Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-07-21
2001-02-06
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S004100, C536S018600, C568S749000, C568S750000, C568S751000, C568S752000, C568S753000
Reexamination Certificate
active
06184367
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for production of 4-aryl-2-butanol. The invention particularly, relates to a process for the production of two biologically active molecules (−) betuligenol and (−) betuloside having the general formula (1) as given below:
BACKGROUND
Taxol is isolated from the leaves of
Taxus wallichiana.
Taxol, a highly oxygenated diterpenoid molecule and a potent anticancer drug was first isolated from the stem bark of
Taxus brevifolia.
Thereafter, it is also been isolated from other Taxus species including Himalayan yew
Taxus wallichiana.
Various types of cancers have been treated with taxol and the results in the treatment of ovarian and breast cancers are very promising. Taxol has recently been approved by the Food and Drug Administration of the United States for the treatment of ovarian and breast cancers. Taxol, a structurally complicated and chemically labile molecule needing special and careful extraction and separation procedures for its isolation from plant materials. Unfortunately, most of the works are proprietary and have not been published. The American workers have used alcohol to extract taxol from the stem bark of
T. brevifolia
and separation of taxol from the alcoholic extract uses column chromatography over silica with 2% methanol in chloroform as the eluting solvent to yield a mixture of taxol and cephalomannine. Taxol can be separated and isolated from the mixture with a yield of 0.01% either by repeated column chromatography over silica or by high performance liquid chromatography. Taxol has also been isolated from the Himalayan yew
Taxus wallichiana
with a yield of 0.02%. The isolation process involves extracting the stem bark with methanol, partitioning of the methanolic extract between water and chloroform and isolating taxol from the chloroform soluble fraction by chromatography over silicagel.
Taxus wallichiana
known as the Himalayan yew is available in India. The applicants have investigating the different parts of this plant from different Himalayan regions of India for isolation of naturally occurring analogues of taxol, its important precursors and other biologically active compounds. During the course of investigation the applicants have isolated 2 compounds of 4-aryl-2-butanol namely betuligenol having formula C
10
H
14
O
2
, mp 69-70° C., [&agr;]
n
+20 (C1, MeOH) and betuliloside having formula C
16
H
24
O
7
mp 187-188°, [&agr;]
n
+22° (C1, MeOH) from the leaves of
T. wallichiana.
Both compounds are known and they have previously been isolated from the plant
Acer nikoense.
No isolation process has been mentioned in the paper (T. Inoue, Y. Ishidate, M. Fujita, M. Kubo, M. Fukushima and M. Nagai, J. Pharm. Soc. Jpn. 98, 41 (1978): Chem, Abstr. 88, 133254 (1978). However, (−) betuligenol, a laevoisomer of the compound of formula 1 where R═H has been isolated by the applicants from the leaves of
Taxus wallichiana.
Now, the applicants have been able to isolate the dextro-isomer of (−) betuligenol which is the compound of formula 1 where R═H. The process of isolation of (−) betuligenol from the leaves of
Taxus wallichiana
involves extraction of leaves with methanol. Isolation of (−) betuligenol with a yield of 0.05% from the methanol extract was achieved by partitioning of the methanol extract between water and chloroform and chromatography of the chloroform soluble fraction over silica gel (S. K. Chattopadhyay V. K. Tripathi. R. S. Thakur, R. P. Sharma and S. P. Jain,
Indian J. Chem
33B. 409-411 (1994). Compound of formula 1 where R=glucose has not been isolated before from the leaves of
T. wallichiana
although its laevoisomer, betuloside has previously been isolated by the applicants from the leaves of the above plant (S. K. Chattopadhyay et al.,
Indian J. Chem.
33B, 409-411 (1994). The process of isolation of betuloside consists of extraction of the leaves of
T. wallichiana
with methanol, partitioninig of the methanol extract between water and ethyl acetate and column chromatography of the ethyl acetate fraction to give betuloside with a yield of 0.04%. Now, it has recently been reported that both the compounds of formula (1) where R═H or glucose significantly exhibit anti-inflammatory properties by reducing the nitric oxide (NO) production (S. Fushiya, Y. Kabe, Y. Ikegaya and F. Takano,
Planta Medica
64, 598-602 (1998). Inflammatory macrophages play a key role in inflammatory process by secreting large amount of mediators that control the initiating process of inflammation. Nitric oxide (NO) is one of the critical mediators produced by inducible NO synthase in inflammatory macrophages when stimulated by bacterial products like lipopolysaccharide (LPS) and some cytokines. Nitric oxide (NO) produced by inducible NO synthase plays a role in non specific immune defence against tumors, parasitic fungi, bacteria and protozoa. Moreover, NO is known to be responsible for the hypotension observed in endotoxin shock. Activation of inflammatory macrophages resulting in the production of large amounts of NO is considered to be critical for lethal toxicity. Glucocorticoid and immuno suppressive agents strongly inhibit NO production. Now, it has been reported recently that compounds of formula (1) where R═H or glucose also suppress the NO production. As NO is one of the critical mediators in inflammation, both compounds of formula (1) where R═H or glucose possess significant anti-inflammatory properties by suppressing the production of NO.
During the chemical investigation done by the applicants on the leaves of
T. wallichiana
collected from different parts of India, the applicants have been able to isolate two molecules of 4-aryl-2-butanol compounds of the formula (1) wherein if R═H the compound is (−) betuligenol and wherein if R=glucose the compound is (−) betuloside with yields of 0.2 and 0.2% respectively. Thus, the leaves of
Taxus wallichiana
could be a viable source for the above two important molecules.
OBJECTS OF THE INVENTION
Thus, the main object of the present invention is to provide a process for production of 4-aryl-2-butanols of general formula (1) shown below:
which obviates the drawbacks of the earlier methods.
Another object of the present invention is to provide a process which gives the higher yields 0.2% each of these compounds than the known process (0.05 and 0.04% respectively).
Yet another object of the invention is to provide a process which avoids the use of chromatographic separation and makes the process cost effective.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for production of 4-aryl-2-butanols, of the general formula (1) given below:
from the leaves of
Taxus wallichiana
which comprises: (a) defatting air dried, pulverized leaves with aliphatic hydrocarbon solvents, (b) extracting the defatted leaves with chlorinated solvents and polar solvents successively at room temperature, (c) concentrating the chlorinated solvent soluble fraction to a residue and treating the residue with aqueous solution of alkali and extracting with chlorinated solvent, (d) acidifying the alkali layer with mineral acid and extracting with ethyl acetate and concentrating the ethyl acetate phase to give compound of formula 1 where R═H, (e) concentrating the polar solvent fraction from step (b) to a residue and treating the residue with aqueous solution of alkali and extracting with chlorinated solvent, and (f) acidifying the alkali phase with mineral acid and extracting with ethyl acetate and concentrating the ethyl acetate to give compound of formula 1 where R=glucose.
In one embodiment, the aliphatic hydrocarbon solvent used in step (a) are selected from petroleum ether and hexane.
In another embodiment, the chlorinated solvents used in step (b) are selected from chloroform and dichloromethane.
In another embodiment, the chlorinated solvents used in step (b) are selected from chloroform and di
Chattopadhyay Sunil Kumar
Kumar Sushil
Sharma Ram Prakash
Council of Scientific and Industrial Research
O'Sullivan Peter
Perkins Coie LLP
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