Ethanethiol → 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione

HRID 901221Notes

Reaction equation

HRID 901221 reaction equation
C(S)C.[H-].[Na+].[CH2:6]([O:8][C:9](=[O:30])[C:10]1[CH:15]=[C:14]([F:16])[C:13](SCC)=[N:12][C:11]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)C.C([O:33]C(=O)C1C=C(F)C(SCC)=NC=1Cl)C.C(OC(=O)C1C=C(F)C=NC=1NCC1C=CC(OC)=CC=1)C.ClC(OC(Cl)=O)(Cl)Cl>[Ni].C(O)C>[F:16][C:14]1[CH:13]=[N:12][C:11]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:6](=[O:33])[O:8][C:9](=[O:30])[C:10]=2[CH:15]=1

Participants

9

Reactant 6

HCID 6343EthanethiolHCID 10426DiphosgeneHCID 24758Sodium hydrideHCID 589458085-Fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester2×HCID 596996322-Chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl esterHCID 596996366-Ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester

Product 1

HCID 596996236-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 702EthanolSolvent

Procedure

2,6 Dichloro-5-fluoro-nicotinic acid was selected as a starting material to make the compounds of structure (Ia) with fluoro substitution at 6-position of naphthyridine moiety. 2,6 Dichloro-5-fluoro-nicotinic acid was esterified by treating with thionyl chloride followed by refluxing with dry ethanol to yield 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester, depicted by formula 21 in Scheme 10. This ester gave 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, depicted by formula 22 in Scheme 10, when reacted with ethanethiol and sodium hydride. 6-Ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 23 in Scheme 10, was prepared by amination of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, which was converted into 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 24 in Scheme 10, by refluxing with ethanol and raney nickel. 5-Fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester was then reacted with trichloromethylchloroformate to yield 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione, depicted by formula 25 in Scheme 10. The sequence of reactions is shown in Scheme 10.

Sources & evidence

ORD record
ord-8a3fc5ead2f24c1490cff1d80d9a8070
Source dataset
uspto-grants-2008_04
Patent number
US07361760B2

Reaction notes

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