DIELS-ALDER RING-OPENING PROCESS

Abstract

The invention is directed to a process for the ring-opening of a cycloadduct obtainable from a reaction of a furanic compound and a diene, said process comprising contacting the cycloadduct with an acidic mixture comprising sulfuric acid and an activating agent to obtain a ring-opened product. The present invention is particularly directed a continuous process.

Claims

1. A process for the ring-opening of a cycloadduct comprising a cylcoadduct according to formula I, ##STR00023## wherein R.sub.1 and/or R.sub.2 are independently selected from the group consisting of H, C.sub.1-C.sub.20 alkyl, CHO and hydrazones, oximes, hemiacetals and acetals thereof, CH.sub.2OH and esters and ethers thereof, CO.sub.2H and esters thereof, and amides and tertiary amines of CH.sub.2NH.sub.2 and optionally polymer supported; preferably wherein R.sub.1 and R.sub.2 both are H or methyl, or R.sub.1 is hydrogen and R.sub.2 is methyl; R.sub.3 and/or R.sub.4 are independently selected from the group consisting of CH.sub.3, acetals, hemiacetal, hydrazones and oximes of CHO, CH.sub.2OH and esters and ethers thereof, CO.sub.2H and esters thereof, amides and tertiary amines of CH.sub.2NH.sub.2, and an electron withdrawing group that is preferably selected from the group consisting of H, CF.sub.3, CCl.sub.3, CBr.sub.3, CIs, NO.sub.2, CN, SO.sub.2Q, SO.sub.3Q, COQ, COF, COCl, COBr, COI, C(O)Q, CO.sub.2Q, C(O)NQ, and C(═NT)Q, wherein Q and T are independently H, or linear or branched C.sub.1-C.sub.8-alkyl, optionally substituted with halogens and optionally polymer supported, or R.sub.3 and R.sub.4 together represent —(CO)X(CO)—, wherein X═O, CH.sub.2, NH, NMe, NEt, NPr, NBu, NPh, or S; preferably R.sub.3 and R.sub.4 together represent —(CO)O(CO)—, —(CO)NMe(CO)—, —(CO)NEt(CO)— or —(CO)NPr(CO)—; or R.sub.2 and R.sub.4 together represent —CH.sub.2ZC(O)—, wherein Z is selected from the group consisting of O, NH and S; wherein represent a single or double bond, preferably a single bond; wherein said process comprises contacting the cycloadduct with an acidic mixture comprising sulfuric acid and an activating agent to obtain a ring-opened product.

2. The process according to claim 1 where the activating agent is selected from the group consisting of acylating agent, triflating agent, sulfonating agent, carbamylating agent, carbonylating agent, or combinations thereof, preferably wherein the activating agent is an acylating agent, more preferably an acylating agent selected from the group consisting of acetic anhydride, acetyl chloride, propionic anhydride, butyric anhydride, isobutyric anhydride, trimethylacetic anhydride, mixed anhydrides thereof, or combinations thereof, most preferably the activating agent comprises acetic anhydride.

3. The process according to claim 1 wherein the ring-opened product comprises a ring-opened cyclohexene product according to formula II, an aromatized product according to formula III or a combination thereof ##STR00024## wherein OAct represents a remnant of the activating agent, preferably wherein OAct represents an acylate, triflate, sulfonate, carbamylate, carbonylate, or combinations thereof, more preferably wherein OAct represents —OSO.sub.2CF.sub.3, —OSO.sub.2Y, —OC(O)NYZ, —OC(O)Y wherein Y and Z are independently H, linear or branched C.sub.1-C.sub.2a-alkyl, phenyl or benzyl; and R.sub.1-R.sub.4 as well as the solid-dashed bond are as defined for formula I and/or hydrolysates thereof.

4. The process according to claim 3, wherein isolated ring-opened cyclohexene product according to formula II is brought into contact with a heterogeneous catalyst to give aromatized product according to formula III.

5. The process according to claim 1, wherein the cycloadduct and the acidic mixture are contacted at a temperature in the range of −80 to 200° C., preferably in the range of −40 to 150° C., more preferably in the range of −20 to 100° C., even more preferably most preferably in the range of 0 to 80° C., most preferably in the range of 10 to 60° C. such as about 20° C.

