• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:SU1001857A3
    申请号:SU792832051
    申请日:1979-10-17
    公开日:1983-02-28
    发明作者:Бире Хельмут；Капп Йоахим-Фридрих；Беттхер Ирмгард
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new derivatives of pyriI of the general formula doC2,1-vZhinazolinone
    where X Vg is a carboxyl cyano group or an alkoxycarbonyl group;
    a hydrogen atom or a methyl group;
    R ^ -R ^ is hydrogen or halogen,
    SC — Cd — alkyl groups, trifluoromethyl groups, carboxyl or alkoxycarbonyl groups, thiocyanogroups, nyl groups, py, at from R2.-R - hydrogen, which are methylthio groups, methylsulfonic groups, methylsulfonyl methylsulfoimidoyl group conditions, that 2 or 3 groups are biologically active compounds or intermediates for their preparation and can find application in medicine.
    A known method of producing quinazolone derivatives by condensation of anthranilic acid with formamide by heating [Ί}.
    The purpose of the invention is based on a method known in organic chemistry for the preparation of new pyrido ^ 2,1-vZhinazolinone derivatives of formula (1), which are biologically active compounds or intermediates for their preparation.
    This goal is achieved by the fact that according to the method for producing 'compounds of formula (1), a pyridine derivative of the general formula (|)
    )
    h 1001857 where R ^ -R 5 have the above meanings ^
    an amino group or halogen, condensed with a phenyl derivative of the general formula (111)
    vood z
    where X and have the above meanings;
    V is hydrogen or an alkyl group;
    Z - halogen or amino, 15 and isolating the desired product where X ili'alkoksikarbonilnaya cyano group, or hydrolysed and isolated compound of formula (I), wherein X - gruppo carboxyl and in case neobho- Μ gence compound of formula (I), where is R ^ -R "A methylthio group is oxidized and isolated compound of formula (I), wherein R ^ -R ^ - motilsulfinilnye group or a methylsulfonyl group, and if desired, a compound of formula 25 (I), wherein R ^ -Rg- - methylsulfinyl group, is reacted with an azide alkali metal and emit the target product, where R ^ -R ^. ~ methylsulphoyim- 30 milking group.
    Biologically active compounds have anti-inflammatory, antipyretic, analgesic and anti-allergic activity.
    In addition, they have a phosphodieste 35 | inhibitory effect. The stomach tolerates the compound of formula (I) satisfactorily, their toxicity is relatively low. The compounds of formula (.1) are suitable in combination with carriers conventional for galenic pharmacy for the treatment of acute and chronic inflammatory processes of polyarthritis, neurodermatitis, asthmatic bronchitis or hay fever.
    PRI me R 1. a) To a solution of 15.1 G of 2-amino-5-methylbenzoic acid in 200 ml of ethylene glycol monobutyl ether is added, g: 'potassium carbonate powder 7.6; N-ethylmorpholine 15, ’2,5-dibromopyridine 28, and me-g di (II) 1.8 bromide and stirred for 6 hours at 180 ° C. under argon atmosphere. After distilling off the solvent under the vacuum created by the water-jet pump, the residue is dissolved in 1 L of ethyl acetate and first washed with 1 N acetic acid, then with sodium bicarbonate solution. The organic phase is concentrated and the residue is recrystallized from chloroform. 15.2 g of 8-bromo-2-methyl-11H-pyrido-£ 2,1-vZhinazolin-11-one are obtained with a melting point of 204 ° C.
    a g ) To a solution of 1.7 g of 2-chloro-5 ~ methylbenzoic acid in 3θ ml of diethylene glycol dimethyl ether is added, g: N-ethylmorpholine 1.5; potassium carbonate powder 0.7; copper (H) bromide 100 and 2-amino ~ 5-bromopyridine 2 and the mixture is heated under nitrogen atmosphere for 14 hours to 16 ° C. After distillation under dilution of the solvent, the treatment is carried out similarly to a ^. 1.2 g of 8-bromo-2-methyl-11H-pyrido-2,1-c ^ quinazolin-11-one are obtained.
    _ B) To a solution of 14.8 g of 8-bromo-2-methyl-11H-pyrido £ 2,1-β-quinazolin-11-one in 500 ml of carbon tetrachloride, 11 g of bromosuccinimide and 0.5 g of azobisisobutyronitrile are added and irradiated with a lamp of 500 W, while the solution is boiled with reflux. After distillation of the solvent, the residue is dissolved in about 2 L of chloroform, the organic layer is washed with water, and after distillation of the solvent, 18 g of 8-bromo-2-bromomethyl-11H-pyrido £ 2,1-v] -quin zolin-11-one with t .pl. 208 ° C (toluene).
    c <) 3.7 g of 8-bromo-2-bromomethyl-11H-pyrido [2,1-bZ quinazolin-11-one is added to a solution containing, g: sodium cyanide 1.5; [otassium iodide 0.2; water 3 ml and ethanol 50 ml and the mixture is boiled for 15 minutes with reflux. After cooling, the formed nitrile crystallizes, it is filtered under vacuum, washed with water and a small amount of ethanol, and recrystallized from acetonitrile.
    Obtain 2.2 g of 8-bromo-11-oxo-11 H-pyrido | [2,1-in! quinazolin-2-acetonitrile with so pl. 240 ° C.
    c ^) To a solution of 17.3 g of 8-bromo-2-bromomethyl-11H-pyrido [2,1-v ^ quinazolin-11-one in 500 ml of chloroform, a previously prepared complex is added
    3.1 g of potassium cyanide and 16.9 g of dibenzo-18-crown-6, as well as another 3.1 g of potassium cyanide and boiled for 30 min with reflux, then stirred overnight at room temperature. The solution is then chromatographed by washing with toluene from a silica gel column.
    8.5 g of 8-bromo-11-oxo-11H-pyrido [2,1-b] quinazolin-2-acetonitrile are obtained with a melting point of 24 ° C (tetrahydrofuran-water).
