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

HRID 1514397Notes

Reaction equation

HRID 1514397 reaction equation
[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

Participants

4

Reactant 2

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-44b01532e130439fb79140173460168f
Source dataset
uspto-grants-2012_07
Patent number
US08222251B2

Reaction notes

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