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 1476391Notes

Reaction equation

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]

Participants

Conditions

Temperature: 100 °C

Procedure

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]+

Workup

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

Sources & evidence

ORD record: ord-f5a6f83e72f84dcfa48eab1808c963f9
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09018382B2

Reaction notes

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