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

HRID 1397133

Reaction equation

HRID 1397133 reaction equation
[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

Participants

5

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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 stifling. 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].

Workup

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

Sources & evidence

ORD record
ord-d188960803b04d2f94bc2bfb69f83b26
Source dataset
uspto-grants-2014_12
Patent number
US08901147B2

Linked notes

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