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

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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.

[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:

[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.

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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 methoxymethylchloride (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. [0014] The description and specific examples, while indicating embodiments of the invention, are intended for purposes 50 of illustration only and are not intended to limit the scope of the invention. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features, or other embodiments incorporating different combinations the stated of features. Specific Examples are provided for illustrative purposes of how to make and use the compositions and methods of this invention and, unless explicitly stated otherwise, are not intended to be a representation that given embodiments of this invention have, or have not, been made or tested. 55 [0015] As used throughout, ranges are used as a shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein ate hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

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[0016] Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material. The recitation of a specific value herein, whether referring to respective amounts of components, or other features of the embodiments, is intended to denote that value, plus or minus a degree of variability to account for errors 5 in measurements. For example, an amount of 10% may include 9.5% or 10.5%, given the degree of error in measurement that will be appreciated and understood by those having ordinary skill in the art. [0017] As used herein, the term "alkyl" means a linear or branched hydrocarbon chain with preferably between 1 and 10 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and suitable isomers of pentyl and hexyl, wherein the methyl group is preferred. 10 [0018] As used herein, the term "substituted or unsubstituted phenyl" describes a phenyl group whose phenyl ring is substituted if necessary one or more times. Further, the term "substituted" means that any one or more hydrogenos on the designated atom is replaced with a selection from the indicated group provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. [0019] As used herein, the term "comprising" means that other steps and other components that do not affect the end 15 result may be utilized. The term "comprising" encompasses the expressions consisting of’ and consisting essentially of." The use of singular identifiers such as "the" "a," or "an" is not intended to be limiting solely to the use of a single component, but may include multiple components. [0020] As used herein the term "room temperature" means the ambient temperature ot an typycal laboratory, which is usually about that of Standard Temperature and Pressure (STP). As used herein, a purified" or "isolated" compound 20 means the compound has been separated from the reaction mixture in which it was formed. [0021] As used herein the term "increased pressure" refers to a pressure above 1 atmosphere as is commonly understood by one of skill in the art. Conversely, as used herein, the term "reduced pressure" means a pressure of below 1 atmosphere as commonly understood by one of skill in the art. [0022] As used herein, the expressions "carrier" or "orally acceptable carrier" as used throughout this description 25 denote any safe and effective materials for use herein. Such materials include, water solvents, etc., that may contain a humecant such as glycerine, sorbitol, xylitol and the like. The carrier or orally acceptable carrier also may include additional components that are generally acceptable to a person skilled in the art. [0023] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with 30 the tissues of human beings and animals without excessive toxicity, irritation, allergie response or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0024] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of 35 acidic residues such as carboxylic acids, and the like. [0025] As used herein, the term "effective amount" refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination as an active ingredient. [0026] The present invention provides a chemical synthetic sequence that is cost effective, has an easy work-up and purification methodology, and has scale-up compatability for the production of the active substance magnolol and de- 40 rivatives or analogues thereof. The chemical synthetic sequence is easily reproducible on a large scale throngh simple and high-yield synthetic steps that lead to high-quality final products. The embodiments of the invention encompass a method of producing a compound of formula (I)

wherein R reprensents H, alkyl, a substituted or unsubstituted phenyl group; or its pharmaceutically or orally acceptable

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salts. Accordingly, derivatives and analogues of magnolol include those in which R is not H. The method preferably comprieses:

(a) reacting a compund of formula (II) 5

with bromine in an organic solvent to obtain a compound of formula (III) 15

25 (b) reacting the compound of formula III with MOM-Cl in an organic solvent in the presence of an organic base to produce a compound of formula (IV)

(c) reacting the compound of formula IV with R-CH=CH-CH 2-Br, wherein R is defined as above, in an organic solvent 40 with magnesium and ethyl bromide to effect the coupling for an efficient amount of time to obtain a compound of formula V

55 (d) converting the compound of formula V with a suitable agent in an organic solvent to obtain a compound of formula I (e) optionally, converting the compound of formula I to its pharmaceutically or orally acceptable salts.

[0027] In one preferred embodiment, the invention encompasses a method of producing magnolol wherein R is hy-

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drogen, or a derivative or analogue of magnolol wherein R is methyl or a phenyl. More preferably, the invention encompasses a method of producing magnolol wherein R is hydrogen. [0028] In another embodiment, the invention encompasses a method of producing magnolol or a derivative or analogue thereof, wherein the first process includes reacting 2,2’-bisphenol with bromine at room temperature in an organic solvent 5 selected from the group consisting of chloroform dichloromethane, dichloroethane, dimethylsulfoxide, dimethylforma- mide, acetonitrile, tetrahydrofuran, diethylether, hexane, acetone, methanol, ethanol, benzene, toluene. More preferable, the organic solvent is selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran, methanol. [0029] In yet another embodiment the invention encompasses a method of producing magnolol or a derivative or analogue thereof, wherein step of protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol with methoxymeth- 10 ylchloride (MOM-Cl) in an organic solvent in the presence of an organic base includes using an organic base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, piperidine, lutidine, imidazole. More preferably, the organic base is selected from the group consisting of diisopropylethylamine, pyridine, piperidine and lutidine. [0030] In yet a further embodiment, the invention encompasses a method of producing magnolol or a derivative or analogue thereof, wherein the suitable agent used to remove the MOM group is selected from the group consisting of 15 boron halides, trimethylsilane iodide, and trimethylsilane chloride (TMS-Cl). More preferably, the agent is trimethylsilane chloride (TMS-Cl). Those skilled in the art are capable of determining a suitable agent capable of removing the MOM group (or deprotecting the MOM-containing derivative), using the guidelines provided herein, [0031] The reaction may be carried out for a period of time sufficient to obtain the desired product. A "sufficient" amount of time depends in part on the desired extent of reaction and the reaction conditions, such as temperature. One of 20 ordinary skill in the art can easily monitor the reaction to determine when a sufficient am ount of time has transpired. The preferred amount of time is generally about 30 minutes to about 48 hours, preferably about 24 hours. [0032] A preferred embodiment of the invention encompasses a method of producing magnolol (5,5’-diallylbiphenyl- 2,2’-diol) or a derivative or analogue thereof comprising reacting 2,2’-bisphenol with bromine in an organic solvent such as chloroform to obtain 5,5’-dibromo-2,2’-bisphenol, subsequently protecting the two hydroxyl groups of 5,5’-dibromo- 25 2,2’-bisphenol with methoxymethylchloride (MOM-Cl) in an organic solvent such as dichloromethane in the presence of an organic base such as diisopropylethylamine 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 such as tetrahydrofuran with magnesium and ethyl bromide to effect the coupling and to obtain MOM ether of 5,5’- diallylbiphenyl-2,2’-diol or a derivative or analogue thereof (depending on whether the allyl bromide is substituted with 30 other than hydrogen), and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or its analogue compounds with a suiatble deprotecting agent such as trimethylsilane chloride (TMS-Cl) in an organic solvent such as methanol to obtain magnolol or a derivative or analogue thereof. Magnolol or a derivative or analogue thereof can be optionally converted to their orally or pharmaceutically acceptable salts by a person having ordinary skill in the art. [0033] In another embodiment, the invention encompasses a method of producing magnolol comprising reacting 2,2’- 35 bisphenol with bromine in chloroform to obtain 5,5’-dibromo-2,2’-bisphenol, subsequently protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol with methoxymethylchloride (MOM-Cl) in dichloromethane in the presence of diisopropylethylamine to obtain MOM ether of 5,5’-dibromo-2,2’-bisphenol, further reacting the MOM ether of 5,5’-dibromo-2,2’-bisphenol with allyl bromide in tetrahydrofuran with magnesium and ethyl bromide to effect the coupling and to obtain MOM ether of 5,5’-diallylbiphenyl-2,2’-diol, and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol with 40 trimethylsilane chloride (TMS-Cl) in methanol to obtain magnolol. Magnolol can optionally be converted to its orally or pharmaceutically acceptable salts by a person having ordinary skill in the art. [0034] In another embodiment, the invention encompasses a method according to claim 9. [0035] In yet another embodiment, the invention encompasses a method of producing MOM ether of 5,5’diallylbiphenyl- 2,2’-diol or a derivative or analogue thereof comprising reacting 2,2’-bisphenol with bromine at room temperature in an 45 organic solvent such as chloroform to obtain 5,5’-dibromo-2,2’-bisphenol, subsequently protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol with methoxymethylchloride (MOM-Cl) in an organic solvent such as dichloromethane in the presence of an organic base such as diisopropylethylamine 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 such as tetrahydrofuran with magnesium and ethyl bromide to effect the coupling and to obtain MOM 50 ether of 5,5’-diallylbiphenyl-2,2’-diol, or a derivative or analogue thereof. [0036] In a further 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 chloroform to obtain 5,5’-dibromo-2,2’- bisphenol, and subsequently protecting the two hydroxyl groups of 5,5’-dibromo-2,2’-bisphenol with methoxymethylchloride (MOM-Cl) in dichloromethane in the presence of diisopropylethylamine to obtain MOM ether of 5,5’-dibromo-2,2’- 55 bisphenol, and further reacting the MOM ether of 5,5’-dibromo-2,2’-bisphenol with allyl bromide in tetrahydrofuran through the involvement of magnesium turnings and ethyl bromide to obtain MOM ether of 5,5’-diallylbiphenyl-2,2’-diol. [0037] In yet another embodiment, the invention encompasses a method of producing magnolol (5,5’-diallylbiphenyl- 2.2’-diol) or a derivative or analogue thereof comprising obtaining MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative

