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 1676370ノート

反応式

HRID 1676370 の反応式
[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

参加物

5

反応物 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

生成物 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-carboxamide収率 15.4%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-36439a5898674d68ab0317ff67557fe2
出典データセット
uspto-grants-2011_08
特許番号
US08003662B2

反応ノート

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