6. The process according to claim 1, wherein said process is carried out with a molar ratio of the activation agent to cycloadduct in the range of 30:1 to 1:10, preferably in a range of 20:1 to 2:1 such as about 10:1.

7. The process according to claim 1, wherein said process is carried out with a molar ratio of sulfuric acid to cycloadduct of at least 0.01:1, preferably in the range of 2:1 to 0.05:1, more preferably in a range of 1:1 to 0.1:1 such as about 0.5:1.

8. The process according to claim 1, wherein said process comprises heating of the ring-opened product, preferably heating to a temperature in the range of 0 to 150° C., more preferably in a range of 15 to 100° C., most preferably in the range of 40 to 80° C.

9. The process according to claim 8, wherein said heating is maintained for a maximum of 48 hours, more preferably for a maximum of 24 hours, even more preferably a maximum of 10 hours and even more preferably a maximum of 6 hours, most preferably a maximum in the range of 30 minutes to 3 hours.

10. The process according to claim 1, wherein said process comprises removing at least part of unreacted activating agent, preferably by evaporation of said unreacted activating agent, more preferably by removing said unreacted activating agent by evaporation thereof under reduced pressure, most preferably by evaporation at a pressure in the range of 0 to 1 bar, preferably in the range of 0.1 to 150 mbar, more preferably in the range of 1 to 100 mbar, even more preferably in the range of 5 to 50 mbar.

11. The process according to claim 10, wherein the removed unreacted activating agent is recycled into the process.

12. The process according to claim 1, wherein said process comprises isolation of the ring-opened product, preferably isolation comprising solidification of the ring-opened product, more preferably wherein said solidification of the ring-opened product comprises concentration of the ring-opened product, addition of an anti-solvent, cooling and combinations thereof.

13. The process according to claim 1, wherein contacting the cycloadduct with an acidic mixture provides a slurry or solution comprising the ring-opened cyclohexene product according to formula II, which slurry or solution is then heated to form the aromatized product according to formula III, optionally catalyzed by a heterogeneous catalyst, followed by isolation of said aromatized product by evaporation crystallization.

14. The process according to claim 13, wherein contacting the cycloadduct and the acidic mixture is carried out at 5 to 35° C. for 15 to 30 minutes and/or the slurry or solution is heated for 15 to 120 min at 20-100° C., preferably 30 to 90 minutes at 60-90° C.

15. The process according to claim 1, wherein said process is a continuous process.

16. The process according to claim 1, wherein said process is free of a solvent extraction step.

17. The process according to claim 1, wherein said process further comprises the step of hydrolyzing the ring-opened product to obtain a phthalic acid, preferably a phthalic acid according to formula IV. ##STR00025##

Description

EXAMPLE 1: PRODUCTION OF 3-MPA WITHOUT IN SITU EVAPORATION

[0066] A jacketed-reactor was cooled to −20° C. then acetic anhydride (12700 g) was added, with stirring. Sulfuric acid (1597 g) was then added slowly to limit the exotherm. When the internal temperature was <2° C., the solid Diels-Alder adduct of 2-methylfuran and maleic anhydride (5625 g) was added using a solid doser, maintaining an internal temperature of under 6° C. After complete addition, the mixture was warmed to 60° C., and held for 6 hours. The reaction mixture was then cooled to ˜0° C. This caused a solid to precipitate. The solid was isolated by filtration and washed with ice-cold water (2000 ml) and dried in a vacuum oven (35° C., 2 mbar). Nuclear magnetic resonance (NMR) confirmed this product to be very clean 3-methylphthalic anhydride (2738 g, 54%). The filtrates were concentrated by vacuum distillation (50° C., ˜20 mbar), then when no more distillate was observed, the concentrated mixture was stirred vigorously and cooled to 0° C., then ice-cold water (5600 g) was added. The mixture was again cooled to 0° C., then the formed solid was isolated by filtration, and washed with ice-cold water (1500 ml) and dried in a vacuum oven (35° C., 2 mbar). NMR confirmed this product to be quite clean 3-methylphthalic anhydride (3-MPA, 1268 g, 25%).

