Production of tri-methyl benzene derivatives

Abstract

The present invention relates to the production of tri-functional aromatic molecules from diformylfuran, in particular to the production of tri-methyl benzene derivatives such as for example trimellitic acid or 1,2,4-tri(aminomethyl)benzene from diformylfuran and its derivatives.

Claims

1. A process for the preparation of a compound of Formula (I) ##STR00030## wherein X and Y independently are optionally substituted heteroatoms; each R.sup.2 independently is H, alkyl, alkenyl or aryl; R.sup.3 and R.sup.4 independently are H or CN, provided that at least one of R.sup.3 and R.sup.4 is CN; the process comprising a.) dehydration/aromatization of a compound of the Formula (II) ##STR00031## wherein X and Y independently are optionally substituted heteroatoms; R is a C.sub.1-4 alkylene group which may optionally be substituted with one or more R.sup.1; R.sup.1 is a linear, branched and/or cyclic, saturated or unsaturated hydrocarbon group which optionally bears one or more functional groups; R.sup.2 independently is H, alkyl, alkenyl or aryl; and R.sup.3 and R.sup.4 independently are H or CN, provided that at least one of R.sup.3 and R.sup.4 is CN; to obtain a compound of the Formula (III) ##STR00032## wherein X, Y, R, R.sup.2, R.sup.3 and R.sup.4 are defined as above; followed by deprotection of the compound of Formula (III); or b.) carrying out the dehydration/aromatization and the deprotection of the compound of Formula (II) in a single step.

2. The process according to claim 1, wherein X and Y are O or X and Y are S.

3. The process according to claim 1, wherein R is CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH(CH.sub.3)CH(CH.sub.3) or CH.sub.2C(CH.sub.3).sub.2CH.sub.2.

4. The process according to claim 1, wherein R.sub.2 is H.

5. The process according to claim 1, wherein X and Y are O and R is CH.sub.2CH.sub.2.

Description

EXAMPLE 1

Production of 2,5-bis(1,3-dioxolan-2-yl)furan

(1) ##STR00019##

(2) 3 g of diformylfuran (DFF) and 50 mg of Amberlyst 15 are suspended in 80 mL of toluene and 9 g of ethylene glycol. The mixture is refluxed in a Dean-Stark apparatus for 4 h. After filtration of Amberlyst, 80 mL of ethyl acetate is added and the organic phase is washed 3 times with 30 mL of water. The organic phase is dried over MgSO.sub.4 and evaporated to get a near pure product.

EXAMPLE 2

Diels-Alder Reaction of 2,5-bis(1,3-dioxolan-2-yl)furan and acrylonitrile

(3) ##STR00020##

(4) In a carousel tube fitted with a PTFE septum screw cap, 2,5-bis(1,3-dioxolan-2-yl)furan (1.87 g; 8.81 mmol) was weighted. Then, acrylonitrile (2.33 g; 44.0 mmol) and ZnCl.sub.2 (281 mg; 2.06 mmol) were added. The reaction mixture was stirred at 60 C. during 43 h. The conversion is 87% to an endo/exo mixture of adducts C. The reaction mixture was concentrated in vacuo. This crude product was purified by flash chromatography (silica gel, EtOAc/cyclohexane) to afford 1.64 g of expected adducts (1.14 g endo and 0.50 g exo) as a slight yellow solids, global isolated yield is 70%.

EXAMPLE 3

Conversion of Diels-Alder Adducts of Previous Example to 2,5-bis(1,3-dioxolan-2-yl)benzonitrile

(5) ##STR00021##

(6) In a carousel tube fitted with a PTFE septum screw cap, endo adduct C (1.0 g; 3.77 mmol), dimethyl sulfoxide (5 ml) and sodium methoxide solution (25 wt. % in methanol; 169 mg; 0.75 mmol) will be charged. The reaction mixture will be stirred at 100 C. during 1 h.

(7) After cooling, the crude product will be diluted with dichloromethane (20 ml). The mixture will be washed with water (10 ml). The aqueous phase will be extracted with dichloromethane (20 ml) and the organic phase will be washed with water (10 ml, 3 times). After drying (MgSO.sub.4), the solvent will be evaporated to afford 887 mg of an oily liquid (93%).

EXAMPLE 4

Deprotection of 2,5-bis(1,3-dioxolan-2-yl)benzonitrile to 2,5-Diformylbenzonitrile

(8) ##STR00022##

(9) To a stirred solution of 2,5-bis(1,3-dioxolan-2-yl)benzonitrile (200 mg; 0.81 mmol) in THF (10 ml), 1N HCl solution (10 ml) will be added at room temperature. The mixture will be heated at 80 C. for 1 h and cooled to room temperature. The reaction mixture will be extracted with chloroforme (10 ml, 3 times). The combined chloroform solution will be dried (anhydrous MgSO.sub.4), filtered and evaporated under reduced pressure to give 126 mg (98%) of 2,5-Diformylbenzonitrile.

