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    • 专利摘要:
    Antiallergic and antiasthmatic compounds of the formula <IMAGE> I of which 9-phenylamino-6-methyl-4-oxo-6,7-dihydro-4H-pyrido(1,2-a)pyrimidine-3- carboxylic acid and optically active antipodes and salts thereof are examples.
    公开号:SU906379A3
    申请号:SU782704104
    申请日:1978-12-28
    公开日:1982-02-15
    发明作者:Хермец Иштван；Месарош Золтан；Брайнинг Тибор；Вираг Шандор；Вашвари Лелле；Хорват Агнеш；Надь Габор；Манди Аттила；Сютш Тамаш；Биттер Иштван；Шебештьен Дьюла
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    where R and R are as defined above; L is a halogen atom or a hydro-strong group, is reacted with a compound of the general formula J 3 l 4 R and R have the indicated meanings predominantly in the presence of an acid binding agent in an inert organic solvent at a temperature from room temperature to the boiling point of the reaction mixture, followed by isolation of the desired product or, if necessary, the resulting compound of formula I, in which the dotted line does not indicate a valence bond, is oxidized to a compound of formula I, in which the dotted line means double bond, or is subjected to decarboxylation to obtain a compound of formula 1, 1 wherein R - is hydrogen, or is subjected Roliz guide for preparing a compound of formula I, wherein R - carboxyl grupTselevye Products isolated as bases or salts or optical isomers ac tive. The compound of general formula J with physiologically compatible inorganic and organic acids form salts, for example hydrochlorides, hydrobromides, hydrodiodes, sulfates, nitrates, maleate phosphates, succinates, acetates, tartrates, lactates, fumarates, citrates, etc. Compounds of general formula J, - containing carboxyl groups, form salts with physiologically compatible bases. For example, alkali metal salts such as sodium potassium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts, salts formed with organic amines such as triethylamine and ethanol amine salts can be mentioned. The invention also extends to optical and geometric isomers and tautomers of the compounds of the common yurmula I. The structure of the geometrical properties of 90 4 Mer becomes evident using formulas 1A and 1B) Tautomeric equilibrium is depicted using the scheme A Lg) VY. The transformation according to the proposed method is performed mainly in the presence of an acid binding agent. As such agents, predominantly alkali metal carbonates (e.g., sodium or potassium carbonate) are taken into account. alkali metal bicarbonates (e.g. sodium or potassium bicarbonate), alkaline metal salts of weak organic acids (e.g., acetate, sodium) or an excess of amine of general formula IIJ. The reaction is carried out in the presence of an inert solvent. As the reaction medium, predominantly aromatic hydrocarbons (for example, benzene, toluene, xylene), ethers (for example, ethyl acetate) are used. alcohols, (for example, methanol, ethanol), or dimethyl formamide. In the reaction, as may be suggested, a compound of the general formula R 4NR N-4 is obtained as an intermediate PRODUCHT where the dotted lines have the same meaning. This compound can be isolated, but -can be. Also process further beat intermediate separation, i.e. oxidize. Preferably, the reaction mixture containing 1 p (x intermediate compound is exposed to
    air oxygen, and oxidation occurs.
    If starting materials are used where Ij is a hydroxyl rpynnovi, the reaction can be carried out in the presence of a water-removing agent, for example, dicyclohexylcarbodiimide.
    The compounds of general formula I obtained by the proposed method can be isolated from the reaction mixture in a known manner. In many cases, a salt or hydrate of a compound of general formula 1 is obtained, which is filtered or centrifuged. If operated in an aqueous medium, the final product can be shaken with a suitable organic solvent and recovered by evaporation of the organic extract. If working in an organic solvent medium, then the compound of general formula I can be obtained by removing the organic solvent. The resulting product can be purified by recrystallization or chromatography.
    Compounds of general formula I can be obtained by one or several known transformations and transferred to other compounds of formula I. Subsequent group conversion is undertaken in a known manner under the reaction conditions customary for reactions of this type.
    The derivative containing the carboxyl group can be decarboxylated by heating, and a corresponding compound arises containing hydrogen instead of the carboxyl group. Decarboxylation is undertaken predominantly in the presence of an acid, for example, phosphoric.
    Esters of general formula 1 can be treated with acids or bases and hydrolyzed to the corresponding carboxylic acids of general formula 1.
    Alkaline hydrolysis is carried out by heating with bovine flux in an aqueous or alcoholic medium; Acids can be liberated from the alkali metal salts formed by acidification. By hydrolysis with mineral acids, the free carboxylic acid is obtained directly.
    The obtained compound of general formula I can be isolated in a known manner from its salt formed with an acid or a base. Compounds of OH-L of formula 1, having a basic character, can be converted into salts by reacting with inorganic or organic acids. Salt formation follows in a known manner in an inert solvent using an acid in an equivalent amount or in excess.
    Compounds of general formula I containing acidic groups (carboxyl) can interact with bases, for example, alkali metal hydroxides, alkaline earth metal hydroxides, organic amines, and salts formed with bases are obtained.
