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    • 专利摘要:
    The pyrimid-4-one derivatives of the general formula I, in which the symbols have the meaning given in Claim 1, as well as the corresponding pyrimid-4-thione derivatives, are valuable drugs which possess activity both as histamine H1 antagonists and as histamine H2 antagonists. They are prepared by reacting an isocytosine derivative of the formula II, in which Q represents a reactive radical which is displaced by an amine during the reaction, with an amine of the formula III. The compounds thus obtained are converted into the corresponding pyrimid-4-thione derivatives by reaction with phosphorus pentasulphide. <IMAGE>
    公开号:SU791235A3
    申请号:SU762434655
    申请日:1976-12-29
    公开日:1980-12-23
    发明作者:Генри Браун Томас；Джон Дюрант Грэхэм；Робин Ганеллин Чарон
    申请人:Смит Клайн Энд Френч Лабораториз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of pyrimidone-4 derivatives of the formula MLSLu e-C // ty- {cf /) where Het is a 4-imidazole ring, a 2-pyridyl ring possibly substituted by a Cjf-C 4 alkyl, possibly replaced by a lower Cj-C - alkyl, - alkoxy or halogeno or 2-thiazolyl ring, U - sulfur atom or methylene group, 2 hydrogen atom or - alkyl, Het - thienyl, pyridyl or thiazolyl possibly substituted by lower alkyl lower alkoxy group or condensed with a benzene ring, which possess biological activity. A known method for producing amino derivatives of pyrimidine compounds by the interaction of chloropyrimidines with amino compounds 1J. The aim of the present invention is to obtain new pyrimidone-4 derivatives, which can be used biologically as axTHBHtax compounds. This goal is achieved by the method of obtaining compounds of formula (I), which consists in the fact that the isocytoinin formula "A Wi. where Het and Z are as defined above, d is an alkyl-thio, benzylthio group or halogen, and is reacted with an amine of the formula t ti-CHt-y- (CHt) f- / fH, where Het and Y have the meanings given by -BVsaK. The process is preferably carried out in a solvent, for example, pyridine. Example 1. (5-Methyl-4-imidazolylmethylthio) -ethylamino-5- (4-pyridylmethyl) -pyrimidone-4 hydrochloride. 1J To a stirred mixture of sodium wire (5.6 g) and dry ether (150 ml) cooled in a bath with
    (because} with ice and salt, (4-pyridyl) propionate (43.45 g) and ethyl formate (19.6 g) b are added. The mixture is stirred for 18 hours at room temperature, evaporated to dryness, and the residue They are treated with thiourea (18.45 g) and ethanol (130 ml) and heated under reflux for 7 hours. Smeg is evaporated to dryness, the residue is dissolved in water, and the solid is precipitated by adding glacial acetic acid to pH 4. White solid particles washed with ethanol to obtain 5- (4-pyridylmethyl) -2-thiouracil, mp 320-324 ° C, decomp.),
    2J A solution of 5- (4-pyridylmethyl) -2-thioyracil (11.0 g) of methyl iodide (7.2 g) and sodium hydroxide (2.1 g) in water (50 ml) and ethanol (100 ml) is stirred at 60 ° C for 30 minutes, gradually cooled and filtered to obtain 5- (4-pyridylmethyl) 2-methylthiopyrimidone-4, mp 179-182 s (ethanol).
    3) A thoroughly mixed mixture of 5- (4-pyridylmethyl) -2-methylthiopyrimidone-4 (5.9 g) and 2- (5-methyl) -4-imidazolylmethylthioethylamine (4.3 g) is heated at 155-150 ° C 5 h and gradually cooled. The residue is triturated with water and treated with an ethanolic solution of hydrogen chloride to obtain the compound indicated in the preparation, m.p. 228-233 S.
    Example 2. Hemihydrate trichlorohydrate (2-thiazolylmethyl) ethylamino-5- (4-pyridylmethyl) -pyramidone-4.
    A thoroughly mixed mixture of 5- (4-pyridylmethyl) -2-methylthiopyrimidone (1.55 g) and 2- (2-thiazolylmethylthio) -ethyl amine (1.16 g) is heated at 135-140 ° C with frequent: stirring .; After cooling, the reaction mixture is triturated in water, acidified with a dilute solution of hydrogen chloride in ethanol, evaporated to dryness, and the residue is recrystallized from methanol to obtain the specified compound, m.p. IQO-igS C.
    Example 3. (3-Bromo-2-pyridylmethylthio) -ethylamino 3-5- (4-pyridylmethyl) -pyrimidone-4 dihydrochloride.
    5- (4-Pyridylmethyl) -2-methylthiopyrimidone-4 (1.1 g) reacts with 2- (3-bromo-2-pyridylmethylthio) -ethylamine (1.15 g) according to example 2. The reaction mixture is triturated with hot water, acidified with a dilute solution of hydrogen chloride in ethanol, evaporated to dryness, and the residue is recrystallized from ethanol to give the title compound, mp 211215 ° C (dec.) .Of
    Example 4. (5-Methyl-4-imidazolylmethylthio) -ethylamine 1-5- (2-thienylmethyl) -pyrimidone-4 dihydrochloride.
