Thionyl Chloride → 2-(3-(t-Butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester

HRID 490942Notes

Reaction equation

HRID 490942 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:43])[CH:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:43])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH:29]=1)[O:19][P:16]([CH: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 67373866Methyl 2-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-2-hydroxyacetateHCID 67375341(1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acid

Product 1

HCID 873759452-(3-(t-Butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl esterYield 90.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-5 °C

Procedure

Following a procedure reported by Hoffmann, M., Synthesis (1986), 557A, a solution of (R)-1-(benzyloxycarbonyl)amino-2-methylpropylphosphonic acid (691.0 mg, 2.41 mmol) in 8 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this solution was added thionyl chloride (0.21 mL, 2.88 mmol) and stirred at −5° C. for 25 minutes. Racemic 2-hydroxy-2-(3-(t-butoxycarbonylamino)phenyl)ethanoic acid methyl ester (683.4 mg, 2.43 mmol) was added as a solution in 2 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 4 days (total reaction time 87 hrs), the reaction had almost gone to completion (95%). To this reaction mixture 5 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), acidified to pH 2 with concentrated HCl, and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a mixture of product and starting material. Purification via SiO2 gel flash column chromatography (CH2Cl2, then methanol) provided 1.1966 g (90%) of 2-(3-(t-butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester; as a mixture of diastereomers.

Workup

  1. temperatureto warm to ambient temperature
  2. stirringAfter stirring for 4 days (total reaction time 87 hrs)
  3. washThe solution was washed with ether (2×)
  4. extractionextracted with ethyl acetate (3×)
  5. dry with materialThe combined ethyl acetate extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give
  9. additiona mixture of product
  10. customPurification via SiO2 gel flash column chromatography (CH2Cl2

Sources & evidence

ORD record
ord-b29f470c363e4b2babe7e2c725afbedc
Source dataset
uspto-grants-2009_05
Patent number
US07528173B2

Reaction notes

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