EXAMPLE 5

Oxidation of 2,5-Diformylbenzonitrile to 2-cyanoterephthalic acid

(10) ##STR00023##

(11) 31.8 g (200 mmol) of 2,5-Diformylbenzonitrile, 80 g of dioxane, 35.2 g of sodium hydrogen carbonate, and 200 g of water will be mixed with stirring. 410 g of an aqueous 13.5% by weight sodium hypochlorite solution adjusted to a pH of 9 will be added dropwise over 1 hour while maintaining the internal temperature of the reaction system at 50 C. or less, and the resulting mixture will be stirred for 1 additional hour. Then, 7.2 g of urea will be added and the resulting mixture will be stirred for 20 minutes. Furthermore, 24 g of 98% by weight sulfuric acid and 300 g of water will be added. Precipitated crystals will be formed; they will be filtered, washed with water, and dried to obtain about 35 g (yield: about 92%) of 2-cyanoterephthalic acid. The purity will be 98% or more.

EXAMPLE 6

Hydrolysis of 2-cyanoterephthalic acid to trimellitic acid

(12) ##STR00024##

(13) 6.5 g (34 mmol) of 2-cyanoterephthalic acid will be added to a solution of NaOH (2.93 g) in water (26 g). The resulting solution will be heated to reflux (115 C.) for 5 hours. After cooling, 70 ml of water will be added and the solution will be acidified to pH=1 by dropwise addition of 95% sulfuric acid. A white solid precipitate will be formed. The white solid precipitate will be filtrated and washed 3 times with 10 ml of water. After drying (60 C., 10 mbar, 2 h), 6.86 g of trimellitic acid (96% yield) will be obtained.

EXAMPLE 7

Production of 2,5-bis(1,3-dioxolan-2-yl)furan

(14) ##STR00025##

(15) A suspension of diformylfuran (12 g, 96.7 mmol) in toluene (200 ml) is taken in a round bottomed flask with Dean-Stark apparatus. Ethylene glycol (35 g, 563 mmol) and Amberlyst-15H (250 mg) are added to the reaction mixture and the reaction mixture is left refluxing overnight. The reaction mixture is allowed to cool down to room temperature, and filtered to remove acid catalyst. The filtrate is diluted with ethyl acetate (200 ml). The organic phase is washed with sodiumbisulphite solution (3 times) and finally with water. The organic phase is dried over anhydrous Na.sub.2SO.sub.4. The filtrate is concentrated and dried to obtain 16 g (yield: 78%) of 2,5-bis(1,3-dioxolan-2-yl)furan.

(16) The product was characterized by NMR spectroscopy.

(17) .sup.1H NMR (400 MHz, CDCl.sub.3): 6.40 (2H, s), 5.93 (2H, s), 4.12-3.98 (8H, m).

EXAMPLE 8

Diels-Alder Reaction of 2,5-bis(1,3-dioxolan-2-yl)furan and acrylonitrile

(18) ##STR00026##

(19) 2,5-bis(1,3-dioxolan-2-yl)furan (10 g, 47.13 mmol) was taken in a high pressure tube. Added acrylonitrile (12 ml, 183.18 mmol) and ZnCl.sub.2 (1 g, 7.7 mmol) to the tube and the tube was tightly closed. The reaction mixture was left stirring at 65 C. for 48 h. Complete consumption of the starting materials was confirmed by Thin layer chromatography (eluent: 50% EtOAc/cyclohexane). The reaction mixture was cooled down to room temperature, and diluted with dichloromethane (250 ml). The organic phase was washed with NaHCO.sub.3 solution and water. Finally the organic phase was dried over anhydrous Na.sub.2SO.sub.4. The filtrate was concentrated and dried. The crude mixture was purified by column chromatography to isolate the endo/exo mixture of Diels-Alder product (9.6 g, yield: 77%).

(20) The product was characterized by NMR spectroscopy.

(21) .sup.1H NMR (400 MHz, CDCl.sub.3): 6.58 (0.72H, d, J=6 Hz), 6.55 (0.72H, d, J=6 Hz), 6.45 (0.28H, dd, J=0.8 & 6 Hz), 6.28 (0.28H, d, J=5.6 Hz), 5.44 (0.28H, d, J=0.7 Hz), 5.35 (0.72H, s), 5.29 (0.28H, s), 5.22 (0.72H, s), 4.14-3.92 (8H, m), 3.15 (0.72H, dd, J4 &9.6 Hz), 2.65 (0.28H, dd, J=4 & 8 Hz), 2.43 (0.72H, dd, J=9.6 & 11.6 Hz), 2.25 (0.28H, dd, J=4 & 11.6 Hz), 1.94 (0.28H, dd, J=8.4 & 11.6 Hz), 1.68 (0.72H, dd, J=4 & 11.6 Hz).

