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    • 专利摘要:
    An optically active or racemic fused pyrimidine derivative of the formula I <IMAGE> (I) has pharmaceutical activity in decreasing serum lipids, cholesterol deposits and, in general, against atherosclerosis.
    公开号:SU969165A3
    申请号:SU772452003
    申请日:1977-02-11
    公开日:1982-10-23
    发明作者:Хермец Иштван；Месарош Золтан；Вираг Шандор；Вашвари Лелле；Хорват Агнеш；Кнолль Йожеф；Шебештьен Дьюла；Давид Агоштон
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    d 39691654 group, and can also be where R, R, n have the indicated carboxyl or alkoxycarboxylate values, are reacted by NIL, where alkyl with 1 atoms with an aldehyde of the general formula carbon.a; () -CHO (ill) Rg is hydrogens or together form s where ON and p have the indicated meanings, a valence bond; or its anilyl, followed by separation of the R-hydrogen or hydroxy group; the base product RQ is hydrogen, phenyl, alkyl with 1–4 nor, an acid additive salt or carbon opatoma, a carboxy, thyme isomer, or a kisalkoxycarbonyl group, jo lots in its esters or saponification of the esters where alkyl with 1- t carbon atoms in the acid. genus, cyano group, methylamino. In this case, the method is preferably a group, a carbamoyl group, carried out in the temperature range possibly substituted by one or (-20) -iOO C. two alkyls with 1-atoms is In addition, the reaction is carried out by a carbon carbon, hydrate, - the absence of a solvent, pa, a group of the formula - (CHg) ,, Moreover, the reaction is carried out in the presence of SOP-alkyl, where q is 1 or 2, because of the protonic solvent, and the alkyl has 1- (carbon atoms). In addition, the reaction is in nature, or a group of the formula 20 in the absence of an aprotic solvent. CO-NH-N Re preferably RQ is benzylidene, furfurylidene is the use of aprotic or nitrofurfurylidene, or a bipolar solvent. R and Rg together form a group. Suitable examples of proton pu- (CH-) p-, in which fi-S solvents are as follows: 3 -6; rlcanols containing from 1 to 6 atoms of R - oxygen or sulfur; Carbon, for example, methanol, ethanol, p o or 1, isopropanol, glycerin, etc., aliLa provided that if p O, then. Ticarboxylic acids, for example, R and R. - are hydrogens; zo Uravjina, vinegar; formamide, etc. R and R are hydrogens or together form an apolar bond, the valence bond dissolves; leu can use hydrocarbons, R. - phenyl or carboxy; for example, benzene, toluene, xylene, and RA together form a valence, etc .; Chlorinated hydrocarbons, CONNECTION „example chloroform, tetrachloride R - hydrogen; carbon, chlorobenzene, etc .; simple R - carboxy or alkoxycarbosters, for example, diethyl, tetrahydroxy, where alkyl with roFURane, dioxane, etc. 1-4 carbon atoms; as bipolar solvents, if - f carbon / ™ ° use dimethylforma RJ — hydrogen amide, dimethylacetamide, dimethyl sulfon and fL — together form a valence ketones, for example acetone, ethyl methyl ketone, etc .; nitrobenzene; R - Hair dryer or nitrophenyl; acetonitrile; hexamethylphosphorotriamide. with and together form the valence, etc. 5 o - You can also use mixtures. communication; The compounds listed are 11. Hi is hydrogen,; pp implementation of the method, with the same Rg - carboxy or alkoxycarbonium. use a basic group where alkyl with 1-4 jo or acid catalysts. In carbon catalysts, as well as catalyst sites, they may also have diluted their salts, or their optical isomers, to dull the appropriately vyatsemic or optically active compound. solvent. Such dissolution of the general formula of the body, such as acetic acid or formic acid 155, can occur in two p-ions (because they can act on the acid catalysts and are B-solvents at the very time.
    quality of acid catalysts can be used. inorganic silt organic acids, for example, hydrochloric, sulfuric, los-lauric, acetic, etc.
    Piperidine, diethylamine, and bifunctional catalysts such as piperidine acetate and pyridine, which can act as both acidic and basic catalysts, can be used as basic catalysts.
    The resulting compounds of the general formula (O, if desired, can be converted into their acid addition salts. Use fiowHo acids, for example, hydrochloric, hydrocystic, phosphoric, lactic, tartaric, maleic, nicotinic, etc.
    The optically active compounds of the formula (|) can be obtained either by separating the racemic compound of the formula (|) with known methods, or by using optically active starting compounds.
