With the rapid development and complex challenges of chemical substances, the synthesis of new drugs is usually one of the most effective ways to increase yield.156072-84-3, name is 5-Chloro-2-cyano-3-methylpyridine, molecular formula is C7H5ClN2, molecular weight is 152.58, as common compound, the synthetic route is as follows.Computed Properties of C7H5ClN2
A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and 1 ,1?-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110 C for 4 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60% EtOAc/hexanes to afford 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76 % yield). LC/MS (ESI+) m/z = 153.1 (M+H) . To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90 C for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2 x). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2 x). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a vacuum oven at 40 C for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89% yield). LC/MS (ESI+) m/z = 172.0 (M+H) +. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H).
At the same time, in my other blogs, there are other synthetic methods of this type of compound,156072-84-3, 5-Chloro-2-cyano-3-methylpyridine, and friends who are interested can also refer to it.
Reference:
Patent; AMGEN INC.; ALLEN, Jennifer R.; AMEGADZIE, Albert; BOURBEAU, Matthew P.; BROWN, James A.; CHEN, Jian J.; CHENG, Yuan; FROHN, Michael J.; GUZMAN-PEREZ, Angel; HARRINGTON, Paul E.; LIU, Longbin; LIU, Qingyian; LOW, Jonathan D.; MA, Vu Van; MANNING, James; MINATTI, Ana Elena; NGUYEN, Thomas T.; NISHMURA, Nobuko; NORMAN, Mark H.; PETTUS, Liping H.; PICKRELL, Alexander J.; QIAN, Wenyuan; RUMFELT, Shannon; RZASA, Robert M.; SIEGMUND, Aaron C.; STEC, Markian M.; WHITE, Ryan; XUE, Qiufen; (759 pag.)WO2016/22724; (2016); A1;,
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