Patent Description:
<NUM>-(Hydroxymethyl)furfural (HMF) is a versatile intermediate that can be obtained in good to moderate yield from biomass sources such as naturally occurring carbohydrates, including fructose, glucose, sucrose and starch. <NUM>,<NUM>-Diformylfuran (DFF) is one of the most important derivatives of HMF which has huge applications in the synthesis of polymers, antifungal agents, drugs and ligands. DFF can also be used to produce unsubstituted furan. In spite of its proven usefulness, DFF is not readily available commercially. Selective oxidation of HMF is the only industrially feasible route to DFF. However, there is currently only one industrial process exist which use biomass-derived feedstock for bulk production of HMF. Indeed, lab scale purification of HMF has also proved to be a troublesome operation. HMF could be distilled out by long exposure to temperatures but impurities associated with the synthetic mixture tend to form tarry degradation products. A process that converts a carbohydrate to DFF that avoids the costly HMF isolation step would have an economic advantage. In this direction few researchers have attempted carbohydrate conversion to DFF.

<NUM>-((methylthio)methyl)-<NUM>-furfural (MTMF) is a new class of sulfur derivative of HMF. This molecule presently not having known applications, but in future it may be a valuable intermediate due to its sulfur functionality. The introduction of sulfur may make MTMF a precursor for the synthesis of some pharmaceutical intermediates. Especially, this molecule could be a starting material for the cheap production of Ranitidine (Zantac).

There are some methods existed in the prior art for glucose conversion to DFF however, all of these strategies have used two or more catalysts for separate purpose (oxidation catalyst + dehydration catalyst) with external source of oxygen. The methods reported on fructose conversion to DFF are limited for fructose molecule but not applicable for complex carbohydrates such as glucose or sucrose. Zhang et al. reported a complex homogeneous catalytic system (AlCl<NUM>·<NUM><NUM>O/NaBr and vanadium compound) assisted with molecular O<NUM> in DMF solvent for DFF formation from glucose (<NPL>). Xiang et al. achieved one-pot, two-step synthesis of DFF by catalytic conversion of glucose over homogeneous catalyst system CrCl<NUM>·<NUM><NUM>O/NaBr/NaVO<NUM>·<NUM><NUM>O, and a DFF yield of <NUM>% based on glucose was obtained (<NPL>). Yang et al, reported a combination of Fe<NUM>O<NUM>-SBA-SO<NUM>H and K-OMS-<NUM> successfully catalyzed direct synthesis of DFF from fructose via acid catalyzed dehydration and successive aerobic oxidation in one-pot reaction (<NPL>). Ghezhali et al, reported that mixtures of ChCl and DMSO are attractive media to promote the direct conversion of fructose to DFF with <NUM>% yield in the presence of a bifunctional acid/redox catalyst i.e. HPMoV catalyst (<NPL>). Kashparova et al. reported two step procedure for synthesis of DFF from fructose using H<NUM>SO<NUM> (<NUM> mol %) as acid catalyst and [Pip*(O)][BF<NUM>] as a oxidation agent in ionic liquids (<NPL>). Xu et al, used Amberlyst-<NUM> for the acid-catalyzed dehydration of fructose into HMF, followed by the in situ oxidation of HMF to DFF catalyzed by polyaniline-VO(acac)<NUM> with <NUM>% yield (<NPL>).

Article titled "<NPL> reports glucose conversion to DFF with <NUM>% yield in one-pot process using three different catalysts such as hydrotalcite (HT) for glucose isomerisation to fructose, Amberlyst-<NUM> for fructose dehydration to HMF and Ru/HT for HMF oxidation to DFF in O<NUM> atmosphere. Stepwise addition of catalyst improved DFF yield up to <NUM>% from fructose and <NUM>% from glucose, respectively. In this process three different catalysts were used along with an external O<NUM>. In addition to that reaction one has to filter once HMF was formed to separate the acid catalyst. Then oxidation catalyst was added for oxidation step which induce operational complications.

Article titled "<NPL> reports graphene oxide, a metal-free carbon based material as an efficient and recyclable bifunctional catalyst in the direct synthesis of DFF from fructose. A DFF yield of <NUM>% was achieved in a one pot and one-step reaction (O<NUM>, <NUM>) and the DFF yield could be further increased to <NUM>% in a one pot and two-step reaction (N<NUM>, <NUM> and O<NUM> <NUM>). This process required external O<NUM> (<NUM>/min). In addition to that it is limited to fructose (a relatively soft carbohydrate compared to glucose and sucrose) conversion to DFF.

