Sodium Bicarbonate → 1-(4-(5-Isopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

HRID 1695991Notes

Reaction equation

HRID 1695991 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:24].C(=O)(O)[O-].[Na+]>O1CCOCC1.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]>[CH:12]([N:8]1[C:7](=[O:15])[C:6]2([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]2[C:4]2[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23]([NH:22][CH3:21])=[O:24])=[CH:31][CH:30]=3)[N:11]=[CH:10][C:9]1=2)([CH3:14])[CH3:13]

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 177502733-Methyl-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureaHCID 866515712-chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

Product 1

HCID 513520731-(4-(5-Isopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylureaYield 22.1%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-Chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (98 mg, 0.330 mmol) was mixed with PdCl2(dppf) (48.3 mg), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (100 mg, 0.363 mmol) and saturated sodium bicarbonate solution (2 mL, sat.) in 1,4-dioxane (4 mL). The suspension was heated by microwave irradiation at 100° C. for 30 minutes. The suspension was filtered, the solids washed with methanol then DMSO and the filtrate evaporated in vacuo. The resulting solid was purified by mass-triggered preparative HPLC eluted with 20-35% 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 (30 mg 22% yield) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.55 (m, 6 H) 1.62 (s, 3 H) 2.80 (s, 3 H) 3.50 (td, J=12, 4 Hz, 1 H) 3.68 (td, J=12, 4 Hz, 1 H) 3.79 (d, J=12 Hz, 1 H) 4.14 (m, 1 H) 4.62 (dd, J=12, 4 Hz, 1 H) 4.66 (m, 1H) 7.62 (d, J=8 Hz, 2 H) 8.10 (d, J=8 Hz, 2H) 8.13 (s, 1H). MS [M+H] Found 411.

Workup

  1. filtrationThe suspension was filtered
  2. washthe solids washed with methanol
  3. customDMSO and the filtrate evaporated in vacuo
  4. customThe resulting solid was purified by mass-triggered preparative HPLC
  5. washeluted with 20-35% 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-a1b2d3471bd846ff8dd3adb05c37d46c
Source dataset
uspto-grants-2012_04
Patent number
US08163755B2

Reaction notes

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