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Step 2: Methyl 4-bromo-lH-pyrrole-2-carboxylate[00174] To a dry round bottom flask containing dry MeOH (60 mL) was added sodium (5 g, 257.7 mmol) portionwise. After all the sodium was dissolved, the solution was slowly added to a flask which contained l-(4-bromo-lH-pyrrol-2-yl)- 2,2,2-trichloroethanone (50.0 g, 171.8 mmol) in MeOH (860 mL) through a dropping funnel giving a yellow reaction mixture. After the addition was complete, the reaction was stirred for an additional 10 minutes, then concentrated and cooled in an ice bath. The resulting solid that precipitated was collected by vacuum filtration and washed with water until neutral pH. The solid was dried to yield 25 g (71%) of the title compound as a white solid. LCMS (condition A): m/z = 204.0 -ve. 1H NMR (400MHz, DMSO-i?) δ ppm: 7.16 (1H, d, 1.2H), 6.89 (1H, d, 1.2H).
71%
With sodium;
To a dry round bottom flask containing dry MeOH (60 mL) was added sodium (5 g, 257.7 mmol) portionwise. After all the sodium was dissolved, the solution was slowly added to a flask which contained l-(4-bromo-lH-pyrrol-2-yl)- 2,2,2-trichloroethanone (50.0 g, 171.8 mmol) in MeOH (860 mL) through a dropping funnel giving a yellow reaction mixture. After the addition was complete, the reaction was stirred for an additional 10 minutes, then concentrated and cooled in an ice bath. The resulting solid that precipitated was collected by vacuum filtration and washed with water until neutral pH. The solid was dried to yield 25 g (71%) of the title compound as a white solid. LCMS (condition A): m/z = 204.0 -ve. XH NMR (400MHz, DMSO-d6) δ ppm: 7.16 (1H, d, 1.2H), 6.89 (1H, d, 1.2H).
Example 2 4-Bromo methyl 2-pyrrole acetate: To a solution of 4-bromo-2-trichloroacetyl pyrrole (8.0 g, 27.8 MMOL) in methanol (20 mL) was slowly added sodium methoxide (4.37M, 6.5 ML, 28.4 MMOL) over 20 minutes at 0 C and the resulting reaction mixture stirred for 30 minutes. The reaction mixture was concentrated in vacuo, and diluted with ethyl acetate (100 mL). The organic solution was washed with brine, dried over MGS04, and concentrated IFA VACUO then the crude product was recrystallized from hexane to afford the title compound as a white solid (4.6 g). HPLC RT 5. 66 MIN.
Example 1C. 4-Bromo-2-methoxycarbonylpyrrole[00120] To a solution of Example IB (20 g, 68 mmol) in methanol (100 mL), a solution of NaOMe (IM in MeOH, 34 mL, 34 mmol) was added slowly. This mixture was then stirred at ambient temperature for Ih after which it was diluted with water (300 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic layer and extracts were washed with water (2 x 50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave 4-Bromo-2- methoxycarbonylpyrrole (Example 1C, 12 g, 85%) as a white solid. LC-MS, [M-H]+ = 203. 1H NMR (DMSO-de, 400MHz): δ 12.31 (brs, IH), 7.16 (s, IH), 6.81 (s, IH), 3.75 (s, 3H).
82%
for 0.166667h;
Step 2: Synthesis of 4-Bromo-1H-pyrrole-2-carboxylic acid methyl ester To a solution of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone, (28.9 g, 0.1 mol) in 500 mL methanol was added 25% NaOMe/MeOH (35 mL, 0.15 mol) dropwise. The reaction was complete in 10 minutes. The mixture was evaporated to dryness and solidified with icy water. The product was filtered off, washed with water until neutral, then dried to give 16.49 g (82%) of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester. MS: 203.96, 205.96 M+H+. H1-NMR (DMSO-d6): δ (ppm) 12.28 (s, 1H), 7.15 (m, 1H), 6.80 (m, 1H), 3.74 (s, 3H).
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