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or analogue thereof and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative or analogue thereof to magnolol or a derivative or analogue thereof. [0038] In yet another embodiment, the invention encompasses a method of producing magnolol comprising obtaining MOM ether of 5,5’-diallylbiphenyl-2,2’-diol and converting the MOM ether of 5,5’-diallylbiphenyl-2,2’-diol with trimethyl- 5 silane chloride (TMS-Cl) in methanol to obtain magnolol. [0039] In yet another embodiment, the invention encompasses a method of producing magnolol (5,5’-diallylbiphenyl- 2,2’-diol) or a derivative or analogue thereof comprising converting MOM ether of 5,5’-diallylbiphenyl-2,2’-diol or a derivative or analogue thereof in an organic solvent with a suitable agent to obtain magnolol or a derivative or analogue thereof. 10 [0040] In yet another embodiment, the invention encompasses a method of producing magnolol 5,5’-diallylbiphenyl- 2,2’-diol comprising converting MOM ether of 5,5’-diallylbiphenyl-2,2’-diol in methanol with trimethlsilane chloride to obtain magnolol.

SPECIFIC EMBODIMENTS OF THE INVENTION 15 [0041] The following examples illustrate specific embodiments of the method for producing magnolol or a derivative or analogue thereof. [0042] Preparation of 5,5’-dibromo-2,2’-bisphenol (formula III)

[0043] To a stirred solution of 2,2’-bisphenol (1.0g, 5.3 mmol) in chloroform (20 mL) was added slowly a solution of 30 bromine (1.97 mL, 16.1 mmol) in chloroform (10 mL) in dropwise manner at room temperature. After 2h, the reaction mixture was quenched with 10% sodium bisulphite and then extracted with ethyl acetate (2x50 mL). The combined

extracts were washed with brine, dried over anhydrous Na 2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography to give 5,5’-dibromo-2,2’-bisphenol in 1.72 g, (93% yield) as a white solid m.p 186-189°c 35 Preparation of MOM ether of 5,5’-dibromo-2,2’-bisphenol (formula IV)

[0044]

50 [0045] A solution of 5,5’-dibromo-2,2’-bisphenol (1.0 g, 2.9 mmol) in dry dichloromethane was added diisopropylethyl amine (7.3ml, 21.5 mmol) at 0 °C. The resulting solution was stirred over 30 min and then MOM-Cl was added (1.7 mL, 10.75 mmol) at the same temperature. The mixture was allowed to stir for overnight and then quenched with water The aqueous layer was extracted twice with dichloromethane (2x50 mL). The combined organic layers were dried over 55 anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to afford MOM ether in 1.19 g (95% yield) as a white solid, m.p. 120-122.