    1001357 6
    d) A solution of 41.7 g of concentrated sulfuric acid and 23 ml of water is treated with 4 g of 8-bromo-11-oxo-11H-pyrido (2,1-v1hinazolin-2-acetonitrile and stirred for 3 hours at 120 e C. After cooling 5 the solution is poured into a mixture of 400 ml of ice water and the pH is adjusted to 4-5 with sodium acetate.
    3.9 g of crystals of 8-bromo-11-OKco-l1H-pyrido £ 2,1-vZhinazolin-U-2-acetic acid are obtained with a melting point of 271 ° C (dimethylformamide-water).
    Example 2 a) A solution of 2.1 g of 2- (4-amino-3-carboxyphenyl) propionic acid in 5 ml of ethylene glycol mono * 5 butyl ether was stirred with 1.4 g of powdered potassium carbonate and
    1.2 g of N-ethylmorpholine 0.5 h at room temperature. Then add 3.0 g of 2.5 ~ dibromopyridine and 150 ml of 20 copper bromide (P) and the mixture is heated under nitrogen atmosphere for 7 hours to 180 ° C (bath temperature). After distilling off the solvent under vacuum, the residue was dissolved in ethyl acetate and washed with diluted 25 ml acetic acid.
    After extraction with acid-base, the organic acid fraction is recrystallized from ethanol to give 1.5 g of 2- (8-bromo-11-oxo-. 30
    -11H-pyrido £ 2,1-b] quinazolin-2-yl) ~ -propionic acid with so pl. 251 ° C (dimethylformamide-water).
    B) Preparation of the starting material: 2- (4-amino-3-carboxyphenyl) propionic acid or its ester is produced as follows.
    B and ) To a solution of 35.7 g of chloral hydrate in 480 ml of water are added 36.9 g of sodium sulfate, 38.6 g of ethyl 2- (4-aminophenyl) propionic acid, 120 ml of water, 17 ml of concentrated hydrochloric acid and a solution
    43.9 g of ammonium oxychloride in 200 ml of water and the reaction mixture slowly ( heated to boiling for 45 minutes, then kept at boiling temperature for 10 minutes and cooled. The product precipitated as an oil was dissolved in ethyl acetate and washed with water. After separation, the acid the base, the organic acid fraction is concentrated and recrystallized from acetonitrile to give 25 g of 2 ~ (4- (2-hydroxyimino) -acetamidophenyl) propionic acid with a melting point of 1 ° C.
    B 2 ) 13 g of 2-ϋ4- (2-hydroxyimino) -acetamidophenyl 3-propionic acid are transferred in portions into 55 g of sulfuric acid (specific weight 1.84), which is preheated to 50 ° C. Furthermore, the temperature reaches 70 ° C. After completion of the addition, it is heated to 80 ° С for another 10 min, then it is poured into 300 ml of ice water and extracted with ethyl acetate. Recrystallization from acetonitrile gave 10 'g of 2- (5 _ izotinil) -propionic acid with m.p. 224 ° C.
    B e ) To a solution of 2.2 g of 2- (5-isatinyl) · propionic acid in 22 ml of water and 3 ml of a 32% sodium hydroxide solution are added dropwise over 20 minutes
    2.9 g of hydrogen peroxide (30%) and then stirred for another 20 minutes. After the reaction mixture was acidified with 2N hydrochloric acid (pH 2 ~ 3), the organic material was extracted with ethyl acetate and then * recrystallized from acetonitrile. 1.8 g of 2- (4-amino- 3_ carboxyphenyl) propionic acid are obtained with a melting point of 179 ° C.
    1¾) 3 g of 2- (4-amino-3 ~ carboxyphenyl) propionic acid is dissolved in 500 ml of hydrochloric acid in methanol (^ 3%) and left for two days at a temperature of about 20 ° C. After concentration, the residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution and recrystallized.
    2.8 g of methyl 2- (4-amino-3 _ carboxyphenyl) propionic acid with t.pl.151 ° C (acetonitrile).
    Example Z. a) Under the conditions of Example B), from 2-bromo-5 ~ chloropyridine and 2- (4-amino-3 _ carboxyphenyl) propionic acid, 3 ~ (8-chloro ~ 11 / oxo-11 H-pyrido [* 2.1 β-quinazolin-2-yl) -propionic acid with a melting point of 234 ° C.
    b) The starting 2-bromo- 5_ chloropyridine is obtained analogously to the method known from the literature, as follows.
    To a solution of 14 g of 2-amino-5 ~ kporpiridin in 30 ml of water and 45 ml of hydrobromic acid (63% in water) 17 ml of bromine are added and the mixture is cooled to 0 ° C. When controlling the temperature, a solution of 21 g of sodium nitrite in 30 ml of water is added dropwise at such a rate that the temperature of the mixture does not exceed 5 ° C. Then, with cooling, a solution of 45 g of sodium hydroxide in 115 ml of water is added. The precipitated crystals are filtered off under vacuum, washed with water and recrystallized first from acetone, then again from ethanol. Obtain 10 g of 2-bromo-5-chloropyridine with so pl. 68 ° C.
    Ί 1001
    L ρ and M ρ 4. a) Under the conditions of Example 2a), 2- (6-chloro-1 1) methyl ester is obtained from 2,3-dichloropyridine and 2- (4-amino ~ 3-carboxyphenyl) propionic acid methyl ester / 5 2ppo-11H-pyrido {_2,1-b] quinazolin-2-yl) -propionic acid.
    _B) The latter is converted by heating with dilute soda liquor into 2- (b-chloro-11-oxo-11H-pyrido £ 2,1-c] 16 quinazolin-2-yl) -propionic acid.
    Example 5. Under the conditions of Example 2a) br0m from 2-fluoro-5 _ ~ pyridine and 2- (4-a.mino-W-carboxyphenyl) propionic acid, 2- (8-fluoro-11 - 15
    -oxo-11H-pyrido ^ 2,1-b] quinazolin 72-yl) -propionic acid, m.p. 221 C (dimethylformamide-water).
