Methanol → N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine

HRID 1812335Notes

Reaction equation

HRID 1812335 reaction equation
F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH2:55])[CH:53]=2)[CH:48]=[CH:47][N:46]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO>O1CCOCC1.[NH4+].[Cl-].C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:55][C:52]4[CH:53]=[C:54]5[C:49]([CH:48]=[CH:47][N:46]=[CH:45]5)=[CH:50][CH:51]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 887MethanolHCID 2724254Sodium bis(trimethylsilyl)amideHCID 14660277Isoquinolin-7-amineHCID 666116314-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 66600115N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amineYield 31.3%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 25517Ammonium ChlorideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
0 °C

Procedure

A glass microwave reaction vessel was charged with 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (400 mg, 0.643 mmol) and isoquinolin-7-amine (139 mg, 0.965 mmol) (Ark Pharm, Inc, Libertyville, Ill.) in dioxane (2 mL) and the reaction mixture was cooled at 0° C. To this solution, sodium bis(trimethylsilyl)amide (1.0N in THF, 2 mL, 2 mmol) was mixed. The red solution was stirred at 0° C. for 1 h and 25° C. for 16 h. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc (3×). The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated under a vacuum. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 5% 2M NH3.MeOH in DCM, to provide N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (150 mg, 31.3% yield) as a yellow solid. m/z (ESI, positive ion): 746 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.63 (s, 3H) 2.82 (s, 3H) 3.06-3.10 (m, 4H) 3.57 (s, 2H) 3.70 (s, 3H) 3.75 (s, 3H) 4.86 (s, 4H) 6.84-6.97 (m, 4H) 7.30 (t, J=6.85 Hz, 4H) 7.72 (d, J=5.48 Hz, 1H) 7.74-7.79 (m, 1H) 7.82-7.88 (m, 1H) 8.35 (d, J=5.67 Hz, 1H) 8.39 (d, J=2.35 Hz, 1H) 8.58 (d, J=1.76 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 9.13 (s, 1H) 12.19 (s, 1H).

Workup

  1. customA glass microwave reaction vessel
  2. extractionextracted with EtOAc (3×)
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl
  5. dry with materialdried over MgSO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated under a vacuum
  8. custompurified by chromatography through a silica gel column (40 g)
  9. washeluting with a gradient of 0% to 5% 2M NH3

Sources & evidence

ORD record
ord-dc9b04e2dc244cdc8833bd5c8b1bdcbd
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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