    1) Ethnl-2-thienyl program (33.3 g ethyl formate (14.1 i) and sodium (4.2 g react in ether (120 ml) while cooling the mixture in a bath with a mixture of salt and ice. Ether is removed evaporation and the residue is refluxed with thiourea
    (13.8 g) and ethanol (100 ml). Ethanol is removed by evaporation, and the residue is dissolved in water, acetic acid is added, which results in the precipitation of 5- (2-thienylmethyl) -2-thiouracil (38%), m.p. 212-215 ° C (ethanol).
    2) 5- (2-Thieni; 1methyl) -2-thiouracil (4,5) is heated at 65 s with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8 and), water (75 ml) and ethanol (150 ml), which results in 5- (2-thienylmethyl) -2-methylthiopyrimidone-4 (89%), so pl. 170.5-171.5 s (ethanol).
    3) A positively mixed mixture of 5- (2-thienylmethyl) -2-methylthiopyrimidone-4 (1.43 g) and 2- (5-methyl-4-imidazolylmethylthio) -ethylamine (1.03 g) is heated at 140 ° C 6 The cooled residue is spilled up to the doda and treated with a dilute ethanolic solution of hydrogen chloride to give the compound in 40% yield, m.p. 172-17 bs (ethanol-acetonitrile). Dichlorohydrate is passed from top to bottom through a 1PA 400 ion exchange resin, eluted with 1N hydrochloric acid, the eluate is evaporated to dryness and recrystallized from ethanol / acetonitrile to give the corresponding dibromohydrate, mp. 199-203 ° C.
    Example 5. Hemihydrate trichlorohydrate of 2- 2- (5-methyl-4-imidazolylmethylthio) -ethylamino-5- (2-pyridylmethyl) -pyrimidone-4.
    1) Ethyl Jb-2- (pyridyl) propionate (19.24 g) is added to a stirred mixture of sodium wire (2.5 g) and dry ether (80 ml) cooled in a carbon dioxide bath.
    and ethyl formate (8.5 g). The mixture is stirred for 21 hours at room temperature, evaporated to dryness, the residue is treated with thiourea (8.2 g) and ethanol (70 ml) and boiled under reflux for 7.5 hours. The mixture is evaporated to dryness, and the residue is dissolved in water, added acetic acid is added to pH 5. The white precipitate is filtered, taken with water and recrystallized from a mixture of water and acetic acid to obtain 5- (2-pyridylmethyl) -2-thiouracil, m.p. -262-7 with (with decomposition.).
    2) A solution of 5- (2-pyridylmethyl) -2-thiouracil (6.6 g) of methyl iodide (4.3 g) and sodium hydroxide
    (2.5 g) in water (100 ml) and ethanol (100 ml) is stirred at 70 ° C for 30 minutes, gradually cooled and glacial acetic acid is added to
    pH 5. The solution is partially evaporated and cooled in an ice bath. The precipitate is filtered off and recrystallized from ethanol to obtain 5- (2-pyridylmethyl) -2-methylthiopyrimidone-4, so pl. 195-197 ,.
    3) A thoroughly mixed mixture of 5- (2-pyridylmethyl) -2-methylthiopyrimidone-4 (4.7 g) and 2- (5-methyl-4-imidazolylmethylthio) -ethylamine (3.4 g) is heated at 130-135s 7 parts. The cooled residue is triturated with a diluted ethanolic solution of hydrogen chloride to obtain the title compound, m.p. 207-210 ° C (aqueous ethanol).
    Example 6. 2-f2- (5-methyl-4-imidazolylmethylthio) -ethylamino-5- (3-pyridylmethyl) -pyrimidone-4 trichlorohydrate.
     1) Ethyl (3-pyridyl) propionate (38.9 g) is added to a stirred mixture of sodium wire (5.0 g) of dry ether (150 ml) cooled in an ice bath for more than 2.5 hours. and ethyl formate (17.0 g). The mixture was stirred for 22 hours at room temperature, evaporated to dryness, and the residue was treated with thiourea (16.5 g) and ethanol (130 ml) and heated to reflux for 8 hours. The mixture was evaporated to dryness, the residue was dissolved in water and added with acetic acid. acid to pH 5, to obtain 5- (3-pyridylmethyl) -2-thiouracil, so pl. 271 ± 4s (with dec., Acetic acid, water).
    2) A solution of 5- (3-pyridylmethyl) -2-thiouracil (11.0 g), methyl iodide (7.1 g) sodium hydroxide (4.2 g) in water (150 ml) and ethanol (15-0 ml ) stirred at
    40 minutes, gradually cool and add acetic acid to pH 5. The solution is partially evaporated, cooled and filtered to obtain 5- (3-pyridylmethyl) -2-methylthiopyrimidone-4, mp 247–9 ° C (excess ethanol — acetic acid) .
    3) A thoroughly mixed mixture of 5- (3-pyridylmetl l) -2-methylthiopyrimidone-4 (6.55 g) and 2- (5-methyl-4-imidazolylmethylthio) -ethyls (4.8 g) is heated at 130- 135 C 7 h. The cold mixture is triturated with hot water and treated with a dilute solution of hydrogen chloride in ethanol to give the title compound, m.p. 234-241 ° C (ethanol water).
