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Patent Issued for One Pot Multicomponent Synthesis of Some Novel Hydroxy Stilbene Derivatives with Alpha, Beta-Carbonyl Conjugation under Microwave...

May 20, 2014



Patent Issued for One Pot Multicomponent Synthesis of Some Novel Hydroxy Stilbene Derivatives with Alpha, Beta-Carbonyl Conjugation under Microwave Irradiation

By a News Reporter-Staff News Editor at Cancer Weekly -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Sharma, Abhishek (Palampur, IN); Sinha, Arun Kumar (Palampur, IN); Kumar, Rakesh (Palampur, IN); Sharma, Naina (Palampur, IN), filed on March 26, 2010, was published online on May 6, 2014 (see also Council of Scientific and Industrial Research).

The assignee for this patent, patent number 8716532, is Council of Scientific and Industrial Research (New Delhi, IN).

Reporters obtained the following quote from the background information supplied by the inventors: "Stilbene and its derivatives have been widely reported to possess a plethora of industrial and pharmaceutical applications. In particular, the hydroxy substituted stilbenoids have been found to be privileged structural motifs in diverse bioactive natural products. For instance, various dihydroxy stilbene derivatives based on lithospermic acid, a polyphenolic compound found in Salvia miltorrhiza (Planta Med. 1984; 50, 227-228, Phytochemistry 1994, 37, 907-908) have been implicated as potent antidiabetic agents as they display significant inhibitory activity against protein tyrosine phosphatase (PTP1B) enzyme (Bioorg. Med. Chem. Lett. 2007, 17, 4481). Similarly, the salvionolic acid derivatives, isolated from genus Salvia, have been widely studied and ascribed numerous biological activities including antitumoral, anti-inflammatory, gastric and antioxidant activities (US 2003/0086987A1 and US 2002/0197274A1). In yet another instance, the multiconjugated stilbenes like 1,4-bis-styrylbenzenes are reported to possess important applications as in vivo magnetic resonance imaging agents for diagnosis and monitoring of various neurodegenerative ailments like Alzheimer's disease owing to their strong amyloid fibril (A.beta.) plaque binding ability (J. of Med. Chem., 2007, 50, 4986). In addition, the 1,4-bis-styrylbenzenes have also been used as optical brighteners (U.S. Pat. No. 4,371,475). Similarly, resveratrol, a phytoalexin, present in grapes and other fruits (J. Burns, T. Yokota, H. Ashihara, M. E. J. Lean, A. Crozier, J. Agric. Food Chem., 2002, 50, 3337; G. J. Soleas, E. P. Diamandis, D. M. Goldberg, Clin. Biochem., 1997, 30, 91); resveratrol (3,4',5-trihydroxy-(E)-stilbene) and a major component of red wine, has been implicated as a potent cardio-protective agent, thus lending credence to the conjecture that red wine consumption retards cardio-vascular mortality. In addition, several epidemiological and immunological studies have identified resveratrol as a potent therapeutical agent for Alzheimer's disease and cancer (Science, 1997, 275, 218). Combretastatin A-4, a stilbene isolated from the African bush willow, Combretum, has been found to be a potent anti-cancer agent, binding strongly to tubulin and displaying selective toxicity towards tumor vasculature (U.S. Pat. No. 4996; Brit. J. Cancer, 1999, 81, 1318; Brit. J. Cancer, 1995, 71, 705). Combretastatin A-4 is able to elicit irreversible vascular shutdown within solid tumors, leaving normal vasculature intact (E. Hamel, C. M. Lin, Biochem. Pharmacol., 1983, 32, 3863; D. J. Chaplin, G. R. Pettit, C. S. Parkins, S. A. Hill, Brit. J. Cancer, 1996, 74, S86; G. G. Dark, S. A. Hill, V. E. Prise, G. M. Tozer, G. R. Pettit, D. J. Chaplin, Cancer Res., 1997, 57, 1829). In addition, intensive investigations of several other stilbenes have brought forth their immense potential as versatile pharmacophores (Pettit, G. R.; Grealish, M. P.; Jung, M. K.; Hamel, E.; Pettit, R. K.; Chapuis, J. C.; Schmidt, J. M. J. Med. Chem., 2002, 45, 2534-2542; Kim, S.; Ko, H.; Park, J. E.; Jung, S.; Lee, S. K.; Chun, Y.-J. J. Med. Chem., 2002, 45, 160-164). In view of their immense medicinal importance, there have been numerous efforts at devising efficient synthetic methodologies towards 2- or 4-hydroxy substituted stilbene derivatives and their analogues. For instance, 3,4 dihydroxy styryl cinnamate, a lithospemic acid based antidiabetic stilbene derivative, has been synthesized through a lengthy 9 step synthetic strategy via Wittig olefination of corresponding hydroxy benzaldehydes. The presence of the hydroxy function in target compounds not only required additional protection-deprotection steps but also precluded the use of any alternate synthetic strategy (Bioorg. Med. Chem. Lett. 2007, 17, 4481). Similarly, the naturally occurring salvianolic acid was synthesized in a tedious 8 step linear reaction sequence involving protection of hydroxy function, Wittig olefinations and deprotection of the hydroxy group which results in a significant decrease in the overall synthetic efficiency (Tetrahedron 55 (1999) 6923-6930). In yet another instance, a majority of the conventional synthetic methods for medicinally important 1,4-bis-styrylbenzenes comprise tedious multistep sequences involving wittig, and protection, deprotection strategies (J. Med. Chem. 2007, 50, 4986-4992).

