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    • 专利摘要:
    2-Aminopyrimidones which are histamine H2- antagonists having the structure in which Het is a nitrogen-containing 5- or 6-membered fully unsaturated heterocyclic group, m is 0 or 1, Y is methylene, oxygen or sulphur, n is 2 or 3, Z is hydrogen or lower aikyl, A is an alkylene group or an alkylene group interrupted by oxygen or sulphur, and B is hydrogen or a methyl, cycloalkyl, heteroaryl, phenyl, naphthyl, benzodioxolyl or dihydroben- zodioxinyl group, are prepared by a process in which an amine Het-(CH2)mY(CH2)nNH2 is reacted with a 2-nitroaminopyrimidone of structure The new 2-nitroaminopyrimidone intermediates are prepared by reacting nitroguanidine with an oxoester RO2C-CH(COZ)-A-B where R is lower alkyl.
    公开号:SU944504A3
    申请号:SU792747652
    申请日:1979-04-10
    公开日:1982-07-15
    发明作者:Генри Браун Томас
    申请人:Смит Клайн Энд Френч Лабораториз Лтд (Фирма)；
    IPC主号:
    专利说明:

    Union of Soviet
    Socialist
    Republic (11) 944 504
    State Committee
    USSR for inventions and discoveries
    O P AND SANI E
    Inventions
    TO PATENT (61) Supplementary to patent - (22) Stated 04/10/79 (21) 2,747,652 / 23-04 (23) Priority - (32) 11/04/78 (31) 14049/78 (33) United Kingdom
    Published on July 15th, 2017. Bulletin No. 26
    Date of publication of the description 15.07.82 (51> M. Cl. 3
    C 07 D 401/14 (53) UDC 547.854. .2.08.07 (088.8) '(72) Author of the invention (71) Applicant
    Alien
    Thomas Henry Brown (UK)
    Foreign company ”Smith Kline and French Laboratories Ltd.
    (Great Britain)
    (54) METHOD FOR PRODUCING 2-AMINO-PYRIMIDO DERIVATIVES
    The invention ^ relates to an improved method n2 for the preparation of 2-aminopyrimidone derivatives having the activity of histamine H ^ antagonists.
    A known method for producing derivatives of 2-aminopyrimidone of the general formula ' (I) wherein Het is unsubstituted imidazolyl or substituted with alkyl C ^ - Cd, 2-pyridyl substituted with an amino group, halogen, one or more alkoxy groups with 1-4 carbon atoms; type 1-4;
    y is methylene or sulfur;
    B is a hetero group from among ^ consisting in the fact that 2-alkylLthio-. Pyrimidone-4 of formula (I) where B has the indicated meanings, is reacted with amine | 0 of formula (III) Het-CCH ^) ^ - Y (CH g ) n HH ^.
    when heated, usually at 140-180 ° C. Yu.
    - However, the method is characterized by insufficiently high yield of the target 15 products.
    The purpose of the invention is to increase the yield of target products.
    This goal is achieved in that according to the method for producing 20 derivatives of 2-aminopyrimidone of the general i formula:
    where Het is unsubstituted imidazolyl or substituted by alkyl (C ~ C, 2-pyridyl substituted by an amino group, halogen, one or more 5 alkoxy groups with 1-4 carbon atoms, or 2-thiazolyl;
    gp - 0 or 1;
    y is methylene or sulfur; 10 η - 2 or 3;
    B - furyl, naphthyl, 6- ( 2,3_ dihydro-1,4-benzodioxiyl), 5 (1,3 ~ benzodioxolyl), unsubstituted pyridyl or 5- substituted with one or more alkylMi or alkoxy. in which alkyl C ^ (C or phenyl substituted with one or more alkali forces with 1-4 carbon atoms, by reacting a 2-substituted pyrimidone ~ 4 of the general formula
    where B has the indicated meanings, with an amine of the general formula y (01¾¾ LU where Het, m, Y and η-have the indicated
    - 'values, .. t when heated, use 2-nitro: amino derivative of pyrimidone 4 of the general formula (II) and the process is carried out at 80-140 ° C.
    The process is carried out in ethanol, n-propanol or pyridine by boiling.
    The process is carried out using an excess of the amine of the general formula (111).
    The method can be carried out in the absence of a solvent at 80-170, usually 120-140 °, or in a solvent at the boiling point of the reaction mixture.
    As the solvent, pyridine, picoline or mixtures of picolines, a lower alkanol such as 50 ethanol, n-propanol, a mixture of water with alkanol, 1,2-ethanediol, ketones such as acetone, 2-butanone, or a polar aprotic solvent can be used such as dimethylformamide, dimethyl-55
    The process is preferably carried out in ethanol, n-propanol or pyridine by boiling.
    The method can be carried out both with an equimolar ratio of the reactants, and using an excess of one of the reactants.
    The use of an excess of an amine of the general formula (ill) is preferred.
    The compounds obtained by the proposed method have activity H (£ histamine antagonists, are used as inhibitors of gastric acid secretion, as well as agents that inhibit the effect of histamine on blood pressure.
    The starting compounds of formula (II) can be prepared by reacting the corresponding α-oxoester with nitroguanidine.
    The proposed method allows to increase the yield of target products to 75 “94% compared with the known method, where the yield for these products is 53-73%.
    Synthesis of starting products.
    Example 1. A mixture of 6-methylpyridin-3 ~ carboxaldehyde (51.57 g), malonic acid (44.80 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100 ° C for 3 hours and allowed to cool. After this, the mixture was evaporated to dryness, water was added to the residue, the solid was filtered off and crystallized from ethanol-acetic acid, 3 ~ (6-methyl-4-pyridyl) acrylic acid (41.25 g) was obtained, mp. 213.5-215.5 ° C.
    A mixture of 3- (6-methyl-3-pyridyl) acrylic acid (50.70 g), absolute ethanol (350 ml) and concentrated sulfuric acid (25 ml) was stirred at reflux for 18 hours with stirring and then ethanol (- ^ 250 ml) evaporated. The residue was poured into ice-cold aqueous ammonia, after which the mixture was extracted with ether. The ether extracts are washed with water and evaporated to an oily residue, which crystallizes upon standing to give 3 (6-methyl-3-pyridyl) acrylate, mp. 36-37 ° C.
    3- (6-Methyl-3-pyridyl) acrylic acid ethyl ester (60.36 g) was hydrogenated in ethanol at 35 ° C and 355 kPa using a palladium carbon catalyst (10%, 1.0 g). The mixture was filtered, the filtrate was evaporated, hemiacetamide, dimethyl sulfoxide, hexamethylphosphoramide, sulfolane, acetonitrile t nitromethane.
    944 (3 chayut ethyl (6-methyl-3 _ pyridyl) propionic acid as an oil.
    A mixture of 8- (6-methyl ~ 3_ pyridyl) propionic acid ethyl ester 5 (1.31 g) and formic acid ethyl ester (7.43 g) was added dropwise to a stirred suspension of sodium hydride (50% suspension in oil 4, 07 g) in dry 1,2-dimethoxyethane 10 (25 ml) at / h 0 ° C. The mixture was then allowed to warm to room temperature, stirred overnight, and then poured into ice water (300 g). The mixture was extracted with 15 rum ethers, the aqueous phase was adjusted to pH 5,4 with hydrochloric acid, the precipitated solid was collected to give ethyl 2-formyl-W - (6-methyl ~ 3 "Pyridyl) -propionic acid (10.5 g 20 70%), so pl. 142-4 ° C.
    PRI me R 2. A mixture of ethyl ester of formic acid (III g) and 2-butanol (108 g) is added dropwise to a stirred mixture of sodium hydride 25 in oil (50 wt.% / Weight, 72 g) in dry 1 , 2-dimethoxyethane, after which the mixture is left to stand overnight. Then 80 ml of ether are added and a solid precipitate is filtered off (101 g) 30 'cyanoacetamide (69.5 g), piperidine acetate } obtained by adding piperidine to acetic acid (7 ml) and water (18 ml) until the medium pH is became basic, and water (400 ml) ^ 5 was added to this solid residue and ί the mixture was refluxed for 2 hours, after which it was allowed to cool. The mixture was acidified with acetic acid and the precipitated solid precipitate was crystallized from aqueous ethanol to give 3 ~ cyano-5,6-dimethyl ~ 2-hydroxypyridine (48.5 g).