    As aldehydes of the general formula (i), it is possible to use benaldehyde, vanillin, isovanillin, trimethoxybenzaldehyde, o-chlorobenzaldehyde, P-chlorobenzaldehyde, glyoxylic acid monohydrate, glyoxylic acid, methyldioxybenzaldehyde, 5-nit | miners, miners; hydroxy enzaldegid, verat roOy aldehyde, anisic aldehyde, salicyl aldehyde, dimethylaminobenzaldehyde, phthalaldehyde, terephthalaldehyde, formaldehyde
     L.
    The compounds of general formula (I) are active in the treatment of atherosclerosis, affecting not only serum lipids, but also reducing the amount of lipids deposited on the vascular walls, and especially cholesterol.
    The compounds of general formula (I) are also moderately toxic. In rabbits (when administered orally, the preparation) is more than 2000 mg / kg.
    The pharmacological activity of the compounds prepared in accordance with the invention is determined by various experimental tests. In tab. summarizes the results of anti-sclerotic activity obtained on the model of atherosclerosis in rabbits receiving cholesterol with food.
    Table 1 796 From table. 1, it follows that compounds C and I) lead to a significant decrease in serum and aorta lilides, as well as cholesterol levels, A is ethyl zbir 6-methyl-9 (M-methyl-2-pyrrolyl) methylene-oxo- 6.7, 8.9 tetrahydro-.H-pyridoC1, 2-7-pyramidine-3 carboxylic acid; B - 6-methyl-9 {chloro-phenyl) -methylene-oxo-6.7 8.9 ethyl ester of tetrahydro-H-pyrido (1, 2a) pyrimidine-3-carboxylic acid. C - 6-methyl-9- (ethoxycarbonylmethylene) -oxoxo-6,7,8,9-tetra-hydro-H-pyrido (, 2a-pyrimidine-3-carboxylic acid ethyl ester .1) -6-methyl-3 -ethoxycarbonyl- -oxo-6, 7,8,9-tetrahydro-H-pyrido-and 2a pyrimidinyl-9 acetic acid. In the control group, the rabbits are given a normal diet, while the rabbits of the control group II are given, except for it, 2 g of cholesterol. It has been found that the test compounds, in contrast to chlorosybate, do not lead to an increase in liver weight in animals. The results obtained in rats are given in Table. 2. T and l and c and 2 E - ethyl, ether 9- (ethoxycarbonylmethylene) - ii-oKCO-fi, 7,8,9-tetrahyd-. ro-H-pyridoI, 2-5 pyrimidine 3 carboxylic acid. F is 9- (carboxylmethyl) -L-oxo-1,6,7,8,9a-hexahydro-CH-pyridoi ethyl ester, 2a | pyrimidine-3-carboxylic acid. 5 G - ethyl eLir 9- (carboxyl. Methyl) -4-OXO-6, 7,8,9-tetraparido-H-pyrido {1,2a pyrimidine-3-carboxylic acid. H is 9-methoxycarbonylmethylene) -6-methyl-oxo-6,7,8,9-tetrahydro-G-pyrido (1,2a;) pyrimidine-3-carboxylic acid methyl ester. Other compounds produced in accordance with the invention show a marked effect on the central nervous system (CNS). Thus, some compounds show marked activity as anesthetics, antipyretic and antiinflammatory agents, tranquilize the activity of drugs, protect the liver, have antidepressant, antibacterial, antituberculosis and antiasthmatic activity. The compounds prepared according to the inventive method can also be used as starting compounds for the preparation of other pharmacologically active compounds. Example. A mixture of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido (pyrimidine and 10.6 g of benzaldehyde is stirred at ifCPC, after which 10 ml of ethanol are added and the reaction mixture was incubated overnight. The precipitated crystals were filtered off. After recrystallization from ethanol, white 3-ethoxycarbonyl-9- (1-hydroxybenzyl) -6-methyl-oxo-6, 7,8,9-tetrahydro-AN- pyrido (1, 2, -a) pyrimidine, mp 186-187 C. Calculated: C 66.65; H 6, i8; N 8.18. Found: C 66, 6.50; N 8.19. Example 2. Analogously to Example 1, using chloral as an aldehyde component or chloral hydrate, 3 ethoxycarbonyl-.9 are obtained (1 - P1DROXYL-2,2,2-trichloroethyl-6-methyl- -oxo-6, 