    Example Under the conditions of Example 2a) of 2-bromo-W, 5-dichloropyridine 20 (prepared from 2-amlno-W, 5 _ ~ dichloro pyridine according to Example Sv) and methyl 2- (4-amino-W-carboxyphenyl) propionic acids get 2- (6,8-dichloro- 25 -11-oxo-11H-pyrido £ 2,1-b] quinazolin-2-yl) propionic acid methyl ester, mp. 138 ° C (ether-acetonitrile).
    Example . A mixture of 1.4 g of methyl 2- (6,8-dichloro-11-oxo-30 -11H-pyrido £ 2,1-b] quinazolin-2-yl) propionic acid, 10 ml of water and 10 ml of concentrated sulfuric acid mix. 4 hours at 120 ° C (bath temperature). 35
    After cooling, dilute with 10 ml of ice water and adjust to pH 4-5 with sodium hydroxide solution. After extraction with ethyl acetate, drying and concentration of the organic phase 40, 1.1 g of 2- (6.8-dichloro-1-oxo-11H- pyrido-2 2,1-b] quinazolin-2-yl) propionic acid, m.p. 241 ° C (dimethylfomamide-water).
    Example 8. a) Under the conditions of Example 45, 2a), 2- (7-methyl-11-) methyl ester is obtained from 2-chloro-4-methylpyridine and 2- (4-amino-3carbo, xiphenyl) propionic acid methyl ester oxo-11-pyrido £ 2,1-b] quinazolin-2-yl) -propionic acid, so pl. 120 ° C (acetonitrile).
    [B) · This product under the conditions of example 7 is hydrolyzed to 2- ( 7_ methyl-11-oxo-11H-pyrido [2,1-b] quinazolin- 35 -2-yl) -propionic acid, so pl. 26 7 C (acetic acid).
    Example 9. a) Under the conditions of the medalist 4a) from 2-chloro-6-methylpyridine and
    Ι57 8 'methyl ester of 2 (-4-amino-3-carboxyphenyl) propionic acid give 2- (9 ~ methyl-11-oxo-11H-pyrido £ 2,1-b] quinazolin-2-yl) - propionic acid.
    B) -Posleny the conditions of Example 7 was hydrolyzed to 2- (9 _ methyl-11-oxo-11H-pyrido £ 2,1-b] quinazolin-2-yl) ~ propionic acid.
    Example 10a) Under the conditions of Example 2a), 2- (8-methyl-11-oxo-11 H-pyrido methyl ester is obtained from 2-bromo- 5_ methylpyridine and methyl * ether 2- (4-amino ~ 3 _ carboxyphenyl) propionic acid {~ 2,1-in] quinazolin-2-yl) -propionic acid, so pl. 151 ° C (acetonitrile).
    J>) This product is hydrolyzed under the conditions of Example 7 to 2- (8-methyl-11-oxo-11H-pyrido £ 2,1-b] quinazolin-2-yl) propionic acid, m.p. 233 ° C (acetonitrile).
    Example 11. Under the conditions of Example 2a), 2- (8-trifluoromethyl-11-oxo-11H-) is obtained from 2-bromo-5-trifluoromethylpyridine and 2- (4-amino-3 ~ carboxyphenyl) propionic acid pyrido ^ 2,1-b] quinazrlin-2-yl) - 'propionic * acid.
    Example 12. a) Under the conditions of Example B), from 2-chloro-6-methyl-4-trifluoromethyl-pyridine and 2- (4-amino-3-carboxyphenyl) propionic acid methyl ester, 2- (9-methyl-7) methyl ester is obtained -tri-fluoromethyl-11-oxo-11H-pyrido 2,1-quinazolin-2-yl) 'propionic acid.
    D b) This product by hydrolysis under the conditions of example 8 gives 2- (9 - methyl ~ 7 “trifluoromethyl-11-oxo-11H-pyrido 2,1-quinazolin-2-yl) -propionic acid, so pl. 232 ° C (acetonitrile).
    Example 13 · a) Under the conditions of Example 2a), from 2- (4-amino-3 ~ carboxy> xiphenyl) propionic acid methyl dibromo * 4-methylpyridine and 2- (4-amino-3 ~ carboxylic acid) methyl ester, 2- (8-bromo- 7 _ methyl-11oxo-11H-pyrido ^ 2,1-b] quinazolin-2-yl) propionic acid, m.p. 150 ° C (acetonitrile).
    jb) From this product, by hydrolysis under the conditions of Example 7, 2- (8-bromo ~ 7methyl-11-oxo-11H-pyrido £ 2,1-b] quinazolin-2yl) propionic acid is obtained, m.p. 2b5 ° C (acetic acid).
    Example 14. Under the conditions of Example 2a) of 2,5-dichloro ~ _ 3-methylpyridine and 2- (4-amino-W-carboxyphenyl) propionic acid, 2- (8-chloro-6-methyl-11.-OKCO- 11 H-pyrido £ 2,1-b} quinazolin-2-yl) -propionic acid, m.p. 22b ° C (dimethylformamide-water). 5 Example 15 · Under the conditions of example 2a), 5.2 g are reacted. 2- (4-amino-3-carboxyphenyl) -propionic acid methyl ester with 4.7 g of 2-bromo-5 ~ methylthiopyridine, the reaction is treated-> 0, and the reaction mixture is obtained
    3.3 g of 2- (8-methylthio-11-oxo-11H-pyrido [2,1-b] quinazolin-2-yl) propionic acid methyl ester, mp 113 *. 114 ° C (diethyl ether). fifteen
    Example 16. The 2- (8-methylthio-11-OKCO-11H-pyrido ^ 2,1-b] quinazolin-2-yl) gpropiono 1,3-methyl ester. hydrochloric acid is saponified as described in Example 7, the reaction mixture is treated, and 1.0 g of 2- (8-methylt.io-11-oxo-11 H-pyrido 2,1-quinazolin-2-yl) is obtained propionic acid with so pl. 213-214 ° C (dimethylformamide water). 25
    EXAMPLE 17- C 190 mg of 2- (8-methylthio-11-oxo-11H-pyrido £ 2,1-в ^ quinazolin-2-yl) -propionic acid add 10 ml of glacial acetic acid and 5 ml of chloroform, K. mixture at> - 30 add 70 mg of 30% hydrogen peroxide, mix for 2 days at a temperature of 20 ° C, add another 7 mg of 30% hydrogen peroxide and mix for another day. The reaction mixture was con- 35 centered under vacuum, the residue was recrystallized from methanol to give 140 mg of 2- (8-methylsulfonyl-11-oxo-11H - pyrido £ 2,1-a ^ quinazolyl-2-yl) -propionic acid with t .pl. 40 225-22b ° C.
