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    • 专利摘要:
    Pyrimidones which are histamine H2-antagonists have the structure in which D is hydrogen or an aminoalkyl group, X is oxygen or sulphur, Y is oxygen, sulphur or methylene, n is 2 or 3, Z is hydrogen or lower alkyl, A is Ci-C5 alkylene in which one methylene group can be replaced by oxygen or sulphur, and B is hydrogen, methyl, C3-C6 cycloalkyl, or an aryl or heteroaryl group.
    公开号:SU999971A3
    申请号:SU792724499
    申请日:1979-02-12
    公开日:1983-02-23
    发明作者:Генри Браун Томас；Джон Айф Роберт
    申请人:Смит Клайн Энд Френч Лабораториз Лтд (Фирма)；
    IPC主号:
    专利说明:

    dilmethyl) -4-pyrimidone trihydrochloride, so pl. 218-220 C (decomp.). The melting point of the mixed sample with the product of example (a) II does not depress the melting point. Example 2 1. A solution of ethyl 2-formyl-3-5- (1,3-benzodioxolyl propionate (7, 5 g) in methanol (20 ml is added to a solution of sodium methylate in methanol (obtained from -0.689 g of sodium and 50 ml of methanol) and nitroguanidine (3.12 g) is added to this mixture with stirring. The mixture is boiled under reflux 18 h and evaporated to dryness. The residue obtained is dissolved in water (200 ml) and the solution of crastyruot is chloroform. The aqueous phase is acidified with acetic acid to pH 5, a white solid is precipitated. A solid is obtained. 2-Nitroamino-5-C5- (1,3-benodeodioxolyl) methylZ-4-pyrimidone (4.08 g) is obtained, mp 200-202 ° C. The sample is recrystallized from aqueous acetic acid solution, melting point mp 201.5-202, 2. A mixture of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine (3.50 g, 0.016 mol), 2-nitroamino-5-5- ( The 1,3-benzodioxolyl) methyl 4-pyrimi / ene (4.64 g / 0.016 mol) and absolute ethanol (25 ml) are refluxed for 24 hours and evaporated to dryness. The residue is treated with an excess of 2 n. hydrochloric acid and the mixture is filtered. The filtrate is treated with a solution of sodium hydrogencarbonate, which leads to the formation of a resinous precipitate, which is separated. This substance is washed with water and treated with an excess of an ethanolic solution of hydrogen chloride, then evaporated to dryness. The residue is recrystallized three times from ethanol. (5-dimethylaminomethyl-2-furylmethylthio ethyl 1 in3-5-B- (1,3-benzodioxolyl methyl-4-pyrimidone hydrochloride (0.85 g), m.p. 147-148 C. P p and, m e p 3 1. A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) is stirred at 100 ° C for 3 hours and left BEFORE cooling. The mixture is evaporated to dryness, water is added to the residue, and a solid is isolated and recrystallized from a mixture of ethanol and acetic acid. 3- (6-methyl-3-pyridyl) acrylic acid is obtained. (41.25 g), m.p. 213.5-215.5 C. 2. A stirred mixture of 3- (6-methyl 3-p iridyl) acrylic acid (50.70 g absolute ethanol (350 ml) and concentrated sulfuric acid (25 ml) is refluxed for 18 h and evaporated with ethanol (about 250 ml). The residue is poured into a mixture of ice and ammonia water and the resulting the mixture is extracted with ether. The ether extracts are washed with water and evaporated to an oily product, which crystallizes on standing, and ethyl-3- (6-methyl-3-pyridyl) acrylate is obtained, m.p. 36-37.C. 3. Ethyl 3- (b-methyl-3-pyridyl) acrylate (60.36 g) is hydrogenated in ethanol.ol at and at a pressure of 355 kPa in the presence of palladium supported on activated carbon as catalyst (10%; 1, 0 g). The mixture is filtered and the filtrate is evaporated. Ethyl 3- (6-methyl-3-pyridyl) propionate is obtained as an oil. 4. Ethyl 3- (6-methyl-3-pyridyl) propionate (57.79 g), and ethyl formate (23.71 g) are added over 2, 5 hours to a stirred mixture of metallic sodium (6.88 g) and ether (200 ml) cooled in a