    A thoroughly mixed mixture of 3 _ cyano ~ 5, b-dimethyl-2-hydroxypyridine 45 (42 g) and phosphorus pentachloride (81 g) is heated at 120-140 ° C for 2 hours. Phosphorus chloride is evaporated under reduced pressure and ice-cold water is added to the residue. (500 g). The mixture was adjusted χ to pH 7 with sodium hydroxide solution and extracted with ether. The ether extract was evaporated to an oily residue which was crystallized from ethyl efirNetroleyny ether (b.p.. 6D-8o ° C) to give 2-chloro-3-cyano ~ 5,6-ridin dimetilpi- 55 (25.3 g), t .pl, 83-7 ° C.
    A mixture of 2-chloro-3 “cyano-5,6-dimethylpyridine (21.5 g), semicarbazide guide
    6 rochloride (24.0 g) of sodium acetate (42.3 g), 225 ml of water and methanol are hydrogenated at 50 ° C and 344 kPa using a skeletal nickel cat-i lyser (5 g).
    The mixture was poured into water (750 ml) and filtered. The filtered solid. The residue is suspended in water (130 ml), 70 ml of concentrated cd | hydrochloric acid are added and the mixture is heated at ROOS for one hour, then formalin (40 wt.% / Weight) 120 ml is added and the mixture is heated for another 0.5 h, after which the mixture was left to stand until cooling. Sodium acetate (95 g) and water (250 ml) were added to the mixture, after which it was extracted with ether, the extract was washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6, dimethyl-3-pyridinecarboxaldehyde ( 13.24 g, 60%), mp 6O-7O ° C.
    A mixture of 2-chloro-5,6-dimethyl-3 “pyridine-carboxaldehyde (16.85 g), malonic acid (11.45), piperidine (10 ml) and pyridine (100 ml) is refluxed for one hour and evaporated to a butter consistency. This oil is dissolved in sodium hydroxide solution and extracted with chloroform, then the aqueous phase is acidified with hydrochloric acid and extracted with chloroform. This last extract was washed with water and evaporated to give 3 “(2-chloro ~ 5,6-dimethyl-3 _ pyridyl) acrylic acid (18.3 g, 87%) mp. 150-8 ° C. Acrylic acid is esterified using ethanol and sulfuric acid, ethyl ether is obtained, so pl. 85 ~ 8 ° C.
    Ethyl ether (32.7 g) in ethanol ; (500 ml) is hydrogenated at 2530 ° C and 344 kPa using palladium. carbon catalyst (5%, 3 g). The mixture was filtered and the filtrate was evaporated to an oil, which was partitioned between chloroform and 2N hydrochloric acid. The aqueous phase was alkalinized to an alkaline reaction with sodium hydroxide solution, extracted with chloroform and the extract was evaporated to give 3 “(5,6-dimethyl-3“ pyridyl) propionic acid ethyl ester (21.8 g, 80%) as an oil.
    Ethyl Ether Reaction
    45.6-dimethyl-8-pyridyl) propionic acid with ethyl formate and sodium hydride in dimethoxyethane at room temperature leads to the formation of ethyl
    Ί '944 504 th ester of 3 (5,6-dimethyl-3-pyridyl) -2 formylpropionic acid, so pl. 148 ~ 9 ° C.
    Example 3.2-chloro-4-cyanopyridine (115.5 g) in a mixture of methanol-di-5 san 1: 1 (850 ml) is added to a solution of sodium methylate prepared from 20.8 g of sodium in methanol (285 ml), a mixture refluxed for 2.5 hours and then allowed to cool. Then the mixture is filtered, and the filtrate volume is reduced by evaporation to -200 ml, after which 200 ml of water is added. The precipitated solid precipitate is filtered off,> 5 is obtained.
    2-methoxy-4-cyanopyridine (57.2 g, 51%), mp. 93-95 ° C.
    A mixture of 2-methoxy ~ 4-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.24 g), sodium acetate (69.86 g), 20 ethanol (1200 ml) and water (370 ml) is hydrogenated at 344 kPa s using a skeletal nickel catalyst of 1.0 g. The mixture was evaporated to a volume of 450 ml, 900 ml of 25 water was added and then left to stand at 0 ° C overnight. The mixture is filtered *, the solid residue is washed with water and dissolved in 10% hydrochloric acid (950 ml). Formalin (36% weight / Sv / volume 420 ml) is added to this solution, after which the mixture is heated for 30 minutes, allowed to cool and a solution of sodium acetate (290 g) in water (840 ml) is added. The mixture was extracted with 35 ether and the combined extracts were washed successively with an aqueous solution of potassium carbonate and water, then dried and evaporated to give 2-methoxypyridin-4-carboxal-o-dehyd (20.53 g, 35%), so pl. ЗЗ-З ^ С. This compound, recrystallized from petroleum ether, has a melting point of 33 _ 36 ° C.
    Condensation of 2-methoxypyridin-4-carboxaldehyde with malonic acid, followed by esterification with hydrogenation at 344 kPa, formylation of the product with formic acid ethyl ester In the presence of 5H sodium hydrides, 2-formyl-3- (2-labels: ethyl- 4-pyridyl) propionic acid as an oil.
    Example 4. Replacing 2-methoxypyridin-4-carboxaldehyde under the conditions of Example Z'na 4-methoxypyridin-2-carboxaldehyde gives ethyl 3 ~ (4-methoxy-2-prridyl) propionic acid as an oil, formylation which gives 2-formyl-3- (4-methoxy-2-pyridyl) propionic acid ethyl ester.
    Example 5 · A mixture of 2-methoxy ~ 5 ~ cyanopyridine (61, 26 g) semicarbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) is hydrogenated at 344 kPa using a skeletal nickel catalyst (1.0 g).
    The mixture was evaporated to a volume of - »500 ml, 100 ml of water was added and the mixture was allowed to stand at 0 ° C overnight. The mixture is filtered, the solid residue is washed with water and dissolved in 1000 ml of 10% hydrochloric acid. Formaldehyde (36% w / v 450 ml) was added, then the mixture was boiled for 15 minutes, allowed to cool and sodium acetate (298.5 g) in water (900 ml) was added to the solution. This mixture was extracted with ether (3 x 500 ml), and the combined extracts were washed successively with an aqueous solution of potassium carbonate and water, after which they were dried and evaporated to give 6-methoxypyridine-8-carbox7 aldehyde (31.5 g, 50%), t pl. 489 ° C.
    A mixture of 6-methoxypyridyl-3-carboxaldehyde (2.34 g), malonic acid monoethyl ester (4.51 g), pyridine (12 ml) and piperidine (6 drops) was refluxed for 5 hours, after which it was evaporated to give an oil . The oil was partitioned between- ( ether and diluted aqueous ammonia. The ether layer was separated, washed with water and evaporated to an oil which crystallized upon standing to give 3 ~ (6-methoxy-3-pyridyl) acrylic acid ethyl ester (2.8 g , 79%), mp 49-52 ° С.
    3 ”(6-methoxy-3-pyridyl) acrylic acid ethyl ester (32.33 g) in ethanol (160 ml) was hydrogenated with 344 kPa gec and 40 ° C using a palladium carbon catalyst (5%, 0.2 g) . The mixture was filtered and the filtrate was evaporated to give ethyl ester> 3 ~ (6 * · methoxy-3-pyridyl) propionic acid (32.7 g) as an oil.
    A mixture of ethyl 3 - (6-methoxy-3 _ pyridyl) propionic acid (32.74 g) and ethyl formate (17.22 g) was added dropwise over 1, 5 h to a stirred suspension of sodium hydride in oil ( 50%, 9.38 g) in 1,2-dimethoxyethane (50 ml), cooled to -2 ° C, after which the mixture was left overnight at room temperature and then poured onto ice. The mixture was extracted with ether and the aqueous phase adjusted to pH 5.0 with 2N. sulfuric acid. The oil precipitated as a result crystallizes upon standing, and 2-formyl-Z * (b-me-и toxi-3-pyridyl) prolionic acid ethyl ester (25.9 G, 70%) is obtained, mp 91.5-94 ° C. Recrystallized from aqueous ethanol, the sample has a so pl. 93 “4 ° C.
