Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2002-05-24
2003-04-22
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S443000, C556S444000, C556S446000, C556S486000, C560S254000, C560S255000, C568S607000, C568S630000, C568S631000, C568S636000, C568S659000, C568S660000
Reexamination Certificate
active
06552213
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new stereoselective method for the preparation of tris-O-substituted-(E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene derivative of the general formula (I) which is a key intermediate in the synthesis of trans-resveratrol (I, R
2
=R
2
=R
3
=H). The invention also provides a method for the exclusive synthesis of trans-isomer of compounds of general formula (I) without any contamination of cis-isomer.
BACKGROUND OF THE INVENTION
Polyhydroxylated trans-stilbenes, the natural products, have been found to exhibit interesting biological activities. Trans-resveratrol has been found to raise the level of high-density lipoproteins (HDL) and lower the level of low-density lipoproteins (LDL) in human beings thereby reducing the risk of clogging arteries and consequent myocardial infarctions (Toppo, F. U.S. Pat. No. 6,048,903). Many 5-alkenyl resorcinols show antileukemic activity (Alonso, E; Ramon, D. J; Yus, M.
J. Org. Chem
. 1997, 62, 417-421; Thakkar, K; Geahlen, R. L.; Cushman, M.
J. Med. Chem
. 1993, 36(20), 2950-2955) and anti-tumor properties (He, K.; Zheng, Q. Y.; Zheng, B. L.; Kim, C. H. WO 2000/037021). Plant material containing trans-resveratrol has been used as a herbal medicine for the treatment of hyperlupemia and liver diseases in China and Japan for many centuries (Kimura, K. M. et al.
Shoyqakugaku Zasshi
1987, 83, 35-58).
Further investigations led to identification of many important biological functions including inhibition of lypooxygenase activity (Kimma, Y. et al.
Biochem. Biophys. Acta
. 1985, 834, 275), inhibition of anaphylactoid (Ragazy et al.
Pharmacol. Ref. Commun
. 1988, 79, 20) and protection of lipoproteins against oxidative and free radical damage (Frankel E. N. et al.
Lancet
1979, 1, 1017).
It has been reported that piceatannol, a known antileukemic principle in the seeds of
Euphorbia lagascae
, inhibits the PTK (protein-tyrosine kinase) activities of P40 as well as P56
lck
by binding to the substrate binding sites (Geahlen, R. L.; McLaughlin, J. L.
Biochem. Biophys. Res. Commun
. 1989, 165, 241-245). Thakkar et al. studied a series of hydroxylated trans-stilbenes and reported enhanced activity for inhibition of the lymphoid cell lineage-specific protein-tyrosine kinase P56
lck
which plays an important role in lymphocyte proliferation and immune function.
In view of the vital biological activities of the polyhydroxylated trans-stilbenes, there have been a few methods reported for the synthesis of these compounds. For example, trans-resveratrol is synthesized by the Wittig reaction of 3,5-dimethoxybenzyltriphenyl phosphonium salt with p-anisaldehyde in the presence of n-butyl lithium. The mixture of cis-and trans olefins so obtained is demethylated with large amount of boron tribromide to get very low yield of the product (Toppo, F. U.S. Pat. No. 6,048,903). This method suffers from the low yield, low quality and use of expensive and hazardous reagents, which prevents from employing this method on commercial scale. Similar low yields are reported employing condensation of phosphonate esters with aromatic aldehydes followed by demethylation using pyridine hydrochloride (WO 2000/021368). In case of piceatannol, tetramethoxystilbene precursor is synthesized by the Witting reaction and the methyl groups are then removed by demethylation reaction with pyridine hydrochloride (Drewes, S. E; Fletcher, I. P.
J. Chem. Soc. Perkin Trans. I
, 1974, 961-962) or with boron tribromide (Bajaj, R; Gill, M. T.; McLaughlin, J. L.
Rev. Latinoamer Quim
. 1987, 18, 79-80).
Use of trimethylsilyl protecting groups followed by witting reaction to get the hydroxy-trans-stilbene products has also been reported (Reimann, E.
