Cesium carbonate → 4-(3,4-Dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

HRID 576102Notes

Reaction equation

HRID 576102 reaction equation
[NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]3[C:21](=[CH:22][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:25]=3)[C:20]([CH3:37])([CH3:36])[NH:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([C:5]4[N:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=4)=[CH:24][CH:25]=3)[C:20]([CH3:37])([CH3:36])[NH:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 216436-Amino-3-chloropyridazineHCID 667885324-(3,4-Dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Product 1

HCID 498052784-(3,4-Dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolineYield 60%

Reagents, catalysts & solvents 3

HCID 53485975CID 53485975CatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

3-amino-6-chloropyridazine (420 mg, 3.23 mmol) was added to a mixture of 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (700 mg, 1.68 mmol) which was prepared in Step D of Example 10, cesium carbonate (1.58 g, 4.85 mmol) in DMF (50 mL) and water (10 mL). The reaction mixture was deoxygenated with argon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (66 mg, 0.081 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane) gave 4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (387 mg, 60% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.01 (d, J=2.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.98-6.90 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 4.74 (s, 2H), 4.07 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (dd, J=13.0, 5.5 Hz, 1H), 1.64 (s, 3H), 1.60 (s, 3H); ESI MS m/z 399 [M+H]+.

Workup

  1. customThe reaction mixture was deoxygenated with argon
  2. temperaturecooled
  3. extractionextracted with dichloromethane (3×)
  4. washThe combined organic extracts were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane)

Sources & evidence

ORD record
ord-62bb82d308844962844ec7edf9282162
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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