Chloromethyl benzoate → 3-{2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-oxido-7-oxo-7-phenyl-2,4,6-trioxa-3-phosphahept-1-yl benzoate

HRID 1360622Notes

Reaction equation

HRID 1360622 reaction equation
[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH2:13][P:14](=[O:17])([OH:16])[OH:15])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=2.C(N(CC)[CH:22]([CH3:24])[CH3:23])(C)C.Cl[CH2:28][O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:30]([O:29][CH2:28][O:17][P:14]([CH2:13][CH2:12][N:8]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]2[C:2](=[O:1])[C:10](=[O:11])[C:9]1=2)(=[O:15])[O:16][CH2:28][O:29][C:30](=[O:37])[C:23]1[CH:22]=[CH:24][CH:36]=[CH:31][CH:32]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1

Participants

5

Reactant 3

HCID 79257Chloromethyl benzoateHCID 81531DiisopropylethylamineHCID 6918236Perzinfotel

Product 1

HCID 114894143-{2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-oxido-7-oxo-7-phenyl-2,4,6-trioxa-3-phosphahept-1-yl benzoateYield 99%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
65 °C

Procedure

A solution of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (20.16 mmol, 5.25 g) in dry DMF (120 mL) was treated with N,N-diisopropylethylamine (80.64 mmol, 14 ml) for ½ hour at ambient temperature. Benzoic acid chloromethyl ester (60.49 mmol, 10.32 g, synthesis described below) was added at ambient temperature under exclusion of moisture. The reaction mixture was heated to 65° C. for 20 hours. The temperature was then raised to 72° C. and stirred at 72° C. for 16 hours after which the reaction was completed. The mixture was cooled to room temperature and partitioned between 10% sodium bicarbonate and ethyl acetate. After separation of the layers the aqueous phase was again extracted with ethyl acetate (6×) until there was no more product in the water phase (by silica gel TLC, 7% 2M ammonia in methanol and 93% chloroform). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was flash chromatographed on 400 g silica gel using a solvent mixture of 1% 2M ammonia in methanol and 99% chloroform. Gradually the percentage of ammonia in methanol was increased to 7% and 93% chloroform. The solvent was evaporated in vacuo to yield the desired product (10.5 g, 99%; glass like material). MS (ES−): m/e 527 (M−H).

Workup

  1. temperatureThe temperature was then raised to 72° C.
  2. temperatureThe mixture was cooled to room temperature
  3. custompartitioned between 10% sodium bicarbonate and ethyl acetate
  4. customAfter separation of the layers the aqueous phase
  5. extractionwas again extracted with ethyl acetate (6×) until there
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. customevaporated to dryness
  10. customchromatographed on 400 g silica gel using
  11. additiona solvent mixture of 1% 2M ammonia in methanol and 99% chloroform
  12. temperatureGradually the percentage of ammonia in methanol was increased to 7% and 93% chloroform
  13. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-0a99176a335044df9d470533abf56938
Source dataset
uspto-grants-2011_02
Patent number
US07879825B2

Reaction notes

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