1,4-Dioxane → tert-butyl (3S)-4-((1R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate

HRID 1621806Notes

Reaction equation

HRID 1621806 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:29]=1.CC([O-])=O.[K+].O1CCOCC1>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.O>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[N:29]=2)=[CH:51][CH:50]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 517044Potassium AcetateHCID 595482094-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineHCID 685129855-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

Product 1

HCID 66611873tert-butyl (3S)-4-((1R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylateYield 61.3%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolvent2×

Conditions

Temperature
100 °C

Procedure

A 1-L round-bottomed flask was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (11.90 g, 32.4 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51; 13.72 g, 35.6 mmol), KOAc (10.18 g, 104 mmol), dioxane (180 mL), and water (36.0 mL). Nitrogen gas was bubbled through the mixture for 10 min. Bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.295 g, 3.24 mmol) was added and a reflux condensor was attached to the flask. The mixture was heated at 100° C. under nitrogen overnight (17 h). After cooling to ambient temperature, water was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (330 g of silica gel, 5% to 75% EtOAc/hexanes) to give tert-butyl (3S)-4-((1R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (13.35 g, 19.87 mmol, 61.3% yield) as a light-yellow foam. m/z (ESI, +ve) 672.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.46 (m, 1H) 8.19-8.24 (m, 1H) 7.19-7.25 (m, 4H) 6.83-6.90 (m, 4H) 4.82 (d, J=11.93 Hz, 4H) 3.97-4.07 (m, 1H) 3.81 (s, 3H) 3.80 (br s, 1H) 3.79 (s, 3H) 3.31-3.44 (m, 2H) 3.08-3.18 (m, 1H) 2.69-2.77 (m, 1H) 2.55 (s, 3H) 2.42-2.48 (m, 2H) 1.39-1.46 (m, 12H) 1.00 (d, J=6.26 Hz, 3H).

Workup

  1. customNitrogen gas was bubbled through the mixture for 10 min
  2. temperatureAfter cooling to ambient temperature
  3. extractionthe mixture was extracted with EtOAc (3×200 mL)
  4. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified by column chromatography (330 g of silica gel, 5% to 75% EtOAc/hexanes)

Sources & evidence

ORD record
ord-af3ef29e6ea345719d39c75a969926a3
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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