1,4-Dioxane → HCID 68194840, compound

HRID 2169646Notes

Reaction equation

HRID 2169646 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)=[O:26].O1CCOCC1.C([O-])(O)=O.[Na+]>[Pd].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:7](=[O:18])[CH:6]4[CH2:19][O:20][CH2:21][CH2:22][N:5]4[C:4]=3[N:3]=2)=[CH:30][CH:29]=1)=[O:26]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 177502733-Methyl-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureaHCID 86651587HCID 86651587, compound

Product 1

HCID 68194840HCID 68194840, compoundYield 8.2%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a 5 mL microwave vial were added 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x55, 190 mg, 0.585 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (404 mg, 1.463 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (24.07 mg, 0.029 mmol). After the vial was sealed, dioxane (2 mL) and aqueous saturated NaHCO3 (0.500 mL) were added, and the mixture was degassed by bubbling nitrogen through a syringe needle for 10 minutes. The mixture was heated in a microwave to 120° C. for 60 minutes. Since the reaction was not complete, another 0.025 equivalents of palladium catalyst were added, and the mixture was heated in the microwave to 130° C. for another 60 minutes. DMF (1 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC using a gradient of 15-25% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave the title compound as a white powder (21 mg, 8.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.56-1.74 (m, 2H), 2.58-2.69 (m, 4H), 2.97 (td, J=12.8, 3.8 Hz, 1H), 3.41 (t, J=10.9 Hz, 1H), 3.47-3.63 (m, 3H), 3.88-4.05 (m, 3H), 4.14-4.24 (m, 2H), 4.39 (d, J=11.9 Hz, 2H), 6.05-6.15 (m, 1H), 7.45-7.55 (m, 2H), 8.15-8.23 (m, 2H), 8.46 (s, 1H), 8.75 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C22H26N6O4, 439.2; found 439.5.

Workup

  1. customAfter the vial was sealed
  2. customthe mixture was degassed
  3. customby bubbling nitrogen through a syringe needle for 10 minutes
  4. temperaturethe mixture was heated in the microwave to 130° C. for another 60 minutes
  5. filtrationthe mixture was filtered by syringe
  6. filtrationfilter
  7. customThe crude product was purified by preparatory HPLC

Sources & evidence

ORD record
ord-df31d74764c24c6083a993d6b5cb7f0f
Source dataset
uspto-grants-2015_06
Patent number
US09045496B2

Reaction notes

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