(22) .sup.13C NMR (100 MHz, CDCl.sub.3): 137.6/137.5, 133.7, 133.7, 120.1, 119.7, 101.4, 101.4, 101.1, 101, 91.3, 91.2, 91.1, 90.8, 66.3, 66.2, 65.9, 65.9, 65.8, 65.8, 33.9, 33.8, 31.1, 27.9.

EXAMPLE 9

Conversion of Diels-Alder Adducts of Previous Example to 2,5-bis(1,3-dioxolan-2-yl)benzonitrile

(23) ##STR00027##

(24) A solution of Diels-Alder product mixture (6 g, 22.6 mmol) in dimethyl sulfoxide (40 ml) was taken in a round bottomed flask, and added grinded powder of KOH (2.5 g, 44.56 mmol) to the solution. The suspension was left stirring at room temperature for 2 h. Complete consumption of the starting material was confirmed through Thin layer chromatography (eluent: 40% EtoAc/cyclohexane). Diluted the reaction mixture with dichloromethane (200 ml). The organic phase was washed with water (3-4 times). The organic phase was dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and dried to obtain the pure product (5.1 g, yield: 91%). The product was used for the next step without any further purification.

(25) The product was characterised by NMR spectroscopy.

(26) .sup.1H NMR (400 Hz, CDCl.sub.3): 7.83 (1H, d, J=4 Hz), 7.69 (1H, dd, J=4 & 8 Hz), 7.62 (1H, d, J=8 Hz), 5.98 (1H, s), 5.83 (1H, s), 4.23-4.05 (8H, m). .sup.13C NMR (100 MHz, CDCl.sub.3): 141.9, 140.6, 131.9, 130.9, 128.1, 117.1, 111.6, 102.2, 101.9, 66.1, 65.6.

EXAMPLE 10

Deprotection of 2,5-bis(1,3-dioxolan-2-yl)benzonitrile to 2,5-Diformylbenzonitrile

(27) ##STR00028##

(28) A solution of 2,5-bis(1,3-dioxolan-2yl)benzonitrile (4.9 g, 19.82 mmol) in acetone (60 ml) was taken in a round bottomed flask. Diluted HCl (2-3N aqueous solution, 60 ml) was added to the reaction mixture and the reaction mixture was left stirring at room temperature for 5-6 h. Concentrated the reaction mixture under reduced pressure, and extracted the organic compounds into dichloromethane (360 ml). The combined organic phase was further washed with water and dried over anhydrous Na.sub.2SO.sub.4. The filtrate was concentrated and dried to obtain pure product (2.6 g, yield: 83%).

(29) The product was characterised by NMR spectroscopy.

(30) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.33 (1H, dd, J=0.4 & 1.6 Hz), 8.27 (1H, ddd, J=0.5, 1.5 & 8 Hz), 8.23 (1H, d, J=8 Hz). .sup.13C NMR (100 MHz, CDCl.sub.3): 189.4, 188.0, 140, 139.8, 134.9, 133.8, 130.6, 115.2, 114.9.

EXAMPLE 11

Oxidation of 2,5-Diformylbenzonitrile to Trimellitic Acid

(31) ##STR00029##

(32) A solution of 2,5-Diformylbenzonitrile (1.4 g, 8.8 mmol) in dimethylformamide (20 ml) was taken in a round bottomed flask. Added oxone (potassium peroxymonosulfate) (5.4 g, 17.57 mmol) to the reaction mixture and the suspension was left stirring at room temperature for 5-6 h. Complete consumption of the starting material was confirmed by Thin layer chromatography. The reaction mixture was filtered to remove the precipitate (most of the inorganic salt). Distilled out dimethylformamide from the filtrate at reduced pressure and dried the residual solid (about 2 g). The residual solid was characterized by Liquid Chromatography Mass Spectroscopy (LCMS) and isolated trimellitic acid after purification by reverse phase column chromatography. Trimellitic acid was isolated after column chromatography.

(33) The product was characterised by NMR spectroscopy.

(34) .sup.1H NMR (400 MHz, DMSO-d6): 8.22 (1H, d, J=1.5 Hz), 8.11 (1H, dd, J=1.7 & 8 Hz), 7.56 (1H, d, J=8 Hz).

(35) .sup.13C NMR (100 MHz, DMSO-d6): 168.4, 167.5, 166, 137.4, 132.4, 132.2, 131.8, 129.5, 128.7.