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To a stirred solution of 4-nitroindole (4.0 g, 24.6 mmol) in CH2Cl2 (50 mL) were added catalytic amount of DMAP (Catalyst) and Boc2O (5.9 g, 27.1 mmol) at 0 C., and the resulting reaction mixture was stirred at room temperature for additional 3 h. The mixture was diluted with CH2Cl2, and washed with water. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure to give 1-Boc-4-nitroindole as white solid (6.14 g, 95% yield). MS (ESI) m/z 262.1
95.8%
dmap; In toluene; at 20℃; for 1.75h;Product distribution / selectivity;
Step 1: Preparation of 4-Nitro-indole-1-carboxylic acid tert-butyl ester (2) To a 5 L four-necked round bottom flask equipped with mechanical stirrer, nitrogen inlet, thermocouple, and condenser was charged 182.3 g (1.124 mol) of 4-nitroindole, 1400 mL toluene, and 2.7 g of DMAP. At room temperature, solid BOC2O (270.0 g 1.237 mol, 1.10 eq) was added in portions over about 45 minutes to the stirring mixture while maintaining moderate gas evolution. After stirring the resulting solution for 1 hour, HPLC analysis showed the reaction to be complete with no starting material. The batch was quenched with 500 mL water, transferred to a separatory funnel and the phases were split. The organic layer was washed with 500 mL brine, concentrated to a slurry, diluted with 1000 ml heptane, filtered, and washed with fresh heptane. The filter cake was dried under vacuum at RT to constant weight to afford 206.0 gram of pale yellow solid. A second crop of 20.0 gram of product was isolated as post-precipitate from the mother liquors. The overall yield was 226.0 gram, 95.8% yield of pale yellow solid (100 area % HPLC).
With hydrogen;palladium on activated charcoal; In ethanol; at 20℃; under 2585.81 Torr; for 8.0h;
To a stirred solution of 1-Boc-4-nitroindole (6.14 g, 23.4 mmol) in EtOH (100 mL) was added 10% Pd/C (614 mg) under N2. The resulting mixture was shaken under hydrogen (H2, 50 psi) at room temperature for 8 h. The mixture was filtered through a pad of Celite, and washed with EtOH. The filtrate was concentrated under reduced pressure to give the product 1-Boc-4-aminoindole as off-white solid (5.23 g, 96% yield). MS (ESI) m/z 233.2
With hydrogen;5% Pd(II)/C(eggshell); In toluene; at 20℃; under 2585.81 Torr; for 7.0h;
Step 2: Preparation of 4-amino-indole-1-carboxylic acid tert-butyl ester (3)To a 500 mL Paar shaker hydrogenation flask was charged 118.0 g of toluene solution from Step 1 containing (14.6 g, 0.0555 mol) of <strong>[913836-24-5]4-nitro-indole-1-carboxylic acid tert-butyl ester</strong> (2) and 0.36 g of 5 wt % Pd-C Degussa Type E101 NO/W (50% water wet). The yellow-green mixture was hydrogenated at about 50 psi at room temperature for about 7 hours until no further hydrogen uptake and HPLC analysis showed the reaction to be complete. Note: Batch should be analyzed quickly when hydrogen uptake is complete since indolene by-product forms due to over hydrogenation. (Extended reaction time results in yield loss via over hydrogenation). The mixture was filtered through Celite, washed with toluene, dried by azeotrope distillation, and concentrated to a batch weight of 120 grams of toluene solution of product. This solution was used directly in Step 3.
With hydrogen;5% Pd(II)/C(eggshell); In toluene; at 20℃; under 2585.81 Torr; for 3.0h;
To a 2.5 liter Paar shaker hydrogenation flask was charged 40.0 g (0.152 mol) of, 500 mL of toluene and 1.0 g of 5 wt % Pd-C Degussa Type E101 NO/W (50% water wet). The yellow-green mixture was hydrogenated at about 50 psi at room temperature for about 3 hours until no further hydrogen uptake and HPLC analysis showed the reaction to be complete. Note: batch should be analyzed quickly when hydrogen uptake is complete since about 5-15% of indolene by-product forms due to over hydrogenation. (Extended reaction time results in yield loss via over hydrogenation). The mixture was filtered through Celite, washed with toluene, and concentrated.Multiple hydrogenation batches were combined and concentrated to 140 gram crude orange oil. The material was purified by chromatography with 25% EtOAc: 75% hexane and eluted to afford 121 gram of pure product as an orange oil in 100 area % by HPLC in an overall yield of 88%. The indolene by-product 12 must be removed in this step otherwise it carries through to later steps.
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