Cesium carbonate → (S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

HRID 1621796Notes

Reaction equation

HRID 1621796 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][B-](F)(F)F)[C@@H:44]([CH3:53])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C(O[Pd]OC(=O)C)(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[CH:3]=[C:2]([CH2:48][N:45]4[CH2:46][CH2:47][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43][C@@H:44]4[CH3:53])[CH:7]=[N:6][C:5]=3[F:8])[N:10]=2)=[CH:19][CH:20]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 666005044-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineHCID 71501917potassium (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate

Product 1

HCID 66611415(S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylateYield 84.4%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (8.99 g, 18.73 mmol), potassium (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate (6.00 g, 18.73 mmol), diacetoxypalladium (0.210 g, 0.937 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.893 g, 1.873 mmol), and cesium carbonate (18.31 g, 56.2 mmol) in THF (100 mL) and water (10.0 mL) was heated at 80° C. overnight. After cooling to ambient temperature, the mixture was passed through a short plug of Celite® (diatomaceous earth), washing with EtOAc (3×30 mL). The combined organic filtrates were concentrated and purified by flash chromatography (silica gel, 5% to 50% ethyl acetate/hexanes) to give (S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (10.39 g, 15.80 mmol, 84% yield) as a pale-yellow foam. m/z (ESI, +ve ion) 658 (M+H)+.

Workup

  1. temperatureAfter cooling to ambient temperature
  2. washwashing with EtOAc (3×30 mL)
  3. concentrationThe combined organic filtrates were concentrated
  4. custompurified by flash chromatography (silica gel, 5% to 50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-34ee4210c24b4e73bda31faacf1d4968
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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