    Example 18 ,. In the conditions of Example 17 is oxidized with 2.85 g of methyl 2- (8-methylthio-11-oxo-11H-pyrido £ 2,1-a ^ quinazolin-2-yl) -propio- 45 new acid, the reaction mixture was treated to give 2.2 g of methyl 2- (8-methylsulfinyl-11-oxo-11H-pyrido , 1-c] quinazolin-2-yl) -propionic acid methyl ester, m.p. 1601b2 ° C (methanol).
    EXAMPLE 19'a) 1.6 g of 6-chloronic-tinic acid, 2.2 g of 2- (4-amino-3 “carboxyphenyl) propionic acid methyl ester and 20 mg of potassium iodide are treated with 4 ml of glycoldemetipic ether and stirred under argon for 6 hours at 150 ° C. The reaction under vacuum, treated with ethanol to give 750 mg · metylovogo efi: ra 2- (carboxy _ 7 ~ 11-oxo-11H-pyrido ~ 2,1-a] quinazolin-2-yl) -propionic acid as a crude product. v b) 120 mg of the crude product obtained in this way are saponified as described in Example 7; -yl) -propionic acid with a melting point of 318-319 C.
    权利要求:
    Claims (1)
    [1]
    (5) METHOD FOR OBTAINING PERIDES DERIVATIVES | 2.1 -VDHINAZAZOLONONA The invention relates to a method for producing new pyridoi2, 1-vZhinazolinone derivatives of the general formula: 5 Q x if Sr v-c i K where X is cyano group, carboxyl or alkoxycarbonyl group; R is a hydrogen atom or a methyl group; hydrogen or halogen, CA-CI - alkyl groups, trifluoromethyl groups, carboxyl or alkoxycarbonyl groups, thiocyano groups, methylthio groups, methylsulfinyl groups, methylsulfonyl groups, methylsulfimidoyl groups, provided that 2 or 3 groups from R2. hydrogen, which are biologically active compounds or intermediates for their preparation and can be used in medicine. A known method for producing quinazolone derivatives by condensation of anthranilic acid with formamide by heating 13. The purpose of the invention is based on a method known in organic reaction chemistry for preparing new pyrido derivatives of 2,1-v-quinazolinone of formula (1), which are biologically active compounds or intermediate products for their preparation. This goal is achieved by the fact that according to the method of producing compounds of formula (1), a pyridine derivative of the general formula (| J Cd-CtL31 where R, have the above meanings - amino or halo, condenses with a phenyl derivative of the general formula (III / where X and R have the above values; V is a hydrogen or an alkyl group; Z is a halogen or an amino group and the desired product is isolated, where X is a cyano group or an alkoxycarbonyl group, or is hydrolyzed, and compounds of the formula (1) where X is a carboxyl group and, if necessary, the compound is (1 /, where is a methylthio group, oxidizes and isolates a compound of the formula (J, where R, LR are methylsulfinyl groups or methylsulfonyl groups, and, if necessary, a compound of formula (I), where f i-Rg- is methylsulfinyl groups interaction with azide of alkali metal and isolate the target product, where R / iRc is methylsulfonic doyl group., Biologically active compounds possess anti-inflammatory, antipyretic, analgesic and antiallergic activity. In addition, they have phosphodieste (a disruptive effect. The stomach tolerates a compound of the formula (O) satisfactorily, their toxicity is relatively low. The compounds of formula (1) are suitable in combination with the usual carriers for treating acute and chronic inflammatory processes of polyarthritis, Neido dermatitis, asthmatic bronchitis or hay fever. EXAMPLE 1 (a) To a solution 15, 1 of 2-amino-5-methylbenzoic acid in 200 ml of ethylene glycol monobutyl ether, are added, g: potassium carbonate powder 7, 6; N-ethylmorpholine 15, 2,5-d bromopyri in 28, and bromide meth di (It) 1.8 and stirred for 6 hours under argon atmosphere.After distilling off the solvent under a vacuum created by a water-jet pump, the residue is dissolved in 1 liter of ethyl acetate and first washed with 1N acetic acid, then sodium bicarbonate solution 574. The organic phase is concentrated and the residue is recrystallized from chloroform to give 15.2 g of 8-bromo-2-methyl-11H-pyrido-2,1-1-hinazolin-11-one with m.p. . ) To a solution of 1.7 g of 2-chloro-5 methylbenzoic acid in 30 ml of diethylene glycol dimethyl ether, g: N-ethylmorpholine 1.5; potassium carbonate powder 0.7; copper bromide (11) 100 and 2-amino-5-bromopyridine 2 and the mixture is heated under nitrogen and up to 160 ° C. After distilling off with a dilution of the solvent, the treatment is carried out similarly to a. 1.2 g of 8-bromo-2-methyl-11H-pyrido-2, 1-in quinazolin-11-one are obtained. B) To a solution of 1t, 8 g of 8-bromo-2-methyl-11H-pyridoG2, 