Hydrochloric Acid → 5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-yloxy)-phenyl]-amide

HRID 595145Notes

Reaction equation

HRID 595145 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:17])[C:10]([C:14]([OH:16])=O)=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:35][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C:52]1[CH:78]=[CH:77][C:55]([O:56][C:57]2[C:58]3[CH:59]=[C:60]4[O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][C:61]4=[CH:62][C:63]=3[N:64]=[CH:65][N:66]=2)=[C:54](C)[CH:53]=1.Cl>CN(C=O)C>[F:35][C:54]1[CH:53]=[C:52]([NH:51][C:14]([C:10]2[C:9](=[O:17])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][NH:12][CH:11]=2)=[O:16])[CH:78]=[CH:77][C:55]=1[O:56][C:57]1[C:58]2[CH:59]=[C:60]3[O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][C:61]3=[CH:62][C:63]=2[N:64]=[CH:65][N:66]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 602042075-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acidHCID 866848304-(4-Amino-2-Methyl-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalene

Product 1

HCID 566437095-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-yloxy)-phenyl]-amideYield 40%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a suspension of 5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8 d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) in anhydrous DMF (56 ml) were added HATU (15.65 g, 41.2 mmol) and i-Pr2NEt (18 mL, 104 mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5 min. To the solution was added 4-(4-Amino-2-Fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene 7a (7.9 g, 32.5 mmol) slowly. The reaction mixture was stirred for 3 h at room temperature and was poured into aqueous 1N HCl solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2Cl2 to obtain 9a as a light-yellow solid (5.9 g, 40%), mp 188-190° C. HPLC purity 97%; 1HNMR (400 MHz, DMSO) δ 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 6.89 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+616.6. found 616.5.

Workup

  1. stirringThe reaction mixture was stirred for 3 h at room temperature
  2. customThe solid that formed
  3. filtrationwas filtered
  4. washwashed with distilled water
  5. customdried
  6. customThe crude product was purified by silica gel chromatography
  7. washeluting with 1-5% of MeOH in CH2Cl2

Sources & evidence

ORD record
ord-cf03c6c4ea8e48f48350018d8cc1d5f6
Source dataset
uspto-grants-2016_01
Patent number
US09242991B2

Reaction notes

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