Ethylenediamine → 6-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525667ノート

反応式

HRID 525667 の反応式
Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[N:39](COCC[Si](C)(C)C)[N:38]=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O.COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:35]2[NH:39][N:38]=[CH:37][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1

参加物

12

反応物 6

HCID 3301EthylenediamineHCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 2724141Tetrabutylammonium FluorideHCID 447552015-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleHCID 899068275-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

生成物 1

HCID 1180449976-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

試薬・触媒・溶媒 5

HCID 178418476HCID 178418476、化合物触媒HCID 702Ethanol溶媒HCID 962Water溶媒HCID 80711,2-Dimethoxyethane溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
75 °C

実験手順

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 19.1, 87 mg, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (130 mg, 0.401 mmol), Pd(PPh3)2Cl2 (14.06 mg, 0.020 mmol), Na2CO3 (85 mg, 0.801 mmol), DME (850 μL), water (243 μL) and EtOH (121 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 h. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol, centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 8% to 13% in 10 min). The resulting intermediate was treated with ethylene diamine (33.7 μL, 0.499 mmol) and 1 M TBAF in THF (1.496 mL, 1.496 mmol) and stirred at 75° C. for 24 h. The solvent was evaporated off under reduced pressure to give a, diluted with EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a. The crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min) to yield the title product as yellow wax. UPLC-MS (Condition 3) tR=0.92 min, m/z=422.2 [M+H]+, m/z=420.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.44 (t, J=5.87 Hz, 2H) 3.55 (q, J=5.46 Hz, 2H) 4.63 (br. s, 1H) 6.48 (d, J=2.20 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.70-7.84 (m, 1H) 7.84-7.91 (m, 2H) 8.15 (d, J=1.96 Hz, 1H) 8.71 (d, J=2.20 Hz, 1H) 10.26 (s, 1H).

後処理

  1. customwas sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 125° C. for 20 h
  4. additionThe RM was diluted with DME (3 mL)
  5. additiontreated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol
  6. filtrationthe supernatant was filtered
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a residue which
  9. customwas purified by preparative SFC (Column NH2, from 8% to 13% in 10 min)
  10. customThe solvent was evaporated off under reduced pressure
  11. customto give a,
  12. washwashed 3 times with sat. aq. NaHCO3, brine
  13. dry with materialdried over Na2SO4
  14. customthe solvent was evaporated off under reduced pressure
  15. customto give a
  16. customThe crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min)

出典と根拠

ORDレコード
ord-b5f791e03aed4955844253f38d583af9
出典データセット
uspto-grants-2016_05
特許番号
US09340537B2

反応ノート

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