"Various other commercially important stilbene derivatives have been accessed through diverse reaction methodologies, including Wittig, modified Julia olefination, reaction of benzyllithium with benzaldehydes followed by dehydration, Perkins reaction, cross metathesis of styrenes, Suzuki reaction with .beta.-halostyrenes, decarbonylative Heck reaction between acid chloride and styrene, Heck arylation-desilylation of vinylsilane followed by Heck arylation of styrenes formed in situ and palladium catalysed arylation of styrenes with halobenzene (G. R. Pettit, M. P. Grealish, M. K. Jung, E. Hamel, R. K. Pettit, J.-C. Chapuis, J. M. Schmidt, J. Med. Chem., 2002, 45, 2534; M. Roberti, D. Pizzirani, D. Simony, R. Rondanin, R. Baruchello, C. Bonora, F. Buscemi, S. Grimaudo, M. Tolomeo, J. Med. Chem., 2003, 46, 3546; H. Meier, U. Dullweber, Tetrahedron Lett., 1996, 37, 1191; J. Yu, M. J. Gaunt, J. B. Spencer, J. Org. Chem., 2002, 67, 4627; D. A. Alonso, C. Najera, M. Varea, Tetrahedron Lett., 2004, 45, 573; E. Alonso, D. J. Ramon, M. Yus, J. Org. Chem., 1997, 62, 47; G. Solladie, Y. Pasturel-Jacope, J. Maignun, Tetrahedron, 2003, 59, 3315; S. Chang, Y. Na, H. J. Shin, E. Choi, L. S. Jeong, Tetrahedron Lett., 2002, 43, 7445; S. Eddarir, Z. Abdelhadi, C. Rolando, Tetrahedron Lett., 2001, 42, 9127; M. B. Andrus, J. Liu, E. L. Meredith, E. Nartey, Tetrahedron Lett., 2003, 44, 4819; T. Jeffery, B. Ferber, Tetrahedron Lett., 2003, 44, 193; N. F. Thomas, K. C. Lee, T. Paraidathathu, J. F. F. Weber, K. Awing, Tetrahedron Lett., 2002, 43, 3151).

