Nos. 10306126; 6049137; J. Am. Chem. Soc., 70,
2295, (1948); J. Am. Chem. Soc., 72, 5198 (1950); J. Am. Chem. Soc., 80, 3645
(1958); J. Org. Chem., 23, 544-549 (1958); Chem. Berichte, 92, 2958-2961 (1959);
Tertrahedron, 31, 235 (1975); Can. J. Chem., 63, 153 (1985). Although, the above
methods have been proven to be useful, they suffer from one or more process
deficiencies. For example, in some instances processes of this type necessarily
involve resort to sub-ambient temperatures, which of course, involves some
considerable process control and lead to reaction mixtures.
It, therefore, becomes an object of the invention to provide rapid and economical
process for the preparation of substituted 4-vinylphenols from cheaper and
commercially available 4-hydroxy phenylaldehydes as well as to eliminate the
disadvantages associated with the above patents and papers.
In conclusion, the present invention discloses a simple and economical process for
preparing vinylphenols starting from relatively cheaper and economical material 4-
hydroxyphenylaldehydes and malonic acid in the presence of organic acid and organic
base under microwave condition. Other objectives and advantages of the present
invention will be apparent as the description progresses.
Objectives of the invention
The main object of the present invention is to prepare high valued food flavouring
substituted 4-vinylphenols from 4-hydroxyphenylaldehydes.
Yet another object of the present invention is to employ eco-friendly microwave
technique for the preparation of substituted 4-vinylphenols.
Still another object of the invention is much shorter reaction time in minutes than
hours required in conventional method.
Yet another object of the invention is to develop a process to prepare substituted 4-
vinylphenols in good yield.
Yet another object of the invention is to develop a simple process for the preparation
of substituted 4-vinylphenols in high purity with minimum side products such as
cinnamic acid and polymerized product.
Yet another object of the present invention is to develop a microwave-assisted process
for the preparation of substituted 4-vinylphenols where both condensation and
decarboxylation occurred in one step while two individual steps are required in
conventional methods.
Yet another object of the present invention is to develop a microwave-assisted process
for the preparation of substituted 4-vinylphenols, which occurred in one step without
any addition of decarboxylating agent, which is essential in conventional methods.
Yet another object of the invention is to develop a process to prepare substituted 4-
vinylphenols in one pot.
Yet another object of the invention is to develop a process in which the acid is
selected from a group of organic acids consisting of formic acid, acetic acid, propionic
acid and others.
Yet another object of the invention is to develop a process in which some of
condensing organic acids and organic bases such as piperidine and acetic acid are
approved FEMA GRAS, which makes our process even safer and eco-friendly.
Still another object of the invention is to develop a process in which the mole ratio of
the reactant to the organic base is ranging from 1:1 to 1: 20.
Still another object of the invention is to develop a process in which the mole ratio of
the reactant to the organic acid is ranging from 1:1 to 1: 20.
Yet another object of the invention is to develop a process wherein the solvent used is
selected from a group of organic acids or organic base in such a manner that it acts
dual role as a solvent as well as a reagent.
Yet another object of the invention is to develop a process for easy workup as well as
purification of the product.
Yet another object of the invention is to develop a process where vinylphenols are
obtained by elongation of chain from C6-C1 (i.e.phenylaldehydes) to C6-C2 (i.e.
vinylphenols via intermediate decarboxylation) while vinylphenols are generally
obtained by shortening of the chain from C6-C3 (cinnamic acid) to C6-C2
(vinylphenols) in conventional and biotransformation methods.
Yet another object of the invention is to develop a process where the microwave
induced method is also efficient and rapid to prepare not only vinylphenol (hydroxy
styrene) from 4-hydroxyphenylaldehydes but also styrene from phenylaldehydes other
than 4-hydroxyphenylaldehydes.
Still another object of the invention is to develop a process which utilizes less or nonhazardous
chemicals.
Still another object of the invention is to develop a process, which requires cheaper
chemical reagents.
Yet another object of the invention is to develop industrially viable process towards
formation of high valued substituted 4-vinylphenols.
Yet another object of the invention is to develop economical process towards
formation of high valued substituted 4-vinylphenols.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of
commercially important perfumery and food flavouring substituted 4-vinylphenols
(i.e. hydroxystyrenes^ such as 4-vinylguaiacol, 4-vinylphenol, 2,6-dimethoxy-4-
vinylphenol, 2-hydroxy-4-vinylphenol, 3-hydroxy-4-vinylphenol and many others in
one pot under microwave irradiation utilizing cheaper substrates in the form of
malonic acid and substituted phenylaldehydes. The regents used are in the form of a
base selected from a group of organic bases consisting of pyridine, piperidine,
collidine, triethylamine and an acid selected from a group of organic acids consisting
of formic acid, acetic acid, propionic acid and others. The final product i.e. substituted
4-vinylphenols was obtained in moderate yield varying from 37-51 % within 20
minutes. It is worthwhile to mention that this microwave-assisted unique process is in
fact an unexpected result of two individual steps (i.e. condensation and
decarboxylation) observed for the first time during reaction of substituted 4-~
