Methanol → HCID 89650224, compound

HRID 515948Notes

Reaction equation

HRID 515948 reaction equation
[Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]

Participants

6

Reactant 4

HCID 887MethanolHCID 66779574HCID 66779574, compoundHCID 89651551HCID 89651551, compoundHCID 178418310HCID 178418310, compound

Product 1

HCID 89650224HCID 89650224, compoundYield 53%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (50 mg, 0.14 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.35 mL, 0.35 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate prepared in Example 2 Step B (0.7 mL, 0.35 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give (S)-2-[[(2S,3S,4R,5R)-5-(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester as a white solid (50 mg, 52%).

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. stirringstirred for 2 h
  3. customto quench
  4. customthe reaction
  5. customThe mixture was purified by flash chromatography (5-10% MeOH in DCM)

Sources & evidence

ORD record
ord-2747381571bf49aa93b7a9c0922d4d17
Source dataset
uspto-grants-2015_08
Patent number
US09108999B2

Reaction notes

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