Oxalyl chloride → 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide

HRID 1253633

Reaktionsgleichung

Reaktionsgleichung von HRID 1253633
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1.C(Cl)(=O)C(Cl)=O.[NH2:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:36][C:37]3[CH:41]=[CH:40][O:39][N:38]=3)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1

Komponenten

7

Edukt 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 18102163-IsoxazolamineHCID 468558533-(8-(2-Chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoic acid

Produkt 1

HCID 461839163-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a suspension of 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoic acid (100 mg, 0.25 mmol; prepared by the general method shown in scheme 2) in DCM at 0° C. was added oxalyl chloride (43.7 μl, 0.49 mmol) followed by a drop of DMF. The reaction was stirred at 0° C. for 15 min then warmed to RT for 1 h. The volatile solvents were removed under reduced pressure and the residue was dissolved in DCM. To the reaction mixture was added 3-aminoisoxazole (54.6 μl, 0.74 mmol) and N,N-diisopropylethylamine (42.9 μl, 0.25 mmol). After the reaction mixture was stirred at RT for 3 h, the solvent was then removed in vacuo. The residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water] and the fractions containing the product were combined and concentrated in vacuo. The remaining crude mixture was stirred with EtOAc and sat. Na2CO3. The organic layer was separated and washed with brine, separated, then dried with sodium sulfate and concentrated to give 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide (33.0 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (1H, s), 9.48 (1H, s), 8.81 (1H, s), 8.24 (1H, s), 7.95-8.10 (2H, m), 7.76-7.86 (1H, m), 7.56-7.74 (3H, m), 7.46 (1H, d, J=8.0 Hz), 7.05 (1H, s), 3.12 (3H, s), 2.24 (3H, s); Mass Found: LC-MS (ESI): m/e=472/474

Aufarbeitung

  1. customprepared by the general method
  2. customat 0° C.
  3. temperaturethen warmed to RT for 1 h
  4. customThe volatile solvents were removed under reduced pressure
  5. dissolutionthe residue was dissolved in DCM
  6. stirringAfter the reaction mixture was stirred at RT for 3 h
  7. customthe solvent was then removed in vacuo
  8. customThe residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water]
  9. additionthe fractions containing the product
  10. concentrationconcentrated in vacuo
  11. stirringThe remaining crude mixture was stirred with EtOAc and sat. Na2CO3
  12. customThe organic layer was separated
  13. washwashed with brine
  14. customseparated
  15. dry with materialdried with sodium sulfate
  16. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-20b768b1b01f4ab9a1c39efe082d21f6
Quelldatensatz
uspto-grants-2013_06
Patentnummer
US08455495B2

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