tert-butyl phenyl carbonate

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

Conditions: temp:130.01; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 60° C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75% (NMR).

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 60° C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75% (NMR).

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl phenyl carbonate (25.60 mL, 138.0 mmoles) was added to a stirred solution of 1,6-diaminohexane (15.30 g, 131.7 mmoles) in absolute EtOH (150 mL) in a 250 mL RB flask. The apparatus was fitted with a condenser and heated to 78° C. overnight under a blanket of nitrogen and then allowed to cool to room temperature. The solvent was stripped off the reaction mixture in vacuo (rotary evaporator) yielding a pale pink oily residue. CH2Cl2 (200 mL) was added to the residue and the resultant solution extracted with 3×200 mL portions of de-ionised water. For each extraction the pH of the aqueous phase was monitored and adjusted with HCl (aq, 2M) such that the pH of the aqueous layer was 3<pH<7 [only required for 1st extraction, needing ca. 60-70 mL HCl (aq, 2M)]. The aqueous phases were collected in a Erlenmeyer flask containing aqueous NaOH (aq, 100 mL, 3M). Ensuring that the pH of the collected aqueous extracts was ≧14 the resulting aqueous phase was extracted with CH2Cl2 (3×150 mL). These organic phases were recombined, evaporated to a volume of ca. 200 mL and subjected to the above pH modulated purification protocol for a second time by first extracting with water [3×200 mL, 3<pH<7 modulation with HCl (aq, 2M), again only required for 1st extract needing ca. 45-55 mL HCl (aq, 2M)], basicifying these aqueous extracts with NaOH (100 mL, 3M) and extracting with CH2Cl2 (3×150 mL). The CH2Cl2 extracts were combined, reduced in volume to 200 mL and then dried over anhydrous MgSO4, filtered, and stripped to dryness on a rotary evaporator for a period of 20 minutes to yield 6-(tert-butoxycarbonylamino)hexylamine as a peach oil. This peach oil was then subjected to a short path distillation using a Kugelrohr apparatus with an oven temperature of 180° C. and at a vacuum pressure of 0.160 torr, the receiver bulb was cooled by means of a dry-ice/acetone bath. Yield: 13.1 g (46%, colourless oil). 1H NMR (CDCl3) δ 1.14 (s, 2H, —NH2), 1.26-1.37 (m, 4H, —CH2—), 1.37-1.52 (s+m, 9H+4H, t-Bu+—CH2—), 2.67 (t, 2H, >NCH2—), 3.09 (q, 2H, —C(═O)NCH2—), 4.60 (bs, 1H, —C(═O)NH—). The apparatus was fitted with a condenser to cool to room temperature in vacuo (rotary evaporator) yielding a pale pink oily residue the resultant solution extracted with 3×200 mL portions of de-ionised water For each extraction the pH of the aqueous phase only required for 1st extraction The aqueous phases were collected in a Erlenmeyer flask containing aqueous NaOH (aq, 100 mL, 3M) was extracted with CH2Cl2 (3×150 mL) evaporated to a volume of ca. 200 mL purification protocol for a second time by first extracting with water [3×200 mL, 3<pH<7 modulation with HCl (aq, 2M) for 1st extract extracting with CH2Cl2 (3×150 mL) dried over anhydrous MgSO4 filtered stripped to dryness on a rotary evaporator for a period of 20 minutes

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

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

Procedure: To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet and temperature probe is added 1,4-diaminocylcohexane P1 (152.2 g, 1332.9 mmol), EtOH (1 L) and t-butyl phenyl carbonate (250 mL, 1351.5 mmol). The reaction mixture is wrapped with Al foil and heated using a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.). A brown solution is obtained and an internal temperature of 73.8° C. is recorded after 2.5 h. After heating for 18 h the now heterogeneous reaction mixture is allowed too cool. The mixture is filtered to remove bis-Boc protected amine, which precipitated as a white solid. The filtrate is concentrated in vacuo to a thick peach colored syrup. The mixture is transferred to an Erlenmeyer flask and the transfer is completed with CH2Cl2 (50 mL). To the mixture H2O (100 mL) is added (pH=9) followed by concentrated HCl (180 mL to pH=2) resulting in the precipitation of the (4-aminocyclohexyl)carbamic acid tert-butyl ester as a hydrochloride salt. The mixture is swirled vigorously until a thick slurry is obtained. Additional CH2Cl2 is added to maximize the amount of precipitate and the slurry is filtered (additional product is obtained from this filtrate #1, as described below). The solid is washed with Et2O (1.4 L). To free-base the HCl salt H2O (500 mL) is added followed by NaOH (2.5N, to pH=12). The mixture is extracted with CH2Cl2 (3×). The combined organic extracts are washed with H2O (3×400 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give (4-aminocyclohexyl)carbamic acid tert-butyl ester P2a (92.89 g) as a white solid. To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet heated a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.) A brown solution is obtained After heating for 18 h the now heterogeneous reaction mixture is allowed too cool The mixture is filtered to remove bis-Boc precipitated as a white solid The filtrate is concentrated in vacuo to a thick peach colored syrup To the mixture H2O (100 mL) is added (pH=9)

