Lithium Hexamethyldisilazide → 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812004Notes

Reaction equation

HRID 1812004 reaction equation
F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[F:46][C:47]1[CH:48]=[C:49]([NH2:55])[CH:50]=[N:51][C:52]=1[O:53][CH3:54].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[F:46][C:47]1[CH:48]=[C:49]([NH:55][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[CH3:35])=[CH:4][N:3]=2)[CH:50]=[N:51][C:52]=1[O:53][CH3:54]

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 666112714-(2-fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666000674-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 82.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (752 mg, 1.20 mmol) and 5-fluoro-6-methoxypyridin-3-amine (175.0 mg, 1.231 mmol) were dissolved in THF (12.0 mL) and the flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethylbenzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred under nitrogen. After 15 min, the reaction was treated with ice water (1.5 mL) and diluted with DCM (150 mL). The solution was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (744.3 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (s, 1H), 8.66 (d, J=2.35 Hz, 1H), 8.17 (d, J=2.54 Hz, 1H), 8.03 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.81 (d, J=8.41 Hz, 2H), 7.40 (d, J=8.41 Hz, 2H), 7.24-7.14 (m, 4H), 7.90-7.81 (m, 4H), 4.87 (d, J=5.09 Hz, 2H), 4.77 (d, J=5.48 Hz, 2H), 4.21 (q, J=7.04 Hz, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.98 (s, 3H), 2.58 (s, 3H), 1.67 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 750 (M+H)+.

Workup

  1. temperaturethe flask was cooled in an ice water bath under nitrogen
  2. dry with materialThe solution was dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified on a silica gel
  6. filtrationfilter (150 mL fritted filter with 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH)
  7. customThe fractions with product were collected
  8. concentrationconcentrated
  9. customdried under high vacuum

Sources & evidence

ORD record
ord-e3b1e1c457624f5f907cd65daaa50ad1
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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