Reference of 709652-82-4 , The common heterocyclic compound, 709652-82-4, name is 2-Amino-5-bromonicotinonitrile, molecular formula is C6H4BrN3, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route.
Example 126 Step 1: (6-amino-5-cyanopyridin-3-yl)boronic acid and 2-amino-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)nicotinonitrile To a stirred solution of 2-amino-5-bromonicotinonitrile (100 mg, 0.51 mmol) and 1,2- dimethoxyethane (4 mL) in a microwave vial equipped with a stirbar was added bis(pinacolato diborane) (175 mg, 0.66 mmol), potassium acetate (149 mg, 1.52 mmol) and 1,1′- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (21 mg, 0.025 mmol). The mixture was purged with nitrogen gas for 5 min and the reaction mixture was stirred at 90 C for 3 h. The reaction mixture was filtered through a celite bed and washed with dichloromethane (10 mL). The filtrate was concentrated to dryness in vacuo affording a crude mixture of (6-amino-5-cyanopyridin-3-yl)boronic acid and 2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile used for the next step without any further purification. Step 2: 2-amino-5-(4-cyclopropyl-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purin-2- yl)nicotinonitrile 2-chloro-4-cyclopropyl-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine (50 mg, 0.18 mmol) and a crude mixture of (6-amino-5-cyanopyridin-3-yl)boronic acid and 2-amino-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile (120 mg) was dissolved in acetonitrile (2.5 mL) and degassed water (0.5 mL) in a microwave vial equipped with a stirbar. To the solution was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (12.7 mg, 0.018 mmol), potassium acetate (25 mg, 0.25 mmol) and sodium carbonate (27 mg, 0.25 mmol) and the mixture was microwaved at 140 C for 40 min. The reaction mixture was filtered through a celite bed and washed with dichloromethane (10 mL). The filtrate was concentrated to dryness in vacuo. The resulting residue was purified by RP-HPLC affording 2-amino-5-(4-cyclopropyl-6,6-dimethyl-8,9-dihydro-6H- [l,4]oxazino[4,3-e]purin-2-yl)nicotinonitrile (4.1 mg, 6%, two steps): LCMS RT = 5.07 min, m/z = 362.2 [M + H]+.
The synthetic route of 709652-82-4 has been constantly updated, and we look forward to future research findings.
Reference:
Patent; F. HOFFMANN-LA ROCHE AG; GENENTECH, INC.; ESTRADA, Anthony; HUESTIS, Malcolm; KELLAR, Terry; PATEL, Snahel; SHORE, Daniel; SIU, Michael; (260 pag.)WO2016/142310; (2016); A1;,
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