7,8,9-tetrahydro-F-pyrido (1,2a) pyrimidine T. mp after recrystallization from ethanol is 165-166 C. The yield is 6U. Calculated,%: C (3.83; H it, it7;. "7.30; Ct 27.70. Found,%: C 43.70; H, 51; N7.39; Ct 27.37. Example 3. A mixture of 118 g of 3 ethoxy-sicarbonyl-6-methyl-oxo-6,7,8,9-tetrahydro-H-pyrido C 1, 2a) pyrimidine and 30 g of paraformaldehyde in 12J30 ml of eta996 is heated for L h, after 15 g of paraformaldehyde is added to the reaction mixture, which is then mixed for 1 h. After this, another 15 g of paraformalDe is added ide, and the resulting mixture was heated at reflux. 1 h. The reaction mixture is evaporated, the resulting residue is dissolved in 1200 ml of water and shaken sequentially with benzene and chloroform. After drying, the chloroform solution is evaporated and the residue is recrystallized from ethanol twice, after which a yellow 3 ethoxycarbonyl-9- (dihydroxymethyl) -6-methyl-4-oxo-6,7,8,9-tetrahydro-N-pyrido (1 , 2a | pyrimidmn, mp 119-120 pp. Calculated,%: C 56.75; H 6.8; M9 ;. Found,: C 56.89; H 6.80; H9,. Example (. g 3-ethoxycar bonyl-9-Cl-hydroxylbenzyl) -6-methyl-o-co-6, 7,8,9-tetrahydro-4n-pyrido (1,2a) pyrimidine is boiled in a mixture of 100 p1 ethanol and 10 ml (15% by weight) of a solution of hydrogen chloride in ethanol. After cooling, the precipitated precipitate: the yellow crystals are filtered and Recrystallized from ethanol to obtain 3-ethoxycarbonyl-9-benzyl 410 den-6-methyl-oxo-6,7 8 9 tetrahydro-4H-pyrido (1,2a) -pyrimidine. The resulting product does not depress the melting point of the mixed sample with the product obtained in the example of Example 5. 23.6 g of ETOxycarbonyl-b-methyl-oxo-6, 7,8,9-tetrahydro-H-pyrido (1,2a) pyrimidine and 10.6 g of benzaldehyde are heated in 10 ml ethanol and 5 ml (15% by weight) of a solution of hydrogen chloride in ethanol. The obtained 3-ethoxycarbonyl-9- (1-hydroxylbenzyl) -6-methyl- -ok-- co-6, 7,8,9-tetrahydro- "H-pyrido (1,2a-L pyrimidine is converted without isolation into yellow). ethoxycarbonyl-9-benzylidene-6-methyl-4-oxo-6, 7,8,9-tetrahydro-tH-pyridoO. 2a) pyrimidine with further heating and stirring. Mp of the title compound after recrystallization from ethanol. Yield 70%. Calculated,%: C, 70.35; And 6.22; N 8.6. Found,%: C 70.2 C; H 5.99; N, 8.60. Analogously to Example 5 and using the corresponding starting materials, the compounds listed in Table 2 are obtained. 3 "
    D
    I X C
    Yu
    : "
    Example i. 23.6 g of 3-ethoxycarbonyl-7-methyl-α-oxo-6, 7, .8.9 tetparMflpo-AH-RMpMAofl, 2a) pyrimidine and 10.0 glyoxylic acid monohydrate are reacted and the resulting 3 ethoxycarbonyl-7 methyl-9 - carboxy- (1 -hydroxymethyl) -oxo-6, 7g8.9 tetrahydro-H-pyrido {1,2a) pyrimidine is heated in 150 ml of ethanol with stirring for 3 h. After cooling, the crystals are filtered and recrystallized from ethanol, get 3 ethoxycarbonyl-7-methyl-9- (carboxymethylene) -oxo-6,7 8,9-tetrahydro-1 H-pyridoi, .a) pyrimidine with T.pl. 110-PL ° C. Output 5U. Calculated,%: C 57.53; H 5.52; N9.58; Found,%: C 57.32; H 5.60; N9.56. PRI + EP 75. The mother benzene layer obtained in Example 17 was evaporated in vacuo. The residue was dissolved in 10 g-w of ethanol, after which 15 ml of ethanol containing 16 hydrogen chloride was added. After recrystallization from ethanol, 3,6-dimethyl-9- (5 Nitro-2-furfurylidene) -k-OKco- (, 7,8,9-tetrahydro-4H-pyrido (1,2a pyrimidinium hydrochloride with mp 215 -21b ° C. Calculated: C 53, H, 78; M 12, tA; C1 10.50. Found,%: C 53.22; H i, 83; N12.55; C1 10.55. Example 76 Zethoxycarbonyl-) - (1 -enylaminobenzyl / -6-methyl-ioxo-6,7, B, 9-tetrahydro-4H-pyrido (V, 2a) pyridine, obtained by using 3-rd guy deist VII (7.2 g 3-ethoxycarbonyl-G) -methyl- -oxo-6,7,8,9-tetrahydro-I-pyrido (1,2a |) pyrimidine and 3b, 2. .96 5 benzaniline, stirred in a water bath for 8 h, after which receive 3 ethoxycarbonyl-9-benzylidene-6-me yl-4-oxo 6, 7,8,9-tetrahydro-H-pyrido (1,1a) -pyrimidine. The reaction mixture is dissolved in 300 ml of benzene and shaken with 5% hydrochloric acid. The benzene phase is dried, the residue is recrystallized from ethanol twice. Yellow 3 ethoxycarbonyl-9 benzylidene-6-methyl-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine is obtained with a melting point of 138139 ° C This product, being mixed with the product obtained in accordance with Example 2, does not give a melting point depression. Example 77. 55.6 g of Zethoxycarbon 1L-9 Scarboxymethylene -ioxo-6, 7,8,9-tetrahydro-fH-pyrido (.1, 2a pyrimidine is converted into suspension in 400 ip of ethanol. The reaction mixture is poured with gaseous hydrogen chloride with stirring and external cooling, then left to stand at room temperature overnight. Ethanol is distilled off under reduced pressure, and then the resulting residue is recrystallized from ethanol to give 3 ethoxycarbonyl-9- (ethoxycarbonylmethyI) -O-6, 7,8,9 -tetrahydro-4H-pyrido (1.2 a) 120-121 C. The yield of pyrimidine with TPL 3Q%. With 58.82; H 5.92; Calculated, N 9.15. C 58.72; H 5.70; Found,% - N 9.29 Analogously to Example 77, using the appropriate starting materials, the compounds given in Table K are obtained.
    25
    969165
    26 T Clic li
    Co (3n -215 (s - 2, methanol).
    Note. +215.5 with 2, methanol.
    Example 87 I, G 3-ethoxycarbonyl-6-methyl-α-oxo-6, 7, rahydro-H-pyrido4 1,2a) pyrimi ing-A acetic acid is heated in a mixture with 23 g of ethanol and 5 ml of sulfuric acid for 5 m, after which the ethanol is distilled off under reduced pressure and the residue is poured on ice and shaken with chloroform. The chloroform solution is dried and evaporated under reduced pressure to give 3-ethoxycarbonyl-6-methyl-D-oxo-6,7 ethyl ester, 8,9-tetrahydro-H-pyrido (1, 2a) pyrimidine-9 acetic acid as non-crystallizing yellow oil, yield 50%.
    C, 59.62; H 6.88;
    %
    Calculated
    N b.
    Г 60, П2; H 6.9 (1;
    %,%
    N8.65.
    Example 88. Analogously to Example 87, using ethoxycarbonyl-6-methyl-9- (3-carboxymethylene Jt-OKco-6,7, 8.9 tetrahydro-CH-pyrido (1,2a pyrimidine) as the starting material 3, ethoxycarbonyl-6 is obtained -m "tyl-9- (ethoxycarbonylmethylene) -4-oxo-6,7,8,9-tetrahydro-H-pyrido (1,2aj pyrimidine.
    The product does not depress the melting point of the doped sample with the product obtained in Example 78.
    权利要求:
    Claims (1)
    [1]
    Example 8, 1.7 g of 3-ethoxycarbonyl-6-methyl-and-oxo-6, 7,8,9-tetrahydro-H-pyrido- (1, 2a pyrimidine-9-acetic acid is heated in a mixture With 4.6 g of ethanol, O, 25-g of sulfuric acid and 25 ml of chloroform, and water that is liberated during the etherization, the Q separator is continuously collected. The reaction mixture is shaken in two portions of 3) ml (5 by weight sodium carbonate solution, dried and distilled chloroform under reduced pressure to obtain 3-ethoxycarbonyl-6-methyl-oxo-6,7 ethyl ester, 8,9-tetrahydroH-pyridoi, 2a) pyrimidine-3 acetic acid as non-crystallizing its oil. Calculated,%: C 59.62; H 6.88; Ы 8,69. Found,%: C 59.7P; H 6.98; W8, liA. Example 90 .. Analogously to Example 89, using erboxymethylene) -oxo-6, 7, 8.9 tetrahydroH-pyrido (1,2a) pyrimidine as the starting compound 3H-ethoxycarbonyl-6-methyl-9 C as the starting compound, 3-ethoxycarbonyl-6-meti-l-9- (ethoxycharbonylmethylene) - -oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2a; pyrimidine with mp. C. This product with mixing with the products obtained in examples 78 and 87 does not depress the melting point. Example 91.3.84 g of 