Lithium Hexamethyldisilazide → HCID 54693458, compound

HRID 1436887Notes

Reaction equation

HRID 1436887 reaction equation
[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]

Participants

5

Reactant 3

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

Product 1

HCID 54693458HCID 54693458, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-e4f54d7f7d7b4d8a821990e1934b316e
Source dataset
uspto-grants-2009_11
Patent number
US07619086B2

Reaction notes

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