Trimethyl orthoformate → tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate

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Reaction Steps

7-Amino-3-bromo-9H-carbazole-1-carboxamide (0.78 g, 1.282 mmol, Example 480B) was dissolved in methanol (40 mL)+THF (20.0 ml). potassium acetate (0.126 g, 1.282 mmol) acetate was added until pH ˜4-5. Trimethyl orthoformate (6 ml, 54 mmol) was added, followed by a solution of ˜2.9 mmol of tert-butyl bis(2-oxoethyl)carbamate in 10 ml CH2Cl2 (Example 409A). The reaction mixture was stirred at room temperature for 5 minutes, then sodium cyanoborohydride (503 mg, 8 mmol) was added and the mixture stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and diluted aqueous NaHCO3 solution (500 ml water+25 ml saturated solution). The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuum. The crude product was dissolved in MeOH+DCM, filtered through a Strata X-C strong cation exchange cartridge (2×5 g adsorbent). The cartridge was washed with methanol and the product eluted with 1+1 mixture of 2M NH3 in MeOH and DCM to give 0.49 g tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate. Estimated purity ˜50%. The material was used “as is” in the next reaction. MS (ESI) m/e+=473/475 (1 Br isotope pattern).

Provenance & Evidence