2- -6,7-dihydro-4//pyrimido isoquinolin-4-ones

Fluorophenyl)-l ]-hydroxy-2,3,4,1 ]-tetrahydro-6/7-pyrimido[],2-Z)]-isoquinolin-6-one was obtained in the reaction of l-(4-fluorophenyl)-3-oxo-],3-dihydro-2-benzofuran-l-carboxamide and 1,3-diaminopropane in boiling toluene (01BMCL339). 

Reaction of 2-chloro-6,7-dihydro-4//-pyrimido[6,1 -a]isoquinolin-4-ones with liquid NH3 in a pressure bomb at 85 °C for 4h, and with primary and secondary amines in boiling CHCI3 (98MIP15), and anilines in boiling i-PrOFI (00MI17) yielded 2-amino-6,7-dihydro derivatives or their 2,3,6,7-tetrahydro-2-imino tautomers. 

Aryloxy-9,10-dimethoxy-6,7-dihydro-4//-pyrimido[6,1 -a]isoquinolin-4-ones formed in the reaction of 2-chloro derivative and phenols in the presence of K2CO3 in DMF at 90 °C for 2. 5 h or in boiling 2-PrOH for 6-24 h (00MIP20). When 2-isobutylphenol was used the reaction was carried out in the presence of BuLi in THF at —78 °C. 

Treatment of pyrimidine-2-thione 184 with A1C13 yielded 6-oxo-6,7-dihydro-4//-pyrimido[6,l-tf]isoquinolin-4-thione 185 (Equation 37) <1998MI337>. Cyclization of 6,7-diethoxy-2-propylaminocarbonyl-l,2,3,4-tetrahydroisoquinoline-l-acetonitrile using NaOMe afforded 9,10-diethoxy-2-imino-3-propyl-l,2,4,6,7,l lb-hexahydropyrimido[6,l-tf]isoquinolin-4-one <1995S863>. Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquinazoline-2,4-dione 186 in polyphosphoric acid (PPA) afforded l,2,3,5,6,7-hexahydropyrimido[3,2,T /]quinazoline-l,3,7-trione 187 (Equation 38) <1997CHE96>. 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Ethyl l-(arylimino)-l//-pyrido[l,2-c]pyrimidine-3-carboxylates exhibited anti-inflammatory activities in the carrageenan mouse paw edema model <2001JME1011>. 2-Arylimino-2,3,6,7-tetrahydro- <2000W020/058308> and 2-aryloxy-6,7-dihydro-477-pyrimido[6,l- ]isoquinolin-4-ones <2000W020/0558309> were patented as PDE inhibitors and as useful agents for treatment of respiratory disorders, respectively. 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

Oxidation of dimethyl l-phenyl-2-oxo-l,2-dihydro-llb//-pyrimido[2,l-a]-isoquinoline-3,4-dicarboxylate (64) by potassium permanganate either in acetone or in aqueous potassium hydroxide, followed by treatment with ethereal diazomethane, gave isocarbostyril and methyl oxanilate, respectively (67CB1094). Oxidation of 4-phenyl-2//-pyrimido[2,l-a]isoquinolin-2-one with potassium permanganate in a 1 5 mixture of pyridine and 2 N potassium hydroxide yielded 2-(2-carboxyphenyl)-6-phenylpyrimidin-4(3//)-one (72CB108). 2-Methyl-4//-pyrimido[2,l-a]isoquinolin-4-one and 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione with potassium permanganate afforded phthalimide in low yield. 

Catalytic hydrogenation of 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-diones (93) and 3,3-diethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (94) over Pt02 and Pd/C catalysts gave l,3,4,6,7,llb-hexahydro-2/7-pyrimido[2,l-a]isoquinoline-2,4-diones (95) [69YZ649 71JPP71/09466]. From the mother liquid of compounds 93 (R = H, R1 = Et and R = R1 = Et) 3-ethyl-2-hydroxy-6,7-dihydro-and -8,9,10,1 l-tetrahydro-4//-pyrimido[2,l-a]isoquinolin-4-ones, and 3,3-diethyl-l,3,4,llb-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione, also could be isolated as minor products. Reduction of 3,3-diethyl-l,3,4,6,7,llfo-hexahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (95, R = R1 = Et, R2 = H) with LAH in tetrahydrofuran at 70°C for 9 h afforded 3,3-diethyl-l,3,4,6,7,llb-hexahydro-2//-pyrimido[2,l-a]isoquinoline (96). 

Cyclization of ethyl JV-(l-isoquinolyl)-2-ethylmalonamate at 200°C yielded 3-ethyl-2-hydroxy-4//-pyrimido[2,l-a]isoquinoline-4-one (69YZ-649). 3,3-Diethyl-3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (65) was obtained by heating ethyl JV-(l-isoquinolyl)-2,2-diethylmalonamate (66) in acetic acid at 160-170°C for 4.5 h. 

Cyclization of 3-(l-imino-l,2-dihydro-2-isoquinolyl)propionic acid (273), prepared by the reaction of 1-aminoisoquinoline and acrylic acid or propi-olactone, afforded 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2-one (274) in the presence of p-toluenesulfonic acid (72GEP2142792). 

Photochemical rearrangement of /i ydro-l-hydroxy-3-methyl-6,7-dihydropyridazino[3,2-a]isoquinolinium hydroxide (354) to 2-methyl-6,7-dihydro-4//-pyrimido[2,l-a]isoquinoline-4-one (355) occurred in methanol irradiating for 4-10 h with a 200 W high-pressure mercury lamp through a quartz tube under nitrogen at room temperature [77H(8)377]. 

V-(2-Arylethyl)ureas (405) and malonic acid in phosphoryl chloride at 105-110°C gave 2-chloro-6,7-dihydro-4//-pyrimido[2,l-a]isoquinolin-4-ones (406) (81GEP3006478 90T1323). 

Dihydro-4H-pyrimido[6,l-fl]isoquinolin-4-one 148 did not blocked nicotinic acid adenosine dinucleotide phosphate signaling (09NCB220). 

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