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

HRID 1812002Notes

Reaction equation

HRID 1812002 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.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[N:51][CH:52]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:46][C:47]4[CH:52]=[N:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)=[N:3][CH:4]=[C:5]([CH:34]([C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=4)[CH3:35])[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1

Participants

6

Reactant 3

HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 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 66611946N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 51.5%

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 (764.7 mg, 1.218 mmol) and 5-amino-2-methoxypyridine (162.9 mg, 1.312 mmol) were dissolved in THF (12 mL) and the flask was cooled in an ice water bath while being stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethyl benzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred at 0° C. After 40 min, the reaction was treated with ice water (1.5 mL), diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH to 40:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (about 40° C.) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg). 1H NMR (CDCl3, 400 MHz) δ 11.57 (s, 1H), 8.65 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.35 Hz, 1H), 8.14 (d, J=2.35 Hz, 1H), 7.89 (dd, J=8.71 Hz, 2.45 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.40 (d, J=8.02 Hz, 2H), 7.24-7.14 (m, 4H), 6.90-6.81 (m, 4H), 6.70 (d, J=8.80 Hz, 1H), 4.87 (d, J=4.89 Hz, 2H), 4.77 (d, J=5.09 Hz, 2H), 4.23-4.16 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 732 (M+H)+.

Workup

  1. temperaturethe flask was cooled in an ice water bath
  2. stirringthe reaction was stirred at 0° C
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified on a silica gel
  7. filtrationfilter (150 mL fritted funnel with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH to 40:1 DCM/MeOH)
  8. customThe fractions with product were collected
  9. concentrationconcentrated
  10. customdried under high vacuum in a water bath (about 40° C.)

Sources & evidence

ORD record
ord-309bf6fdb39f48f3b3572b69f7b9d9d4
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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