    Compounds of general formula I containing R as substituents other than hydrogen have an asymmetry center and may be in the form of racemates or optically active antipodes. The optically active antipodes of these compounds of general formula 1 can be obtained using optically active starting materials of the general formulas and or the compound of general formula I that is present as a racemate is divided into its optical antipodes. The racemic separation can be carried out in a known manner, for example, the racemate is reacted with a suitable optically active base, for example, with an optically active threo-1 - (p-nitrophenyl) -2-a and 1Nopropane-1, 3-DIOL) forming the diastereomeric salt pair. Based on the different physical properties of both salts, for example, crystallization, and the optically active compounds of general formula 1 are liberated from the salts by reacting with strong bases.
    The starting compounds can be prepared by known methods.
    The compounds of general formula 1 have an inflammation intensity reducing, analgesic, inhibiting platelet agoheiayuyu, antiatherogenic. The traditional antagonistic, antibacterial and antifungal effects affecting the central nervous system are effective against and Cons and regulate the function of the heart and blood circulation. Especially it is necessary to emphasize their action against allergies and asthma. On this basis, compounds of general formula 1 can be used in medicine and veterinarian.
    Allergic reactions that occur due to the interaction of antigens and antibodies manifest themselves in different ways about different organs and tissues. Disodium chromoglycate (1, (2-carboxychromon-6-ylox) -2-hydroxypropane, Inta1) is widely used as an anti-asthma medicine, but it is not effective in oral administration and therefore can only be used with inhalation application of a complex auxiliary device (Spinhaler). It has been found that compounds of general formula I, used as
    orally or intravenously or inhalatively, they cure allergic symptoms.
    The efficacy of the compounds of general formula I is proved using a standard test, which serves to determine the antiallergic effect. The experiments were conducted on rats with the PCA-test Ovary and with the Churck test, and disodium chromoglycate was used as a comparative substance. Studies Conducted with the RSL test gave the following results, .v., Mm / kg:
    9 Phenylamino-6-methyl-4-OXO-6, hydroAN-pyrido (1,2-a) pyrimidine-3-carboxylic acid1,3
    (-) 9 0enylamino-6-methyl-4-oxo-6, 7 Dihydroin-pyrido (1,2-a) pyrimidine 3-carboxylic acid 1,2
    Disodium Chromoglycate1.0
    As can be seen from the data obtained, a typical representative of the compounds according to the invention is also effective when administered orally, while disodium chromoglycate expands its effect intravenously. For intravenous administration, compounds of the general formula t are more effective than the compared compound.
    The toxicity of compounds of general formula 1 is low: LD {(studied in rats and mice) p. O, above 500 mg / kg.
    The percentage activity of the named compound in the PCA test with a single intravenous dose of 320 mmol, respectively. 10 mmol at 100 acc. 601
    The daily dose of the active substance can be very different and depends on the age, weight and condition of the patient, type of drug. With oral administration, the daily dose is generally at 0.05–15 mg / kg, with intravenous administration or inhalation at 0.001–5 mg / kg. This amount of active substance may also be distributed into several separate doses throughout the day. The indicated doses are purely indicative. According to the requirements of a particular case and medical prescriptions, it can deviate from them upward and downward.
    Example 1.100.0 g (0 mol) 9-bromo-6-methyl-A-oxo-6, 7,8,9-tetrahydro-pyrido (1,2-a) pyrimidine-3-carboxylic acid and 100 ml of aniline introduced into 800 ml of methanol. The mixture is heated while stirring to form a solution. The solution is cooled to room temperature and then stirred for two to three days. The precipitated crystals are filtered and washed with methanol. 64.0 g (61.4) of 9-phenylamino-b-methyl-oxo-b, 7-dihydro-, -H-pyrido (1, L-a) pyrimidine-3-carboxylic acid are obtained, which after recrystallization from methanol melts at 172-173 °.
    Found, |: C 6.22; H 5.08; N lit, 15.
    Calculated: С 6,6А; H 5.09;
    N And, 13.
    Example 2 To a solution of O, A g (9.22 mol) of sodium hydroxide in 10 ml of water was added 2.0 g (6.15 mol) of ethyl ester 9 Phenylamino-6-methyl-4-oxo-6, 7- Dihydro-4H-pyrido (1,2-a pyrimidine-3-carboxylic acid. The suspension is stirred at 60-70 ° C until everything is dissolved (about 2-3 hours). The solution is neutralized with a 10% aqueous salt After clarification the solution is acidified with 10% aqueous hydrochloric acid to pH 2.
    The precipitated crystals are filtered, and washed with water. 1.5 g of (81.5) 9-Aenylamino-6-methyl-4-oxo-6, 7 Dihydro-N-pyrido (1,2-a) pyrimidine-3-carboxylic acid are obtained, which melt at IBO-1b2. C. After
    recrystallization from methanol m.p. rises to 172-173 ° C,
    Found,%: C 6i, 60; H 5.00; N and, 11.
    Calculated, C 6h, 6h; H 5.09;
    N U, 13.
