Water → Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate

HRID 1621403Notes

Reaction equation

HRID 1621403 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O.O1CCOCC1.O.ClC1N=C(C)N=C2C=1N=CN2C1CCCCO1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[N:3]=2)=[CH:12][CH:13]=1

Participants

9

Reactant 7

HCID 962WaterHCID 312751,4-DioxaneHCID 62885Benzeneethanamine, alpha-methyl-, phosphate (1:1)HCID 517044Potassium AcetateHCID 595482094-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineHCID 59548218(5-((4-(tert-Butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-yl)boronic acidHCID 595482686-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Product 1

HCID 60156087Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylateYield 75.2%

Reagents, catalysts & solvents 1

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Catalyst

Conditions

Temperature
100 °C

Procedure

A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51) (20 g, 52.0 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (Example 34, Step 3) (21.15 g, 62.4 mmol), potassium acetate (8.12 mL, 130 mmol), and Amphos (bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (1.913 g, 2.70 mmol) in p-dioxane (300 mL, 3528 mmol) and water (60 mL, 52.0 mmol) contained in a 1 L 3 neck round-bottomed flask was stirred at 100° C. overnight. The solution was partitioned between water and EtOAc and the organic layer was separated, washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25.2 g, 39.1 mmol, 75% yield). m/z (ESI, positive ion) m/z 644 (M+H)+.

Workup

  1. customThe solution was partitioned between water and EtOAc
  2. customthe organic layer was separated
  3. washwashed with water
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give the crude product which
  8. customchromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g)
  9. washeluting with a gradient of 10% to 50% EtOAc in hexane

Sources & evidence

ORD record
ord-2fe60eaab596495f9ceb1ddca5ad4220
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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