Lithium Hexamethyldisilazide → HCID 66611607, compound

HRID 1621563Notes

Reaction equation

HRID 1621563 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]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[F:45][C:46]1[CH:47]=[C:48]([NH2:54])[CH:49]=[N:50][C:51]=1[O:52][CH3:53].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:45][C:46]1[CH:47]=[C:48]([NH:54][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:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=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]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=3)=[CH:4][N:3]=2)[CH:49]=[N:50][C:51]=1[O:52][CH3:53]

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 60155988HCID 60155988, compound

Product 1

HCID 66611607HCID 66611607, compoundYield 53.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (602.4 mg, 0.9816 mmol) and 5-fluoro-6-methoxypyridin-3-amine (159.0 mg, 1.119 mmol) were dissolved in THF (10 mL) and the reaction flask was cooled in an ice water bath. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 3.0 mL, 3.0 mmol) was added via syringe, and the reaction was stirred under nitrogen for 35 min. Then, the reaction was diluted with water (20 mL) and then extracted with DCM. Brine was added to the biphasic mixture and extraction with DCM was continued. Water and MeOH were also added to the aqueous phase to help break up emulsions. The organic extracts (about 350 mL total) were combined and washed with brine (50 mL). The brine layer was extracted with DCM, and all of the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; 100:1 DCM/MeOH) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (384.7 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (br s, 1H), 8.63 (d, J=1.96 Hz, 1H), 8.17 (d, J=2.15 Hz, 1H), 8.00 (d, J=12.32 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.82 (d, J=8.02 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.41 Hz, 2H), 7.15 (d, J=8.41 Hz, 2H), 6.90-6.81 (m, 4H), 4.86 (s, 2H), 4.77 (s, 2H), 4.01 (s, 5H), 3.82 (s, 3H), 3.80 (s, 3H), 2.96 (s, 3H), 2.58 (s, 3H). m/z (ESI, pos. ion) 736 (M+H)+.

Workup

  1. temperaturethe reaction flask was cooled in an ice water bath
  2. extractionextracted with DCM
  3. additionBrine was added to the biphasic mixture and extraction with DCM
  4. additionWater and MeOH were also added to the aqueous phase
  5. washwashed with brine (50 mL)
  6. extractionThe brine layer was extracted with DCM
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified on a silica gel
  11. filtrationfilter (150 mL fritted funnel with about 2 inches of silica gel; 100:1 DCM/MeOH)

Sources & evidence

ORD record
ord-e094ffad81b8402995dc6ff94eba9cd2
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

Loading…