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Preparation of MOM ether of 5,5’-diallylbiphenyl-2,2’-diol

[0046]

15 [0047] A solution of ethyl bromide (0.34 mL, 4.64 mmol) was added in portions to magnesium turnings(0.222 g, 9.3 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere when all the ethyl bromide (half of the magnesium present) had reacted, the reaction mixture was chilled in ice bath and a solution of MOM ether of 5,5’-dibromo-2,2’-bisphenol (1.0 g, 2.32 mmol) in dry THF (20 mL) was added slowly dropwise under nitrogen atmosphere The resulting mixture was 20 stirred at room temperature for 24h and then allyl bromide (2 mL) was added slowly at 0 °C The mixture was allowed to stir for another 3h at room temperature and then quenched with ammonium chloride solution (15 mL). The aqueous layer was extracted twice with ethyl acetate (2x50 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure The resulting crude product was purified by flash column chromatography to give pure allyl derivative in 59 g, 80% yield as colourless liquid. 25 Preparation of MOM ether of 5,5’-di((E)-but-2-enyl)-2,2’-bis(methoxymethoxy)-biphenyl

[0048]

[0049] The synthesis of the MOM ether of 5,5’-di((E)-but-2-enyl)biphenyl-2,2’-diol was similarly carried out as described for the synthesis of MOM ether of mangnolol, and the MOM ether of 5,5’-di((E)-but-2-enyl)biphenyl-2,2’-diol was obtained. 45 in 70% yield.

Preparation of MOM ether of 5,5’-icinnamylbiphenyl-2,2’-diol

[0050] 50

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15 [0051] The synthesis of the MOM ether of 5-5’-dicinnamylbiphenyl-2-2’-diol was also similarly carried out as described for the synthesis of MOM ether of magnolol, and the MOM ether of 5-5’-dicinnamylbiphenyl-2-2’-diol was obtained in 72% yield.

Preparation of 5-5’-dicinnamylbiphenyl-2-2’-diol (magnolol) 20 [0052]

[0053] To a stirred solution of MOM ether of 5,5’-diallul-2,2’-bisphenol (1 g, 2.8 mmnl) in methanol (10 m) and was 35 added TMSCl (0.35 mL, 2.8 mmol)dropwise at 0 °C. The resulting solution was stirred at 25 °C for 1h. After completion as indicated by TLC, the mixture was quenched with a solution of saturated sodium bicarbonate and extracted twice with ethyl acetate (2x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to give the pure magnolol in 0.6 g, (90% yield) as a white solid, m.p. 101-103 °C. 40 Preparation of 5,5’-di((E)-but-2-enyl])biphenyl-2,2-diol

[0054]

[0055] The synthesis of 5.5’-di((E)-but-2-enyl])biphenyl-2,2-diol was also similarly carried out as described for the

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synthesis of magnolol, and 5.5’-di((E)-but-2-enyl])biphenyl-2,2’-diol was as obtained in 91% Yield.

Preparation of 5,5’-dicinnamylbiphenyl-2,2’-diol

5 [0056]

20 [0057] The synthesis 5,5’-dicinnamylbiphenyl-2,2’-diol was also similarly carried out as described for the syntheses of magnolol, and 5,5’-dicinnamylbiphenyl 2,2’-diol was obtained in 89% yield.

25 Claims

1. A method of producing a compound of formula (I)

wherein R represents H, alkyl, a substituted or unsubstituted phenyl; or a pharmaceutically or orally acceptable salt 45 thereof, comprising:

(a) reacting a compund of formula (II);

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with bromine in an organic solvent to obtain a compound of formula (III);

15 (b) reacting the compound of formula III with MOM-Cl in an organic solvent in the presence of an organic base to obtain a compound of formula (IV);

(c) reacting the compound of formula IV with R-CH=CH-CH2-Br, wherein R is defined as above, in an organic solvent with magnesium and ethyl bromide to obtain a compound of formula V;

(d) converting the compound of formula V with an suitable deprotecting agent in an organic solvent to obtain a 50 compound of formula I; and (e) optionally, converting the compound of formula I to its pharmaceutically or orally acceptable salts.

