Potassium Carbonate → tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate

HRID 1812212

反応式

HRID 1812212 の反応式
Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:10][C:7]1[N:8]=[CH:9][C:4]([C@H:2]([N:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]2[CH3:11])[CH3:3])=[CH:5][CH:6]=1

参加物

5

反応物 3

HCID 11430Potassium CarbonateHCID 7023035(S)-1-Boc-3-methylpiperazineHCID 666000025-(1-Bromoethyl)-2-fluoropyridine

生成物 1

HCID 68514890tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate収率 35.4%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile溶媒

反応条件

温度
70 °C

実験手順

A mixture of 5-(1-bromoethyl)-2-fluoropyridine (Example 146, Step 2; 8.95 g, 43.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (9.22 g, 46.1 mmol) (CNH Technologies Inc.) in acetonitrile (200 mL) was treated with K2CO3 (7.27 g, 52.6 mmol) and KI (1.456 g, 8.77 mmol). The mixture was placed into a pre-heated (70° C.) oil bath and allowed to stir under an inert atmosphere overnight. The heating bath was then removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with chloroform (200 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with chloroform (1×100 mL). The combined organic layers were then washed with a saturated brine solution, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes) to provide tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (5.02 g, 15.52 mmol, 35.4% yield) (lower Rf diastereomer) as a viscous yellow-orange oil. m/z (ESI, +ve) 324.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 1H); 7.75 (td, J=8.0, 2.2 Hz, 1H); 6.90 (dd, J=8.5, 2.8 Hz, 1H); 3.94 (br. s., 1H, =); 3.55 (br. s., 1H); 3.37 (br. s., 2H); 3.20 (br. s., 1H); 2.71 (ddd, J=11.3, 7.6, 3.5 Hz, 1H); 2.43 (dd, J=9.6, 5.5 Hz, 2H); 1.43 (s, 9H); 1.38 (d, J=6.8 Hz, 3H); 0.99 (d, J=6.3 Hz, 3H).

後処理

  1. customThe heating bath was then removed
  2. temperatureto cool to ambient temperature
  3. additionThe reaction mixture was diluted with chloroform (200 mL) and water (300 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with chloroform (1×100 mL)
  6. washThe combined organic layers were then washed with a saturated brine solution
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes)

出典と根拠

ORDレコード
ord-e10912219e4b4d55b1dcc236c3d53732
出典データセット
uspto-grants-2013_01
特許番号
US08362241B2

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