(3S,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml round bottomed flask equipped with a Dean-Stark trap and a condenser was added isosorbide (27.61 grams, 189 mmoles, available from Archer Daniels, Midland, Ill., USA), succinic acid (10.63 grams, 90 mmoles, available from Sigma Aldrich) and toluene (200 mL). The reaction mixture was heated gradually under inert atmosphere to about 120° C. (external bath temperature). The reaction mixture was heated at reflux overnight during which about 3 mL water was collected in the Dean Stark trap. The reaction mixture was cooled to room temperature and the crude product was collected as a brownish residue. Toluene was removed by decanting, and the crude product was dissolved in dichloromethane (600 mL) and washed with saturated solution of NaHCO3 (2×200 mL), followed by deionized water (1×200 mL). The solution was dried over MgSO4, and the solvent removed in vacuo and then dried under vacuum for 24 hrs, to affordan fluffy off-white solid. The product was further dried in a vacuum oven (about 200 mm-Hg at 120° C.) overnight, then cooled to room temperature to give a transparent solid material (15 grams). Glass transition (Tg) by DSC: 35° C., Viscosity at 130° C.: 515 cPs, viscosity at 60° C.: 7.3×106 cPs. To a 500 ml round bottomed flask equipped with a Dean-Stark trap and a condenser The reaction mixture was heated was collected in the Dean Stark trap The reaction mixture was cooled to room temperature the crude product was collected as a brownish residue Toluene was removed by decanting the crude product was dissolved in dichloromethane (600 mL) washed with saturated solution of NaHCO3 (2×200 mL) The solution was dried over MgSO4 the solvent removed in vacuo dried under vacuum for 24 hrs The product was further dried in a vacuum oven (about 200 mm-Hg at 120° C.) overnight cooled to room temperature

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of NaH (60% mineral oil suspension, 3.28 g, 82.1 mmol) in DMF (135 mL) at 0° C. was added a solution of isobide (10.00 g, 68.4 mmol) in DMF (10 mL) dropwise. After addition, the reaction mixture was stirred at 0° C. for 30 min, then BnBr (14.04 g, 82.1 mmol) was added too. The resulting mixture was allowed to stir at rt overnight and concentrated in vacuo. The residue was dissolved in water (100 mL), and extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as yellow oil (10.36 g, 64.1%). After addition to stir at rt overnight concentrated in vacuo The residue was dissolved in water (100 mL) extracted with EtOAc (200 mL×3) The combined organic phases were washed with brine (200 mL×3) dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of isosorbide (60.00 grams, 0.41 moles), mercaptoacetic acid (83.21 grams, 0.90 moles), toluene (300 mL), and methane sulfonic acid (1.00 grams, 10 mmoles) was heated to reflux. Water was separated from the toluene/water azeotrope using a Dean Stark distillation trap. After four hours at reflux, a total of 15 mL of water was collected in the trap. The reaction mixture was cooled and washed with saturated aqueous sodium bicarbonate (2×200 mL) and brine (100 mL). The solution was dried over magnesium sulfate and then concentrated under reduced pressure. The product was a colorless oil. (Yield: 106.10 grams). was heated to reflux Water was separated from the toluene/water a Dean Stark distillation trap After four hours at reflux a total of 15 mL of water was collected in the trap The reaction mixture was cooled washed with saturated aqueous sodium bicarbonate (2×200 mL) and brine (100 mL) The solution was dried over magnesium sulfate concentrated under reduced pressure