    Example 6. Reaction of 3 ~ (2-furyl) propionic acid ethyl ester with 1.1 equivalent of formic acid ethyl ester and 1.0 equivalent of sodium hydride in 1,2 dimethoxyethane at room temperature leads to 2-formyl-3 “ethyl ester (2 -furyl) propionic acid as an oil (75% yield).
    Example 7 · A mixture of 3 * (3-methoxyphenyl) propionic acid ethyl ester (100 g) and formic acid ethyl ester was added dropwise with stirring to sodium metal (11 g) in ether (500 ml) (at 0 ° C. The mixture was stirred it is evaporated to dryness at room temperature for 16 hours, the residue is dissolved in water and extracted with ether, after which the extracted aqueous phase is adjusted to pH 4 with hydrochloric acid and re-extracted with ether, then this ether (second) extract is evaporated to dryness and 2-formyl ethyl ether is obtained ~ 3 “(3-methoxyphenyl) propionic acids (46.05 g).
    Example 8. Ethyl ester of 3- (3,4,5-trimethoxyphenyl) propionic acid is reacted with ethyl ester of formic acid and sodium hydride in 1, 2-dimethoxyethane, to obtain ethyl 2-formyl-3- (3,4,5 -trimethoxyphenyl) propionic acid in 44% yield.
    Example 9. 2,3 - dihydro-1,4-benzodioxin-6-carboxaldehyde; (mp 41-43 ° C, obtained by the interaction of 1 with 3,4-dioxibenzaldehyde with ethanedisulfonic acid dimethyl ether and potassium hydroxide) are condensed with monoethyl malonic acid ester in pyridine using piperidine as a catalyst, 3- (6- (2,3 - dihydro-1-, 4-benzodioxinyl) acrylic acid ethyl ester, mp 49-53 ° С, which is reduced with hydrogen in the presence of 10
    944504 In the case of palladium-carbon catalyst, the resulting product is condensed with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give ethyl ether
    2- formyl-3-6- (2,3-dihydro-ί, 4-benzodioxinyl) propionic acid in the form of an oil.
    Example 10. A mixture of 3- (1-naphthyl) propionic acid ethyl ester (18.01 g) and formic acid ethyl ester (8.88 g) was added to a suspension of sodium hydride (57% suspension in oil, 4.43 g) in 1,2-dimethoxyethane with stirring at 5 ° C, the resulting mixture was stirred at 5 ° C for one hour and then left to warm to room temperature. 300 ml of water are added and the mixture is extracted with chloroform, the extracted aqueous phase is adjusted to pH 4 with hydrochloric acid, extracted again with ether and the extract is evaporated, 2-formyl-3 - (1-naphthyl) propionic acid ethyl ester ((6.05 g) in kind of oil.
    Example 11. A solution of sodium methylate (from 0.535 g sodium) in dry methanol (40 ml) was added dropwise to a stirred suspension
    3-Fluoro-2-methyl-4-nitropyridine-M-oxide (2 g) in dry methanol (50 ml) and the mixture was stirred overnight. An additional amount of sodium methylate (from 0.053 g of sodium) is added to the mixture, after which it is refluxed for one hour. The mixture was neutralized with hydrochloric acid and evaporated to dryness. The residue was extracted with chloroform and the extract was evaporated to dryness to give 3,4-dimethoxy-2-methylpyridin-Y-oxide.
    Trifluoroacetoacetic anhydride (4.0 ml) was added dropwise to a stirred solution of 3,4-dimethoxy-2-methylpyridin-Y-oxide (1.91 g) in methylene chloride (25 ml) and the mixture was allowed to stand at room temperature for 8 days. during which trifluoroacetic anhydride (4.77 ml) is added in two portions. . The mixture is evaporated to dryness, the residue is dissolved in chloroform · and extracted with an aqueous solution of sodium bicarbonate, purified on a column of silica gel with elution with a mixture of methanol - chloroform (1: 9)> 2-hydroxymethyl-3,4-dimethoxypyridine is obtained (1.6 g )
    2-hydroxymethia-3,4-dimethoxypyridin- k when reacted with thionyl chloride in chloroform gives 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, so pl. 158-9 ° C (decomp.), Which, when reacted with urotropine hydrochloride and sodium hydride in ethanol, gives 2- (3,4-dimethoxy-2-pyridylmethylthio) ethylamine.
    Synthesis of target compounds.
    Example 12. A thoroughly stirred mixture of 2- (5 - methyl-4-imidazolylmethylthio) ethylamine (0.86 g) and 2-nitroamino-5 ~ (3 ~ pyridylmethyl) -4-pyrimidone (1.24 g) is heated at 130 ~ 5 ° C for 11.5 hours. The mixture was allowed to cool and was washed with hot water and then treated with a solution of hydrogen chloride in ethanol,. the product obtained is recrystallized from ethanol-methanol to give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5 _ (3 ~ pyridylmethyl) -4-p £ | rimidone trihydrochloride, mp 2OZ - 5 ° C, with a yield of 75%.
    Example 13- Similarly, using 3 “(4-imidazolyl) propylamine,
    4- (5 - methyl-4-imidazolyl) butylamine, 2-nitroamino-5- (3-pyridylmethyl) -4-pyrimidone and using the same molar proportions of the reagents, get 2- (3 _ (4-imidazolyl) propylamino] - 5 (3 ~ pyridylmethyl) -4-pyrimidone trihydrochloride, mp 208.5-212 ° and 2- [4- (5methyl-4-imidazolyl) butylamino] -5 _ (3 - pyridylmethyl) -4 ~ pyrimidone trihydrochloride , mp 242-6 °, with 7θ% yield.
    Example ΐ4. A solution of 3 (5 "methyl-4-imidazolilmetiltio1propilamina (1.64 g) and 2-nitroamyno-5 _ (pyridylmethyl) -4-pyrimidone (1.97 g) in pyridine was refluxed for 20 hours, after which the pyridine was removed by evaporation The residue is crystallized from ethanol containing hydrogen chloride, and then recrystallized from a mixture of ethanol - methanol, to obtain 2- [3 _ (5 ~ methyl-4-imidazolylmethylthio)] - 5 “(3-pyridylmethyl) -4-pyrimidone trihydrochloride, mp 233 “6 ° C.
    Examples 15, 16, 17. Using the method of example 14 in the reaction of 2-nitroamino-5 ~ (3-pyridylmethylU4-pyrimidone with 1.1 molar equivalent of 2- (4-methyl-2-pyridylmethylthio) ethylamine, 4- (3-chloro -2-pyridyl) butylamine and 2- (4-methoxy-225
    SO
    944 504 12
    -pyridylmethylthio) ethylamine respectively receive:
    2- [2- (4-methyl-2-pyridylmethylthio) ethylamino] -5 “(3Pyridylmethyl) -4-py'rimidone, mp 128-9 ° (example 15).
    2-Ϊ4- (3-chloro-2-pyridyl) butylamino] ~ 5 ~ (3-pyridylmethyl) -4-pyrimidone, mp 146-7.5 ° (example 16).
    2- [2- (4-methoxy-2-pyridylmethylthio) ethylamino] -5 _ (3-pyridylmethyl) -4-pyrimidone, mp. 99-100 ° (example 17) "
    Example 18. A mixture of 2- (3,4-dimethoxy-2-pyridylmethylthio) ethylamine (0.95 g, 4.16 mmol), 2-nitroamino-5 - (3 ~ pyridylmethyl) -4-pyrimidone (0.925 g, 3 , 74 mmol) and pyridine (3.5 ml) are refluxed for 24 hours and then evaporated to dryness. The residue was purified on a silica gel column, eluting with a methanol chloroform mixture (1: 7) and recrystallized from ethanol, to give 2- (2- (3,4-dimethoxy-2-pyridylmethylthio) ethylamino] -5 _ (3-pyridylmethyl) -4- pyrimidone, mp 121-1, 5 ° C.
    EXAMPLE 19 · Using the method of Example 14, 2-nitroamino-5 ~ (Ztntridylmethyl) -4-pyrimidone is reacted with 1.1 molar equivalents of 4- (3 “amino-2-pyridyl) butylamine to give 2- [4 - (3-amino-2-pyridyl) boo ~. tilamino] -5 _ (3 - pyridylmethyl) -4-pyrimidone, mp 130-1.5 ° С.