    Example 7. 2- 2- (3-bromo-2-pyridylmethylthio) -ethylamino-5- (2-pyridylmethyl) -pyrimidone-4 tribromhydrate.
    Carefully stirred mixture of 5- (2-pyridylmethyl) -2-methylthiopyrimidone-4 (1.5 g) and 2- (3-bromo-2-pyridylmethylthio) -ethylamine (1.6 g) is heated at in b h. After cooling
    The residue is triturated with hot water and treated with dilute hydrobromic acid to obtain the indicated compound with a yield (44.5%), mp 225-230 s (with decomposition, an excess of methanol is water).
    Example 8. 2- 1,2- (5-methyl-4-imidazolylmethylthio) -ethylamino-3- 5- (2-thiazolylmethyl) -pyrimidone-4 trichlorohydrate.
    1) A solution of 2-thiazolacrylic acid (26.76 g) and concentrated sulfuric acid (10 ml) in ethanol (150 ml) is refluxed for 18 hours. The solution is partially evaporated with BcUOT and dissolved in water. The resulting solution is extracted with ether, and the ether extracts are evaporated to give 2-thiazol-acrylic acid ethyl ester.
    2) Ethyl 2-thiazolacrylate (14.8 g) is dissolved in ethanol (170 ml) and hydrogenated under pressure.
    50 psi (3.51 kgf / cm) using 10% palladium x carbon, resulting in ethyl 2-thiazolyropionate.
    five
    3) To a stirred mixture of sodium prsevoloki (1.8 g) and dry ether
    (65 ml), cooled in an ice bath, ethyl 2-thiazol propionate was added
    (14.2 g) and ethyl formate (5.9 g) for more than 2.5 hours. The mixture is stirred for 21 hours at room temperature, evaporated to dryness, the residue is treated with thiourea (5.8 g) and ethanol (60 ml), and boil with a reverse chiller for 9 h. A solid is obtained as in Example 5 (1), which results in 5- (2-thiazolmethyl) -2-thioiracyl, m.p. 275-280 ° C (with decomp., G. Acetic acid).
    4) A solution of 5- (2-thiazolmethyl) -20-thiouracil (4.8 g) of methyl iodide
    (3.0 g) and sodium hydroxide (0.9 g) in water (76 ml) and ethanol (150 ml) are stirred at 70 ° C for 30 minutes. Get a solid product from example 5 (2),
    5 from which 6- (2-thiazolmethyl) -2-methylthiopyrimidone-4 is obtained, m.p. 181-282, (excess ethanol).
    5) A thoroughly mixed mixture of 5- (2-thiazolmethyl-2) -methylthiopyrimide0-4 (1.4 g) and 2- (5-methyl-4-imidazolylmethylthio) -ethylamine (1.0 g) is heated at 145-150 From 6 hours. The cooled residue is triturated with hot water and treated with diluted
    5 ethanolic hydrogen chloride solution to obtain the specified compound, so pl. 208-21lc (excess ethanol-water).
    Example 9. Tribromhydrate (2-thiazolylmethylthio) -ethyla0 No2-5- (3-pyridylmethyl) -pyrimidone-4.
    The reaction is carried out with 5- (3-pyridylmethyl) -2-methylthiopyrimidone-4 (1.74 g) with 2- (2-thiazolylmethylthio) ethylamine (1.30 g) according to Example 2. Reaction
    5 the mixture is dissolved in hot water and treated with dilute hydrobromic acid to obtain the indicated compound, m.p. 229233, (excess methanol-water). Example 10. Tribromhydrate (3-bromo-2-pyridylmethylthio) -ethylamino 3-5- (3-pyridylmethyl) -pyrimidone-4. 5- (3-Pyridylmethyl) -2-methylthiopyrimidone-4 is reacted (1.27 g with 2- (Z-bromo-2-pyridylmethylthio) -ethyl amine (1.35 g) of Example 2. The reaction mixture is triturated with gher whose water and treated with dilute hydrobromic acid to obtain the specified compound, so pl., 217-220, (excess methanol). Found: C 31.1; H 3.2 / N 10.2 54.5; Br47 , BrNgOS-HBg Calculated,% (for C-dN-c): C 32.0, H 3.1, N 10.4; S 4.8 / g: 47.4. Example 11. Instead of - ( 4-pyridyl) propionate according to example 1 uses ethyl-} b- (2-methoxy-3-pyridyl) -propionate, methyl- | b- (3-methoxy-2-pyridyl) -propionate, ethyl-p - ( 3,4-dimethyl oxy-2-pi idyl) propionate, ethyl- - (3-quinolyl) -propionate, ethyl- (% - (4-isoquinolyl) -propionate, and get, respectively, 2- 2- (5-methyl-4-imidazolylmethylthio) -ethylamino - 