EXAMPLE 2: PRODUCTION OF 3-MPA WITH IN SITU EVAPORATION

[0067] To a reactor was charged acetic anhydride (420 ml) and this was cooled to around 0° C. with stirring, using an ice bath. Sulfuric acid (32 ml) was then added dropwise to limit the exotherm. This mixture was allowed to cool to ˜1° C., then the solid Diels-Alder adduct of 2-methylfuran and maleic anhydride (200 g) was added portion-wise over a period or around 45 minutes, maintaining an internal temperature of under 6° C. After complete addition, the mixture was warmed to 50° C., and the reactor was set-up for vacuum distillation. Acetic acid and acetic anhydride (365 g total) were then removed by vacuum distillation at around 30 mbar. After around 4 hours, the reaction mixture was cooled to 0° C. with an ice/water bath, then ice-cold water (160 ml) was added dropwise, maintaining an internal temperature of less than 50° C. This yield a slurry, from which the solid was isolated by filtration, and washed with ice-cold water (200 ml) and dried in a vacuum oven (35° C., 2 mbar). NMR confirmed this product to be very clean 3-methylphthalic anhydride (129.4 g, 71.9%).

EXAMPLE 3: PREPARATION OF REACTION INTERMEDIATE 1

[0068] To a reactor was charged acetic anhydride (42 ml) and this was cooled to around 0° C. with stirring, using an ice bath. Sulfuric acid (3.08 ml) was then added dropwise to limit the exotherm. This mixture was allowed to cool to ˜1° C., then the solid Diels-Alder adduct of 2-methylfuran and maleic anhydride (20 g) was added portionwise over a period or around 10 minutes, maintaining an internal temperature of under 15° C. The reaction was left to stand in an ice-bath for 60 minutes, during which time a solid precipitated. This was isolated by filtration and washed with ice-cold water (50 ml). NMR confirmed this product to be the corresponding ring-opened cyclohexene, a di-acetylintermediate (reaction intermediate 1).

EXAMPLE 4: CONVERSION OF REACTION INTERMEDIATE 1 TO 3-MPA

[0069] To a reactor was charged reaction intermediate 1 (100 mg), acetonitrile (1 ml) and silica (200 mg). This mixture was allowed to stir 1 hour at ambient temperature, then was analyzed by NMR. This showed almost complete conversion to 3-methylphthalic anhydride.

EXAMPLE 5: PURIFICATION OF 3-MPA WITHOUT ACTIVATED CARBON

[0070] To a reactor was charged crude 3-MPA (25 g—isolated from reaction mixture) and toluene (300 ml). The mixture was heated to reflux resulting in separation of a very small amount of brown oil. The light-colored solution was separated by decantation, and then cooled with stirring to induce crystallization. The formed solid was isolated by filtration and then washed with toluene (2×25 ml). This yielded a white solid (17.7 g, 71%). Concentration of the filtrates by rotary evaporation yielded a further white solid (5.8 g, 23%). NMR confirmed both isolated solids were confirmed to be highly pure 3-MPA.

EXAMPLE 6: PURIFICATION OF 3-MPA WITH ACTIVATED CARBON

[0071] To a reactor was charged crude 3-MPA (25 g—recovered from the reaction filtrates, and dark brown in color) and toluene (100 ml). The mixture was heated to reflux resulting in separation of the mixture into a biphasic system—predominantly a red colored solution, with a small amount of dark oil present. The red colored solution was separated by decantation and activated charcoal (4 g) was added. This was stirred at 100° C. for 30 minutes then filtrated while hot to remove the activated charcoal. The mixture was then cooled with stirring to induce crystallization. The formed solid was isolated by filtration and then washed with toluene (2×25 ml). This yielded a white solid (11.6 g, 46%). Concentration of the filtrates by rotary evaporation yielded a further white solid (7.3 g, 29%). NMR confirmed both isolated solids were confirmed to be highly pure 3-MPA.