2. The method acoording to claim 1 wherein R is hydrogen, methyl or phenyl.

55 3. The method according to claim 1 wherein the organic solvent in (a) is chloroform.

4. The method according to claim 1 or claim 3 wherein the organic solvent in (c) is tetrahydrofuran.

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5. The method according to claim 1, claim 3 or claim 4 wherein the suitable deprotecting agent in (d) is trimethylsilane chloride.

6. A method according to claim 1 wherein the compound of formula (I) is magnolol (5,5’-diallylbiphenyl-2,2’-diol), the 5 method comprising:

(a) reacting 2,2’-bisphenol with bromine in chloroform to obtain 5,5’-dibromo-2,2’-bisphenol; (b) reacting 5,5’-dibromo-2,2’-bisphenol with methoxymethylchloride (MOM-Cl) in dichloromethane with diisopropylethylamine to obtain MOM ether of 5,5’-dibromo-2,2’-bisphenol; 10 (c) reacting the said MOM ether of 5,5’-dibromo-2,2’-bisphenol with allyl bromide in tetrahydrofuran with magnesium and ethyl bromide to obtain MOM ether of 5,5’-diallylbiphenyl-2,2’-diol; (d) converting the said MOM ether of 5,5’-diallylbiphenyl-2,2’-diol with a suitable deprotecting agent to obtain magnolol; and (e) optionally, converting magnolol to its pharmaceutically or orally acceptable salts. 15 7. The method according to claim 6 wherein the reaction of (c) is carried out at room temperature.

8. The method according to claim 6 wherein the suitable deprotecting agent in (d) is trimethylsilane chloride.

20 9. A method of producing compound of formula V,

comprising reacting a compound of formula IV

with R-CH=CH-CH2-Br, wherein R represents H, alkyl, a substituted or unsubstituted phenyl, in an organic solvent 55 for a sufficient amount of time to obtain a compound of formula V, and optionally comprising the additional step of converting the compound of formula V to a compound of formula I

12 EP 2 539 310 B1

15 10. The method according to claim 9, wherein the organic solvent is tetrahydrofuran.

11. The method according to claim 10, wherein the reaction is carried out with magnesium and ethyl bromide to affect the coupling.

20 12. The method according to claim 11, wherein the reaction is carried out at room temperature.

13. The method according to claim 11, wherein the molar ratio of magnesium and ethyl bromide is 2 to 1.

14. The method according to claim 12, wherein R is hydrogen. 25 15. The method according to claim 9, wherein the compound of formula V is reacted with trimethylsilane chloride in methanol to obtain a compound of formula I, optionally wherein R is hydrogen.

30 Patentansprüche

1. Ein Verfahren zum Erzeugen einer Verbindung von Formel (I),

in welcher H, Alkyl, ein substituiertes oder unsubstituiertes Phenyl oder dessen pharmazeutisch oder oral annehm- 50 bares Salz durch R dargestellt sind und wobei das Verfahren Folgendes umfasst:

(a) Reagieren einer Verbindung von Formel (II)

13 EP 2 539 310 B1

10 mit Brom in einem organischen Lösungsmittel, um eine Verbindung von Formel (III) zu erhalten;

25 (b) Reagieren der Verbindung von Formel III mit MOM-C1 in einem organischen Lösungsmittel in Gegenwart einer organischen Base, um eine Verbindung von Formel (IV) zu erhalten;

(c) Die Verbindung von Formel IV mit R-CH=CH-CH 2-Br-wobei R wie oben definiert ist - in einem organischen Lösungsmittel mit Magnesium und Ethylbromid reagieren, um eine Verbindung von Formel V zu erhalten;

14 EP 2 539 310 B1

(d) die Verbindung von Formel V mit einem geeigneten Entschützungsmittel in einem organischen Lösungsmittel 20 umwandeln, um eine Verbindung von Formel I zu erhalten; und (e) wahlweise die Verbindung von Formel I in ihre pharmazeutisch oder oral annehmbaren Salze umwandeln.

