Reference of 915006-52-9 ,Some common heterocyclic compound, 915006-52-9, molecular formula is C5H4BrIN2, 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.
To a mixture of 6-bromo-2-iodopyridin-3-amine (100 mg, 0.34 mmol), 1,2-dimethoxy-4-(prop-1-yn-1-yl)benzene (74 mg, 0.42 mmol), lithium chloride (18 mg, 0.42 mmol), sodium carbonate (180 mg, 1.68 mmol) and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol) in a screw cap vial was added DMF (2 mL). The vial was fitted with a Teflon-lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 100 C. for 16 h. LCMS analysis shows formation of two isomers, in approximately 3:1 ratio. 1H NMR analysis suggested the major product to be 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (5A-1). The reaction mixture was diluted with EtOAc (50 mL), poured into a separatory funnel and washed with 10% aqueous LiCl solution (2*10 mL) and saturated aqueous NaCl solution (10 mL), dried (Na2SO4), filtered and the filtrate was concentrated. The crude product was dissolved in a small amount of DCM and purified on a silica gel column chromatography with a 15 min gradient from 0%-100% DCM/EtOAc to afford 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 5A-1) that was contaminated with Intermediate 5A-2, 5-bromo-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine, m/z (303, M+1), 80 mg (67%). To a mixture containing 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 5A-1) and Intermediate 5A-2 (100 mg, 0.29 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (111 mg, 0.36 mmol), and Pd(dppf)C12 (10.5 mg, 0.014 mmol) in a screw cap vial was added THF (2.5 mL) followed by 3M aqueous solution of tripotassium phosphate (0.10 mL, 0.3 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C. for 3 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3*10 mL). The extracts were combined, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified on silica gel column chromatography eluting with a 10 min gradient from 5%-100% DCM/EtOAc. No separation was observed. A mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5B) and the regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate was isolated (100 mg, 77% yield), m/z (550, M+1) and was used as such in subsequent step. A mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5B) and regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (95 mg, 0.21 mmol) was dissolved in MeOH (5 mL) and transferred to a Parr bottle. The mixture was purged with nitrogen. Pearlman’s Catalyst (25 mg, 0.036 mmol) was added and the bottle was pressurized with hydrogen gas (50 psi) and shaken for 22 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated. The resulting residue was dissolved in a small amount of DCM and charged to a silica gel column, which was eluted over a 10 min gradient with 1%-5% MeOH/DCM to afford a mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5C) and the regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (82 mg, 80%), m/z (452, M+H). The mixture of isomers (tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (Intermediate 5C) and tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (80 mg, 0.18 mmol) were suspended in 4 N HCl in dioxane (4 mL, 16.00 mmol), stirred for 30 min, and concentrated to dryness. The resulting residue was suspended in diethyl ether (1 mL) and the solids were filtered and dried to give a mixture of 2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine (Intermediate 5D) and 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as bis HCl salts (50 mg, 65%), m/z (352, M+H).
In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles. 915006-52-9, 6-Bromo-2-iodopyridin-3-amine, other downstream synthetic routes, hurry up and to see.
Reference:
Patent; BRISTOL-MYERS SQUIBB COMPANY; Dyckman, Alaric J.; Dodd, Dharmpal S.; Mussari, Christopher P.; Sherwood, Trevor C.; Whiteley, Brian K.; Gilmore, John L.; Kumar, Sreekantha Ratna; Pasunoori, Laxman; Srinivas, Pitani Veera Venkata; Duraisamy, Srinivasan Kunchithapatham; Hegde, Subramanya; Anumula, Rushith Kumar; US2019/185469; (2019); A1;,
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