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a stirred apparatus with distillation head, 190.0 g (1.3 mol) of isosorbide (“Sorbon” from Ecogreen Oleochemicals) and 187.5 g (1.3 mol) of octanoic acid (caprylic acid) are initially charged at 80° C. together with 0.38 g of aqueous sodium hydroxide solution (18% by weight strength, aqueous) as catalyst. With stirring and under a flow of nitrogen (10-12 liters per hour), the reaction mixture is initially heated to 180° C., where the water of reaction begins to distill off. The reaction is then heated to 190° C. over a period of 1 hour and to 210° C. over a further 2 hours. After 210° C. is reached, the esterification is continued until an acid value of <1 mg KOH/g is reached. This gives 345.7 g of amber isosorbide caprylate (97% of theory). The pH (5% by weight in ethanol/water 1:1) is 5.9. The pH was measured according to DIN EN 1262. to distill off The reaction is then heated to 190° C. over a period of 1 hour and to 210° C. over a further 2 hours After 210° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: p-Toluenesulfonyl chloride (2722 g, 14.28 mol) was added to a solution of isosorbide (869 g, 5.95 mol) in pyridine (5000 mL) in portions with stirring at 0° C. After the reaction mixture was stirred at ambient temperature overnight, the mixture was poured into ice-water (5000 mL) with stirring, and extracted with DCM (4000 mL×3). The combined organic layers were washed successively with water (3000 mL×3), 1 N aqueous HCl (3000 mL×3, pH=6), and saturated aqueous NaHCO3 (3000 mL×2), and dried over anhydrous Na2SO4. After removal of the solvent via vacuum, ethanol (1000 mL) was added. The resulting precipitate was filtered, and washed with ethanol to give the desired product as a white solid. After the reaction mixture was stirred at ambient temperature overnight with stirring extracted with DCM (4000 mL×3) The combined organic layers were washed successively with water (3000 mL×3), 1 N aqueous HCl (3000 mL×3, pH=6), and saturated aqueous NaHCO3 (3000 mL×2) dried over anhydrous Na2SO4 After removal of the solvent via vacuum, ethanol (1000 mL) was added The resulting precipitate was filtered washed with ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven dried, two neck round bottomed flask equipped with a Teflon magnetic stir bar was charged with 3.00 g of isosorbide (20.5 mmol), 5.30 g potassium t-butoxide (47.2 mmol), and 50 mL of anhydrous DMF. This heterogeneous mixture was stirred for 30 minutes at room temperature, then brought to about 0 degrees Celsius in an ice/saturated brine bath. While stirring and under argon, 3.90 mL of allyl bromide (45.2 mmol) was added dropwise via syringe. After addition was complete, the ice bath was removed and the solution warmed to room temperature. The reaction was continued for 4 hours at room temperature under argon. After this time, the heterogeneous solution was filtered to remove potassium bromide and other solids. The filtrate was then transferred to a 250 mL boiling flask containing a Teflon stir bar, was diluted with 50 mL of methylene chloride and 50 mL of water, and vigorously stirred. The biphasic solution was poured into a 250 mL separatory funnel and the bottom organic layer removed into a 125 mL Erlenmeyer flask. This solution was then diluted with another 50 mL volume of water, the resultant biphasic solution mixed as before, and the organic phase was extracted, dried with anhydrous magnesium sulfate and concentrated in vacuo, producing a light yellow oil, 4.12 g (89%). This material was spectroscopically confirmed by GC/MS (EI), providing one signal (m/z 226.1) corresponding to (3R,3aR,6S,6aR)-3,6-bis(allyloxy)hexahydrofuro[3,2-b]furan (diallyl isosorbide, B). An oven dried two neck round bottomed flask equipped with a Teflon magnetic stir bar brought to about 0 degrees Celsius in an ice/saturated brine bath While stirring and under argon After addition the ice bath was removed the solution warmed to room temperature The reaction was continued for 4 hours at room temperature under argon After this time, the heterogeneous solution was filtered to remove potassium bromide and other solids containing a Teflon stir bar was diluted with 50 mL of methylene chloride and 50 mL of water vigorously stirred The biphasic solution was poured into a 250 mL separatory funnel the bottom organic layer removed into a 125 mL Erlenmeyer flask This solution was then diluted with another 50 mL volume of water the resultant biphasic solution mixed as before, and the organic phase was extracted dried with anhydrous magnesium sulfate concentrated in vacuo producing a light yellow oil, 4.12 g (89%)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-neck 250 mL round-bottomed flask equipped with a dean stark trap and a condenser was added isosorbide (40.0 g, 273.9 mmol, obtained from Archer Daniels), malic acid (30.60 g, 228.22 mmol, obtained from Sigma-Aldrich), and FASCAT 4201 dibutyl tin oxide catalyst (0.07 g, 0.1 wt %, obtained from Arkema Inc.). The mixture was slowly heated under argon to 120° C., during which time the reagents melted. The temperature was then raised to 180° C., and condensation began around 150° C. The reaction mixture was stirred at 180° C. overnight (˜20 h). A total of 3.0 mL water was collected in the dean stark trap. The reaction mixture was cooled under argon to ˜100° C. and discharged into an aluminum tray and cooled to room temperature to give 63 g of product as a glassy material. Tg(DSC)=23.2° C.; viscosity @130° C.=1019 cps; viscosity @70° C.=8.08×105 cps. Mn(GPC)=567; Mw(GPC)=868; Pd(GPC)=1.53. To a 3-neck 250 mL round-bottomed flask equipped with a dean stark trap and a condenser The temperature was then raised to 180° C. condensation began around 150° C A total of 3.0 mL water was collected in the dean stark trap The reaction mixture was cooled under argon to ˜100° C. cooled to room temperature

