Triethylamine → 4-(2-(5-fluoro-6-methoxypyridin-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 1811981Notes

Reaction equation

HRID 1811981 reaction equation
[CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32](O)[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:58][S:59]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)(=[O:61])=[O:60]>C(Cl)Cl.O>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:10]=3)=[CH:17][C:18]([CH:32]([N:65]3[CH2:66][CH2:67][N:62]([S:59]([CH3:58])(=[O:61])=[O:60])[CH2:63][CH2:64]3)[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 31297Methanesulfonyl chlorideHCID 7091611-(Methylsulfonyl)piperazineHCID 666112271-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol

Product 1

HCID 666001254-(2-(5-fluoro-6-methoxypyridin-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 42.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent3×

Procedure

1-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (867.1 mg, 1.418 mmol) was dissolved in DCM (22 mL) and the flask was cooled in an ice water bath. Then, triethylamine (0.90 mL, 6.5 mmol) and methanesulfonyl chloride (0.41 mL, 5.3 mmol) were added, and the reaction was stirred under nitrogen. After 20 min, the reaction was diluted with DCM (125 mL) and treated with water (25 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dissolved in DCM (15 mL). Triethylamine (0.90 mL, 6.5 mmol) and 1-methanesulfonylpiperazine (753.9 mg, 4.591 mmol) were added and the reaction was stirred under nitrogen at room temperature overnight. Then, the reaction was treated with water (20 mL) and diluted with DCM. The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to 50:1 DCM/MeOH to 30:1 DCM/2 N ammonia in MeOH to 15:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH). The product eluted with 50:1 DCM/MeOH. The fractions with product were collected, concentrated, and repurified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH, to elute impurities to 40:1 DCM/MeOH, to elute product) to give 4-(2-(5-fluoro-6-methoxypyridin-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 (456.7 mg). 1H NMR (CDCl3, 400 MHz) δ 11.87 (s, 1H), 8.72 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.35 Hz, 1H), 8.07 (d, J=12.32 Hz, 2.15 Hz, 1H), 7.97 (d, J=2.35 Hz, 1H), 7.22 (t, J=8.51 Hz, 4H), 6.91-6.82 (m, 4H), 4.93-4.76 (m, 4H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.55 (q, J=6.78 Hz, 1H), 3.16 (t, J=4.60 Hz, 4H), 2.69 (s, 3H), 2.60 (s, 3H), 2.58-2.49 (m, 4H), 1.38 (d, J=6.65 Hz, 3H). m/z (ESI, pos. ion) 758 (M+H)+.

Workup

  1. temperaturethe flask was cooled in an ice water bath
  2. customThe layers were separated
  3. extractionthe aqueous phase was extracted with DCM
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutiondissolved in DCM (15 mL)
  8. stirringthe reaction was stirred under nitrogen at room temperature overnight
  9. customThe layers were separated
  10. extractionthe aqueous phase was extracted with DCM
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. custompurified on a silica gel
  15. filtrationfilter (150 mL fritted filter with about 2 inches of silica gel; DCM to 50:1 DCM/MeOH to 30:1 DCM/2 N ammonia in MeOH to 15:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH)
  16. washThe product eluted with 50:1 DCM/MeOH
  17. customThe fractions with product were collected
  18. concentrationconcentrated
  19. customrepurified on a silica gel
  20. filtrationfilter
  21. wash(150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH, to elute impurities to 40:1 DCM/MeOH, to elute product)

Sources & evidence

ORD record
ord-f71f1ac5f4eb42f2a9d8f974e63429e1
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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