EXAMPLE 7: CONTINUOUS PRODUCTION OF 3-MPA

[0072] A 8:1 molar mixture of acetic anhydride and concentrated sulfuric acid was prepared by adding sulfuric acid slowly to stirred acetic anhydride and cooling with an ice bath. This mixture was used as feed solution for the process. A continuously-stirred tank reactor (CSTR) was then heated to the desired temperature for contacting the cycloadduct (i.e. the Diels-Alder adduct) and acid mixture. A known volume of the acetic anhydride and concentrated sulfuric acid mixture was pumped into a CSTR reactor. The dosing of solid Diels-Alder adduct of 2-methylfuran and maleic anhydride from a solid-doser was then started at the desired rate. When the desired amount of solid Diels-Alder adduct had been added, the acetic anhydride and concentrated sulfuric acid pump was started at the desired rate. At the same time, a pump was started to pump the product mixture out of the CSTR at the desired rate, thus defining the residence time in the CSTR. The product mixture was pumped through a tubular reactor which was heated to the desired temperature, and had a length selected to determine the desired residence time. Samples from the CSTR and the tubular reactor were periodically taken to check progression and stability (by NMR, using an internal standard). In a specific example, a temperature of 25-30° C. was applied to the CSTR, and a residence time of around 20 minutes, resulting in no residual Diels-Alder adduct being present, and about 79% molar yield of reaction intermediate and ˜19% molar yield of 3-methylphthalic anhydride exiting the CSTR (time-averaged over about 150 minutes). Passing this product solution through the tubular reactor at 60° C. for a residence time of around 24 minutes resulted in a product solution comprising about 54% molar yield of 3-methylphthalic anhydride.

EXAMPLE 8: RING-OPENING/AROMATIZATION WITH LESS H.SUB.2.SO.SUB.4

[0073] ##STR00012##

[0074] To a stirred flask containing acetic anhydride (113.4 g, 105 ml, 4 eq.) was added sulfuric acid (2.76 g, 1.5 ml, 0.1 eq.) and the mixture was cooled to ˜0° C. (ice/water bath). To this was added 2-methylfuran:maleic anhydride Diels-Alder adduct (50 g) portion-wise over ˜30 minutes. After complete addition, the mixture was heated to 50° C., held for 1 hour, and analyzed by NMR. Significant levels of the desired aromatic anhydride are present, but predominantly undesired retro-Diels-Alder has taken place, with >50 mol % maleic anhydride observed to be present.

EXAMPLE 9: RING-OPENING/AROMATIZATION WITH AQUEOUS WORK-UP

[0075] ##STR00013##

[0076] To a stirred flask containing acetic anhydride (113.4 g, 105 ml, 4 eq.) was added sulfuric acid (13.8 g, 7.5 ml, 0.52 eq.) and the mixture was cooled to ˜0° C. (ice/water bath). To this was added 2-methylfuran:maleic anhydride Diels-Alder adduct (50 g) portion-wise over ˜30 minutes. After complete addition, the mixture was heated to 50° C. and held for 4 hours. To the mixture was charged deionized water (25.0 g, 25.0 ml, 5 eq.) at a rate which maintained an internal temperature of <80° C., then the mixture was cooled to ˜5° C. (ice/water bath). This caused a white solid to precipitate, and this was isolated by filtration and washed with ice-cold water (15 ml). The solid was dried in a vacuum oven (35° C., 10 mbar) to yield a white powder (28.11 g, 61.7%). Analysis by NMR confirmed the isolated product to be reasonably clean 3-methylphthalic anhydride. Analysis of the filtrate by NMR showed it to contain trace amounts of 3-methylphthalic acid.

EXAMPLE 10: RING-OPENING/AROMATIZATION TO MALEIMIDES

[0077] ##STR00014##

[0078] To a stirred flask was charged acetic anhydride (422 mg, 391 μL, 4 eq.) followed by sulfuric acid (50.8 mg, 27.6 μL, 0.52 eq.) and the mixture was cooled to 0° C. (ice/water bath). To this was added N-ethyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide (200 mg), portionwise over 10 minutes, maintaining a temperature below 10° C. and the mixtures was stirrer until the solids dissolved. The mixture was then heated to 60° C. and held for 2.5 hours, with the mixture being analyzed after 30, 60, 90 and 150 minutes by NMR. This shows a reasonably clean conversion, with around 20% N-ethylphthalimide having been formed after 150 minutes.