<CIT> disclosed a one-pot, two-step, catalytic process to prepare <NUM>,<NUM>-diformylfuran from a source of fructose or other carbohydrates. The <NUM>,<NUM>-Diformylfuran is prepared from a source of fructose in a one-pot, two-step reaction, in a single solvent system process, using a vanadium catalyst. In this process two different catalysts such as Bio-Rad AG-50W resin (acid catalyst) and V<NUM>O<NUM> (oxidation catalyst) were used along with external O<NUM>. This process is limited to fructose (a relatively soft carbohydrate compared to glucose and sucrose) conversion to DFF.

Article titled "<NPL> reports a choline chloride/DMSO solvent for the direct synthesis of diformylfuran from carbohydrates in the presence of heteropolyacids. The DFF yield of <NUM>% was obtained from fructose under optimized conditions. This process involves use of mix solvent system such as mixture of choline chloride and dimethyl sulfoxide. External O<NUM> is also required for this process. The process is limited to fructose (relatively soft carbohydrate compared to glucose and sucrose) conversion to DFF.

Article titled "<NPL> reports a one-pot strategy for directly converting fructose into <NUM>,<NUM>-diformylfuran (DFF) over Mo-containing Keggin heteropolyacids (HPAs) in open air. They reported yield of <NUM> % to DFF is over Cs<NUM>H<NUM>PMo<NUM> polyoxometalate after deliberate optimization of the reaction conditions.

Article titled "<NPL> reports acid-catalyzed conversions of levoglucosan to platform chemicals with various solvents. Dimethyl sulfoxide (DMSO) mainly catalyzed the conversion of levoglucosan into <NUM>-(hydroxymethyl)furfural (HMF), <NUM>,<NUM>-furandicarboxaldehyde, and the sulfur ether of HMF.

DMSO has a low ability to transfer protons, which helps to avoid further contact of HMF with catalytic sites and stabilizes HMF. In this work author provided effect of solvents on dehydration of levoglucosan with Amberlyst <NUM>. They found MTMF as a major product when levoglucosan dehydrated in DMSO with Amberlyst <NUM>. But, they have not quantified the abundance of MTMF in reaction.

Article titled "<NPL> reports a single step, single pot process with sulfonated graphitic carbon nitride as catalyst to give depending on the specific reaction conditions either HMF, or DFF, or a mixture of DFF and MTMF.

There are only three methods existed for glucose conversion to DFF. However, all of these strategies have used two or more catalyst systems for separate purposes (e.g. oxidation catalyst and dehydration catalyst) with external source of oxygen. The methods reported on fructose conversion to DFF are limited for fructose molecule but not applicable for more complex carbohydrates such as glucose or sucrose.

Therefore, there is need in the art to develop a process which will overcome prior arts drawbacks. Accordingly, the present invention provides a cost effective, single catalyst, single solvent; no oxidation source and simple catalytic process that can be convert a series of carbohydrate to DFF without the isolation of HMF.

The main objective of the present invention is to provide a single step, single pot process for the synthesis of furan derivatives from carbohydrates.

Another objective of the present invention is to provide a single step, single pot process for the synthesis of <NUM>,<NUM>-di(formyl)furan (DFF) and <NUM>-((methylthio)methyl)-<NUM>-furfural (MTMF) from carbohydrates.

The invention is defined by the appendant claims. Subject-matter described in the description which is not covered by the claims does not form part of the invention.

Accordingly, the present invention provides a single step, single pot process for the synthesis of furan derivative from carbohydrate comprises stirring the reaction mixture of carbohydrate in solvent in presence of catalyst at temperature in the range of <NUM> to <NUM> and <NUM>, respectively, for a period in the range of <NUM> to <NUM> hrs to afford corresponding furan derivative.

The carbohydrate is selected from fructose, glucose or sucrose.

The furan derivative is selected from <NUM>,<NUM>-di(formyl)furan (DFF) or <NUM>-((methylthio)methyl)-<NUM>-furfural (MTMF).

The catalyst is selected from sulfuric acid (H<NUM>SO<NUM>) or Sn-Mont (Tin hydroxide nanoparticles-embedded montmorillonite).

The solvent is Dimethyl sulfoxide (DMSO).

The yield of corresponding furan derivative is in the range of <NUM> to <NUM>%, preferably <NUM> to <NUM>%.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In line with the above objectives, the present invention provides a single step, single pot process for the synthesis of furan derivatives selected from <NUM>,<NUM>-di(formyl)furan (DFF) and <NUM>-((methylthio)methyl)-<NUM>-furfural (MTMF) from carbohydrates.