bath (ice with salt). The mixture was stirred for 20 hours and the ether removed by evaporation. Thiocarbamide (22.76 g) and ethanol (175 ml) were added to the residue, then the mixture was heated under reflux for 7 hours and evaporated to dryness. Water (200 ml) is added to the residue and the mixture is acidified with acetic acid to pH 8. The solid is filtered and the mixture is crystallized from a mixture of methanol and acetic acid. 5- (6-Matil-3-pyridylmethyl) -2-thiouracil- (17, J24-g) are obtained; m.p. ..5. Methyl iodide (13.79 g) is added to a stirred solution of 5- (b-methyl-U-pyridylmethyl) -2-thiouracil (22.66 g) and oxide hydrate. Sodium (8.0 g) in water (250 ml) and the mixture is heated at 1 h, then stirred at room temperature overnight. Acetic acid is added to .per 5 and the mixture is evaporated to a volume of 50 ml. The solid is filtered and recrystallized from a mixture of ethanol and acetic acid. 5- (6-methyl-3-pyridylmethyl) 2-methylthio 4-pyrimidone (10.16 g) is obtained, m.p. 197-197.5 “C. . 6. A mixture of 2- (5-dimethylaminometi1P2-furylmethylthio) ttilamine (1.30 g), 5- (6-methyl-4-pyridylmethyl) -2-methyl: thio-4-pyrimidone (1.41 g) and pyridine ( 10 ml) is refluxed for 46 h and evaporated to dryness. The residue is washed with hot water and oil. treated with an excess of hydrogen chloride in ethanol, then evaporated to dryness. The residue is recrystallized from aqueous echinol containing hydrogen chloride. Receive (5-dimethylaminomethyl-2-furylmethylthio) ethylamino Dg5- (6-ysch1-3-pyridylmethyl) -4 pyrimidone trihydrochloride, so pl. 210-214 C. Sample recrystallized from aqueous ethanol. containing hydrogen chloride, has t. pl. 224-227 “C. Example 4, a) 1. H-6utyl lithium in hexane (1.58 M, 50 ml) is added to a mixture of 2- (dimethylaminomethyl) thiophene (10 g) and dry tetrahydrofuran (50 ml), stirred and kept under nitrogen at an atmosphere of temperature is lower in a bath filled with ice and salt. The mixture was allowed to warm to room temperature and stirred; : 2 more hours. Paraformaldehyde (4.2 g) is added in portions over 0.5 h, with the temperature being kept below during this period. Mixture, per mixing session at: room temperature nepaTi) e still b, 5 hours and. poured into water. The aqueous mixture is extracted with ether and the extracts evaporated to dryness. A solution of hydrogen chloride in ethanol, dry eLir is added to the residue and the solid is filtered off. 2 (dimethylaminomethyl) -5- (oxime; thyl) thiophene hydrochloride (9.33 g) are obtained. A sample recrystallized from a mixture of ethyl acetate JI 2-propanol, has so pl. 134-137C. 2. A solution of 2- (dimethylaminomethyl) 5- (hydroxymethyl) thiophene hydrochloride (8.0 g), in concentrated hydrochloric acid (50 ml) is added dropwise to a stirred solution of cysteamine hydrochloride (4.37 g) in a concentrated hydrochloric acid (50 ml) cooled in an ice bath. During the addition, the temperature of the mixture is maintained below. The mixture was allowed to warm to room temperature and, after stirring overnight, was poured into water. The aqueous is adjusted to pH 12 by the addition of 2N. dilute sodium hydroxide solution and extract with ethyl acetate (750 ml). The extract is dried and evaporated to an oil, which is dissolved in dry ether. An ethanolic solution of hydrogen chloride is then added and the solid SQfi substance is filtered off. Half-hourly 2- (5- and methyl-2-thimel methylthio) ethylamine. Dihydrochloride (8.44-gG; mp 190-1-194; 3.2- (5-dimethylaminomethyl-2-hydroxyethylthio) ethylamine dihydrochloride (2, 0 g) is added to a solution of sodium ethylate (prepared with 0.304 g sodium) in ethanol (60 ml) and the mixture is refluxed with NIKOM for 2 hours. The cooled mixture is filtered and 2-nitroamino-5g is added to the filtrate (3 -pyriylmethyl) -4-pyrimido (1.63 g) and refluxed for 40 hours, then evaporated to dryness. The residue is triturated with water to a powder and crystallized from ethyl acetate Tata. Get 2-t2- (5-dimethylaminomethyl-2-thienylmethylthio) ethylamino-5- (3.