Thionyl Chloride → HCID 178501871, compound

HRID 490946Notes

Reaction equation

HRID 490946 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)[O:19][P:16]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 67375341(1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acidHCID 178501772HCID 178501772, compound

Product 1

HCID 178501871HCID 178501871, compoundYield 55.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-5 °C

Procedure

A solution of (1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acid (4.27 g, 14.9 mmol) in 50 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this was added thionyl chloride (1.20 mL, 16.5 mmol) and the reaction mixture was stirred at −5° C. for 40 minutes. 2-(3-(N′,N″-Di(t-butoxycarbonyl)guanidino)phenyl)-2-hydroxyethanoic acid methyl ester (5.60 g, 13.2 mmol) was added to the reaction mixture as a solution in 15 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 3 days, 20 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), combined and concentrated in vacuo to give a mixture of product and starting material. The product was purified by flash column chromatography (10%-100% ethyl acetate/methylene chloride), followed by methanol to give 5.07 g (55%) of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester.

Workup

  1. temperatureto warm to ambient temperature
  2. stirringAfter stirring for 3 days
  3. washThe solution was washed with ether (2×)
  4. concentrationconcentrated in vacuo
  5. customto give
  6. additiona mixture of product
  7. customThe product was purified by flash column chromatography (10%-100% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-ed7cd82c3818434a951caff915cc857b
Source dataset
uspto-grants-2009_05
Patent number
US07528173B2

Reaction notes

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