hydroxyphenylaldehydes with malonic acid in one step without addition of
decarboxylating agent. In addition to above, it is also noticed that presence of
hydroxy substitution at 4 position of phenylaldehyde is an essential requirement
towards formation of vinylphenol in one step under microwave condition. It is also
important to note that conducting the above reaction by conventional method instead
of microwave provides only cinnamic acid even when substituted 4-hydroxy
phenylaldehydes is taken as a starting materials.
Brief description of the accompanying drawings
Figure 1 is 'H NMR (300 MHz) spectra of vinylguaiacol (4-hydroxy-3-methoxy
styrene) (in CDC^) as mentioned in Example I.
Figure 2 is 13C NMR (75.4 MHz) spectra of vinylguaiacol (4-hydroxy-3-methoxy
styrene) (in CDCb) as mentioned in Example I
Figure 3 is DEPT-135 NMR spectra of vinylguaiacol (4-hydroxy-3-methoxy styrene)
(in CDCh) as mentioned in Example I
Detailed description of the Invention
Accordingly, the present invention provides a microwave assisted single pot process
for the preparation of 4-vinylphenol or its derivatives of general formula (I)
(Figure Removed)
Formula I
Wherein R, = OH or OCH3, R4 = -CH-CH2 and rest R2, R3, R5 and Re = H, OH or
OCH3 or combinations thereof, the said process comprising steps of:
a. reacting 4-hydroxyphenylaldehydes or its derivatives with malonic acid
in presence of an organic base and an organic acid under microwave
irradiation for a period ranging between 1 and 20 minutes,
b. cooling the mixture, pouring the cooled mixture into ice-cold water,
extracting with an organic solvent, separating the organic layer,
c. washing the organic layer of step (b) with dilute hydrochloric acid
followed by saturated sodium chloride solution, drying the washed
organic layer over anhydrous sodium sulphate, filtering and
evaporating the organic layer under reduced pressure to obtain a liquid
residue,
d. purifying the liquid residue of step (c ) over silica gel column, eluting
with a mixture of hexane ethyl acetate, and
e. obtaining the required 4-hydroxyvinylphenols or its derivative of
formula (1).
One embodiment of the present invention provides a process, wherein the organic
base used the step (a) is selected from a group consisting of pyridine, piperidine,
collidine, triethylamine and/or mixtures thereof.
Another embodiment, the organic acid used in step (a) selected from a group
consisting of formic acid, acetic acid, propionic acid and/or mixtures thereof.
Still another embodiment, the ratio of 4-hydroxy-phenylaldehydes or its derivative and
malonic acid used ranges between 1:1 and 1:3.
Yet another embodiment, the ratio of 4-hydroxyphenylaldehydes or its derivatives and
organic acid used ranges between 1:1 and 1:20.
Yet, another embodiment provides a process, wherein in step (a) the ratio of 4-
hydroxyphenylaldehydes or its derivatives and organic base used ranges between 1:1
and 1:20.
In yet another embodiment, the ratio of 4-hydroxyphenylaldehydes or its derivative
and organic base is in the range of 1: 10.
In another embodiment of the present invention, the reaction takes place in shortest
reaction time ranging from 1 to 20 minutes preferably 1-6 minutes which is
remarkable reduction in the reaction time than the conventional as well as
biotransformation process.
In yet another embodiment, in step (a), the reaction is taking for a period ranging
between 1 and 6 minutes.
In yet another embodiment, the organic solvent used in step (b) is selected from a
group consisting of toluene, dichloromethane, chloroform and ethylacetate.
In yet another embodiment, the condensation and decarboxylation is performed in a
single step.
Yet another embodiment, the decarboxylation is performed without adding any
decarboxylation agent.
Yet another embodiment, the said organic acid used in step (a), also acts as a solvent
in addition to a reagent.
One more embodiment, the frequency of microwave irradiation ranges from 2000 to
2450 HMz.
Another embodiment, the yield of compound of formula (1) is in the range of 35% to
55%.
In another embodiment of the invention relates to a process of preparing substituted
cinnamic acid derivative, wherein the said method is efficient in the preparation of
substituted cinnamic acid derivative in a yield ranging between 72 to 88%.
Yet another embodiment, 4-vinylphenols or its derivatives are obtained by elongation
of aldehyde carbon of 4-hydorxyphenyl aldehyde or its derivative.
In another embodiment, the invention provides easily purification of the required
product and the process is eco-friendly.
In yet another embodiment of the present invention, provides substituted 4
vinylphenols in high purity with no or minimum side products.
In yet another embodiment of the present invention, provides ecofriendly and
economical industrial process for the preparation of substituted 4-vinylphenols in
good yield.
In yet another embodiment of the present invention, provides a unique process where
4-vinylphenols are obtained via elongation of chain from C6-C1 (phenylaldehydes) to
C6-C2 (vinylphenols) whereas conventional and microbial transformation discloses
the formation of vinylphenols via shortening of chain from C6-C3 (cinnamic acids) to
C6-C2 (vinylphenols).
Flavour and fragrance chemistry represent one of the important branches of natural
product which is in great demand for food, perfumery, and pharmaceutical industries.
Several methods including chemical synthesis, biotechnology and natural extraction
are being carried out by the scientific community for the smooth production of aroma
chemicals. Some of vinylphenols and related styrenes are widely used in fragrances
and flavours as safe aroma molecules for human consumption, though, high
concentration of vinylphenols sometimes produce an off-note in flavours. Beside,
vinylphenols are also known to possess a wide range of biological activities including
