Ammonium Hydroxide → (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate

HRID 1426888

反応式

HRID 1426888 の反応式
[N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[Li]C(CC)C.Br[C:36]1[C:37]([O:43][CH3:44])=[N:38][CH:39]=[C:40]([F:42])[CH:41]=1.[NH4+].[OH-]>CC(OC)(C)C.[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>[F:42][C:40]1[CH:41]=[C:36]([C@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:37]([O:43][CH3:44])=[N:38][CH:39]=1

参加物

10

反応物 5

HCID 14923Ammonium HydroxideHCID 643455N-Boc-pyrrolidineHCID 644020SparteineHCID 404270063-Bromo-5-fluoro-2-methoxypyridineHCID 178418400CID 53628100

生成物 1

HCID 86691710(R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate収率 63%

試薬・触媒・溶媒 4

HCID 167845palladium(II) acetate触媒HCID 3007855Zincchloride触媒HCID 118705180Tris(tert-butyl)phosphonium tetrafluoroborate触媒HCID 15413tert-Butyl methyl ether溶媒

反応条件

温度
-78 °C

実験手順

A solution of tert-butyl pyrrolidine-1-carboxylate (4.09 mL, 23.4 mmol) and (−)-sparteine (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to −78° C. and sec-BuLi (20 mL, 28.0 mmol, 1.4 M in cyclohexane) was introduced drop-wise by cannula, keeping the internal temperature under −78° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (21.0 mL, 21.0 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 10 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 3-bromo-5-fluoro-2-methoxypyridine (5.05 g, 24.5 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol) and t-Bu3P-HBF4 (0.407 g, 1.40 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (1 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite® and washed with Et2O. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5% EtOAc/hexanes to give product (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate as yellow oil (4.34 g, 63% yield).

後処理

  1. customunder −78° C
  2. customthe internal temperature below −65° C
  3. stirringThe resulting light suspension was stirred at −78° C. for 10 minutes
  4. temperaturewarmed to ambient temperature
  5. stirringAfter stirring overnight at ambient temperature
  6. stirringthe reaction was stirred for 1 hour
  7. filtrationThe resulting slurry was filtered through Celite®
  8. washwashed with Et2O
  9. filtrationThe organic layer was filtered
  10. concentrationconcentrated
  11. customthe crude product was purified by silica column chromatography
  12. washeluting with 5% EtOAc/hexanes

出典と根拠

ORDレコード
ord-a69fe1c12c67459faf1f3b72a95f985c
出典データセット
uspto-grants-2015_01
特許番号
US08933084B2

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