Cesium carbonate → Tert-butyl 6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

HRID 1431088Notes

Reaction equation

HRID 1431088 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:21][C:10]3([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[C:27]([Cl:29])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+].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].O1CCOCC1>[C:17]([O:16][C:14]([N:12]1[CH2:13][C:10]2([CH2:9][N:8]([C:5]3[CH:6]=[N:7][C:2]([NH:1][C:23]4[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[C:27]([Cl:29])[CH:28]=4)=[CH:3][CH:4]=3)[CH2:21]2)[CH2:11]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-oneHCID 66743230Tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Product 1

HCID 66742401Tert-butyl 6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylateYield 25%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 24436Sodium SulfateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a 250 mL round-bottomed flask, tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (870 mg, 3.00 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (670 mg, 3.00 mmol), xantphos (260 mg, 449 μmol), Cs2CO3 (2.93 g, 8.99 mmol) and Pd2(dba)3 (137 mg, 150 μmol) were combined with dioxane (25.0 ml) to give a dark brown solution. The reaction mixture was heated to 100° C. under argon and stirred for 20 h. The reaction was cooled to 25° C., diluted with DCM, and Na2SO4 was added. The mixture was filtered over celite, the filter cake was washed with DCM and the filtrate was conc. in vacuo to a dark brown semisolid. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 5% MeOH in DCM). The impure material was repurified by flash chromatography (silica gel, 220 g, 0% to 4% MeOH in DCM) to afford 0.320 g (25%) of the title compound as a light yellow powder. (M+H)+=433/435 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.12 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 6.82 (d, J=1.5 Hz, 2H), 4.12 (s, 4H), 4.01 (s, 3H), 3.80 (s, 4H), 1.45 (s, 9H).

Workup

  1. customto give a dark brown solution
  2. temperatureThe reaction was cooled to 25° C.
  3. additionwas added
  4. filtrationThe mixture was filtered over celite
  5. washthe filter cake was washed with DCM
  6. customThe crude material was purified by flash chromatography (silica gel, 220 g, 0% to 5% MeOH in DCM)
  7. customThe impure material was repurified by flash chromatography (silica gel, 220 g, 0% to 4% MeOH in DCM)

Sources & evidence

ORD record
ord-00a1ea50b0da431ea135037311daa0fa
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

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