142217-80-9

142217-79-6

142217-80-9

Step (1) Preparation of Intermediate IX: In a 20L sealed and nitrogen-filled reaction flask, 3.8kg of zinc powder and 10wt% hydrochloric acid (12.5L) were added sequentially and stirred at room temperature for 10-15 minutes, followed by diafiltration, and washed with purified water to neutral. Next, it was washed with 3.0 L of ethanol and 4.5 L of tetrahydrofuran and dried under vacuum at 40±2°C for 4-4.5 hours to obtain about 3 kg of activated zinc powder. The activated zinc powder needs to be sealed and stored under vacuum for backup. In a 100L reactor, after evacuation and replacement of nitrogen, add 40L of tetrahydrofuran dried by A-type molecular sieve. Under stirring, 3 kg of dry activated zinc powder and 1.3 L of dibromomethane were added, and the mixture was cooled to -70~-55°C. Then 1140 ml of titanium tetrachloride was added dropwise with continuous stirring for 1 hour. The temperature was then increased and the reaction was carried out for 48±0.5 h. The reaction was kept sealed during the reaction. The prepared enolization reagent was cooled to -20°C and a solution of 1.2 kg of Intermediate VIII dissolved in 20 L of dichloromethane was slowly added dropwise at -30°C. After the dropwise addition, the temperature was raised to 15-20 °C and the reaction was continued with stirring for 180 ± 10 min. The end point of the reaction was monitored by TLC. The reaction solution was transferred to a 200 L reaction vessel (containing a mixed system of 30 L of dichloromethane, 100 L of pure water and 10 kg of sodium bicarbonate) and stirred for 60-70 min. The mixture was separated using a stainless steel centrifuge and the filter cake was washed twice with dichloromethane (16L). The filtrates were combined and the aqueous phase was subjected to secondary extraction with dichloromethane (16L x 2). The combined organic phases were concentrated to dryness under vacuum at 25-30°C to afford 6-benzyloxy-9-((1S,3R,3S)-4-benzyloxy-3-benzyloxymethyl-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine (Intermediate IX) as a yellow powder in a single-step yield of 88% and purity of 93.6%.