-pyridylmethyl) -4-pyrimidone (hygroscopic), which is treated with hydrobromic acid and crystallized from methanol, get trihydrobromide, so pl. 23.3-237 C. b) 1. Cysteamine hydrochloride (9.95 g) is dissolved in concentrated hydrochloric acid (50 ml) and the solution is cooled to. 2-Oxymethylthiophene (10 g) is added dropwise to a stirred solution, which survive at temperatures below 5c. Mixture lane | Censure overnight at room temperature, adjusted to pH 10 with concentrated sodium hydroxide solution, and extracted with ethyl acetate. The extracts are evaporated, the residue is distilled at 158-1b4C (760mmHg). 2- (3-thienylmethylthio) ethylamine is obtained, which is converted to the hydrochloride salt by treatment with an ethanolic solution of hydrogen chloride and ether, m.p. lOB-llO C. 2.2- (2-Thienylmethylthio) ethylamine hydrochloride (2 g) in ethanol (25 mp) is added to a solution of sodium ethylate (prepared from 0.218 g of sodium) in ethanol and the mixture is stirred for 0.5 h. 2 -Nitroamino-5- (3-pyridylmethyl) -4-pyrimidone (2.34 g) and the mixture is heated under reflux for 40 h, then evaporated to dryness. Pyridine (50 ml) was added to the residue and the mixture was heated under reflux for 24 hours and evaporated. The residue is crystallized from a mixture of ethanol and ethyl acetate and further purified on a column of silica gel using as a. eluent a mixture of ethyl acetate with methanol (5: 1) and recrystallization from 2-propanol. (2-Thienylmethylthio) ethylamino-5- (3-pyridylmethyl) -4-pyrimidone is obtained, m.p. 145-148 C. 3. (2-Thienylmethylthio) ethylamino-g5- (3-pyridylmethyl) -4-pyrimidone is reacted with an excess of dimethyl- (methylene) ammonium, iodide in dimethylformamide at room temperature. (5-Dimethylaminomethyl-2-thienylmethylthio) ethylamino-5- (3-pyridylmethyl) -4-pyrimidone is obtained. Example5. 1. 3-Chlorperoxybenzoic acid (10.35 g) is added -. 2-nitroamino-6- (3-pyridylmethyl) 4-pyrimidone (12.35 g) in acetic acid (300 ml) are added to the mixture and the mixture is stirred at room temperature for 18 h; at 5 h, then allow to cool to room temperature. The solid is filtered and purified by reprecipitation from a dilute solution of sodium hydroxide by the addition of hydrochloric acid. Get 2-nitroamino-5- (3-pyridylmethyl) -4-pyrimidone pyrid-M-oxide, so pl. (different). 2. A mixture of N-oxide (1.84 g) and 2t5-dimethylaminomethyl) -2-furylmethyl,
    thio) ethylamine (2.14 g) is heated on a water bath, ethanol is added and the mixture is heated under reflux for 30 h, then evaporated to dryness. The residue is washed with water and the oil is crystallized from 2-propanol. 2-C2- (5-dimethylaminomethyl-2-furylmethylthi) ethylamino J-5- (3-pyridylmethyl} -4-pyrimidone-pyrid-N-OXide, m.p. 50-55 ° C,.
    Example 1. A mixture of e.t. formate (111 g) and 2-butanol (108 g) is added dropwise to a stirred suspension of sodium hydride (50% w / w in oil / 72 g) in dry dimethoxyethane and the mixture is allowed to stand overnight. . Ether was added, and the solid (101 g) was filtered off. Cyanoacetamide (6.5 g) was added to this solid, py: peridate, prepared by adding (piperidine (with piperidine) to acetic acid (7 tan), water (18). ml) until the mixture is 100: no alkaline, and water (400 ml), the mixture is boiled under reflux for 2 hours and allowed to cool. The mixture is added with acetic acid and a solid precipitated as a precipitate. etol nola, 3-cyano-5, b-dimethyl 2-oxypyridine (43.5 g) is obtained.
