Process for the synthesis of 5-((2-methyl-1h-imidazol-1-yl)methyl)furan-2-carbaldehyde and of nitrones from 5-((2-methyl-1h-imidazol-1-yl)methyl)furan-2-carbaldehyde

Patent metadata

Field	Value
Publication number	US-2025084070-A1
Application number	US-202218722322-A
Country	US
Kind code	A1
Filing date	Dec 19, 2022
Priority date	Dec 21, 2021
Publication date	Mar 13, 2025
Grant date	—

Abstract

A process for synthesizing 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-carbaldehyde from a mixture comprising a carbohydrate, an alkali or alkaline-earth metal chloride, hydrochloric acid, water, an organic solvent, namely a water-insoluble polar aprotic solvent, and optionally a phase-transfer agent, proceeds via the formation of 5-(chloromethyl)furan-2-carbaldehyde, without isolating this synthesis intermediate. A process also synthesizes a compound of formula (III) below:

from 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-carbaldehyde.

First claim

1 .- 15 . (canceled)

16 . A method for the preparation of a compound of formula I:

comprising the following successive steps:
(i) preparing a mixture comprising a carbohydrate, an alkali or alkaline-earth metal chloride, hydrochloric acid, water, and an organic solvent, the mixture being heated to a temperature within a range of from 35° C. to 90° C., the organic solvent being a water-insoluble polar aprotic solvent, and the carbohydrate being a monosaccharide, a polysaccharide or a mixture thereof;
(ii) cooling the mixture obtained from step (i) to give a cooled mixture, separating the cooled mixture into an aqueous phase and an organic phase, and recovering the organic phase, the organic phase comprising the organic solvent and a compound of formula II:

(iii) mixing 2-methylimidazole and the organic phase obtained from step (ii), the 2-methylimidazole being in molar excess relative to the compound of formula II; and
(iv) recovering the compound of formula I formed following step (iii).

17 . The method according to claim 16 , wherein the carbohydrate is a monosaccharide.

18 . The method according to claim 16 , wherein the organic solvent is toluene.

19 . The method according to claim 16 , wherein, during step (i), an amount of hydrochloric acid is within a range of from 3 to 7 molar equivalents relative to an amount of monosaccharide units present in the carbohydrate.

20 . The method according to claim 16 , wherein, during step (i), an amount of chloride ions supplied by the alkali or alkaline-earth metal chloride is within a range of from 1.2 to 2.6 molar equivalents relative to an amount of monosaccharide units present in the carbohydrate.

21 . The method according to claim 16 , wherein the alkali or alkaline-earth metal chloride is selected from the group consisting of magnesium chloride and lithium chloride.

22 . The method according to claim 16 , wherein the phase-transfer agent is a quaternary ammonium halide, an amount of which is within a range of from 0.001 to 0.01 molar equivalents relative to an amount of monosaccharide units present in the carbohydrate.

23 . The method according to claim 1 , wherein step (i) comprises the following steps:
(i1) preparing a composition comprising the carbohydrate, the alkali or alkaline-earth metal chloride, the hydrochloric acid, and the water; and (i2) adding the composition obtained from step (i1) to the organic solvent heated to a temperature within a range of from 35° C. to 90° C.; or (i1) adding the carbohydrate to the organic solvent heated to a temperature within a range of from 35° C. to 90° C.; (i2) preparing a composition comprising the alkali or alkaline-earth metal chloride, the hydrochloric acid, and the water; and (i3) adding the composition obtained from step (i2) to the heated organic solvent comprising the carbohydrate obtained from step (i1); or (i1) preparing a composition comprising the carbohydrate and the water; (i2) preparing a composition comprising the organic solvent, the hydrochloric acid, and the alkali or alkaline-earth metal chloride, the composition being heated to a temperature within a range of from 35° C. to 90° C.; and (i3) adding the composition obtained from step (i1) to the heated composition obtained from step (i2); or (i1) preparing a composition comprising the organic solvent, the hydrochloric acid, the alkali or alkaline-earth metal chloride, and the water, the composition being heated to a temperature within a range of from 35° C. to 90° C.; and (i2) adding the carbohydrate to the heated composition obtained from step (i1); or (i1) preparing a composition comprising the carbohydrate, the organic solvent, and the alkali or alkaline-earth metal chloride, the composition being heated to a temperature within a range of from 35° C. to 90° C.; and (i2) adding a solution of hydrochloric acid to the heated composition obtained from step (i1).

24 . The method according to claim 16 , wherein step (ii) comprises, after the cooling step and before the separation step, a step of filtering the cooled mixture in order to remove solid materials present.

25 . The method according to claim 16 , wherein an amount of 2-methylimidazole during step (iii) is within a range of from 2.0 to 3.0 molar equivalents relative to an amount of the compound of formula II.

26 . The method according to claim 16 , wherein the mixture obtained during step (iii) comprising the 2-methylimidazole and the organic phase obtained from step (ii) is maintained at a temperature within a range of from 50° C. to 90° C. for a period of time within a range of from 2 to 8 hours.

27 . The method according to claim 16 , wherein step (iii) comprises the following steps:
(iii1) adding, at room temperature, a fraction of the organic phase obtained from step (ii) to the 2-methylimidazole; (iii2) heating the composition obtained from step (iii1) to a temperature within a range of from 50° C. to 90° C.; and (iii3) adding a remaining fraction of the organic phase obtained from step (ii) to the heated composition obtained from step (iii2); or (iii1) adding the 2-methylimidazole to the organic phase obtained from step (ii) heated to a temperature within a range of from 50° C. to 90° C.

28 . A method for the preparation of a compound of formula III:

comprising the following steps:
(a) preparing a compound of formula I by the process according to claim 16 ;
(b) reacting the compound of formula I obtained in step (a) with a compound of formula R 1 —NO 2 in a presence of a reducing agent, in order to form the compound of formula III; and
(c) recovering the compound of formula III,
wherein R 1 is selected from the group consisting of linear or branched C 1 -C 20 alkyls, C 3 -C 20 cycloalkyls not substituted or substituted with one or more linear or branched aliphatic hydrocarbon chains, and C 6 -C 20 aryls not substituted or substituted with one or more linear or branched aliphatic hydrocarbon chains.

29 . The method according to claim 28 , wherein step (b) comprises the following steps:
(b1) preparing a composition comprising the compound of formula I obtained in step (a), an ammonium salt and a water/ethanol mixture; (b2) adding the compound R 1 —NO 2 to the composition obtained in step (b1); and (b3) adding zinc as the reducing agent to the composition obtained in step (b2) maintained at a temperature in a range of from 15° C. to 25° C. during the addition step.

30 . The method according to claim 29 , wherein the composition resulting from step (b3) is maintained at a temperature in a range of from 15° C. to 25° C. for a period of time within a range of from 4 to 6 hours.

31 . The method according to claim 16 , wherein, in step (i), the mixture further comprises a phase-transfer agent.

32 . The method according to claim 16 , wherein, in step (i), the mixture is heated to a temperature within a range of from 55° to 75°.

33 . The method according to claim 16 , wherein the carbohydrate is fructose.

34 . The method according to claim 31 , wherein step (i) comprises the following steps:
(i1) preparing a composition comprising the carbohydrate, the alkali or alkaline-earth

Assignees

• Michelin & Cie

Inventors

• Jean-Baptiste-Dit-Dominique Francois
• Sutter Marc
• Ivanov Sergey
• Ngo Robert
• Marty Luana

Classifications

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D407/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title