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

Procedure: To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet and temperature probe is added 1,4-diaminocylcohexane P1 (152.2 g, 1332.9 mmol), EtOH (1 L) and t-butyl phenyl carbonate (250 mL, 1351.5 mmol). The reaction mixture is wrapped with Al foil and heated using a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.). A brown solution is obtained and an internal temperature of 73.8° C. is recorded after 2.5 h. After heating for 18 h the now heterogeneous reaction mixture is allowed too cool. The mixture is filtered to remove bis-Boc protected amine, which precipitated as a white solid. The filtrate is concentrated in vacuo to a thick peach colored syrup. The mixture is transferred to an Erlenmeyer flask and the transfer is completed with CH2Cl2 (50 mL). To the mixture H2O (100 mL) is added (pH=9) followed by concentrated HCl (180 mL to pH=2) resulting in the precipitation of the (4-aminocyclohexyl)carbamic acid tert-butyl ester as a hydrochloride salt. The mixture is swirled vigorously until a thick slurry is obtained. Additional CH2Cl2 is added to maximize the amount of precipitate and the slurry is filtered (additional product is obtained from this filtrate #1, as described below). The solid is washed with Et2O (1.4 L). To free-base the HCl salt H2O (500 mL) is added followed by NaOH (2.5N, to pH=12). The mixture is extracted with CH2Cl2 (3×). The combined organic extracts are washed with H2O (3×400 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give (4-aminocyclohexyl)carbamic acid tert-butyl ester P2a (92.89 g) as a white solid. To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet heated a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.) A brown solution is obtained After heating for 18 h the now heterogeneous reaction mixture is allowed too cool The mixture is filtered to remove bis-Boc precipitated as a white solid The filtrate is concentrated in vacuo to a thick peach colored syrup To the mixture H2O (100 mL) is added (pH=9)

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

Procedure: To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (140 mg, 0.42 mmol) in 5 mL dry THF at 0° C. under Ar atmosphere was added NaH (50 mg, 60% in oil, 1.26 mmol) in 4 portions. The mixture was then stirred at rt for 20 min followed by the addition of tert-butyl phenyl carbonate (244 mg, 1.26 mmol) with a syringe. The reaction was allowed to stir at rt for 3 h and quenched onto ice (30 g). The mixture was extracted with EtOAc (2×40 mL) and the combined organic phase was dried over MgSO4. After solvent removal, the residue was chromatographed to afford tert-butyl 2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a white solid (120 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.39 (m., 2H), 7.37-7.32 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 1.75 (s, 9H); MS (ESI) m/z 431 (M+H+). to stir at rt for 3 h quenched onto ice (30 g) The mixture was extracted with EtOAc (2×40 mL) the combined organic phase was dried over MgSO4 After solvent removal the residue was chromatographed

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

Procedure: Tert-butyl phenyl carbonate (0.421 mL, 2.270 mmol) was added to a solution of 2-methylpropane-1,2-diamine (200 mg, 2.270 mmol) in EtOH (4.5 mL) and the reaction mixture was heated at reflux overnight. The mixture was concentrated and the residue diluted in water. The mixture was acidified with 2N HCl to pH 4 and washed with DCM. The aqueous layer was treated with 1M NaOH (2 mL) and extracted with DCM. The combined organic layers were dried with MgSO4, filtered and concentrated to afford tert-butyl 2-amino-2-methylpropylcarbamate (158 mg, 37% yield) as a colorless oil. MS (apci) m/z=188.9 (M+H). the reaction mixture was heated at reflux overnight The mixture was concentrated the residue diluted in water washed with DCM The aqueous layer was treated with 1M NaOH (2 mL) extracted with DCM The combined organic layers were dried with MgSO4 filtered concentrated

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

Procedure: To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (140 mg, 0.42 mmol) in 5 mL dry THF at 0° C. under Ar atmosphere was added NaH (50 mg, 60% in oil, 1.26 mmol) in 4 portions. The mixture was then stirred at rt for 20 min followed by the addition of tert-butyl phenyl carbonate (244 mg, 1.26 mmol) with a syringe. The reaction was allowed to stir at rt for 3 h and quenched onto ice (30 g). The mixture was extracted with EtOAc (2×40 mL) and the combined organic phase was dried over MgSO4. After solvent removal, the residue was chromatographed to afford tert-butyl 2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a white solid (120 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.39 (m., 2H), 7.37-7.32 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 1.75 (s, 9H); MS (ESI) m/z 431 (M+H+). to stir at rt for 3 h quenched onto ice (30 g) The mixture was extracted with EtOAc (2×40 mL) the combined organic phase was dried over MgSO4 After solvent removal the residue was chromatographed

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 60° C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75% (NMR).