1-Hydroxybenzotriazole → tert-Butyl 4-(4-((4-(2-(2-(methylamino)-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

HRID 1485189ノート

反応式

HRID 1485189 の反応式
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-:38])=O)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1[C:49]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.Cl.CN>C1COCC1.CN(C=O)C>[CH3:49][NH:45][C:36](=[O:38])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[N:26]=1

参加物

8

反応物 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 6364545Methylamine hydrochlorideHCID 68282842Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate

生成物 1

HCID 86675718tert-Butyl 4-(4-((4-(2-(2-(methylamino)-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate収率 69%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.130 g, 0.220 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.036 g, 0.26 mmol) and EDCl (0.051 g, 0.26 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.879 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Methylamine hydrochloride (0.059 g, 0.88 mmol) was added in one portion, and the reaction was stirred at room temperature for 60 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (80 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-60% methanol in EtOAc) to give the title compound (I56) (0.091 g, 69% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.61 (s, 1H), 7.93-7.86 (m, 1H), 7.63-7.56 (m, 2H), 7.24-7.12 (m, 4H), 6.96-6.89 (m, 2H), 3.54-3.42 (m, 6H), 3.14-2.93 (m, 8H), 2.56 (d, J=4.6 Hz, 3H), 1.42 (s, 9H). LCMS Method C: rt 6.27 min; m/z 599.3 [M+H]+.

後処理

  1. stirringthe reaction was stirred at room temperature for 60 hours
  2. customThe volatiles were removed in vacuo
  3. additionthe residual solution was diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (80 mL)
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (70 mL)
  6. washwashed with water (100 mL), brine (100 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give a pale yellow solid
  11. customThe crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

出典と根拠

ORDレコード
ord-1374d181deaa4ec295c776a6f9ca247c
出典データセット
uspto-grants-2016_08
特許番号
US09421205B2

反応ノート

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