Vinyl ether → (E)-8-cyclopentyl-6-(2-hydroxyvinyl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

HRID 641638Notes

Reaction equation

HRID 641638 reaction equation
Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH:21]([O:23]CCCC)=[CH2:22].C1(N(C)C2CCCCC2)CCCCC1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl-].[Li+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC=C)=C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2](/[CH:22]=[CH:21]/[OH:23])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

10

Reactant 7

HCID 8024Vinyl etherHCID 8108Butyl vinyl etherHCID 24210N-Methyl dicyclohexylamineHCID 433294Lithium ChlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 592588576-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one

Product 1

HCID 59258935(E)-8-cyclopentyl-6-(2-hydroxyvinyl)-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (336 mg, 1.0 mmole), 1-(vinyloxy)butane (501 mg, 5.0 mmole), N-cyclohexyl-N-methylcyclohexanamine (254 mg, 1.3 mmole), tri-tert-butylphosphonium tetrafluoroborate (8.70 mg, 0.03 mmole), lithium chloride (127 mg, 3.0 mmole), tris(dibenzylideneacetone)dipalladium(0)) (27.5 mg, 0.03 mmole) and 1,4-dioxane (10 ml) were added to a reaction vial equipped with a stir bar. The reaction vial was flushed with nitrogen, capped, and heated at 75° C. for 75 min. LCMS data indicated that both the intermediate vinyl ether and the product were obtained (4:6). The reaction mixture was cooled to ambient temperature, filtered through Celite and washed with dioxane (10 ml). The filtrate and washing were combined, and para-toluene sulfonic acid monohydrate (761 mg, 4.0 mmole) was added. The reaction was stirred at ambient temperature for 1 h. At this point LCMS data indicated that all of the intermediate vinyl ether hydrolyzed to the desired product. The solvent was removed under reduced pressure to a residue, and ethyl acetate (120 ml) was added, and washed with aqueous potassium carbonate solution (5 wt/v %), water, and brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to a yellow solid residue, which was crystallized from boiling heptane. Upon cooling to ambient temperature, yellow crystals formed and collected by filtration to give the title compound (190 mg, 62% yield) after two steps.

Workup

  1. customvial equipped with a stir bar
  2. customThe reaction
  3. customvial was flushed with nitrogen
  4. customcapped
  5. customthe product were obtained (4:6)
  6. temperatureThe reaction mixture was cooled to ambient temperature
  7. filtrationfiltered through Celite
  8. washwashed with dioxane (10 ml)
  9. washThe filtrate and washing

Sources & evidence

ORD record
ord-d578d07db16e476b902fbd2ecb67cc78
Source dataset
uspto-grants-2010_04
Patent number
US07696213B2

Reaction notes

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