Water → methyl (R)-alpha-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate

HRID 726646Notes

Reaction equation

HRID 726646 reaction equation
[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13]I)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[Cl:49])[N:45]=[C:44](Br)[C:43]([CH2:51][P:52]([O:56][CH3:57])([O:54][CH3:55])=[O:53])=[CH:42]2.O>C1C=CC=CC=1.CC(N(C)C)=O.[Cu].[Zn].[Pd](Cl)Cl>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:13][C:44]1[C:43]([CH2:51][P:52]([O:54][CH3:55])([O:56][CH3:57])=[O:53])=[CH:42][C:41]2[C:46](=[CH:47][C:48]([Cl:49])=[C:39]([Cl:38])[CH:40]=2)[N:45]=1)[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]

Participants

9

Reactant 4

HCID 962WaterHCID 80271Tri-o-tolylphosphineHCID 11416215(S)-Methyl 2-Boc-amino-3-iodopropionateHCID 540461326,7-Dichloro-3-dimethylphosphonomethyl-2-bromoquinoline

Product 1

HCID 53893680methyl (R)-alpha-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionateYield 63.3%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 10290809Zinc copper coupleCatalystHCID 241BenzeneSolvent2×HCID 31374DimethylacetamideSolvent2×

Procedure

A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.66 g, 2 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml) was added to a zinc-copper couple (0.31 g). The resulted mixture was sonicated at 40°-45° C. under nitrogen for 2.5-3 h until no starting material remained (as judged by TLC). Tri-o-tolylphosphine (0.06 g, 0.2 mmol) and palladium chloride (0.02 g, 0.1 mmol) were added followed by a solution of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline (0.4 g, 1 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml). The resulted mixture was stirred under nitrogen at 50°-60° C. for 2.5-3 h and then allowed to cool. Water was added and the mixture was filtered through Celite, the latter was washed with ethyl acetate. The combined organic phases were separated, dried, (MgSO4) and concentrated in vacuo. The residue was coevaporated several times with toluene to remove most of the dimethylacetamide and then purified on a silica gel column using 0-2% methanol in chloroform as eluent to give 0.33 g of methyl (R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate.

Workup

  1. customThe resulted mixture was sonicated at 40°-45° C. under nitrogen for 2.5-3 h until no starting material
  2. temperatureto cool
  3. filtrationthe mixture was filtered through Celite
  4. washthe latter was washed with ethyl acetate
  5. customThe combined organic phases were separated
  6. customdried
  7. concentration(MgSO4) and concentrated in vacuo
  8. customto remove most of the dimethylacetamide
  9. custompurified on a silica gel column

Sources & evidence

ORD record
ord-8e3d42c3d3194c7fad4c88d391e1e112
Source dataset
uspto-grants-1998_01
Patent number
US05710139

Reaction notes

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