1-b1-quinazolin-11-one in 500 ml of carbon tetrachloride, 11 g of bromosuccinimide and 0.5 g of azobisisobutyronitrile are added and irradiated with a 500 W lamp while the solution is boiled with reflux. After distilling off the solvent, the residue is dissolved in about 2 liters of chloroform, the organic layer is washed with water, and after distilling off the solvent, 18 g of 8-bromo-2-bromomethyl-11H-pyrido 2, 1-b1-quinazoline 11-one with m.p. (toluene). c) 3.7 g of 8-bromo-2-bromomethyl-11H-pyrido 2, 1-v3 quinazolin-11-one is added to a solution containing, g: sodium cyanide 1.5; potassium iodide 0.2; water 3 ml and ethanol 50 ml and the mixture is boiled for 15 minutes under reflux. After cooling, the resulting nitrile crystallizes out, is filtered off under suction, washed with water and a small amount of ethanol and recrystallized from acetonitrile. 2.2 g of 8-bromo-11-oxo-11H-pyrido2, 1-v3 quinazoline-2-acetonitrile are obtained, m.p. 2iO ° C. c) To a solution of 17.3 g of 8-bromo-2-bromomethyl-11H-pyrido12, 1-in quinazolin-11-one in 500 ml of chloroform was added a pre-prepared complex of 3.1 g of potassium cyanide and 16.9 g of dibenzene 18-krone-6, as well as another 3.1 g of potassium cyanide and boil for 30 minutes with reflux, then stir overnight at room temperature. Then the solution is chromatographed, washed with toluene from a silica gel column. 8.5 C 8-bromo-11-oxo-11H-pyrido 2, i-quinazolin-2-acetonitrile are obtained with m.p. (tetrahydrofuran-water). 5 10 d) Solution of Jtl, 7 g of concentrated sulfuric acid and 23 ml of water is treated with t g of 8-bromo-11-OXO-11H-Pyrido 2, 1-b1 quinazoline-2-acetonitrile and stirred for 3 hours at. After cooling, the solution is poured into a mixture of 0 ml of water and ice and the pH is adjusted to 4-5 with sodium acetate. Get g of crystals of 8-bromo 2,1-inzinazolin-2-acetic acid with so pl. (dimethylformamide-water). Example 2 a) A solution of 2.1 g of 2- (4-amino-3-carboxyphenyl) propionic acid in 5 ml of ethylene glycol mono butyl ether is mixed with 1 g of powdered potassium carbonate and 1.2 g of N - ethyl morpholine 0.5 hours at room temperature. Then, 3.0 g of 2,5-dibromopyridine and 150 ml of copper bomide (| 1) are added and the mixture is heated under nitrogen atmosphere for 7 hours at 180 ° C (bath temperature). After distilling off the solvent under vacuum, the residue is dissolved in ethyl acetate and washed with partitioned acetic acid. After extraction with the acid - base, the organic acid fraction is recrystallized from ethanol and 1.5 g of 2- (8-bromo-11-oxo-11H-pyridoC2, 1-in quinazolin-2-yl) -propionic acid are obtained, m.p. (dimethylformamide-water). B) Preparation of the starting product: 2- (t-amino-3-carbr-x-phenyl) -propionic acid or its ester is produced as follows. B) To pA; a solution of 35.7 g of chloral hydrate in 480 ml of water is added with B, 9 g of sodium sulfate, 38.6 g of ethyl ester of 2- (4-aminophenyl) -propionic acid, 120 ml of water, 17 ml of concentrated hydrochloric acids and a solution of 43.9 g of ammonium hydroxychloride in 200 ml of water and the reaction mixture is slowly heated to boiling for 45 minutes, then kept for 10 minutes at the boiling point and cooled. The product precipitating out as an oil is dissolved in ethyl acetate and washed with water. After separation of the acid-base, the organic acid fraction is concentrated and recrystallized from acetonitrile. Get 25 g of 2- (4- (2-hydroxyimino) -acetamidophenyl) -propionic acid with so pl. . bgr) 13 g of 2-P4- (2-hydroxyimo) -acetamidophenyl 3 propionic acid are transferred in portions to 55 g of sulfuric acid 76 lots (unit weight 1.8), which is preheated to. At the same time the temperature reaches. After the addition is complete, the mixture is heated for another 10 minutes, then poured into 300 ml of water with ice and extracted with ethyl acetate. After recrystallization from acetonitrile, 10 g of 2- (5-isotinyl) propionic acid are obtained with a mp. . (C) To a solution of 2.2 g of 2- (5-isatinyl) propionic acid in 22 ml of water and 3 ml of a 32% sodium hydroxide solution, 2.9 g of hydrogen peroxide (30%) are added dropwise over 20 minutes and then stirred for another 20 minutes. After acidifying the reaction mixture with 2 hydrochloric acid (pH 2-3), the organic material is extracted with ethyl acetate and then recrystallized from acetonitrile. Obtain 1.8 g of 2- (4-amino-3-carboxyphenyl) -propionic acid with so pl. . 