Diisopropylethylamine → N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine

HRID 645931Notes

Reaction equation

HRID 645931 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=1.CC[N:35](C(C)C)C(C)C>C(O)CCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:24]2[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][N:27]=[C:22]([NH2:35])[N:23]=2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:27]=[C:26]([NH2:35])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 59264626(2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methanamine

Product 2

HCID 25070006N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamineHCID 25070326N2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine

Reagents, catalysts & solvents 1

HCID 62761-PentanolSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (81.1 mg, 0.261 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (51.6 mg, 0.261 mmol), and DIEA (0.09 mL, 0.52 mmol, 2 eq) in 1-pentanol (1.3 mL) was stirred at 80° C. for 30 min. The mixture was transferred to a pressure vessel and ammonia gas was bubbled through the mixture at rt for 15 min. The mixture was stirred at 100° C. 14 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min as eluent to provide N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=127 nM] as light yellow solid (Example 3) and N2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=2825 nM] (Example 4) as light yellow solid. For Example 3: 1H NMR (DMSO-d6) δ ppm 8.12 (1H, s), 8.01 (1H, d, J=0.8 Hz), 7.82 (1H, d, J=8.2 Hz), 7.43-7.65 (6H, m), 7.17 (1H, t, J=5.7 Hz), 6.57 (2H, br. s.), 4.51 (2H, t, J=5.9 Hz), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1). For Example 4: 1H NMR (DMSO-d6) δ ppm 8.17-8.28 (1H, m), 8.00 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.23-7.72 (7H, m), 6.68 (2H, s), 4.39 (2H, s), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1).

Workup

  1. customThe mixture was transferred to a pressure vessel
  2. customammonia gas was bubbled through the mixture at rt for 15 min
  3. stirringThe mixture was stirred at 100° C
  4. custom14 h
  5. concentrationThe mixture was concentrated under reduced pressure
  6. customThe crude product was purified by column chromatography on a 40 g of Redi-Sep™ column
  7. customover 14 min

Sources & evidence

ORD record
ord-aa49d7b202ce45d0a308549fc304e225
Source dataset
uspto-grants-2010_04
Patent number
US07705018B2

Reaction notes

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