[0079] To a stirred flask was charged acetic anhydride (394 mg, 365 μL, 4 eq.) followed by sulfuric acid (47.5 mg, 25.8 μL, 0.52 eq.) and the mixture was cooled to 0° C. (ice/water bath). To this was added N-ethyl-4-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide (200 mg), portionwise over 10 minutes, maintaining a temperature below 10° C. and the mixtures was stirrer until the solids dissolved. The mixture was then heated to 60° C. and held for 2.5 hours with the mixture being analyzed after 30, 60, 90 and 150 minutes by NMR. This shows a reasonably clean conversion, with around 30% 3-methyl-N-ethylphthalimide having been formed after 30 minutes, and leading to more than 80% 3-methyl-N-ethylphthalimide after 150 minutes.

[0080] To a stirred flask was charged acetic anhydride (368 mg, 341 μL, 4 eq.) followed by sulfuric acid (44.2 mg, 24.0 μL, 0.52 eq.) and the mixture was cooled to 0° C. (ice/water bath). To this was added N-ethyl-4,6-dimethyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide (200 mg), portionwise over 10 minutes, maintaining a temperature below 10° C. and the mixtures was stirrer until the solids dissolved. The mixture was then heated to 60° C. and held for 2.5 hours with the mixture being analyzed after 30, 60, 90 and 150 minutes by NMR. This shows a reasonably clean conversion, with around 90% 3,6-dimethyl-N-ethylphthalimide having been formed after 60 minutes, and complete conversion to 3,6-dimethyl-N-ethylphthalimide after 150 minutes.

EXAMPLE 12: RING-OPENING/AROMATIZATION OF METHYL 7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-CARBOXYLATE

[0081] ##STR00015##

[0082] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath) was charged sulfolane (72.3 mg, 57.3 μL—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. Methyl 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (463.8 mg, 1 eq.) was added dropwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 10 minutes at ˜0° C., then heated to −60° C. and held for a further 3 hours. The mixture was then analysed at various intervals by NMR. After 3 hours, 12% of the desired aromatic (methyl benzoate) has formed, with the rest of the mixture mainly ring-opened reaction intermediates.

EXAMPLE 13: RING-OPENING/AROMATIZATION OF DIMETHYL 7-OXABICYCLO[2.2.1]HEPTA-2,5-DIENE-2,3-DICARBOXYLATE

[0083] ##STR00016##

[0084] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath) was charged sulfolane (72.3 mg, 57.3 μL—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. Dimethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (632.1 mg, 1 eq.) was added dropwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 10 minutes at ˜0° C., then heated to ˜60° C. and held for a further 3 hours. The mixture was then analyzed at various intervals by NMR. After 3 hours, a combined 32% yield of two aromatic products was observed (thought to correspond to dimethyl 3-hydroxyphthalate and dimethyl 3-acetoxyphthalate) in a ˜1:1 ratio.

EXAMPLE 14: RING-OPENING/AROMATIZATION OF DIMETHYL 1,4-DIMETHYL-7-OXABICYCLO[2.2.1]HEPTA-2,5-DIENE-2,3-DICARBOXYLATE

[0085] ##STR00017##

[0086] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath) was charged sulfolane (72.3 mg, 57.3 μL—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. Dimethyl 1,4-dimethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (716.5 mg, 1 eq.) was added dropwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 10 minutes at ˜0° C., then heated to ˜60° C. and held for a further 3 hours. The mixture was then analyzed at various intervals by NMR. After 3 hours, a combined 83% yield of two aromatic products was observed, corresponding to dimethyl 4-hydroxy-3,6-dimethylphthalate and dimethyl 4-acetoxy-3,6-dimethylphthalate had formed in a ˜3:1 ratio.

EXAMPLE 15: RING-OPENING/AROMATIZATION OF 7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-CARBONITRILE

[0087] ##STR00018##

[0088] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath) was charged sulfolane (72.3 mg, 57.3 μL—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. 7-Oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile (364.3 mg, 1 eq.) was added dropwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 10 minutes at ˜0° C., then heated to ˜60° C. and held for a further 3 hours. The mixture was then analysed at various intervals by NMR. After 3 hours, a 51% yield of benzonitrile was observed, with the rest of the mixture mainly ring-opened reaction intermediates.

