18-Crown-6 → HCID 21480634, compound

HRID 1490213Notes

Reaction equation

HRID 1490213 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35](F)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1

Participants

6

Reactant 4

HCID 2855718-Crown-6HCID 31268PyrrolidineHCID 12016072HCID 12016072, compoundHCID 178418339Butyllithium

Product 1

HCID 21480634HCID 21480634, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a cooled solution (0° C.) of pyrrolidine (0.417 mL, 5.00 mmol, 5 eq) in tetrahydrofuran (10 mL) under nitrogen was added n-butyllithium (2.5M in hexane, 1.92 mL, 4.80 mmol, 4.8 eq). This was followed by 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)-piperidin-4-ol (described in example 58) (0.400 g, 1.00 mmol) in tetrahydrofuran (10 mL). The bath was removed and the solution warmed to room temperature over 1.5 h. No reaction was evident after stirring for 18 h. To accelerate the reaction, 18-crown-6 (0.528 g, 2.00 mmol, 2.0 eq) was added and the solution was heated to 60° C. for 5 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (35 mL, eluent: 50% ethyl acetate in hexane) to yield 0.450 g (quantitative) of the title compound. TLC analysis (Rf 0.23, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.35 (dd, J=1.7, 4.6 Hz, 1H), 7.63 (dd, J=1.8, 7.9 Hz, 1H), 7.22 (m, 4H), 7.12 (dd, J=7.9, 4.6 Hz, 1H), 6.93 (m, 4H), 4.27 (br s, 1H), 3.48 (s, 2H), 3.21 (m, 4H), 2.85 (m, 2H), 2.76 (m, 2H), 2.63 (d, J=1.3 Hz, 2H), 2.01 (m, 6H), 1.70 (m, 2H) MS (CI, CH4) m/z 452 (M+1,100), 480 (M+29,12), 434 (16) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (60° C., 16 pascal, 18 h) to yield a white solid, mp 249°-253° C.

Workup

  1. customThe bath was removed
  2. additionwas added
  3. temperaturethe solution was heated to 60° C. for 5 h
  4. customThe reaction was quenched with water (30 mL)
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe combined organic extracts were dried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. customThe reaction product was purified by flash chromatography over silica gel (35 mL, eluent: 50% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-470f27d1de594827b7093ef6df4ef4b0
Source dataset
uspto-grants-1997_10
Patent number
US05681840

Reaction notes

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