Dec. 3, 2020  91  US 2020/0379345 Al  Synthesis Example 1-1-3  Synthesis of Intermediate 3  Synthesis Example 1-1-4  Synthesis of Intermediate 4  Synthesis Example 1-1-5  Synthesis of Intermediate 5  Synthesis Example 1-1-6  Synthesis of PAG-1  Synthesis Example 1-1-2  Synthesis of Intermediate 2  Synthesis Example 1-1-1  Synthesis of Intermediate 1  [0172]  In a flask under nitrogen atmosphere, 225 g of  Reactant 1, 182 g of Reactant 2 and 4.4 g of copper(!) iodide  were dissolved in 700 g ofN-methylpyrrolidone, which was  heated at 70°  C. Then, 102 g of triethylamine was added  dropwise to the solution, which was aged at an internal  temperature of 80°  C. for 24 hours. After the extinction of  Reactant 1 was confirmed by GC, the reaction system was  cooled, and 1,000 g of water was added dropwise to quench  the reaction. This was followed by extraction with 2,000 mL  of toluene, ordinary aqueous workup, solvent distillation,  and recrystallization from hexane. There was obtained 233  g of Intermediate 1 as white crystals (yield 90% ).  [0173]  Under nitrogen atmosphere, a flask was charged  with 119 g of Intermediate 1 and 500 g of acetic acid, and  Intermediate 1 was dissolved at 30°  C. With the temperature  kept below 40°  C., 41 g of 35 wt % aqueous hydrogen  [0177]  Under nitrogen atmosphere, 0.6 g of sodium  hydride was suspended in 56 g of THF, and the suspension  [0176]  Under nitrogen atmosphere, a flask was charged  with 14.2 g of Intermediate 4, 9.0 g of benzyltrimethylam› monium 1,1-difluoro-2-hydroxyethane-l-sulfonate, 70 g of  MIBK, and 50 g of water, which were stirred for 30 minutes.  The organic layer was taken out, washed with water, and  concentrated under reduced pressure. Hexane was added to  the concentrate for washing. There was obtained 15.2 g of  Intermediate 5 as oily matter (yield 94%).  [0175]  In a flask under nitrogen atmosphere, a Grignard  reagent was prepared from 26.8 g of 4-bromofluorobenzene,  3.7 g of metallic magnesium, and 60 g of THF. Once the  reaction system was cooled, a solution of 21.8 g of Inter› mediate 3 in 25 g ofTHF was added thereto. Below 20°  C.,  16.6 g oftrimethylsilyl chloride was added dropwise to the  solution, which was aged in an ice bath for 2 hours. After  aging, the reaction system was cooled, 100 mL of saturated  ammonium chloride aqueous solution was added dropwise  to quench the reaction. This was followed by extraction with  150 mL ofMIBK, ordinary aqueous workup, solvent distil› lation, and recrystallization from hexane. There was  obtained 28.3 g of Intermediate 4 as white crystals (yield  94%).  [0174]  Under nitrogen atmosphere, a flask was charged  with 15 .6 g oflntermediate 2, 1.0 g of p-toluenesulfonic acid  monohydrate, 15.2 g of Reactant 3, and 70 g of toluene,  which was heated under reflux at 105°  C. for 7 hours. After  the distinction of Intermediate 2 was confirmed by TLC, the  reaction solution was ice cooled, and 1.0 g of triethylamine  was added to quench the reaction. Further, 50 mL of  saturated sodium hydrogencarbonate aqueous solution was  added to the reaction solution, after which the desired  compound was extracted with 50 mL of toluene. This was  followed by ordinary aqueous workup, solvent distillation,  and purification by silica gel column chromatography (elu› ent: 15/1 hexane/ethyl acetate). There was obtained 21.8 g of  Intermediate 3 as colorless oily matter (yield 98% ).  peroxide was added dropwise to the solution. At the end of  addition, the solution was aged at 40°  C. for 20 hours. At the  end of aging, the reaction system was cooled. A solution of  20 g of sodium thiosulfate pentahydrate in 400 g of water  was added dropwise to quench the reaction. Then 1,300 mL  of toluene and 300 mL of ethyl acetate were added to extract  the reaction product. This was followed by ordinary aqueous  workup, solvent distillation, and recrystallization from  hexane. There was obtained 115 g oflntermediate 2 as white  crystals (yield 92% ).  -continued  NaH  THF  Intermediate 5  PAG-1 