EXAMPLE 16: RING-OPENING/AROMATIZATION OF 1,4-DIMETHYL-7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-CARBONITRILE

[0089] ##STR00019##

[0090] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath) was charged sulfolane (72.3 mg, 57.3 μL—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. 1,4-Dimethyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile (448.7 mg, 1 eq.) was added dropwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 10 minutes at ˜0° C., then heated to ˜60° C. and held for a further 3 hours. The mixture was then analysed at various intervals by NMR. After 3 hours, a 5% yield of 2,5-dimethylbenzonitrile was observed, with the rest of the mixture mainly ring-opened reaction intermediates.

EXAMPLE 17: RING-OPENING/AROMATIZATION OF LACTONE DIELS-ALDER ADDUCT

[0091] ##STR00020##

[0092] To a stirred flask containing acetic anhydride (300 mg, 277.8 μL, 4 eq.) was added sulfuric acid (36.0 mg, 19.6 μL, 0.5 eq.) and the mixture was cooled to ˜0° C. (ice/water bath). To this was added 7,7a-Dihydro-3H-3a,6-epoxyisobenzofuran-1(6H)-one (111.8 mg) portion-wise over ˜15 minutes. After complete addition, the mixture was heated to 80° C. and held for 1 hour. The mixture was analyzed by NMR which showed a quantitative conversion to phthalide.

EXAMPLE 18: RING-OPENING/AROMATIZATION OF LACTONE DIELS-ALDER ADDUCT

[0093] ##STR00021##

[0094] To a stirred flask containing acetic anhydride (38.49 g, 41.56 ml, 4 eq.) was added sulfuric acid (4.81 g, 2.61 ml, 0.52 eq.) and the mixture was cooled to ˜0° C. (ice/water bath). To this was added 1,6,7,7a-tetrahydro-1-oxo-3H-3a,6-Epoxyisobenzofuran-7-carboxylic acid (20 g) portion-wise over ˜60 minutes. After complete addition, the mixture was heated to 45° C. and held for 14 hours. The mixture was cooled to ˜5° C. (ice/water bath) causing a solid to precipitate, and this was isolated by filtration. The solid was dried in a vacuum oven (35° C., 10 mbar) to yield a dark brown powder (10.18 g). Analysis by GCMS confirmed the isolated product to a ˜1:3 ratio of the desired product 1,3-dihydro-3-oxo-4-isobenzofurancarboxylic acid:phthalide (produced by decarboxylation).

EXAMPLE 19: H.SUB.2.SO.SUB.4.AC.SUB.2.O SYSTEM

[0095] ##STR00022##

[0096] To a stirred reactor containing acetic anhydride (1229 mg, 1138 μL, 4 eq.), cooled to 0° C. (ice/water bath), was charged sulfolane (72.3 mg, 57.3 μL, 0.2 eq.—internal analytical standard) and then sulfuric acid (148 mg, 80.2 μL, 0.5 eq.) and the mixture was stirred for 5 minutes at 0° C. 1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (542 mg, 1 eq.) was added portionwise, maintaining a temperature below 10° C. Following complete addition, the mixture was stirred for 20 minutes at ˜0° C., then heated to ˜60° C. and held for a further 4 hours. The mixture was then sampled while hot (to prevent crystallization) and analyzed by NMR. This showed the reaction to be incomplete, but a combined yield of 87% for the ring-opened reaction intermediate and 3-methylphthalic anhydride was observed.

EXAMPLE 20: H.SUB.2.SO.SUB.4.AC.SUB.2.O SYSTEM

[0097] A process similar as described in Cava et al. JACS 78 (1956) 2303-2304 was carried out, albeit using methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (i.e. a 2-methylfuran:maleic anhydride Diels-Alder adduct) as starting material. As from Cava et al., it is unclear exactly how the process was performed (either by adding the Diels-Alder adduct at high temperature, or by adding it at low temperature and then heating), two reactions were performed: [0098] 1) To a stirred flask containing acetic anhydride (21.6 g, 20 mL, 19 eq.) was added sulfuric acid (4 drops, ˜90 mg, 0.08 eq.), and the mixture was heated to 120° C. To this was added 2-methylfuran:maleic anhydride Diels-Alder adduct (2 g) and the mixture was held at 120° C. for 1 hour, then analyzed by high performance liquid chromatography mass spectrometry (LCMS). [0099] 2) To a stirred flask containing acetic anhydride (21.6 g, 20 mL, 19 eq.) was added sulfuric acid (4 drops, ˜90 mg, 0.08 eq.), and the mixture was cooled to ˜0° C. (ice/water bath). To this was added 2-methylfuran:maleic anhydride Diels-Alder adduct (2 g) and when the solid had dissolved, the mixture was heated to 120° C., held for 1 hour and then analyzed by LCMS.