antibacterial, antifungal and hypolipidemic activities etc. (William, A. A., David, J.
M. and Priyotosh, C., Phytochemistry, 42(5), 1321-1324 (1996); Adriana, C., Leticia,
G., Maria, S., Elizdath, M., Hugo, A. J., Francisco, D., German, C. and Joaquin, T.,
Arzneim.-Forsch./Drug Res., 51(11), 535-544 (2001)). In addition to above,
vinylphenols and related styrenes are also found as versatile intermediates for a wide
range of products (Stuart, R. R., Colette, S. M. and David, J. L., Biorganic &
Medicinal Chemistry, 2(6), 553-556 (1994); Atsushi, M., Takeo, K. and Yoshinobu,
I., Reactive & Functional Polymers, 37, 39-47, (1998); Michel, C. B., Adriano, L. M.
and Igor, T., J. of Molecular Catalyst A: Chemical, 143, 131-136 (1999) and Pedro, J.
C., Barbara, G. and Miguel, A. R., Tetrahedron Letters, 41, 979-982 (2000).
The widespread natural vinylphenols and related styrenes are obtained from a variety
of plants e.g. 2-methoxy-4-vinylphenol, also known as vinylguaiacol (FEMA GRAS
NO. 2675) is obtained from the pods of Hibiscus esculentus (okra) and Digitaria
exilis and also found in cooked apple, grapefruit juice (Citrus paradisi), feijoa fruit
(Feijoa sellowiand), Vitis vinifera, strawberry fruit, raw asparagus, leaves and stalks
of celery, crispbread, white wine, red wine, coffee, partially fermented tea, roasted
peanuts (Arachis hypogea), raw beans, red sage (Taxus sage) and other natural sources
(Jennifer, M. A. and Glesni, M., Phytochemistry, 29 (4), 1201-1207 (1990); Hanna,
P., Michael, N., Uri, Z., Russell, L. R. and Steven, N., J. Agric. Food Chem., 40, 764-
767 (1992) and Lasekan, O.O., Teixeira, J.P. F. and Salva, T. J. G., Food Chemistry,
75, 333-337 (2001)). In addition to above, 4-vinylguiacol is also present in several
coffee plants wherein out of more than 100 different chemical constituents, 4-
vinylguiacol is identified as one of the most powerful potent odorants on the basis of
aroma extract dilution analysis (AEDA) (Flavour Science Recent Developments, ed.
Taylor, A.J. and Mottram, D.S., The Royal Society of Chemistry, pp.200-205
(1996)). Similarly, 4-vinylguiacol is also found as one of the most odour active
compounds in roasted white sesame seeds which are widely used as a flavouring
material in food stuffs. In Asia, the oil isolated from the roasted sesame seed is used
in seasoning of many dishes, while in Europe and United States, the roasted seeds are
used in bakery products (Progress In Flavour Precursor Studies, ed. Schreier, P.,
Winterhalter, P., Allured Publishing Corporation, USA, 343-360 (1993) and Toshiro,
W., Akira, Y., Shiro, N. and Shigero, T., J. of Chromatography A, 793, 409-413
(1998)). On the same lines, 4-vinylphenol, also known as 4-hydroxystyrene, (FEMA
GRAS NO. 3739) is found in cooked apple, black currants (buds), raw asparagus,
tomato, cognac, white wine, red wine, rose wine, coffee, green tea, partially fermented
tea, microbial fermented tea, heated soyabean, Boletus edulis, coriander seed
(Coriandrum sativum), oil of vetiver (Vetiveria zizamioides), olive oil and other
natural sources (Souleymane, S. and Jean C., Phytochemistry, 12, 2925-2930, (1973);
Takayuki, S. and Osamu, N., Phytochemistr', 21(3), 793, (1982); Makoto, O.,
1
Kazumasa, W., Haruki, N. and Kiyoyuki, Y-; Tetrahedron, 43(22), 5275-5280,
(1987); Saez, J. J. S., Garraleta, M. D. H. and Otero, T. B., Analytica Chimica Acta,
247(2), 295-297, (1991); Vicente, F., Ricardo, L., Ana, E. and Juan, F. C., J. of
Chromatography A, 806 349-354, (1998); Nicholas, J.W., Arjan, N., Craig, B. F. and
Gray, W., Current Opinion in Biotechnology, 11, 490-496 (2000); Rainer, P.,
Alexander, S. and Horst, P, FEMS Microbiology Letters, 205, 9-16 (2001); Ricardo,
L., Margarita, A., Juan, C. and Vicente, F., J. of Chromatography A, 966, 167-177
(2002); Kuroda, K. and Dimmel, D.R., J. of Analytical and Applied Pyrolysis, 62,
259-271 (2002); Kuroda, K., Izumi, A., Mazumder, B. B., Ohtani, Y. and Sameshima,
K., J. of Analytical and Applied Pyrolysis, 64, 453-463 (2002) and Daniel, F., Ivano,
V. and Colin, E. S., J. of Chromatography A, 967, 235-242 (2002)). Apart from the
above-mentioned vinylphenols, there are several other styrenes, which are found in
different plants and are known for various applications. For example, styrene, also
known as ethylene benzene (FEMA GRAS NO. 3233), is found in Psidium guajava
(guava fruit), Annus comosus (pineapple), Arachis hypogea (roasted peanuts) and also
in dairy and beverage products. Similarly, o-vinylanisole (FEMA GRAS No. 3248) is
found in Origanum vulgare, whereas, 4-vinylveratrole and 2,4,5-lrimethoxy-lvinylbenzene
are found in rum, coffee and in several other natural products
(Nagashima, F., Murakami, Y. and Asakawa, Y., Phytochemistry, 51, 1101-1104
(1999).
In the pretext of above discussion, 4-vinylphenols and related styrenes can
unhesitatingly be counted as greatly valued to humankind. However, the limited
percentage of these substituted 4-vinylphenols in plant kingdom is not sufficient to
fulfill the world demand. As a result, a large quantity of 4-vinylphenols and related
styrenes are made synthetically as well as through microbial transformation where the
production of styrenes from cinnamic acid has been the most extensively investigated
method. A number of chemical methods are reported in literature for the preparation
of vinylphenols and related styrenes (Alwyn, S., J. of Organometallic Chemistry, 247,
117-122, (1983); Matthias, B., Hartmut, F. and Klaus, K., Tertahedron Lettrs, 35(47),
(1994); Cavani, F. and Trifiro, F., Applied Catalysis A: General, 133, 219-239 (1995);
Atsushi, T., Atsushi, M., Takeo, K. and Yoshinobu, I., Reactive & Functional
Polymers, 37, 39-47, (1998); Takaya, M., Roy, A.P., Douglas, J. T. and Hajime, Y.,
Journal of Catalysis, 206, 272-280 (2002)), 'however, the most widely used chemical