2. Das Anspruch 1 entsprechende Verfahren, wobei R Wasserstoff, Methyl oder Phenyl ist.

25 3. Das Anspruch 1 entsprechende Verfahren, wobei das organische Lösungsmittel in (a) Chloroform ist.

4. Das Anspruch 1 oder Anspruch 3 entsprechende Verfahren, wobei das organische Lösungsmittel in (c) Tetrahy- drofuran ist.

30 5. Das Anspruch 1, Anspruch 3 oder Anspruch 4 entsprechende Verfahren, wobei das geeignete Entschützungsmittel in (d) Trimethylsilanchlorid ist.

6. Ein Anspruch 1 entsprechendes Verfahren, wobei die Verbindung von Formel (I) Magnolol (5,5’-diallylbiphenyl-2,2’- diol) ist und das Verfahren Folgendes umfasst: 35 (a) Reagieren von 2,2’-bisphenol mit Brom in Chloroform, um 5,5’-dibromo-2,2’-bisphenol zu erhalten; (b) Reagieren von 5,5’-dibromo-2,2’-bisphenol mit Methoxymethylchlorid (MOM-C1) in Dichlormethan mit Di- isopropylethylamin, um MOM-Ether von 5,5’-dibromo-2,2’-bisphenol zu erhalten; (c) Reagieren des besagten MOM-Ethers von 5,5’-dibromo-2,2’-bisphenol mit Allylbromid in Tetrahydrofuran 40 mit Magnesium und Ethylbromid, um MOM-Ether von 5,5’-diallylbiphenyl-2,2’-diol zu erhalten; (d) Umwandeln des besagten MOM-Ethers von 5,5’-diallylbiphenyl-2,2’-diol mit einem geeigneten Entschüt- zungsmittel, um Magnolol zu erhalten; und (e) wahlweise Magnolol in seine pharmazeutisch oder oral annehmbare Salze umwandeln.

45 7. Das Anspruch 6 entsprechende Verfahren, wobei die Reaktion von (c) bei Raumtemperatur durchgeführt wird.

8. Das Anspruch 6 entsprechende Verfahren, wobei das geeignete Entschützungsmittel in (d) Trimethylsilanchlorid ist.

9. Ein Verfahren zum Erzeugen einer Verbindung von Formel V, 50

15 EP 2 539 310 B1

das das Reagieren einer Verbindung von Formel IV 20

35 mit R-CH=CH-CH2-Br umfasst, wobei H, Alkyl, ein substituiertes oder unsubstituiertes Phenyl durch R dargestellt sind, und wobei das Reagieren in einem organischen Lösungsmittel für eine hinreichend lange Zeit erfolgt, um eine Verbindung von Formel V zu erhalten, und wobei das Reagieren wahlweise den weiteren Schritt umfasst, die Verbindung von Formel V in eine Verbindung von Formel I umzuwandeln.

10. Das Anspruch 9 entsprechende Verfahren, wobei das organische Lösungsmittel Tetrahydrofuran ist.

16 EP 2 539 310 B1

11. Das Anspruch 10 entsprechende Verfahren, wobei die Reaktion mit Magnesium und Ethylbromid durchgeführt wird, um die Kopplung zu bewirken.

12. Das Anspruch 11 entsprechende Verfahren, wobei die Reaktion bei Raumtemperatur durchgeführt wird. 5 13. Das Anspruch11 entsprechende Verfahren, wobei dasMolverhältnis von Magnesium zum Ethylbromid 2zu 1beträgt.

14. Das Anspruch 12 entsprechende Verfahren, wobei R Wasserstoff ist.

10 15. Das Anspruch 9 entsprechende Verfahren, wobei die Verbindung von Formel V mit Trimethylsilanchlorid in Methanol reagiert wird, um eine Verbindung von Formel I zu erhalten, wahlweise wobei R Wasserstoff ist.