5- (2-methoxy-3-pyri dilmethyl) -pyrimidone-4, 2- 2- (5-methyl-4-imidazolylmethylthio) -ethyl snoZ-5- (3-methoxy-73-pyr dilmethyl) -pyrimidone-4, 2 - 2- (5-methyl-4-imidazolylmethylthio) -ethylamino -5- (3,4-dimethoxy-2-pyridylmethyl) -pyrimidone-4, (5-methyl-4-ymidazolylmethio) -ethylamino -5- ( 3-quinolylmethyl) -pyrimidone-4, (5-methyl-4-imidazolylmethylthio) -ethylamino J-5- (4-isoxynolylmethyl) -pyrimidone-4. The starting compounds can be obtained from the corresponding aldehydes of heterocyclic carboxylic acids by condensing them with malonic acid and subsequent processes of hydrogenation and esterification. Example On. Replacing 2- (3-methoxy-2-pyridylmethylthio) -ethylah on 2- (3-chloro-2-pyridylmethylthio) -ethylamine, 2- (3-fluoro-2-pyridylmethio-thio) ethylamine, 2- (3- iodo-2-pyridylmethylthio) -ethylamine instead of 2- (5-methyl-4-imidazolylmethylthio) -ethylamine of example 6 results in 2- 2- (3-methoxy-2-pyridylmethylthio) -ethyls1-MinoZ-5- (3-pyridylmethyl ) -pyrimidone-4, so pl. 155.-156 ,, 2- 2- (3-chloro-2-pyridylmethylthio) -ethylamino -5- (3-pyridylmethyl) -pyri midon-4, T..Sh1. 134-135,5 C, 2- (3-fluoro-2-pyridylmethylthio) -ethylamino -5- (3-pyridylmethyl) -pyrimidone-4, so pl. 107.5-109.5 ° C, 2- 2- (3-iodo-2-pyridylmethylthio) -ethylamino -5-, (3-pyridylmethyl) -pyrimidone-4, so pl. 111.5-113.5 ° C. Example 12. 1) Reaction of 2-chloro-3-nitropyridine with 2- (2-cyanoethyl) -malonic acid diethyl ether and sodium hydride in tetrahydrofuran results in 1- (3-nitro-2-pyridyl) -1,1- Bis (carboxy) butyronitrile, so pl. 93,594, which after hydrolysis in an alkaline medium and acidification forms 2- (3-cyanopropyl) -3-nitropyridine hydrochloride, m.p. 142-145 ,. Reduction with hydrogen in the presence of palladium gives 3-amino-2- (3-cyanopropyl) -pyridine, and treating the latter with sodium nitrate and sulfuric acid, followed by heating, results in 2- (3-cyanopropyl) -3-oxypyridine. Methylation with ppm methyl and sodium ethylate in dimethyl sulfoxide and the subsequent reduction with lithium aluminum hydride results in 4- (3-methoxy-2-pyridyl) -butylamine. Reduction of 3-amino-2- (cyanopropyl) -3-hydroxypyridine with lithium aluminum hydride results in 4- (3-amino-2-pyridyl) -butylamine. Diazotization of 4- (3-amino-2-pyridyl) -butylamine at pH 1 and treatment with copper chloride or bromide with copper results in 4- (3-chloro-2-pyridyl) -butylamine and 4- (3-bromo- 2-pyridyl) butylamine. 2) Replacing 2- (5-methyl-4-imidazolylmethylthio) -ethylamine in example b with 4- (4-imidazolyl) -butylamine and 4- (3-methoxy-2-pyridyl) -butylamine results in 2-4- (4-imidazolyl) -butylaminno} -5- (3-pyridylmethyl) -pyrimidone-4, so pl. 144-145 s, 2- 4- (3-methoxy-2-g (iridyl) -butylamino {-5- (3-pyridylmethyl) -pyrimidone-4, mp 117-118 ° C. Example 13. Reaction acetoacetic acid ethyl ester and 3- (chloromethyl) -pyridine results in o1- (3-pi. redylmethyl) -acetoacetic acid ethyl ester, which forms 5- (3-pyridylmethyl) -6-methyl-2-thioiracyl, mp 332335 C, in the processing of thiourea and sodium ethoxide. Replacing 5- (3-pyridylmethyl) -b-methyl-2-thiouracil with 5- (4-pyridylmethyl) -2-thiouracil in Example 1 results in 2- 2- (5-methyl-4-imidazolylmethylthio) -ethylamino -5- (3-pyridylmethyl) -6-methylpyrimidone -4, mp 128-13l C, 5- (3-pyridylmethyl) -6-methyl-2-methylthiopyrimidone-4, mp 208-211 ° C.
    Example 14. Trichlorohydrate (5-methyl-4-imidaeolylmethylthio) -ethylamino-5- (3-quinolylmethyl) -pyrimidone-4.
    1) A solution of 3-quinolyl acrylic acid (63.71) and concentrated sulfuric acid (25 ml) in ethanol
    (350 ml) is refluxed for 18 hours. The product obtained according to Example 8 (1) gives 3-quinolyl acrylic acid ethyl ester, m, pl. 86, (from a mixture of ethanol and water). Found,%: C 73.8; H 5 "B; N 6.2.