In an embodiment, the present invention provide a single step, single pot process for the synthesis of furan derivative from carbohydrate comprises stirring the reaction mixture of carbohydrate in solvent in presence of catalyst at temperature in the range of <NUM> to <NUM> and <NUM>, respectively, for the period in the range of <NUM> to <NUM> hrs to afford corresponding furan derivative.

The catalyst is selected from Sulfuric acid (H<NUM>SO<NUM>) or Sn-Mont (Tin hydroxide nanoparticles-embedded montmorillonite).

The <NUM>,<NUM>-di(formyl)furan and <NUM>-((methylthio)methyl)-<NUM>-furfural are produced directly from carbohydrates (e.g. fructose, glucose and sucrose) in one-pot process with single solvent (DMSO) system. <NUM>,<NUM>-di(formyl)furan is produced in high yield (<NUM>-<NUM>%) from carbohydrates using catalytic amount of concentrated H<NUM>SO<NUM> (<NUM> mol %). While, <NUM>-((methylthio)methyl)-<NUM>-furfural is produced in good to moderate yield (<NUM>-<NUM>%) from carbohydrates using Sn-Mont catalyst.

The process for the synthesis of furan derivative is depicted in scheme <NUM> below:
<CHM>.

The results are presented in Table <NUM> shows distribution of dehydration products on different acid catalysts using glucose. Initially, dehydration of glucose is started with the Sn-Mont catalyst at <NUM> in DMSO. After <NUM>, glucose is consumed completely with <NUM>% yield of HMF (Table <NUM>, entry <NUM>). Next experiment is performed at <NUM>, the product distribution is <NUM>% HMF and <NUM>% MTMF [<NUM>-((methylthio)methyl)-<NUM>-furfural] (Table <NUM>, entry <NUM>). Interestingly, selectivity to MTMF is increased at <NUM> with <NUM>% yield (Table <NUM>, entry <NUM>). DMSO decomposes at high temperature (<NUM>) on Sn-Mont to polysulfides which helped to convert HMF to MTMF. In presence of SnCl<NUM>·<NUM><NUM>O, dehydration followed by chlorination of glucose is facilitating to the <NUM>-(chloromethyl)furfural (Table <NUM>, entry <NUM>). Amberlyst-<NUM> and heteropoly acid (H<NUM>PW<NUM>O<NUM>) are found ineffective for this reaction (Table <NUM>, entry <NUM>, <NUM>). Interestingly, in presence of conc. H<NUM>SO<NUM> glucose is directly converted to DFF in <NUM>% yield. Under experimental conditions DMSO behaves as an oxidation agent as well as reaction medium (Table <NUM>, entry <NUM>).

The result in table <NUM> shows dehydration of fructose and sucrose. In DMSO, fructose and sucrose are heated at <NUM> with Sn-Mont, MTMF is produced in <NUM>% and <NUM>%, respectively (Table <NUM>, entry <NUM> and <NUM>). Similarly, with concentrated H<NUM>SO<NUM> fructose and sucrose are transformed into DFF with <NUM>% and <NUM>%, respectively (Table <NUM>, entry <NUM> and <NUM>).

Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Into an aqueous solution of SnCl<NUM>·<NUM><NUM>O (<NUM>, <NUM>), montmorillonite (<NUM>) was added lot wise under stirring at room temperature. After complete addition of montmorillonite, mixture was stirred further for <NUM>. Then mixture was filtered, residue was washed with plenty of water (millipore water) until neutral filtrate. Residue was dried in oven at <NUM> for <NUM>, ground in mortar pestle and kept in glass bottle.

A solution of carbohydrates (fructose/glucose/sucrose, <NUM>) in DMSO (<NUM>) was heated at <NUM> for <NUM>, under stirring in the presence of conc. H<NUM>SO<NUM> (<NUM> or <NUM>, <NUM> mol%). Because small quantities of Me<NUM>SO<NUM> and Me<NUM>S (Unpleasant odour) were produced during the reaction, the outgoing gas was bubbled through bleach (NaOCl) to oxidize the Me<NUM>S and fully destroy the odour. The reaction was monitored by quantitative HPLC analysis with an external standard. Once the highest yield of DFF was achieved, the reaction mixture was cooled to room temperature. Diluted with dichloromethane (<NUM>), washed with saturated solution of NaHCO<NUM> (<NUM> x <NUM>) and water (<NUM> x <NUM>). Separated organic phase was evaporated and passed through silica (<NUM>-<NUM> mesh size). The yield of pure DFF as a yellow crystalline solid was <NUM> (<NUM>% calculated on fructose used), <NUM> (<NUM>% calculated on glucose used) and <NUM> (<NUM>% calculated on sucrose used).