"The following prior art references are disclosed as below: Journal of Org. Chem., 2001, 66, 8135, discloses a method for the synthesis of combretastatin A-4 (both cis and trans isomeric forms) through Wittig method and Perkin condensation method. Natural Product Research., 2006, 20, 247, discloses a method for the improved synthesis of resveratrol through two step process Wittig reaction and Heck coupling. Synthesis, 2006, 273, discloses a method for the synthesis of biologically important trans-stilbenes via Ru-catalyzed cross metathesis. J. Med. Chem., 2005, 48, 6783, discloses a method for the synthesis of resveratrol analogue with high ceramide-mediated proapoptotic activity on human breast cancer cells. Molecules, 2004, 9, 658, discloses a method for synthesis of stilbenes via the Knoevenagel condensation. Carbohydrate Research., 1997, 301, 95, discloses a method for the synthesis of hydroxy stilbenes and their glycosides through Wittig reaction. Bioorg. Med. Chem. Lett. 1998, 8, 1997, discloses a method for the asymmetric synthesis of antimitotic combretadioxolone with potent anti-tumor activity. Tetrahedron, 2004, 60, 5563, discloses a method for the synthesis of resveratrol and their analogues using Heck reaction in organic and aqueous solvents. J. Med. Chem., 2002, 45, 2534, discloses a method for the synthesis of hydroxy stilbenes and benzophenones through Wittig reaction. U.S. Pat. No. 20040147788 A1 discloses a method for the synthesis of stilbene derivatives through Wittig reaction. U.S. Pat. No. 20040015020 A1 discloses a method for the synthesis of E-isomer of stilbene through halide assisted conversion of corresponding Z-isomer. J. Med. Chem., 2003, 46, 3546, discloses a method for the synthesis of resveratrol and their analogues through addition of aromatic aldehydes and appropriate ylide. Journal of Org. Chem., 1961, 26, 5243, discloses a method for the synthesis of stilbene and heterocyclic stilbene analogues. Journal of Chem. Soc., 1954, 3596, discloses a method for the synthesis of stilbenes through dehydrogenation from diarylethanes. U.S. Pat. No. 6,048,903 discloses a method for the synthesis of E-resveratrol by Wittig reaction comprising benzyltriaryl phosphonium salt and anisaldehyde in the presence of n-butyl lithium. Organic Synthesis Collective Volume I, 1941, 441-442 and Volume IV, 1963, 731-734, disclose a method for the preparation of styrenes by decarboxylation of cinnamic acids with quinoline in the presence of copper powder at 200-300.degree. C.

"Some of other typical prior art references include U.S. Pat. Nos. 6,844,471, 6,552,213, 20040152629 A1; 6361815; 5569786; European Pat. Nos. EP 0331983; Tetrahedron lett., 1980, 21, 2073; Synthesis, 1977, 58, J. Chem. Soc. Perkin Trans. I, 1974, 961; J. Chem. Soc., 1963, 2875; Chem. Pharm. Bull., 1992, 40, 1130; Bioorg. Med. Chem. Lett. 2007, 17, 4481, Tetrahedron 55 (1999) 6923-6930.

"Amongst the above mentioned synthetic methodologies for hydroxy stilbenes, the palladium catalysed Heck reaction between hydroxy styrenes and halobenzenes has remained a prominent approach due to the easy availability of variously substituted halobenzenes, remarkable ability of palladium catalyst to withstand a wide range of functional groups coupled with the possibilty to conduct multicomponent reactions using appropriately substituted reactants. However, the Heck approach for hydroxy substituted stilbenes has also been recognized to be tedious and inefficient due to the preponderant tendency of hydroxy styrenes for polymerization. Consequently, a majority of the prevalent Heck approaches for hydroxy stilbenes comprise multistep protection-deprotection sequences (Natural Product Research, Vol. 21, No. 6, 20 May 2007, 564-573, Natural Product Research, Vol. 20, No. 3, March 2006, 247-252, Tetrahedron Letters 47 (2006) 5811-5814.) which not only utilize harsh reagents but also further burden the overall synthetic efficiency of the method.

"In order to address the above concerns, it therefore, becomes an object of the invention to develop a method, wherein the hydroxy styrenes are formed from the corresponding benzaldehydes, cinnamic acids or their derivatives and then allowed to react in situ with appropriately substituted halobenzenes under Heck like conditions to give the desired stilbene derivatives without any need for isolation of reaction intermediates or protection-deprotection steps. The above one pot approach would not only remove the currently indispensable and synthetically inefficient isolation of reaction intermediates obtained from sequential condensation, decarboxylation and Heck reactions but also provide the desired stilbenes in enhanced yields as it would allow the hydroxystyrenes to in situ join the desired Heck coupling pathway instead of the competing wasteful polymerization pathways.