Revendications 15 1. Un procédé de fabrication d’un composé de formule (I)

30 dans lequel R représente H, un alkyle, un phényle substitué ou non substitué ; ou un des sels pharmaceutiquement ou oralement acceptables de ceux-ci, comprenant :

(a) la réaction d’un composé de formule (II) ; 35

avec du brome dans un solvant organique pour obtenir un composé de formule (III) ; 45

55 (b) la réaction du composé de formule III avec MOM-CI dans un solvant organique en présence d’une base organique pour obtenir un composé de formule (IV) ;

17 EP 2 539 310 B1

(c) la réaction du composé de formule IV avec R-CH=CH-CH 2-Br, dans laquelle R est défini tel que ci-dessus, dans un solvant organique avec du bromure de magnésium et d’éthyle pour obtenir un composé de formule V ;

30 (d) la conversion du composé de formule V avec un agent de déprotection approprié dans un solvant organique pour obtenir un composé de formule I ; et (e) optionnellement, la conversion du composé de formule I en ses sels pharmaceutiquement ou oralement acceptables.

35 2. Le procédé selon la revendication 1 dans lequel R est un hydrogène, un groupe méthyle ou phényle.

3. Le procédé selon la revendication 1 dans lequel le solvant organique dans (a) est du chloroforme.

4. Le procédé selon la revendication 1 ou la revendication 3 dans lequel le solvant organique dans (c) est du tétrahy- 40 drofurane.

5. Le procédé selon la revendication 1, la revendication 3 ou la revendication 4 dans lequel l’agent de déprotection approprié dans (d) est du chlorure de triméthylsilane.

45 6. Un procédé selon la revendication 1 dans lequel le composé de formule (I) est du magnolol (5,5’-diallylbiphényl- 2,2’-diol), le procédé comprenant :

(a) la réaction de 2,2’-bisphénol avec du brome dans du chloroforme pour obtenir du 5,5’-dibromo-2,2’- bisphénol ; 50 (b) la réaction de 5,5’-dibromo-2,2’-bisphénol avec du méthoxyméthylchlorure (MOM-Cl) dans du dichloromé- thane avec de la diisopropyléthylamine pour obtenir un éther MOM de 5,5’-dibromo-2,2’-bisphénol ; (c) laréaction dudit étherMOM de 5,5’-dibromo-2,2’-bisphénol avec du bromure d’allyle dansdu tétrahydrofurane avec du bromure de magnésium et d’éthyle pour obtenir un éther MOM de 5,5’-diallylbiphényl-2,2’-diol; (d) la conversion dudit éther MOM de 5,5’-diallylbiphényl-2,2’-diol avec un agent de déprotection approprié pour 55 obtenir du magnolol ; et (e) optionnellement, la conversion du magnolol en ses sels pharmaceutiquement ou oralement acceptables.

7. Le procédé selon la revendication 6 dans lequel la réaction de (c) est effectuée à la température ambiante.

18 EP 2 539 310 B1

8. Le procédé selon la revendication 6 dans lequel l’agent de déprotection approprié dans (d) est du chlorure de triméthylsilane.

9. Un procédé pour produire un composé de formule V, 5

20 comprenant la réaction d’un composé de formule IV

avec R-CH=CH-CH2-Br, dans lequel R représente H, un alkyle, un phényle substitué ou non substitué, dans un 35 solvant organique pendant suffisamment de temps pour obtenir un composé de formule V, et optionnellement comprenant l’étape additionnelle de conversion du composé de formule V en un composé de formule I

10. Le procédé selon la revendication 9, dans lequel le solvant organique est du tétrahydrofurane.

11. Le procédé selon la revendication 10, dans lequel la réaction est effectuée avec du bromure de magnésium et 55 d’éthyle pour réaliser le couplage.

12. Le procédé selon la revendication 11, dans lequel la réaction est effectuée à la température ambiante.

19 EP 2 539 310 B1

13. Leprocédé selon larevendication 11,dans lequelle rapport molairede bromure de magnésium et d’éthyle estde 2 à 1.

14. Le procédé selon la revendication 12, dans lequel R est un hydrogène.

5 15. Le procédé selon la revendication 9, dans lequel le composé de formule V est mis en réaction avec du chlorure de triméthylsilane dans du méthanol pour obtenir un composé de formule I, optionnellement dans lequel R est un hydrogène.

20 EP 2 539 310 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6544409 B [0002] • US 20060140885 A [0002]

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