Sodium Bicarbonate → 1-(2-((3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride

HRID 1510780Notes

Reaction equation

HRID 1510780 reaction equation
[ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][C@H:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C[O-].[Na+].CO.[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[N:27][CH:26]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([CH2:36][CH2:35][N:32]4[C:33]5[C:28](=[N:27][CH:26]=[C:25]([F:24])[CH:34]=5)[CH:29]=[CH:30][C:31]4=[O:38])[CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1

Participants

9

Reactant 5

HCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 23694274Sodium methanolate methanolHCID 578152751,5-Naphthyridine-1(2H)-acetaldehyde, 7-fluoro-2-oxo-HCID 68932414(3S)-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)pyrrolidin-3-amine hydrochloride

Product 1

HCID 689295701-(2-((3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochlorideYield 39.8%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 62 mg of (3S)—N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)pyrrolidin-3-amine hydrochloride in 3 mL of methanol, 0.10 g of a 28% sodium methoxide/methanol solution, 37 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 60 μL of acetic acid, 0.12 g of molecular sieves 3A and 11 mg of sodium cyanoborohydride were added at room temperature, and the mixture was stirred at the same temperature for 1 hour 10 minutes. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=30:1, thereto were added ethyl acetate and a 4 mol/L hydrogen chloride/ethyl acetate solution, and the solid was filtered off to obtain 33 mg of 1-(2-((3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride as a yellow solid.

Workup

  1. customthe organic layer was separated
  2. extractionthe aqueous layer was extracted with ethyl acetate
  3. washthe resultant solution was washed with a saturated aqueous sodium chloride solution
  4. dry with materialdried over anhydrous magnesium sulfate
  5. distillationthe solvent was distilled off under reduced pressure
  6. customThe resultant residue was purified by basic silica gel column chromatography
  7. additionmethanol=30:1, thereto were added ethyl acetate
  8. filtrationa 4 mol/L hydrogen chloride/ethyl acetate solution, and the solid was filtered off

Sources & evidence

ORD record
ord-1257142c72434ef892c1a6d38e271f25
Source dataset
uspto-grants-2012_07
Patent number
US08211908B2

Reaction notes

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