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

HRID 2386283Notes

Reaction equation

HRID 2386283 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.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:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]5([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 44119149N-Cyclopropyl-N'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaHCID 781653442-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

Product 1

HCID 581698151-Cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaYield 44.4%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (260 mg, 0.782 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (402 mg, 1.33 mmol), saturated aqueous NaHCO3 (2 ml) and PdCl2(dppf) (51.1 mg, 0.063 mmol) in 1,4-dioxane (5 ml) was irradiated in the microwave at 110° C. for 30 minutes The reaction mixture was diluted with THF and passed through 0.45 μM PTFE syringe filter (washed with small amount of THF). The filtrate was purified by preparative HPLC (eluting with a gradient of 20-45% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). The fractions containing the desired product were combined and were evaporated under reduced pressure. Then NaHCO3 aqueous solution was added (in order to adjust the pH to basic) and extracted with EtOAc (THF was added to dissolve the precipitate). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (164 mg, 0.347 mmol, 44% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.45 (m, 2H) 0.58-0.71 (m, 2H) 1.36 (s, 3H) 1.70 (t, J=19.20 Hz, 3H) 2.50-2.61 (m, 1H) 3.19-3.31 (m, 1H) 3.53-3.73 (m, 2H) 3.94-4.11 (m, 2H) 4.12-4.25 (m, 1H) 4.34-4.52 (m, 1H) 4.52-4.70 (m, 1H) 6.46 (d, J=2.53 Hz, 1H) 7.45-7.55 (m, 2H) 8.14-8.23 (m, 2H) 8.39 (s, 1H) 8.54 (s, 1H). MS [M+H] found 473.

Workup

  1. customwas irradiated in the microwave at 110° C. for 30 minutes The reaction mixture
  2. custompassed through 0.45 μM PTFE syringe
  3. filtrationfilter
  4. wash(washed with small amount of THF)
  5. customThe filtrate was purified by preparative HPLC (
  6. washeluting with a gradient of 20-45% ACN (containing 0.035% TFA) in water (containing 0.05% TFA)
  7. additionThe fractions containing the desired product
  8. customwere evaporated under reduced pressure
  9. additionThen NaHCO3 aqueous solution was added (in order
  10. extractionextracted with EtOAc (THF
  11. additionwas added
  12. dissolutionto dissolve the precipitate)
  13. dry with materialThe combined organic phases were dried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-411978c3697e44778316ac894b4eed52
Source dataset
uspto-grants-2012_09
Patent number
US08268819B2

Reaction notes

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