tert-butyl 2-(hydroxymethyl)-2,5-dihydropyrrole-1-carboxylate

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

Procedure: Diisopropylazodicarboxylate (1.4 g) was added to a suspension of methyl 3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxybenzoate (Intermediate 13, 2.58 g), tert-butyl 2-hydroxymethyl-2,5-dihydropyrrole-1-carboxylate (Prepared according to Morriello et al, Bioorg. Med. Chem, 2008, 16(5), 2156; 1.27 g) and triphenylphosphine (1.82 g) in anhydrous THF (20 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (4.13 g) as a light brown oil. The volatiles were removed in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25%

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

Procedure: To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product. the solvent was evaporated the solution was filtered concentrated The resulting residue was dissolved in DCM washed with 0.6N NaOH (2×25 mL) the layers were separated The organic layer was dried with Na2SO4 the solvent was evaporated The crude product was purified eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes

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

Procedure: To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product. the solvent was evaporated the solution was filtered concentrated The resulting residue was dissolved in DCM washed with 0.6N NaOH (2×25 mL) the layers were separated The organic layer was dried with Na2SO4 the solvent was evaporated The crude product was purified eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes

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

Procedure: Diisopropylazodicarboxylate (1.4 g) was added to a suspension of methyl 3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxybenzoate (Intermediate 13, 2.58 g), tert-butyl 2-hydroxymethyl-2,5-dihydropyrrole-1-carboxylate (Prepared according to Morriello et al, Bioorg. Med. Chem, 2008, 16(5), 2156; 1.27 g) and triphenylphosphine (1.82 g) in anhydrous THF (20 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (4.13 g) as a light brown oil. The volatiles were removed in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25%

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

Procedure: To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product. the solvent was evaporated the solution was filtered concentrated The resulting residue was dissolved in DCM washed with 0.6N NaOH (2×25 mL) the layers were separated The organic layer was dried with Na2SO4 the solvent was evaporated The crude product was purified eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes