3-Fluorophenol → HCID 44600362, compound

HRID 882767Notes

Reaction equation

HRID 882767 reaction equation
[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@H:14]3[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]3[C:20](=[O:22])[CH3:21])=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.FC1C=C(O)C=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@H:14]3[CH2:18][C@H:17]([OH:19])[CH2:16][N:15]3[C:20](=[O:22])[CH3:21])=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 97433-FluorophenolHCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 46855230HCID 46855230, compound

Product 1

HCID 44600362HCID 44600362, compoundYield 64.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a heterogeneous mixture of (2R,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone (139 g, 448.5 mmol), 3-fluoro-phenol (52 mL, 462 mmol), and triphenylphosphine resin (1.52 mmol/g loading, 339 g, 516 mmol) in CH2Cl2 (4.3 L) was slowly added DIAD (91 mL, 462 mmol) over 15 min. The mixture was stirred at rt for 15 h. The resin was filtered off and washed with CH2Cl2 (4 L). The filtrate was concentrated and partitioned between methyl tert-butyl ether (MTBE; 2 L) and water (2 L). The aqueous layer was extracted with additional MTBE (2×1.8 L). The combined organic layers were concentrated to a volume of 2 L and extracted with 1 N HCl(aq) (2 L). The acidic aqueous layer was washed with MTBE (1 L) and then basified to pH>12 with 50% NaOH(aq) (118 mL). The basic aqueous layer was extracted with CH2Cl2 (2×1.5 L) and the combined organics were dried with MgSO4, filtered, and concentrated to an oil. The oil was optionally purified by FCC (0 to 5% 2 M NH3 in MeOH/95% CH2Cl2) to provide the title compound (89 g, 49%). MS (ESI): mass calcd. for C22H30FN3O3, 403.2; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.28-7.19 (m, 1H), 6.74-6.54 (m, 3H), 5.12-5.05 (m, 0.91H), 5.02-4.95 (m, 0.91H), 4.93-4.79 (m, 0.18H), 4.13-4.02 (m, 1H), 3.88-3.60 (m, 5H), 2.96-2.82 (m, 1H), 2.70-2.27 (m, 6H), 2.1-1.55 (m, 11H).

Workup

  1. customover 15 min
  2. filtrationThe resin was filtered off
  3. washwashed with CH2Cl2 (4 L)
  4. concentrationThe filtrate was concentrated
  5. custompartitioned between methyl tert-butyl ether (MTBE; 2 L) and water (2 L)
  6. extractionThe aqueous layer was extracted with additional MTBE (2×1.8 L)
  7. concentrationThe combined organic layers were concentrated to a volume of 2 L
  8. extractionextracted with 1 N HCl(aq) (2 L)
  9. washThe acidic aqueous layer was washed with MTBE (1 L)
  10. extractionThe basic aqueous layer was extracted with CH2Cl2 (2×1.5 L)
  11. dry with materialthe combined organics were dried with MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated to an oil
  14. customThe oil was optionally purified by FCC (0 to 5% 2 M NH3 in MeOH/95% CH2Cl2)

Sources & evidence

ORD record
ord-6519997a76d64d1693c66020cf25bf0a
Source dataset
uspto-grants-2012_08
Patent number
US08236792B2

Reaction notes

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