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Synthesis of Magnolol and Its Analogue Compounds Synthese Von Magnolol Und Analog-Verbindungen Synthèse De Magnolol Et Ses Composés Analogues

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Synthesis of Magnolol and Its Analogue Compounds Synthese Von Magnolol Und Analog-Verbindungen Synthèse De Magnolol Et Ses Composés Analogues (19) TZZ ¥¥_Z_T (11) EP 2 539 310 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 37/055 (2006.01) C07C 37/62 (2006.01) 16.07.2014 Bulletin 2014/29 C07C 39/21 (2006.01) C07C 41/48 (2006.01) C07C 41/52 (2006.01) C07C 43/313 (2006.01) (2006.01) (2006.01) (21) Application number: 10705965.1 C07C 43/30 A61K 31/05 A61P 31/04 (2006.01) (22) Date of filing: 25.02.2010 (86) International application number: PCT/US2010/025378 (87) International publication number: WO 2011/106003 (01.09.2011 Gazette 2011/35) (54) SYNTHESIS OF MAGNOLOL AND ITS ANALOGUE COMPOUNDS SYNTHESE VON MAGNOLOL UND ANALOG-VERBINDUNGEN SYNTHÈSE DE MAGNOLOL ET SES COMPOSÉS ANALOGUES (84) Designated Contracting States: • SUBRAMANYAM, Ravi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Belle Mead HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL NJ 08502 (US) PT RO SE SI SK SM TR (74) Representative: Jenkins, Peter David (43) Date of publication of application: Page White & Farrer 02.01.2013 Bulletin 2013/01 Bedford House John Street (73) Proprietors: London WC1N 2BF (GB) •Colgate-Palmolive Company New York, NY 10022 (US) (56) References cited: • Indian Institute Of Chemical Technology US-A1- 2006 140 885 Andhra Pradesh (IN) • J. RUNEBERG: "Phenol Dehydrogenations" (72) Inventors: ACTA CHEMICA SCANDINAVICA, vol. 12, 1958, • REDDY, Basi, V., Subba pages 188-192, XP002575197 cited in the Nacharam (IN) application • YADAV, Jhillu, S. • M.R. AGHARAHIMI, N.A. LEBEL: "Synthesis of Hyderabad (IN) (-)-Monoterpenylmagnolol and Magnolol" JOURNAL OF ORGANIC CHEMISTRY, vol. 60, 1995, pages 1856-1863, XP002575198 ISSN: 0022-3263 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 539 310 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 539 310 B1 Description FIELD OF THE INVENTION 5 [0001] The embodiments of the invention relate to a method of producing magnolol or its analogue compounds. The embodiments also relate to a pharmaceutically or orally acceptable compostion comprising magnolol or its analogue compounds prepared according to the method described herein. BACKGROUND OF THE INVENTION 10 [0002] Magnolol (5,5’-diallylbiphenyl-2,2’-diol or 5,5’-dially-2,2’-bisphenol), together with honokiol, are the major in- gredients found in magnolia extracts. It is well recognized in the art that magnolia extracts have e found, among other things, applications in compositions to treat bacteria and/or inflammation related oral diseases. See, e.g., U.S. Patent No. 6,544,409, and U.S. patent application publication No U.S. 2006/0,140,885, the disclosures of which are incorporated 15 by reference herein in their entireties. 20 25 [0003] Studies have further revealed that magnolol, as an independent active substance, also plays an important role in other pharmacological processes besides its anti-bacterial and anti-inflammatory activities. For example, magnolol has been shown to exhibit a beneficial capability of protecting the myocardium against infaction and reperfusion injury. 30 It has also been shown that magnolol protects neurons against chemical hypoxia by KCN in cortical neuron-astrocyte mixed cultures, More recently, it is reported that magnolol possesses an antioxidant activity 1000 times greater than α- tocopherol, implicating magnolol’s great potential in food and pharmaceutical applications. All these divergent uses reveal that there is a great need for high quality and affordable magnolol.See Wen-Hsin Huang et al., The Chinese Pharmaceutical Journal, 2006, 58, 115, 122, Min-Min Lee et al, Chinese Journal of Physiology, 2000, 43, 61-67. 35 [0004] Currently, there are several synthetic methods of producing magnolol reported in the art one of which is described in a paper by J. Runeberg, Acta Chem Scand, 1958, 12, 118-192, wherein the key reactant methyl ether of 5,5’-dibromo- 2,2’-bisphenol was reacted with allyl bromide in tetrahydrofuran (THF) in the presence of ethylmagnesium bromide to obtain methyl ether of 5,5’-diallylbiphenyl-2 2’-diol as shown below: 40 45 50 [0005] This reaction requires refluxing conditions, and provides a low yield of the desired product. Furthermore, the subsequent step of removing the methyl group of methyl ether of 5,5’-diallylbiphenyl-2,2’-diol to obtain magnolol requires 55 even higher temperature, and the reaction mixture is difficult to separate and purify, thereby resulting in a low yield of magnolol. [0006] Other reported synthetic methods of producing magnolol in the art also suffer similar problems, such as low yields, difficulty in purification the high cost of synthesis, and/or not practical or compatible for industrial scale. See, e.g. 2 EP 2 539 310 B1 Wen-Hsin Huang et al., The Chinese Pharmaceutical Journal, 2006, 58, 115-122; and Wenxin Gu et al., Tetrahedron: Asymmetry, 1998, 9, 1377-1380. Therefore, there exists a practical need in the art to develop a synthetic method to produce high quality and affordable magnolol, as well as derivatives and analogues thereof. 