Methanol → HCID 89651324, compound

HRID 515944Notes

Reaction equation

HRID 515944 reaction equation
[F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]

Participants

6

Reactant 4

HCID 887MethanolHCID 66779574HCID 66779574, compound2×HCID 89650994HCID 89650994, compoundHCID 178418310HCID 178418310, compound2×

Product 1

HCID 89651324HCID 89651324, compoundYield 62.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent5×

Procedure

To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 539 μmol) prepared in Preparation 6 in THF (24 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (1.35 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (2.7 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.68 mL, 0.68 mmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (1.35 mL, 0.68 mmol) were added. The reaction mixture was then stirred at room temperature for 3 h. Methanol (6 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (0.2 g, 62%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 1 h
  2. stirringThe reaction mixture was then stirred at room temperature for 3 h
  3. customto quench
  4. customthe reaction
  5. customThe mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM)
  6. customdried in vacuo

Sources & evidence

ORD record
ord-89babe4f8c3e49c499debb5574780147
Source dataset
uspto-grants-2015_08
Patent number
US09108999B2

Reaction notes

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