    Example 3. 2,, 35 mol) E-bromo-b-methyl-oxo-6, 7,8.9 ethyl ester of tetrahydro-4H-pyrido (1,2-pyrimidine-3-carboxylic acid) is dissolved in 6 ml of methanol. The solution is mixed with 1.8 ml of aniline. The reaction mixture is left to stand at room temperature for two days and then the solvent is distilled under vacuum. 5 ml of benzene is added to the residue, the precipitated crystals are filtered off. The filtrate is evaporated in a vacuum and the residue is mixed with 7.6 ml of aqueous sodium alkaline. The mixture is stirred at room temperature for 3 hours and the solution is obtained. Neutral solution The aqueous phase is separated from the precipitated oil by decanting and the oil is triturated with a small amount of methanol. The crystals are filtered off and washed with water to give 0.8 g (42.1) melting at 162-16 ° С 9-l-phenylamino-6-methyl-o-6-7, 7 Dihydro-H-pyrido (1, 2-a) pyrimidine-3-carboxylic acid. After recrystallization from MBanol, m.p. 171 172 ° C.
    Found,%: C 6i “, 70; H 5.12-, N T, 20.
    Calculated,%: C 6, .H 5.09;
    N 1.13.
    Example C. They work according to the method proposed in Example 3, however, instead of aniline, o-toluidine is used. 0.8 CiO.I) 9 (2-methylphenyl) -amino-L-ytyl-oxo-6, 7-dihydro 4H-pyrido {l, 2-a pyrimidine-3 carboxylic acid, which, after recrystallization from methanol, has a mp. WITH.
    Found,%: C 65.0 {, H 5, BO ;.
    N 13.39. .
    C,., H ,.
    Calculated,%: C 65.58; H 5.50; N 13.60.
    Example 5. 0.0 g (0.127 mol of 9-bromo-6-methyl-oxo-6, 7,8,9-tetrahydro + H-pyro ethyl (1,2-a pyrimidine 3 carboxylic acid ethyl ester) is dissolved in Wo ml of dimethyl sulfoxide and
    26 ml (0.285 mol) of aniline are added. The solution is allowed to stand at room temperature for J, -k day, then diluted with 100 ml of water and shaken three times with 50 ml of benzene. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from ethanol, and 2i, 5 g (59,) ethyl phenylamino-6 methyl-oxo-6, 7-dihydro-H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is obtained, with t.G1L. 119-120 ° C.
    Found,%: C 66.30; And 5.80; N 12.83.
    ,
    Calculated, I: C 66.5; H 5.8E; N 12.91.
    Example 6 0.5 g (2.00 mole of 9-hydroxy-6-methyl-oxo-6, 7-dihydro-DN-pyridoO, 2-a-pyrimidine-3-carboxylic acid ethyl ester, dissolved in 5 ml of anhydrous ethanol. The solution is mixed with 0.3 g (3.00 mol of aniline and 3 m is boiled with reverse
    phlegm. Then the reaction mixture is cooled, the precipitated crystals are filtered and washed with a small amount of ethanol. Obtain 0.3 g (46.1) of ethyl ester of 9-phenylamino-6-methyl-4-oxo-6, 7-Dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, t, square at 119-120 €.
    Found,: C 65, “b; H 5.90; N 12.82.
     .
    Calculated,%: C, 66.45; H 5.89; N 12.19.
    Example 7. 10, About g (31,83 mol) of ethyl ether 9-bromo-6-methyl-4-oxo-6, 7,8,9-tetragi dro-4H-pyrido (1, 2-a) pyrimidine 3 -carboxylic acid is dissolved in 100 ml of anhydrous ethanol. The solution is mixed with 6.9 ml (63.66 mmol) of N-methylaniline and then the mixture is boiled for 8 hours with reverse reflux. After the reaction, the solvent was distilled off under reduced pressure. The residue is mixed with 100 ml of aqueous hydrochloric acid and extracted twice with 30 ml of chloroform. The combined organic phases are dried over calcined sodium sulphate and then evaporated in vacuo. The residue is dissolved in 25 ml of methanol and left to stand in a refrigerator overnight. The precipitated crystals are filtered. 15-20 ml of solvent are distilled off from the filtrate in vacuo, the residue becomes 9 in t in a refrigerator. The dropped crystals are filtered and washed with a small amount of methanol. 2.8 g (25.9%) melted at 126-129 C of ethyl ester of 9- (tilanilino) -6-methyl-oxo-6.7 dihydrr-4H pyrido (1, 2-a) pyrimidine 3 are obtained to the side acid After recrystallization from methanol, m.p. rises to 131-1 33 S. :. It was found,%: C 67.40; H 6.35; m p, g, 9 RCM Calculated,%: From 67.25; And 6.23; N, 12.38. EXAMPLE 8: 2.0 g (6.97 mol) of 9-bromo-6-methyl-4-oxo-6, 9-tetrahydroH- are introduced into 20 ml of methanol. pyrido (1,2-a) pyrimidine-3-carboxylic acid and 1.72 g of p-bromoaniline. The mixture is heated with stirring until everything is dissolved. The solution is cooled to room temperature and stirred for 2-3 days. The precipitated crystals are filtered. and washed with methanol. 