1,4-Dioxane → HCID 178465306, compound

HRID 447253Notes

Reaction equation

HRID 447253 reaction equation
[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)=[C:4]([F:19])[C:3]=1[CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1.O1CCOCC1.[CH2:31]([NH:33][C:34]([NH:36][C:37](SC)=NC(=O)NCC)=[O:35])[CH3:32].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:31]([NH:33][C:34]([NH:36][C:37]1[NH:1][C:2]2[C:3]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[C:4]([F:19])[C:5]([C:9]3[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:13][CH:14]=3)=[CH:6][C:7]=2[N:8]=1)=[O:35])[CH3:32]

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 734081491-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)ureaHCID 866679372-(5-(4,5-Diamino-2-fluoro-3-(tetrahydrofuran-2-yl)phenyl)pyrimidin-2-yl)propan-2-ol

Product 1

HCID 178465306HCID 178465306, compoundYield 94%

Reagents, catalysts & solvents 1

HCID 1118Sulfuric AcidSolvent

Procedure

To a stirring suspension of 2-[5-(4,5-diamino-2-fluoro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (21) (111.3 g, 334.9 mmol) and 1,4-dioxane (556.5 mL, Sigma-Aldrich 360481) was added 1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (93.36 g, 401.9 mmol, CB Research and Development) followed by a pH 3.5 buffer (1.113 L), prepared by dissolving NaOAc trihydrate (158.1 g) in 1N aqueous H2SO4 (1.100 L). The reaction mixture was stirred at reflux overnight (HPLC showed complete conversion), cooled to room temperature, and poured portion-wise (frothing) into a stirring solution of aqueous saturated NaHCO3 (2.23 L) giving pH 8-9. This was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving 22 as an off-white yellowish solid (135.2 g, 94% yield; 99% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 429.58 (2.03 min). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.

Workup

  1. customprepared
  2. temperatureat reflux overnight (HPLC showed complete conversion)
  3. customgiving pH 8-9
  4. stirringThis was stirred for 30 minutes
  5. filtrationthe solid was collected by filtration
  6. washwashed copiously with water to neutral pH
  7. customThe solid was dried under reduced pressure

Sources & evidence

ORD record
ord-5bacee368f7a40ea8c2a49eea3be0ef4
Source dataset
uspto-grants-2013_07
Patent number
US08481551B2

Reaction notes

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