Tetrahydro-4H-pyran-4-one → (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol

HRID 2063364Notes

Reaction equation

HRID 2063364 reaction equation
[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30]3([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1

Participants

5

Reactant 3

HCID 121599Tetrahydro-4H-pyran-4-oneHCID 2724682Lithium diisopropylamideHCID 58222544(S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine

Product 1

HCID 58222532(S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-olYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (100.0 mg, 0.374 mmol) in anhydrous THF (4.0 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq.), and the reaction mixture was stirred at −78° C. After stirring for 2 h tetrahydro-4H-pyran-4-one (68.6 μL, 0.75 mmol, 2.0 eq.) was added. The reaction was then stirred at RT for 16 h and quenched with saturated aqueous sodium ammonium chloride solution. Volatile solvent was evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane). Crystallization from ether-hexane afforded the product (b-1) as a solid (111.3 mg, 81.0%). 1H NMR (CDCl3, 400 MHz). δ ppm 5.3 (broad s, 1H), 4.98 (broad s, 1H), 4.00 (dd, J=3.4 Hz, 1H), 3.97 to 3.79 (m, 7H), 3.79 to 3.71 (m, 2H), 3.60 (td, J=11.6, 2.7 Hz, 1H), 3.45 (broad s, 1H), 2.39 (m, 2H), 1.86 (d, J=13.2 Hz, 2H), 1.38 (d, J=6.8 Hz, 3H); LC-MS m/z (method A)=368/370 [M+H]+, RT=1.93 min.

Workup

  1. additionwas added
  2. stirringThe reaction was then stirred at RT for 16 h
  3. customquenched with saturated aqueous sodium ammonium chloride solution
  4. customVolatile solvent was evaporated in vacuo
  5. additionthe crude was diluted with ethyl acetate
  6. washThe organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane)
  11. customCrystallization from ether-hexane

Sources & evidence

ORD record
ord-32a75d974ede4de0b377d05990ee604e
Source dataset
uspto-grants-2012_10
Patent number
US08288381B2

Reaction notes

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