    2. The cMfecb of 3-cyano-5,6 dimethyl-2-hydroxypyrene Dine (42 g) and phosphorus pentachloride (81 g), which is thoroughly permutated, is heated at 140-1 ° C 2 h. Phosphoryl chloride is distilled off under reduced pressure and ice water (500 g) is added to the residue. The mixture is adjusted to pH T with an aqueous solution of sodium hydroxide and extracted with ether. The ether extracts are evaporated to form an oil, which crystallizes from a mixture of ether and petroleum ether, t. Bale. BO-YAO with. Get 2-chloro-3-cyano-5, b-dimethylpyridine (25.3 g), t, mp, VZ-vT C.
    3, Mixture of 2-chloro-3-1I1ano-5,6-di. Methyl pyridine (21.5 g), semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml). Hydrated under pressure. 344 kPa when in the presence of skeletal Nickel-Sr) -Rönö 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 heated at 1 h. Formalin (40% w / w, 120 ml) is added, the mixture is heated at 0.5 h and left are cool. Sodium acetic acid (95 g) and water (250 MP) are added, the mixture is extracted with ether and the extracts of npowHBanT with a 5% aqueous solution of carbonate carbonate. LIA, then evaporated
    2-CHLOR-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, 60%), t, pl. 69-70C
    4. A mixture of 2-HLOR-5,6-dimethyl-Zpyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) is boiled under reflux. 1 h
    and evaporated to an oil. This oil is dissolved in a solution of sodium hydroxide and extracted with chloroform (extracts are discarded). The water of the Phase is acidified with hydrochloric acid and extracted with chloroform. X o | Yufor 1menny extracts prprmdvayuF n evaporated. Get 3- (2 sikschr-8,6dimetil-3-P1FIDIL) acrylic imcno-Ey (18.3 g, 87%), so pl. 150-158 0, This acid is etheficiItoch. By ester action of etrol and sulfuric acid |, ethyl ester is obtained with t. Il. 8588 s.
    5. Ethyl-3- (2-zsh01 -5,6-immet L3-pyridyl) acre lat (32.7 g) d e-Eog le (500 mp) Mdfirat At 25--30 С
    and a pressure of 344 kPa with palladium on the activated carbon (5%; 3 g) as cattigitator. filter out the shreds and F1gl atpdr to oil, paenpejie unvr between chlorine oil and 2N. coimtioil acid. The aqueous phase is neemeAM ti iam with an aqueous solution of hydrate of oxide andat-. ri, extracts of chloramphenolite and hlopoforyunnyarnvakng extracts. Get ethyl-3- (5,6-dimethyl-3-p1CHRIDTS1L propionate (21.8 g, 88.%) as Kacaia
    6. The interaction of ethyl-3- {5, b-ymethyl-3-pyridyl) propionate with ethylpolyamine and sodium hydride in the medium Dég methoxyethylacch) and the comiaphic temperature gives 3- (5,6-dimethyl-3-pyridi) 2 - formylpropionate, so pl. 148-149 C,
    7. Nitroguanidine (6.05 g) is added to a solution of usajffo.A methyl butyl radiation from 1.45-g) in 5x methanol (65 mp) and smbcg hits tyt.
    with invert Amplum 0.7S h. Add 3- (5,6-diu: tyl-3g- | 1 rip l) 2-formylpioate (14.8 g) and boil the mixture with an oepatTHtat fridge for 40 h then evaporated to dryness. Water (40 mp) is added to the residue and the mixture is extracted with chloroformate (3 KC paicvtl from (asy)). The aqueous phase is brought to
    to pH 6 with hydrochloric acid and
    The solid was distilled off and recrystallized with an emulsion of dimethyl formate or ethanol. 5 (5,6-dimethyl-3-pyridylmvtil) 2-nitromino-4-psc) Imidoi are obtained, m.p. 212-213 C.