    Calculated,%: C 74.0; H 5.8, N 6.2
    2) 3-Quinolyl acrylate (51.68 g) is dissolved in ethanol (170 ml) and hydrogenated at 37 s and under pressure
    50 psi (3.5 kgf / cm) using 10% palladium carbon and get 3-quinoline propionic acid ethyl ester.
    3) to the stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) while cooling with ice, add 3-quinoline propionate acid ethyl ester for more than 3 hours
    (47.99 g) and ethyl formate (16.3 g). The mixture was stirred for 20 hours at room temperature, evaporated to dryness, and the residue was treated with thiolucine (15.9 g) and ethanol (130 ml) and heated to reflux for 7 hours. The mixture was evaporated to dryness, and the residue was dissolved in water and acetic acid added to pH 4. The mixture is filtered to obtain 5- (3-quinolmethyl) -2-thiouracil, m.p. 281286 ° C (dec, from a mixture of acetic acid and water).
    4) A solution of 5- (3-quinrylmethyl) -2-thiouracil (17.51 g) of methyl iodide (9.2 g) and sodium hydroxide (5.4 g in water (200 ml) and ethanol (200 ml) is stirred at 75 With 1 h, gradually cooled and acetic acid is added to pH 4 to obtain 5- (3-kinolmethyl) -2-methylthiopyrimidone-4, t, mp 215.5-218 ° C (from ethanol).
    5) Mix thoroughly.
    5- (3-quinolmethyl) -2-methylthiopyrimidone-4 (2.1 g) and 2- (5-methyl-4-imidazoylmethylthio) -ethylamine (1/3 g) are heated at 150-155 C b h. The cooled mixture triturated with hot water and treated with a dilute ethanolic solution of hydrogen chloride to obtain the indicated compound, m.p. 184-189 C (from a mixture of ethanol and water).
    Example 15. 2- 12- (2-thiazolylmethylthio) -ethylaminoZ-5- (3-quinolylmethyl) -pyrimidone-4 trichlorohydrate.
    Carefully stirred mixture of 5- (3-quinolmethyl) -2-methylthio-4-pyrimidone (2.0 g) and 2- (2-thiazolylmethylthio) -ethyl amino (1.2 g) is heated at 4 hours. After cooling, the residue is triturated with hot water and treated with a dilute ethanolic solution of hydrogen chloride to obtain the title compound, mp. 217, 5-221,5C Giz mixture of ethanol and water).
    Found,%: C 45.9, H 4.3, N 13.3 / S 2.2; C1 19.7.
     , -NS
    Calculated: C 46,3; H 4.3 / N 13.5 / S 12.4; C1 20.5.
    Example 16. 1) 2- (6-Methyl-3-Pyridyl) -acrylic acid, m.p. 213-213.5C obtained by condensation of 6-methylpyridine-2-carboxaldehyde with malonic acid in pyridine with a piperidine catalyst, and transformed into the corresponding ethyl ester, so pl. 36-37, which is reduced to obtain ethyl-3- (6-methyl-3-pyridyl) propionate (oil),
    2) Treatment of ethyl-3- (6-methyl-3-pyridyl) propionate with sodium and ethyl formate in example 1 gives 5- (6-methyl-3-pyridylmethyl) -2-thiouracil, mp.240-241 0, which transform H 5- (b-methyl-3-pyridylmethyl) -2-methylthio-4-pyrimidone, mp 19 7-19 8.5 ° C
    5 in example 1.
    3) Treatment of 5- (6-methyl-3-pyridylmethyl) -2-methylthio-4-pyrimidone 2- (5-methyl-4-imidazolylmethylthio) -ethylamine, 2- (2-thiazolylthio) -ethylamin, 2- ( 3-bromo-2-pyridylmethylthio) -ethylamine, 4- (5-methyl-4-and 1 -dazolyl) butylamine, 4- (3-methoxy-2-pyridyl) butylamine, 4- (3-chloro-2-pyridyl) butyl Mr., 4- (2-pyridyl) butylamine,
    5 4- (3-ethoxy-2-pyridyl) butylamine
    according to Example 1, gives 2 -2- (5-methyl-4-imidazolylmethylthio) ethylamino -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 210-214 ° C,
    0
    2- 2- (2-thiazolylmethylthio) ethylamino -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 187-190s,
    2- 2- (3-bromo-2-pyridylmethylthio) 5 ethylamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride, so pl. 193-196 С,
    2- 4- (5-methyl-4-imidazolyl) butylamino J-5- (6-methyl-3-pyridylmethyl) 0 -4-pyrimidone trihydrochloride, m.p. 189-190 s,
    (3-methoxy-2-pyridyl) butylamino} -5- (6-methyl-3 pyridylmethyl) -4-pyrimidone trihydrochloride, so pl. 5 209-210 ° С
     (3-chloro-2-pyridyl) butyl amino 3-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone isolated as a free base, m.p. 132-133 C, 0 (2-pyridyl) butylamino} -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone, isolated as a free base, m.p. 156.5-157.5 s,
    2- 4- (3-ethoxy-2-pyridyl) butyl5 amino -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone, isolated as a free base, m.p. 104-105c.
