Aniline → Ethyl 6-acetyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate

HRID 502938Notes

Reaction equation

HRID 502938 reaction equation
NC1C=CC=CC=1.C(OC=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.[C:23]([O-])(=O)[CH2:24][C:25]([O-:27])=[O:26].[CH2:30]([O:32][C:33]([C:35]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:46](=[O:48])[CH3:47])[CH:42]=2)[NH:37][CH:36]=1)=[O:34])[CH3:31].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56]Br)=[CH:52][CH:51]=1.C(OCC)(=O)C(OCC)=[O:60].[O-]CC.[Na+]>>[CH2:30]([O:32][C:33]([C:35]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:46](=[O:48])[CH3:47])[CH:42]=2)[NH:37][CH:36]=1)=[O:34])[CH3:31].[C:25]([CH2:24][CH2:23][C:35]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:46](=[O:48])[CH2:18][C:12](=[O:60])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:42]=2)[N:37]([CH2:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[CH:36]=1)([OH:27])=[O:26]

Participants

9

Reactant 7

HCID 6115AnilineHCID 6871Diethyl (ethoxymethylene)malonateHCID 7268Diethyl OxalateHCID 9084Malonate IonHCID 680214-Fluorobenzyl bromideHCID 735356Ethyl 6-acetyl-1,4-dihydro-4-oxo-3-quinolinecarboxylateHCID 2723922Sodium ethoxide

Product 2

HCID 735356Ethyl 6-acetyl-1,4-dihydro-4-oxo-3-quinolinecarboxylateHCID 86615219HCID 86615219, compound

Procedure

Scheme 2 below shows an illustrative chemical pathway for the synthesis of the compounds described above in Table 2. The 1,4-dihydro-6-acetyl-4-oxoquinoline-3-carboxylic acid ethyl ester 8 was prepared according to Koga et al., Journal of Medicinal Chemistry 23:1358-1363, 1980, by reacting the appropriate aniline with diethyl ethoxymethylenemalonate followed by thermal cyclization of the malonate derivative obtained. Alkylation of compound 8 with 4-fluorophenylmethylbromide in alkaline medium led to derivative 9 that was condensed with diethyl oxalate in presence of the sodium ethoxide to afford 4-[3-carboxyethyl-1,4-dihydro-1-(4-fluorophenyl)methyl-4-oxoquinolin-6-yl]-2,4-dioxobutanoic acid, ethyl ester 10 (RDS 1606). Alkaline hydrolysis of the latter compound to provide 4-[3-carboxyethyl-1,4-dihydro-1-(4-fluorophenyl)methyl-4-oxoquinolin-6-yl]-2,4-dioxobutanoic acid 11 (RDS 1607) was carried out with aqueous 1N sodium hydroxide at room temperature, while hydrolysis of the quinolinecarboxylate ester 9 to afford corresponding acid 12 required 20% aqueous sodium hydroxide (Scheme 2).

Workup

  1. customScheme 2 below shows an illustrative chemical pathway for the synthesis of the compounds

Sources & evidence

ORD record
ord-054520bb315b4f1cadf5351ae818b530
Source dataset
uspto-grants-2010_08
Patent number
US07776883B2

Reaction notes

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