"It is worthwhile to mention that we had earlier disclosed a microwave induced process for the preparation of substituted stilbenes and its analogs (U.S. Patent No. 20070276172 A1). However, the above approach employing Perkin reaction between hydroxy benzaldehydes and phenyl acetic acids was limited towards the synthesis of stilbenes (C.sub.6--C.sub.2--C.sub.6 chain) possessing a single ethylinic linkage which severely precluded an access towards immensely important multiconjugated stilbenes possessing an .alpha., .beta.-unsaturated carboxylic acid moiety i.e. (C.sub.6--C.sub.2--C.sub.6--C.sub.3 chain). In contrast, such an introduction of extra C.sub.3 chain to stilbene moiety (C.sub.6--C.sub.2--C.sub.6 chain) is not possible using our above patent (U.S. Patent No. 20070276172 A1). Further, the present invention not only gives a new one pot approach towards Heck coupling of in situ formed hydroxy styrenes, but also provides an unprecedented opportunity to conduct simultaneous multicomponent reactions in one pot leading to a novel single step synthesis of a range of medicinally important multiconjugated stilbene derivatives including antidiabetic lithospermic acids etc. which had hitherto been accessed only through tedious multistep protocols.

"In view of the above discussion, it is quite evident that there is a need for developing efficient synthetic protocols for hydroxy substituted stilbene derivatives and analogues in view of the current limitations like lengthy mutistep protocols, use of harsh protection-deprotection reagents and low yields of final products etc. It, therefore, becomes an object of the invention to provide a rapid, economical and one pot multicomponent process for the preparation of 2- or 4-hydroxy substituted stilbene derivatives from cheap and commercially available substituted arylaldehydes and halobenzenes so as to eliminate the disadvantages associated with the above patents and papers. It is worthwhile to mention that microwave-assisted (A. K. Bose, B. K. Banik, N. Lavlinskaia, M. Jayaraman, M. S. Manhas, Chemtech, 1997, 27, 18; M. Larhed, Hallberg, Drug Discovery Today, 2001, 6(8), 406) chemical transformation is a new emerging technique which is generally known for ecofriendly, rapid and high yielding process. However, such an effect of microwave is unique in the above invention in a way that a one pot multicomponent reaction involving condensation, decarboxylation and Heck coupling would occur simultaneously without either the need for decarboxylation/protection-deprotection agents or isolation of highly reactive intermediates.

"Keeping in view the above problems, we disclose a unique and novel one pot process to prepare 2- or 4-hydroxystilbene derivatives and their analogues in one step from 2- or 4-hydroxy substituted arylaldehydes, malonic acid and halobenzenes in the presence of a base, palladium catalyst, triphenylphosphine and solvent. In fact, we have already observed that while trying to emulate Knoevenagel Doebner condensation (B. S. Furniss, A. J. Hannaford, V. Rogers, P. W. G. Smith, A. R. Tatchell, In: Vogel's Textbook of Practical Organic Chemistry, Fourth Edn. (ELBS, UK), 1978, 802), reaction under microwave (A. K. Bose, B. K. Banik, N. Lavlinskaia, M. Jayaraman, M. S. Manhas, Chemtech, 1997, 27, 18; M. Larhed, Hallberg, Drug Discovery Today, 2001, 6(8), 406; C. Kuang, H. Senboku, M. Tokuda, Tetrahedron, 2002, 58, 1491; N. Kuhnert, Angew. Chem. Int. Ed, 2002, 41, 1863), 4-hydroxy substituted benzaldehydes produce aryl styrenes instead of the expected cinnamic acids (A. K Sinha., B. P Joshi., A Sharma., U.S. Pat. No. 6,989,467, 2006). The above finding coupled with the limitation of using hydroxy styrene in a linear reaction sequence for a Heck type synthesis of stilbene derivatives prompted us to explore a one pot multicomponent strategy wherein hydroxy styrenes are initially formed and then allowed to couple in situ with appropriately substituted halobenzenes to give diverse bioactive compounds bearing the stilbene scaffold. Hence, in the beginning, we decided to react 3,4-dihydroxy benzaldehyde with malonic acid and bromobenzaldehyde in a unique one pot Knoevenagel Doebner Heck reaction methodology utilizing a base, palladium catalyst and triphenylphosphine under microwave irradiation. To our delight, our above premise was proven when the expected product, a novel multiconjugated stilbene cinnamic acid derivative was formed in a short reaction time albeit in a low yield. Thereafter, the amount of malonic acid was increased and various combinations of bases, palladium catalyst and solvents were used to optimize the reaction conditions which produced the product in moderate to good yield. The same method was applied on other 2- or 4-hydroxy substituted benzaldehydes which upon condensation with malonic acid and subsequent coupling with various substituted halobenzenes, successfully provided various other novel multiconjugated stilbene derivatives, wherein, three or more reaction steps involving condensation, decarboxylation, and Heck coupling got completed in a single step."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention provides a process for the preparation of some novel commercially important multiconjugated 2- or 4-hydroxy substituted stilbene derivatives such as analogues of lithospermic acid, bis-styrylbenzenes, salvianolic acid, resveratrol, pterostilbene, and many others under microwave irradiation from the one pot multicomponent reaction of substituted arylaldehydes, malonic acid and halobenzenes with at least one hydroxy substituent at 2- or 4-position of arylaldehyde in the presence of a base, Pd catalyst, PPh.sub.3 and solvent. The base is selected from a group consisting of collidine, triethylamine, pyridine, piperidine, sodium acetate, ammonium acetate, imidazole, methyl imidazoles, DBU and the like. Palladium catalyst is selected from a group consisting of palladium acetate, palladium nanoparticles, palladium chloride, tetrakis(triphenylphosphine)palladium(0) etc. Solvent for the process is selected from a group consisting of dimethylformamide, polyethylene glycol, dimethoxyethane, glycol, NMP, DMA, toluene, pyridine, ionic liquids and the like. The final products 2- or 4-hydroxy substituted stilbene derivatives are obtained in good to moderate yields varying from 25-66% within 1 min-16 hrs. It is worthwhile to mention that this microwave-assisted unique process is in fact an unexpected and novel result of three-four individual steps consisting of condensation of substituted arylaldehydes and malonic acid, decarboxylation and coupling of hydroxy styrene with halobenzenes occurring in one pot with at least one hydroxy substituent at 2- or 4-position of arylaldehyde without addition of any decarboxylating or protection-deprotection agents. It is also important to note that the developed one pot multicomponent process provides 2- or 4-hydroxy substituted stilbene derivatives in enhanced yields and reduced times in comparison to when the same reactions are conducted separately through the sequential isolation of reaction intermediates. Further that conducting the above reaction by conventional method instead of microwave provides the corresponding cinnamic acids as major products and low yield of stilbene derivatives, even when 2- or 4-hydroxy substituted arylaldehyde are taken as starting materials.

