Ethyl isocyanate → N-[4-(4-Ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamide

HRID 1641273Notes

Reaction equation

HRID 1641273 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([NH:22][NH2:23])=O)=[CH:10][CH:9]=1)=[O:6].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([N:36]1[C:37](=[O:38])[NH:23][N:22]=[C:20]1[CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:26]=[C:2]([F:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:35]

Participants

4

Reactant 2

HCID 8022Ethyl isocyanateHCID 595531273-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methylpiperidin-1-yl)-benzamide

Product 1

HCID 59553115N-[4-(4-Ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamideYield 87.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methyl-piperidin-1-yl)-benzamide (0.35 g, 0.77 mmol) in tetrahydrofuran (10 ml) is added ethylisocyanate (60 mg, 1.1 eq). The mixture is stirred at room temperature for 15 hours before being evaporated to dryness to give the urea intermediate as a solid (0.34 g). MS: 522 (M+1). Urea intermediate (0.1 g, 0.19 mmol) in 5% NaOH (2 ml) is heated at 100° C. for five hours. The mixture is then extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate then ethyl acetate containing a few drops of ammonium hydroxide to give N-[4-(4-ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamide as a white solid (21 mg). Mp: 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.27 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.57-6.95 (m, 7H), 5.27 (s, 2H), 3.78 (m, 4H), 2.77 (t, J=11.4 Hz, 2H) 1.68 (m, 3H), 1.20 (brs, 6H), 0.95 (brs, 3H). MS: 504 (M+1).

Workup

  1. custombefore being evaporated to dryness

Sources & evidence

ORD record
ord-6b25c194285c481986a52dcfd1da3f69
Source dataset
uspto-grants-2012_02
Patent number
US08114873B2

Reaction notes

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