[0100] The same reaction was then performed using preferred conditions according to the present invention: [0101] 3) To a stirred flask containing acetic anhydride (21.6 g, 20 mL, 19 eq.) was added sulfuric acid (4 drops, ˜90 mg, 0.08 eq.), and the mixture was heated to 120° C. To this was added 2-methylfuran:maleic anhydride Diels-Alder adduct (2 g) and the mixture was held at 60° C. for 1 hour, then analyzed by LCMS.

[0102] All reaction 1-3 proceeded to give the desired aromatic product, but the ratio of acetic anhydride:sulfuric acid gives rise to higher levels of undesired retro-Diels-Alder reaction (decomposition products). Adding the Diels-Alder adduct to the mixture at elevated temperature gives significantly poorer results than adding it at low temperature, and heating of the mixture at 120° C. gives rise to significant levels of (dark coloured) impurities (when compared to heating at ˜60° C.).

COMPARATIVE EXAMPLE 1: H.SUB.2.SO.SUB.4./SULFOLANE SYSTEM AT LOW TEMPERATURE

[0103] In a process similar to that described in Newman et al. JOC 42 (1977) 1478-1479, H.sub.2SO.sub.4 and sulfolane were used.

[0104] To a reactor containing concentrated sulfuric acid (42 ml), cooled to −55° C. (iso-propanol (IPA)/dry-ice bath) with stirring, was added sulfolane (17 ml). This caused the mixture to become quite viscous. 1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (10 g, 1 eq.) was added at a rate such that the temperature did not exceed −45° C. Stirring at <−45° C. was labored due to the viscosity, but nearer to −45° C. the stirring was acceptable. After complete addition, the reaction was allowed to warm slowly to room temperature over ˜3 hours, and then the mixture was poured into ice (167 g). This resulted in formation of a precipitate. When the ice had melted, the formed solid was isolated by filtration, washed with water and dried in a vacuum oven (35° C., 2 mbar) to yield a light yellow solid (3.2 g, 32%). This was analyzed by NMR and confirmed to be reasonably pure 3-methylphthalic acid. The remaining aqueous phase was extracted with EtOAc (2×50 ml) and the organic phase was washed with water, dried (Na.sub.2SO.sub.4), filtered and reduced to yield a dark brown oil which solidified partially on standing (2.5 g, 25%). This was analyzed by NMR and confirmed to be reasonably clean 3-methylphthalic acid with a small amount of 3-methylphthalic anhydride present.

COMPARATIVE EXAMPLE 2: H.SUB.2.SO.SUB.4./SULFOLANE SYSTEM AT HIGHER TEMPERATURE

[0105] In a process similar to that described in Newman et al. JOC 42 (1977) 1478-1479, H.sub.2SO.sub.4 and sulfolane were used.

[0106] To a reactor containing concentrated sulfuric acid (42 ml), cooled to 5° C. (ice/water bath) with stirring, was added sulfolane (17 ml). 1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (10 g, 1 eq.) was added at a rate such that the temperature did not exceed 7° C. After complete addition, the reaction was allowed to warm slowly to room temperature over ˜2 hours, and then the mixture was poured into ice (167 g). This resulted in formation of a precipitate. When the ice had melted, the formed solid was isolated by filtration, washed with water and dried in a vacuum oven (35° C., 2 mbar) to yield a yellow solid (1.2 g, 12%). This was analyzed by NMR and confirmed to be impure 3-methylphthalic acid. The remaining aqueous phase was extracted with EtOAc (2×50 ml) and the organic phase was washed with water, dried (Na.sub.2SO.sub.4), filtered and reduced to yield a dark brown oil (1.4 g, 14%). This was analyzed by NMR and confirmed to be an impure mixture of 3-methylphthalic acid and 3-methylphthalic anhydride in a ˜6:1 ratio.