Water → tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate

HRID 2207693ノート

反応式

HRID 2207693 の反応式
[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:21]=1.C(NC(C)C)(C)C.O>COC(C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:21]=2)[C:3]1=[O:18]

参加物

8

反応物 4

HCID 962WaterHCID 7912DiisopropylamineHCID 89649283tert-Butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamateHCID 90014635HCID 90014635、化合物

生成物 1

HCID 90014756tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate収率 88.4%

試薬・触媒・溶媒 3

HCID 83717Copper iodide触媒HCID 178418476HCID 178418476、化合物触媒HCID 15413tert-Butyl methyl ether溶媒

実験手順

In a 5 L three-necked flask with overhead paddle stirrer and a nitrogen inlet. tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 4) (104.79 g, 415.32 mmol) was suspended in tert-Butyl methyl ether (2100 mL). 2-Iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 6) (166.34 g, 456.85 mmol) was added followed by diisopropylamine (174.63 mL, 1246 mmol) and the mixture was stirred over 20 mins. To the suspension was added copper iodide (1.58 g, 8.31 mmol) followed by bis(triphenyl-phosphine)palladium (II) dichloride (2.92 g, 4.15 mmol) and the mixture was stirred at room temperature for 3 hours. Water (1000 mL) was added and the mixture stirred for 30 mins. The phases were separated and the organic phase, washed with water (2×500 mL), dried over magnesium sulphate, filtered and evaporated to a tan foam, 230 g. The material was purified in three batches of approximately 75 g by column chromatography using an 800 g (Biotage 75 L) column and eluting with a gradient of acetone in iso-hexane. This gave the title compound (D7) (179.3 g) in good purity by NMR and consistent spectroscopically with that produced by Method 1.

後処理

  1. stirringthe mixture was stirred at room temperature for 3 hours
  2. stirringthe mixture stirred for 30 mins
  3. customThe phases were separated
  4. washthe organic phase, washed with water (2×500 mL)
  5. dry with materialdried over magnesium sulphate
  6. filtrationfiltered
  7. customevaporated to a tan foam, 230 g
  8. customThe material was purified in three batches of approximately 75 g by column chromatography
  9. washeluting with a gradient of acetone in iso-hexane

出典と根拠

ORDレコード
ord-f23beb3f1c834630ba34ea586864423d
出典データセット
uspto-grants-2016_06
特許番号
US09376445B2

反応ノート

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