1) 3 g of 2- (4-amino-3 carboxyphenyl) propionic acid is dissolved in 500 ml of hydrochloric acid in methanol (3) and left for two days at a temperature of about 20 ° C. After concentration, the residue is dissolved in ethyl acetate, washed with sodium bicarbonate solution and recrystallized. Obtain 2.8 g of methyl 2- (4-amino-3-carboxyphenyl) propionic KIS.LOTY with so pl.151 ° C (acetonitrile). Example a) Under the conditions of Example 3), from 2-bromo-5 chloropyridine and 2- (4-amino-3 carboxyphenyl) propionic acid, 3- (8-chloro-T170XO-11H-pyridoG2, 1-vzinazolin-2-yl ) -propionic acid with so pl. . B) The starting 2-bromo-5-chloropyridine is prepared in a manner similar to that known from the literature, as follows. To a solution of 14 g of 2-amino-5 chloropyridine in 30 ml of water and 45 ml of hydrobromic acid (63 in water) 17 ml of bromine are added and the mixture is cooled to 0 ° C. While controlling the temperature, a solution of 21 g of sodium nitrite in 30 ml of water is added dropwise at such a rate that the temperature of the mixture does not exceed 5 C. Then, while cooling, a solution of 45 g of sodium hydroxide in 115 ml of water is added. The precipitated crystals are filtered off under vacuum, washed with water and recrystallized first from acetone, then again from ethanol. 10 g of 2-bromo-5-chloropyridine are obtained with a mp. 68 ° C. 71 Lreemer +. a) Under the conditions of example 2a), from 2,3 dichloropyridine and 2 - (- amino-Zcarboxyphenyl) -propionic acid methyl ester, 2 (b-chloro-T1-. xo-11H-pyrido 2,1-v-quinazoline methyl ester -2-and-propionic acid. B) The latter is converted into 2- (b-chloro-11-OXO-11H-pyrido [2, 1-quinazolin-2-yl) -propionic acid by heating with diluted soda liquor. Example 5. Under the conditions of Example 2a, from 2-bromo-5-fluoro-pyridium II (4-a.mino-3-carboxyphenyl) propionic acid, half- 2- (8-fluoro 11-oxo-11H-pyrido 2 , 1-aj quinazolin-2-yl) -propionic acid, m.p. 22 (dimethylformamide-water). Example Under the conditions of Example 2a), from 2-bromo-3 5-Dichloropyridine (obtained from 2-am 1Ho-3, 5-dichloropyridine according to the example of Sv) and methyl 2- (α-amino-3-carboxyphenyl) propionic acid, 2- (6,8-dichloro-11-oxo-11H-pyridoG2, 1-1-hinazolin-2-yl) -propionic acid methyl ester, m.p. 138 ° C (ether acetonitrile). EXAMPLE 7 Mixture, kg of methyl 2- (6,8-dichloro-11-oxo-11H-pyrido 2, 1-in quinazolin-2-yl) propionic acid, 10 ml of water and 10 ml concentrated sulfuric acid is stirred. h at (bath temperature). After cooling, dilute with 10 ml of ice and water and adjust the pH with sodium hydroxide solution. After extraction with ethyl acetate, drying and concentrating the organic phase, 1.1 g of 2- (6,8-dichloro-1-oxo-11H-pyrido-2, 1-in quinazolin-2-yl) propionic acid are obtained, m.p. (dimethylphosphine-water). Example 8. a) Under the conditions of example 2a) from 2-chloro-4-methylpyridine and 2 - (- amino-3-carbo, methyl, xyphenyl) propionic acid methyl ester, 2- (7-methyl-11-OXO) methyl ester -11-pyrido 2, 1-in quinazolium-2-yl-propionic acid, mp 120 C (acetonitrile). IJb). This product, under the conditions of Example 7, is hydrolyzed to 2- (7-methyl-11-oxo-11H-pyrido | 2, 1-vZhinazolin- - ..., ..-, j-If. - - -2-yl) - propionic acid, so pl. 2b (acetic acid). Example 9 a) Under conditions when measure ka) from 2-chloro-6-methylpyridine and 78 ethyl ester 2 (-j-aMMHO-BKapboxyphenyl) -propionic acid, methyl 2- (9 methyl 11-oxo- 11H-pyrido (2, 1-in quinazolin-2-yl} -propionic acid. B) The formations in the conditions of example 7 are hydrolyzed to 2- (9-methyl-11-oxo-11H-pyrido 2, 1-in quinazoline -2-yl) propionic acid. Example 10a) Under the conditions of Example 2a), 2-CB-methyl methyl ester obtained from 2-bromo-5-methylpyridine and 2- (t-amino-3-carboxyphenyl) propionic acid methyl ester 11oxo-11 H-pyridor, 1-h quinazolin-2-yl) -propionic acid, so pl. 151 s (auetonitrile). J)) This product is hydrolyzed under the conditions of Example 7 to 2- (8-methyl-11-oxo-11H-pyrido 2, 1-quinazolin-2-yl) propionic acid, m.p. 233 ° C (acetonitrile). PRI me R 11. The conditions of example 2a) from 2-bromo-5-trifluoromethylpyridi-a and 2- (-amino-3-carboxyphenyl) propionic acid are 2- (8-trifluoromethyl-11-oxo- 11H-pyrido 2,1 -in quinazrlin-2-yl) propionic acid. Example 12. a) The 8 conditions of Example 3a) from 2-chloro-6-methyl-A-trifluoromethyl-pyridine and 2- (4-amino-3-carboxyphenyl) -propionic acid methyl ester are 2- (9-methyl-methyl) 7-tri-fluoromethyl-11-oxo-11H-pyrido 2,1-in quinazolin-2-yl) g-propionic acid. Hb) This product, by hydrolysis under the conditions of Example 8, gives 2- (9-methyl-7-trifluoromethyl-11-oxo-11H-pyrido 2,1-to quinazolin-2-yl) -propionic acid, m.p. (acetonitrile). Example 13. a) Under the conditions of Example 2a), from 2, 5-dibromo-methylpyridine and 2-C-amino-3-carboxyphenyl) -propionic acid methyl ester, 2- (8-bromo-7-methyl- 11oxo-11H-pyrido 2, 1-in quinazolin-2-yl) propionic acid, so pl. (acetonitrile). jb) From this product by hydrolysis under the conditions of Example 7, 2- (8-bromo-7-methyl-11-oxo-11H-pyrido. 