methods for preparing styrenes involve decarboxylation of trans-cinnamic acids which
is carried out by heating under reflux the cinnamic acids at 200-300°C for several
hours in quinoline in the presence of copper powder (Organic Synthesis
Collective Volume I, 441-442 (1941) and Volume IV, 731-734 (1963); Robert, A. S.,
Charles, R. D. and Leo, A. P., Tertrahedron Letters, 49, 4447-4450 (1976)).
Similarly, catalytic oxidation of 1,1 -diphenylethane (l,l-di-(4-hydroxyphenyl)ethane)
provides styrene (i.e. 4-hydroxy-3-methoxystyrene) (Perfume and Flavor Chemicals
(Aroma Chemicals), ed. Steffen, A., Allured Publishing Corporation, Vol II, 1891
(1994)). In addition to chemical methods, several microbial transformations are also
reported for the preparation of styrenes especially substituted vinylphenols (Masumi,
T. and Kazuo, A., Tetrahedron Letters, 40, 6595-6598 (1999) and Encyclopedia of
Food and Color Additives, ed. George, A.B., CRC Press, Inc., Vol II, 1705 (1996)).
So far, the published biotransformation including patent processes for the production
of styrenes provide relatively low yields since vinylphenols and related styrenes get
further degraded to other side products e.g. biotransformation of ferulic acid provides
not only the main product 4-vinylguaiacol but also vanillin, vanillic acid and
protocatechuic acid as side products, depending upon biocatalyst and conditions
(Takuya, K., Yasurou, I., Shinji, F., Kiyoshi, I. and Kimio, I, J. of Fermentation and
Engineering, 82(1), 46-50, (1996); Lee, I, Volm, T. G. and Rosazza, J. P. N., Enzyme
and Microbial Technology, 23, 261-266, (1998)). Some other fermentation processes
are also known in which ferulic acid is decarboxylated to 4-vinylguaiacol. A wellknown
example is the production of wheat beer where a specific top-yeast produces 4-
vinylguiacol from ferulic acid in high concentration. This high concentration of 4-
vinylguiaeol imparts a characteristic flavour to the beer and greatly adds to its value
(Understanding Natural Flavours, ed Pigget, J.R. and Patterson, A., Blackie Academic
& Professional, New York , pp.211-227 (1994)). Similarly, several other
microorganisms, fungi, yeast and bacteria are able to decarboxylate a large number of
substituted cinnamic acids into corresponding substituted styrenes including
vinylphenols from hydroxycinnamic acids (Yasuyuki, H. and Santoshi, T., Archives of
Biochemistry and Biophysics, 359(2), 225-230, (1998); Edlin, D. A. N., Narbad, A.,
Gasson, M. J., Dickinson, J. R. and Lloyd, D., Enzyme and Microbial Technology, 22,
232-239 (1998); Masumi, T. and Kazuo, A., Tetrahedron Lettrs, 40, 6595-6598,
(1999); Tripathi, U, Rao, S. R. and Ravishankar, G. A., Process Biochemistry, 38,
419-426, (2002)).
All the above methods have various limitations, for example, low yield, expensive
reagents and formation of unwanted side products. Keeping in view the above
problems, we disclose a unique and novel microwave-assisted process to prepare 4-
vinylphenols and related styrenes (Examples I, II, III) in one step from hydroxy
substituted phenylaldehydes and malonic acid in the presence of an organic base and
an organic acid (Jean, J. V. E. and Delphine, R., Tetrahedron, 55, 2687-2694 (1999)).
In fact, it is a chance observation in which we were trying to emulate Knoevenagel
Doebner condensation (Furniss, B.S., Hannaford, A.J., Rogers, V., Smith, P.W.G.
and Tatchell, A.R: In: Vogel's Textbook of Practical Organic Chemistry, fourth Edn.
(ELBS, UK), 802 (1978)) reaction under microwave irradiation because of advantages
inherent with microwave especially shorter reaction time, minimum or no side
products, and overall environmental friendly conditions (Bose, A.K., Banik, B.K.,
Lavlinskaia, N., Jayaraman, M. and Manhas, M.S., Chemtech, 27, 18-24, (1997);
Larhed, M. and Hallberg, Drug Discovery Today, 6(8), 406-416, (2001); Kuang, C.,
Senboku, H. and Tokuda, M., Tetrahedron, 58, 1491-1496, (2002) and Kuhnert, N.,
Angew. Chem. Int. Ed., 41, 1863-1866, (2002)). With this intention, microwave
assisted condensation of 3,4,5-trimethoxybenzaldehyde and malonic acid was
performed towards formation of 3,4,5-trimethoxycinnamic acids (Example IV)
followed by its dehydrogenation to obtain a rarer natural 3-(3,4,5-
trimethoxy)phenylpropionic acid (Example V) since a large number of biologically
active 3-phenylpropionic acids have been found in nature and some of substituted 3-
phenylpropionic acids are intermediate for synthesis of useful organic compounds as
well as synthesis of various drugs such as anti-aids, nonsteroidal, anti-inflammatory
drug and dopamine D3 receptor antagonist drug (Das, B.; Kashinatham, A.; Srinivas,
K.V.N.S. Planta Medica, 62, 582, (1996); Johannes, G.V.; Gerarad, R.; Richard, G.
Tetrahedron Letters, 39 8329-8332, (1998); Kamperdick, C.; Phuong, N.M.; Sung,
T.V., Schmidt, J. Phytochemistry, 52, 1671-1676, (1999); Susanne, H.R.; Kerry, C.A.;
Dae, D.M.; Duncan, J.N.; Christopher, H.L.; Rita, H.M.; Mary, L.E.; Nanette, N.F.;
Martin, S.W.; Kjell, S.A.; Matt, Z.J.; Arvid, C.; Lin, C.H., J. Med. Chem., 44, 4716-
4732, (2001)). With the success of the preparation of 3,4,5-trimethoxycinnamic acid
and its dihydro product (3,4,5-trimethoxy dihydrocinnamic acid), a large number of
other substituted benzaldehydes (i.e. 4-methoxybenzaldehyde or 3,4-
dimethoxybenzaldehyde or 2,4,5-trimethoxybenzaldehyde or
dioxymethylenebenzaldehyde or 3-chlorobenzaldehyde or 4-nitrobenzaldehyde etc.)
were found successful under microwave towards formation of corresponding cinnamic
acids (i.e. 4-methoxycinnamic acid or 3,4-dimethoxybenzaldehyde or 2,4,5-
trimethoxycinnamic acid or dioxymethylene cinnamic acid or 3-chlorocinnamic acid
or 4-nitrocinnamic acid etc.) including 3-hydroxycinnamic acid (Example VII).
Surprisingly, microwave assisted condensation of 3-methoxy-4-hydroxybenzaldehyde
