In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 26663-77-4 as follows. Application In Synthesis of Methyl benzimidazole-5-carboxylate
To a solution of methyl 1H-benzo[d]imidazole-5-carboxylate (0.90 g, 5.1 mmol) in DMF(20 ml) was added NaH (0.25 g, 6.2 mmol), and the reaction mixture was stirred at room temperature for 30 mm. Then (2-(chloromethoxy)ethyl)trimethylsilane (0.94 g, 5.6 mmol) wasadded and the reaction mixture was stirred at room temperature for 2 hours. When LCMS showed that the reaction completed, the reaction mixture was diluted with EtOAc (100 mL), washed with H20 (100 mL x 2) and brine (100 mL), dried over Na2504 and concentrated under reduced pressure to afford crude product as an oil, which was purified by column chromatography on silica gel (eluted with petroleum ether/EtOAc = 1:1) to afford mixture ofmethyl 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazole-5-carboxylate and methyl 1- ((2-(trimethylsilyl)ethoxy) methyl)- 1 H-benzo [d] imidazole-6-carboxylate as an oil. LC/MS (m/z): 307 (M+H).To a solution of LiA1H4 (0.30 g, 7.8 mmol) in THF (20 ml) was added solution of Step A product (1.2 g, 3.9 mmol) in THF (30 mL) at 0C, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. When TLC showed that the reaction completed, the reaction mixture was quenched with sat. aq. NH4C1 (50 mL) and the mixture was filteredthrough a pad of celite. The filtrate was extracted with EtOAc (100 mL), washed with H20 (100 mL) and brine (100 mL), dried over Na2504 and concentrated under reduced pressure to afford mixture of (1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo [d] imidazol-5-yl) methanol and (1- ((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-6-yl)methanol as an oil, which was used in next step without further purification. ?H NMR (CDC13, 400 MHz) oe 8.03 (s, 1H), 8.02(s, 1H), 7.86-7.79 (m, 2H), 7.64 (s, 1H), 7.61-7.55 (m, 1H), 7.43 (d, J= 7.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 5.59 (s, 4H), 4.90 (s, 2H), 4.87 (s, 2H), 3.59-3.53 (m, 4H), 0.99-0.91 (m, 4H), 0.00 (s, 9H).To a solution of Step B product (0.3 g, 1.1 mmol) in DCM(10 ml) was added SOC12 (0.8 ml, 10.8 mmol) dropwise at 0C, then the reaction mixture was stirred at room temperature for 3 hours. When TLC showed that the reaction completed, the reaction mixture was diluted with DCM (50 mL), washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford a mixture of 5-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d] imidazole and 6-(chloromethyl)- 1 -((2- (trimethylsilyl) ethoxy)methyl)-1H-benzo[d]imidazole as an oil, which was used in next step without further purification. LC/MS (m/z): 297 (M+H).To a solution of Intermediate 2 (0.20 g, 0.65 mmol), Step C product (0.29 g, 0.97 mmol) in acetone (4 ml) and DMF (2 ml) was added K2C03(0.27 g, 1.9 mmol). The reaction mixture was then heated to 60 C and stirred for 6 hours. When LCMS showed that the reaction completed, the reaction mixture was diluted with EtOAc (1 OOmL), washed with H20 (100 mL)and brine (100 mL), dried over Na2504 and concentrated under reduced pressure to afford crude product as an oil, which was purified by column chromatography on silica gel (eluted with Petroleum ether/EtOAc = 1:1) to afford a mixture of tert-butyl 2-(4-hydroxy-2-oxo-1-((1-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-5 -yl)methyl)- 1,2,5 ,7-tetrahydrofuro [3,4- b]pyridine -3 -carboxamido)acetate and tert-butyl 2-(4-hydroxy-2-oxo- 1 -((1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-6-yl) methyl)- 1,2,5,7- tetrahydrofuro [3,4- b]pyridine-3-carboxamido)acetate as a solid. LC/MS (m/z): 571 (M+H).
According to the analysis of related databases, 26663-77-4, the application of this compound in the production field has become more and more popular.
Reference:
Patent; MERCK SHARP & DOHME CORP.; MSD R&D (CHINA) CO., LTD.; CAI, Jiaqiang; CRESPO, Alejandro; DU, Xiaoxing; DUBOIS, Byron Gabriel; LIU, Ping; LIU, Rongqiang; QUAN, Weiguo; SINZ, Christopher; WANG, Liping; (61 pag.)WO2016/49100; (2016); A1;,
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