Application of 89-71-4,Some common heterocyclic compound, 89-71-4, name is Methyl 2-methylbenzoate, molecular formula is C9H10O2, 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.
2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromo-succinimide (1.96 g, 11 mmol) and 2,2′-azobis(2-methyl-propionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 hours cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1-2 %) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89 %) of 2-bromomethyl-benzoic acid methyl ester as a solid. 1H-NMR (CDCl3): delta 7.97 (d, 1H, J = 7.6 Hz), 7.45-7.52 (m, 2H), 7.38 (dt, 1H, J = 1.2 Hz and J = 7.6 Hz), 4.96 (s, 2H), 3.95 (s, 1H). To a solution of 2-amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (100 mg, 0.20 mmol) and pyridine (0.18 ml, 2.0 mmol) in acetonitrile (1 ml) at room temperature was added benzyl chloroformate (0.28 ml, 2.0 mmol) in 10 aliquots over 48 hours. The solution was then taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate (3 x 10 ml), brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The resulting oil crystallized upon standing for 2 days. The precipitate was filtered off and washed with diethyl ether (3 x 1 ml) affording after drying in vacuo 59 mg (47 %) of 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid. 1H-NMR (CDCl3): delta 10.60 (s, 1H), 7.60-7.92 (m, 4H), 7.38 (m, 5H), 5.26 (s, 2H), 4.30-5.10 (m, 3H), 3.40-4.00 (m, 2H), 1.57 (m, 9H), 1.15 (m, 9H). To a solution of 1 N hydrochloric acid in ethyl acetate (1.0 ml) was added 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (52 mg, 0.08 mmol). The solution was stirred at room temperature for 48 hours. A precipitate was filtered off which afforded 42 mg (90 %) of 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride as a solid. 1H-NMR (DMSO-d6): delta 10.45 (s, 1H), 9.40 (s, 1H), 9.25 (s, 1H), 7.89 (m, 4H), 7.39 (m, 5H), 5.22 (s, 2H), 4.39 (d, 1H, J = 15 Hz), 4.28 (m, 1H), 3.95 (m, 2H), 3.79 (m, 1H), 3.20 (m, 1H), 2.70 (m, 1H), 1.48 (s, 9H). To a solution of the above 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride (42 mg, 0.072 mmol) in ethanol (0.5 ml) was added hydrazine (68 mul, 0.22 mmol). The solution was stirred at 80 C for 5 hours and at room temperature for 16 hours. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with dichloromethane (5 x 1 ml). The combined dichloromethane washes were evaporated in vacuo affording 20 mg (67 %) of 5-(S)-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil. 1H-NMR (CDCl3): delta 10.55 (bs, 1H), 7.37 (m, 5H), 5.23 (s, 2H), 3.92 (s, 2H), 2.60-3.10 (m, 3H), 1.53 (s, 9H). To a solution of the above 5-(S)-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (20 mg, 0.048 mmol) in acetonitrile (1 ml) at 0 C was added diisopropylethylamine (18 l, 0.15 mmol) and 2-bromomethyl-benzoic acid methyl (12 mg, 0.048 mmol). The solution was stirred at 0 C for 3 hours and at room temperature for 16 hours. Di-tert-butyl dicarbonate (21 mg, 0.096 mmol) was then added to the solution. The solution was then stirred at room temperature for 16 hours. The solution was taken into ethyl acetate (30 ml), washed with 0.5 N hydrochloric acid (3 x 10 ml), saturated sodium bicarbonate (3 x 10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo. The solid residue was purified by silica gel chromatography using a 5 % mixture of ethyl acetate/hexane as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 10 mg (33 %) of 2-(benzyloxycarbonylamino)-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid. 1H-NMR (CDCl3): delta 10.59 (s, 1H), 7.81 (m, 1H), 7.52 (m, 1H), 7.39 (m, 7H), 5.25 (s, 1H), 4.22-5.00 (m, 4H), 4.40-4.80 (m, 2H), 2.80-3.10 (m, 2H), 1.55 (s, 9H), 1.25 (s, 9H). To a solution of the above 2-benzytoxycarbonylamino-5-(S)-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (9 mg, 0.014 mmol) in methanol (2 ml) was added 10 % Pd/C (4 mg). The mixture was stirred under hydrogen (1 atm.) for 3 hours and then filtered. The filtrate was evaporated in vacuo affordi…
The synthetic route of 89-71-4 has been constantly updated, and we look forward to future research findings.
Reference:
Patent; NOVO NORDISK A/S; Ontogen Corporation; EP1214324; (2006); B1;,
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