methyl 3-chloro-1H-pyrrole-2-carboxylate

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 3-chloro-1H-pyrrole-2-carboxylate (18.86 mmol, 1.0 equiv.) was dissolved in MeOH—H2O (2:1, 120 ml); at 0° C., LiOH.H2O (75.4 mmol, 4 equiv.) was added and the mixture was stirred for 16 h at 25° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (60 ml) and extracted with ethyl acetate (2×50 ml). The aqueous phase was adjusted to pH 3-4 with 1 M HCl, and the resulting solid was filtered out. Yield: 90% The methanol was concentrated under reduced pressure the aqueous residue was diluted with water (60 ml) extracted with ethyl acetate (2×50 ml) the resulting solid was filtered out

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 3-chloro-1H-pyrrole-2-carboxylate (18.86 mmol, 1.0 equiv.) was dissolved in MeOH—H2O (2:1, 120 ml); at 0° C., LiOH.H2O (75.4 mmol, 4 equiv.) was added and the mixture was stirred for 16 h at 25° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (60 ml) and extracted with ethyl acetate (2×50 ml). The aqueous phase was adjusted to pH 3-4 with 1 M HCl, and the resulting solid was filtered out. Yield: 90% The methanol was concentrated under reduced pressure the aqueous residue was diluted with water (60 ml) extracted with ethyl acetate (2×50 ml) the resulting solid was filtered out

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,4-Dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (47.4 mmol, 1.0 equiv.) was added to a solution of sodium methanolate (284.5 mmol, 6.0 equiv.) in methanol (126 ml), and the mixture was heated for 1.5 h at boiling temperature. The reaction mixture was cooled to 25° C., the solvent was concentrated under reduced pressure, the residue was taken up in diethyl ether (470 ml), and the mixture was stirred for 30 min. The resulting solid (sodium chloride) was filtered out, and the filtrate was dried over K2CO3 and concentrated under reduced pressure. The residue was taken up in DCM (600 ml), extracted with 2 N HCl (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 83% the mixture was heated for 1.5 h the solvent was concentrated under reduced pressure The resulting solid (sodium chloride) was filtered out the filtrate was dried over K2CO3 concentrated under reduced pressure extracted with 2 N HCl (2×150 ml) dried over Na2SO4 concentrated under reduced pressure without being purified further

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,4-Dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (47.4 mmol, 1.0 equiv.) was added to a solution of sodium methanolate (284.5 mmol, 6.0 equiv.) in methanol (126 ml), and the mixture was heated for 1.5 h at boiling temperature. The reaction mixture was cooled to 25° C., the solvent was concentrated under reduced pressure, the residue was taken up in diethyl ether (470 ml), and the mixture was stirred for 30 min. The resulting solid (sodium chloride) was filtered out, and the filtrate was dried over K2CO3 and concentrated under reduced pressure. The residue was taken up in DCM (600 ml), extracted with 2 N HCl (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 83% the mixture was heated for 1.5 h the solvent was concentrated under reduced pressure The resulting solid (sodium chloride) was filtered out the filtrate was dried over K2CO3 concentrated under reduced pressure extracted with 2 N HCl (2×150 ml) dried over Na2SO4 concentrated under reduced pressure without being purified further

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

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

Procedure: To a stirred solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (1.00 g, 6.30 mmol) in DMF (15 mL) was added NaH (0.45 g, 18.80 mmol, 99%, dry) and the contents were stirred for 1 h at ambient temperature. NH2Cl (42.0 mL, 0.327 g, 6.30 mmol) was added at −10° C. to the reaction mixture and the contents were stirred for another 30 min at −10° C. The solvents were removed under reduced pressure and the residue was extracted with MTBE. The MTBE layer was passed through anhydrous Na2SO4 and concentrated under reduced pressure to give a brown solid. The crude residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to give a methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (0.750 g, 69.0%) as a yellow solid. LCMS Condition B-23: retention time 0.68 min, [M+1]=175.1. 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 6.11 (d, J=2.8 Hz, 1H), 6.28 (s, 2H), 7.06 (d, J=2.8 Hz, 1H). the contents were stirred for another 30 min at −10° C The solvents were removed under reduced pressure the residue was extracted with MTBE concentrated under reduced pressure to give a brown solid The crude residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes)

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

Procedure: The commercially available methyl 3-chloro-1H-pyrrole-2-carboxylate (1.50 g, 94.0%, yellow solid) was synthesized according to Fang et al., J. Med. Chem., 53:7967-7978 (2010) using 2-methyl-1-pyrroline (0.831 g, 10.0 mmol, commercial), NCS (10.7 g, 80.0 mmol) and NaOMe in MeOH (3M, 20 mL, 60.0 mmol). LCMS Condition B-41: retention time 1.71 min, [M+1]=160.10. 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.25 (t, J=3.0 Hz, 1H), 6.86 (t, J=3.0 Hz, 1H), 9.17 (br s, 1H).

