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

HRID 1812278Notes

Reaction equation

HRID 1812278 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]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[CH:46]([C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:46]([C:49]1[CH:50]=[C:51]([NH:57][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[N:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]3)[CH3:35])=[CH:4][N:3]=2)[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 666002395-Isopropyl-6-methoxypyridin-3-amineHCID 66611822HCID 66611822, compound

Product 1

HCID 66612093(R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Examples 145 and 146) 0.380 g, 0.598 mmol) and 5-isopropyl-6-methoxypyridin-3-amine (0.149 g, 0.897 mmol) in 3 mL THF at 0° C. was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.69 mL, 2.69 mmol) dropwise via syringe over 1 min. The dark red reaction was allowed to stir 30 min and was quenched by addition of saturated aq. NH4Cl. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 20-100% EtOAc/hexane followed by 10% MeOH/EtOAc to elute the desired product. The product-containing fractions were concentrated to afford (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.097 g, 0.124 mmol, 21% yield) as a red oil. m/z (ESI, +ve ion) 782 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.15-8.29 (m, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.15-7.25 (m, 4H), 6.77-6.96 (m, 4H), 4.71-4.97 (m, 4H), 3.95 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.53 (q, J=6.8 Hz, 1H), 3.11-3.20 (m, 5H), 2.69 (s, 3H), 2.47-2.63 (m, 7H), 1.38 (d, J=6.7 Hz, 3H), 1.21 (d, J=6.8 Hz, 6H).

Workup

  1. customThe dark red reaction
  2. customwas quenched by addition of saturated aq. NH4Cl
  3. customThe reaction was partitioned between water and DCM
  4. extractionThe aqueous layer was extracted with DCM 3 times
  5. dry with materialthe combined organics were dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. additionThe material was treated with DCM
  9. custompurified by silica gel chromatography (80 g column)
  10. washto elute the desired product
  11. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-638dd51b1d3643c698bbdcfe20c93903
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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