3-ethoxy carbonyl-6-methyl-9- (carboxymethylene - -oxo-6,7,8,9 tetrahydro-H- pyrido (1,2a) pyrimidine is suspended in LOO ml of methanol. The mixture is saturated with gas by stirring at 0-5P, and the reaction mixture is left overnight in a refrigerator .. The reaction mixture is evaporated under reduced pressure and the residue is mixed with 200 ml of water. Precipitated crystals are filtered, washed with boya and recrystallized from n-pnol. 3-methoxycarbonyl-6-methyl-9 (methoxycarbonylmethylene) -oxo-6, 7,8,9-tetrahydro-AN-pyridoCl, 2a) pyrimidine, m.p. 135-137 s. You hop move 8P. Calculated: G 57.53; H 5.52; 99.58; Found,%: C 57.66; H 5, TV 9.60. Example 92: 50 g of 3-ethoxycar bonyl-6-methyl-oxo-6,7,8,9-tetrahydroH-pyrido; 2a () pyrimidine-9-yl-acetic acid is dissolved in methanol and hydrogen chloride gas is passed through at -10 ° C for 5 hours. The reaction mixture is left overnight at room temperature, and 96 28 is then evaporated in vacuo. The residue is dissolved in water and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. After extraction with benzene and evaporation of the solution, 3-methoxycarboxy-6-methyl-o-6-co 7, 7,8,9-tetrahydro-H-pyridoC1 methyl ester, .a | pyrimidine methyl ether, m.p. 101-103 0 (after recrystallization from ethyl acetate). Exit b7. Calculated,%: C 57.2t; H 6.17; N9.52. Found,%: C 57.57; N b. N9.50. Example 93 58.8 g of methyl ester 3 of methoxycarbonyl-6-methyl-oxo-6, 7,8,9-tetrahydro-4H-pyrido2,2a) pyrimidine-9-acetic acid is mixed with an aqueous solution of sodium hydroxide. The reaction mixture is neutralized with hydrochloric acid. The precipitated crystals are filtered off to give 3-carboxy-6-methyl- | -oxo-6, 7,8,9-tetrahydro-H-pyridoch, 2a) pyrimidine-9-acetic acid. 75% yield. M.p. (with decomposition, after recrystallization from propanol). Calculated: C 5.13; H 5.30; M10.52. Found,%: C 5,17; And 5.32; Y10.31. Example 9. 0.65 g of magnesium is reacted with 20 ml of ethanol in the presence of O, 1 g of iodine as a catalyst. 1.7 g of Zethoxycarbonyl-6-methyl-α-oxo-b, 7,8,9-tetra hydro-H-pyrido ((1,2 1,2) pyrimidine-9-acetic acid in 300 g ml of ethanol. Reacting: The mixture is heated to boiling point, filtered and the filtrate is evaporated in vacuo. Thus, g of crude 3-ethoxycarbonyl-6-me, / -, o "/ and tyl-5-oxo-6,7,8 are obtained. , 9-tetrahydro-H - pyridoi, 2a; -pyrimidine-9-acetate. Mp. ZbO ° C (decomposition, after recrystallization from a mixture of ethanol and ethyl acetate. Calculated, 4: C 55.05; H 5, 60; L9,17, Found,: C 5.18; H 5.68; M8.93. Example 95. 50 g 3- {ethoxy to rbonylmethyl) -6-leto-oxo-6,7, 8,9-tetragiDr-H-pyrido- (1,2a pyrimidine is reacted with 28.2 g of 5 nitro-2-furfural and obtained 2996 ny; i- (ethoxycarbonylmethyl) 6 methyl-9-C (5-nitro-2-furyl-hydroximoyl | - "- oxo-b, 7,8,9-tetrahydroH-pyrido (1,2a) pyrimidine without intermediate isolation is boiled in a mixture 600 ml of benzene and 2 ml (16 by weight) of a solution of hydrogen chloride in ethanol in a flask equipped with a water trap, and then the reaction mixture is evaporated under reduced pressure. The residue obtained is recrystallized twice. 3. Ethanol containing hydrogen chloride. Get 3 toxicarbonylmethyl) -6-methyl-E- (5-nitpo-2-pyrpyridyl) -3-ox-6,7,8,9-tetrahydro-H-pyridoi1, 2-pyridinyl hydrochloride Yield 72. Calculated, ° / ,: С 52.76; H, 92; M 10, C1 8.65. Found,%: C 52.98; H 4.86; H10.26; C1 8.63. Example 96 5g of 3-ethoxycarbanoyl-b-methyl-oxo + H-pyridoC, 2a) pyrimidine-9-acetic acid is stirred for 1 hour at 70-80 ° C. in 50 Mil of 10% sodium hydroxide solution. After cooling to room temperature, the pH of the solution is adjusted to 3 with the addition of hydrochloric acid solution. The precipitated white crystalline substance is filtered off, promoted and dried. 