6-Methoxy-3-pyridinylamine → N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine

HRID 1621644Notes

Reaction equation

HRID 1621644 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)[CH:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[CH:19]=[C:18]([C:17]3[C:12]([NH:63][C:60]4[CH:61]=[N:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:23]=[C:22]([CH3:24])[N:21]=2)=[CH:28][CH:29]=1

Participants

5

Reactant 3

HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 666001976-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine

Product 1

HCID 66600292N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amineYield 95%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Lithium bis(trimethylsilyl)amide (Acros, Morris Plains, N.J.; 1.0M solution in THF/ethyl benezene) (0.599 mL, 0.599 mmol) was added dropwise to a solution of 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (124.0 mg, 0.200 mmol) and 6-methoxypyridin-3-amine (0.037 mL, 0.300 mmol) in THF (3.0 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 1 h. Excess LiHMDS was quenched by the addition of sat. aq. NH4Cl (5 mL), and the resulting mixture was partitioned between EtOAc (50 mL) and half-sat. aq. NH4Cl (15 mL). The organic layer was separated, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 12 g, 0 to 10% MeOH/DCM) furnished N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (137.7 mg, 0.190 mmol, 95% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.36 (d, J=2.54 Hz, 1H); 8.06-8.11 (m, 2H); 7.54 (br. s., 1H); 7.18 (d, J=7.43 Hz, 4H); 6.84-6.90 (m, 4H); 6.75 (d, J=8.80 Hz, 1H); 6.56 (s, 1H); 4.77 (br. s., 4H); 3.93 (s, 3H); 3.80 (s, 6H); 3.42 (br. s., 2H); 3.19 (br. s., 4H); 2.76 (s, 3H); 2.65 (s, 3H); 2.50 (br. s., 4H). m/z (ESI, +ve ion) 561.2 (M-piperazine sulfonamide)+.

Workup

  1. customExcess LiHMDS was quenched by the addition of sat. aq. NH4Cl (5 mL)
  2. customthe resulting mixture was partitioned between EtOAc (50 mL) and half-sat
  3. customThe organic layer was separated
  4. washwashed with brine (10 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customChromatographic purification of the residue (ISCO, 12 g, 0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-e4e4fd07613142099841538afe09c65f
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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