(vanillin) with malonic acid failed to provide expected 3-methoxy-4-hydroxycinnamic
acid (ferulic acid) but it provided a good smelling liquid compound, which is
identified as 4-vinylguaiacol on the basis of spectral data (Example I). 'H NMR. of
liquid compound showed 14 protons (Example I) which is expected for protons of
ferulic acid (Example VI), however, we found two different dolublet at 5 5.19 (1H, d),
and 6 5.66 (1H, d), besides a double of doublet at 8 6.6 (2H, dd), which was unlike'
ferulic acid where two doublets appear at 5 5.7 (1H, d), and at 8 6.7 (1H, d). Similarly,
'3C NMR of liquid compound indicates the presence of 9 carbons (Example I) without
presence of carbonyl group instead of 10 carbons including carbonyl group as
expected for ferulic acid. DEPT-135 confirms the presence of one CH2 at 8C 111.8.
Overall spectral data indicates the presence of 4-vinylguaiacol and not the ferulic acid
as expected. Finally, mass spectra confirm the structure liquid as 4-vinyl guaiacol
(99.4% purity by GC).
In conclusion, our invention discloses a simple and economical process for preparing
vinylphenols starting from relatively cheaper and economical material 4-
hydroxyphenylaldehydes and malonic acid in the presence of organic acid and organic
base under microwave condition, which avoids the use of cinnamic acid and
decarboxylating agent and longer reaction time.
EXAMPLES
The following examples are given by way of illustration of the present invention
and should not be construed to limit the scope of the present invention.
The starting material substituted phenylaldehydes including 4-hydroxy
phenylaldehydes such as vanillin, 4-hydroxybenzaldehydephenylpropane derivatives
1
or the like, can be obtained from commercial sources. Kenstar microwave oven (2450
MHz, 1200 Watts) is used for all the given reactions.
Example I
Synthesis of 4-vinylguaiacol (by microwave irradiation method): A mixture of
vanillin (2.50 g, 0.0164 mol), malonic acid (3.41 g, 0.0328 mol), piperidine (3-5 ml)
and acetic acid (10-20 mL) were taken in a 100 ml Erlenmeyer flask fitted with a
loose funnel at the top. The flask was shaken well and placed inside the microwave
oven and irradiated for 1-7 minutes in parts. The cooled mixture was poured into icecold
water and extracted with ethyl acetate. The organic layer was washed with dil
HC1., saturated sodium chloride and then organic layer dried over sodium sulphate.
The solvent was evaporated under reduced pressure to obtain liquid which was
purified on silica gel column chromatography using mixture of hexane and ethyl
acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 51% yield; 'H
NMR (CDC13) 6 6.96 (3H, m, 3,5,6-Ar), 6.70 (1H, dd, J=7.8 Hz, CH=CH2), 5.93 (1H,
s, OH), 5.66 (1H, d, J= 17.6, cis-CH=CH2), 5.19 (1H, d, J= 10.9 Hz, trans- CH^CHA
3.90 (3H, s, OMe); 13C NMR (CDCb) 5 147.1 (C-l), 146.07 (C-2), 137.1 (CH=CH2),
130.7 (C-4), 120.4 (C-6), 114.9 (C-5), 111.8 (CH=CH2), 108.5 (C-3), 56.2 (OCH3).
Example II
Synthesis of 4-vinylphenol (4-hydroxystyrene) (by microwave irradiation
method): A mixture of 4-hydroxybenzaldehyde (1.0 g, 0.0082 mol), malonic acid
(1.69g, 0.0163 mol), triethylamine (2-4 mL) and acetic acid (10-15 mL) were taken in
a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken
well and placed inside the microwave oven and irradiated for 2-8 minutes in parts.
The cooled mixture was poured into ice cold water and extracted with ethyl acetate.
The organic layer was washed with sodium bicarbonate, dil HCL, saturated sodium
chloride and then organic layer dried over sodium sulphate. The solvent was
evaporated under reduced pressure to obtain liquid which was purified on silica gel
column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4),
provided sweet and pleasant smelling liquid in 40% yield; *H NMR (CDCb) 5 7.31
(2H, d, J=8.5 Hz, H-2 and H-6), 6.81 (2H, d, J=8.8 Hz, H-3 and H-5), 6.67 (1H, dd,
J= 17.8 Hz, 11.3 Hz, (CH=CH2), 5.51 (1H, s, OH), 5.2 (1H, d, J= 17.8, cis-
CH=CH2), 5.14 (1H, d, J= 11.3 Hz, trans-O^CH^; 13C NMR (CDCb) 8 155.5 (C-
1), 136.5 (CH=CH2), 130.9 (C-4), 128.0 (C-3 and C-5), 115.8 (C-2 and C-6), 112.0
(CH=CHZ).
Example III
Synthesis of 3,5-dimethoxy-4-vinylphenol (by microwave irradiation method): A
mixture of 4-hydroxy- 3,5-dimethoxy benzaldehyde (2.5 g, 0.013 mol), malonic acid
(2,80 g, 0.027 mol), piperidine (2-5 mL) and formic acid (10-20 mL) were taken in a
100 ml Erlenmeyer flask fitted with a loose runnel at the top. The flask was shaken
well and placed inside the microwave oven and irradiated for 2-8 minutes in parts.
The cooled mixture was poured into ice cold water and extracted with ethyl acetate.
The organic layer was washed with dil HC1., saturated sodium chloride and then
organic layer dried over sodium sulphate. The solvent was evaporated under reduced
pressure to obtain liquid which was purified on silica gel column chromatography
using mixture of hexane and ethyl acetate (9:1 to 6:4), provided a viscous liquid in
37% yield; 'H NMR (CDC13) 5 6.73(1 H, s, H-3 and H-5), 6.62 (1H, dd, CH=CHA
5.61(1H, d, J= 18.6 Hz, cis-CH=CH2), 5.16(1H, d, J= 10.8, trans- CH=CHb); 13C
NMR (CDCb) 5 147.4 (C-2 and C-6), 137.2 (C-l), 135.1 (CH=CH2), 129.5 (C-4),
112.2 (CH=CH2), 103.3 (C-3 and C-5), 56.0 (2-OMe).
Example IV
Synthesis of 3,4,5-trimethoxycinnamic acid (by microwave irradiation method):
A mixture of 3,4,5-trimethoxybenzaldehyde (5.0 g, 0.025 mol), malonic acid (5.30 g,
0.050 mol), piperidine (4-8 mL) and acetic acid (25-35 mL) were taken in a 100 ml
Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and
placed inside a microwave oven and irradiated for 4-8 minutes in parts. The cooled
mixture was poured into ice cold water and then acidified with 5% HC1. The
precipitated yellow solid was filtered and recrystallized with aq. ethanol to afford
3,4,5-trimethoxycinnamic acid in 88% yield; mp 127 °C (lit mp 126-128 °C) whose