"Accordingly, the present invention provides novel multiconjugated hydroxy stilbene derivatives with the general formula 1:

"##STR00001## wherein, at least one substituent being OH amongst R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.10, and rest of substituents amongst R.sub.1 to R.sub.10, being H, OH, OCH.sub.3, CH.sub.3COO, halogen group, nitro group, CH.dbd.CH--COOH, C.sub.6H.sub.3 -(4-OH,3-OMe), C.sub.6H.sub.4--CH.dbd.CH--CO--C.sub.6H.sub.4-(4-OMe), CH.sub.2--CH.sub.2--CH.sub.3 or combinations thereof.

"In an embodiment of the present invention, the representative compounds of the general formula 1 comprising; i. 4-((E)-prop-2-enoic acid)-3',4'-dihydroxystilbene, ii. 4-((E)-prop-2-enoic acid)-4'-hydroxy-3',5'-dimethoxystilbene, iii. 2'-(propyl)-4-hydroxy-3,4',5'-trimethoxystilbene, iv. 4-hydroxy-3,4',5-trimethoxy stilbene, v. 4-hydroxy-3-methoxy, 3'4'-dioxymethylenestilbene, vi. 2-(4-hydroxy-3-methoxystyryl)thiophene, vii. (E,E)-1,4-Bis(4-hydroxy, 3-methoxy)styrylbenzene, viii. ((E,E)-1,4-Bis(4-hydroxy-3-methoxy)styrylbenzene, ix. ((E,E)-1,4-Bis(4-hydroxy-3,5-dimethoxy)styrylbenzene, x. ((E,E)-4,4'-Bis(4-hydroxy-3,5-dimethoxy)styrylbiphenyl, xi. ((E,E,E)-1,3,5-Tris(4-hydroxy-3,5-dimethoxy)styrylbenzene, xii. (E,E)-1,4-Dimethoxy-2,5-bis(4-hydroxy-3-methoxy)styryl-benzene, xiii. (E,E)-9,10-Bis(4-hydroxy-3,5-dimethoxy)styrylanthracene, xiv. (E,E)-2-Fluoro-1,4-bis(4-hydroxy-3,5-dimethoxy)styryl-benzene, xv. 4-hydroxy-3-methoxy-4'-(3-(1-(4-methoxyphenyl))-2-propen-1-one) stilbene.