1.7 g (64.6% O (-bromophenyl) amino-6-methyl-oxo-6, 7-dihydro-H-pyriro (1,2-a) pyriglydine-3-carboxylic acid, 1 LOTH are obtained which, after recrystallization from methanol, has a melting range of 202-20% found: C 51.15; H 3, aO; N 10.90; Br 21, 21. C ,, 0. Calculated,%: C 51 , 08; H 3.75; N 11.17; In d 21,. Example 9. It was worked according to the procedure proposed in Example 1, however, it comes from (-) 9-bromo-6-methyl 4-ca-6, 7,8,9-tetrahydro-H-pyrido (1, 2-pyrimidine-3-carboxylic acid. In a yield, (-) - 9-phenyl amino-6-methyl-4-oxo-6,7-Dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, which melts at C. Found,%: C 64.51; H l, 96; N 1.01. Calculated.%: C, H 5.09; N H, 13. Examples 10-13 (see table. 1) 2.9 g (0.01 mol) E-bromo-6 -methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid was dissolved in 5 ml of dimethyl sulfoxide. 0.02 mol of the indicated in table was added to the solution. 1 aromatic amylamine. The reaction mixture at room temperature 9 is left to stand in an open vessel for three days and then mixed with 20 ml of water. The precipitated crystals are filtered, washed with water and then dried. The crude product is recrystallized from the table. 1 solvent. An example. 1 +, 35 g (0.05 mol) of 9-bromo-6 methyl-α-oxo-6, 7, 8,9-tetrahydro-4K-pyrido (1,2-a) pyrimidine-3 carboxylic acid is dissolved in 100 ml of anhydrous chloroform; and ml (0.15 mol) of n-butylamine are added to the solution. The reaction mixture was allowed to stand at room temperature for three days and then mixed with 70 ml of water. The pH of the aqueous phase is set to 2 with vigorous stirring with 10% aqueous acid. HCt is separated. The organic phase is separated, the aqueous portion is shaken 2 times with 50 ml of chloroform. The combined organic phases are dried over calcined sodium sulphate and the solvent is distilled off under low pressure. The residue crystallizes from methanol. 4.3 g (31%) of 9 n-butylamino-b-methyl-oxo-6, 7-diHydro-J-pyrido (1,2-a) pyrimidine-3-carboxylic acid with m.p. Found,% -. C 61, H 7.08; 15.06. C44. : Calculated,%: C 60.63; H 6.91; IN 15.15. Example 15. 5.0 g (1.64 mol) of ethyl ester 6-me. Tyl-9- (L-methylanilino) -4-oxo-6,7,8, 9-tetrahydro- (H-pyrido (1, 2-a) pyrimidine-3-carboxylic acid is dissolved in 100 ml of chloroform. Bail solution T 9 h with reverse reflux with simultaneous blowing of air. Then the solvent is distilled off in vacuo, the residue is crystallized from ethanol to yield 2.9 g (58, lt%) of 6-methyl-9- (1-methylanilino) ethyl ester -ox, o-6,7-dihydro-4H-pyrido (1,2-a) pyrimidine 3 1sarboxylic acid The product melts at YO-142 This product obtained according to Example 7 does not show a melting point depression. Found: C 67 , H 6.36; N12.38. Calculated but,% C b7, H 6.23; N 12.38. Example 1b. 2.9 g (0.01 9 6rom-6-methyl-oxo-6,7,8,9 tetrahydro-CH-pyrido { 1,2-a) pyrimidine-3-carboxamide is dissolved in 20 ml of acetonitrile. 0.025 mol of benzylamine is added to the solution. The mixture is boiled for 4-5 h, then the precipitated substance is filtered, washed with water and then dried. With 2% - 9-benzylamino-6-methyl-β-oxo-6, 7-dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxamide, m.p. 1901924. Found,%: C 65.95; H 5, N 18,10,. (.7H,%: C 66.00; H 5, Calculated, N 18.11. Example 17- Work according to the procedure described in Example 16, however, n-b-thylamine is used as the amine. With a 50% yield get 9- (n-butylamino) 6-methyl-i (-OKCo-6, 7 -dihydro-4H-pyrido (1,2-a) pyrimidine 3-carboxamide, with so pl. 178-180 C. Found : C 61.00; H 6.79; N 20, W. I: C 61.07; H 6.95; It is mined, N 20; Example 18. To a solution of 0, sodium bicarbonate in 20 ml of water is added 1 , 0 g (3i3t mol) 9-anilino-6-methyl- (-oxo-6,7,8,9-tetrahydro- + I-pyridoM, 2-a-pyrimidine-3-carboxylic acid. The suspension is stirred at In-9o C with simultaneous blowing air. About that, everything was transferred to the solution, stirred for another 0.5 h and then the solution was cooled | to room temperature. The pH was adjusted with noMoii bio hydrochloric acid. The precipitated crystals were filtered, washed with water and then dried. 