5 SUMMARY OF THE INVENTION [0007] In one embodiment,the invention encompasses a method of producing magnolol (5,5’-diallylbiphenyl-2,2’-diol) or its analogue compounds comprising reacting 2,2’-bisphenol with bromine at room temperature in an organic solvent to obtain 5,5’-dibromo-2,2’-bisphenol, subsequently protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol 10 with metoxymethylchloride (MOM-Cl) in an organic solvent in the presence of an organic base to obtain MOM ether of 5,5’-dibromo-2,2’-bisphenol, and further reacting the MOM ether of 5,5’-dibromo-2,2’-bisphenol with a substituted or unsubstituted allyl bromide in an organic solvent with magnesium and ethyl bromide to effect the coupling and thus obtain MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative or analogue thereof, and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative or analogue thereof with a suitable agent to obtain magnolol or a derivative 15 or analogue thereof. [0008] In another embodiment, the invention encompasses a method of producing MOM ether of 5,5’-diallylbiphenyl-- 2,2’-diol comprising reacting 2,2’-bisphenol with bromine at room temperature in an organic solvent to obtain 5,5’-dibromo- 2,2’-bisphenol, subsequently protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol with methoxymethylchlo- ride (MOM-Cl) in an organic solvent in the presence of an organic base to obtain MOM ether of 5,5’-dibromo-2,2’- 20 bisphenol, and further reacting the MOM ether of 5,5’-dibromo-2,2’-bisphenol with a substituted or unsubstituted allyl bromide in an organic solvent with magnesium and ethyl bromide to effect the coupling and thus obtain MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or its analogue compounds. [0009] In yet another embodiment, the invention encompasses an intermediate compound of MOM ether of 5,5’- diallylbiphenyl-2,2’-diol, or a derivative or analogue thereof. 25 [0010] In yet a further embodiment, the invention encompasses a method for producing magnolol (5,5’-diallylbiphenyl- 2,2’-diol) or a derivative or analogue thereof comprising obtaining an intermediate compound of MOM ether of 5,5’- diallylbiphenyl-2,2’-diol or a derivative or analogue thereof, and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’- diol or a derivative or analogue thereof with a suitable agent to obtain magnolol or a derivative or analogue thereof. [0011] In yet a further embodiment, the invention emcompasses a method for producing magnolol (5,5’-diallylbiphenyl- 30 2,2’-diol) or a derivative or analogue thereof comprising converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative or analogue thereof with a suitable agent to obtain magnolol or a derivative or analogue thereof. DETAILED DESCRIPTION 35 [0012] The following definitions and non-limiting guidelines must be considered in reviewing the description of this invention set forth herein. The headings (such as "Background" and "Summary,") and sub-headings (such as "Compo- sitions" and "Methods") used herein are intended only for general organization of topics within the disclosure of the invention, and are not intended to limit the disclosure of the invention or any aspect thereof. In particular, subject matter disclosed in the "Background" may include aspects of technology within the scope of the invention, and may not constitute 40 a reaction of prior art. Subject matter disclosed in the "Summary" is not an exhaustive or complete disclosure of the entire scope of the invention or any embodiments thereof. Classification or discussion of a material within a section of this specification as having a particular utility (e.g., as being an "active" or a "carrier" ingredient) is made for convenienc e, and no inference should be drawn that the material must necessarily or solely function in accordance with its classification herein when it is used in any given composition. 45 [0013] The citation of references herein does not constitute an admission that those references are prior art or have any relevance to the patentability of the invention disclosed herein. Any discussion of the content of references cited in the Introduction is intended merely to provide a general summary of assertions made by the authors of the references, and does not constitute an admission as to the accuracy of the content of such references.
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