    EXAMPLE 17: 1) A mixture of ethyl formate (111 g) and 2-butanone (108 g) is added dropwise to a stirred mixture of sodium hydride in oil (50 wt.%, 72 g) and the mixture is kept in over night Ether (800 ml) was added and the solid (101 g) was filtered off. Cyanoacetamide (69.5 g), piperidine acetate, obtained by adding piperidine to acetic acid (7 ml) and water (18 ml), are added to the solid until the mixture is alkaline, and the mixture is heated under reflux for 2 hours. With a subsequent cooling. The mixture is acidified with acetic acid and the solid that has precipitated is recrystallized from aqueous ethanol to give 3-cyano-5, b-dimethyl-2-hydroxypyridine (43.5 g).
    2} A finely divided mixture of 3-cyano-5, b-dimethyl-2-hydroxypyridine (42 g) and phosphorus pentachloride (81 g) is heated for 2 hours at 140-160 ° C. Phosphoryl chloride is removed by distillation under reduced pressure and to the residue
    added water (500 g). The mixture was adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extracts are evaporated to an oil which is crystallized from petroleum ether (so-called boiling point BO-C0 C) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g), so pl. 83-87 ° C.
    3) A mixture of 2-chloro-3-cyano-5, -6-dimethylpyridine (21.5 g), semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol ( 475 ml) is subjected to hydrogenation at 50 psi (3.52 kgf / cm) temperature using Rane’s coated Nickel catalyst.
    (5 g). The mixture was added to water (750 ml) and filtered. The filtered solid is suspended in water (130 ml), concentrated hydrochloric acid (70 ml) is added and the mixture is heated at 100 ° C for 1 h, formalin (40% by weight, 120 ml) is added and the mixture is heated at 1/2 h and then allow it to cool. Sodium acetate (95 g) and water (250 ml) are added, the mixture is extracted with ether and the extract is washed with 5% aqueous potassium carbonate followed by evaporation to give 2-chloro-5, b-dimethyl-pyridine carboxaldehyde (13.24 g , 60%), so pl. 69-70 C.
    4) A mixture of 2-HLOR-5,6-dimethyl-3-pyridine-carboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) is heated under reflux to 1 h and evaporated to an oily product. This oil is a solution of Yu-g
    B 2 and, sodium hydroxide solution, and extracted with chloroform (discarded). The aqueous phase is acidified with hydrochloric acid and extracted with chloroform. The chloroform extracts are washed with water and evaporated to give 3- (2-chloro-5,6-dimethyl-3-pyridyl) acrylic acid (18.3 g, 87%), so pl. 150-158 ° C. This acid is esterified with ethanol and sulfuric acid to give ethyl ester, so pl. 85-88 C.
    5) Ethyl-3- (2-ChLOR-5,6-dimethyl-3-pyridyl) acrylate (32.7 g) in ethanol (500 ml) is subjected to hydrogenation at 25–30 ° C and 50 psi
    (3.52 kgf / cm) using palladium on charcoal as a 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 is alkalinized with aqueous sodium hydroxide, extracted with chloroform, and the chloroform extracts are evaporated to give ethyl 3 - (5, b-dimethyl-3-pyridyl) propionate
    (21.8 g, 80%) as an oil.
    6) The reaction of ethyl-3- (5,6-dimethyl-3-pyridyl) propionate with ethyl formate and sodium hydride in dimethoxyethane according to example 14 gives 2- (5,6-dimethyl-3-pyridyl) -2-formylpropionate, t mp 148-149 ° C. Sequential treatment of this ester with thiourea and methyl iodide of Example 1 gives 5- (5,6-dimethyl-3-pyridylmethyl) -2-methylthio-4-pyrimidone, and the reaction of this compound with 2- (3-bromo-2-pyridylmethylthio) ethylaIno at 140c for 6 h gives (3-bromo-2-pyridylmethylthio) ethylamino -5- (5,6-dimethyl-3-pyridylmethyl) -4-pyrimidone, 105-107V.
    Example 18. 1) 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) are treated by hydrogenation at 50 psi
    (3.52 kgf / cm2) about the use of skeletal nickel catalyst Rache
    (1.0 g) The mixture was evaporated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand overnight. The mixture is filtered, the solid is filtered with water and dissolved in hydrochloric acid (1000 ml). The formaldehyde solution (36%, 450 ml) is added, the mixture is heated for 15 minutes, cooled and added to a solution of sodium acetate
    (298.5 g) in water (900 ml). This mixture is extracted with ether (3 500 ml), the combined extracts are successively washed with aqueous potassium carbonate and water, dried and evaporated to give 6-methoxypyridine-3-carboxald. (31.5 i-, 60%), so pl. 48-43c.
    2) A mixture of b-methoxypyridine-3-carboxaldehyde (2.34 g), monoethyl malonate (4.51 g), pyridine (12 MJS) and piperidine (6 drops) is heated under reflux for 5 hours and evaporated to an oily product. The oil is partitioned between ether and dilute aqueous ammonia. The ether layer is washed with water and evaporated to an oil, which is crystallized by settling to obtain ethyl-3-. (b-methoxy-3-pyridyl) acrylate (2.8 g, 79%), so pl. 49-52c
    3) Ethyl-3- (b-methoxy-3-pyridyl) acrylate (32.33 g) in ethanol (160 ml) is hydrogenated at 50 psi (3.52 kgf / cm) and using a catalyst - palladium on coal (5%, 0.2 g). The mixture is filtered and the filtrate is evaporated to give ethyl-3 (6-methoxy-3-pyridyl) propionate
    (32.7 g) in the form of oil.