    Example 20. When refluxed for 16 hours, 2-nitroamino-5- (3-pyridylmethyl) pyrimidone in pyridine with 1.5 molar equivalent of 3_ (2-thiazolyl) propylamine received 2- (3 “(2-thiazolyl) ) propylamino] -5 _ (3-pyridylmethyl) -4-pyrimidone, mp 168-172 ° С.
    Example 21. When applying the same. the molar equivalent of 2- (2-thiazolylmethylthio) ethylamine give 2-C2- (2-thiazolylmethylthio) ethylamino] -5 _ - (3 “pyridylmethyl) ~ 4-pyrimidone trihydrochloride, so pl. 178-180.5 ° C, with 76% yield.
    Example 22. A solution of 4- ( 3_ methoxy-2-pyridyl) butylamine (5.48 g) and 2-nitroamino-5 _ (6-methyl-3-pyridylmethyl) -4-pyrimidone (7.95 g) in pyridine (200 ml) was refluxed for 18 hours and evaporated to dryness. The residue was extracted with warm propanol (200 ml) and the solution was acidified with hydrochloric acid. The crystalline precipitate (10.83 g, 74%) was filtered off and recrystallised 2- [4- (3-metok13 'B-2-pyridyl) butylamino] -5' (6-methyl-3 _ pyridylmethyl) 4-pyrimidone trihydrochloride (7 53 g), mp 184-8 ° C. Example 23. A mixture of 5 ~ (5,6-pyridylmethyl) -2-nitroamino-4-pyrimidone and 1.1 molar equivalent of 2- (5 “methyl-4-imidazolylmethylthio) ethylamine is heated at 130 ° C. for 5 hours, after which it is refluxed in ethanol for 12 hours, evaporated to- 1 dry, and 2- (2- (5-methyl-4-imidazolylthio) ethylamino] -5 (5,6-dimethyl-
    3 - pyridylmethyl) -4-pyrimidone monohydrate, mp 115 ° (softening at 98 °).
    Example 24 A mixture of 5 - (5,6-dimethyl-3 _ pyridylmethyl) -2-nitroamines-4-pyrimidone and 1.2 molar equivalents of 2- (Z-bromo-2-pyridylmethylthio) ethylamine was refluxed in ethanol 48 h, evaporated to dryness, give 2 ~ t2 “(3“ bromo-2-pyridylmethyl) ethylamino] -5- (5,6-dimethyl-3 _ pyridylmethyl) -4-pyrimidone, so pl. 1O5-7 ° C.
    'Example 25. Equimolar amounts of 5 “(5,6-dimethyl-3 ~ pyridylmethyl) -2-nitroamino-4-pyrimidone and
    4- (3-ethoxy-2-pyridyl) butylamine in ethanol is refluxed for 24 hours. An additional 0.1 molar equivalent of amine is added and the mixture is refluxed for the next 24 hours. After this, the mixture is evaporated to dryness, and 2- [4- (3-methoxy-2-pyridyl) butylamino] ~ 5 “(5,6-dimethyl-3 ~ pyridylmethyl) -4-pyrimidone dihydrate, so pl. 93 “94 ° C.
    Example 26. An equimolar mixture of 2-nitroamino-5 (6-methoxy-3 * -pyridylmethyl) 4-pyrimidone and 2- (5 ~ me, tyl-4-imidazolylmethylthio) ethylamine in ethanol is refluxed for 18 hours. Solid precipitate, 'formed upon cooling, recrystallized from ethanol to give 2-t2- (5 ~ methyl-4-imidazolylmethylthio // ethylamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone, mp 197-8, 5 ° with 63% yield.
    EXAMPLE 27 · equimolar mixture of 2-5-amine derivatives _ (6-methoxy-3 ~ -piridilmetil) -4-pyrimidone and 2- (2-tiazolilmetiltio) ethylamine in ethanol was refluxed 18h. The solid precipitate formed upon cooling is recrystallized from ethanol to give 2- [2- (2-thiazolylmethylthio) ethylamino] -5 ~ (6-methoxy10
    SO
    T. Sub.
    944 504 111
    -3 ~ pyridylmethyl) -4-pyrimidone 7 _ 95 ° C, in 60% yield.
    Examples 28 and 29 When refluxed for 18 hours, 2-nitroamino ~ 5- (2-methoxy-4-pyridyl. * * Methyl) -4-pyrimidone with equimolar amounts of 2- (5 - methyl-4-imidazolyl methylthio) ethylamine and 2- (2-thiazolylmethylthio) ethylamine respectively give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5 ~ (2-methoxy-4 ~.-Pyridylmethyl) -4-pyrimidone, mp 117-8 ° (Example 28), and 2- (2- (2-thiazolylmethylthio) ethylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone, mp 105.5-6.5 (example 29).
    Example 30. A mixture of 2- (2-thiazolylmethylthio) ethylamine (2.0 g) and 2-nitroamine-5- (3 ~ methoxybenzyl) -4-pyrimidone (1.58 g) was heated for 4 hours at 130 ° C. Then the mixture was triturated with hot water and the precipitate was recrystallized from 2-propanol to obtain 2- [2- (2-thiazolylmethylthio) ethylamino] ~ -5- (3-methoxybenzyl) -4-pyrimidone (0.93 g), t pl. 122-4 °). The sample is treated with a solution of hydrogen chloride in ethanol and, after recrystallization from a mixture of isopropanol - methanol, a product is obtained with mp 104-6 °, and its analytical data correspond to hemihydrate.
    Example 31. 2-Nitroamino-5 _ - (3,4,5-trimethoxybenzyl) 4-pyrimidone (1.12 g) and 2- (5 _ methyl-4-imidazolylmethylthio) ethylamine (0.65 g) are heated at 130-5 ° 12 h. After cooling, the mixture is washed with hot water and after treatment with a solution of hydrogen chloride in ethanol, followed by recrystallization from ethanol, 2- [2- (5 ~ methyl-4-imidazolylmethylthio). Ethylamino] ~ 5 ~ (3, 4,5-trimethoxybenzyl) -4-pyrimidone dihydrochloride, mp 171-4 °.
    Example 32 A mixture of 2- (5-methyl-4-imidazolilmetiltio) ethylamine (1.54 g), 2-5-amine derivatives "T5 _ (1,3-benzodioxolyl) methyl] -4-pyrimidone (2.5 g) and ethanol (20 ml) is refluxed for 24 hours. A solution of hydrogen chloride in ethanol is added to the hot solution, 2- (2 * - {5-methyl-4-imidazolylmethylthio) ethylamino] ~ 5 _ - (5- (1,3-benzodioxolyl) methyl) -4-pyrimidone dihydrochloride (2.2 g), this product is dissolved in water, the solution is adjusted to pH 8 with water15
    15- 944504 th sodium bicarbonate solution, after which the free base is filtered. This free base is recrystallized from ethanol containing hydrogen chloride to obtain a dihydrochloride sample with a melting point of 2326 ° C. Example 33. A mixture of 2-nitroamino-5 ~ [5 “(2,3-dihydro-1,4-benzodioxinyl) methyl] -4-pyrimidone (3.04 g) 2- (5 ~ methyl-4-imidazolylmethylthio) ethylamine · (1.92 g) and ethanol (20 ml) are refluxed for 21 hours, then evaporated to dryness, the residue washed with hot water, recrystallized twice from ethanol containing hydrogen chloride, get 2 '- {2- (5 ~ methyl-4-imidazolylmethylthio) octylaminoZ ~ 5 ~ Еb- (2,3 ~ dihydro-1,4-benzodioxinyl) methyl] -4-pyrimidone dihyd-20 rochloride, mp. 210-13 °.