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-neck 250 mL round-bottomed flask equipped with a dean stark trap and a condenser was added isosorbide (40.0 g, 273.9 mmol, obtained from Archer Daniels, Midland, Ill.), itaconic acid (32.39 g, 248.9 mmol, obtained from Sigma-Aldrich), and FASCAT 4201 dibutyl tin oxide catalyst (0.07 g, 0.1 wt %, obtained from Arkema Inc.). The mixture was slowly heated under argon to 120° C., during which time the reagents melted. The temperature was then raised to 180° C., and condensation began around 150° C. The reaction mixture was stirred at 180° C. overnight (˜20 h). Thereafter, vacuum (1-2 mm-Hg) was applied for ˜30 min. A total of 3.0 mL water was collected in the dean stark trap. The reaction mixture was cooled under argon to ˜100° C. and discharged into an aluminum tray and cooled to room temperature to give 65 g of product as a glassy material. Tg(DSC)=19.5° C.; viscosity @130° C.=769 cps; viscosity @70° C.=6.63×105 cps. Mn(GPC)=689; Mw(GPC)=1245; Pd(GPC)=1.80. To a 3-neck 250 mL round-bottomed flask equipped with a dean stark trap and a condenser The temperature was then raised to 180° C. condensation began around 150° C Thereafter, vacuum (1-2 mm-Hg) was applied for ˜30 min A total of 3.0 mL water was collected in the dean stark trap The reaction mixture was cooled under argon to ˜100° C. cooled to room temperature

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L Parr reactor equipped with a double turbine agitator and distillation apparatus was charged 483.3 g isosorbide, 186.2 g succinic acid, and 2.0 g VERTEC AC422 catalyst (organic titanate obtained from Johnson Matthey, Tex.). The contents were heated to 180° C. over 3 h and allowed to stir for an additional 4 h; the temperature was then raised to 195° C. and the reaction mixture was allowed to stir overnight, during which 35 g water were collected. The pressure was then reduced to 200 mm-Hg for ˜1 h, after which the temperature was raised to 200° C. and the pressure was reduced to ˜1-2 mm-Hg for 1 h. The mixture was stirred for ˜2 hours at 200° C. under nitrogen and reduced pressure (1-2 mm-Hg) for an additional 1 h, after which the mixture was cooled under nitrogen and discharged into an aluminum pan at 120° C. During the reaction a total of 55 g of water was collected. NMR indicated the presence of residual isosorbide. About 150 g of the product was then added to a 1 L Erlenmeyer flask, dissolved in dichloromethane (˜300 mL), and washed with saturated NaHCO3 (2×200 mL) followed by washing with water (1×200 mL). The solution was dried with MgSO4, rotovapped to remove solvent, and dried on a vacuum pump overnight to give an off-white fluffy solid. The product was further dried in a vacuum oven (˜200 mm-Hg at 120° C.) overnight. The product was cooled to room temperature to give a glassy material (70 g). Tg(DSC)=33° C.; viscosity @130° C.=439 cps; viscosity @65° C.=1.7×106 cps. Mn(GPC)=1078; Mw(GPC)=1276; Pd(GPC)=1.18. To a 1 L Parr reactor equipped with a double turbine agitator and distillation apparatus the temperature was then raised to 195° C. were collected The pressure was then reduced to 200 mm-Hg for ˜1 h after which the temperature was raised to 200° C. the pressure was reduced to ˜1-2 mm-Hg for 1 h The mixture was stirred for ˜2 hours at 200° C. under nitrogen reduced pressure (1-2 mm-Hg) for an additional 1 h after which the mixture was cooled under nitrogen discharged into an aluminum pan at 120° C During the reaction a total of 55 g of water was collected About 150 g of the product was then added to a 1 L Erlenmeyer flask dissolved in dichloromethane (˜300 mL) washed with saturated NaHCO3 (2×200 mL) by washing with water (1×200 mL) The solution was dried with MgSO4 to remove solvent dried on a vacuum pump overnight to give an off-white fluffy solid The product was further dried in a vacuum oven (˜200 mm-Hg at 120° C.) overnight The product was cooled to room temperature

