Isatin → HCID 54137095, compound
Reaction equation
[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C1[N:16]2[C:17]3C(C=CC2=CN=1)=CC=CC=3.C(OC(=O)C)(=[O:27])C.C(OC(=O)CC)(=O)CC>>[N:1]1([C:17]([NH2:16])=[O:27])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]Participants
Procedure
CHART B discloses one of the general processes for the transformation of isatin (III) to amide or ketone (VI) and the subsequent conversion of this compound to imidazo[1,5-a]quinoline (I). The substituted isatin precursors (III) are either commercially available or are known to those skilled in the art. Following the general procedure of Camp (Arch. Pharm., 237, 687 (1899)) the appropriately substituted isatin (III) was acylated with either acetic anhydride or propionic anhydride to provide isatin amide (IV). Generally these reactions were carried out in a solvent such as THF in the presence of dimethylaminopyridine, between 20-25° and that of the solvent system at reflux. Reaction of isatin amide (IV) with 1 N sodium hydroxide or 1 N potassium hydroxide at reflux, in the presence or absence of THF, provides the appropriately substituted 2-hydroxyquinoline-4-carboxylic acid (V). Alternatively, the substituted 2-hydroxyquinoline-4-carboxylic acid (V) may be formed directly from isatin (III) by reaction of isatin (III) with malonic acid in THF at reflux and then removal of the solvent under reduced pressure, heating the crude material in water at reflux. This is the preferred method when R4 and R6 are hydrogen and R7 is --Cl. Reaction of the acid (V) with thionyl chloride at reflux provides an intermediate acid chloride (V-A) upon concentration. Exposure of this crude acid halide (V-A) to the desired amine in an inert solvent such as methylene chloride or THF in the presence of an acid scavenger such as Hunig's base or triethylamine between 0→25° gives the desired amide intermediate (VI).
Sources & evidence
- ORD record
- ord-fee5ef54edfe470f9e18459368fa2151
- Source dataset
- uspto-grants-1999_08
- Patent number
- US05935970
Reaction notes
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