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US 2014/0275236 A1Published application
Novel anti-neurodegenerative natural compounds isolated from Alpiniae Oxyphyllae Fructus and their total synthesis
AssigneeUniversity of Macau
InventorsMing Yuen LEE, Zaijun ZHANG, Guohui LI
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Abstract
This invention is directed to novel compounds isolated or derived from Alpiniae oxyphyllae fructus, chemically synthesized novel compounds, methods of preparing the novel compounds and uses thereof as neuroprotectants or drugs for treating neurodegenerative diseases such as Parkinson's disease.
Claims31
A compound with Formula I:
- wherein R1 and R3 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, alkenly, alkynyl, aryl, heteroaryl, carboxy, alkyloxy, hydroxyl, amino, nitro, alkylthio, acyl, cyano, acylamino, halo and ester;
- and
- R2 and R4 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, heteroaryl, alkyoxy, acyl, acylamino and halo.
A method of preparing (4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) and stereoisomers thereof, comprising the steps of
- a) reacting 4-methylanisole with isoburyryl chloride to obtain 1-(2-methoxy-5-methylphenyl)-2-methypropan-1-one;
- b) reacting said 1-(2-methoxy-5-methylphenyl)-2-methypropan-1-one with triethyl phosphonoacetate to obtain ethyl-(2E)-3-(2-methyloxy-5-methylphenyl)-4-methypent-2-enoate;
- c) reacting ethyl-(2E)-3-(2-methyloxy-5-methylphenyl)-4-methypent-2-enoate with Pd/C in ethanol under H2 atmosphere to obtain ethyl 3-(2-methyloxy-5-methylphenyl)-4-methypentanoate;
- d) reacting ethyl 3-(2-methyloxy-5-methylphenyl)-4-methypentanoate with LAH in THF to obtain 3-(2-methyloxy-5-methylphenyl)-4-methypentanl-1-ol;
- e) reacting 3-(2-methyloxy-5-methylphenyl)-4-methypentanl-1-ol with MsCl to obtain 3-(2-methyloxy-5-methylphenyl)-4-methypentyl methylsulfonate;
- f) reacting 3-(2-methyloxy-5-methylphenyl)-4-methypentyl methylsulfonate with NaCN in DMF to obtain 4-(2-methyloxy-5-methylphenyl)-5-methylhexanenitrile;
- g) reacting H2O2 with a suspension of 4-(2-methyloxy-5-methylphenyl)-5-methylhexanenitrile and K2CO3 in DMSO to obtain 4-(2-methyloxy-5-methylphenyl)-5-methylhexanamide;
- h) reacting 4-(2-methyloxy-5-methylphenyl)-5-methylhexanamide with NaOH to obtain 4-(2-methyloxy-5-methylphenyl)-5-methylhexanoic acid;
- i) obtaining said (4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) by reacting 4-(2-methyloxy-5-methylphenyl)-5-methylhexanoic acid with HBr;
- j) separating said (4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) by Chiral Prep-HPLC to obtain said stereoisomers;
- wherein said stereoisomer is ((S)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid) or ((R)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid).
8 more elements
A compound with Formula II:
- wherein R1 and R3 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, alkenly, alkynyl, aryl, heteroaryl, carboxy, alkyloxy, hydroxyl, amino, nitro, alkylthio, acyl, cyano, acylamino, halo and ester;
- and R2 and R4 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, heteroaryl, alkyoxy, acyl, acylamino and halo.
A method for preparing an isolated and purified compound from A. oxyphyllae fructus, comprising the steps of:
- a) extracting samples of A. oxyphyllae fructus with aqueous alcohol solution under low pressure hot reflux and removing the solvent to obtain a crude extract;
- b) reconstituting said crude extract in step (a) with ethanol to obtain ethanol extract solution;
- c) absorbing said ethanol extract solution into silica gel and removing ethanol to obtain silica gel extract;
- d) extracting said silica gel extract with organic solvents successively under normal pressure hot reflux to obtain bioactive parts;
- e) fractionating said bioactive parts and eluting with solvent mixture with increasing polarity to obtain a first bioactive fraction;
- f) purifying said first bioactive fraction of step (e) to obtain said compound;
- wherein said compound is selected from the group consisting of ((R)-4-(2-hydroxy-5-methylphenyl)-5-methylhexanoic acid), ((4S)-4-(3-hydroxy-3-methyl-6-oxocyclohex-1-enyl)-5-methylhexanoic acid) and ((4R)-4-(3-hydroxy-3-methyl-6-oxocyclohex-1-enyl)-5-methylhexanoic acid).
4 more elements
Dependencies are inferred from the claim text.