Water → HCID 46835601, compound

HRID 640694Notes

Reaction equation

HRID 640694 reaction equation
[CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])=[CH:17][CH:16]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 680214-Fluorobenzyl bromideHCID 136747Ethyl 2-methyl-3-pyrrolecarboxylate

Product 1

HCID 46835601HCID 46835601, compoundYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (106.26 g, 0.694 mol) (prepared by the method of: Wee, A. G. H.; Shu, A. Y. L.; Djerassi, C. J. Org. Chem. 1984, 49, 3327-3336) in anhydrous DMF (1.0 L), under nitrogen, was added sodium hydride (60% in oil, 30.5 g, 0.763 mol, 1.1eq.) in 5 portions over 1 hour. When gas evolution ceased, 4-fluorobenzyl bromide (131.13 g, 0.694 mol) in anhydrous DMF (0.2 L) was added via pressure equalized addition funnel over 45 minutes. The mixture was allowed to stir at room temperature for 16 hours after the addition was complete, then was poured into water (1.4 L) in a 4 L separatory funnel. The mixture was extracted with diethyl ether (5×1.0 L) and the combined organic phases were washed with brine (3.0 L) and dried (Na2SO4). Filtration, rinsing of the filter cake with diethyl ether (0.5 L) and concentration in vacuo (approx. 20 Torr) gave the crude product and DMF. Residual DMF was removed on a cold finger trap rotary evaporator at full pump vacuum in a 40° C. water bath to give the crude benzylate pyrrole as an orange oil. The crude product was purified by chromatography on a column of silica gel (125 mm OD, 1 kg 230-400 mesh, packed with hexanes-EtOAc 95:5) eluted with hexanes:EtOAc (95:5, 2.0 L) and hexanes:EtOAc (90:10, 8.0 L) while collecting 500 mL fractions, using the flash technique. Fractions 4-18 were combined to afford ethyl 1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate (172.3 g, 95%) as a clear, pale yellow, viscous liquid. TLC (Merck, hexanes:EtOAc 85:15, UV-+, cerium molybdate-+): Rf=0.26; LCMS (Eclipse XDB-C8, 0.8mL/min, gradient 80:20 to 5:95 H2O (+0.1% HOAc):CH3CN—5 minutes, APCl, +mode): RT-3.711 min, m/e=262.1 (base), 263.2 (30); 1H-NMR (300 MHz, CDCl3): δ=1.33 (t, J=7.06 Hz, 3H), 2.43 (s, 3H), 4.26 (q, J=7.06 Hz, 2H), 5.00 (s, 2H), 6.52 (d, J=3.20 Hz, 1H), 6.58 (d, J=3.20 Hz, 1 H), 6.92-7.04 (m, 4H).

Workup

  1. additionaddition funnel over 45 minutes
  2. additionafter the addition
  3. extractionThe mixture was extracted with diethyl ether (5×1.0 L)
  4. washthe combined organic phases were washed with brine (3.0 L)
  5. dry with materialdried (Na2SO4)
  6. filtrationFiltration
  7. washrinsing of the filter cake with diethyl ether (0.5 L) and concentration in vacuo (approx. 20 Torr)
  8. customgave the crude product and DMF
  9. customResidual DMF was removed on a cold finger trap
  10. customrotary evaporator at full pump vacuum in a 40° C. water bath
  11. customto give the crude benzylate pyrrole as an orange oil
  12. customThe crude product was purified by chromatography on a column of silica gel (125 mm OD, 1 kg 230-400 mesh, packed with hexanes-EtOAc 95:5)
  13. washeluted with hexanes:EtOAc (95:5, 2.0 L) and hexanes:EtOAc (90:10, 8.0 L)
  14. customwhile collecting 500 mL fractions

Sources & evidence

ORD record
ord-757adac77b8c4dfe8e3e09196c945d68
Source dataset
uspto-grants-2010_04
Patent number
US07692014B2

Reaction notes

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