<NUM>H NMR (<NUM>, CDCl<NUM>), δ ppm <NUM> (s, <NUM>, furan H), <NUM> (s, <NUM>, CHO); <NUM>C NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (s, 2CH) <NUM> (s, 2C) <NUM> (s, 2CHO).

A solution of carbohydrates (fructose/glucose/sucrose, <NUM>) in DMSO (<NUM>) was heated at <NUM> for <NUM>, under stirring in the presence of Sn-Mont (<NUM>). Because small quantities of decomposition products of DMSO (Unpleasant odour) were produced during the reaction, the outgoing gas was bubbled through bleach (NaOCl) to oxidize the Me<NUM>S and fully destroy the odour. The reaction was monitored by quantitative HPLC analysis with an external standard. Once the highest yield of MTMF was achieved, the reaction mixture was cooled to room temperature and filtered to separate the catalyst. Catalyst bed was washed with dichloromethane (<NUM>) further mother liquor was washed with water (<NUM> x <NUM>). Separated organic phase was evaporated and passed through silica (<NUM>-<NUM> mesh size). The yield of pure MTMF as a brown crystalline solid was <NUM> (<NUM>% calculated on fructose used), <NUM> (<NUM>% calculated on glucose used) and <NUM> (<NUM>% calculated on sucrose used).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (s, <NUM>) <NUM> (s, <NUM>) <NUM>-<NUM> (d, J=<NUM>, <NUM>) <NUM>-<NUM> (d, J=<NUM>, <NUM>) <NUM> (s, <NUM>); <NUM>C NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (s, CH<NUM>) <NUM> (s, CH<NUM>) <NUM> (s, CH) <NUM> (s, CH) <NUM> (s, C) <NUM> (s, C) <NUM> (s, CHO).

TLC analysis was performed using Merck <NUM> aluminium-backed silica plates, and the compounds were visualized under UV light (<NUM>). Conversion of carbohydrates was calculated by using Agilent HPLC (column: Hi-Plex USP L17, detector: RI and mobile phase: millipore water with <NUM>/min flow). Yield of dehydration product of carbohydrates calculated by using Agilent HPLC (column: Poroshell <NUM> EC-C18, <NUM>, detector: UV and mobile phase: <NUM>% acetic acid in millipore water: acetonitrile (<NUM>:<NUM>) with <NUM>/min flow). Pure products were characterized and confirmed by <NUM>H-NMR and <NUM>C-NMR using CDCl<NUM> (<NUM>%, TMS) as solvent on <NUM> frequency Bruker instrument. The products were also confirmed using QP-Ultra <NUM> GC-MS Shimadzu instrument, RTX-<NUM> column, helium as carrier gas, EI mode and ionization source temperature <NUM>.

Initially, dehydration of glucose was started with the Sn-Mont catalyst at <NUM> in DMSO. After <NUM>, glucose was consumed completely with <NUM>% yield of HMF (Table <NUM>, entry <NUM>). Next experiment was performed at <NUM>, the product distribution was <NUM>% HMF and <NUM>% MTMF [<NUM>-((methylthio)methyl)-<NUM>-furfural] (Table <NUM>, entry <NUM>). Interestingly, selectivity to MTMF was increased at <NUM> with <NUM>% yield (Table <NUM>, entry <NUM>). Presence of Lewis acid and Brønsted acid sites are unique features of Sn-Mont which facilitates the glucose isomerisation to fructose on its Lewis acid sites and dehydration of in-situ formed fructose to HMF on its Brønsted acid sites. DMSO decomposes at high temperature (<NUM>) on Sn-Mont to polysulfides which helped to convert HMF to MTMF. In presence of SnCl<NUM>·<NUM><NUM>O, dehydration followed by chlorination of glucose was facilitating to the <NUM>-(chloromethyl)furfural (Table <NUM>, entry <NUM>). Amberlyst-<NUM> and heteropoly acid (H<NUM>PW<NUM>O<NUM>) were found ineffective for this reaction (Table <NUM>, entry <NUM>, <NUM>). Interestingly, in presence of conc. H<NUM>SO<NUM> glucose was directly converted to DFF in <NUM>% yield. Under experimental conditions DMSO behaves as an oxidation agent as well as reaction medium (Table <NUM>, entry <NUM>).