    PRI me R s 34-36. Reaction of 2- (5 ~ methyl-4-imidazolylmethylthio) ethylamide ^ a with equimolar amounts: 2-nitroamino-5 ~ (4-methoxy-2-pyridylmethyl) -4-pyrimidone, 2-nitroamino-5- (2-furylmethyl) -4-pyrimidone and 2-nitroamino ~ 5- (1-naphthylmethyl) -4-pyrimidone gives 2- [2- (5methyl-4-imidazolylmethylthio) ethylamino] -5- (4-methoxy-2-pyridylmethyl) -4, respectively -pyrimidone (example 34), 2- £ 2- (5 “methyl-4-imidazolylmethylthio) ethylamine 0} -5 (2-furylmethyl) -4-pyrimidone (example 35) and 2- [2- (5 ~ methyl-4 -imidazolylmethylthio) ethylamino] -5 ~ (1-naphthylmethyl · 4-pyrimidone, made in the form of dihydrochloride, mp 228-230 ° (Example 36).
    权利要求:
    Claims (2)
    [1]
    This invention relates to an improved method for the treatment of the 9Lumenia of 2-aminopyrimidone derivatives possessing the activity of Histamine Zntagonists. A known method for the preparation of derivatives of 2-aminopyrimidone of the general formula HeHCH j) y (CH j :) where H t is unsubstituted imidazolyl or substituted by C 4 alkyl, 2 pyridyl, substituted by an amino group, halide, one or more alkoxy groups with 1-4 carbon atoms; m and n - 1-4; y is methylene or sulfur; B is a heterogroup from the number that 2-alkyl / 1-thiopyrimidone-4 of the formula nkAlkS jA O, where B has the indicated meanings, is reacted with an amine of formula (III) Het- (CH, j) -Y (CH, j) nNH (i when heated, usually at 140-180C til. - However, the method is characterized by an insufficiently high yield of the target products. The purpose of the invention is to increase the yield of the target products. The goal is achieved by the method of producing 2-aminopyrimidone derivatives of general i formula; CIS), „- at (CIS) where Het is unsubstituted imidazolyl or substituted by alkyl C. Cd, 2- pyridyl substituted by amino, halo, one or more alkoxy groups with 1-carbon atoms, or 2-tilzolyl; m is O or 1; y is methylene or sulfur; n - 2 or 3; B is furyl, naOtil, 6- (2,. Hydro-1, 4-benzodioxy) 5- (1.3 benzodioxolyl), n substituted pyridyl or substituted by one or several alkylMy or alkoxy, in which alkyl. or phenyl substituted with one or more alkyl with 1-carbon atoms by reacting a 2-substituted pyrimidone-general formula. oi where B has the indicated meanings, with an amine of the general formula He1- (CHg),) Bn: g, (it where Het, m, Y and Pymeyut specified values, when heated, use 2-nitro; amino-derivative of pyrimidone of the general formula ( and) and the process is carried out with SO-UO C. The process is carried out in ethylene, n-panol or pyridine during boiling. The process is carried out using an excess of amine of the general formula (ill). The method can be carried out in the absence of a solvent at 80 -170, usually 120-1 0 ° or in a solvent at the boiling point of the reaction mixture. idin, picoline or bc picolines, a lower alkanol, such as ethanol, n-propanol, a mixture of water with an alkanol, 1,2-ethanediol, ketones, such as acetone, 2-butanone, or a polar aprotic solvent, such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, sulfolane, acetonitrile nitromethane. Preferably, the process is carried out in ethanol, n-propanol or pyridine with boiling. The method can be carried out both with an equimolar ratio of the reactants and using an excess of one of the reactants. It is preferable to use. Excess amine of the general formula (ill). The compounds obtained according to the proposed method have the activity of H rf-histamine antagonists, which are used as inhibitors of gastric acid secretion, as well as agents that inhibit the action of histamine on blood pressure. The starting compounds of formula (II) can be prepared by reacting the corresponding f) -o-ether with nitroguanidine. . The proposed method allows to increase the yield of target products up to, compared to a known method, where the yield for these products is 53-73. Synthesis of raw materials. Example 1 A mixture of 6-methylpyridin-3-carboxaldehyde (51.57 g), malonic acid (4.80 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100 ° C for 3 hours and allowed to cool. Thereafter, the mixture is evaporated to dryness, water is added to the residue, the solid is filtered off and crystallized from ethanol-acetic acid mixture, to obtain 3 (6-methyl-4-pyridyl) acrylic acid 41,25 rj, so pl. 213.5-215 ,. A mixture of 3- (6-methyl-3 pyridyl) acrylic acid (50.70 g), absolute ethanol (350 ml) and concentrated sulfuric acid (25 ml) is heated under reflux for 18 hours with stirring and then ethanol (ml) evaporated. The residue was poured into ice-water ammonia, after which the mixture was extracted with ether. The ether extracts are washed with water and evaporated to an oily residue, which crystallizes upon standing, to obtain 3- (6-methyl-3 Pyridyl) acrylate, m.p. ZB-37 ° e. Ethyl ester of 3- (6-methyl-3 pyridyl) acrylic acid (60.3b g) is hydrogenated in ethanol at 35 ° C and 355 kPa using a palladium catalyst on carbon (10%, 1.0 g). The mixture is filtered, the filtrate is evaporated, a half of ethyl ester 3 (6 methyl-3 pyridyl) propionic acid is obtained as an oil. A mixture of 8- (6-methyl-3 pyridyl) propionic acid ethyl ester (1.31 g) and formic acid ethyl ester (g) was added dropwise to a stirred suspension of sodium hydride (50 suspension in oil +, 07 g) in dry 1,2-dimethoxyethane (25 ml) at fjQ ° C. The mixture was then allowed to warm to room temperature, stirred overnight, and then poured into ice water (00 g). The mixture is extracted with ether, the aqueous phase is adjusted to pH 3 with hydrochloric acid, the precipitated solid is separated, a 2-formyl-3- (6-methyl-3-pyridyl) propionic acid ethyl ester is obtained (10.5 g, 70 ), so pl. . PRI me R
    [2]
    2  A mixture of formic acid ethyl ester (IM g) and 2-butanol (108 g) was added dropwise to a stirred mixture of sodium hydride in oil (50 weight D / weight, 72 g) in dry 1,2-dimethoxyethane, after which the mixture was left They are worth the night.  Then 80 ml of ether are added and the solid precipitate is filtered off (101 g) Cyanoacetamide (69.5 g), piperidine tat obtained by adding piperidine to acetic acid (7 ml) and water (18 ml) until the pH of the medium is basic, and water C + OO m is added to ST / Sf y solid residue and the mixture is heated under reflux for 2 hours, then left to cool.  The mixture is acidified with acetic acid and the precipitated solid precipitated is crystallized from aqueous ethanol to give 3 Cyano-5,6-dimethyl-2-hydroxypyridine (8.5 g).  A thoroughly stirred mixture of 3-Cyano-5 6-dimethyl-2-hydroxypyridine (2 g) and phosphorus pentachloride (81 g) is heated at 120–1 ° C for 2 h.  Phosphorus oxychloride is evaporated under reduced pressure and ice water (500 g) is added to the residue.  The mixture was adjusted to pH 7 with sodium hydroxide solution and extracted with ether.  The ethereal extract is evaporated to an oily residue, which is crystallized from an episode mixture. Ethyl ether (m. Kia  60-80C), receive 2-chloro-3-Cyano-5,6-dimethylpyridine (25.3 g), t. pl .  A mixture of 2-chloro-3-cyano-5,6-dimethyl-ipidine (21.5 g), semicarbazide hydrochloride (24.0 g) sodium acetate (+2.3 g), water 225 ml and methanol is hydrogenated at 50 ° C and kPa using skeletal nickel catalysts (5 g).  The mixture was poured into water (750 ml) and filtered.  