1,4-Dioxane → 1-methyl-3-(4-(6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

HRID 2386221Notes

Reaction equation

HRID 2386221 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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]>[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=4)[C:7](=[O:19])[C:6]4([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]4[C:4]=3[N:3]=2)=[CH:32][CH:31]=1)=[O:28]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 177502733-Methyl-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureaHCID 86651564HCID 86651564, compound

Product 1

HCID 513520701-methyl-3-(4-(6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaYield 23%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (118 mg), PdCl2(dppf) (43.6 mg), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (124 mg, 0.447 mmol), saturated sodium bicarbonate solution (1.5 mL), and 1,4-dioxane (3 mL) was heated by microwave irradiation at 100° C. for 45 minutes. The reaction mixture was diluted with 2 mL of methanol, filtered then purified by mass-triggered preparative HPLC eluted with 20-30% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column to give the title compound (36 mg) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.72 (s, 3H) 2.80 (s, 3H) 3.57 (m, 1H) 3.70 (m, 1H) 3.85 (s, 3 H) 3.89 (d, J=12 Hz, 1H) 4.15 (dd, J=12, 4 Hz, 1H) 4.19 (d, J=12 Hz, 1H) 4.71 (m, 1H) 4.95 (d, J=12 Hz, 1H) 5.30 (d, J=12 Hz, 1H) 6.24 (d, J=4 Hz, 1H) 7.55 (d, J=4 Hz, 1H) 7.63 (d, J=8 Hz, 2H) 8.07 (d, J=8 Hz, 2H) 8.12 (s, 1H). MS [M+H] Found 463.

Workup

  1. filtrationfiltered
  2. customthen purified by mass-triggered preparative HPLC
  3. washeluted with 20-30% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column

Sources & evidence

ORD record
ord-85e31cbc9b4a42af9eb7cd26d57b563d
Source dataset
uspto-grants-2012_09
Patent number
US08268819B2

Reaction notes

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