Cesium carbonate → 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile

HRID 515188노트

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HRID 515188 반응식
[C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)#[N:2].[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[C:8]([CH3:9])[C:3]=2[C:1]#[N:2])[CH2:26]1

참가 물질

7

반응물 3

HCID 10796Cesium carbonateHCID 27591633-FluoropyrrolidineHCID 86699756Trifluoro-methanesulfonic acid (2-cyano-3-methyl-5-morpholin-4-yl-phenyl)ester

생성물 1

HCID 866997552-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile수율 50.8%

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 634876Binap, (A+-)-촉매HCID 8028Tetrahydrofuran용매

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온도
90 °C

실험 절차

A solution of affording trifluoro-methanesulfonic acid (2-cyano-3-methyl-5-morpholin-4-yl-phenyl)ester (0.43 g, 1.22 mmol), (3R)-3-fluoro-pyrrolidin (0.19 g, 1.47 mmol) and caesium carbonate (1.6 g, 4.92 mmol) in tetrahydrofuran (25 ml) is degassed and flushed with Argon for 30 min followed by the addition of palladium(II) acetate (6.0 mg, 0.03 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23 mg, 0.04 mmol). The resulting mixture is stirred at 90° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is poured onto water (30 ml) and extracted with ethyl acetate (3×50 ml).The combined organic layers are washed with water (2×20 ml), brine (2×20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, 15% ethyl acetate/hexane) affording 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile (0.18 g, 0.62 mmol, 50%).

후처리

  1. customflushed with Argon for 30 min
  2. customAfter completion of the reaction (monitored by TLC)
  3. additionthe mixture is poured onto water (30 ml)
  4. extractionextracted with ethyl acetate (3×50 ml).The combined organic layers
  5. washare washed with water (2×20 ml), brine (2×20 ml)
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe crude product is purified by flash column chromatography (silica gel, 15% ethyl acetate/hexane)

출처 및 근거

ORD 기록
ord-d2af3348a5234bbf9c3d523c757a7708
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09108936B2

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