The filtered solid | residue is suspended in water (130 ml), 70 ml of concentrated hydrochloric acid is added and the mixture is heated at IEE for one hour, then formalin is added (G weight. (weight) 120 ml and the mixture is heated for another 0.5 h, after which the mixture is left to stand until cooling.  Sodium acetate (95 g) and water (250 ml) are added to the mixture, then it is extracted with ether, the extract is washed with aqueous potassium carbonate and evaporated to give 2-chloro 5,6, -dimethyl-3 pyridinecarboxal-: dehyd (t3, g, 60), t. square 60-70 C.  A mixture of 2-chloro-5,6-dimethyl-3-pyridine-carboxaldehyde (16.85 g), malonic acid (11,), piperidi; on (10 ml) and pyridine (100 ml) kip jj-flT with brotherly refrigerator for an hour and evaporated to the consistency of oil.  This oil is dissolved in sodium hydroxide solution and extracted with chloroform, then the aqueous phase is acidified with hydrochloric acid and extracted with chloroform.  This last extract was washed with water and evaporated to give 3- (2-chloro-5,6-dimethyl-3-pyridyl) acrylic acid (18.3 g, 87) t. square  150-8C.  Acrylic acid is esterified using ethanol and sulfuric acid to give ethyl ester, t. square  85-8 ° C.  Ethyl ether (32.7 g) in ethanol; (500 ml) is hydrogenated at 25-30 ° C and: Z kPa using palladium-.  go catalyst on coal (5%, 3 g).  The mixture is filtered and the filtrate is evaporated to an oil, which is partitioned between chloroform and 2N hydrochloric acid.  The aqueous phase is alkalinized to alkaline with sodium hydroxide solution, extracted with chloroform and the extract evaporated to give ethyl ester 3 (5,6-dimethyl-3-pyridyl) propionic acid (21.8 g, 80%) as an oil.  The interaction of ethyl 3-C5,6-dimethyl-8-pyridyl) propionic acid with ethyl formic ester and sodium hydride in dimethoxyethane at room temperature leads to the formation of ethyl 3-(5, b-dimethyl-3 pyridyl) - 2 formylpropionic acid, t. square  .  Example 3 2-Hop-β-cyanopyridine (115.5 g) in methanol-dioxane 1: 1 {850 ml) is added to a solution of sodium methoxide prepared from 20.8 g of sodium in methanol (285 m mixture is boiled under reflux 2.5 hours and then allowed to cool.  . The mixture is then filtered, and the volume of the filtrate is reduced by evaporation to-200 ml, after which 200 ml of water is added.  The precipitated solid is filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 5U).  t. square  93-95 S.  A mixture of 2-methoxy-β-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.2 g), sodium acetate (B9.86 ethanol (1200 ml) and water (370 ml) is hydrogenated at 3 kPa using skeletal nickel catalyst 1 , 0g.  The mixture is boiled down to a volume of 450 ml, 900 ml of water are added and then left to stand at overnight.  The mixture is filtered, the solid residue is washed with water and dissolved in 10% hydrochloric acid (950 ml).  Formalin (BW weight / / volume 20 ml) was added to this solution, after which the mixture was heated for 30 minutes, allowed to cool, and a solution of sodium acetate (290 g) in water (ml) was added.  The mixture is extracted with ether and the combined extracts are successively washed with an aqueous solution of potassium carbonate and water, then dried and evaporated to give 2-methoxypyridine-4-car-oxal dehyd (20.53 g, 35), t.  square   This compound, recrystallized from petroleum ether, has m.  square  33-36 ° C.  Condensation of 2-methoxypyridine-β-carboxaldehyde with malonic acid followed.  Arrangement and hydrogenation at kPa, formulating the product with formic acid ethyl ester) in the presence of sodium hydride, results in 2-formyl-3- (2-labels: si-4-pyridyl) propionic acid ethyl ester as an oil.  An example.  Replacement of 2-methoxypyridine-β-carboxaldehyde under the conditions of the example of Kn-methoxypyridin-2 -. carboxaldehyde gives 3- (-methoxy-2-pyridyl) propionic acid ethyl ester as an oil, the formylation of which gives 2-formyl-3 (methoxy-2-pyridyl) propionic acid ethyl ester.  Example 5  A mixture of 2-methoxy-5 cyanopyridine (61, 2b g) semicarbazide hydrochloride (76, j g), sodium acetate (7. 92 g), ethanol (1300 ml) and water (00 ml) are hydrogenated at kPa using a skeletal nickel catalyst (1.0 g).  The mixture is evaporated to a volume of 500 ml, 100 ml of water are added and the mixture is left to stand at room temperature overnight.  The mixture is filtered, the solid residue is washed with water and dissolved in 1000 ml of 10% hydrochloric acid.  Formaldehyde is added (ST. weight. (volume {50 ml) / then the mixture is boiled for 15 minutes, allowed to cool and sodium acetate (298.5 g) in water (90Q ml) is added to the solution. This mixture is extracted with ether (3 x 500 ml and the combined extracts washed with an aqueous solution of potassium carbonate and water, after which they are dried and evaporated, get 6-methoxypyridine-8-ka. rbo, csg aldehyde (31.5 g, 50%), t.  square  .  A mixture of 6-methoxypyridyl-3 carboxaldehyde (2.3 g), malonic acid monoethyl ester C, 51 g), pyridine (12 ml) and piperidine (6 drops) is refluxed for 5 hours, then evaporated to give an oil .  The oil is partitioned between ether and dilute aqueous ammonia.  The ether residue is separated, washed with water and evaporated to the consistency of an oil which crystallizes on standing; to obtain 3- (6-methoxy-3-pyridyl) acrylic acid ethyl ester (2.8 g, 791), t.  square  49-52p.  Ethyl ester 3 (6-methoxy-3-pyridyl) acrylic acid (32.33 g) in ethanol (160 ml) was hydrogenated at 3 kPa and 40 ° C using a palladium on carbon catalyst (5%, 0.2 g).  The mixture is filtered and the filtrate is evaporated to give 3- (6-methoxy-3-pyridyl) propionic acid ethyl ester (32.7 g) as an oil.  A mixture of 3- (6-methoxy-3-pyridyl) propionic acid ethyl ester (32.7 g) and formic acid ethyl ester (17.22 g) is added dropwise over 1i5 hours to a stirred suspension of sodium hydride in oil ( 50 (9.38 g) in 1,2-dimethoxyethane (50 ml), cooled to -2 ° C, after which the mixture was left overnight at room temperature and then poured onto ice.  The mixture is extracted with ether and the aqueous phase is adjusted to pH 5.0 with 2N.  sulfuric acid.  The resulting precipitated oil crystallizes on standing, and ethyls are obtained:} 2-formyl-3 ester (6-methoxy-3 pyridyl) prolonic acid ester (25.9 g, 70), t.  square  91 ,.  The sample recrystallized from aqueous ethanol is m.  square   Spreader 6.  The reaction of 3 (2-furyl) propionic acid ethyl ester with 1.1 equivalents of ethyl formic ester and 1.0 equivalents of sodium hydride in 1,2 dimethoxyethane at room temperature leads to 2-formyl-3 (2-furyl) propionic ester kit LOT in the form of butter (75 yield).  Example 7  A mixture of methoxyphenyl-propionic acid ethyl ester SSS (100 g) and formic acid ethyl ester is added dropwise with stirring to metallic sodium (11 g) in ether (500 ml) at 0 ° C.  The mixture is stirred at room temperature for 16 hours and evaporated to dryness.  The residue is dissolved in water and extracted with ether, then the extracted aqueous phase is brought to pH k with hydrochloric acid and re-extracted with ether, then this ethereal (second) extract is evaporated to dryness, to obtain 2-formyl-3 ethyl ester a) propionic acid (, 05 g).  Example 8  The 3 (3 J 5 trimethoxyphenyl) propionic acid ethyl ester is reacted with formic acid ethyl ester and sodium hydride in 1,2-dimethoxyethane to give 2-formyl-3- (3. , 5 trimethoxyphenyl) propionic acid in% yield.  Example 9  2,3-dihydro-1, -benzodioxin-6-carboxaldehyde.  