65.5) 9-anilino-6-methyl-4-oxo-6,7-D hydro - i py to do (1,2 - a) pyrimid of n - 3-carbonic acid, with mp 152 -15 C. Recrystallization from methanol, m.p. 172-17 + C. The product with the compound obtained according to Example 1 does not show a melting point depression. Found,% -C (12 5.22; N I, 10... O: C 6, .H 5.09; Calculated, N. U. mole Example 19. 2, E g (0.01 mol) ( -) 9-bromo-6-methyl-n-oxo-6,7,8,9-tetrahydro-4H-pyrido (T, 2-a) pyrmidine 3-carboxylic acid (, c 2, methanol) is dissolved in 5 ml p methyl acetate and 3.8 g (0.022 mol) p-bromoaniline are added. The solution is left to stand at room temperature in an open state for three days and then mixed with 20 ml of methanol. The precipitated crystals are filtered and washed with methanol. , 7 g ("5.2%) (-) - 9- (4-bromoanv (Lino) -6-methyl-1-oco-6, 7,8,9-tetrahydro-CI Pirido (1,2-a a) pyrimidine-3-carboxylic acids with mp 210-211 C, Found: C, 51.25; And 3.80; N10.90; BV 21.2. BCU about VUViCalculated,%: C 51.08; H, 3.75; N11.17; 8g 21.2. Example 20. 5.0 g (0.016 mol) of ethyl ether 9 bromo-6-methyl-4-oxo-6, 7,8,9-tetrahydro + I-pyrido (1, 2-a) pyrimidine-3-carboxylic acid is dissolved in 50 ml of ethanol and 3.5 ml (0.032 mol) of N-methylaniline are added. The reaction mixture is boiled under nitrogen atmosphere for 8-9 hours. Then the solution is mixed with 50 ml hydrochloric acid and shaken three times with 25 ml of dichloromethane. The combined organic phases are dried over calcined sodium sulphate and evaporated under reduced pressure. A dark oil remains which crystallizes upon the addition of a small amount of methanol. 3.0 g (55.2%) of 6-methyl-9-CH-methylanilino) -4-oxo-6,7 ethyl ester, 8,9-tetrahydroH-pyrido (1,2-a) pyrimidine are obtained. 3 carboxylic acids with so pl. 175-178 0. C 67.25 H 6.80; Found,; W12.16. C, 66.85; H 6.79; W2.30. Example 21. To a solution of 5 g of sodium hydroxide in 300 ml of water was added 20 g (58.56 mol) of ethyl 6-methyl-9-C methylanilino) -oxo-6, 7,8,9-tetrahydro-H- pyrido (1,2-a) pyrimidine-3-carboxylic acid. The suspension is stirred at 6070.degree. C. for 15 hours. The crystals are then filtered and washed with water. The crude product is recrystallized from this -.15 nol. 9.0 g (57.1) of 6-methyl 9- (-methylanilino) - | -oxo-6.7 are obtained. 8,9-tetrahydro-H-pyrido (1,2-a) piri Judah, with mp, 188–18 ° C. Found,%: C 71, b9; H 7.30: M15.39. Calculated C, 71.35; H 7.11; N15.60. Example 2 .., 7 g (0.50 mo of 9-bromo-6-methyl-4-oxo-6, 9 tetra hydro-4H-pyrido {1,2-a) pyrimid n-3-carboxylic acid is dissolved in 250 ml of acetoitriat a and 100 ml of aniline are added. The solution is stirred at room temperature under an atmosphere of nitrogen for two days, then mixed with 1000 ml of water and stirred for another 30 minutes. The crystals are filtered off, washed with water and KI nt t then in 1400 ml of methanol. Get it. 128.8 g (86.1) 9-anilino-6-methy-4-oxo-6, 7.8, 9-tetra of gidro-4H-pyrido {1, 2-a) pyrimidine-3 carboxylic acid, with so pl. 198-199 ° C. Found,%: C 6 (, 50; H 5.99; M13.81. (1, H N303 Calculated,% C 6i, 20; H 5.72; N 1.0. 23. To a solution of 0.5 Example 10 ml of WATER sodium dohydroxide per mole) 9 anilibate 1.0 g (3.3 but 6-methyl-t-oKco-6,7,8,9-tetrahydro i (rido {1.2 -a) pyrimi di n-3-karboxylic acid. The solution at 70-80 is stirred under a nitrogen atmosphere for 5 hours and then cooled to room temperature. The precipitated crystals are filtered and washed with water to obtain 0.4 g (46.9%) 9 α-anilino-6-methyl-6 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one, with a mp of 1bO. After recrystallization from acetonitrile, mp, C. Found, C 70.95; H 6., 82; H16.3 7., Calculated,%: C 70.56, - H 6.7T ;. N16.46 ... Example 24. 