5-Chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde → 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one

HRID 1881734Notes

Reaction equation

HRID 1881734 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][C@H:3]1[OH:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]>ClCCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:4][C@H:3]2[OH:22])[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]

Participants

5

Reactant 2

HCID 580017855-Chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde2×HCID 585793871-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one

Product 1

HCID 468463881-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 31 as a free base: 60 mg, 0.196 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 33.6 mg, 0.196 mmol) in DCE (5 ml) and Methanol (0.5 ml) was stirred at rt for 5 h. LCMS showed desired compound Rt 2.16 [M+H]+ 460 and not starting material, sodium triacetoxy borohydride (125 mg, 0.588 mmol) was added. The mixture was stirred under nitrogen at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (62.3 mg, 0.294 mmol) was added. The mixture was stirred at room temperature for 3 h. Full conversion to the amine was observed by LCMS desired compound Rt 2.02 [M+H]+ 462. It was quenched with saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), filtered, and concentrated affording 78.5 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (35 mg, 0.072 mmol, 36.8% yield) as a white solid.

Sources & evidence

ORD record
ord-2595a53fabcb443194d59309489812bf
Source dataset
uspto-grants-2012_11
Patent number
US08318940B2

Reaction notes

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