9-Methyl-6,7,8,9-tetrahydro-4//-pyrido

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Reduction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-a]pyrimidin-4-one 353 with sodium borohydride in water at 0°C yielded perhydropyrido-pyrimidinone 354 (82JOC4780). 

Nitro-4-oxo-l, 6,7,8-tetrahydro-4/f-pyrido[l, 2-a]pyrimidines 534 (R = 6-, 7-, and 8-Me) or 538 were also obtained from 9-formyl-4-oxo-1,6,7,8-tetrahydro-4i/-pyrido[l,2-a]pyrimidine-3-carboxylates 536 with Clayfen in 24-54% yields (90JOC6198), or from 9-bromo-6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 537 with sodium nitrite in 40-62% yields (87H869). From the reaction mixture of 9-formyl-6-methyltetrahydropyridopyrimidine-3-carboxylate 536 (R = 6-Me) both 32% of 9-nitro derivative 534 (R = 6-Me) and 5% of dinitro compound 535 (R = Me) were isolated following column chromatography (90JOC6198). 

Methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 18 reacted with the iminium salt formed in situ from N-formylpiperidine, N-methylformanilide, N, A -diethylbenzamide, and phosphoryl chloride in 1,2-dichloroethane to yield 9-aminomethylene-6,7,8,9-tetrahydro or 9-acyl-l,6,7,8-tetrahydropyridopyrimidin-4-ones 556 and 557 (Scheme 36) (85JHC593). The iminium salt formed from N, /V-diethylacetamide and N, A/-ethylisobutyramide was unreactive under the above reaction condi-... 

The side chain hydroxy group of 3-(2-hydroxyethyl)-2-methyl-9-methoxy-4//-pyrido[l,2-u]pyrimidin-4-one, and that of its 6,7,8,9-tetrahydro derivative was acylated with MeS02Cl in the presence of NEts in CH2CI2 at room temperature (95MIP4, 96MIP2). The hydroxy group of 2-[4-(4-hydro-xybenzoyl)benzyloxy]-3-methyl-4//-pyrido[l, 2-u]-pyrimidin-4-one, its 6-methyl derivative and 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4//-pyrido[l, 2-u]pyrimidin-4-one was alkylated with 4-(2-chloroethyl)morpholine hydrochloride and 4-picolyl chloride hydrochloride (96EUP733633). 

Mercapto-3-methyl-4//-pyrido[],2-rz]pyrimidin-4-one and its 6,7,8,9-tetrahydro derivative were S-alkylated with 4-substituted benzylbromides (96EUP733633). 

A sulfoxide was obtained by oxidation of 8-[(4-trifluoromethylmercapto-phenyl)methoxy] derivative 358 with 36% H2O2 in AcOH (98MIP7) and by oxidation of l-[2-(4-thiomorfolin-l-yl)acetyl]-7-(3-methoxyphenyl)-A-methyl-A- [3,5-bis(trifluoromethyl)phenyl]ethyl -5-oxo-1,2,3,5-tetrahydro-pyrido[l,2,3-i/ ]quinoxaline-6-carboxamide with 3-chloroperbenzoic acid (01MIP12). A 7-[(4-fluorophenylsulfonyl)methyl] derivative was obtained by oxidation of a 7-[(4-fluorophenylsulfanyl)methyl]perhydropyrido[l,2-u] prazine with 3-chloroperbenzoic acid in CHCI3 (01EUP1074257). 

CN 3-[2-[4-(6-Fluoro-l,2-benzisoxazol-3-yI)-l-piperidinyl]ethyI]-6,7,8,9-tetrahydro-2-methyl-4//-pyrido[ 1,2 a]pyrimidin-4-one... 

Meszaros, Hermecz et al. transformed the quaternary 6,7.8,9-tetrahydro-pyrido[1.2-u]pyrimidinium salts (204) with acid to the carboxylic acids (205 R1 = H)257 and with sodium hydrogen carbonate solution to the l,6,7,8-tetrahydropyrido[l,2- ]pyrimidines (205 R = alkyl).7x2 8 From the alkaline hydrolysis reaction mixture, compounds 206 and 207 were also isolated.133 The quaternary salt (204 R = Me) was transformed with hydrazine hydrate to 6-methylpiperidone and with ammonia to 6-methyl-4-oxo-6.7,8,9-tetrahydro-4//-pyrido[1.2- ]pyrimidine-3-carboxamide and its A-methyl derivative.133... 

Reaction of ethyl 9-(dimethylaminomethylene)-4-oxo-6,7,8,9-tetrahy-dropyrido[ 1,2-a]pyrimidine-3-carboxylate 539 with Clayfen in refluxing dichloromethane for 2.5 hours afforded a mixture of 9-nitro-1,6,7,8-tetrahydro (534 R = 6-Me),9,9-dinitro-6,7,8,9-tetrahydro(535 R = Me), and ethyl 7,9-dinitro-l,6-dihydro-6-methyl-4//-pyrido[l,2-a]pyrimidine-3-carboxylate 540 in 50%, 12%, and 12% yields, respectively (90JOC6198). 

Tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-l-one maleate. 

A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N- dimethylformamide was stirred overnight at 85°-90°C. After cooling the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of N,N-dimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]-pyrimidin- 4-one melting point 170°C. 

Treatment of 9-(ethoxymethoxy)-3- 2-[4-(6-fiuoro-l, 2-benzisoxazol-3-yl)-1,2,5,6-tetrahydro-1 -pyridyl] and -1 -piperidyl]ethyl -2-methyl-4 -pyrido-[l,2-<3]pyrimidin-4-ones with cone. HCl afforded 9-hydroxy derivatives (95MIP4, OOMIPIO). 

Of much interest is the recent discovery of substances closely related to the harmala alkaloids in animals. One of these is adrenoglomerulotropine, a hormone of the pineal body, the chemical identity of which has been indicated as 2,3,4,9-tetrahydro-6-methoxy-i-methyl-iH-pyrido (3,4,6) indole. This substance is identical to 6-methoxyletrahydroharman which has been shown to be formed in vivo from 5-methoxy tryptamine and acetaldehyde. 6-methoxytetrahydroharman is an isomer of tetrahydro-harmine, one of the alkaloids in Banisteriopsis, and in the African Leptactinia densillora. One more substance, 6-methoxyharmalan, has been shown to derive, at least in vitro, from melatonin, which results from the methylation of acetylserotonin. The enzyme which makes this possible, hydroxyindole O-methyl transferase, has only been found in the pineal body. (Naranjo, in Efron et al. 

Decarboxylation and oxidation products of 1,2,3,4-tetrahydro-P-carbohne-3-carboxylic acids derived from formaldehyde, 9H-pyrido(3,4-fo]indole (norharmane, 2-127), and acetaldehyde, 1-methyl-9//-pyrido[3,4-fo]indole (harmane, 2-127), were identified in a number of foods at levels up to 700 mg/kg, although more typically their concentrations in smoked, cooked and fermented foods range from a few mg/kg to 1-2 orders of magnitude less. Typical norharmane and harmane findings in pan-fried, minced meat, beef patties or ground beef prepared at temperatures of 175-230 °C and... 

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