4- pyrimido

Dimethoxy-2-(arylimino)-2,3,6,7-tetrahydro-4//-pyrimido[6,1 -n]iso-quinolin-4-ones were N-alkylated with A-(catalytic amount of I2 in boiling 2-butanone in 13-67% yields (00MIP19). 

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. 

Cyclocondensation of a-aryl-2-pyridylacetamides and 2-(3,4-dihydroiso-quinolin-l-yl)acetamide with Et2C03 in the presence of NaOEt in boiling EtOH afforded 4-aryl-2,3-dihydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones (99JHC389) and 6,7-dihydro-4//-pyrimido[6,1 -a]isoquinoline-2,4-dione (98MIP15), respectively. 

Cyclization occurred at the N-3 atom when 4-(3-bromopropylaruino)-l, 6,7,1 1 b-tctrahydro-2//-pyrimido[6,l -zz -isoquinoline was treated with NaH to give a tetracyclic derivative <2003M1271>. 9,10-Dimethoxy-2-(arylimino)-2,3,6,7-tetrahydro-4//-pyrimido[6,l- ]isoquinolin-4-ones were N-3-alkylated with iV-(ra-bromoalkyl)phthalimides in the presence of K2C03 and a catalytic amount of I2 in boiling 2-butanone in 13-67% yields <2000W020/058308>. Treatment of the 2-[(4-methoxyphenyl)methyl] derivative of 2,3,6,7-tctrahydro-l //,5//-pyrido[3,2,l-/ylqninazolinc-... 

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-pyridineacetamides 197 with Me2NCH(OMe)2 afforded 3//-pyrido[l,2-f]pyrimidin-3-ones 198 (Equation 42) <1998WO98/027098, 2000USP6147080>. Reaction of l-(2-aminocthyl)-l, 2,3,4-tetrahydroisoquino-lincs with CS2, C(OEt>4, and nitroguanidine gave 1,2,3,6,7,1 1 h-hexahydro-4//-pyrimido[6,l -<2 isoquinoline-4-thiones, 4-ethoxy-1,6,7,1 lb-tetrahydro-2//-pyrimido[6,l -zz isoquinolines, and 4-(nitroimino)-l,2,3,6,7,l lb-hexahydro-... 

Partial saturation of the pyridazino ring of 3-acylamino-4//-pyrimido[l,2-A pyridazin-4-ones and the pyrazino ring of 3-acylamino-4//-pyrazino[l,2-tf]pyrimidin-4-ones in EtOH/AcOH system using Pd/C catalyst, resulted in the respective 6,7,8,9-tetrahydro derivatives in good yields <2000JHC783>. 

Amino 4-oxo 4//-pyrimido[l,2-4]pyridazin-3-diazonium tetrafluoroborates 73 underwent ring transformation into l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 74 on heating in dry MeOH. Yields dropped drastically when EtOH, instead of MeOH, was used as solvent (Equation 6) <2002ARK143>. 

The [l,2,4]triazolo[4, 3 3,4]pyrimido[2,l-c][l,2,4]triazines 253 were prepared (75G1029) by cyclization of hydrazine 251 with phenacyl bromides, which took place via 252. 

Mild hydrolysis of ethyl 4-oxo-4//-pyrimido[l,2-a]pyridazine-3-carboxylate in 0.1 N sodium hydroxide solution at room temperature afforded monoethyl (3-pyridazinylamino)methylenemalonate (68TL33). 

The thermal cyclization of isopropylidene A-(2-unsubstituted 4-pyrimidinyl)aminomethylenemalonates gave 4//-pyrimido[l, 6-a]pyrim-idin-4-ones (90JMC1963), while that of isopropylidene (2-substituted 4-pyrimidinyl)aminomethylenemalonates afforded 5-hydroxypyrido[2,3- /] pyrimidines (90SL549). 

USP3969506]. Reductive cyclization of 2-methylthio-l-(2-nitrobenzyl]-6-pyrimidines (515) with stannous chloride gave 6,1 l-dihydro-4//-pyrimido[2,l-fc]quinazolin-4-ones (516) (78JHC77). 

Pyrrolo[ l, 2 -3,4]pyrimido[2,l,6-a/]pyrrolizine (40a) was obtained in 10% yield by a reaction of the sodium salt of pyrrole-2-aldehyde with vinylene-l,2-bistriphenylphosphonium iodide (39)in boiling toluene. The intermediate (yields shown in Scheme 1) were isolated from a reaction in boiling benzene. Compound 40a is diatropic and on refluxing in acetic anhydride it gives 40b. The position of substitution is in accordance with HMO calculations.44... 

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). 

Isomeric 1-oxo-l//- and 3-oxo-3//-pyrimido[l,2-a]quinolines [79CPB2927 95MI1] and 4-amino-2-oxo-2//- and 2-amino-4-oxo-4//-pyrimido[2,l-a]iso-quinolines (33 and 34) (95MI1) could be distinguished on the basis of the uCo band, as it appears at higher wavenumbers (>1655 cm-1 vs <1635 cm-1) in the case of l-oxo-l//-pyrimido[l,2-a]quinolines and 2-amino-4-oxo-4//-pyrimido [2,1 -ajisoquinolines than at their isomeric 3-oxo-3H and 4-amino-2-oxo-2// derivatives. 

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). 

Diamino-4//-pyrimido[2,l-a]isoquinolin-4-ones (102) were obtained by reduction of 2-amino-3-nitroso- and 3-phenylazo-4//-pyrimido[2,l-a]isoquinoline-4-ones (101) with sodium dithionite (73GEP2261009). 

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). 

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