tert-butyl 1H-pyrrole-2-carboxylate

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: The title compound (mp 158°-160° C.) was prepared from 2-chloro-5,11-dihydro-5,11-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (t-butoxycarbonyl)pyrrole in a manner analogous to that described in Example 23.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5,11-dihydro-5-ethyl-11-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.21 g), (t-butoxycarbonyl)pyrrole (0.25 g), potassium acetate (0.20 g), Pd(PPh3)2Cl2 (0.030 g), and 1-methyl-2-pyrrolidinone (2.5 mL) were heated in a sealed tube at 140° C. for 14 h. After removing the solvent, water was added and the product was extracted with CH2Cl2, dried (anhyd Na2 SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/methylene chloride, 1:9) and was further purified by preparative plate chromatography (ethyl acetate/methylene chloride, 1:9) to give, after recrystallization from ethyl acetate/hexanes, 0.020 g of the title compound, mp 161°-162° C. After removing the solvent, water was added the product was extracted with CH2Cl2 dried (anhyd Na2 SO4) filtered evaporated The residue was chromatographed over silica gel (ethyl acetate/methylene chloride, 1:9) was further purified by preparative plate chromatography (ethyl acetate/methylene chloride, 1:9) to give after recrystallization from ethyl acetate/hexanes, 0.020 g of the title compound, mp 161°-162° C.

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

Procedure: The Boc pyrrole trimer (5) (0.2 g, 0.40 mmol) in a dry round bottomed flask was treated with 4M HCl in dioxane (2.5 mL). The reaction mixture was stirred at room temperature for 30 minutes during which time a precipitate (5′) formed. The solvent was removed and the residue dried under vacuum. The residue was dissolved in dry DMF (2.5 mL) and the Boc pyrrole trimer acid (6) (0.194 g, 0.40 mmol, 1 equiv.) was added followed by EDCI (0.115 g, 0.6 mmol, 1.5 equiv.) and DMAP (0.058 g, 0.47 mmol, 1.2 equiv.). The reaction mixture was stirred for 48 hours then diluted with EtOAc (50 mL) and washed with 10% HCl solution (3×30 mL) and saturated NaHCO3 solution (3×30 mL). The organic layer was dried over MgSO4 then concentrated in vacuo to give an orange solid 0.185 g (54%). 1H NMR d6-DMSO δ 9.95 (2H, s, N—H), 9.93 (2H, s, N—H), 9.86 (1H, s, N—H), 9.08 (1H, s, Boc-N—H), 7.47 (1H, d, J=1.8 Hz, Py-H), 7.25 (1H, d, J=2.2 Hz, Py-H), 7.24 (2H, d, J=2.0 Hz, Py-H), 7.22 (1H, d, J=1.6 Hz, Py-H), 7.07 (2H, d, J=1.6 Hz, Py-H), 7.07 (1H, d, J=2.0 Hz, Py-H), 6.91 (2H, d, J=1.9 Hz, Py-H), 6.89 (1H, s, Py-H), 6.84 (1H, s, Py-H), 3.86 (3H, s, N—CH3), 3.86 (6H, s, N—CH3), 3.85 (3H, s, N—CH3), 3.84 (3H, s, N—CH3), 3.81 (3H, s, N—CH3), 3.74 (3H, s, O—CH3), 1.46 (9H, s, Boc-H). formed The solvent was removed the residue dried under vacuum The residue was dissolved in dry DMF (2.5 mL) The reaction mixture was stirred for 48 hours washed with 10% HCl solution (3×30 mL) and saturated NaHCO3 solution (3×30 mL) The organic layer was dried over MgSO4 then concentrated in vacuo

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

Procedure: The Boc pyrrole trimer (5) (0.6 g, 1.2 mmol) was dissolved in MeOH (5 mL) and treated with NaOH solution (0.1 g in 5 mL H2O). The reaction mixture was stirred overnight then heated at 60° C. for 2 hours. The MeOH was removed in vacuo and the aqueous fraction extracted with EtOAc (25 mL). The aqueous layer was adjusted to pH 2-3 with 1M HCl solution then extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid. The solid was suspended in Et2O (10 mL) and collected on a filter then dried in vacuo to give an orange solid 0.431 g (74%). 1H NMR d6-DMSO δ 12.11 (1H, s, OH), 9.89 (1H, s, N—H), 9.86 (1H, s, N—H), 9.09 (1H, s, Boc-N—H), 7.43 (1H, d, J=1.9 Hz, Py-H), 7.22 (1H, d, J=1.7 Hz, Py-H), 7.06 (1H, d, J=1.7 Hz, Py-H), 6.90 (1H, s, Py-H), 6.86 (1H, d, J=1.9 Hz, Py-H), 6.84 (1H, s, Py-H), 3.85 (3H, s, N—CH3), 3.83 (3H, s, N—CH3), 3.82 (3H, s, N—CH3), 1.46 (9H, s, Boc-H); 13C NMR d6-DMSO δ 161.9, 158.4, 158.4, 152.8, 122.8, 122.7, 122.5, 122.4, 122.3, 120.2 (CH), 119.5, 118.4 (CH), 117.0 (CH), 108.4 (CH), 104.7 (CH), 103.8 (CH), 78.2, 36.1 (CH3), 36.0 (CH3), 28.1 ([CH3]3). The MeOH was removed in vacuo the aqueous fraction extracted with EtOAc (25 mL) then extracted with EtOAc (3×30 mL) The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid collected on a filter then dried in vacuo