spectral data was found similar to the reported values 'H NMR (CDCb) 5 7.73 (1H,
d, J=16.0 Hz, -CH=CH-COOH), 6.78 (2H, s, H-2 & H-6), 6.38 (1H, d, J=16.0 Hz,
CH=CH-COOH), 3.91 (9H, s, 3-OCH3, 4-OCH3 & 5-OCH3); 13 C NMR: 6 172.6
(COOH), 153.8 (C-3 and C-5), 147.4 (C-4), 140.8 (CH=CH-COOH), 129.8 (C-l),
116.8 (CH=CH-COOH), 105.8 (C-2 and C-6), 61.4 (4-OCH3), 56.5 (3-OCH3 and 5-
OCH3).
Example V
Synthesis of 3-(3,4,5-trimethoxy)phenylpropionic acid (by microwave irradiation
method): 3,4,5-trimethoxycinnamic acid (0.72g, 0.003 mole), PdCl2 (55 mg, 0.31
mmol), 10% sodium hydroxide (6-10 mL) were suspended in a 100 ml Erlenmeyer
flask and added formic acid (8-12 mL) in parts. The mixture was irradiated with
microwave for 3-5 min. till disappearance of starting material. The cooled mixture
was poured into ice cold water, acidified with 5% HC1 and extracted with
dichloromethane (3x 10 mL). The organic layer was washed with water and dried
over anhydrous Na2SO4- The solvent was evaporated and the crude solid product was
recrystallized with a mixture of ethylacetate and hexane to provide 3-(3,4,5-
trimethoxy)phenylpropionic acid as a white solid in 84% yield; mp 102 °C (lit mp
101-102 °C); ' H NMR (CDC13) 5 6.70 (2H, s,H-2 and H-6), 3.84 (9H, s, 3-OCH3,
4-OCH3), and 5-OCH3), 2.92 (2H, t, Ar-CH2-CH2-COOH), 2.70 (2H, t, -CH;-CH7-
COOH); 13 C NMR: 6 178.1 (COOH), 153.1 (C-3 & C-5), 135.87 (C-4 & C-l) 105.3
(C-2 & C-6), 60.8.0 (4-OCH3), 56.1 (3-OCH3 & 5-OCH3), 35.5 (Ar-CH2-), 31.0 (-
CFb-COOH).
Example VI
Synthesis of ferulic acid (by conventional method): A mixture of vanillin (2.50 g,
0.0164 mol), malonic acid (3.41 g, 0.0328 mol), piperidine (3-5 mL) and acetic acid
(10-20 mL) were taken in a round bottom flask and the reaction mixture was refluxed
for 5-6 hours instead of microwave irradiation as mentioned in Example I. The
cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The
organic layer was washed with dil HC1., saturated sodium chloride and then organic
layer dried over sodium sulphate. The solvent was evaporated under reduced pressure
to obtain solid which was recrytallised with mixture of methanol and hexane,
provided ferulic acid as a solid compound mp 169 °C (lit mp 168-171 °C) in 65%
yield; 'H NMR (DMSO-d6) 5 12.13 (1H, s, COOH), 7.48 (1H, d, Ar-CH=CHCOOH),
7.27 (1H, s, H-3), 7.07 (1H, d, H-6), 6.78 (1H, d, H-5), 6.36 (1H, d, -
CH=CH-COOH), 3.81 (3H, s, 2-OCH3); 8 168.9 (COOH), 149.8 (C-l), 148.7 (C-2),
145.4 (CH=CH-COOH), 126.6 (C-4), 123.7 (C-5), 116.4 (C-3 & C-6), 111.8
(CH=CH-COOH), 56.4 (2-OCH3).
This experiment clearly indicates that utilization of microwave technique is important
for the preparation of 4-vinylguaiacol from vanillin and malonic acid (Example I).
Example VII
Synthesis of 3-hydroxycinnamic acid (by microwave irradiation method): A
mixture of 3-hydroxybenzaldehyde (1 g, 0.008 mol), malonic acid (1.69 g, 0.016 mol),
piperidine (Ito 3 mL) and acetic acid (10-20 mL) were taken in a 100 ml Erlenmeyer
flask and irradiated under microwave for 2-8 minutes in parts. The cooled mixture
was poured into ice cold water and extracted with ethyl acetate. The organic layer was
washed with dil HC1., saturated sodium chloride and then organic layer dried over
sodium sulphate. The solvent was evaporated under reduced pressure to obtain crude
solid which was recrystallised with methanol, provided a white solid in 76% yield;
193 °C (lit mp 194 °C); *H NMR (CDC13) 5 6.73(1H, s, H-3 and H-5), 6.62 (1H, dd,
H-7), 5.61(1H, d, J= 10.9 Hz trans, H-8), 5.16(1H, d, J= 17.6, cis-H-8), ; 13C NMR
(CDC13) 6 147.4 (C-2 and C-6), 137.2 (C-l), 135.1 (C-7), 129.5 (C-4), 112.2 (C-8),
103.3 (C-3 and C-5), 56.0 (2 OMe). This experiment clearly indicates that utilization
of microwave technique as well as presence of hydroxy at 4-position of
phenylaldehydes is important for the preparation of 4-vinylphenols (Example I, II and
III).
The main advantages of the present invention are
The main advantage of the present invention is a process to prepare high valued food
flavouring substituted 4-vinylphenols from 4-hydroxyphenylaldehydes.
A process to employ ecofriendly microwave technique for the preparation of
substituted 4-vinylphenols.
1. A process to prepare 4-vinylphenols in much shorter reaction time in minutes.
2. A process to prepare substituted 4-vinylphenols in good yield (37-55%).
3. A process for the preparation of substituted 4-vinylphenols in high purity with
minimum or no side products such as cinnamic acid and polymerized product.
4. A process to develop a microwave-assisted preparation of substituted 4-
vinylphenols where both condensation and decarboxylation unexpectedly
occurred in one-step, which otherwise requires two individual steps in
conventional methods.
5. A process to prepare substituted 4-vinylphenols in one pot.
6. A process in which the base is seiccied from a group of organic bases
consisting of pyridine, piperidine, collidine, triethylamine and others.
7. A process in which the acid is selected from a group of organic acids
consisting of formic acid, acetic acid, propionic acid and others.
8. A process in which the mole ratio of the reactant to the organic base is ranging
from 1:1 to 1:20.
9. A process in which the mole ratio of the reactant to the organic acid is ranging
from 1:1 to 1:20.
10. A process wherein the solvent used is selected from a group of organic acids
or organic base in such a manner that it plays dual role both as a solvent as
well as a reagent.
11. A process for easy workup as well as purification of the product.
12. A process which utilizes less or non-hazardous chemicals.
13. A process, which requires cheaper chemical reagents.
14. A process to develop industrially viable process towards formation of high
valued substituted 4-vinylphenols.
15. A process to develop economical process towards formation of high valued
substituted 4-vinylphenols.




