Sodium Bicarbonate → 1-isopropyl-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide

HRID 85426ノート

反応式

HRID 85426 の反応式
Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:37]3[CH:42]=[N:41][C:40]([N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:13])[CH3:12]

参加物

6

反応物 3

HCID 516892Sodium BicarbonateHCID 162179462-(Piperazin-1-yl)pyridine-5-boronic acid, pinacol esterHCID 545966296-bromo-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide

生成物 1

HCID 545966251-isopropyl-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide

試薬・触媒・溶媒 2

HCID 178418807HCID 178418807、化合物触媒HCID 218864351,4-Dioxane--water (1/1)溶媒

反応条件

温度
100 °C

実験手順

In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (90 mg, 0.2 mmol), {1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (88 mg, 0.3 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (4.95 mg, 0.006 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (50.9 mg, 0.61 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. Upon cooling down, any solids that crashed out were filtered. DCM/MeOH (1:1) was added, the contents pre-absorbed on silica gel, and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was then further purified by reverse-phase HPLC (15% to 80% CH3CN in water with 0.1% TFA), which afforded the product as a TFA salt. CH3CN was evaporated and a saturated solution of sodium bicarbonate was added to the water layer followed by DCM/isopropanol (70:30). The organic layer was separated, and the aqueous layer was further extracted with DCM/isopropanol (70:30). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. DMF was added along with some water, and after sitting overnight, the solids that precipitated were filtered. EtOAc was added along with some hexanes, the contents sonicated, and the solids that precipitated were filtered and dried to afford the title compound as an off-white solid (29.5 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.59-8.68 (m, 2H) 8.35 (s, 1H) 8.00-8.12 (m, 2H) 7.83 (s, 1H) 6.92 (d, J=8.84 Hz, 1H) 6.03 (s, 1H) 5.13 (quin, J=6.63 Hz, 1H) 4.47 (br. s., 1H) 4.46 (br. s., 1H) 3.42-3.56 (m, 4H) 3.20-3.27 (m, 1H) 2.76-2.85 (m, 4H) 2.16 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H). LC-MS (ES) m/z=528.1 [M+H]+

後処理

  1. customIn a 25 mL sealable tube under nitrogen were combined
  2. customthe resulting mixture was degassed with nitrogen for 10 min
  3. customthe vessel was sealed
  4. temperatureUpon cooling down
  5. filtrationany solids that crashed out were filtered
  6. additionDCM/MeOH (1:1) was added
  7. customthe contents pre-absorbed on silica gel
  8. custompurified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH)
  9. customThe collected product was then further purified by reverse-phase HPLC (15% to 80% CH3CN in water with 0.1% TFA), which

出典と根拠

ORDレコード
ord-ca92bf1a3a444262b1ce91ccaac8c2dd
出典データセット
uspto-grants-2014_09
特許番号
US08846935B2

反応ノート

読み込み中…