Naphthyridinones, synthesis

A palladium-catalyzed amidation of halo(hetero)aromatics substituted in the ortAo-position by a carbonyl function with a primary or secondary amine has been introduced as an alternative to the Friedlander condensation for the synthesis of naphthyridinones (and quinolinones) (Scheme 32) <2004OL2433>. 

Most such naphthyridinones have been made by primary synthesis (see Chapter 1) and some by hydrolysis of halogeno-1,5-naphthyridines (see Section 3.2.3). Other preparative routes are illustrated by the following examples. 

Note Most of these naphthyridinones have been made by either primary synthesis (see Chapter 1) or alkylation of tautomeric 1,5-naphthyridinones (see Section 4.1.2). A third route, involving direct oxylation, is illustrated here. 

Note All reported alkoxy-l,6-naphthyridines appear to have been made by primary synthesis (see Chapter 8), alcoholysis of halogeno-l,6-naphthyri-dines (see Section 10.2.1), or O-alkylation of 1,6-naphthyridinones (see Section 11.1.2). 

Two important routes to 1,8-naphthyridinones have been covered already by primary synthesis (Chapter 22) and the hydrolysis of halogeno- 1,8-naphthyridines... 

Note Alkoxy/aryloxy-l,8-naphthyridines have been made by primary synthesis (see Chapter 22), by alcoholysis/phenolysis of halogeno-l,8-naphthyridines (see Section 24.2), by alkylation of 1,8-naphthyridinones (see Section 25.1.2), and by two minor procedures illustrated here. 

The only reported route to such naphthyridinones is by primary synthesis (see Section 30.1), but a few do occur naturally as alkaloids in several Oleaceae species jasminine, methyl 8-methyl-6-oxo-5,6,7,8-tetrahydro-2,7-naphthyri-dine-4-carboxylate (75, R = C02Me) 577 jasminidine, 1-methyl-1,4-dihydro-... 

Chloronicotinoyl chloride 95 was used as the starting compound in the synthesis of hetaryl annulated 1,6-naphthyridines. Its reactions with 4,5-dihydro-1//-imidazolines 96a or tetrahydropyrimidines 96b gave the corresponding A-acyl derivatives 97a,b, which underwent cyclization with potassium Arf-butoxide to yield imidazo- 98a or pyrimido[l,2-gr[[l,6]naphthyridinones 98b, respectively. Compounds 98a,b exhibit antiallergic and anti-inflammatory activitives (1990JHC189, 1990USP5070086). 

Diazotization of the amine of 313 with sodium nitrite in 10% H2S04 afforded naphthyridinone 314, used as the starting compound in the synthesis of the antagonist of benzodiazepine receptors 315 (1993USP5367078, 1994USP5424433, 1994USP5424434). 

Much later, an alternate synthesis of naphthyridinones and quinoli-nones was discovered. Palladium-catalyzed amidation of halo aromatic rings with an ortho carbonyl group with primary or secondary amides to from substituted naphthyridinones and quinolinones (Scheme 97) (04OL2433). 

Naphthyridines have been prepared by means of a Niementowski synthesis from ethyl 2-amino-6-phenylnicotinate and by means of Friedlander synthesis from 2-aminonicotinaldehydes. Ethyl 2-amino-6-phenylnicotinate (IX lll), which is readily prepared from ethyl a-ethoxycarbonyl acetimidate and benzoylacetaldehyde, condenses with the simple esters (DC-122 R = H, CH3, CfiHs) in the presence of sodium to give good yields of 1,8-naphthyridinones (IX-113). 

Design, synthesis and bioiogicai activity of a novel series of naphthyridinone derivatives as potent p38a MAP kinase inhibitors for the treatment of rheumatoid arthritis... 

Ferraritii PL, Mori C, Primofiore G, Calzolari L (1990) One step synthesis of pyrimido[l,2-rj] [l,8]naphthyridinones, pyrido[l,2-a]pyrimidinones and 1,8-naphthyridinones. Antihypertensive agents. V. J Heterocycl Chem 27 881-886... 

Chung and co-workers [24] at Merck reported a multikilogram synthesis of naphthyridinone 55, a p38 MAP kinase inhibitor for the treatment of rheumatoid arthritis, Crohn s disease, and psoriasis. An improved biphasic Suzuki coupling of chloronaphthyridinone 52 and 2,4-difluorophenylboionic acid 53, catalyzed by Pd(OAc) gave drug precursor 54 in 91% yield (Scheme 9.14). 

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