We Claims:
A microwave assisted single pot process for the preparation of 4-vinylpheiK or its derivatives of general formula (I)



(Formula Removed)
Wherein R, = OH or OCH,, R4 = -CH-CH, and rest R2, R3, R5 and R„ II OH or OCH3 or combinations thereof, the said process comprising steps of:
a. reacting 4-hydroxyphenylaldehydes or its derivatives with malonic acid
in presence of an organic base and an organic acid under microwave
irradiation for a period ranging between 1 and 20 minutes,
b. cooling the mixture, pouring the cooled mixture into ice-cold watei.
extracting with an organic solvent, separating the organic layer.
c. washing the organic layer of step (b) with dilute hydrochloric acid
followed by saturated sodium chloride solution, drying the washed
organic layer over anhydrous sodium sulphate, filtering and evaporatim
the organic layer under reduced pressure to obtain a liquid residue.
d. purifying the liquid residue of step (c) over silica gel column, elutmt'
with a mixture of hexane ethyl acetate, and
e. obtaining the required 4-hydroxyvinylphenols or its derivative o:
formula (1).
A process of claim 1, wherein the step (a) the organic base used is selected from a group consisting of pyridine, piperidine, collidine, triethylamine and o\ mixtures thereof.
A process of claim 1, wherein the step (a) the organic acid used is selected from a group consisting of formic acid, acetic acid, propionic acid and m mixtures thereof.
A process of claim 1, wherein in step (a) the ratio of 4-hydro\\ phenylaldehydes or its derivative and malonic acid used ranges between I ; and 1:3.