    8. The substance of 2- (5-dimethylamine and 2-furylmethyloethyl amine (1.39 g), 5- (5,6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone (1g51 g) of ethanol (25 ml) is boiled t with reversible
    refrigerator for 48 hours and evaporated to dryness. The residue is triturated with water, iodine is discarded, treated with an ethanolic hydrogen chloride solution and recrystallized three times from methanol / c. ethanol. (5-Dimethylaminomethyl-2-Lurylmethylthio) ethylamino-5- (5, b-dimethyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 221-224 ° C:
    Example. 1. 2-Chloro-4-cyano pyridine (115.53 g) in a mixture of methanol and dioxane (1: 1.850 ml) is added to a solution of sodium methylate (prepared from 20.8 g of sodium) in methanol (285 ml) and the mixture is boiled with a fridge for 2.5 hours, then left to cool. The mixture is filtered, the volume of the filtrate is reduced by evaporation to V200 ml and water (400 ml) is added. A solid is filtered off and 2-methoxy4-cyanopyridine is obtained (57.2 g; 51%), m.p. 93-95.5С. ,
    2. A mixture of 2-methoxy-4-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.24 g), sodium acetate (69.86 g) / ethanol (1200 ml) and water (370 ml) is hydrogenated under pressure
    344 kPa using René’s skeletal nickel catalyst (1.0 g. The mixture was evaporated to a volume of 450 ml, water (900 ml) was added and the mixture was left to stand overnight. The mixture was drawn, the solid was washed with water and dissolved in 10 % hydrochloric acid (950 ml). Formalin (36% w / w, 420 ml) was added, the mixture was boiled for 30 minutes, allowed to cool and added to sodium acetate (280 g) in water (840 ml) The mixture is extracted with ether (3x500 ml) and the combined extracts are successively washed with an aqueous solution of potassium carbonate and water, dried and pack ivayut give 2-methoxypyridine-4-carboxaldehyde.... (20.53 g, 35%), mp 33-35 ° C. A sample recrystallized from petroleum ether, has a m.p. 33Zb C...
    3. Condensation of 2-methoxypyridine4-carboxaldehyde with malonic acid lot and subsequent esterification, hydrogenation, as in Example 3/1 / - / 1 I / and formylation of the product with ethyl formate and sodium hydride gives ethyl 2-formyl-3- (2-megoxy -, 4pyridyl) propionate in the form of oil. Treatment of this oil with nitroguanidine and sodium methylate according to the procedure of Example 6 / VII / results in 2-nitroamino-5- (2-methoxy-4-iridylmethyl) -4-pyrimidone with 59% yield, t. square 194-195, (from an aqueous solution of acetic acid).
    4. A mixture of 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine (2.50 g), 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone (2.77 g) and ethanol (15 ml ) Boil with a reverse stirrer for 19 hours, then evaporate. The residue is triturated to a powder with hot water, which gives (5-dimethylaminomethyl-2 furylmethylthio) ethylamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone. A mixture of this pioimidone (3.04 g), 2, n. a solution of hydrogen chloride in ethanol (20 ml) and ethanol (80 ml) is heated under reflux for 48 hours and evaporated to dryness. The residue is recrystallized from a mixture of methanol and ethanol. (5dimethylaminomethyl-2-furylmethylthio) ethylamino-5- (2-hydroxy-4-pyridylmethyl-4-pyrimidone trihydrochloride is obtained, mp 181-185 with.
    EXAMPLE 8 1. Ethyl-3- (6-methyl-3-pyridyl) propionate is formed with ethyl formate and sodium hydride in 1, 2-dimethoxyethane. Get ethyl-2-fmil-3- (6-methyl-3-pyridyl) propionate, so pl. 142-144 C.
    2. Ethyl-2-formyl-3- (6-methyl-3-pyridyl) propionate solution (1.55 g)
    in methanol (20 ml) is added to a solution of sodium methoxide (from 0.161 g of sodium) in methanol (20 ml). BbJCitJeH nitroguanidine (0.729 g) is added over 5 minutes, the mixture is stirred, boiled with an overhead reflux condenser all night and evaporated to dryness. The residue is dissolved in water (50 4 L) and the solution is extracted with chloroform (2x25 ml, the extracts are discarded), then acidified to pH-5 with acetic acid. The precipitated solid is filtered and recrystallized from a mixture of methanol and acetic acid. I get 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone (0.5 g), mp. 215-216 C.