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

Procedure: Alternately, compounds of formula (I) can be synthesized by the general sequence shown in Scheme 3. Commercially available 5-methyl-3,4-dihydro-2H-pyrrole 13 was treated with N-chlorosuccinimide followed by sodium methoxide to generate methyl 3-chloro-1H-pyrrole-2-carboxylate 14. Compound 14 was N-aminated and the product 15 was acylated to yield methyl 3-chloro-1-(methoxycarbonylamino)-1H-pyrrole-2-carboxylate 16. Compound 16 was treated with ammonia to yield 5-chloropyrrolo[1,2-f][1,2,4]triazine-2,4-diol 17. Compound 10 can be obtained from 17 by transition metal mediated Suzuki cross-coupling reactions with boronic acids or esters. Compound 17 gave 2,4,5-trichloropyrrolo[1,2-f][1,2,4]triazine 18 on treatment with chlorinating agents for example, POCl3 and then displacement of the C4 chloro with amines gave regioselectively 19. Using different palladium reagent/ligand combinations we could achieve regioselective Suzuki cross-couplings at C2 and C5 to generate compounds of general formula (I).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of methyl 3-chloro-1H-pyrrole-2-carboxylate (2.50 g, 15.7 mmol) and DMF (10 mL) at 0° C. was added 60% sodium hydride (0.816 g, 20.4 mmol). After 15 min, O-(2,4-dinitrophenyl)hydroxylamine (3.74 g, 18.8 mmol) was added and the mixture was stirred at 0° C. for 1 hr before warming to RT. After 18 hrs, the mixture was diluted with 10% NaCl and extracted with EtOAc. The organic fractions were dried with sodium sulfate and purified by silica gel chromatography using 10-30% Hexanes:EtOAc to afford a crude, brown oil. The oil was taken up in Et2O and treated with 4 N HCl in dioxane. The resulting off-white precipitate was collected by filtration to afford methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate hydrochloride. before warming to RT After 18 hrs extracted with EtOAc The organic fractions were dried with sodium sulfate purified by silica gel chromatography EtOAc to afford a crude, brown oil The resulting off-white precipitate was collected by filtration

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

Procedure: A solution of phosphorous oxychloride (3.21 ml, 34.5 mmol) was added dropwise over a period of 15 min to a 0° C. solution of DMF (2.67 ml, 34.5 mmol) under nitrogen. The mixture was allowed to warm to RT and stirred for 30 min. Dichloroethane (20 mL) was added and the reaction mixture cooled to 0° C. A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (5 g, 31.3 mmol) in dichloroethane (20 mL) was added dropwise over 30 min. The reaction mixture was warmed to RT and allowed to stir for 1 h. The flask was placed in an oil bath at 90° C. and stirred for 30 min. The reaction mixture was cooled to RT, a solution of sodium acetate (25 g, 305 mmol) in water (25 mL) was added and stirred for 15 min. Methylene chloride (100 mL) was added and the layers separated. The aqueous layer was extracted with methylene chloride (2×25 mL), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude material was purified by column chromatography (hexanes: EtOAc; 10-100%) to afford three isolated materials. The first compound to elute was a mixture of starting materials and product. The second fraction to elute was evaporated and recrystallized from a minimal amount of EtOAc to afford methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (1.2 g, 6.40 mmol, 20% yield) as yellowish crystals. The third fraction to elute was evaporated and recrystallized from hexanes: EtOAc to afford methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate (1.05 g, 18% yield) as a tan solid. Methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate: 1H NMR (400 MHz, DMSO-d6): 6 ppm 14.0 (br. s., 1H), 9.64 (d, 1H) 7.01 (s, 1H) 3.82 (s, 3H). MS: m/z 188.0 (M+1). Methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate: 1H NMR (400 MHz, DMSO-d6): 6 ppm 14.0 (br. s., 1H) 9.77 (s, 1H) 7.77 (s, 1H) 3.80 (s, 3H). MS: m/z 188.0 (M+1). the reaction mixture cooled to 0° C The reaction mixture was warmed to RT to stir for 1 h The flask was placed in an oil bath at 90° C. stirred for 30 min The reaction mixture was cooled to RT stirred for 15 min the layers separated The aqueous layer was extracted with methylene chloride (2×25 mL) dried over sodium sulfate filtered evaporated The crude material was purified by column chromatography (hexanes: EtOAc; 10-100%) to afford three isolated materials The first compound to elute a mixture of starting materials and product The second fraction to elute was evaporated recrystallized from a minimal amount of EtOAc

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc. The organic layer was separated, washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (br. s., 1H), 7.34-7.84 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3 H). LCMS: m/z 200.0 (M−1). then warmed to room temp over 2 hours The organic layer was separated washed with 1N sodium hydroxide dried over MgSO4 filtered evaporated to a residue Purification