Acetone → N-(3-Fluoro-4-(2-(1-isopropylpiperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676370노트

반응식

HRID 1676370 반응식
[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:41][C:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH:42]([CH3:43])[CH3:41])[CH2:22][CH2:23]3)[S:17][C:10]=12

참가 물질

5

반응물 3

HCID 180AcetoneHCID 5049666Sodium triacetoxyborohydrideHCID 58949489N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

생성물 1

HCID 58949541N-(3-Fluoro-4-(2-(1-isopropylpiperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide수율 15.4%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 35.0 mg, 0.0625 mmol), propan-2-one (36.3 mg, 0.625 mmol), NaBH(OAc)3 (66.3 mg, 0.313 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified by preparative reverse phase HPLC to afford product (5.8 mg, 15.4%). LRMS (APCI pos): >99% purity, 254 nm, m/e 602 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.52 (d, 1H), 8.39 (d, 1H), 8.26 (d, 1H), 8.05 (m, 1H), 7.69 (m, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.34-7.46 (m, 3H), 6.70 (d, 1H), 3.12-3.41 (m, 6H), 2.33 (m, 2H), 1.97 (m, 2H), 1.28 (d, 6H).

후처리

  1. customhad been consumed (overnight)
  2. customThen the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×100 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a crude product
  9. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1
  10. customv/v) to afford crude product
  11. customThe crude product was further purified by preparative reverse phase HPLC

출처 및 근거

ORD 기록
ord-36439a5898674d68ab0317ff67557fe2
출처 데이터셋
uspto-grants-2011_08
특허 번호
US08003662B2

반응 노트

불러오는 중…