Two synthesis methods of N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl)benzocarboxamide _Industrial additives

N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl)benzomethane Background and overview of two synthetic methods of amides

N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl) carboxamide is synthesized Intermediate of BTK inhibitor Acalabrutinib. On October 31, 2017, AstraZeneca’s second-generation BTK inhibitor Acalabrutinib was approved by the FDA at an extremely fast pace. The approved indication is for patients with mantle cell lymphoma who have failed at least one first-line treatment in the past.

N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl)benzomethane Two synthetic methods for amide preparation

N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl)benzomethane Report on two synthesis methods of amides 1.

Step 1,

Add 1000mL water to compound 13 (120g, 1.28mol), then add compound 14 (236.2g, 1.28mol), then add hydrogen peroxide (87.1g, 2.56mol), heat the reaction system to 70°C, and The reaction was carried out at this temperature for 8 hours, and then lowered to room temperature. The solid obtained was filtered and washed with 100 mL of water. The solid was vacuum dried at 40° C. for 8 hours to obtain 302 g of a light yellow solid.

Step 2,

Add 260 mL of tetrahydrofuran to compound 15 (180g, 0.65mol), add pinacol diborate (181g, 0.72mol), potassium magnesium carbonate acetate (127.0g, 1.3mol), and then add Pd (PPh₃)₄ (38.1g, 0.033mmol), heated to reflux temperature under nitrogen protection and reacted for 8 hours, then cooled the reaction solution to room temperature, added 150mL of water, and Extract with ethyl acetate (2*300mL), dry the organic phase with anhydrous sodium sulfate, concentrate to obtain a light yellow solid, recrystallize with ethyl acetate to obtain a light yellow solid, vacuum dry at 40°C for 8 hours, and obtain a light yellow solid: 195.2g.

N-(pyridin-2-yl)-4-(4,4,5,5-tetramethylL-1,3,2-dioxaborolan-2-yl)benzomethane Report 2 on two synthesis methods of amides

Step 1,

To a mixture of 4-bromobenzoic acid (5g, 24.8mmol) and pyridin-2-amine (4.68g, 49mmol) in pyridine (30mL), POCl₃(11.4g, 74mmol). The suspension was stirred at room temperature for 20 minutes. The reaction was poured into water (100 mL) and extracted with ethyl acetate (3×40 mL). The organic phase was washed with saturated aqueous NaCl solution (2×50 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and evaporated. Purify by column chromatography using ethyl acetate/petroleum = 1:9 to 1:1 to obtain the product 4-bromo-N-(pyridin-2-yl)benzamide (3.28g, 48%). LC-M Methylpyridine S m/z=277.0[M+1]+.

Step 2,

Place 4-bromo-N-(pyridin-2-yl)benzamide (2g, 7.22mmol), 4,4,5,5-tetrakis(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.75g, 10.83mmol), PdCl2 (dppf) (527mg, 0.72mmol) ) and KOAc (235 mg, 2.4 mmol) in toluene (30 mL) was heated to 110°C for 6 hours. The reaction was evaporated and water (100 mL) was added. This was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated. Purify by column chromatography using ethyl acetate/petroleum ether = 1:4~1:1 to obtain the product N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl L-1 ,3,2-dioxaborolan-2-yl)benzocarboxamide (2g, 85%).

References

[1] [Invented in China] CN201811616540.7 A method of preparing Acalabrutinib

[2] [Invented in China] CN201811153123.3 Aminonorzane derivatives and their preparation methods and applications