Diethyl (ethoxymethylene)malonate → HCID 178507815, compound

HRID 1168490Notes

Reaction equation

HRID 1168490 reaction equation
[N+](C1C=CC=CC=1N)([O-])=O.ICl.C(OC=C(C(OCC)=O)C(OCC)=O)C.[NH2:28][C:29]1[CH:47]=[C:46]([I:48])[CH:45]=[CH:44][C:30]=1[NH:31][CH:32]=[C:33]([C:39]([O:41]CC)=O)[C:34]([O:36]CC)=O.OC1C2C(=C([N+]([O-])=O)C=C(I)C=2)N=CC=1C(OCC)=O.NC1C=C(I)C=C2C=1N=CC(C(OCC)=O)=C2O.[Cl:87][C:88]1[CH:95]=[CH:94][C:91]([CH2:92][NH2:93])=[CH:90][CH:89]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>[NH2:28][C:29]1[CH:47]=[C:46]([I:48])[CH:45]=[C:44]2[C:30]=1[N:31]=[CH:32][C:33]([C:34]([NH:93][CH2:92][C:91]1[CH:94]=[CH:95][C:88]([Cl:87])=[CH:89][CH:90]=1)=[O:36])=[C:39]2[OH:41]

Participants

9

Reactant 7

HCID 6871Diethyl (ethoxymethylene)malonateHCID 69462-NitroanilineHCID 24640Iodine chlorideHCID 660364-ChlorobenzylamineHCID 22992123HCID 22992123, compoundHCID 178469662HCID 178469662, compoundHCID 178469670HCID 178469670, compound

Product 1

HCID 178507815HCID 178507815, compound

Reagents, catalysts & solvents 1

HCID 246701,1'-Biphenyl, mixt. with 1,1'-oxybis(benzene)Solvent

Procedure

6-Oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides The preparation of specific examples of heterocycle W1.1 is described in Chart A. 2-Nitroaniline is iodinated with iodine monochloride to afford A.1 (Wilson, et.al., Aust. J. Chem., 1983, 36, 2317-2326) which is heated with diethyl ethoxymethylenemalonate in a mixture of diphenyl ether/biphenyl, initially at 150° C. to generate diethyl 2-[(2-amino-4-iodoanilino)methylene]malonate and then at 240° C. to cyclize this intermediate to ethyl 4-hydroxy-6-iodo-8-nitro-3-quinolinecarboxylate (A.2). Stannous chloride reduction of A.2 affords ethyl 8-amino-4-hydroxy-6-iodo-3-quinolinecarboxylate A.3 which reacts with 4-chlorobenzylamine to give 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide A.4. Intermediate A.4 reacts with ethyl orthoformate to give N-(4-chlorobenzyl)-8-iodo-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide (A.5). Palladium mediated carbonylation of A.5 in presence of tributyl tin hydride or trioctylsilane (Kotsuki et. al., Synthesis 1996, 470) affords A.6 which is reductively aminated with morpholine and sodium cyanoborohydride to give A.7. Specific examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart B. Palladium catalyzed coupling of A.5 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) gives B.1 (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. or Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula B.2 (Z=CH2OH).

Workup

  1. customto afford A.1 (Wilson, et.al., Aust. J. Chem., 1983, 36, 2317-2326) which
  2. customat 240° C.

Sources & evidence

ORD record
ord-aaff59a0208d4f268e1e31535e238792
Source dataset
uspto-grants-2003_09
Patent number
US06624159B2

Reaction notes

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