Diisopropylethylamine → tert-Butyl (3R,4R)-4-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate

HRID 711581

반응식

HRID 711581 반응식
[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@@H:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1

참가 물질

5

반응물 3

HCID 81531DiisopropylethylamineHCID 583175754,6-dichloro-2-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-1H,2H,3H-pyrrolo[3,4-c]pyridin-3-oneHCID 68077633tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate

생성물 1

HCID 86654746tert-Butyl (3R,4R)-4-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate수율 11%

시약·촉매·용매 1

HCID 6342Acetonitrile용매

반응 조건

온도
85 °C

실험 절차

A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (320 mg, 0.862 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (280 mg, 1.293 mmol) and DIPEA (0.226 mL, 1.293 mmol) in ACN (5 mL) was stirred at 85° C. overnight. UPLC indicated the presence of starting material, so the mixture was stirred at 85° C. overnight. UPLC showed about 50% conversion. Additional stirring at 85° C. for 3 d and at 100° C. overnight did not appreciably increase the conversion, so the reaction was stopped and the solvent was removed. The resulting crude material was reconstituted in MeOH/DMF (10 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (50%, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (51 mg, 11%). [M+H] calc'd for C26H32ClFN4O6, 552. found, 552.

후처리

  1. stirringso the mixture was stirred at 85° C. overnight
  2. stirringAdditional stirring at 85° C. for 3 d and at 100° C. overnight
  3. temperaturedid not appreciably increase the conversion
  4. customthe solvent was removed
  5. custompurified via preparative HPLC
  6. washeluting with water (0.05% TFA) and ACN (50%, 0.035% TFA)
  7. customthe ACN was removed via rotary evaporation
  8. washwashed with EtOAc (2×200 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. customThe organic phase was stripped to dryness via rotary evaporation

출처 및 근거

ORD 기록
ord-bf2d7dcc83d6440d99a475f68e27c4d5
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09181255B2

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