In DMSO, fructose and sucrose were heated at <NUM> with Sn-Mont, MTMF was produced in <NUM>% and <NUM>%, respectively (Table <NUM>, entry <NUM> and <NUM>). Similarly, with concentrated H<NUM>SO<NUM> fructose and sucrose were transformed into DFF with <NUM>% and <NUM>%, respectively (Table <NUM>, entry <NUM> and <NUM>).

The basic criterion for the solvent selection is that glucose should soluble in selected solvents. Therefore some solvent such as N,N-dimethylformamide (DMF), H<NUM>O and <NUM>-Butyl-<NUM>-methylimidazolium chloride [Bmim][Cl] were chosen for glucose dehydration reaction. When glucose was dissolved in DMF and <NUM> mol% H<NUM>SO<NUM> subsequently heated at <NUM> for <NUM>. Levulinic acid (<NUM>%) was formed along with excess humin after complete consumption of glucose (Table <NUM>, entry <NUM>). On the other hand, under experimental conditions in presence of water, HMF (<NUM>%) and levulinic acid (<NUM>%) were formed after full glucose conversion (Table <NUM>, entry <NUM>). In presence of <NUM>-Butyl-<NUM>-methylimidazolium chloride ([Bmim][Cl]) DFF was not formed at all (Table <NUM>, entry <NUM>). Thus from above experiments it is concluded that, other than DMSO all other solvents were not suitable for the production of DFF from glucose.

In the catalyst optimisation study different concentration (<NUM>, <NUM>, <NUM> mol%) of H<NUM>SO<NUM> (Table <NUM>) is screened. With <NUM> mol% of H<NUM>SO<NUM>, glucose was consumed completely with <NUM>% of HMF and <NUM>% DFF (Table <NUM>, entry <NUM>). While using <NUM> mol% of H<NUM>SO<NUM>, DFF was produced in <NUM>% yield (Table <NUM>, entry <NUM>). On the other hand, in presence of <NUM> mol% of H<NUM>SO<NUM>, DFF yield was dropped to <NUM>% (Table <NUM>, entry <NUM>). Higher catalyst concentration than <NUM> mol% has induced negative effect on DFF yield due to excess humin formation.

The range of temperatures from <NUM>-<NUM> is studied in Table <NUM>. At <NUM>, product distribution was <NUM>% HMF and <NUM>% DFF with complete conversion of glucose (Table <NUM>, entry <NUM>). While increasing temperature to <NUM>, DFF yield was increased to <NUM>% (Table <NUM>, entry <NUM>). However, at <NUM> DFF was obtained in <NUM>% yield which was comparable to the result obtained at <NUM>.

Effect of Sn-Mont loading was studied for the MTMF production and results are presented in Table <NUM>. When lower than <NUM> loading of Sn-Mont was used, conversion of glucose wasn't reached to <NUM>% (Table <NUM>, entry <NUM> and <NUM>). While, more than <NUM> loading of Sn-Mont was used, MTMF was formed in <NUM>% yield which is comparable to the results obtained with <NUM> Sn-Mont loading (Table <NUM>, entry <NUM> and <NUM>). Thus <NUM> loading was found optimum loading and same amount was used for further experiment.

Dehydration of glucose was studied over Sn-Mont at different temperature (<NUM>-<NUM>) in DMSO solvent (Table <NUM>). At <NUM>, product distribution was <NUM>% of HMF and <NUM> % of MTMF (Table <NUM>, entry <NUM>). While at <NUM>, product distribution was <NUM>% of HMF and <NUM>% of MTMF (Table <NUM>, entry <NUM>). However, at <NUM>, MTMF was obtained in <NUM>% yield which was comparable to the result obtained at <NUM>.

Claim 1:
A single step, single pot process for the synthesis of furan derivative from carbohydrate comprising a step of stirring a reaction mixture of carbohydrate in a solvent in presence of a catalyst at a temperature in the range of <NUM> to <NUM> for a time period in the range of <NUM> to <NUM> hrs to obtain corresponding furan derivative, wherein the furan derivative is <NUM>,<NUM>-di(formyl)furan;
wherein the carbohydrate is selected from the group consisting of fructose, glucose or sucrose;
wherein the solvent is dimethyl sulfoxide; and
wherein the said catalyst is sulfuric acid.