Process for preparing 2,5-disubstituted 3-alkylthiophenes
The present invention relates to a process for preparing 2,5-disubstituted 3-alkyl-thiophenes and more particularly to a process for preparing them that comprises an acylation reaction in position 5 of 2-substituted 3-alkylthiophenes. This process does not need reagents which are difficult to handle and does not need anhydrous conditions or inert atmosphere. The resulting product is obtained in high purity.
1 . Process for preparing 2,5-disubstituted 3-alkylthiophenes of formula
in which
A represents a CH 3 , R 2 CH 2 , HOCH 2 or R 2 CH(OH)— group,
B represents a CHOH or CH 2 group,
R 1 represents H or a C 1 -C 5 alkyl group,
R 2 represents a C 1 -C 5 alkyl group,
R 3 represents H or a C 1 -C 5 alkyl group or a C 1 -C 5 haloalkyl group, or a halogen chosen from fluorine, chlorine and bromine,
which comprises:
(a) reaction of a compound of formula
in which
A represents a CHO, CH 3 , R 2 CH 2 or R 2 —CO— group, and
R 1 and R 2 have the meanings given above;
with a compound of formula
in which
X represents OH, halogen or a group of formula
or a group of formula
—OCOOR 4 (VI)
in which
R 4 represents a C 1 -C 5 alkyl, an optionally substituted benzyl or an option-ally substituted aryl, and
R 3 has the meanings given above;
to give a compound of formula
in which
A, R 1 , R 2 and R 3 have the meanings given above; and
(b) reduction of the compound of formula IV thus obtained to give the compound of formula I.
2 . The process of claim 1 for the preparation of 2,5-disubstituted 3-alkylthio-phenes of formula
in which
A represents a CH 3 or R 2 CH 2 group,
which comprises:
(a) reaction of a compound of formula
in which
A represents a CH 3 or R 2 CH 2 group,
with a compound of formula
to give a compound of formula
in which
A represents a CH 3 or R 2 CH 2 group, and
(b) reduction of the compound of formula IV thus obtained to give the compound of formula I.
3 . The process of claim 1 for the preparation of 2,5-disubstituted 3-alkylthiophenes of formula
in which
A represents a CH 3 , R 2 CH 2 , HOCH 2 or R 2 CH(OH)— group,
which comprises:
(a) reaction of a compound of formula
in which
A represents a CHO or R 2 —CO— group,
with a compound of formula
to give a compound of formula
in which
A represents a CHO or R 2 —CO group, and
(b) reduction of the compound of formula IV thus obtained to give the compound of formula I.
4 . The process of claim 1 in which the reaction mentioned in point (a) is performed with a compound of formula III, in which X represents halogen, in the presence of a Lewis acid and in a solvent chosen from chlorinated solvents and deactivated aromatic solvents in the presence of AlCl 3 and in methylene chloride, in which the molar ratio of compound III/Lewis acid/compound II is between 0.9-1.5/0.9-1.5/1.
5 . Process according to claim 1 , in which the reduction mentioned in point (b) is performed by means of a single reductive treatment of the compound of formula
to give the compound of formula
in which
A represents a CH 3 or R 2 CH 2 group, and
B represents a CH 2 group.
6 . Process according to claim 5 , in which the said reductive treatment is performed with sodium borohydride or sodium cyanoborohydride in the presence of trifluoro-acetic acid.
7 . Process according to claim 1 , in which the reduction mentioned in point (b) is performed by means of a first reduction reaction (b 1 ) of the compound of formula
to give the hydroxylated intermediate compound of formula
in which
A represents a CH 3 , R 2 CH 2 , HOCH 2 or R 2 CH(OH)— group, and
B represents a CHOH group;
optionally followed by a second reduction reaction (b 2 ) of the said hydroxylated intermediate of formula I to give a final compound of formula
in which
A represents a CH 3 or R 2 CH 2 group, and
B represents a CH 2 group.
8 . Process according to claim 7 , in which the reduction mentioned in point (b) is performed by means of the said reduction reactions (b 1 ) and (b 2 ) successively.
9 . The process according to claim 7 , in which the first of the said reduction reactions (b 1 ) is performed by treatment with metal hydrides selected from the group consisting of sodium borohydride, lithium aluminium hydride, boranes, and mixtures thereof, or by treatment with aluminium isopro-poxide.
10 . The process of claim 7 , in which the second of the said reduction reactions (b 2 ) is performed by treatment with a borohydride in the presence of a strong acid selected from the group consisting of trifluoroacetic acid, methanesulphonic acid, sulphuric acid, and mixtures thereof, or with zinc iodide or by catalytic hydrogenation.
11 . The process of claim 7 , in which the second of the said reduction reactions (b 2 ) is performed by catalytic hydrogenation of the hydroxylated intermediate of formula I (B═CHOH) dissolved in a suitable solvent at a hydrogen pressure of between 1 and 10 bar, at a temperature of between 15 and 60° C., in the presence of a hydrogenation catalyst chosen from palladium and platinum, supported on an inert support in a neutral or acidic medium.
12 . Process according to claim 7 , in which the said hydroxylated intermediate compound of formula
in which
A represents a CH 3 , R 2 CH 2 , HOCH 2 or R 2 CH(OH)— group, and
B represents a CHOH group
is purified by crystallization.
13 . Process for preparing 2,3-dimethyl-5-benzylthiophene of formula
which comprises:
(a) the reaction of the compound of formula
with a compound of formula
in which X represents halogen;
to give the compound of formula
(b 1 ) the reduction of compound IVb to give the hydroxylated intermediate compound of formula
and
(b 2 ) the reduction of the hydroxylated intermediate compound Ic to give 2,3-dimethyl-5-benzylthiophene (Ia).
14 . The process of claim 13 , in which the reaction (a) is performed in the presence of a Lewis acid and a molar ratio of compound III/Lewis acid/compound II ranges from 0.9-1.5/0.9-1.5/1, the reduction reaction (b 1 ) is preformed by treatment wit a metal hydride, and the reduction reaction (b 2 ) is performed by treatment with a borohydride in the presence of a strong acid selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, or sulfuric acid, or in the presence of zinc iodide or by catalytic hydrogenation.
15 . The process of claim 13 , in which the hydroxylated intermediate compound of formula Ic is purified by crystallization.
16 . The process of claim 4 , wherein the solvent is benzoyl chloride.
17 . The process of claim 4 , wherein the molar ratio of compound III/Lewis acid/compound II is 1/1/1.
18 . The process of claim 7 , wherein the second reduction reaction (b 2 ) is performed by treatment with sodium borohydride.
19 . The process of claim 7 , wherein the second reduction reaction (b 2 ) is performed by treatment with sodium borohydride and trifluoroacetic acid.
20 . The process of claim 7 , wherein the hydrogenation catalyst is palladium supported on an inert support.
21 . The process of claim 7 , wherein the inert support is selected from the group consisting of carbon, alumina, silica, zeolite, and mixtures thereof.
22 . The process of claim 7 , wherein the inert support is carbon.
23 . The process of claim 13 , wherein the hydroxylated intermediate compound of formula 1c is purified by crystallization from n-heptane.
24 . The process of claim 11 , wherein the suitable solvent is an alcohol or a mixture of water and the alcohol.
25 . The process of claim 11 , wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof.
26 . The process of claim 11 , wherein the alcohol is methanol.
26 . The process of claim 11 , wherein the hydrogenation catalyst is palladium.