EP2340239A2 - Synthèse de myrtucommulone a et d'analogues à la myrtucommulone - Google Patents

Synthèse de myrtucommulone a et d'analogues à la myrtucommulone

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Publication number
EP2340239A2
EP2340239A2 EP09778162A EP09778162A EP2340239A2 EP 2340239 A2 EP2340239 A2 EP 2340239A2 EP 09778162 A EP09778162 A EP 09778162A EP 09778162 A EP09778162 A EP 09778162A EP 2340239 A2 EP2340239 A2 EP 2340239A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
optionally substituted
methyl
defined above
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09778162A
Other languages
German (de)
English (en)
Inventor
Johann Jauch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universitaet des Saarlandes
Original Assignee
Universitaet des Saarlandes
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Filing date
Publication date
Application filed by Universitaet des Saarlandes filed Critical Universitaet des Saarlandes
Publication of EP2340239A2 publication Critical patent/EP2340239A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/713—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the synthesis of myrtucommulone and related compounds as well as syncarpic acid and derivatives thereof.
  • Myrtucommulone A was first isolated in 1974 from the common myrtle Myrtus communis L 1, a native of the Mediterranean shrub (Y. Kashman, A. Rotstein, A. Lifshitz, Tetrahedron 1974, 30, 991-997), three years later along with other myrtucommulones also from other representatives of Myrtaceae (M. Lounasmaa, H. -S. Puri, CJ Widen, Phytochemistry 1977, 16, 1851-1852).
  • Myrtucommulone A is of great pharmaceutical interest because it is highly effective against Gram-positive bacteria (A.Rotstein, A. Lifshitz, Y. Kashman, Antimicrob. Agents Chemother 1974, 6, 539-542) and has antioxidant properties (A Rosa, M. Deiana, V. Casu, G. Corona, G. Appendino, F. Bianchi, M. Ballero, MA Dessi, Free Rad. Res. 2003, 37, 1013-1019). Latest
  • the invention accordingly relates in a first aspect to a process (variant 1) for the preparation of compounds of general formula I: in the
  • R 1 is H, C M2 alkyl, allyl or optionally substituted aralkyl,
  • R 2 is Ci, i 2 -alkyl, AIIyI 1 optionally substituted aryl or an optionally substituted aromatic heterocyclic radical
  • R 3 is H, methyl or ethyl
  • R 4 is optionally substituted by CO 2 H or SO 3 H-substituted C 1- 12 -alkyl, allyl, optionally substituted aryl or an optionally substituted aromatic heterocyclic radical
  • the invention relates to a further process (variant 2) for the preparation of compounds of the general formula I above, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
  • a particularly preferred compound of the formula I in which R 1 is methyl, R 2 and R 4 are / isopropyl, R 3 is H and the two R 5 together are 0, is myrtucommulone A of the formula Ia :
  • R 1 is methyl
  • R 2 is / iso-propyl
  • R 3 is H
  • Another preferred compound of the formula I has the following formula Ic:
  • R and R stand for / so-propyl and R 3 f is...
  • R is H or methyl.
  • a further preferred compound of the formula II in which R 1 is H and R 5 is methyl is dimedone of the formula IIb:
  • V is acetylated
  • the compound of formula VII is deacetylated to a compound of formula II.
  • R 1 in the formulas R 1 -Z and VII is methyl, whereby syncarpic acid IIa is obtained.
  • Ci-1 2 -alkyl in the meanings of R 1 , R 2 , R 4 and R 5 is a straight or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, / so-Buytyl, 2-butyl, terf.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and their isomers.
  • Aryl is phenyl or naphthyl.
  • Aralkyl is aryl-Ci- 4 -alky, wherein aryl is as defined above.
  • Aromatic heterocyclic radicals are aromatic six-membered rings having one or two nitrogen atoms, such as 2- or 3-pyridyl, pyrimidyl, pyrazyl and pyridazyl, and aromatic five-membered rings having one or two
  • the substituents of the aryl or heterocyclic groups are from C 1-4 alkyl, Ci -4 -alkoxy, nitro, halogen (F, Cl, Br and I), cyano, -C (O) -R 1 and -COOR 1 selected wherein R 1 is for stands.
  • step a) an aprotic aliphatic or aromatic solvent is used, which may be polar.
  • Such solvents are, for example, chlorinated aliphatic and aromatic hydrocarbons, such as carbon tetrachloride, chloroform, dichloromethane, dichloroethane and chlorobenzene and mixtures thereof, aromatic hydrocarbons, such as benzene and toluene, open-chain and cyclic ethers, such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane, esters, for example ethyl acetate, and polar solvents such as dimethylsulfoxide and dimethylformamide. Dichloromethane and dimethoxyethane and mixtures thereof are preferred.