3 g of (79.5) 3 carboxy-6-methyl-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-9-acetic acid is obtained, which, when mixed with the product obtained in Example 93, does not depress the melting point. Example 97. Analogously to Example 77 from 6-methyl-oxo-6,7,8,9-tetra hydro-H-pyrido (1,2a; pyrimidium-9-acetic acid) obtained by esterification methyl esyr 6-methyl-1 -oxo-6, 7,8,9-tetrahydro-4H-pyridoP, 2a) pyrimidine-9-acetic acid with a yield of 86, t „pl. 57- $ 8c, Calculated,%: C 61.00; H 6.83; Ы 1-1,86, Found,%: C 61.16; H 6.72; W 11.71. EXAMPLE 98 Analogously to Example 77 from 3, ethoxycarbonyl-6 methyl-9j- (carboxymethyl lene) -4-oxo 6,7,8,9-tetrahydro-i4H-pyridol1, 2a) 1-pyrimidine is obtained in propyl alcohol H-Ch-prop hydroxycarbonyl) - (6-methyl-9 -n-propoxycarbonyl-methylene-g-oxo-6, 7,8,9-tet530 rahydro-H-pyrido (1, 2a) pyrimidine, m.p. 93-9f) C. The product yield is 7oi. Calculated,%: C 62.06; H 6, N8, nit. Found,%: C 62.18; H 6.95; .N8,10. 1l. - "Example 99. 2.1 g of N-benzylidene-6-methyl-oxo-6 7" 8; 9 etrahydro-P-pyrioST, 2a} ciirimidine-3-carbohydrazide and 1.0b g of benzaldehyde in 200 tvi of ethyl alcohol in the presence of 6 drops of concentrated hydrochloric acid, boil for 8 hours under reflux. After cooling the reaction mixture, the precipitated crystalline substance is filtered off; 3.6 g (905) NlS / -bis- (benzylidene) -6-methyl - {- oxo6 7, 8,9-tetrahydroH-pyrido (1.2a ) .. pyrimidine-3 carbohydrazide, m.p., 236; 238 C (from dimethylformamide |. Calculated,%: C 72.3 |, And 5.57; | N1n06.: Found,: C 72.05; And 5 , M13.96. Example 100 1.57 g of 3-ethoxycarbonyl L-6-f methyl-9- (. Carboxy.methyl) -4-oxo-6, 7,8,9-tetrahydro) H-pyrido (1,2a) pyrimidine is dissolved in fO ml of ethyl alcohol. When this methanol solution is slowly added a solution of diazomethane (mol in diztile ether. The reaction mixture is kept at the indicated temperature for 2 h7 and then evaporated. The resulting residue is dissolved in 20 ml of benzene, the solution is extracted twice with a solution of sodium hydroxide with 10 ml of solution ), then washed with water. The organic solution is dried with sodium sulfate "evaporated under reduced pressure, the result is 1.25 g (3-ethoxycarbonyl-6-methyl-9-Smethoxycarbonylmethyl- | -oxo-6, 758,9-tetrahydrO 4H-pyrido (1, 2a) pyramidine in the form of a noncrystallized 1.ceg of a pale yellow oil, Calculated: C 58.43; H 6, M 9.09. Found,: C 57.95 H 6.56; N9.10.: Example .101. 1 , 0 g 3 ethoxycarbonyl- -oxo-4-, 6, 7,8-tetrahydro-I-pyroloC, 2a) pyrimidine in the presence of a few drops of 2P ° th solution of hydrogen chloride in ethyl alcohol is boiled for 5 seconds; fridge, and about The ethoxy 3 ethoxycar6onyl-o- (1-hydroxybenzyl) 4-oxo-, 6,7,8-tetrahydroxypropyl (i1, .l 1-pyrimidine is converted into 3 ethoxycarbonyl-8-benzylidene-oxo-, 6,7, B-tetrahydropyrrolo 3 1,2a} piri, “The crystalline product is filter midintered and washed with ethyl alcohol to obtain 0.8 g (3)) 3-ethoxycarbonyl-B-benzylidene- (-oxo-4,6,7,8-tetrahydropyrrolo (1 , 2a) pyrimidine. After recrystallization from C-propyl alcohol m.p. product 212213 ° (:. Calculated,%: C 68.91; H 5, L9.5, Found,%: C 69.05; H 5.5; M9, Yu. 102. 0.68 g 2-ethoxy; Example carbonyl -1-oxo-5,6-dihydro-1H-pyrimidoP, 2a) quinoline and 0.2b g of benzaldehyde in 10 ml of ethyl alcohol in the presence of a few drops of iiU-Horo solution of hydrogen chloride in ethyl alcohol are boiled for an hour 06 refrigerating fluid forming 2-ethoxycarboxy-5-C1-hydroxybenzyl) -1-oxo-5, 6-dihydro-1H-pyri, (, 1,2a) quinoline is converted to 2-ethoxycarbonyl-5-benzylidene-1 -oxo-5, 6-dihydro-1H-pyrimido (1,2a-quinoline. The reaction mixture is then evaporated under reduced pressure. and, an oily product that is difficult to crystallize and yellow colored is obtained, which is then triturated with diethyl ether. The semi-valuable crystalline product is filtered off and washed with diethyl ether. Half, 0, g (4,6) 2-ethoxycicronbonyl-5-benzylidene-1- oxo-5,6-dihydro-1H-pyrimido {; 1, 2a) quinoline, so pl. 192-19 + C. Calculated,%: C 73.73; .H 5.06; M 7.32. Found,%: C 73, i H 5.02; Y7.75. PRI me R 103. 