Pyrimido isoquinoline-3-carboxylates

Lithiation of 2-(2-alkylphenyl)-l,2,3,4-tetrahydropyrimidines 427 with 1.3 M BuLi in the presence of A/, A/, A, A -tetramethylethylenediamine, then with 1.3 M -BuLi, followed by the addition of a carboxylic acid methyl ester, and treatment of the reaction mixture with pTSA afforded 3,4-dihydro-2/f-pyrimido[2,l-u]isoquinolines 428 after chromatographic work-up (98JMC1050). 

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. 

The reaction of 1-aminoisoquinolines and EMME by heating in boiling DMF for 18 hr yielded pyrimido[2,l- ]isoquinoline-3-carboxylates (1059) (85EUP143001). 

Semiempirical molecular calculations (AMI) suggested that ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylate (20) has a lower heat of formation (by ca 42 kJ mol-1) than its 4-hydroxy-2-oxo tautomer (89AJC2161). 

A nitro group at positions 8,10, and 11 on ethyl 4-oxo-//-pyrimido[2,l-a]-isoquinoline-3-carboxylate was reduced to an amino group by treatment with iron powder and ammonium chloride in boiling aqueous ethanol (85EUP143001). 

Hydrogenation of 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-nitrile in tetrahydrofuran in the presence of ammonia over Raney nickel under 60 psi for 5 h yielded 3-aminomethyl-4//-pyrimido[2,l-a]isoquinolin-4-one (86EUP166439). Reduction of ethyl 4-oxo-4//-pyrimido[2,l-a]isoquino-line-3-carboxylate with diisobutylaluminum hydride in methylene chloride... 

Oxidation of ethyl 7-allyl-10-methoxy-4-oxo-6,7-dihydro-4//-pyrimido-[2,l-a]isoquinoline-3-carboxylate (99) by ozone in methylene chloride at -70°C, then treatment of the mixture with dimethyl sulfide at ambient temperature for 1 h gave either 7-(2-oxoethyl)- or 7-(2,2-dimethoxyethyl) derivatives (105 and 106), depending upon whether methanol was used during the workup (78USP4127720). 

Reaction of 1,2,3,4-tetrahydro-6//-pyrimido [1,2-b]isoquinolin-6-one (116) and maleic acid in boiling ethanol afforded tetracyclic carboxylic acid 117 (88HCA77). 

Reaction of ethyl ll-cyano-4-oxo-7,8,9,10- tetrahydro-4//-pyrimido[l,2-b]-isoquinoline-3-carboxylate (118 with A,iV-dimethylformamide diethyl acetal in boiling benzene in the presence of aluminum chloride afforded 10-dimethylaminomethylene derivative 119 (84KFZ931). 

The hydroxyl group of ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l-a]-isoquinoline-3-carboxylate (20) was methylated with methyl iodide in dry boiling acetone for 5 h in the presence of potassium carbonate, with dimethyl sulfate in methylene chloride in methanol in the presence of Triton B at 20°C for 18 h, with methyl fluorosulfonate in 2.5 M sodium hydroxide at 20°C for 5 h, and with diazomethane in a mixture of diethyl ether and methylene chloride at 20°C for 3 h to give the 2-methoxy derivative (89AJC2161). The hydroxy group of 3-hydroxymethyl-4//-pyrimido[2,l-b]-isoquinolin-4-one was alkylated and acylated with 2-(diethylamino)ethyl chloride in dimethylformamide in the presence of sodium hydroxide, and with acetic anhydride in boiling chloroform in the presence of triethylamine and a few drops of 4-dimethylaminopyridine, respectively (86EUP 166439). 

Oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylic acids and their 6,7-dihydro derivatives were prepared by the hydrolysis of ethyl 4-oxo-4H-pyrimido[2,l-a]isoquinoline-3-carboxylates (97) and their 6,7-dihydro derivatives (98) under acidic (in a boiling mixture of acetic acid and cone, hydrochloric acid) and basic conditions (in 2% sodium hydroxide solution, and in a boiling mixture of 2% sodium hydroxide and ethanol) [78USP4127720 84JAP(K)84/172472 85EUP143001]. 

A-(l//-5-Tetrazolyl)-10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxamide was prepared on treatment of the 3-carboxylic acid with l,l -carbonyldiimidazole in dimethyl-formamide at ambient temperature under nitrogen, then with 5-amino-lH-tetrazole at 100°C for 1 h (85EUP143001). Treatment of lO-(acylamido)-... 

The carboxyl group of 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylic acids was esterified with various alcohols [84JAP(K)84/172490] and was converted into N-substituted 3-carboxamides by treatment with ethyl chloroformate in the presence of triethylamine in methylene chloride, followed by amines and hydroxylamine at 0°C [84JAP(K)84/172490 85EUP143001]. 

Heating 3-bromo-2-methyl-4//-pyrimido[2,l -a]isoquinolin-4-one (152) in 10% sodium hydroxide for 5 h afforded 2-methylimidazo[2,l-a]isoquino-line (190, R = H) and its 3-carboxylic acid derivative (190, R = COOH) in 74% and 19% yields, respectively (80KGS1656). 

Diethyl ethoxymethylenemalonate with 1-aminoisoquinolines in di-methylformamide at 120-140°C for 22 h and with l-amino-3,4-dihydroiso-quinolines in boiling toluene for 15 min gave ethyl 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylates (97 and 98) (78USP4127720 85EUP143001). 

Aminoisoquinoline and ethyl ethoxymethylenecyanoacetate at 105-110°C for 10 min under nitrogen gave ethyl 4-imino-4//-pyrimido[2,l -a]isoquinoline-3-carboxylate (321) in 67% yield. From the mother liquid, condensation product 322 could also be isolated in 27% yield (78USP4127720). 

Flash vacuum pyrolysis of 357 (R = H, Me) at 530°C/0.01 mmHg gave imidazo[2,l-a]isoquinolines (368) with only traces of other products provided that the sublimation temperature was maintained about 25 °C below the melting point (92AJC1811 93T8147). If compounds 357 (R = H) were allowed to melt during the flash vacuum pyrolysis, or if the pyrolysis was carried out in the condensed phase, a number of products was obtained ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l- ]isoquinoline-3-carboxylate (20) was a major component (93T8147). 

Selective inhibition of cyclic AMP-dependent protein kinase by isoquinoline derivatives, among them by ethyl 4,6-dioxo-l,4-dihydro-6//-pyrimido[l,2-b]isoquinoline-3-carboxylate (199) and 4-amino-6-oxo-6//-pyrimido[l,2-h]isoquinoline-3-carboxylate and 3-nitrile (201), was investigated (96MI7). 

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