Ammonium Chloride → 4-(2-((5-Fluoro-6-methoxy-3-pyridinyl)amino)-5-((1r)-1-((2s)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-n,n-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621808Notes

Reaction equation

HRID 1621808 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][C@@H:47]2[CH3:56])[CH3:45])=[CH:14][N:13]=1.[F:57][C:58]1[CH:59]=[C:60]([NH2:66])[CH:61]=[N:62][C:63]=1[O:64][CH3:65].[NH4+].[Cl-]>C1COCC1>[F:57][C:58]1[CH:59]=[C:60]([NH:66][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][C@@H:47]3[CH3:56])[CH3:45])=[CH:14][N:13]=2)[CH:61]=[N:62][C:63]=1[O:64][CH3:65]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 666117444-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 685138894-(2-((5-Fluoro-6-methoxy-3-pyridinyl)amino)-5-((1r)-1-((2s)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-n,n-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 9.23 mL, 9.23 mmol) was added dropwise over 5 min to a mixture of 4-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.000 g, 3.08 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc., 0.656 g, 4.62 mmol) in THF (30.8 mL) at 0° C., and the resulting reddish-brown solution was stirred at 0° C. for 1 h. Saturated NH4Cl (aq., 50 mL) was added and the reaction mixture was partitioned between EtOAc (100 mL) and half-saturated NH4Cl (aq., 50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (80 g of silica gel, 0% to 100% EtOAc/hexanes) gave 4-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.90 g, 2.461 mmol, 80% yield) as a yellow solid. m/z (ESI, +ve) 771.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H); 8.69-8.73 (m, 1H); 8.20-8.24 (m, 1H); 8.08 (dt, J=12.37, 1.05 Hz, 1H); 7.95-7.98 (m, 1H); 7.18-7.24 (m, 4H); 6.82-6.90 (m, 4H); 4.78-4.88 (m, 4H); 4.01 (s, 3H); 3.97-4.01 (m, 1H); 3.81 (s, 3H); 3.78 (s, 3H); 3.18-3.20 (m, 1H); 3.08-3.15 (m, 2H); 2.75-2.87 (m, 2H); 2.67 (s, 3H); 2.56-2.63 (m, 1H); 2.59 (s, 3H); 2.43-2.51 (m, 1H); 1.40 (d, J=6.85 Hz, 3H); 1.07 (d, J=6.26 Hz, 3H).

Workup

  1. customthe reaction mixture was partitioned between EtOAc (100 mL) and half-saturated NH4Cl (aq., 50 mL)
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×100 mL)
  4. washThe combined organic extracts were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified by column chromatography (80 g of silica gel, 0% to 100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-c5796d0c35a34e6794ce291946c0b898
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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