4-Methyl-2-(methylsulfanyl)pyrimidine → 1-Cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one

HRID 2359730

반응식

HRID 2359730 반응식
[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24](N(OC)C)=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24](=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH2:22][CH2:21]1

참가 물질

5

반응물 3

HCID 8212614-Methyl-2-(methylsulfanyl)pyrimidineHCID 2733832Lithium HexamethyldisilazideHCID 224737662-cyclopropyl-N-methoxy-N-methylacetamide

생성물 1

HCID 679835361-Cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

To a solution of 4-methyl-2-(methylthio)pyrimidine (5.63 mL, 40.4 mmol) in THF (20 mL) at −10° C., LiHMDS (60.6 mL, 60.6 mmol) (1N in MBTE) was added dropwise under nitrogen. The reaction mixture coagulated, and stopped stirring. For this, additional THF (40 mL) was added to dissolve the highly viscous mixture. The reaction was warmed up to rt and was stirred for 30 minutes. The reaction mixture was re-cooled to −10° C., then 2-cyclopropyl-N-methoxy-N-methylacetamide (7.47 g, 40.4 mmol) was added dropwise. The reaction mixture was warmed up to rt, then stirred for an additional 2 hours. The reaction was partitioned between ammonium chloride solution and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc] to obtain the desired product, which was still contaminated significantly with the starting material, 4-methyl-2-(methylthio)pyrimidine (5.63 g, 48% yield). The product was carried on to the next step without further purification. MS (ES+): m/z=223.2/224.3 (100/50) [MH+]. HPLC: tR=0.84 minute over 3 minutes. Purity: 77% [HPLC (LC/MS) at 220 nm].

후처리

  1. dissolutionto dissolve the highly viscous mixture
  2. stirringwas stirred for 30 minutes
  3. temperatureThe reaction mixture was re-cooled to −10° C.
  4. temperatureThe reaction mixture was warmed up to rt
  5. stirringstirred for an additional 2 hours
  6. customThe reaction was partitioned between ammonium chloride solution and EtOAc
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was back-extracted
  9. washwashed with brine
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated in vacuo
  12. customThe crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc]

출처 및 근거

ORD 기록
ord-0f5adcc1e14547e1bec4aad91ae0bb58
출처 데이터셋
uspto-grants-2014_04
특허 번호
US08685993B2

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