Lithium Hexamethyldisilazide → HCID 54693458、化合物

HRID 1436887ノート

反応式

HRID 1436887 の反応式
[O:1]=[C:2]([N:8]([CH3:16])[CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5]CC)=O.Cl[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]=[CH:24][C:23]1=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH:9]1[N:8]([CH3:16])[C:2](=[O:1])[C:3]([OH:5])=[C:24]2[CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][C:20]1[CH:19]=[CH:18][C:31]([F:32])=[CH:30][CH:29]=1)[C:23]2=[O:28]

参加物

5

反応物 3

HCID 2733832Lithium HexamethyldisilazideHCID 594556041-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-oneHCID 69067168HCID 69067168、化合物

生成物 1

HCID 54693458HCID 54693458、化合物

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
-78 °C

実験手順

To a cooled (−78° C.) solution of ethyl 2-oxo-2-[N-methyl-N-(pyrimidin-2-yl)methylamino]acetate from the previous step (1.43 g, 5.85 mmol) and 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. for 48 hours. The mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of enantiomers. The hydrogens at positions 4a and 5 were found to have a trans relationship to one another. The enantiomers were separated on a ChiralPak AD column with 1:1 EtOH:MeOH as the mobile phase. The first eluting enantiomer had a positive sign of rotation and the following properties: 1H NMR (400 MHz, CD3OD), δ8.76 (d, J=4.8 Hz, 2H), 7.41 (t, J=4.8 Hz, 1H), 7.23 (dd, J=8.5, 5.5 Hz, 2H), 7.01 (t, J=Hz, 2H), 4.81 (d, J=6.7 Hz, 1H), 4.57 (d, J=15 Hz, 1H), 4.47 (d, J=15 Hz, 1H), 3.63 (m, 1H), 3.2-3.4 (m, 2H), 2.91 (s, 3H), 2.11 (m, 1H), 0.96 (dq, Jd=4.5 Hz, Jq=13 Hz, 1H). ES MS M+1=383. The second eluting enantiomer had a negative sign of rotation and 1H NMR and MS properties identical to that of the first eluting enantiomer.

後処理

  1. temperaturewarmed to room temperature for 2.5 hours
  2. temperatureheated to 40° C. for 48 hours
  3. temperatureThe mixture was cooled to ambient temperature
  4. customthe solvent was removed under vacuum
  5. customThe residual material was purified
  6. washeluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA)

出典と根拠

ORDレコード
ord-e4f54d7f7d7b4d8a821990e1934b316e
出典データセット
uspto-grants-2009_11
特許番号
US07619086B2

反応ノート

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