Tetrahedron Lett
. 1970, 4051-4053). Yet another route comprising the reaction of 3,5-dihydroxyphenylacetate and 3,4-dihydroxybenzaldehyde in acetic anhydride, decarboxylation of the ensuing 3,3′, 4,5′-tetraacetoxystilbene-&agr;-carboxylic acid with copper and quinoline at high temperature, and hydrolysis of the resulting piceatannol tetraacetate with sodium hydroxide is also reported. (Cunningham, J; Haslam, E; Haworth, R. D.
J. Chem. Soc
. 1963, 2875-2883). All these processes for the preparation of trans-resveratrol are reported to proceed in moderate to low yields.
In those cases where Wittig reactions are employed, the undesired cis-isomers are also formed along with the desired trans-isomers to the extent of 52% (trans 48%) when potassium t-butoxide is employed (Ali, M. A.; Kondo, K; Tsuda, Y.
Chem. Pharm. Bull
. 1992, 40(5), 1130-1136). Similarly, cis isomers are formed to the extent of 45% (trans:23%) when sodium hydride is used. (Cushman, M; Nagarathnam, D; Gopal D. et al.
J. Med. Chem
. 1992, 35(12), 2293-2306; Chen, Yi-Ping; Lei, Tong-Kang.
Zhongquo Yiyao Gongye Zazhi
2000, 31(7), 334-336.
In another process, 3,5-dimethoxybenzyl trimethylsilyl ether is treated with lithium metal in the presence of p-anisaldehyde to yield, after dehydration, 3,4′,5-trimethoxystilbene, a penultimate intermediate which requires excess boron tribromide (Alonso, E; Ramon, D. J.; Yus, M.
J. Org. Chem
. 1997, 62(2), 417-421). Similar use of excess boron tribromide has been indicated in WO 01/60774.
A wide variety of demethylating reagents such as boron tribromide, boron tribromide-dimethyl sulfide complex, boron trichloride-dimethyl sulfide complex, pyridine hydrochloride with a catalytic amount of quinoline at elevated temperatures, methyl magnesium iodide etc., are employed. In all these cases, demethylation is always incomplete and the yields and quality are disappointing. To purify the product obtained after dealkylation, costly chromatographic techniques were employed (Thakkar, K; Geahlen, R. L; Cushman, M.
J. Med. Chem
. 1993, 36(20), 2950-2955).
In the synthesis, which involves the Wittig reaction, the mixture of cis- and trans-isomers are separated by column chromatography or irradiated a solution of the mixture to convert cis into trans isomers.
These processes are commercially and technically difficult to be implemented. In addition, main problems in the synthesis of these polyhydroxylated-1,2-diphenylethenes are caused by the instability of this polyphenolic stilbene due to its oxidation, resulting in the formation of unstable radicals and quinones. The final isolation of the product has to therefore be carried out from dark coloured mixture containing multiple components.
OBJECTIVES OF THE INVENTION
The objective of the present invention is to develop a commercial method for preparing polyhydroxy-1,2-diphenylethenes, especially (E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene, with exclusive trans stereo chemistry.
Another objective of the present invention is to overcome the technical difficulties associated with the reported methods and develop a commercial process to manufacture exclusively the trans-isomer.
Yet another objective of the present invention is to provide a simple and effective process without using photochemical reaction in the manufacturing process.
Still another objective is to avoid the use of expensive and hazardous chemicals viz. boron tribromide, lithium, Lithium aluminum hydride, sodium hydride, triethyl phosphite, phosphorus tribromide, etc. in the present process.
SUMMARY OF THE INVENTION
The present invention relates to a process for the stereoselective synthesis of tris-O-substituted-(E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxy phenyl)ethene derivatives of general formula (I), wherein those disadvantages, which have plagued this art, are obviated.
wherein R
1
, R
2
, and R
3
are independantly represented as alkoxyalkyl, allyl, vinyl, silyl, formyl, acyl, arylalkyl or substiuted arylalkyl groups or a combination thereof.
Moreover, the foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from a stereo selectivity standpoint, and affords an almost exclusive formation of the trans-isomer and is also free from the limitations discussed above.
The subject compoun
Andrew Gnanaprakasam
Deshpande Pandurang Balwant
Senthilkumar Udayampalayam Palanisamy
Orchid Chemicals & Pharmaceuticals Limited, India
Shaver Paul F.
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