Sodium Iodide → HCID 89500423, compound

HRID 2178544Notes

Reaction equation

HRID 2178544 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][O:17]C)[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[N:6][CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][CH:16]=[O:17])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 5238Sodium IodideHCID 6397ChlorotrimethylsilaneHCID 123831875HCID 123831875, compound

Product 1

HCID 89500423HCID 89500423, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 1-[5-fluoro-3-(2-methoxyvinyl)pyridin-2-yl]piperidin-2-one a19-2 (620 mg, 2.477 mmol, 1 eq) in acetonitrile (25 ml) is added at 0° C. sodium iodide (557 mg, 3.716 mmol, 1.5 eq) and trimethylsilyl chloride (404 mg, 3.716 mmol, 1.5 eq), and the reaction mixture is stirred at room temperature for 16 hours to form in situ [5-fluoro-2-(2-oxopiperidin-1-yl)pyridin-3-yl]acetaldehyde a19-3. In parallel, 2-(pyrrolidin-3-yl)pyridine enantiomer 2 dihydrochloride a1-67 (654 mg, 2.973 mmol, 1.2 eq) is dissolved in acetonitrile, loaded on a carbonate resin, the resin washed with dichloromethane and the pooled filtrates are evaporated to dryness to afford 2-(pyrrolidin-3-yl)pyridine enantiomer 2 as a free base. The residue obtained is added to intermediate a19-3. NaBH(OAc)3 (1050 mg, 4.954 mmol, 2 eq) is added, the reaction mixture is stirred overnight and is still incomplete. Racemic 2-(pyrrolidin-3-yl)pyridine (0.4 eq) is added, the reaction mixture heated overnight at 90° C. and evaporated to dryness. The residue of evaporation is retaken in dichloromethane. This organis phase is washed with saturated aqueous NaHCO3 (2 times), dried over MgSO4, filtered and evaporated to dryness. The residue obtained is dissolved in acetonitrile (12 ml), HCl 5M (approximately 4 ml) is added and the mixture is stirred at 40° C. for 3 hours. Dichloromethane is then added, and the organic phase washed with saturated aqueous NaHCO3 (2 times), dried over MgSO4, filtered and evaporated to dryness. This residue is purified by flash chromatography over silicagel (12 g; gradient: from CH2Cl2/MeOH 100/0 to 94/6), then by reverse phase chromatography (basic conditions: gradient: acetonitrile/H2O/NH4OH from 20/80/0.1 to 50/50/0.1) to afford 38 mg of 1-(5-fluoro-3-{2-[3-(pyridin-2-yl)pyrrolidin-1-yl]ethyl}pyridin-2-yl)piperidin-2-one 112 as a 80/20 mixture of enantiomers.

Sources & evidence

ORD record
ord-cefb92ba13414183b76f51bab9f9b54d
Source dataset
uspto-grants-2015_06
Patent number
US09067930B2

Reaction notes

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