tert-butyl N,N-bis(2-oxoethyl)carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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). 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 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 the product eluted with 1+1 mixture of 2M NH3 in MeOH and DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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). 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 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 the product eluted with 1+1 mixture of 2M NH3 in MeOH and DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetone-1,3-dicarboxylic acid (13.8 g, 94.96 mmol) and sodium acetate (7.94 g, 96.8 mmol) were added to a solution of bis-(2-oxo-ethyl)-carbamic acid tert-butyl ester (19.1 g, 94.96 mmol) in H2O (118 mL). Benzylamine (10.3 mL, 94.96 mmol) was dissolved in aqueous HCl (3 N, 63 mL) and was subsequently added to the stirring solution of the dialdehyde and the dicarboxylic acid over a 15 minute period. The reaction mixture was stirred for 3 days at room temperature after which the pH was adjusted to 8 by the addition of potassium carbonate. The resulting solution was extracted with methylene chloride (4×70 mL), the organic extracts dried (Na2SO4), filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography, (eluant hexane/EtOAc 9/1 to 1/1, v/v), to give 15.1 g (48%) of 9-benzyl-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a brown oil. Retention time (min)=1.195, method [1], MS (ESI) 331.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.43-7.15 (m, 5H), 4.00-3.81 (m, 4H), 3.21 (bs, 2H), 3.20-2.98 (m, 2H), 2.62 (dd, J=15.9 Hz, 5.5 Hz, 2H), 2.28-2.17 (m, 2H), 1.42 (s, 9H). The resulting solution was extracted with methylene chloride (4×70 mL) the organic extracts dried (Na2SO4) filtered concentrated under vacuum The resulting residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium periodate (20.31 g, 94.96 mmol) in H2O (118 mL) was added to a cooled solution of 3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 94.6 mmol) in THF (158 mL) over a 30 minute period. The resulting white suspension was allowed to stir at room temperature for 3 h. The suspension was filtered and the filtrate concentrated under vacuum to remove the THF. The resulting aqueous solution was used directly in the next reaction. The suspension was filtered the filtrate concentrated under vacuum to remove the THF The resulting aqueous solution was used directly in the next reaction

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium periodate (20.31 g, 94.96 mmol) in H2O (118 mL) was added to a cooled solution of 3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 94.6 mmol) in THF (158 mL) over a 30 minute period. The resulting white suspension was allowed to stir at room temperature for 3 h. The suspension was filtered and the filtrate concentrated under vacuum to remove the THF. The resulting aqueous solution was used directly in the next reaction. The suspension was filtered the filtrate concentrated under vacuum to remove the THF The resulting aqueous solution was used directly in the next reaction

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetone-1,3-dicarboxylic acid (13.8 g, 94.96 mmol) and sodium acetate (7.94 g, 96.8 mmol) were added to a solution of bis-(2-oxo-ethyl)-carbamic acid tert-butyl ester (19.1 g, 94.96 mmol) in H2O (118 mL). Benzylamine (10.3 mL, 94.96 mmol) was dissolved in aqueous HCl (3 N, 63 mL) and was subsequently added to the stirring solution of the dialdehyde and the dicarboxylic acid over a 15 minute period. The reaction mixture was stirred for 3 days at room temperature after which the pH was adjusted to 8 by the addition of potassium carbonate. The resulting solution was extracted with methylene chloride (4×70 mL), the organic extracts dried (Na2SO4), filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography, (eluant hexane/EtOAc 9/1 to 1/1, v/v), to give 15.1 g (48%) of 9-benzyl-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a brown oil. Retention time (min)=1.195, method [1], MS(ESI) 331.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.43-7.15 (m, 5H), 4.00-3.81 (m, 4H), 3.21 (bs, 2H), 3.20-2.98 (m, 2H), 2.62 (dd, J=15.9 Hz, 5.5 Hz, 2H), 2.28-2.17 (m, 2H), 1.42 (s, 9H). The resulting solution was extracted with methylene chloride (4×70 mL) the organic extracts dried (Na2SO4) filtered concentrated under vacuum The resulting residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium periodate (20.31 g, 94.96 mmol) in H2O (118 mL) was added to a cooled solution of 3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 94.6 mmol) in THF (158 mL) over a 30 minute period. The resulting white suspension was allowed to stir at room temperature for 3 h. The suspension was filtered and the filtrate concentrated under vacuum to remove the THF. The resulting aqueous solution was used directly in the next reaction. The suspension was filtered the filtrate concentrated under vacuum to remove the THF The resulting aqueous solution was used directly in the next reaction