1.0 g (3.48. MO 9-bromo 6-methyl-4-oxo- 6,7,8,9 Tetra hydro-4H-pyrido (1,2-a) pyrimidium-3 -carboxylic acid is dissolved in k pyridine and the solution is left to stand at room temperature for three days. The precipitated crystals are filtered and washed with chloroiornum, 0.75 g of (66.9) 916 til-4-oxo-6.7, U, 9-tetrahydro-4H-pyrido (1, 2-a) pyrimidine-9-yl) pyrimidinium bromide are obtained, m.p. 250-252С. After recrystallization from methanol twice, the product melts at 270272 C, Found, - ;;: C 52.16; H 4.98; Ml2.92; W-25.20. Calculated, I: C 52,19; And 5.02; 13, P4; VG 24.80. Examples 25-27 {see that & l. 2). 2.9 g (0.01 mol) of 9-bromo-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid are dissolved in 5 ml of dimethyl sulfoxide. To the resulting solution was added 0.02 mol of an aromatic amine (see Table 2), after which the reaction mixture was left to stand in an open vessel for 3 days. Then 20 ml of water is added to it. The precipitated crystals are washed with water and dried. The resulting crude product is subjected to recrystallization from the table. 2 solvent. Examples (see tab. 3). 0.5 g (2.25 mmol) of 9-hydroxy-6-methyl-4-OXO-6, 7-dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is dissolved in 5 ml of anhydrous ethanol. To the resulting solution was added 2.48 mmol of an aromatic amine (see Table 3), after which the reaction mixture was heated under reflux for 3 hours. then cooled and precipitated crystals are filtered off. The crude product is subjected to recrystallization from the table. 3 solvent. Example 34. The process is carried out according to Example 12, with the difference that 3, instead of 9 bromo-6-methyl-4-oxo6, 9 tetrahydro-4 1-pyrido (1,2-a) pyrimidium-3 n: arbonic acid 9 bromo-4-oxo-6,7,8,9-tetrahydro 4H-pyrido {1, 2-a} pyrimidine-3 carboxylic acid is used. The resulting product is recrystallized from acetonitrile. The result is 9 (phenylamino) -4-oxo-6,7-dihydro-4H-pyrido (1,2-a). Pyrimidine-3 arbonic acid. Exit 50. m.p. 197-198 C. Found,% i C 63.45; H 4.50; , N1f}, 8b jO% i С 63.60; H 4.69; Calculated M14.83. 179 Example 39. Proceed as in Example 22, with the difference that instead of 9-bromo-6-methyl - "- oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-Zcarboxylic acid, 9-bromo- 4-OXO-6,7,8,9 tetrahydro-N-pyrido (1,2-a) pyrimidi-3 carboxylic acid. The crude product is boiled in methanol. 9-anilino-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) and lidine-3 carboxylic acid are obtained. Exit 56, U. M.p. 178-180 0. Calculated,%: C, 63.15; H 5.30; N And, 73. 0,, Found,%: C 63, OA; H 5.22; N,. 918 EXAMPLE tO. Proceed as in Example 2 with the same step that b-methyl-3- (N-methylanilino) -oxo-b, -dihydro-H-pyrido (1, 2-a) pyrimidine-3-carboxylic acid ethyl ester is used. . The crude product is recrystallized from methanol. 6-methyl-9 (M-methylanilio) -4-oxo-6,7-dihydroH-pyrido (. 1,2-a) pyrimidine-3-carboxylic acid is obtained. Found,%. C 65.10; H 5.60; V113.32. “Pn {7g 1. Calculated,%: C b5,55; H 5.50; ,"9. Table 1
    p-ethoxypniline 9 (Toxianilino) -6-methi - | -oxo-6, 7 - dihyPRO-f-pyrido (1, 2-a) pyrim-n-3 -Zcarboxylic acid
    6-Methyl-9- (t-nitrop-nitroaniline
    ANILINO) - 4-OXO-6, 7 - di GI DROPI OIDO
    (1,2-a) pyrimidine-3carboxylic acid
    9-Lnilino-6-mstil-Aniline-oxo-6,7 D hydro-I-pyrido (, 2-a) pyri 1 dyn-3 carbonooic acid
    6-Methyl-9-CtxnopaHH-9b
    p-chloroaniline lino) - "- oxo-6,7-DI, hydro-H-pyrido (1,2-a) pyrimidium-3-carboxylic acid Total product formulas: an example is an example
    210-2P Aceto-63.33 nitrile
    63.12
    li k-2kl Dimethyl- 56, and formamide
    55.99
     Methanol 6.6 6., 52
    12.67
    25
    57.92, 30 12.90
    57.72 10: C ,, example 11: (;, H, example 13 C, bV4 ° -i 25. Aniline 9 - (. 3-Iodophenyl-20.0 229no) -6-methyl-oxo-6 , 7-ligidro (1,2-p) pyrimidin-3-corboxylic acid 26 3-Nitroaniline 6-Petyl-9- (3-nitro 1 |, 9 20 feta il lamy but) - t-oxo-6, 7- Dihydro-H; -pyrido (1,2-a) pyrimidine-3-carboxylic acid 3-chloroaniline 3- (3-chlorophenyllio) - C methi-l-oxo-b, 7-dihydro- H-pyrido 1, 2-a) pyrimidine-3-carboxylic acid
