4-Methylmorpholine → 5-(3-(4-Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid

HRID 2280563Notes

Reaction equation

HRID 2280563 reaction equation
C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:28](O)=[O:29])=[N:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:33][CH3:34])[CH:14]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CO>[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:28]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[N:5][CH:6]=3)=[O:29])=[N:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:33][CH3:34])[CH:14]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 14798Sodium HydroxideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12457877Methyl 5-aminopyridine-2-carboxylateHCID 867295573-(4-Fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid

Product 1

HCID 783193955-(3-(4-Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acidYield 24.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A solution of the 5-aminopicolinic acid methyl ester (15.2 mg, 0.1 mmol), 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (34.57 mg, 0.11 mmol), N-methylmorpholine (21.99 μL, 0.2 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40° C. for 16 hours. 3M aqueous NaOH solution (0.50 mmol, 166.7 μL) and methanol (0.2 mL) was added and the reaction mixture was stirred at 40° C. for 1 hour. The mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient of 1-99% ACN in water and HCl as a modifier to yield 5-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid (32) (10.75 mg, 23%). ESI-MS m/z calc. 434.10, found 435.3 (M+1)+; Retention time: 1.33 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 13.12 (s br, 1H), 11.52 (s, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.45 (dd, J=8.6, 2.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.82 (ddd, J=24.3, 15.6, 6.7 Hz, 3H), 7.36 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.6, 2.8 Hz, 1H), 6.88 (ddd, J=8.5, 2.8 Hz, 1H), 3.70 (s, 3H) ppm.

Workup

  1. filtrationfiltered
  2. custompurification by reverse phase HPLC

Sources & evidence

ORD record
ord-c4e59a467d624e27a20d438430e56c1b
Source dataset
uspto-grants-2015_09
Patent number
US09139529B2

Reaction notes

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