Application of 1001401-62-2,Some common heterocyclic compound, 1001401-62-2, name is 2-(2H-1,2,3-Triazol-2-yl)benzoic acid, molecular formula is C9H7N3O2, 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 1 2-(((3R,6R)-l-(2-(2H-l,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3- yl)amino)isonicotinonitrile Step 1: (2R,55′)-Benzyl 2-methyl-5-((methylsulfonyl)oxy)piperidine-l-carboxylate (2) A solution of (2R,55)-benzyl 5-hydroxy-2-methylpiperidine-l-carboxylate (15.0 g, 60.2 mmol), 4-dimethylamino pyridine (0.74 g, 6.0 mmol), and (( (401 mL) was treated with DIEA (15.8 mL, 90.0 mmol) and cooled at 0 C. Methanesulfonyl chloride (5.9 mL, 75 mmol) in (( (67 mL) was added dropwise and stirring continued at 0 C for 2 h. The reaction was diluted with water and 1 N HQ and the separated organics were washed with brine, dried over MgS04, filtered, concentrated and dried, providing the crude title compound which was used without further purification. LRMS m/z (M+H) 328.3 found, 328.1 required. Step 2: (2R,5R)-Benzyl 5-azido-2-methylpiperidine-l-carboxylate (3) A solution of crude (2R,55)-benzyl 2-methyl-5-((methylsulfonyl)oxy)piperidine- 1 -carboxylate (19.7 g, 60.2 mmol) and sodium azide (6.65 g, 102 mmol) in DMF (86 mL) was heated to 85 C overnight. The reaction was diluted with EtOAc, washed 2x with water, lx with brine, dried over magnesium sulfate, filtered, and concentrated, providing the crude title compound which was used without further purification. LRMS m/z (M+H) 275.3 found, 275.2 required. Step 3: (2R,5R)-Benzyl 5-amino-2-methylpiperidine-l -carboxylate (4) To a solution of (2R,5R)-benzyl 5-azido-2-methylpiperidine-l-carboxylate (15.2 g, 55.4 mmol) in THF (111 mL) was added trimethylphosphine (1.0 M in toluene, 55.4 mL, 55.4 mmol) dropwise over 20 min. The reaction was quenched with water (30 mL) and stirred at RT overnight. The mixture was diluted with dichloromethane, washed 2x with water, lx with brine, dried over magnesium sulfate, filtered, and concentrated, providing the crude title compound as an orange oil which was used without further purification. LRMS m/z (M+H) 249.6 found, 249.3 required. Step 4: (2R,5R)-Benzyl-5-((?ert-butoxycarbonyl)amino-2-methylpiperidine-l-carboxylate (5) A solution of (2R,5R)-Benzyl 5-amino-2-methylpiperidine-l-carboxylate (3.08 g, 12.4 mmol) and 4-dimethylaminopyridine (0.015 g, 0.12 mmol) in dichloromethane (62 mL) was treated with a solution of di-tert-butyl dicarbonate (2.91 mL, 12.5 mmol) in dichloromethane (20 mL) dropwise and stirred at RT overnight. The reaction was concentrated in vacuo, providing the crude title compound which was used without further purification. LRMS m/z (M+H) 349.4 found, 349.3 required. Step 5: tert-Butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate (6) A solution of (2R,5R)-benzyl-5-((/er/-butoxycarbonyl)amino-2-methylpiperidine- 1 -carboxylate (4.32 g, 12.4 mmol) and palladium (10 wt % on activated carbon, 0.300 g, 2.82 mmol) in degassed ethanol (100 mL) and methanol (5 mL) was stirred for 72 h under an atmosphere of hydrogen gas. Additional palladium (10 wt % on activated carbon, 0.10 g, 0.94 mmol) was added, and the reaction was recharged with hydrogen gas and allowed to stir at RT overnight. The degassed mixture was then filtered over celite, washing with EtOH. The filtrate was concentrated to give the titled compound as a crude, light yellow solid which was used without further purification. Step 6: tert-Butyl((3R,6R)-l-(2-(2H-l,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3- yl)carbamate (7) A solution of 2-(2H- 1,2,3 -triazol-2-yl)benzoic acid (4.24 g, 22.40 mmol), tert- butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate (3.20 g, 14.93 mmol), l-hydroxy-7- azabenzotriazole (4.06 g, 29.9 mmol), EDC (5.72 g, 29.9 mmol), and DIEA (15.65 mL, 90 mmol) in DMF (100 mL) was heated at 50 C overnight. The reaction was diluted with saturated, aqu. aHC03 and extracted 2x with EtOAc. The organics were washed with brine, dried over MgS04, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-80% EtOAc in hexanes), providing the title compound. LRMS m z (M+H) 386.4 found, 386.2 required. Step 7: (2-(2H-l,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-amino-2-methylpiperidin-l-yl)methanone (8) A solution of tert-butyl((3R,6R)-l-(2-(2H-l,2,3-triazol-2-yl)benzoyl)-6- methylpiperidin-3-yl)carbamate (3.6 g, 9.3 mmol) in EtOAc (78 mL) was saturated with HC1 (g) and stirred for 2 h. The reaction was concentrated and the residue basified with 1 N NaOH. The mixture was extracted 3x with EtOAc, then the organics were washed with brine, dried over MgS04, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-20% MeOH in CH2C12), providing the title compound. LRMS m/z (M+H) 286.3 found, 286.3 required. Step 8: 2-(((3R,6R)-l-(2-(2H- 1,2,3 -triazol-2-yl)benzoyl)-6-methylpiperidin-3- yl)amino)isonicotinonitrile A solution of (2-(2H-l,2,3-triazol-2-yl)phenyl)((2R,5R)-5-amino-2- methylpiperidin- 1 -yl)methanone (400 mg, 1.40 mmol) 2-fluoroisonicotinonitrile (342 mg, 2.80 mmol), and cesium carbonate (776 mg, 2.383 mmol) in DMSO (4673 muKappa) was heated at 50 C for 48 h. The reaction was cooled, dilut…
The synthetic route of 1001401-62-2 has been constantly updated, and we look forward to future research findings.
Reference:
Patent; MERCK SHARP & DOHME CORP.; KUDUK, Scott, D.; SKUDLAREK, Jason, W.; WO2014/85208; (2014); A1;,
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics