Lithium Hexamethyldisilazide → 5-(Tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

HRID 1436879노트

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HRID 1436879 반응식
C(O[C:4](=[O:17])[C:5]([N:7]([CH3:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])C.[F:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:12]([O:11][C:9]([CH:8]1[N:7]([CH3:16])[C:5](=[O:6])[C:4]([OH:17])=[C:26]2[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:32][CH:31]=1)[C:25]2=[O:30])=[O:10])([CH3:13])([CH3:14])[CH3:15]

참가 물질

5

반응물 3

HCID 2733832Lithium HexamethyldisilazideHCID 690647451-(4-Fluorobenzyl)-5,6-dihydropyridin-2-(1H)-oneHCID 86071508Tert-butyl n-[ethoxy(oxo)acetyl]-n-methylglycinate

생성물 1

HCID 547137575-(Tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
-78 °C

실험 절차

To a cooled (−78° C.) solution of tert-butyl N-[ethoxy(oxo)acetyl]-N-methylglycinate (1.43 g, 5.85 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one from Step 3 of Example 1 (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. After heating for 24 hours, the reaction mixture was quenched with cold diluted HCl, then diluted with methanol, and concentrated 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 diastereomers. The appropriate fractions were collected for the first-eluting diastereomer, diastereomer 1, and this material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA). For the second eluting diastereomer, diastereomer 2, the appropriate fractions were collected and the material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 10%-60% methanol (0.1% TFA) in H2O (0.1% TFA). Diastercomer 1, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 6.84 (m, 2H), 6.62 (t, J=8.7 Hz, 2H), 4.31 (d, J=14.7 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.43 (d, J=6.5 Hz, 1H), 2.91 (m, 2H), 2.69 (m, 1H), 2.57 (s, 3H), 1.42 (m, 1H), 1.21 (m, 1H), 1.15 (s, 9H) ppm. ES MS M+1=405. Diastereomer 2, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.07 (s, 1H), 7.22 (m, 2H), 7.02 (t, J=8.7 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 3.82 (d, J=6.5 Hz, 1H), 3.33 (m, 1H), 2.99 (s, 3H), 2.02 (m, 3H), 1.68 (m, 1H), 1.44 (s, 9H) ppm. ES MS M+1=405.

후처리

  1. temperaturewarmed to room temperature for 2.5 hours
  2. temperatureheated to 40° C
  3. temperatureAfter heating for 24 hours
  4. customthe reaction mixture was quenched with cold diluted HCl
  5. additiondiluted with methanol
  6. concentrationconcentrated under vacuum
  7. customThe residual material was purified
  8. washeluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA)

출처 및 근거

ORD 기록
ord-16057958e5e2439d8138424d8cab8f12
출처 데이터셋
uspto-grants-2009_11
특허 번호
US07619086B2

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