tert-Butyl 4-oxopiperidine-1-carboxylate → tert-Butyl 4-(2-(I-benzylpiperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 1429534Notes

Reaction equation

HRID 1429534 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 674675792-(1-Benzylpiperidin-4-yloxy)-6-bromobenzo[d]thiazoleHCID 178418339Butyllithium

Product 1

HCID 68208482tert-Butyl 4-(2-(I-benzylpiperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of Compound 14A (0.68 g, 1.686 mmol) in dry THF (9.4 ml) at −78° C. under argon was added dropwise BuLi (0.742 ml, 1.855 mmol). After the completion of addition, the reaction mixture was stirred at −78° C. for 1 h. At the conclusion of this period, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.37 g, 1.855 mmol) in THF (1.9 ml) was transferred to the reaction mixture via cannulation. The resulting mixture was stirred and gradually warmed to −20° C., where it stirred for an additional hour. At the conclusion of this period, the mixture was quenched with aq. NaHCO3 (saturated, 20 mL) and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with H2O (3×10 mL) and brine (10 mL), dried (Na2SO4) and then filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to give Compound 14B′ as a white solid (0.63 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.36 (m, 4H), 7.24-7.29 (m, 1H), 5.21 (tt, J=7.9, 3.9 Hz, 1H), 3.98 (br. s., 2H), 3.54 (s, 2H), 3.25 (br. s., 2H), 2.73 (br. s., 2H), 2.38 (t, J=8.7 Hz, 2H), 2.08-2.18 (m, 2H), 1.85-2.03 (m, 5H), 1.75 (d, J=12.1 Hz, 2H), 1.47-1.50 (m, 9H). LC/MS (m/z)=524 (M+H)+.

Workup

  1. additionAfter the completion of addition
  2. stirringThe resulting mixture was stirred
  3. temperaturegradually warmed to −20° C.
  4. stirringwhere it stirred for an additional hour
  5. customAt the conclusion of this period, the mixture was quenched with aq. NaHCO3 (saturated, 20 mL)
  6. extractionextracted with EtOAc (3×15 mL)
  7. washThe combined organic layers were washed with H2O (3×10 mL) and brine (10 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customThe solvent was removed under reduced pressure
  11. customthe resulting residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc)

Sources & evidence

ORD record
ord-6b8d305b81704bfa97f889df1975ba4d
Source dataset
uspto-grants-2015_01
Patent number
US08940716B2

Reaction notes

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