3.28 g of 6-methyl-4-OXO-6, 7,8,9-tetrahydro-4H-pyrido (1,. A) pyrimidine and 3.0 g of dimethyl aminobenzaldehyde, 40 ml of ethyl alcohol and 0.1 ml of concentrated hydrochloric acid are boiled for 2 hours under reflux. Then the solution is cooled and the crystalline substance precipitated in the precipitate is filtered off, passed with ethyl alcohol and dried. 1.6 g (27) of 9- (4-dimethylaminobenzylidene) -6methyl-oxo32-6,7,8,9-tetrahydroH-pyrido (1.2a) pyrimidine are obtained, m.p. after recrystallization from ethyl alcohol. Calculated, -%: C 73.19; H 7.17; N and .3. Found,%: C 73.67; H 7.30; v) if (27 Example 10 ". 1.1 g 6-methyl-ZChM-methyliminomethyl) -2-hydroxy-oxo-6, 7, B, 9-tetrahydro-H-pyrido (1, 2a) pyrimidine and 1 , 0b g of benzaldehyde is boiled in 20 ml of benzene for 90 minutes under reflux. After cooling the reaction mixture, the crystalline product precipitated into the β-precipitate is filtered off. After evaporation of the mother liquor, an additional amount of crystalline material is obtained. A total of 1.15 g of () 9-benzylidene-6-methyl-3- (M-netyliminomethyl) -2-hydroxy-oxo-6,7,8,9-tetrahydro-4H-pyrido (1, 2a) pyrimidine is obtained. m.p. which after recrystallization from ethyl alcohol is 253-255 ° f. Calculated,%: C 69.38; H 6.19; N13.58. C 70, H 6.24; Found,%: Y13.36. Example 105. Analogously to Example 7, from 6-methyl-1,2i3 tpimethylene-ol co-6, 7,3,9-tetrahydro-4H-pyrido {, 1, 2a) pyrimidine, 9- (carboxymethylene) -6-methyl -2,3-trimethylene- -oxo-6, 7, B, 9-tetrahydro-H-pyrido (1,) pyrimidine, m.p. after recapitalization from dimethylformamide (L (decomp. W. Calculated,%. C 6.60; H 6.20; N10.76. Found,: C 6.82; H 6.15; N10.81. Example 106. Analogously to Example 7 from 3 carboxy-4-oxo-4,6,7,8-tetrahydropyrrolo, 2a) pyrimidine, 8- (carboxymethylene) -3-carbox SI-4-OXO-4,6,7,8g are obtained; tetrahydropyrrolo i1,2n1pyrimidine, the melting point of which after recrystallization from dimethylformamide is l / {decomp.). Calculated,%: C 50,%; H 3.1; C11.86. Found,%: C 50, H 3.3; N11.81, Example 107. Analogously to Example 77 from 9- (carboxymethylene) -6-methyl-2, 3-trimethylene-oxo-6,7,8,9-tetrahydro-H-pyrrolo (1,2a) pyrimidH, 9-Cacetoxycarbonylmethylene) 339 is obtained. -6-MRTHn-2, 3 trimethylene - (- oxo-6,7, 9-tetrahydro-4H-pyrrolo (1, 2a pyrimidine, which, after recrystallization from a pythroline eLira, has a melting point of 15.15 ° C. Calculated %: C 66, B5; H 6.99; N9.72. Found,%: C 66, (3; H 7.07; M9, P. The invention The method of obtaining condensed pyrimidines in total (R4-1CH CHV RS) R I, W., where M1 is P or 1, and if O, then R is hydrogen or alkyl with: Cami carbon; R-1 is hydrogen or R, and together form a group of the formula - (CH ::: : CH) 2 where the dotted line indicates the optional valence bond; hydrogen or hydroxy, and g, hydrogen, or R. hydrogen, and R.3, is hydroxymethyl the group, or R / i and R form a valence bond, hydrogen, Lenil substituted by one, two or three alkoxy groups, where alkyl with -C carbon atoms, hydroxy, methylenediaxy, nitro, cyano groups of dialkylamino and / or alkanoyl-amino groups, in which alkyl with 1- carbon atoms and / or halogen atoms; a trihalomethyl group, pyridyl, pyrrol or furyl, possibly substituted by alkyl with 1-4 carbon atoms or a nitro