Triphenylphosphine → racemic 6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

HRID 219276Notes

Reaction equation

HRID 219276 reaction equation
[F:1][C:2]1[C:3]([NH:14][NH:15][C:16](=O)[CH:17]([N:19]2[CH:28]=[CH:27][C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]2=[O:29])[CH3:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si](N=[N+]=[N-])(C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[C:3]2[N:4]([C:16]([CH:17]([N:19]3[CH:28]=[CH:27][C:26]4[N:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]3=[O:29])[CH3:18])=[N:15][N:14]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 78378AzidotrimethylsilaneHCID 5462977Diethyl azodicarboxylateHCID 58015525N'-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide

Product 1

HCID 67503257racemic 6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-oneYield 57.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (400 mg, 982 μmol) and triphenylphosphine (386 mg, 1.4 mmol) were taken up in THF (9.8 mL). TMS-azide (195 μl, 1.4 mmol) was added, followed by slow addition of DEAD (233 μl, 1.4 mmol) and the reaction was stirred at room temperature for 1 hr until complete. The reaction was concentrated and purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH to yield racemic 6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (220 mg, 57% yield) as a tan solid. Separated by preperative SFC (ChiralPak® OJ-H, (20×150 mm, 5 □m), 20% MeOH, 80% CO2, 0.2% DEA; 100 bar system pressure; 70 mL/min; tr: 3.5 min) to yield (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (60 mg, 15% yield). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=390.2 [M+H], calc 389.14 for C20H16FN7O. 1H NMR (400 MHz, CHLOROFORM-d) □ ppm 2.16 (d, J=5.18 Hz, 3 H) 3.97 (s, 3 H) 6.82 (d, J=6.55 Hz, 1 H) 7.01-7.13 (m, 2 H) 7.41-7.49 (m, 1 H) 7.54 (d, J=6.26 Hz, 1 H) 7.61 (s, 1 H) 7.71 (s, 1 H) 8.33 (s, 1 H) 8.78 (d, J=7.73 Hz, 1 H) 8.93 (s, 1 H).

Workup

  1. concentrationThe reaction was concentrated
  2. custompurified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH

Sources & evidence

ORD record
ord-beddb93d14954864b8ddf71addcc8528
Source dataset
uspto-grants-2012_06
Patent number
US08198448B2

Reaction notes

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