    8 Zaminobenzoy, -9- (ZKarboksiAe- 38,2 nap | acid nylamino) -6-me
    Tyl-1-oxo-6,7-Dihydro-lit-pyrido (1, -a} pyrimidine-3 karOonooa acid
    6-Metip-9-O-me- (1.9
    9 m-Toluidine tilpheny amino) - oxo-6,7 Dihydro-iiH-pyrido (, 2-a) pyrimidine-3-carboxylic acid
    6-Meti-9- (2-nao-25.0
    2-Naphthylem tilamino C-ox-6-6, 7-dihydro- [H-oiridoi, 2-a) pyrimidine-3 carboxylic acid
    Table (5.1 170 Table 3
    With HKOj. 59.82 ".." "W 12.31
     Ethanol
     65.58 5.50 13.50
     Ethanol 65.22 5.73 13.28
    , 65, t5, .83 12.10
    187-188 Ethanol 68.87 5, to 11.87 30 Nitro-CH NjO ,, itS,) 3.33 9.93 methane "5.15 Z.Z. 9.76 CJjL.NjO 56.1t 4.12 16.37 06 MetaC 4 -1 5 56.61 A, 07 16.1 (0 72 Lceto-C N NOSe 57.93, 25 12.67 nitrile 57.76, 1b 12,
    3-lminoaceto-9 3-ltsptilphenyl-38rt phenoyl mino) -6-methyl- | -oxo-6, 7-digilro-i-gmrido (1,2-a) pyrimyl-3-carboxylic acid
    ZFtoraniline
    9- (3-Fluorophenyl- "1," -a and isho-b-methyl-1-oxo-6, 7 Dihydro (.1,2-a) pyrimidine-3-carboxylic acid
    1-Naphthylamine
    L-Methyl-9-α-naph-2,6 tylamino-oxo- (, 7-Digi; ro-H-pyrido (1,2-a) pyrimidine-3 carboxylic acid
     4-Lminobenzoi-9- (-CarPoxy-63.5
    MA Acid (yenylamino) -6-methyl-oxo-6, 7-igidro-4 -PirI 1 DO (1,2-a) pyrimidine-3-carboxylic acid
    5P-ANINIZIDIN 6-Cometil-9- (Jl-MeT-
    hydroxyphenylamino) - -oxo-6, 7-dihydro-H-pyrido (1,
    62-Aminophenyl 9- (2-Hydroxyphenyl- 76.6
    amino-b-methyl- ("-oxo-b, 7-dihydro- | H-mrido M, 2-a) pyrimidine-3-carboxylic acid
    73, -Dichloroan-. 5.9 liniylamino) -6-methyl-oxo-6, 7
    -di hydro-tH-pyrido (1,2-d) pyrimidine-3-carboxylic acid
    81 -Lminobiphenyl 9 - (- BiLenilam-7.0
    but) -b-methyl- -ok: CO-6, 7-di GIDRO-JlH
    -pyrido, 2-a) pyrimidine-3-carboxy acids
    73-17 eta-
    Nol
    63.75 5.09 12, "(3
    187-188 Eta-, 60.95, "Z.ZZ
    butt
    61, (And t. SQ 13,
    221-222 Eta- With NDo, 69.15, 93 12.09
    Nol
    (kip -69.28, 91 12.01
    reading)
    230-231 eta- 59.80 k.kO 12.31
    Nol
    59.70. 50 12.13
    195-196 Acheto-C AND. 62.38 5.23 12.8 nitrile
    62.7 | 5.31 12.65
    208-209 Eta-S, Nmob1,3 ", 83 13." I „KM
    Nol
    61.09 1., 77 13.53
    218-219 Eta- CHNOo; 52.28 3.58 M, MOS f.
    52.30 3, 11.25
    2G8-219 Eta- CN. 70.76 5.13 11.25
    olp-i-
    Nol
    70.29 5.01 11.12 Oormula of the invention. A method for producing pyri derivatives to (1,2-a) pyrimidines of the general Formula, where the dotted line means a double bond that you have if necessary; R is hydrogen or C is an alkyl t group; hydrogen, carboxyl, carb ocaca wdna or C alkoxycar l bonyl group; A PiC. -Alkyl, phenyl, benzyl, naphthyl or phenyl group substituted by one or more halogen atoms With g alkyl, nitro, carboxy, alkoxy, acetyl, phenyl or hydroxy groups; R is hydrogen or C an alkyl group, or R and R together with a nitrogen atom form a pyridine ring or their salts, or their optically active isomers, characterized in that with 9 one compound O1 or G1 or its. optically active isomers R and R. quoted values; L is a halogen atom or a hydroxyl group, is reacted with a compound of the general formula OB, where R and R have the indicated meanings, preferably in the presence of an acid binding agent in an inert organic solvent at a temperature from room temperature to the boiling point of the reaction mixture, followed by isolation of the desired product, or, if necessary, the resulting compound of the general formula 1, in which the dotted line does not mean a valence bond, is oxidized to a compound of formula I, in which the dotted and represents a double svlz or subjected to decarboxylation to obtain a compound of formula I, wherein R is hydrogen, or is subjected to hydrolysis to obtain coedinet and Formula 1, wherein the carboxyl group. The desired products are isolated as base or salt, or optically active isomers. Sources of information taken into account in the examination 1. Weigand-Hilgetag. Experimental methods in organic chemistry. M., Himi, 19.68, p. k22.
