Benzothiazol-5-amine → 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)benzo[d]thiazol-5-amine

HRID 1621747Notes

Reaction equation

HRID 1621747 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.[S:45]1[C:49]2[CH:50]=[CH:51][C:52]([NH2:54])=[CH:53][C:48]=2[N:47]=[CH:46]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[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:54][C:52]4[CH:51]=[CH:50][C:49]5[S:45][CH:46]=[N:47][C:48]=5[CH:53]=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

5

Reactant 3

HCID 70749Benzothiazol-5-amineHCID 2733832Lithium HexamethyldisilazideHCID 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 66611977N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amineYield 70.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 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 (Example 128; 60.0 mg, 0.097 mmol) and benzo[d]thiazol-5-amine (29.0 mg, 0.193 mmol)(Maybridge, Trevillet, UK) in THF (1.0 mL) at 0° C. was treated with LiHMDS (1.0 M in THF, Aldrich, St. Louis, Mo.) (483 μL, 0.483 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 15 min, then was quenched with sat. aq. NH4Cl (3 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH to give 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)benzo[d]thiazol-5-amine (51.0 mg, 0.068 mmol, 70.3% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 9.16 (1H, br. s.); 8.99 (1H, s); 8.40-8.54 (2H, m); 7.84 (1H, d, J=8.8 Hz); 7.58 (1H, d, J=8.6 Hz); 7.12-7.25 (4H, m); 6.77-6.92 (4H, m); 4.93 (2H, s); 4.89 (2H, s); 4.15 (2H, s); 3.79 (12H, d, J=18.0 Hz); 3.35-3.51 (2H, m); 2.87-2.97 (2H, m); 2.85 (3H, s); 2.69 (3H, s). m/z (ESI, positive ion) 752 (M+H)+.

Workup

  1. customwas quenched with sat. aq. NH4Cl (3 mL)
  2. extractionThe aqueous layer was extracted with EtOAc (3×20 mL)
  3. dry with materialthe combined organic layers were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash chromatography on silica eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH

Sources & evidence

ORD record
ord-32cf1671c946448f8db23cb228dd9f9c
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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