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

Procedure: The Boc pyrrole trimer (5) (0.6 g, 1.2 mmol) was dissolved in MeOH (5 mL) and treated with NaOH solution (0.1 g in 5 mL H2O). The reaction mixture was stirred overnight then heated at 60° C. for 2 hours. The MeOH was removed in vacuo and the aqueous fraction extracted with EtOAc (25 mL). The aqueous layer was adjusted to pH 2-3 with 1M HCl solution then extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid. The solid was suspended in Et2O (10 mL) and collected on a filter then dried in vacuo to give an orange solid 0.431 g (74%). 1H NMR d6-DMSO δ 12.11 (1H, s, OH), 9.89 (1H, s, N—H), 9.86 (1H, s, N—H), 9.09 (1H, s, Boc-N—H), 7.43 (1H, d, J=1.9 Hz, Py-H), 7.22 (1H, d, J=1.7 Hz, Py-H), 7.06 (1H, d, J=1.7 Hz, Py-H), 6.90 (1H, s, Py-H), 6.86 (1H, d, J=1.9 Hz, Py-H), 6.84 (1H, s, Py-H), 3.85 (3H, s, N—CH3), 3.83 (3H, s, N—CH3), 3.82 (3H, s, N—CH3), 1.46 (9H, s, Boc-H); 13C NMR d6-DMSO δ 161.9, 158.4, 158.4, 152.8, 122.8, 122.7, 122.5, 122.4, 122.3, 120.2 (CH), 119.5, 118.4 (CH), 117.0 (CH), 108.4 (CH), 104.7 (CH), 103.8 (CH), 78.2, 36.1 (CH3), 36.0 (CH3), 28.1 ([CH3]3). The MeOH was removed in vacuo the aqueous fraction extracted with EtOAc (25 mL) then extracted with EtOAc (3×30 mL) The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid collected on a filter then dried in vacuo

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

Procedure: The Boc protected pyrrole dimer (3) (0.25 g, 0.66 mmol) was placed in a dry round bottomed flask and treated with 4M HCl in dioxane (5 mL). The resulting solution became cloudy over a period of 30 minutes. The solvent was removed in vacuo to give a yellow solid (3′) which was then dried under vacuum. The residue was dissolved in dry DMF (9 mL) and the Boc pyrrole acid (2) (0.176 g, 0.726 mmol, 1.1 equiv.) was added followed by EDCI (0.191 g, 0.99 mmol, 1.5 equiv.) and DMAP (0.097 g, 0.79 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 18 hours then diluted with EtOAc (50 mL) and washed with 1M HCl soln (3×50 mL), then saturated NaHCO3 solution (3×50 mL), dried over MgSO4 then concentrated in vacuo to give a tan foam. This solid was suspended in a 1:1 mixture of MeOH and 1M NaOH solution (40 mL) and stirred at room temp for 30 minutes. EtOAc was added and the organic layer washed with saturated NaHCO3 solution (3×50 mL) and dried over MgSO4. Concentration in vacuo gave an off white foam 0.160 g (48%). Mp 134° C. (lit 131-133° C.); 1H NMR d6-DMSO δ 9.90 (1H, s, N—H), 9.86 (1H, s, N—H), 9.13 (1H, s, Boc-N—H), 7.46 (1H, d, J=1.9 Hz, Py-H), 7.21 (1H, d, J=1.7 Hz, Py-H), 7.06 (1H, d, J=1.7 Hz, Py-H), 6.91 (1H, s, Py-H), 6.90 (1H, s, Py-H), 6.85 (1H, s, Py-H), 3.84 (6H, s, N—CH3), 3.81 (3H, s, N—CH3), 3.74 (3H, s, O—CH3), 1.46 (9H, s, Boc-H). was placed in a dry round bottomed flask of 30 minutes The solvent was removed in vacuo to give a yellow solid (3′) which was then dried under vacuum The residue was dissolved in dry DMF (9 mL) washed with 1M HCl soln (3×50 mL) saturated NaHCO3 solution (3×50 mL), dried over MgSO4 then concentrated in vacuo to give a tan foam stirred at room temp for 30 minutes the organic layer washed with saturated NaHCO3 solution (3×50 mL) dried over MgSO4 Concentration in vacuo