    权利要求:
    Claims (1)
    [1]
    Claim
    906379 24 | the unity of the General formula [I or its
    The method of obtaining ’derivatives of pyrido (1,2-a) pyrimidines of the general Formula. Optically active isomers
    I where is the connection;
    R · * dashed line means if necessary double hydrogen or C. an alkyl group;
    hydrogen, carboxyl, carboxamide or ^ -alkoxycarbonyl group;
    R / C is an alkyl, phenyl, benzyl • naphthyl or phenyl group substituted by one or more halogen atoms C ^ alkyl, nitro, carboxy, alkoxy, acetyl, phenyl or hydroxy;
    hydrogen or C - ^ - alkyl group, .. o4 -------.
    IOM, 3 β 4 25. '' ^ 4 or R. and R4 together with the nitrogen atom form a pyridine-30 ring or other salts, isomers, and
    1 'or their optically active-35 centigrade with the fact that coπ 4 p where k and R have the indicated meanings,'
    L is a halogen atom or a hydroxyl group, is reacted with a compound of the general formula - z l HN 'r wherein R 4 and R7 are as defined above, preferably in the presence of an acid-binding agent in inert organic solvent at from room temperature to the reflux temperature of the reaction mixture, with the subsequent isolation of the target product, or, if necessary, the obtained compound of general formula 1, in which the dashed line does not mean a valence bond, oxidize to the compound of formula I, in which the dashed line inia means a double bond, or is decarboxylated to obtain a compound of formula I, where R is hydrogen, or hydrolyzed to obtain a compound of formula 1, where
    R 2 · is a carboxyl group.
    The desired products are isolated in the form of a base or salt, or optically active isomers.
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    同族专利:
    公开号 | 公开日
    NO150280C|1984-09-19|
    LU80659A1|1979-04-13|
    FI65620B|1984-02-29|
    IL56132D0|1979-03-12|
    CA1154766A|1983-10-04|
    ATA901078A|1983-09-15|
    GB2011408A|1979-07-11|
    DK585478A|1979-06-30|
    GR67312B|1981-06-29|
    AT374476B|1984-04-25|
    FI784014A|1979-06-30|
    AU4262878A|1981-06-18|
    NO150280B|1984-06-12|
    NO784392L|1979-07-02|
    NL7812479A|1979-07-03|
    DE2854112A1|1979-07-12|
    FI65620C|1984-06-11|
    IT7869932D0|1978-12-22|
    ES476837A1|1979-06-16|
    GB2011408B|1982-06-30|
    CS909078A2|1985-06-13|
    HU180439B|1983-03-28|
    BE873141A|1979-04-17|
    SE7813225L|1979-06-30|
    PT68924A|1979-01-01|
    AR221712A1|1981-03-13|
    YU296378A|1983-10-31|
    PL119517B1|1982-01-30|
    JPS54112895A|1979-09-04|
    FR2413390A1|1979-07-27|
    SE434056B|1984-07-02|
    PL212205A1|1980-02-25|
    DD143910A5|1980-09-17|
    CS241014B2|1986-03-13|
    US4260612A|1981-04-07|
    FR2413390B1|1982-06-11|
    IL56132A|1982-02-28|
    AU520803B2|1982-02-25|
    CH641800A5|1984-03-15|
    YU278082A|1983-10-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2786056A|1954-05-03|1957-03-19|Merck & Co Inc|Acylamido-hydroxy pteridines and preparation thereof|
    GB1147759A|1965-06-17|1969-04-10|Sterling Drug Inc|Aromatic derivatives and preparation thereof|
    AT286990B|1966-11-02|1971-01-11|Chinoin Gyogyszer Es Vegyeszet|Process for the preparation of new homopyrimidazole derivatives and their salts|
    GB1141249A|1967-05-25|1969-01-29|Parke Davis & Co|New quinazoline compounds and methods for their production|
    US3642797A|1968-06-10|1972-02-15|Sterling Drug Inc|4h-pyridopyrimidin-4-ones|
    JPS50149698A|1974-05-25|1975-11-29|
    HU174693B|1976-02-12|1980-03-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing condensed pyrimidine derivatives|
    US4122274A|1977-05-25|1978-10-24|Bristol-Myers Company|3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones|HU178452B|1979-05-11|1982-05-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing 9-substituted amino-4-oxo-6,7-dihydro-4h-pyrido/1,2-a/pyrimidine derivatives|
    HU183330B|1981-02-13|1984-04-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing new of 2,4,8-triazaphenalenium-salts|
    US5352795A|1986-03-07|1994-10-04|Ciba-Geigy Corporation|Alpha-heterocycle substituted tolunitriles|
    HU201551B|1988-02-03|1990-11-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing 4-oxo-4h-pyridopyrimidine-3-carboxylic acid amide derivatives and pharmaceutical compositions comprising same|
    US5252572A|1988-02-03|1993-10-12|Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt.|Pyridopyrimidine derivatives, pharmaceutical compositions containing them and process for preparing same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77CI1795A|HU180439B|1977-12-29|1977-12-29|Process for producing 9-amino-pyrido-square bracket-1,2-a-square bracket closed-pyrimidine derivatives|
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