Lithium Hexamethyldisilazide → HCID 54693458, 화합물

HRID 1436887노트

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HRID 1436887 반응식
[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]

참가 물질

5

반응물 3

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

생성물 1

HCID 54693458HCID 54693458, 화합물

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
-78 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-e4f54d7f7d7b4d8a821990e1934b316e
출처 데이터셋
uspto-grants-2009_11
특허 번호
US07619086B2

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