5,8-Dichloropyrido[2,3-d]pyridazine → (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone

HRID 1514397Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1514397
[Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:15]1>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:15][C@H:14]2[CH3:13])=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12

Komponenten

4

Edukt 2

HCID 2799155,8-Dichloropyrido[2,3-d]pyridazineHCID 7578227(R)-1-Benzoyl-3-methylpiperazine

Produkt 1

HCID 57657595(R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanoneAusbeute 44 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a reaction vial was added 5,8-dichloropyrido[2,3-d]pyridazine 78 (165 mg, 825 μmol) and (R)-(3-methylpiperazin-1-yl)(phenyl)methanone (337 mg, 1.65 mmol). The mixture was heated to 100° C. for 2 h. After cooling to room temperature, the resultant glassy product was dissolved in dichloromethane (40 mL) and washed with 1×5 mL NaHCO3 and 1×5 mL of brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel column chromatography using a gradient of 70% ethyl acetate in hexanes to 90% EtOAc in hexanes afforded the regioisomeric products. The first eluting product (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (132 mg, 44% yield) was the major product, the second eluting product (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (74 mg, 24% yield) was the minor product. Data for 79: 1H-NMR (400 MHz, CDCl3): δ 9.10 (brs, 1H), 8.47 (dd, J=8.2, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 5.46 (br m, 1H), 4.97-4.40 (series of m, 2H), 3.99-3.20 (series of m, 4H), 1.40 (br m, 3H). MS 367.1 (calc'd) 368.0 (M+H, found). Data for (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone: 1H-NMR (400 MHz, CDCl3): δ 9.27 (dd, J=4.3, 1.6, 1H), 8.39 (J=8.6, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 7.45 (s, 5H), 4.31 (br s, 1H), 4.11 (br s, 1H), 2.68 (m, 5H), 1.27 (br s, 3H). MS 367.1 (calc'd) 368.0 (M+H, found).

Aufarbeitung

  1. temperatureAfter cooling to room temperature
  2. washwashed with 1×5 mL NaHCO3 and 1×5 mL of brine
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by silica gel column chromatography
  7. customafforded the regioisomeric products

Quellen und Nachweise

ORD-Eintrag
ord-44b01532e130439fb79140173460168f
Quelldatensatz
uspto-grants-2012_07
Patentnummer
US08222251B2

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