Acetic Acid → HCID 15981235, compound

HRID 271169Notes

Reaction equation

HRID 271169 reaction equation
[NH2:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=O.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N>C(Cl)Cl.CO>[Cl:20][C:4]1[CH:3]=[C:2]([NH:1][CH2:23][C:22]([OH:26])=[O:25])[CH:18]=[C:17]([Cl:19])[C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 24083Sulfuric acid magnesium salt (1:1)HCID 498716Cyano-borohydrideHCID 15620607Glyoxylic acid, monohydrateHCID 598344606-(4-Amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one

Product 1

HCID 15981235HCID 15981235, compoundYield 17%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

Procedure

A solution of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2H-pyridazin-3-one (25) (500 mg, 1.59 mmol) in methylene chloride (22 mL) and methanol (22 mL) at room temperature was treated with glyoxylic acid monohydrate (292 mg, 3.17 mmol), glacial acetic acid (0.10 mL, 1.74 mmol), a small spatula tip of magnesium sulfate, and resin bound cyanoborohydride (Argonaut Technologies Inc. MP-(CN)BH3, 0.97 g, 2.39 mmol). The reaction mixture was heated to 50° C. for 24 h. The reaction mixture was then cooled to room temperature, filtered through celite, and rinsed with chloroform. A 1N aqueous hydrochloric acid solution (150 mL) was added to the filtrate. The resulting mixture was stirred for 30 min. The organic layer was separated. The water layer was extracted with chloroform (100 mL). The organic layers were combined, methanol (10 mL) was added to dissolve insoluble material and the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was slurried with ether (3 mL) and diluted with petroleum ether (10 mL). The mixture was stirred for 45 min. The solids were collected by filtration and rinsed with petroleum ether. A small amount of higher Rf impurity was present by TLC. The solid was purified by flash chromatography (Biotage 40L) using silica gel eluted with 100% ethyl acetate followed by 0.4% glacial acetic acid in ethyl acetate. The desired fractions were collected and concentrated under vacuum. The solid was diluted with 1:1 methylene chloride:hexanes and concentrated under vacuum. The solid was slurried in petroleum ether, filtered, rinsed with petroleum ether and dried under high vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenylamino]-acetic acid (26) (98.7 mg, 17%) as a white solid; LRMS for C15H15Cl2N3O4 (M+) m/z=372. Molecular Weight=372.2105; Exact Mass=371.0440

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. filtrationfiltered through celite
  3. washrinsed with chloroform
  4. additionA 1N aqueous hydrochloric acid solution (150 mL) was added to the filtrate
  5. customThe organic layer was separated
  6. extractionThe water layer was extracted with chloroform (100 mL)
  7. additionmethanol (10 mL) was added
  8. dissolutionto dissolve insoluble material
  9. dry with materialthe organic layer was dried with magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. additiondiluted with petroleum ether (10 mL)
  13. stirringThe mixture was stirred for 45 min
  14. filtrationThe solids were collected by filtration
  15. washrinsed with petroleum ether
  16. customThe solid was purified by flash chromatography (Biotage 40L)
  17. washeluted with 100% ethyl acetate
  18. customThe desired fractions were collected
  19. concentrationconcentrated under vacuum
  20. additionThe solid was diluted with 1:1 methylene chloride
  21. concentrationhexanes and concentrated under vacuum
  22. filtrationfiltered
  23. washrinsed with petroleum ether
  24. customdried under high vacuum overnight

Sources & evidence

ORD record
ord-aab2ed6c393d4bac90e04cb913704f5d
Source dataset
uspto-grants-2008_11
Patent number
US07452882B2

Reaction notes

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