Preparation of 2-norbornanemethanol_industrial additives

Background and overview^[1]

2-Norbornanemethanol can be used as a pharmaceutical synthesis intermediate.

Preparation^[1]

Step 1: Exo-/Endo-norbornene methyl acetate

Allyl acetate and dicyclopentadiene (DCPD) with a molar ratio of 4:1 based on cyclopentadiene monomer were added to a suitable high-pressure tube reactor and heated at 220°C. Heat in an oil bath and maintain at this temperature for 4 hours. At the end of the reaction, the high-pressure tube was removed from the bath and quenched in a wet ice bath. The tubes were then washed with methanol and methylene chloride and weighed to confirm that no leaks had occurred. The resulting crude monomer sample was analyzed by GC-MS, which showed approximately 7.5% unreacted allyl acetate, 10% exo-/endo-norbornene methanol, 82% exo-/endo-norbornene methyl acetate, and 0.6% (1,2,3)-methyl-4,4a,5,8,8aoctahydro-1,4:5,8-dimethanonaphthalen-2-yl)methanol. Fractionation of the crude mixture resulted in the isolation of norbornene methyl acetate of greater than >99.6% purity.

Step 2: 2-norbornanemethanol

1) Add a mixture of exo-/endo-norbornene methyl acetate (≥99.6% purity, 4.8kg) and methanol (11.2kg) to a suitably sized and jacketed reactor. The reactor is equipped with a stirrer, top condenser, top condensate receiving tank and feed tank with metering pump. The temperature of the reactor is controlled by a special oil circulation device; the reactor pressure is manually controlled, adding nitrogen to increase the pressure and an exhaust port to reduce the pressure. The reactor was purged with nitrogen using three pressure/vacuum swings to remove any oxygen in the reactor headspace.

After this nitrogen purge process, the reactor was kept in full ventilation mode through the top condenser and receiver system and then heated to the initial reaction temperature (45°C). The catalyst solution consisting of sodium methoxide in methanol (25wt%, 0.125kg) was added to the glass feed tank and then metered into the reactor within 15 minutes (addition rate 8.33g/min) while maintaining the reactor temperature ( 45℃). °C). After completion of the catalyst metering, the reactor was maintained at temperature (45° C.) for a further 1.75 hours.

2) After the reaction process is completed, heat the reactor to the solvent stripping temperature (60-68°C) in exhaust mode, and flash the methanol/methyl acetate (4kg) mixture at the top and Collect in top receiving tank. Additional methanol (4 kg) was transferred to the reactor and a second solvent stripping operation was performed to remove the methanol/methyl acetate (4 kg) mixture. Finally, a third solvent stripping operation was performed to remove the methanol/methyl acetate (6 kg) mixture.

After completing this solvent stripping process, acetic acid (0.04kg) was added to the reaction concentrate, which was then transferred out of the reactor and analyzed by GC to confirm completion of the transesterification reaction. The composition of the reaction concentrate was as follows: norbornene methanol 83%, norbornene methyl acetate traces, methanol 17% and MeOAc traces.

3) Add the norbornene methanol reaction concentrate (6kg) to a suitably equipped vacuum distillation system, which includes a distillation tank with an electric heating jacket and a distillation column with stainless steel structural packing (4 theoretical tray), reflux splitter, water-cooled condenser, top condensate receiver and vacuum pump. The tank temperature is controlled by adjusting the heat input on the heating mantle, and the system vacuum is controlled by adjusting the vacuum pressure at the top receiver. The still is initially heated in full venting mode until reflux conditions are established in the distillation column.

The reflux splitter is then started at the desired reflux ratio and fractionation is carried out by periodically removing the liquid fraction from the overhead receiver. GC analysis is used to determine the composition of the overhead fraction. Adjust tank temperature, overhead receiver vacuum, and reflux ratio as needed to affect overhead stream composition. The initial overhead fraction contains mainly methanol and trace amounts of methyl acetate. After removing these solvents, high-purity norbornene methanol is then distilled overhead under the following conditions: overhead temperature (70-75°C), vacuum (4-5mmHg) and reflux ratio (2:1). Once most of the product has been removed from the kettle, the distillation process is terminated. Approximately 90% of the norbornene methanol contained in the starting mixture was recovered as a high purity (≥99.8% assay) product.

4) Add Ru precursor (1.6 mol%) and imidazolium to norbornene methanol. The pressurized reactor was warmed to the desired reaction temperature with CO2/H2 for 17 hours. The reactor was cooled, and the product was extracted with Et2O (3 × 15 mL) to obtain 2-norbornanemethanol.

Main reference materials

[1] U.S.Pat.Appl.Publ.(2015),US20150291634

[2]Ruthenium-CatalyzedHydroformylationofAlkenesbyusingCarbonDioxideastheCarbonMonoxideSourceinthePresenceofIonicLiquids