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Process for the manufacture of ajoene derivatives

Inactive Publication Date: 2014-10-09
DANMARKS TEKNISKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent aims to provide a process for making (E,Z)-ajoene in controllable ratios to solve problems of low yields and expensive purification procedures in the prior art.

Problems solved by technology

Bacterial infections are an increasing problem worldwide.
Isolation from garlic is highly tedious and inefficient as the amount of ajoene available pr.
However, the yields in the above methods have often been poor or purification by HPLC chromatography has been necessary leading to low yields of ajoene at high purification costs.
Furthermore these synthetic approaches often lack control of the (E,Z)-isomeric outcome of the reaction, while still maintaining high yields.

Method used

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  • Process for the manufacture of ajoene derivatives
  • Process for the manufacture of ajoene derivatives
  • Process for the manufacture of ajoene derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compound (3), Allicin

[0066]An acetone solution of DMDO (31 mL, 0.07M, 2.2 mmol) was added dropwise over 15 min to compound (2), diallyldisulphide (0.29 g, 2.0 mmol) in acetone (1 mL) at −50° C. under argon. The resulting light yellow reaction mixture was allowed to stir for 30 min while slowly warming to −20° C. The resulting clear reaction mixture was concentrated in vacuo. The crude residue (0.31 g, 98%) was further purified by column chromatography (eluting with 5% Et2O in pentane) to yield compound (3), allicin (0.31 g, 1.9 mmol, 96% yield, purity >95% and up to 99.9%) as a light yellow liquid.

[0067]The above reaction was repeated under varying condition with respect to solvent and temperature. Remaining parameters were kept the same. As seen in table 1 below the reaction is effective under a number of conditions.

TABLE 1Conversion of diallyldisulphide to allicin (3)EntrySolventTemp2 / Yield1Acetone−100° C., 78° C., −50-−20° C.96%2CH2Cl2−100° C., 78° C., −50-−20° C.90%...

example 2

Synthesis of Compound (1), (E,Z)-Ajoene Using Acetone Solvent

[0068]A solution of compound (3), allicin (0.162 g, 1.0 mmol) in a 40% aqueous acetone solution (1.6 mL) was treated with AcOH (0.011 mL, 0.2 mmol). The resulting mixture was heated to 64° C. for 4 h. The cooled reaction mixture was diluted with 50% aqueous methanol (6 mL) and extracted with pentane (5×10 mL). The aqueous fraction was saturated with solid NH4SO4 and the mixture was extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue (0.16 g) was further purified by column chromatography (eluting with 60-80% EtOAc in pentane) to yield compound (1), (E,Z)-ajoene (E:Z ratio=1:4, 0.025 g, 0.1 mmol, 32% yield) as a light yellow liquid.

[0069]The above reaction was repeated using a variety of acids. Remaining parameters were kept the same as above. Exchange of acid had impact on both yields and E:Z ratios of ajoene as seen in table 2 below:

TABLE 2conversi...

example 3

Synthesis of Compound (1), (E,Z)-Ajoene [E:Z=10:1]

[0071]A solution of compound (3), allicin (0.162 g, 1.0 mmol) in a 10% aqueous benzene solution (1.6 mL) was treated with AcOH (0.011 mL, 0.2 mmol). The resulting mixture was heated to 37° C. for 48 h. The cooled reaction mixture was diluted with 50% aqueous methanol (6 mL) and extracted with pentane (5×10 mL). The aqueous fraction was saturated with solid NH4SO4 and the mixture was extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue (0.15 g) was further purified by column chromatography (eluting with 60-80% EtOAc in pentane) to yield compound (1) (E,Z)-ajoene (E:Z ratio 10:1, 0.023 g, 0.1 mmol, 30% yield) as a light yellow liquid.

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Abstract

The present invention relates to the compound (E,Z)-ajoene of formula (1) for use in treatment of bacterial infections. Another aspect of the present invention is a composition comprising (E,Z)-ajoene of formula (1) and at least one antibiotic. Yet another aspect of the invention relates to a method for manufacturing (E,Z) ajoene of formula (1) wherein the conformation of the internal C═C— bond can be either E or Z or a mixture thereof, said method comprising reacting allicin of formula (3) with an acid in the presence of a solvent to provide (E,Z ajoene) of formula (1) as defined above. Yet another aspect of the invention is (E,Z)-ajoene of formula 1 obtainable by the method described above.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The present invention relates to a chemical process the end product of which exhibits direct medical applications. The product of the chemical process known as ajoene has been found highly useful for the treatment of bacterial infections comprising biofilm forming bacteria by blocking expression of important quorum sensing controlled virulence factors. The invention also relates to a product obtainable by the above chemical process which shows synergistic antimicrobial effects with antibiotics. In particular the present invention relates to the synthesis of ajoene derivatives via an oxidation of diallyldisulphide to allicin which is subsequently treated with an acid to obtain ajoene E,Z isomers in a given ratio. Ajoene may be subjected to oxidation to obtain oxidized variations. Further aspects of the invention involve a composition of ajoene derivatives with an antibiotic and the use of ajoene derivatives for the treatment of bacterial infectio...

Claims

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Application Information

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IPC IPC(8): A61K31/105A61K45/06A61K31/7036
CPCA61K31/105A61K45/06A61K31/7036A61M16/0683C07C319/22A61P11/00A61P17/00A61P31/04Y02A50/30C07C323/65A61K2300/00
Inventor BJARNSHOLT, THOMASHOIBY, NIELSJENSEN, PETER OSTRUPPHIPPS, RICHARDSHANMUGHAM, MEENAKSHI SUNDARAMALHEDE, MARIAHULTQVIST, LOUISE DAHLJAKOBSEN, TIM HOLMTANNER, DAVIDLARSEN, THOMAS OSTENFELDGIVSKOV, MICHAEL
Owner DANMARKS TEKNISKE UNIV
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