Acetic Acid → HCID 86705126, compound

HRID 541552Notes

Reaction equation

HRID 541552 reaction equation
[C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].CC(C)=O.O=C(C1C=CC=CC=1)C[O:19][C:20](=[O:48])[C@H:21]([OH:47])[CH2:22][N:23]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)=[CH:36][CH:35]=1)[NH:24][C:25]([C:27]1[O:31][N:30]=[C:29]([OH:32])[CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].CCN(C(C)C)C(C)C.CC(O)=O>[Zn]>[Cl:46][C:42]1[CH:41]=[C:40]([C:37]2[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:22][C@@H:21]([OH:47])[C:20]([OH:48])=[O:19])[NH:24][C:25]([C:27]3[O:31][N:30]=[C:29]([O:32][CH2:3][O:2][C:1]([O:5][CH:6]([CH3:8])[CH3:7])=[O:9])[CH:28]=3)=[O:26])=[CH:39][CH:38]=2)[CH:45]=[CH:44][CH:43]=1

Participants

9

Reactant 7

HCID 176Acetic AcidHCID 180Acetone2×HCID 5238Sodium IodideHCID 10796Cesium carbonateHCID 81531DiisopropylethylamineHCID 14787051Chloromethyl isopropyl carbonateHCID 178521475HCID 178521475, compound

Product 1

HCID 86705126HCID 86705126, compoundYield 19.1%

Reagents, catalysts & solvents 1

HCID 23994ZincCatalyst

Conditions

Temperature
65 °C

Procedure

A mixture of chloromethyl isopropyl carbonate (15.6 mg, 102 μmol) and NaI (15.3 mg, 102 μmol) in acetone (0.7 mL, 10 mmol) was stirred at 65° C. for 1 hour, then added (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) that had been dissolved in acetone (0.4 mL, 5 mmol) at room temperature and treated with cesium carbonate (13.0 mg, 40 μmol). The resulting mixture was then heated at 40° C. for 1 hour. DIPEA (0.2 mL, 1 mmol) was added and heating continued for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was partitioned between EtOAc (10.0 mL) and water (2.0 mL). The organic layer was washed with saturated aqueous NaHCO3 (3.0 mL), saturated aqueous NaCl (3.0 mL), dried over Na2SO4, filtered, and concentrated. Zinc 90.8 mg, 1.4 mmol) and AcOH (0.5 mL, 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The solids were washed with AcOH (1.0 mL) then filtered. The filtrates were combined and purified by reverse phase preparative HPLC to yield the title compound (3.8 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O9, 548.14. found 548.5.

Workup

  1. temperatureThe resulting mixture was then heated at 40° C. for 1 hour
  2. temperatureheating
  3. waitcontinued for 1 hour
  4. temperatureThe mixture was cooled to room temperature
  5. concentrationconcentrated
  6. customThe residue was partitioned between EtOAc (10.0 mL) and water (2.0 mL)
  7. washThe organic layer was washed with saturated aqueous NaHCO3 (3.0 mL), saturated aqueous NaCl (3.0 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. stirringthe resulting mixture was stirred at room temperature for 1 hour
  12. washThe solids were washed with AcOH (1.0 mL)
  13. filtrationthen filtered
  14. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-97e85896bde443e6bf2fd339dc4d96f3
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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