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

Procedure: A stirred solution of Boc pyrrole dimer (3) (0.805 g, 2.1 mmol) in MeOH (40 mL) was treated with 1M NaOH solution (25 mL). The reaction mixture was stirred at room temperature for 18 hours. The volume was reduced in vacuo and the aqueous solution extracted with EtOAc (50 mL). The solvent was removed from the EtOAc fraction and the residue was treated with 1M NaOH solution (10 mL) for a further 3 hours. This was combined with the previous aqueous fraction and acidified to pH2-3 with 1M HCl solution and the suspension extracted with EtOAc (3×75 mL). The organic fractions were combined, dried over MgSO4 and concentrated in vacuo to give a yellow foam 0.781 g (100%). 1H NMR d6-DMSO δ 12.07 (1H, bs, OH), 9.81 (1H, s, N—H), 9.08 (1H, s, N—H), 7.40 (1H, d, J=1.9 Hz, Py-H), 6.88 (1H, s, Py-H), 6.84 (1H, s, Py-H), 6.83 (1H, s, Py-H), 3.81 (3H, s, N—CH3), 3.80 (3H, s, N—CH3), 1.45 (9H, s, Boc-H); 13C NMR d6-DMSO δ 171.9, 161.9, 158.3, 152.8, 122.6, 122.3, 120.2 (CH), 119.4, 117.0 (CH), 108.3 (CH), 103.7 (CH), 78.3, 36.1 (CH3), 36.1 (CH3), 28.1 ([CH3]3). the aqueous solution extracted with EtOAc (50 mL) The solvent was removed from the EtOAc fraction the residue was treated with 1M NaOH solution (10 mL) for a further 3 hours the suspension extracted with EtOAc (3×75 mL) dried over MgSO4 concentrated in vacuo

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

Procedure: A stirred solution of Boc pyrrole dimer (3) (0.805 g, 2.1 mmol) in MeOH (40 mL) was treated with 1M NaOH solution (25 mL). The reaction mixture was stirred at room temperature for 18 hours. The volume was reduced in vacuo and the aqueous solution extracted with EtOAc (50 mL). The solvent was removed from the EtOAc fraction and the residue was treated with 1M NaOH solution (10 mL) for a further 3 hours. This was combined with the previous aqueous fraction and acidified to pH2-3 with 1M HCl solution and the suspension extracted with EtOAc (3×75 mL). The organic fractions were combined, dried over MgSO4 and concentrated in vacuo to give a yellow foam 0.781 g (100%). 1H NMR d6-DMSO δ 12.07 (1H, bs, OH), 9.81 (1H, s, N—H), 9.08 (1H, s, N—H), 7.40 (1H, d, J=1.9 Hz, Py-H), 6.88 (1H, s, Py-H), 6.84 (1H, s, Py-H), 6.83 (1H, s, Py-H), 3.81 (3H, s, N—CH3), 3.80 (3H, s, N—CH3), 1.45 (9H, s, Boc-H); 13C NMR d6-DMSO δ 171.9, 161.9, 158.3, 152.8, 122.6, 122.3, 120.2 (CH), 119.4, 117.0 (CH), 108.3 (CH), 103.7 (CH), 78.3, 36.1 (CH3), 36.1 (CH3), 28.1 ([CH3]3). the aqueous solution extracted with EtOAc (50 mL) The solvent was removed from the EtOAc fraction the residue was treated with 1M NaOH solution (10 mL) for a further 3 hours the suspension extracted with EtOAc (3×75 mL) dried over MgSO4 concentrated in vacuo

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

Procedure: The title compound (mp 158°-160° C.) was prepared from 2-chloro-5,11-dihydro-5,11-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (t-butoxycarbonyl)pyrrole in a manner analogous to that described in Example 23.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5,11-dihydro-5-ethyl-11-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.21 g), (t-butoxycarbonyl)pyrrole (0.25 g), potassium acetate (0.20 g), Pd(PPh3)2Cl2 (0.030 g), and 1-methyl-2-pyrrolidinone (2.5 mL) were heated in a sealed tube at 140° C. for 14 h. After removing the solvent, water was added and the product was extracted with CH2Cl2, dried (anhyd Na2 SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/methylene chloride, 1:9) and was further purified by preparative plate chromatography (ethyl acetate/methylene chloride, 1:9) to give, after recrystallization from ethyl acetate/hexanes, 0.020 g of the title compound, mp 161°-162° C. After removing the solvent, water was added the product was extracted with CH2Cl2 dried (anhyd Na2 SO4) filtered evaporated The residue was chromatographed over silica gel (ethyl acetate/methylene chloride, 1:9) was further purified by preparative plate chromatography (ethyl acetate/methylene chloride, 1:9) to give after recrystallization from ethyl acetate/hexanes, 0.020 g of the title compound, mp 161°-162° C.