Pyridine → HCID 67331493, compound

Participants

Reaction Conditions

Reaction Steps

The 60 L reactor is charged with PEPPSI™ (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation; 51.0 g; 74.9 mmoles), [2-(7-Chloro-isoquinoline-5-sulfonyl)-ethyl]-carbamic acid tert-butyl ester (1.383 kg; 3.729 moles), phenyl boronic acid (895 g; 4.03 moles), K2CO3 (1.039 kg; 7.518 moles), and ethanol (15 L) under a nitrogen purge. Initially 12 L of ethanol is added to the reactor and the remaining 3 L was used to rinse in the other charges. The reaction is warmed to reflux (78° C.). HPLC indicates a complete reaction after ½ hour. The reaction is cooled to 59° C. using the Huber® circulator. Water (8.7 L) is added to the reaction over 18 minutes. The temperature is decreased from 59° C. to 42° C. during the water addition. The reaction is cooled using the Huber® circulator from 42° C. to 0° C. over 1 hour. The slurry is held at 0° C. for 1 hour. The solid is filtered using a polypropylene pad and washed with 1:1 ethanol:water (3.7 L; chilled). The solid is dried on the filter overnight. The solid is then dried in vacuo at 60° C. for 22 hours. The dry weight of the solid is 2.171 kg. The Pd level in the crude (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is 2196 mcg/g and the solid contains 6.9% water by KF. A 50 L bottom outlet flask is charged with dichloromethane (4 L). The crude (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is charged to the 50 L flask and rinsed in with dichloromethane (1 L). Na2SO4 (1.9 kg) is charged and rinsed in with dichloromethane (0.1 L). Darco G-60® (3.8 kg) is charged to a 20 L Büchi flask and slurried in dichloromethane (12 L). This slurry is transferred to the 50 L flask and rinsed in with dichloromethane (4.9 L). The mixture is stirred for 2 hrs at ambient temperature. A 50 cm stainless steel filter is fitted with a polypropylene pad and charged with Hyflo Super Cel® (1.7 kg). The Hyflo Super Cel® pad is rinsed with dichloromethane (2 L). The contents of the 50 L flask are filtered onto the Hyflo Super Cel® pad. The flask and filter cake are rinsed with dichloromethane (22 L). The filtrate is charged to the 60 L reactor through a 0.45 micron cartridge filter. The contents of the reactor are warmed and concentrated by distillation under slight vacuum (˜640 mm Hg). Approximately 33 L of distillate is collected over 2 hrs at 35-37° C. Ethanol (10 L) is added. The vacuum is adjusted slowly down to 280 mm Hg while continuing the distillation. Once the vacuum is reached, the temperature is increased to maintain the distillation. Once the volume in the reactor reaches ˜10 L, ethanol (6.5 L) is added at such a rate to maintain the volume in the reactor while distilling out solvent. The distillation is stopped once all the ethanol is added. The final volume is ˜10 L. The temperature at the end of the distillation is 56° C. The slurry that forms during the solvent exchange is cooled to 20° C. and held overnight. The slurry is filtered. The solid is washed with 1:1 ethanol:water (1.8 L). The wet cake weight is 1.878 kg. The solid is dried in vacuo at 50° C. to give 1.2306 kg (64.36% yield) (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester. Mass Spectrum (LCMS) m/z=513.62) (M+H).

Provenance & Evidence