2, 1-to quinazolin-2yl) -propionic acid, m.p. 2b5 ° C (acetic acid). Example I. Under the conditions of example 2a} of 2, 5-dichloro-3-methylpyridine; 91 and 2- (C-amino-3 carboxyphenyl) propanoic acid get 2- (8-chloro-6-methyl-11. -OKGO-11H-pyrido 2,1-vinhina zolin-2-yl) -propionic acid m.p. (dimethylformamide-water). PRI me R 15- Under the conditions of Example 2a), 5.2 g of 2 - (- amino-315-zrbock syphenyl) -propionic acid methyl ester are reacted with 4.7 g of 2-bromo-5-methylthiopyridine, and the reaction is carried out a mixture of 3.3 g of methyl 2- (8-methylthio-11-oxo-11H-pyridoC 2,1-vZhinazolin-2-yl) -propionic acid and 3.3 g of methyl ester, mp. 113 (diethyl ether). Pr im im 16. The 2- (8-methylthio-11-OXO-11H-PyridoC2, 1-vZhinazolin-2-yl) propionic acid 1,3-methyl ester was washed as described in Example 7, the reaction mixture was worked up and 1.0 g of 2- (8-methylt.io-11-oxo-11H-yirido-2,1 quinazolin-2-yl) propionic acid is obtained with a mp. 213-214 ° C (dimethylformamide lead). Example 17: To 190 mg of 2- (8-methylthio-11-OXO-11H-pyrido 2, 1-Vyhin zolin-2-yl) -propionic acid, add 10 ml of glacial acetic acid and 5 ml of chloroform, K; the mixture was added 70 mg of hydrogen peroxide, stirred for 2 days at 20 ° C, added another 7 mg of hydrogen peroxide and stirred for another day. The reaction mixture was concentrated under reduced pressure, the residue was recrystallized from methanol, and 140 mg of 2- {8-methylsulfonyl-11-oxr-11H-Pyridots2, 1-vZhinazoli-2-yl) -propionic acid were obtained, mp. 225-226 ° C., Example 18. Under the conditions of the examples 17, 2.85 g of methyl 2- {8-methylthio-11.-OXO-11H-pyridr 2, 1-1-quinazolin-2-yl) propio is oxidized. New acid, process the reaction mixture and obtain 2.2 g of methyl 2- (8-methylsulfinyl-11-oxo-11H-pyrido рид 2, 1-in | quinazolin-2-yl) -propionic acid, so pl. 1bO2b2 C (methanol). EXAMPLE 19a) 1.6 g of 6-chloronicotinic acid, 2.2 g of 2- (4-amino-3-carboxyphenyl) -propionic acid methyl ester and 20 mg of potassium iodide are treated with a ml of glycoldimethyl ester and stirred. in the atmosphere of argon for 6 h at. The reaction mixture is concentrated very strongly under vacuum and treated with ethanol to obtain 750 mg of methyl ethyl (7-arboxy-11-pkso-11H-pyri W f - -. DG2,1-Bj quinazolin-2-yl) -propionic acid in the form crude product b) 120 mg of the crude product thus obtained are scrubbed as described in Example 7, the reaction mixture is worked up to obtain 7 mg of 2- (7-carboxy-11-oxo-11H-pyrido 2, 1-vZhinazolin-2-yl) -propionic acid with so pl. 318-319 C. Formula of the invention 1. A method for producing pyrido derivatives of 2,1-quinazolinone of the formula C) Aip% V H c. LDDM cyano group, carboxyl where X is a group or alkoxycarbonyl group; R-I is hydrogen or methyl group; - hydrogen or halogen; C | - € 4-alkyl groups, trifluoromethyl groups, carboxyl or alkoxycarbonyl groups, thiocyanogroups, methylthio groups, methylsulfinyl groups, methylsulfonyl groups, methylsulfimidoyl groups, provided that 2 or 3 groups of - are hydrogen, characterized in that Formulas Bz-TsL-Y Bt where Rnf the indicated values of j V - an amino group or a halide condense with a yunil derivative of the general formula III vood- j V H-., X and 12 have the indicated values; H is hydrogen or an alkyl group;
    111001857.12
    Z is halogen or amino group, the need for a compound of formula f
    and isolate the desired product, where X is where Rjj-Ry is methylsulfinyl groupgroup or alkoxycarbonyl, is reacted with azide
    group, or hydrolyzed, and excreting alkali metal, and isolating the target
    a compound of formula 1, where X is a carboxyproduct, where the methylsulfimidoylxyl group, and in the case of the necessary group.
    bridges a compound of formula J, where the sources of information
      methylthio group, oxidized, when taken into account in the examination, isolate a compound of the formula, where; 1. Elderfield R. HeterocyclicR-Ry and Ulfinyl groups or Okie compounds, M, I.L. I960
    methyl sulfonyl groups, and in the case of. 6, s. .
