Diethyl ((6-methoxypyridin-2-yl)methyl)phosphonate → (E)-tert-butyl 4-(2-(2-(6-methoxypyridin-2-yl)vinyl)-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoate

HRID 1772711노트

반응식

HRID 1772711 반응식
[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]P(=O)(OCC)OCC)[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH:23]([C:25]1[N:26]=[C:27]2[C:32]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:30]=[C:29]([C:39]3[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=3)[N:28]2[CH:52]=1)=O>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:23]/[C:25]2[N:26]=[C:27]3[C:32]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:31][CH:30]=[C:29]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[CH:41][CH:40]=4)[N:28]3[CH:52]=2)[CH:6]=[CH:5][CH:4]=1

참가 물질

5

반응물 3

HCID 86076821Diethyl ((6-methoxypyridin-2-yl)methyl)phosphonateHCID 117733763tert-Butyl 4-(2-formyl-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoateHCID 178418339Butyllithium

생성물 1

HCID 117728123(E)-tert-butyl 4-(2-(2-(6-methoxypyridin-2-yl)vinyl)-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoate

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

To a solution of diethyl ((6-methoxypyridin-2-yl)methyl)phosphonate (76.2 mg, 0.29 mmol, prepared according to literature procedure: J. Med. Chem. 2005, 48, 5884-5887), n-BuLi (0.184 mL, 0.29 mmol, 1.6 M in hexanes) was added dropwise. After stirring the resulting mixture for 15 min at rt, it was slowly added to a suspension of compound 67a (100 mg, 0.25 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 30 min and quenched with saturated NH4Cl (2 mL). The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give (E)-tert-butyl 4-(2-(2-(6-methoxypyridin-2-yl)vinyl)-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoate, which was subjected to TFA deprotection using the methods described in Example 57, Step A to yield the title compound 7 containing 0.1 eq. of TFA. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 8.11 (m, J=7.8 Hz, 2H), 7.83 (m, J=7.8 Hz, 2H), 7.63-7.69 (m, 1H), 7.69-7.75 (m, 1H), 7.49 (s, 1H), 7.40 (d, J=15.7 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 4.29 (br. s., 4H), 3.92 (s, 3H), 3.80 (br. s., 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H23N5O4: 458.2 [M+H]. found 458.4.

후처리

  1. stirringThe resulting mixture was stirred at rt for 30 min
  2. customquenched with saturated NH4Cl (2 mL)
  3. additionThe reaction mixture was treated with water (20 mL)
  4. extractionextracted with EtOAc (2×40 mL)
  5. washThe combined organic layers were washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue obtained
  10. customwas purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes)

출처 및 근거

ORD 기록
ord-3b441df2af3d4082844f7d51ea1c307f
출처 데이터셋
uspto-grants-2016_02
특허 번호
US09249163B2

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