Process for the synthesis of (E)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol
View Patent ↗A subject-matter of the present invention is a novel process for the synthesis of (E)-stilbene derivatives targeted at obtaining in particular resveratrol and piceatannol.
1. A process for the synthesis of an (E)-stilbene derivative of formula (VI)
in which
A represents hydrogen or an OR 2 group, and
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
said process comprising reacting in a decarboxylation step a compound of formula (III)
in which A, R 1 , R 2 , R′ 1 and R′ 2 are as defined above, R is a linear or branched alkyl group comprising from 1 to 6 carbon atoms to provide a compound of formula (IV)
in which A, R 1 , R 2 , R′ 1 and R′ 2 are as defined above, and in a second reaction step:
a) reducing the compound of formula (IV) to form an alcohol and subsequently dehydrating the alcohol, or
b) reacting the compound of formula (IV) with an arylsulphonylhydrazide to form an arylsulphonylhydrazone and subsequently reacting the arylsulphonylhydrazone with a base,
to obtain the (E)-stilbene derivative of formula (VI).
2. The process of claim 1 , wherein the compound of formula (IV) is reduced in a reduction reaction to form an alcohol of formula (V)
in which
A represents hydrogen or else an OR 2 group,
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
to form 1,2-diarylethanol derivatives of formula (V), and subsequently dehydrating the 1,2-diarylethanol derivatives of formula (V) to form the compounds of formula (VI)
in which A, R 1 , R 2 , R′ 1 and R′ 2 are as defined above.
3. The process of claim 2 , wherein the reduction reaction is carried out in the presence of a metal hydride.
4. The process of claim 2 , wherein the reduction reaction is carried out by hydrogenation of the ketones of formula (IV)
in which
A represents hydrogen or an OR 2 group,
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3.
5. The process of claim 2 , wherein the dehydration of the compound of formula (V) is carried out in the presence of a catalytic amount of strong acid.
6. The process of claim 1 , wherein the compound of formula (IV)
in which
A represents hydrogen or an OR 2 group, and
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
is reacted with an arylsulphonylhydrazide compound to produce an intermediate arylsulphonylhydrazone compound of formula (VII)
in which
Ar represents a phenyl or o-, m- or p-tolyl group,
A represents hydrogen or else an OR 2 group,
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
and subsequently reacting the compound of formula (VII) with a strong base.
7. The process of claim 6 , wherein the compound of formula (VII) is treated in the presence of a compound selected form the group consisting of an alkali metal alkoxide, an alkali metal hydride, an alkaline base, sodium carbonate and potassium carbonate to obtain the compound of formula (VI)
in which
A represents hydrogen or an OR 2 group,
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3.
8. The process of claim 6 , wherein the reaction of the compound of formula (VII) with a strong base is carried out in the presence of a solvent having a boiling point of at least 90° C.
9. The process of claim 6 , wherein the reaction of the compound of formula (VII) with a strong base is carried out in the presence of a nonhydroxylated solvent.
10. The process of claim 1 , further comprising reacting in a condensation step ether/ester derivatives of formula (I) and ether/ester derivatives of formula (II)
in which
A represents hydrogen or else an OR 2 group,
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
R and R′ represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
in the presence of a strong base to provide the compound of formula (III)
11. The process of claim 10 , wherein the ether/esters of formulae (I) and (II) are obtained from hydroxyaromatic acids, hydroxyaromatic esters or etherified hydroxyaromatic acids.
12. The process of claim 11 , wherein the hydroxyaromatic acids are selected from the group consisting of 4-hydroxyphenylacetic acid, resorcylic acid, and 3,4-dihydroxyphenylacetic acid.
13. The process of claim 1 , wherein the (E)-stilbene derivative of formula (VI) is selected from the group consisting of (E)-trimethylresveratrol, (E)-tribenzylresveratrol, and (E)-tetramethylpiceatannol.
14. A process for the synthesis of an (E)-stilbene derivative of formula (VI)
in which
A represents hydrogen or an OR 2 group, and
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3,
said process comprising reacting in a first reaction step a compound of formula (IV)
in which A, R 1 , R 2 , R′ 1 and R′ 2 are as defined above,
with an arylsulphonylhydrazide to obtain an arylsulphonylhydrazone of formula (VII)
in which A, R 1 , R 2 , R′ 1 and R′ 2 are as defined above and Ar represents a phenyl or o-, m- or p-tolyl group, and
further reacting in a second reaction step the arylsulphonylhydrazone of formula (VII) with a base,
to obtain the (E)-stilbene derivative of formula (VI).
15. The process of claim 14 , wherein the second reaction step is carried out in the presence of a strong base.
16. The process of claim 14 , wherein the second reaction step is carried out in the presence of a base selected from the group consisting of an alkali metal alkoxide, an alkali metal hydride, an alkaline base, sodium carbonate and potassium carbonate to obtain the compound of formula (VI)
in which
A represents hydrogen or an OR 2 group, and
R 1 , R 2 , R′ 1 and R′ 2 represent, independently of one another, a linear or branched alkyl group comprising from 1 to 6 carbon atoms or an aralkyl group including from 7 to 16 carbon atoms which is optionally substituted by one or more alkoxy or halogen groups, or wherein R 1 and R 2 for a hydrocarbon chain of structure —(CH 2 ) n — with n=1 to 3.
17. The process of claim 14 , wherein the second reaction step is carried out in the presence of a solvent having a boiling point of at least 90° C.
18. The process of claim 14 , wherein the second reaction step is carried out in the presence of a nonhydroxylated solvent.
19. Compound of formula (III)
in which
R represents a methyl group, and
A represents hydrogen and the R 1 , R′ 1 and R′ 2 groups represent methyl groups or benzyl groups,
or A represents an —OCH 3 group and the R 1 , R′ 1 and R′ 2 groups each represent a methyl group,
or A represents hydrogen, R′ 1 and R′ 2 represent a methyl group and R 1 represents an isopropyl group,
or A represents an —OR 2 group, R′ 1 and R′ 2 represent a methyl group and R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1.
20. Compound of formula (V)
in which
A represents hydrogen and R 1 , R′ 1 and R′ 2 each represent a benzyl group, wherein the compound is 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanol.
21. Compound of formula (VII)
in which
Ar represents a p-tolyl group, and
A represents hydrogen and the R 1 , R′ 1 and R′ 2 groups represent methyl groups or benzyl groups, or
A represents an —OCH 3 group and the R 1 , R′ 1 and R′ 2 groups represent a methyl group, or
A represents hydrogen, R′ 1 and R′ 2 represent a methyl group and R 1 represents an isopropyl group, or
A represents an —OR 2 group, R′ 1 and R′ 2 represent a methyl group and R 1 and R 2 form a hydrocarbon chain of structure —(CH 2 ) n — with n=1.
22. The process of claim 1 , further comprising deprotecting the (E)-stilbene derivative of formula (VI) to provide a polyhydroxystilbene compound.
23. The process of claim 22 , wherein the polyhydroxystilbene compound is resveratrol or piceatannol.
24. The process of claim 2 , wherein the metal hydride is sodium borohydride.