Sodium bis(trimethylsilyl)amide → N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamide

HRID 1812361

Reaktionsgleichung

Reaktionsgleichung von HRID 1812361
[NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][C:23]([O:34][CH3:35])=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[C:23]([O:34][CH3:35])[CH:24]=2)[N:27]=1

Komponenten

5

Edukt 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 666111694-(2-Fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineHCID 71481004HCID 71481004, Verbindung

Produkt 1

HCID 59548437N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamideAusbeute 11,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a stirred solution of N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.0819 g, 0.280 mmol) and 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330 step 5, 0.0621 g, 0.264 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.06 mL, 1.06 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to pH 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fraction was collected and the solvent was evaporated to give a red solid. The solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3. The aqueous phase was acidified to pH about 3 then extracted with 25% IPA in CHCl3. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in about 1 mL DMSO and about 2 mL of water was added. The resulting solid was collected via filtration and washed with copious amount of water and dried to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.015 g, 11% yield) as a dark yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s., 1H) 9.73 (br. s., 1H) 8.79 (br. s., 1H) 8.52 (br. s., 1H) 8.38-8.47 (m, 1H) 8.18 (br. s., 1H) 7.76-7.99 (m, 2H) 3.86 (br. s., 3H) 3.57-3.66 (m, 4H) 3.09-3.21 (m, 4H) 2.45 (br. s., 3H). m/z (ESI, positive ion): 508.0 (M+H)+.

Aufarbeitung

  1. customThe reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL)
  2. extractionthen extracted with 25% isopropanol in chloroform (2×30 mL)
  3. dry with materialThe combined organic phases were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by preparative HPLC
  7. customC18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min)
  8. customThe fraction was collected
  9. customthe solvent was evaporated
  10. customto give a red solid
  11. customThe solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3
  12. extractionthen extracted with 25% IPA in CHCl3
  13. dry with materialThe combined organic phases were dried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. dissolutionThis material was dissolved in about 1 mL DMSO
  17. additionabout 2 mL of water was added
  18. filtrationThe resulting solid was collected via filtration
  19. washwashed with copious amount of water
  20. customdried

Quellen und Nachweise

ORD-Eintrag
ord-b1e8f325fd8845e7960a68727e0db0d7
Quelldatensatz
uspto-grants-2013_01
Patentnummer
US08362241B2

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