  • the molar ratio of the compound of formula II to piperidine or pyrrolidine may generally be in the range of 1: 1, 8 to 1: 2.5. It is preferably about 1: 2.
  • the ratio of the compound of the formula II to the aldehyde R 2 -CHO is generally 1: 1 to 1: 1, 8. It is preferably 1: 1, 5.
  • the temperature at which the reaction of step a) is carried out may generally be from 0 ° C. to the boiling point of the solvent. For reasons of simplicity, room temperature is preferred.
  • the reaction time of the reaction of step a) is e.g. 3 minutes to 2 hours, depending on the temperature. At room temperature, it is preferably about 5 minutes.
  • the two solvents used in step b) may be the same as used in step a). Preferred are dimethoxyethane or THF.
  • the strong base which is suspended in the solvent for the compound III may be selected, for example, from an amide, for example, lithium diisopropylamide, an alcoholate or a hydride. Sodium hydride is preferred.
  • the reaction of stage b) can generally be carried out at a temperature of from 0 ° C. to the boiling point of the solvent.
  • the reaction time is, depending on the temperature, for example, 10 minutes to 5 hours.
  • the reaction is carried out at room temperature for about one hour.
  • the reaction of step b) is preferably carried out under an inert gas atmosphere.
  • a piperidine or pyrrolidine-containing solution of an aldehyde R 2 -CHO, wherein R 2 is as defined above, and a piperidine or pyrrolidine-containing solution of the compound of Formula II combines what is known as Mannichbase Villa or VIIIb as a non-isolated intermediate
  • the solvent of the piperidine or pyrrolidine-containing solution of an aldehyde R 2 -CHO is an aprotic aliphatic or aromatic Solvent that can be polar.
  • solvents are, for example, chlorinated aliphatic and aromatic hydrocarbons, such as carbon tetrachloride, chloroform, dichloromethane, dichloroethane and chlorobenzene and mixtures thereof, aromatic hydrocarbons, such as benzene and toluene, open-chain and cyclic ethers, such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane, esters, for example ethyl acetate, and polar solvents such as dimethylsulfoxide and dimethylformamide. Dichloromethane and dimethoxyethane and mixtures thereof are preferred.
  • the molar ratio of the aldehyde to piperidine or pyrrolidine can be typically in
  • the solution is preferably prepared and stored under an inert gas atmosphere.
  • Suitable solvents for the piperidine or pyrrolidine-containing solution of compound II are the same solvents which have been mentioned above for the piperidine or pyrrolidine-containing solution of the aldehyde R 2 -CHO. Again, methylene chloride or dimethoxyethane or mixtures thereof is preferred.
  • the ratio of the compound of formula II to piperidine or pyrrolidine may typically be in the range of 2.5: 1 to 1: 1, preferably 2.2: 1 to 1, 8: 1 and more preferably 2: 1.
  • the solution is preferably prepared and stored under an inert gas atmosphere.
  • the compound of formula III is prepared by Friedel-Crafts acylation from phloroglucin of formula IX.
  • the solvent of the acid solution of the compound of the formula III may be selected from the same solvents as mentioned above in connection with the solution of the aldehyde and the compound (II). Preference is given to dimethoxyethane.
  • the acid may be any inorganic (eg, HCl, H 2 SO 4 ) or organic (eg, acetic, toluenesulfonic) acid. Particularly preferred is toluenesulfonic acid.
  • the molar ratio of the compound III to toluenesulfonic acid may typically be in the range of 1: 1.5 to 1: 4, preferably 1: 2 to 1: 3, especially 1: 2.6.
  • the solution is preferably prepared and stored under an inert gas atmosphere.
  • a third aspect of the invention is an optimized synthesis of compounds of the formula II, in particular also of syncarpic acid of the formula IIa.
  • syncarpic acid (IIa) is outlined in the following reaction scheme.
  • 1, 3,5-trimethoxybenzene (IV) is subjected to Friedel-Crafts acylation with acetyl chloride.
  • Any suitable solvent for such a reaction for example chlorinated hydrocarbons such as methylene chloride or 1,2-dichloroethane, benzene, nitrobenzene or carbon disulfide may be used. Methylene chloride is preferred.
  • the catalyst may be any suitable Lewis acid such as AICI 3 , FeCl 3 or ZnCl 2 . ZnCl 2 is preferred.