"In another embodiment of the present invention, the said process comprising the steps of: a) reacting substituted arylaldehyde with at least one hydroxy substituent at 2- or 4-position, malonic acid and halobenzene in the presence of a base, palladium catalyst, triphenylphosphine and a solvent by refluxing under conventional or microwave irradiation for a period ranging between 30 min-15 hr. b) transferring the reaction mixture of step (a) and washing the residue with an organic solvent, c) washing the organic solution of step (b) with a mineral acid, brine and water, d) drying the organic layer of step © over a dehydrating agent, filtering and evaporating to dryness to completely remove the solvent to obtain a residue, e) purifying the residue of step (d) on Si-gel (60-120 mesh size) with a mixture of ethylacetate and hexane (9:1 to 6:4) to obtain the required substituted 2-aryl aldehydes of general formula 1.

"In yet another embodiment of the present invention, the base used is selected from the group consisting of collidine, triethylamine, pyridine, piperidine, DBU, sodium acetate, ammonium acetate, imidazole, methyl imidazoles, ammonium formate and a combination there of.

"In yet another embodiment of the present invention, the palladium catalyst used is selected from the group consisting of palladium acetate, palladium nanoparticles, to palladium chloride, tetrakis(triphenylphosphine)palladium(0) and a combination there of.

"In still another embodiment of the present invention, the solvent used is selected from the group consisting of dimethylformamide, polyethylene glycol, dimethoxethane, NMP, DMA, toluene, pyridine, ionic liquids and a combination there of.

"In still another embodiment of the present invention, the mole ratio between substituted arylaldehyde and malonic acid is ranging between 1:1 to 1:4 moles.

"In still yet another embodiment of the present invention, the mole ratio between the substituted arylaldehyde and the base is ranging between 1:1 to 1:6 moles, preferably, 1:3 moles.

"In still yet another embodiment of the present invention, the mole ratio between the substituted arylaldehyde and halobenzene is ranging between 1:1 to 1:2 moles.

"In further yet another embodiment of the present invention, the mole ratio between halobenzene and palladium catalyst is ranging between 1:0.01 to 1:0.04 moles.

"In further another embodiment of the present invention, the mole ratio between halobenzene and triphenylphosphine is ranging between 1:0.01 to 1:0.05 moles.

"In further another embodiment of the present invention, the claimed process is found workable in both monomode at 250 W and 160.degree. C. temperature and multimode microwave at 700-1500 W and 160-180.degree. C. temperatures.

"In yet another embodiment of the present invention, the various substituted stilbene derivatives obtained by the developed process can also be hydrogenated in same pot to provide the biologically important bibenzyl derivatives.

"In yet another embodiment of the present invention, the hydroxylated or methoxylated styrenes obtained in situ via decarboxylation of respective cinnamic acid derivatives also undergo multicomponent reaction of hydroxy substituted benzaldehydes in the same pot in the presence of an ionic liquid.

"In further another embodiment of the present invention, the process for the preparation of 2- or 4-hydroxy substituted stilbene derivatives is carried out in a one pot multicomponent manner wherein condensation, decarboxylation and heck coupling occur simultaneously without either the need for decarboxylating/protection-deprotection agents or individual isolation of highly reactive intermediates in one step."

For more information, see this patent: Sharma, Abhishek; Sinha, Arun Kumar; Kumar, Rakesh; Sharma, Naina. One Pot Multicomponent Synthesis of Some Novel Hydroxy Stilbene Derivatives with Alpha, Beta-Carbonyl Conjugation under Microwave Irradiation. U.S. Patent Number 8716532, filed March 26, 2010, and published online on May 6, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=79&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3937&f=G&l=50&co1=AND&d=PTXT&s1=20140506.PD.&OS=ISD/20140506&RS=ISD/20140506

Keywords for this news article include: Anions, Therapy, Styrenes, Chlorides, Palladium, Legal Issues, Nanoparticle, Benzaldehydes, Nanotechnology, Hydrochloric Acid, Benzene Derivatives, Transition Elements, Emerging Technologies.

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