    4) A mixture of ethyl 3- (6-methoxy-3-pyridyl) propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over 1.5 hours to a stirred suspension of sodium hydride in oil ( 50%, 9.38 g) and 1,2-dimethoxyethane
    (50 ml), cooled to -2 ° C, incubated overnight at room temperature and poured onto ice. The mixture is extracted with ether (discarded) and the aqueous phase is adjusted to pH b by the addition of 2N sulfuric acid. The oil is planted and crystallized upon exposure to the preparation of ethyl 2-formyl-3- (b-methoxy-3-pyridyl) propionate (25.9 g, 70%), mp. 91.5-94 ° C. The sample recrystallized from aqueous ethanol has a mp. 93-94c.
    Sequential treatment of this ester with thiourea and methyl iodide according to Example 1 gives 5- (b-methoxy-3-pyridylmethyl) -2-methylthio-4-pyrimidone, and the reaction of this compound with b- with 2- (5-methyl-4 -imidazolylmethylthio) ethylamine, 2- (2-thiazolylmethylthio) ethylamine, gives (5-methyl-4-imidazolylmethylthio) -ethylamino 1-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and trihydrochloride, m.p. 205-209 C,
    2- 2- (2-thiazolylmethylthio) ethylthio-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone, m.p. 95-97 C.
    Example 19. 1) Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanol / dioxane (1: 1, 850 ml) was added and the mixture is refluxed for 2.5 hours and then allowed to cool. The mixture is filtered, the volume of the filtrate is reduced by evaporation to 200 ml and water (400 ml) is added. The precipitated solid is filtered to give 2-methoxy-4-cyanopyridine (57.2 g, 51%), mp. 93-95.5 ° C.
    2) A mixture of 2-methoxy-4-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.25 g), sodium acetate
    (69.86 g), ethanol (1200 ml) and water
    (370 ml) hydrohexidized at
    50 psi (3.52 kgf / cm) using a skeletal nickel catalyst (1.0 g). The mixture is evaporated to 450 ml, water (900 ml) is added and
    0 the mixture is allowed to stand overnight at 0, the mixture is filtered, the solid is washed and dissolved in 10% hydrochloric acid (950 G4 l). The formaldehyde dehydra solution (36%, 420 ml) is added, the mixture is heated for 30 minutes, allowed to cool, and added to a solution of sodium acetate (280 g) in water (840 ml). The mixture is extracted with ether (3 500 ml
    0 the combined extracts are successively taken up with aqueous potassium carbonate and water, dried and evaporated to give 2-methoxypyridine-4-carboxaldehyde (20.53 g, 35%), so pl. 33-35c. Recrystallized
    5 petroleum ether sample has so pl. 33-36 ° C.
    3) Replacement of 2-methoxypyridin-4-carboxaldehyde with b-methoxypyridine-3-carboxaldehyde in Example 18 (2) and
    0 18 (4) gives ethyl-2-formyl (2-methoxy-4-pyridyl) propionate as an oil.
    Sequential treatment of this ester with thiourea and methyl iodomers, according to Example 1, gives 5- (2-meth5 hydroxy-4-pyridylmethyl) -2-methylthio-4-pyrimidone, and the reaction of this compound for b hours at 2- (5-methyl -4-ikidazolylmethylthio) -ethyl-amine, 2- (2-thiazolylmethylthio) -ethyl-amine gives
    2- 2- (5-methyl-4-imidazolylmethylthio) ethylamino (2-methoxy-4-pyridylmethyl) -4-pyrimidone, m.p. 177178 C,
    2-L2- (2-thiazolylmethylthio) ethyl5 amino | - 5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone, m.p. 105.5-106,
    权利要求:
    Claims (2)
    [1]
    1. A method of producing pyrih don-4 derivatives of the general formula
     f)
    Hfi-CH-y-lCH j-N n o
    where Het is a 4-imidazolyl ring, possibly substituted with C -C-alkyl, 2-pyridyl ring, possibly substituted with lower C-C alkyl, alkoxy group or halogen, or 2-thiazolyl ring, Y - sulfur atom or methylene - group, Z. 15 L 7 is a hydrogen atom or -alkyl, Het-thienyl, pyridyl or thiazolyl, possibly substituted by a lower alkyl / lower alkoxy group or fused to a benzene ring, characterized in that isocytosine of the formula H XI. W, where Het and Z are as defined above, Q — C-C4-alkylthio, ben516 zylthio or halogen, is reacted with an amine of formula: , ".. /," i .. "(where Het and Y are as defined above.