  • the molar ratios between 1, 3,5-trimethoxybenzene, acetyl chloride and zinc chloride are 0.8-1, 2: 1, 0-1, 5: 1, 8-2.2, preferably about 1: 1, 25: 2. Die Reaction can be carried out at temperatures of 0 0 C to 50 0 C for 1 to 8 hours, for example 3 hours. Preference is given to working at room temperature under an inert gas atmosphere. The tube product obtained after usual workup is generally sufficiently pure for use in the next stage.
  • trimethoxyacetophenone (V) is demethylated to trihydroxyacetophenone (VI).
  • Any procedure for an arylalkyl ether Cleavage can be used, for example cleavage with anhydrous tolulphonic acid, Hl or BBr 3 . BBr 3 is preferred.
  • the solvents used are polar aprotic solvents, e.g. chlorinated aliphatic and aromatic hydrocarbons, such as chloroform, methylene chloride, dichloroethane and chlorobenzene, and mixtures thereof. Methylene chloride is preferred.
  • the reaction can be carried out at temperatures of -78 0 C to the reflux of the solvent With BBr 3 , it is carried out at temperatures below 0 0 C under inert gas atmosphere.
  • acetylsyncarpinic acid (VII).
  • dimethyl sulfate or, preferably, a methyl halide having a base such as K 1 CO 3 , KOH, NaOH or preferably an alkanolate in alkanol can be used.
  • the methylation is carried out using methyl iodide and Nathummethanolat / methanol as the base / solvent.
  • the reaction may be carried out at room temperature to the reflux temperature of the solvent for 1.5 to 10 hours, preferably under inert gas atmosphere.
  • Dimedone and the dimedone derivatives of formula IIb can be prepared according to Organic Syntheses, Coli. Vol.2, p. 200, or produced thereon.
  • the following examples illustrate the invention without limiting it.
  • the aqueous phase is extracted 3 times with 100 ml of diethyl ether, the combined organic phases are dried with MgSO 4 . After filtering off the drying agent, the solvent is removed in vacuo. The remaining crude product is pure enough for further reaction. If necessary, the substance can be dissolved in CH 2 Cl 2 and purified by filtration through a little silica gel. Yield: 12.1 g (95%) of 2,4,6-trimethoxyacetophenone.
  • a fresh solution of sodium methoxide (NaOMe) in methanol is prepared under N 2 by dissolving 7.5 g of sodium (330 mmol) in 100 ml of methanol. To 62 ml of this solution (containing 205 mmol NaOMe) is added slowly
  • the ether phase is dried over MgSO 4 , the desiccant is filtered off and the filtrate is concentrated on a rotary evaporator.
  • Solution A 3.6 mmol of isobutyraldehyde (259.6 mg, 328.6 ⁇ l) and 3 mmol of piperidine (255.6 mg, 297.2 ⁇ l) are dissolved in 3 ml of absolute methylene chloride under N 2 .
  • Solution B 3 mmol of syncarpic acid (546.7 mg) and 1.5 mmol of piperidine (127.8 mg, 148.6 ⁇ l) are dissolved in 4 ml of absolute methylene chloride.
  • Solution C 1, 0 mmol Isobutyrylphloroglucin (196.2 mg) and 2.6 mmol anhydrous toluenesulfonic acid (447.6 mg) are dissolved in 2 ml of absolute dimethoxyethane under N 2 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne la synthèse en 6 étapes (variante 1) ou en 5 étapes (variante 2) de myrtucommulone A et de dérivés de celle-ci, ainsi que la synthèse d'acide syncarpinique et de dérivés de celui-ci.
EP09778162A 2008-08-29 2009-08-27 Synthèse de myrtucommulone a et d'analogues à la myrtucommulone Withdrawn EP2340239A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008044993A DE102008044993B4 (de) 2008-08-29 2008-08-29 Synthese von Myrtucommulon A und Myrtucommulon-Analoga
PCT/EP2009/006226 WO2010022953A2 (fr) 2008-08-29 2009-08-27 Synthèse de myrtucommulone a et d'analogues à la myrtucommulone

Publications (1)

Publication Number Publication Date
EP2340239A2 true EP2340239A2 (fr) 2011-07-06

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EP (1) EP2340239A2 (fr)
DE (1) DE102008044993B4 (fr)
WO (1) WO2010022953A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2695874A1 (fr) 2012-08-07 2014-02-12 Universität des Saarlandes Analogues de myrtucommulone
CN113929570B (zh) * 2021-11-02 2024-01-30 湖南中嘉生物医药有限公司 一种桃金娘酮衍生物及其制备方法和用途

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DE102006058450A1 (de) * 2006-12-12 2008-06-19 Eberhard-Karls-Universität Tübingen Zubereitungen zur Hemmung der Prostaglandin E2 Synthese

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010022953A2 *

Also Published As

Publication number Publication date
WO2010022953A2 (fr) 2010-03-04
WO2010022953A3 (fr) 2010-05-27
DE102008044993A1 (de) 2010-03-18
DE102008044993B4 (de) 2011-01-27

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