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1001857A3|1983-02-28|Process for preparing derivatives of pyrido|-quinazolone
    SU602118A3|1978-04-05|Method of producing benzimidazole derivatives or salts thereof
    US6001843A|1999-12-14|Substituted pyridines as selective cyclooxygenase-2 inhibitors
    US4727150A|1988-02-23|Pyridyl methylsulfinyl benzimidazole derivatives
    JPH0768216B2|1995-07-26|Process for producing substituted pyridine-2,3-dicarboxylate esters
    US4216318A|1980-08-05|Heterocyclic alkyl 4-pyrimidones
    RU2653855C2|2018-05-15|Process for preparation of 4-amino-5-fluoro-3-chloro-6-|picolinates
    JPH05255257A|1993-10-05|5,6-disubstituted-3-pyridylmethylammonium halide compound useful to process 5-|-2,3-pyridine dicarboxylic acid
    US4230873A|1980-10-28|Thiophene derivatives
    EP0249950B1|1991-06-19|Aromatic compounds
    US4584381A|1986-04-22|5-|-3-|-2-|pyridines
    US4092419A|1978-05-30|Substituted |pyridines, their preparation and use
    US2449906A|1948-09-21|Oxidation of heterocyclic aromatic nitrogen compounds
    Campbell et al.1971|The synthesis of some substituted methyl pyridinecarboxylates. I. Methyl 6-substituted picolinates, methyl 6-substituted nicotinates, and methyl 2-substituted isonicotinates
    US4156004A|1979-05-22|Substituted |pyridines, and use
    US4233301A|1980-11-11|Novel imidazoazines and imidazodiazines
    CZ20022146A3|2002-09-11|Process for preparing 4-|halogen-1|-phthalazinones
    US4556716A|1985-12-03|Process for the production of 2-halopyridine derivatives
    US2505568A|1950-04-25|Catalytic oxidation of heterocyclic aromatic nitrogen compounds
    US5122608A|1992-06-16|Method for the preparation of substituted and unsubstituted 2,3-pyridine and quinolinedicarboxylic acids
    JPH0710873A|1995-01-13|Indolizine derivative, its production of its use as intermediate
    US4330543A|1982-05-18|Imidazoazines and imidazodiazines
    KR0156327B1|1998-11-16|Benz-or pyridoimidazole derivatives
    JPH10324678A|1998-12-08|Production of pyridine-n-oxides and solution
    CN112174949A|2021-01-05|Quinolizinone compound and preparation method thereof
    同族专利:
    公开号 | 公开日
    NZ191828A|1983-03-15|
    FR2439199A1|1980-05-16|
    GB2034705A|1980-06-11|
    CA1130805A|1982-08-31|
    EP0011142A1|1980-05-28|
    JPS634537B2|1988-01-29|
    PL119174B1|1981-12-31|
    CS216512B2|1982-11-26|
    JPS5557588A|1980-04-28|
    GR73819B|1984-05-03|
    ES485162A0|1981-03-16|
    DD147242A5|1981-03-25|
    ES8103745A1|1981-03-16|
    AU5183279A|1980-04-24|
    US4457927A|1984-07-03|
    AT2146T|1983-01-15|
    PL123430B1|1982-10-30|
    DK154297B|1988-10-31|
    PL123075B1|1982-09-30|
    DE2845766A1|1980-04-30|
    EP0011142B1|1982-12-29|
    PL218993A1|1980-06-16|
    DK438379A|1980-04-19|
    ZA795559B|1980-09-24|
    EG14028A|1982-09-30|
    IL58474D0|1980-01-31|
    IE48852B1|1985-05-29|
    GB2034705B|1982-12-08|
    DE2964431D1|1983-02-03|
    RO78339A|1982-04-12|
    AU529643B2|1983-06-16|
    NO793344L|1980-04-21|
    DK154297C|1989-03-28|
    FI793229A|1980-04-19|
    IE791969L|1980-04-18|
    PT70329A|1979-11-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR4267M|1963-12-19|
    US4033961A|1975-10-07|1977-07-05|Warner-Lambert Company|Pyrido[2-1-b]quinazolin-ones and their methods of preparation|
    DE2557425C2|1975-12-19|1987-03-19|C.H. Boehringer Sohn, 6507 Ingelheim, De|
    US4066767A|1976-11-01|1978-01-03|Warner-Lambert Company|8--11H-pyrido[2,1-b]quinazolin-11-ones and method of treating bronchial asthma using them|
    ES468126A1|1977-03-24|1979-09-01|Hoffmann La Roche|Pyridolquinazoline derivatives|DE3300477A1|1983-01-08|1984-07-12|Boehringer Ingelheim KG, 6507 Ingelheim|NEW HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE|
    US4587339A|1983-10-14|1986-05-06|Sun Chemical Corporation|Nickel complex pigments of bis-azomethines|
    HUT66324A|1991-07-29|1994-11-28|Warner Lambert Co|Quinazoline derivatives as acetylcholinesterase inhibitors and pharmaceutical compositions containing them|
    CA2238283C|1997-05-30|2002-08-20|Cell Pathways, Inc.|Method for identifying compounds for inhibition of neoplastic lesions, pharmaceutical compositions from such compounds and uses of such compounds and compositions for treating neoplastic lesions|
    US5858694A|1997-05-30|1999-01-12|Cell Pathways, Inc.|Method for identifying compounds for inhibition of cancerous lesions|
    US6410584B1|1998-01-14|2002-06-25|Cell Pathways, Inc.|Method for inhibiting neoplastic cells with indole derivatives|
    US6200771B1|1998-10-15|2001-03-13|Cell Pathways, Inc.|Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia|
    US6133271A|1998-11-19|2000-10-17|Cell Pathways, Inc.|Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives|
    US6187779B1|1998-11-20|2001-02-13|Cell Pathways, Inc.|Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives|
    US6369092B1|1998-11-23|2002-04-09|Cell Pathways, Inc.|Method for treating neoplasia by exposure to substituted benzimidazole derivatives|
    US6077842A|1998-11-24|2000-06-20|Cell Pathways, Inc.|Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives|
    US6034099A|1998-11-24|2000-03-07|Cell Pathways, Inc.|Method for inhibiting neoplastic lesions by administering 4-- 2, 3- dihydro-pyrazol-3-ones|
    US6486155B1|1998-11-24|2002-11-26|Cell Pathways Inc|Method of inhibiting neoplastic cells with isoquinoline derivatives|
    US6025394A|1999-01-29|2000-02-15|Cell Pathways, Inc.|Method for treating patients with acne by administering substituted sulfonyl indenyl acetic acids, amides and alcohols|
    US6020379A|1999-02-19|2000-02-01|Cell Pathways, Inc.|Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia|
    US6130053A|1999-08-03|2000-10-10|Cell Pathways, Inc.|Method for selecting compounds for inhibition of neoplastic lesions|
    US6555547B1|2000-02-28|2003-04-29|Cell Pathways, Inc.|Method for treating a patient with neoplasia by treatment with a vinca alkaloid derivative|
    US6569638B1|2000-03-03|2003-05-27|Cell Pathways, Inc|Method for screening compounds for the treatment of neoplasia|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782845766|DE2845766A1|1978-10-18|1978-10-18|PYRIDO ANGLE CLAMP ON 2,1-B ANGLE CLAMP ON -CHINAZOLINONE DERIVATIVES, THEIR PRODUCTION AND USE|
    [返回顶部]