A process of claim 1, wherein in step (a) the ratio of 4
hydroxyphenylaldehydes or its derivatives and organic acid used ranges
between 1:1 and 1:20.
A process of claim 1. wherein in step (a) the ratio of 4
hydroxyphenylaldehydes or its derivatives and organic base used ranges
between 1:1 and 1:20.
A process of claim 6 wherein the ratio of 4-hydroxyphenylaldehydes or its
derivative and organic base is preferably in the range of 1: 10.
A process of claim 1 wherein in step (a) the reaction time period is in the range of 1 to 6 minutes.
A process of claim 1, wherein the step (b) the organic solvent used is selected from a group consisting of toluene, dichloromethane, chloroform of ethylacetate.
A process of claim 1 wherein in step (a), the said organic acid used, also acts as a solvent in addition to a reagent.
A process of claim 1, wherein the frequency of microwave irradiation range from 2000 to 2450 HMz.
A process of claim 1 wherein the yields of compounds of formula (1) is in the rangeof35%to55%.
A process of claim 1, wherein 4-vmylphenols is obtained by elongation stepping up by a carbon atom of an aldehyde carbon of 4-hydorxyphenyl aldehyde or its derivative.

Documents:

2761-DELNP-2004-Abstract-(10-12-2008).pdf

2761-delnp-2004-abstract.pdf

2761-DELNP-2004-Claims-(10-12-2008).pdf

2761-delnp-2004-claims.pdf

2761-delnp-2004-correspondence-others.pdf

2761-delnp-2004-description (complete).pdf

2761-delnp-2004-form-1.pdf

2761-delnp-2004-form-18.pdf

2761-delnp-2004-form-2.pdf

2761-DELNP-2004-Form-3-(10-12-2008).pdf

2761-delnp-2004-form-3.pdf

2761-delnp-2004-form-5.pdf

2761-DELNP-2004-Petition-137-(10-12-2008).pdf


Patent Number 231706
Indian Patent Application Number 2761/DELNP/2004
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 09-Mar-2009
Date of Filing 17-Sep-2004
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110 001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 ARUN KUMAR SINHA IHBT, PALAMPUR
2 BHUPENDRA PRASAD JOSHI IHBT, PALAMPUR
3 ANUJ SHARMA IHBT, PALAMPUR
PCT International Classification Number C07C37/20
PCT International Application Number PCT/IB02/05513
PCT International Filing date 2002-12-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/383,253 2003-03-07 U.S.A.