    [2]
    2. The POP.1 method, distinguished by the fact that the process is carried out in a solvent, for example, in pyridine. Sources of information taken into account during the examination 1. R. Elderfield. Heterocyclic compounds. Ed. Foreign literature. M., 1960, t. B, c. 220
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    同族专利:
    公开号 | 公开日
    BG29722A3|1981-01-15|
    PT65949A|1977-01-01|
    FR2336935B1|1980-03-21|
    HU175171B|1980-05-28|
    FI62668C|1983-02-10|
    IE45082B1|1982-06-16|
    ZM14376A1|1977-08-22|
    IL51040A|1980-12-31|
    FI62668B|1982-10-29|
    EG12439A|1979-09-30|
    NO146396C|1982-09-22|
    JPS6129355B2|1986-07-05|
    SE431544B|1984-02-13|
    RO72475A|1982-10-26|
    NO764370L|1977-06-30|
    DE2658267A1|1977-07-07|
    IT7919107D0|1979-01-05|
    BE849810A|1977-06-23|
    NL7614538A|1977-07-01|
    GR62441B|1979-04-12|
    IT1124740B|1986-05-14|
    DK587076A|1977-06-30|
    NO146396B|1982-06-14|
    AR222290A1|1981-05-15|
    ZA767198B|1977-11-30|
    AU2097676A|1978-07-06|
    IL51040D0|1977-02-28|
    LU76481A1|1977-06-15|
    CA1073458A|1980-03-11|
    PT65949B|1978-06-15|
    MW5076A1|1978-02-08|
    FR2336935A1|1977-07-29|
    SE7614620L|1977-06-30|
    YU311676A|1983-01-21|
    ATA960876A|1980-05-15|
    PL104376B1|1979-08-31|
    FI763664A|1977-06-30|
    MX5119E|1983-03-24|
    DD128588A5|1977-11-30|
    AT360024B|1980-12-10|
    NZ182759A|1978-06-02|
    CH631981A5|1982-09-15|
    IE45082L|1977-06-29|
    ES454656A1|1977-11-16|
    CS203995B2|1981-03-31|
    OA05526A|1981-04-30|
    PH14723A|1981-11-13|
    AU508123B2|1980-03-13|
    JPS5283388A|1977-07-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1419994A|1973-05-03|1976-01-07|Smith Kline French Lab|Heterocyclicalkylaminotheterocyclic compounds methods for their preparation and compositions comprising them|
    IN146736B|1975-10-02|1979-08-25|Smith Kline French Lab|NZ186511A|1977-03-19|1980-11-14|Smith Kline French Lab|3-substituted alkylamino-6-substituted alkyl-1,2,4-triazin-5-ones and pharmaceutical compositions 3-substituted thio-1,2,4-triazin-5-ones|
    IL56265A|1977-12-28|1982-08-31|Om Lab Sa|Process for preparing imidazolyl methylthio guanidine derivatives and a novel intermediate therefor|
    US4539207A|1978-02-13|1985-09-03|Smith Kline & French Laboratories Limited|Pyrimidine compounds|
    IN151188B|1978-02-13|1983-03-05|Smith Kline French Lab|
    PH16240A|1978-04-11|1983-08-11|Smith Kline French Lab|Process for making histamine antagonist|
    ZA792607B|1978-05-30|1980-07-30|Smith Kline French Lab|Nitro compounds|
    PT69886A|1978-07-15|1979-08-01|Smith Kline French Lab|Process for preparing isoureas and isothioureas|
    US4374836A|1978-10-16|1983-02-22|Imperial Chemical Industries Ltd.|Antisecretory heterocyclic derivatives, process for their manufacture and pharmaceutical compositions containing them|
    US4309435A|1978-10-16|1982-01-05|Imperial Chemical Industries Ltd.|Antisecretory guanidine derivatives and pharmaceutical compositions containing them|
    US4496567A|1978-11-13|1985-01-29|Smith Kline & French Laboratories Limited|Phenyl alkylaminopyrimidones|
    US4521418A|1979-02-21|1985-06-04|Smith Kline & French Laboratories Limited|Guanidinothiazolyl derivatives|
    US4255428A|1979-03-24|1981-03-10|Smith Kline & French Laboratories Limited|5--4-pyrimidones|
    JPS55133379A|1979-04-05|1980-10-17|Smith Kline French Lab|Pyrimidone compound|
    EP0017680B1|1979-04-11|1982-04-21|Smith Kline & French Laboratories Limited|Pyrimidone derivatives, process for preparing them and pharmaceutical compositions containing them|
    JPS55145683A|1979-04-26|1980-11-13|Smith Kline French Lab|Pyrimidone derivative|
    CA1155842A|1980-03-29|1983-10-25|Thomas H. Brown|Compounds|
    ZW21281A1|1980-10-01|1981-11-18|Smith Kline French Lab|Amine derivatives|
    IE53068B1|1981-06-15|1988-05-25|Merck & Co Inc|Diamino isothiazole-1-oxides and -1,1-dioxides as gastic secretion inhibitors|
    PT75074B|1981-06-27|1986-02-26|Smith Kline French Lab|Process for preparing certain pyrimidone derivatives and compositions containing them|
    US6417366B2|1999-06-24|2002-07-09|Abbott Laboratories|Preparation of quinoline-substituted carbonate and carbamate derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB5300175|1975-12-29|
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