square  obtained by the interaction of W. + Dioxybenzaldehyde with ethanedisulfonic acid dimethyl ester and potassium hydroxide), condensed with malonic acid monoethyl ester in pyridine using piperidine as a catalyst; ethyl ester 3 (6- (2,3-di-hydroxy-1-, -benzodioxinyl) acryloic acid is obtained , t  square  49-53 ° C, the second is reduced by hydrogen in the presence of a Y of a palladium catalyst on carbon, the resulting product is condensed with formic acid ethyl ester and sodium hydride in 1,2-dimethoxyethane, to obtain 2-formyl-3-6- (2, 3-dihydro-1, -benzodioxyn) propionic acid in the form of oil.  Example 10  A mixture of 3- (1-naphthyl) propionic acid ethyl ester (18.01 g) and formic acid ethyl ester (8.88 g) is added to a suspension of sodium hydride (57 suspended in oil,, g) in 1, 2- dimethoxyethane with stirring, the mixture was stirred at 5 ° C for one hour and then allowed to warm to room temperature.  300 ml of water are added and the mixture is extracted with chloroform, the extracted aqueous phase is adjusted to pH with hydrochloric acid, extracted again with ether and the extract is evaporated, to obtain 2-formyl-3- (1-naphthyl) propionic acid ethyl ester (, 05 g) in the form of oil.  Example 11  A solution of sodium methoxide (from 0.535 g of sodium) in sug (home methanol (kQ ml) is added dropwise to a stirred suspension of 3-fluoro-2-methyl-β-nitropyridine-N-oxide (2 g) in dry methanol (50 ml ) and the mixture is stirred overnight.  An additional amount of sodium methoxide (from 0.053 g of sodium) is added to the mixture, after which it is heated under reflux for an hour.  The mixture is neutralized with hydrochloric acid and evaporated to dryness.  The residue is extracted with chloroform and the extract is evaporated to dryness, to obtain 3, -dimethoxy-2-methylpyridine-M-oxide.  Trifluoroacetoacetic anhydride (", 0 ml) was added dropwise to a stirred solution of 3, -dimethoxy-2-methylpyridine-K-oxide (1.91 g) in methylene chloride (25 ml) and the mixture was left to stand at room temperature 8 days during which trifluoroacetic anhydride (77 ml) was added in two portions.  . The mixture is evaporated to dryness, the residue is dissolved in chloroform and extracted with an aqueous solution of sodium bicarbonate, purified on a column of silica gel with elution with a mixture of methanol: chloroform (1: 9), to obtain 2-hydroxymethyl-3, -dimethoxypyridine (1. 6 g).  2-Oxymethyl-3+ dimethoxypyridine, when interacting with thionyl chloride in chloroform, gives 2-chloromethyl-3, -dimethoxypyridine hydrochloride, t.  square  158-9C (with decomp. ), which, upon reaction with urotropine hydrochloride and sodium hydride in ethanol, gives 2- (3, + dimethoxy-2-pyridylmethylthio) ethylamine.  Synthesis of target compounds.  Example 12  Thoroughly stirred sisil 2- (5 - methyl 4-imide zolylmethylthio) ethylamine (0.86 g) and 2-nitroamino-5- (3- (1iridylmethyl Vt-pyrimidone (1.2 g) is heated at 130-5 With for 11.5 hours .  The mixture is allowed to cool and washed with hot water and then treated with a solution of hydrogen chloride in ethanol, the resulting product is recrystallized from ethanol-methanol, to obtain (5 methyl-4-imidazolylmethylthio) ethylamino-5 (3 pyridylmethyl) -pyrimidone trihydrochloride, t.  square  2–3–5 s, exit 75.  Example 13 - Similarly, using 3- (4-imidazolyl-propylamine, - (5-methyl-4-imidazolyl) butylamine, 2-nitroamino-5- (3-pyridylmethyl) -pyrimidone and using the same molar proportions of reagents, receive (-imidazolyl) propylamino 5 Sz pyridylmethyl) -4-pyrimidone three hydrochloride, t.  square  208.5-212 ° and 2- [4- (5-methyl-imidazolyl) butylamino-5- (3-pyridylmethyl) -4-pyrimidone trihydrochloride, t.  square  , with 70 exit.  Example T4.  A solution of 3- (5-methyl-α-imidazolylmethylthio 1 propylamine (1, g) and 2-nitroamino-5- (pyridylmethyl) -β-pyrimidone (1.97 g) in pyridine is boiled under refluxing with a nickname of 20 hours, after which pyridine is removed by evaporation.  The residue is crystallized from ethanol containing hydrogen chloride, and then recrystallized from ethanol: methanol to give (5 methyl-imidazolylmethylthio) -5- (3-pyridylmethyl) - (- pyrimidone trihydrochloride, m.  square  233b.  Examples 15, 16, 17.  The use of the method of example 1 in the reaction of 2-itroamino-5- (3-pyridylmethyl) - + - pyrimidone with 1.1 molar equivalent of 2- (4-methyl-2-pyridylmethylthio) ethylamine, 4- (3-chloro- 2-pyridyl) butylamine and 2- (4-methoxy-2-pyridylmethylthio) ethylamine, respectively, are obtained: 2-G2- (4-methyl-2-pyridylmethylthio) ethylamino -5- (3 pyridylmethyl) -4-pyrimidone, m.  square  128-9 (example 15).  2- {4- (3-chloro-2-pyridyl) butylamino -5- (3-pyridylmethyl) -4-pyrimidone, t.  square  14b-7.5 {example 16).   (+ methoxy-2-pyridylmethylthio) ethylamino -5- (3-pyridylmethyl) -pyrimidone, m.  square -99-100 (example 17) "Example 18.  A mixture of 2- (3, -Dimethoxy-2-pyridylmethylthio) ethylamine (0.95 g, 4.16 mmol), 2-nitroamino-5 - (Z-pyridylmethylZ-pyrimidone (0.925 g, 3.74 mmol) and pyridine (3.5 ml) is refluxed for 24 hours and then evaporated to dryness.  The residue is purified on a column of silica | gel with elution with a mixture of methanol: chloroform (1: 7) and recrystallized from ethanol to give 2-C2- (3,4-dimethoxy-2-pyridylmethylthio) ethylaminOJJ-5- (3-pyridylmethyl) - 4-pyrimidone, m.  square  121-1.5 ° C.  Approx 19.  Using the method of Example 14, 2-nitroamino-5- (3 pyridylmethyl) -4-pyrimidone is reacted with 1.1 molar equivalent of 4- (3-amino-2-pyridyl) butylamine, to obtain )boo-.  tylamino -5- (3-pyridylmethyl) -4-pyrimidone, m.  square 130-1.5 p.  Example 20  While boiling under reflux for 16 hours, 2-nitroamino-5- (3-pyridylmethyl) pyrimidone in pyridine with 1.5 molar equivalent of 3-. (2-Thiazolyl) propylamine get (2-thiazolyl) propylamino-5 (3 pyridylmethyl) -4-pyrimidone, t.  square  168-172S.  Example 21  When applying the same.  molar equivalent of 2- (2-thiazolylmethylthio) ethylamine get 2-C2- (2-thiazolylmethylthio) ethylamino-5- (3-pyridylmethyl) -4-pyrimidone trihydrochloride, t.  square  178-180 ,, with 7b% yield.  Example 22  A solution of 4- (3-methoxy-2-pyridyl) butylamine (5.48 g) and 2-nitroamino-5- (6-methyl-3-pyridyl-.  methyl) -4-g1irimidone (7.95 g) in pyridine (200 ml) is refluxed for 18 h and evaporated to dryness.  The residue is extracted with warm propanol (200 ml) and the solution is acidified with hydrochloric acid.  The crystalline precipitate (10.83 g, 74%) is filtered off and recrystallized (3-marks 13 c-2-pyridyl) butylamino-5 (6-methyl-3 pyridylmethyl) -pyrimidone trihydrochloride (7.53 g), t.  square  .  Example 23  A mixture of 5 (5.6 pyridylmethyl) -2-nitroamino-4-pyrimidone and 1.1 molar equivalent of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is heated at 130 ° C for 5 hours, after which it is boiled with under reflux in ethanol for 12 hours, evaporated to dryness to obtain 2-G2- (5 methyl- | -imide 1zolylthio) ethylamino -5- (5,6-dimethyl 3-pyridylmethyl) -pyrimidone monohydrate, t.  square  115 ° (softening at Example 2M.  A mixture of 5- (5,6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone and 1.2 molar equivalent of 2- (3-bromo-2-pyridylmethylthio) -ethylamine is heated under reflux in ethanol 8 h, evaporated to dryness, get 2-12- (3-bromo-2-pyridylmethyl) ethylamino} -5- (5 6-dimethyl-3-pyridylmethyl) - -pyrimidone, t.  square  105-7 ° C.  