Diisopropylamine → 4-(4-Bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid

HRID 15914

반응식

HRID 15914 반응식
[Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=1[F:33]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=2[F:33])=[C:16]([F:21])[CH:15]=1

참가 물질

6

반응물 4

HCID 7912DiisopropylamineHCID 1230504-Bromo-2-fluoroanilineHCID 217817434,6-Dichloro-5-fluoropyridine-3-carboxylic acidHCID 178418339Butyllithium

생성물 1

HCID 866015264-(4-Bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid수율 72.1%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매3회

반응 조건

온도
-78 °C

실험 절차

nBuLi (14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirred solution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0° C. After 20 minutes, the reaction mixture was cooled to −78° C. and a solution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10 mL) was added. After 20 minutes, a solution of 4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem. 1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After quenching the reaction mixture with 10% HCl (20 mL), it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride yielded 3.21 g (72%) of clean desired product.

후처리

  1. waitAfter 20 minutes
  2. waitAfter 10 minutes
  3. temperatureto warm to room temperature
  4. customAfter quenching the reaction mixture with 10% HCl (20 mL), it
  5. extractionwas extracted with ethyl acetate
  6. dry with materialThe combined organic extracts were dried (MgSO4)
  7. concentrationconcentrated under reduced pressure

출처 및 근거

ORD 기록
ord-15424217d4374dc0a7fc88055c604f18
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07732616B2

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