group, - and Yai can also be carboxyl or alkoxycarbonyl, where alkyl with 1-4 carbon atoms; hydrogens or together form a valence bond; hydrogen or hydroxy; hydrogen, Lenyl, alkyl with 1-4 carbon atoms, carboxy, alkoxycarbonyl group, where alkyl with 1-4 carbon atoms, cyano group, methylamino group, carbamoyl group, possibly substituted by one or mind with alkyls with 1-4 carbon atoms, carbohydrazide group , a group of formula - (C), - COOKil, where n, 1 or 2, and all has 1-4 carbon atoms, and a group of the formula —CO — NH — N R, benzylidene, LurFURYlidene or nitrourfurylidene, or K.-; Kg together form a group - (CH) -, in which P 3-6; oxygen or sulfur; O or 1; and that if m o, then they are hydrogens; hydrogens or together form a valence bond; Lenyl or carboxy group, together form a valence bond; hydrogen; carboxy or alkoxycarbonyl group, where alkyl with 1-4 carbon atoms. 1, then alkyl with 1-4 carbon atoms; together form a valence bond; phenyl or nitrophenyl; together form a valence bond; hydrogen; a carboxyl or alkoxycarbonyl group, where alkyl with 1-4 carbon atoms, lei, or their optical distinction, in that the active or optical optics of the general Formula 11 No. T Ri R-R.-And n have the indicated. t interaction with aldehyFormuli 111 () m equip these values with a nile, followed by the selection 3596916536
    the method of p, 1, 2 or 3, about t, an acid additive salt or op-l and h and c and the fact that the reaction
    isomer, or by the transfer of the acid to the т is carried out in the presence of aprotic
    lots in its esters or saponification of the ether solvent, in acid. . 5 6. The method according to p, 1,2 or 3, about t 2. The method according to p, 1, about tl and h and l and h and y c and and the fact that the reaction n and and so, That the reaction is carried out in the presence of an aprotic biv temperature range (-20) - POS. Polar solvent.
    3. The method according to claim 1 or 2, distinguish between 1C and with the fact that the reaction is pro-O (Sources of information are dissolved in the presence of a solvent. Taken into account during the examination
    A. The method according to PP. 1-3, about tl and h a- 1. Weigand-Hilgetag. The methods of exgo u and in order that the reaction is a wire experiment in organic chemistry. M., in the npMcyTCtBHH proton solvent. Chemistry 1968
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    同族专利:
    公开号 | 公开日
    SE431334B|1984-01-30|
    IL51388D0|1977-04-29|
    DK152431B|1988-02-29|
    FI770453A|1977-08-13|
    DK59177A|1977-08-13|
    AU2217277A|1978-08-17|
    SE7701375L|1977-08-13|
    AU512470B2|1980-10-16|
    CA1082699A|1980-07-29|
    DD131557A5|1978-07-05|
    AT357539B|1980-07-10|
    FR2340945A1|1977-09-09|
    FI63574C|1983-07-11|
    CS199288B2|1980-07-31|
    FI63574B|1983-03-31|
    AR220675A1|1980-11-28|
    BE851346A|1977-05-31|
    ES455800A1|1978-07-01|
    DE2705778A1|1977-08-18|
    GB1554370A|1979-10-17|
    US4123533A|1978-10-31|
    NO146775C|1982-12-08|
    FR2340945B1|1981-11-27|
    IL51388A|1981-07-31|
    JPS6228793B2|1987-06-23|
    YU33777A|1983-02-28|
    JPS5297996A|1977-08-17|
    DE2705778C2|1990-11-29|
    NO770457L|1977-08-15|
    DK152431C|1988-08-01|
    CH637651A5|1983-08-15|
    HU174693B|1980-03-28|
    IN146173B|1979-03-10|
    PT66184B|1978-07-11|
    NO146775B|1982-08-30|
    NL7701461A|1977-08-16|
    PL109346B1|1980-05-31|
    PT66184A|1977-03-01|
    US4252807A|1981-02-24|
    BG29723A3|1981-01-15|
    ATA84277A|1979-12-15|
    GR62466B|1979-04-13|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU76CI1642A|HU174693B|1976-02-12|1976-02-12|Process for producing condensed pyrimidine derivatives|
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