Tetrahydrofuran → Ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate

HRID 1748368Notes

Reaction equation

HRID 1748368 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C([CH:12]([CH2:16][C:17](Cl)=[O:18])[C:13](Cl)=[O:14])C.C1C[O:23]CC1.C(N([CH2:30][CH3:31])CC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:17](=[O:18])[CH2:16][CH2:12][C:13]([O:14][CH2:30][CH3:31])=[O:23])[CH:6]=[CH:7][CH:8]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 108243-MethoxyanilineHCID 218646082-Ethylbutanedioyl dichloride

Product 1

HCID 14946361Ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate

Procedure

According to Scheme A, ethyl 2-(7-hydroxyquinolin-3-yl)acetate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is treated with ethyl succinyl chloride in a solvent such as THF, a suitably selected tertiary organic base such as triethylamine (TEA), and the like, at a temperature between 0° C. to about 65° C. and the reflux temperature of the solvent, to afford ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate. Subsequent chlorination and cyclization of ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate with phosphoryl chloride and DMF, at temperatures ranging from 0° C. to about 80° C., preferably 0° C. for 20 minutes followed by 75° C. for 1.5 h, provides ethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate (VIa) and ethyl 2-(2-chloro-5-methoxyquinolin-3-yl)acetate (VIb). Reduction of compounds (VIa) and (VIb) employing conditions known to one skilled in the art, for example Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, provides ethyl 2-(7-methoxyquinolin-3-yl)acetate (VII). Demethylation of ethyl 2-(7-methoxyquinolin-3-yl)acetate (VII), employing conditions known to one skilled in the art, for example, HBr in H2O or HOAc, at temperatures ranging from 95° C. to about 110° C., preferably 105° C., for a period of about 48 to 96 h, preferably 96 h. Subsequent esterification of 7-hydroxy-2-quinoline-3-carboxylic acid employing methods previously described provides ethyl 2-(7-hydroxyquinolin-3-yl)acetate (VIII).

Sources & evidence

ORD record
ord-0d34bbdfba7742cbb912c630f7fd8592
Source dataset
uspto-grants-2015_10
Patent number
US09150572B2

Reaction notes

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