5-Amino-2-chloropyridine → (R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621892Notes

Reaction equation

HRID 1621892 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].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][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[Cl:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>C1COCC1>[Cl:56][C:57]1[N:62]=[CH:61][C:60]([NH:63][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:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)=[CH:59][CH:58]=1

Participants

5

Reactant 3

HCID 793055-Amino-2-chloropyridineHCID 2724254Sodium bis(trimethylsilyl)amideHCID 66611822(R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 86647072(R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 76%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.777 mL, 0.777 mmol) was added to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6) 141.2 mg, 0.222 mmol) and 6-chloropyridin-3-amine (Aldrich, St. Louis, Mo.; 57.1 mg, 0.444 mmol) in THF (2.5 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 30 min. Excess sodium bis(trimethylsilyl)amide was then quenched with saturated aqueous NH4Cl (2 mL), and the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were sequentially washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished (R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (125.0 mg, 0.168 mmol, 76% yield) as a yellow-brown oil. 1H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.18-8.24 (m, 1H), 7.21 (td, J=5.7, 2.4 Hz, 5H), 6.89 (s, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.74-4.93 (m, 4H), 3.81 (s, 3H), 3.79 (s, 3H), 3.52-3.59 (m, 1H), 3.15 (br. s., 4H), 2.67 (s, 3H), 2.60 (s, 3H), 2.47-2.58 (m, 4H), 1.38 (d, J=6.7 Hz, 3H). m/z (ESI, +ve) 744.2 (M+H)+.

Workup

  1. customExcess sodium bis(trimethylsilyl)amide was then quenched with saturated aqueous NH4Cl (2 mL)
  2. customthe reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (20 mL)
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
  5. washThe combined organic extracts were sequentially washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customChromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-5fc72f03cac343ab9bae4f48243d0bd4
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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