Dihydropyridines → Ethyl orthoformate

HRID 2090216Notes

Reaction equation

HRID 2090216 reaction equation
[CH:1]([C:3]1C=CC(C#N)=[CH:5][C:4]=1[O:11][CH3:12])=O.NC1C=CN[C:16](=[O:20])[CH:15]=1.FC(F)(F)C(=O)[CH2:24][C:25](OCC=C)=[O:26].N1C=CC=CC1.[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[C:57]3[C:56](=[O:58])[NH:55][CH:54]=[CH:53][C:52]=3[NH:51][C:50](O)([C:59]([F:62])([F:61])[F:60])[CH:49]2[C:64]([O:66][CH2:67][CH:68]=[CH2:69])=[O:65])=[C:44]([O:70][CH3:71])[CH:43]=1)#[N:41]>C(O)C.C(O)(=O)C>[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[C:57]3[C:52](=[CH:53][CH:54]=[N:55][C:56]=3[O:58][CH2:1][CH3:3])[NH:51][C:50]([C:59]([F:62])([F:60])[F:61])=[C:49]2[C:64]([O:66][CH2:67][CH:68]=[CH2:69])=[O:65])=[C:44]([O:70][CH3:71])[CH:43]=1)#[N:41].[CH:12]([O:11][CH2:4][CH3:5])([O:20][CH2:16][CH3:15])[O:26][CH2:25][CH3:24]

Participants

9

Reactant 5

HCID 407038DihydropyridinesHCID 5735304-Amino-1,2-dihydropyridin-2-oneHCID 11194917HCID 11194917, compoundHCID 166592514-Formyl-3-methoxybenzonitrileHCID 68598827HCID 68598827, compound

Product 2

HCID 31214Ethyl orthoformateHCID 68601506HCID 68601506, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent

Procedure

The title compound can be obtained starting from stoichiometric amounts of 4-formyl-3-methoxybenzonitrile (Example 10A), 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and allyl 4,4,4-trifluoro-3-oxobutanoate [Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)]. This entails firstly the dihydropyridine synthesis being carried out in ethanol without addition of additives at the reflux temperature overnight. The initially resulting intermediate allyl 4-(4-cyano-2-methoxyphenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate can then be dehydrated with acetic acid in a literature-based process [cf. Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)]. Subsequently, allyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate can be obtained by reaction with triethyl orthoformate in analogy to the synthesis of Example 29A. Final allyl ester cleavage using Wilkinson's catalyst [tris(triphenylphosphine)rhodium(I) chloride] in acetic acid affords the title compound [cf. Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)].

Sources & evidence

ORD record
ord-8d253e0d3acb4d3291af3baa49085408
Source dataset
uspto-grants-2013_05
Patent number
US08436180B2

Reaction notes

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