Water → (2S)-2-amino-3-(4-amino-5-{[3-({[(2,4-dichlorophenyl)amino]carbonyl}amino)phenyl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)propanoic acid

HRID 2108360ノート

反応式

HRID 2108360 の反応式
Cl[Si](C)(C)C.BrCCBr.C(OC([NH:17][CH:18]([CH2:23]I)[C:19]([O:21]C)=[O:20])=O)(C)(C)C.[NH2:25][C:26]1[C:31]2=[C:32]([C:36]([C:38]3[CH:39]=[C:40]([NH:44][C:45]([NH:47][C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=4[Cl:55])=[O:46])[CH:41]=[CH:42][CH:43]=3)=[O:37])[CH:33]=[C:34](Br)[N:30]2[N:29]=[CH:28][N:27]=1.O>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[NH2:17][C@@H:18]([CH2:23][C:34]1[N:30]2[C:31]([C:26]([NH2:25])=[N:27][CH:28]=[N:29]2)=[C:32]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])=[O:46])[CH:39]=2)=[O:37])[CH:33]=1)[C:19]([OH:21])=[O:20]

参加物

9

反応物 4

HCID 962WaterHCID 5051066Methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoateHCID 167397901-{3-[(4-Amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)carbonyl]phenyl}-3-(2,4-dichlorophenyl)ureaHCID 86760839Chlorotrimethylsilane 1,2-dibromoethane

生成物 1

HCID 57629493(2S)-2-amino-3-(4-amino-5-{[3-({[(2,4-dichlorophenyl)amino]carbonyl}amino)phenyl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)propanoic acid収率 4.8%

試薬・触媒・溶媒 4

HCID 23994Zinc触媒HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)触媒HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 31374Dimethylacetamide溶媒3 回

実験手順

A mixture of zinc dust (300 mg) in dimethylacetamide (DMA) (0.3 mL) at 50° C. was treated with a solution of chlorotrimethylsilane/1,2-dibromoethane (7/5 v/v, 0.04 mL) and the reaction was stirred at room temperature for 30 minutes. A solution of methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (247 mg, 0.75 mmol) in DMA (1 mL) was slowly added and the reaction was stirred for 40 minutes. This mixture was added to a mixture of 95G (35 mg), PdCl2(dppf)2 (7 mg), and CuI (10 mg) in DMA (0.8 mL). The reaction was heated to 80° C. for 18 hours. Water was added and the solid precipitate was collected by filtration. The solid was treated with 33% HBr/AcOH and then concentrate. The residue was dissolved in THF/MeOH and water and treated with LiOH and stirred at room temperature for two hours. The reaction mixture was neutralized with trifluoroacetic acid and purified by preparative reversed phase HPLC to afford the desired product (1.7 mg). Compound 103 had an analytical HPLC retention time=2.906 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=528+.

後処理

  1. stirringthe reaction was stirred for 40 minutes
  2. temperatureThe reaction was heated to 80° C. for 18 hours
  3. filtrationthe solid precipitate was collected by filtration
  4. additionThe solid was treated with 33% HBr/AcOH
  5. concentrationconcentrate
  6. dissolutionThe residue was dissolved in THF/MeOH
  7. additionwater and treated with LiOH
  8. stirringstirred at room temperature for two hours
  9. custompurified by preparative reversed phase HPLC

出典と根拠

ORDレコード
ord-fda981b455f54606b3ddeb265fe1492f
出典データセット
uspto-grants-2009_04
特許番号
US07514435B2

反応ノート

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