Sodium bis(trimethylsilyl)amide → 4-(5-(1-(Tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812316Notes

Reaction equation

HRID 1812316 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25](F)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[F:37][C:38]1[CH:39]=[C:40]([NH2:46])[CH:41]=[N:42][C:43]=1[O:44][CH3:45]>C1COCC1>[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25]([NH:46][C:40]2[CH:41]=[N:42][C:43]([O:44][CH3:45])=[C:38]([F:37])[CH:39]=2)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amide2×HCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 666120234-(5-(1-(Tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666113474-(5-(1-(Tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 91%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 1.279 mL, 1.279 mmol) was added to an orange-brown solution of 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (201.2 mg, 0.533 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 91 mg, 0.640 mmol) in THF (5.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1.5 h. Additional sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.300 mL, 0.300 mmol) was then added, and the resulting mixture was stirred at 0° C. for 30 min. Excess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL), and the resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) furnished 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.0 mg, 0.482 mmol, 91% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.26 (dd, J=12.3, 2.2 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 5.40 (br. s., 2H), 4.02 (s, 3H), 3.67 (dd, J=6.2, 2.8 Hz, 2H), 2.91 (q, J=6.5 Hz, 1H), 2.57 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 0.87 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −139.42 (s, 1 F). m/z (ESI, +ve) 500.3 (M+H)+.

Workup

  1. stirringthe resulting mixture was stirred at 0° C. for 30 min
  2. customExcess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL)
  3. customthe resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL)
  4. extractionThe aqueous layer was extracted with CH2Cl2 (30 mL)
  5. dry with materialthe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customChromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes)

Sources & evidence

ORD record
ord-d8ebeb607fa94e50a339b5767e31fa5e
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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