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 2108360Notes

Reaction equation

HRID 2108360 reaction equation
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]

Participants

9

Reactant 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

Product 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 acidYield 4.8%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 31374DimethylacetamideSolvent3×

Procedure

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+.

Workup

  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

Sources & evidence

ORD record
ord-fda981b455f54606b3ddeb265fe1492f
Source dataset
uspto-grants-2009_04
Patent number
US07514435B2

Reaction notes

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