Example 25  Equimolar amounts of 5- (5,6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone and k- (3-ethoxy-2-pyridyl) butylamine in ethanol are refluxed for 2 hours.  An additional 0.1 molar equivalent of amine is added and the mixture is heated under reflux for the next 2 hours.  After that, the mixture is evaporated to dryness, to obtain (3-methoxy-2-pyridyl) butylamino-5 (5 6 dimethyl-3-pyridylmethyl) - -pyrimidone dihydrate, t.  square  93-3 C Example 2b.  An equimolar mixture of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) 4-pyrimidone and 2- (5-me: ethyl-4-imidazolylmethylthio) ethylamine in ethanol is refluxed for 18 hours.  The solid precipitate formed upon cooling is recrystallized from ethanol to give (5-methyl-imidazolylmethylthio) ethylamino -5- (6-methoxy-3-pyridylmethyl) -pyrimidone, t.  square  197-8,5 ° with 63% yield.  Example 27: An equimolar mixture of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and 2- (2-thiazolylmethylthio) ethylamine in ethano) is boiled under reflux for 18 hours.  The solid precipitate which is formed upon cooling and recrystallized from ethanol gives (2-thiazolylmethylthio) ethylamino} -5- (6-methoxy-3 pyridylmethyl) -pyrimidone, t.  square  , with 60% yield.  28 and 29. When boiling under reflux for 18 h, 2-nitroamino-5- (2-methoxy-A-pyridylmethyl) -pyrimidine with equimolar amounts of 2- (5-methyl-4-imidazolylthio) ethylamine and 2- (2-thiazolylmethylthio) ethylamine, respectively, are obtained (5-methyl-4-imidazolylmethylthio) ethylamino -5- (2-methoxy- -.  -pyridylmethyl) -pyrimidone, t.  square  117-8 (Example 28), and 2-12- (2-thiazolylmethylthio) ethylamino-5- (2-methoxy-pyridylmethyl) - | - pyrimidone, t.  square  105.5-6.5 (Example 29).  Example 30  A mixture of 2- (2-thiazolylmethylthio) ethylamine (2.0 g) and 2-nitroamine-5- (3-methoxybenzyl) -pyrimidone (1.58 g) is heated for k h at 130 ° C.  The mixture is then triturated with hot water and the precipitate is recrystallized from 2-propanol to give 2-G2- (2-thiazolylmethylthio) ethylamino-5- (3-methoxybenzyl) -pyrimidone (0.93 g), t.  square  122-4).  The sample is treated with a solution of hydrogen chloride in ethanol and, after recrystallization from isopropanol-methanol mixture, the product is obtained with t.  square  , and its analytical data correspond to hemihydrate.  Example 31  2-Nitroamino-5- (3, t, 5-trimethoxybenzyl) -pyrimidone (L2 g) and 2- (5-methyl-4-imidazolylmethylthio) -ethylamine (0.65 g) are heated at 130-5 ° 12 h.  After cooling, the mixture is washed with hot water and after treatment with a solution of chloro chloride in ethanol, followed by recrystallization from ethanol, 2- f2- (5-methyl-4-imidazolylmethylthio) ethylamino-5- (3, 5-trimethoxybenzyl) -4-pyrimidone dihydrochloride is obtained , t  square  171- °.  Example 32  A mixture of 2- (5-methyl-α-imidazolylmethylthio) ethylamine (1.5 g), 2-nitroamino-5-G5- (1, 3-benzodioxo-yl) methyl 3-pyrimidium (2.5 g) and ethanol (20 ml) boil under reflux h.  A solution of hydrogen chloride in ethanol is added to the hot solution, while cooling (5-methyl - + - imidazolylmethylthio) ethylamino-5- (5- (1, 3-benzodioxolyl) methyl -4-pyriMidon dihydrochloride (2.2 g) crystallizes , this product is dissolved in water, the solution is adjusted to pH 8 with aqueous 15-3 i5Q f sodium bicarbonate solution, and then the free base is filtered off.  This free base is recrystallized from ethanol containing hydrogen chloride to obtain a sample of the dihydrochloride with m.  square  2326 ° C.  - measures 33.  A mixture of 2-nitroamino-5 C5 (2.3 digidro-1.  -benzodioxinyl) -methyl-β-pyrimidone (3.0t g) 10 2- (5-methyl-4-imidazolylmethylthio) ethylaminses (1.92 g) and ethanol (20 ml) are refluxed for 21 hours, after which is evaporated to dryness, the residue is washed with hot water, re-15 is twice crystallized from ethanol containing hydrogen chloride, get 2G2 (5 methyl-A-imidazolylmethylthio) ethylamino 5-1b- (2,3-dihydro, 4-benzodioxinyl) methyl -4-pyrimidone dihydro aryrochloride, t.  square  210-13 °.  EXAMPLE  The interaction of 2 (5-methyl-imidazolylmethylthio) ethylamine 14a with equimolar amounts: 2-nitroamino-5 (4 methoxy-2-pyridylmethyl} -4 pyrimidone, 2-nitroyl-5- (2-furylmethyl) -4- pyrimidone and 2-nitroamino-5- (1-naphthylmethyl) -4-pyrimidone gives (5-methyl-4-imidazolylmethylthio) ethyl-amino-5 (4 methoxy-2-pyridylmethyl) - respectively.  -4-pyrimidone (example 3), 2-G2- (5-methyl 4-imidazolylmethylthio) ethylamino 5 (2-furylmethyl) -pyrimidone (example 35) and 2-G2- (5-methyl-4-imidazolyl-3 methylthio) ethylamino-5 (1-naphthylmethyl 4-pyrimidone, made in the form of dihydrochloride, t.  square  228-230 (example 36).  Claim 1.  Way Derivatives of 2-aminopyrimidone derivatives of the general formula L-HN () y (CHe) iv where Het is unsubstituted imidazolyl or substituted by alkyl C Cd. , 2-g1Iridyl, substituted by j amino group, halogen.  The path where with HN where, at C, the progress is general pei 2 nd day of 3 hours of water (5th more prince J of cl.  (ordinary or several alkoxy groups with 1 - carbon atoms, or 2-thiazolyl, w - O or 1, Y - methylene or sulfur, n - 2 or 3, B - furyl, naphthyl, 6- (2,3- dihydro 1, A-benzodioxinyl), 5 (1,3 benzodioxolyl), unsubstituted pyridyl or substituted by one or more alkyls or alkoxyls, in which alkyl, or phenyl, substituted by one or more alkoxyls with 1-4 carbon atoms,.  m interaction of 2-substitution of midone-general formula H aL.  B has the indicated value, the other general formulas e1- (CI) (CH), 11H, (III) Het-, III, Y and p have the indicated values, by heating, which is different from that, to increase the target product, a pyrimidone derivative of the formula (C), and the process is carried out 80-140 C.  . The method according to claim.  1, that is, with the fact that the process is ethanol, n-propanol or pyri-process: during boiling.  . The method according to paragraphs.  1 and 2, distinguished by the fact that the process is using an excess of the amine of formula (P1).  Sources of information that are taken into account in the examination.  Application For Germany If 2658267, C 07 D OZ / T, published.  1977 totip).
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    同族专利:
    公开号 | 公开日
    AU4571479A|1979-10-18|
    AU527202B2|1983-02-24|
    MY8500703A|1985-12-31|
    IL57005A|1983-11-30|
    IE790364L|1979-10-11|
    EP0004793A2|1979-10-17|
    PT69464A|1979-05-01|
    IT1118476B|1986-03-03|
    DE2961652D1|1982-02-18|
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    SU906376A3|1982-02-15|
    PL117998B1|1981-09-30|
    ES479469A1|1979-07-16|
    RO76810A|1981-05-30|
    CS210684B2|1982-01-29|
    ATA267079A|1983-04-15|
    PL214792A1|1980-03-24|
    IE48080B1|1984-09-19|
    DD142878A5|1980-07-16|
    PL118404B1|1981-10-31|
    HU180081B|1983-01-28|
    JPS54138580A|1979-10-27|
    KR820002136B1|1982-11-15|
    US4523015A|1985-06-11|
    YU84179A|1983-04-30|
    GR66986B|1981-05-15|
    CY1194A|1983-12-31|
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    NO791225L|1979-10-12|
    EP0004793B1|1981-12-30|
    CA1138453A|1982-12-28|
    EP0004793A3|1979-11-28|
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    DK147379A|1979-10-12|
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    NZ190122A|1982-03-09|
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    优先权:
    申请号 | 申请日 | 专利标题
    GB1404978|1978-04-11|
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