Sodium Carbonate → (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

HRID 1755364Notes

Reaction equation

HRID 1755364 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37]C)=[O:36])O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([OH:37])=[O:36])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 27346513-Methoxycarbonylphenylboronic acid pinacol esterHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86682714(S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 71526081(S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acidYield 25.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.10 g, 0.30 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.096 g, 0.36 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.057 g, 0.122 mmol) and Na2CO3 (0.095 g, 0.912 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 30% acetonitrile/70% water (0.1% TFA V/V) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA V/V) in a linear fashion over 9 min) to afford (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (32 mg, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.97 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 8.13-8.11 (m, 1H), 7.71 (t, 1H, J=7.8 Hz), 7.51 (t, 1H, J=7.8 Hz), 6.69 (d, 1H, J=7.5 Hz), 6.16 (d, 1H, J=8.1 Hz), 4.22-4.17 (m, 1H), 3.63-3.54 (m, 1H), 3.44-3.39 (m, 1H), 2.06-1.95 (m, 3H), 1.67-1.61 (m, 1H), 1.07 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 415, tR=1.669 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.01 min.

Workup

  1. concentrationthen concentrated in vacuo
  2. customThe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10)
  3. customfurther purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm

Sources & evidence

ORD record
ord-c57f4fd96c204bf89c8e5b21fa6190a9
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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