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Finally, German published patent application No. P 27 51 934 and the corresponding U.S. Pat. No. 4,065,488 describe a process wherein isosorbide in a first step is esterified by reaction with a lower alkanoic anhydride, chloride or bromide, in particular acetic acid anhydride, to yield a mixture of isosorbide, isosorbide-2-acrylate, isosorbide-5-acylate and isosorbide-2.5-diacylate. In a second step, isosorbide is extracted from this mixture in order to avoid formation of isosorbide-2.5-dinitrate in the following nitration reaction which is dangerous as explosive. In a third step, the mixture of isosorbide-2-acylate, isosorbide-5-acylate and isosorbide-2.5-diacylate is subjected to nitration with nitric acid and the resulting mixture of isosorbide-2-acylate-5-nitrate, isosorbide-5-acylate-2-nitrate and isosorbide-2.5-diacylate is subjected to partial saponification resulting in a mixture of isosorbide-2-nitrate, isosorbide-5-nitrate and isosorbide. Isosorbide-5-nitrate finally is separated from this mixture by recrystallization from appropriate solvents. Thus, this process also is characterized by a multitude of reaction steps and has the further disadvantage that isosorbide contained in the mixture obtained in the first reaction step, has to be extracted in order to avoid the formation of the explosive isosorbide-2.5-dinitrate in the subsequent nitration reaction. to yield In a second step, isosorbide is extracted from this mixture in order 5-dinitrate in the following nitration reaction which

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (60% dispersion in mineral oil, 493 mg, 12.32 mmol) was added in portions to a stirring solution of dianhydro-D-glucitol (1.5 g, 10.26 mmol) in DMF (20 mL) at room temperature under N2 (g) atmosphere. After 20 min, methyl iodide (639 μL, 10.26 mmol) was added, the mixture stirred for 30 min, cooled to 0° C., followed by stepwise addition of DMF (20 mL) and NaH (493 mg, 12.32 mmol). N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (500 mg, 1.48 mmol, prepared according to Smaill, J. B., et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397) was added after 20 min and the reaction was quenched 30 min later at 0° C. by a slow addition of saturated NH4Cl, followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated to a yellow residue 1b. MS m/z (ESI+), 477 [M+1]. the reaction was quenched 30 min later at 0° C. by a slow addition of saturated NH4Cl followed by extraction with EtOAc (100 mL) The organic layer was washed with H2O (2×100 mL), brine (100 mL) dried over MgSO4 concentrated to a yellow residue 1b

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (60% dispersion in mineral oil, 493 mg, 12.32 mmol) was added in portions to a stirring solution of dianhydro-D-glucitol (1.5 g, 10.26 mmol) in DMF (20 mL) at room temperature under N2 (g) atmosphere. After 20 min, methyl iodide (639 μL, 10.26 mmol) was added, the mixture stirred for 30 min, cooled to 0° C., followed by stepwise addition of DMF (20 mL) and NaH (493 mg, 12.32 mmol). N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (500 mg, 1.48 mmol, prepared according to Smaill, J. B., et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397) was added after 20 min and the reaction was quenched 30 min later at 0° C. by a slow addition of saturated NH4Cl, followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated to a yellow residue 1b. MS m/z (ESI+), 477 [M+1]. the reaction was quenched 30 min later at 0° C. by a slow addition of saturated NH4Cl followed by extraction with EtOAc (100 mL) The organic layer was washed with H2O (2×100 mL), brine (100 mL) dried over MgSO4 concentrated to a yellow residue 1b