    3. The solution of 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone (0.52 g) and 2- (5-dimethylaminomethyl 2-phyrylmethylthio) ethylamine (0.43 g)
    权利要求:
    Claims (1)
    [1]
    in pyridine (20 ml), refluxed for 20 h and evaporated to dryness. The residual oil is dissolved in hot propanol and the solution is acidified with an ethanolic solution of hydrogen chloride. The solid, which crystallizes out during cooling, is filtered off. Poluch) t 2-f2- (5-dimet-laminomethyl-2-methylmethyl-thio) ethylamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone triglrohlorid (0.84 g), so pl. 232-237c. A sample recrystallized from ethanol containing hydrogen chloride has an. square 236-240 ° C. Example 9. Analogously to Example 3, the interaction of 2- {5-dimethylaminomethyl-2-furylmethylthio) e.thylamino with 2-methylthio-5- (3-quinolylmethyl) 4-pyrimidone and with 2-methylthio-5- (2thienylmethyl) -4 -pyrimidone gives 2- {5-dimethylaminome tyl-2-furylmethylthio) ethylamino-5 {3-quinolylmethyl) -4-pyrimidone trihydrochloride, respectively, mp. 228-230 0 and 2- 2 {5-dimethylaminomethyl-2-furylmethylthio) ethylamino-5- (2-thienylmethyl) -4 pyrimidone dihydrochloride, m.p. (decomposed). Example 10. Analogously to Example K a) by the interaction of 2- (5-dimethylaminomethyl-2-furylmethylthio) these amines C a) 2-nitroamino-5- (1-naFtilmethyl) 4-pyrimidone; b) 2-nitroamino-5- (2-naphthylmethyl) 4-pyrimidone; c) 2-nitroamino-5- (2-furylmethyl) -4 pyrimidone; d) 2-nitroamino-5- (b-methoxy-3-pyri dilmethyl) -4-pyrimidonrm is obtained: a) (5-dimethylaminomethyl-2-furylmethylthio) ethylamino3 5- (1-naphthylmethyl) -4-pyrimidone dihydrochloride, t pl. 190-1920C / b) (5-dimethylaminomethyl-2-furylmethylthio) ethylamino3 5- (2-naphthylmethyl) -4-pyrimidone dihydrochloride, m.p. .169-172 seconds; c) 2- (2- (5-dimethylaminrmethyl) -2-furylmvtiltyo) ethylamino-5- (2-furylmethyl) -4-pyrimilone dihydrochloride, / t. pl. 187-189s / g) 2-2- (5 -dimethylaminomethyl-2-fypi methylthio) ethylamino 3 -5- (b-methoxy-3 pyridylmethyl) -4-pyrimidone (base), so pl. 110-113, Example 11. By reacting 2- (2-furylmethylthio) ethylamine with 2-nitroamino-5- {b-methyl-3-pyridyl methyl) -4-pyrimidone, (2-furylmethylthio) ethyl amino-3 is obtained at reflux in pyridine -5- (6-methyl-3-pyridylmethyl) 4-pyrimidone (base), so pl. 166 168 ° C. . Example 12: Reaction of 2- (5dimethylaminomethyl-2-thienylmethylthio-ethylamine and 2- (5-piperidinomethyl-2furylmethylthio) ethylamine with 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone when boiling refluxing gives (5-dimethylaminomethyl-2-thienylmethylthio) ethylamino-3-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone, respectively, mp. 147–9 0 (base) and (5-pypi-pyryl-methyl-2-fyrylmethyl) H-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone with ethylamine, mp 135.5-136, (base). Example 13. Add (. bis-dimethylamino) methane (68 , 4 g) within 20 minutes to the stirred solution (2- urilme tilthio) ethylamino-5- (6-methyl-3-pyrilylmethyl) -4-pyrimidone (38.9 g) in 975 ml and stirred the mixture for 7 hours at room temperature. The mixture is heated to and added in several portions over 7 hours 52.58 g (bis-dimethylamino) methane; the mixture is evaporated at. 194 ml of water are added to the residue, the mixture is adjusted to pH 9-10 with aqueous sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate extracts are evaporated to dryness. Ethanol: a solution of hydrogen chloride was added to the residue and the resulting solid was recrystallized from a mixture of 2-propanol ethanol. (5-Dimethylaminomethyl-2-furylmethylthio) ethylamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone trichlorohydrate was obtained . This product is recrystallized from methanol-ether, to obtain 37 g (65%) of the product with m. Pl. 225-8C. Example 14. 6. A mixture of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) 4-pyrimidone (1.80 g; 6.5 mmol) 2 - (5-dimethylaminomethyl-2-furylmethylthio) ethylamine (1, 61 g; 6.5 mmol) and ethanol (10 ml) are refluxed for 42 hours and evaporated. The residue is washed with hot water, recrystallized from 2-propanol to give 2- {2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamino1-5 (6-methoxy-3-pyridylmethyl) -4-pyoimidone (0.89 g), t. Yub-YuT with. The sample recrystallized from 2 propanol has a melting point of 20 110-113.5 C. 7. A mixture of (5-dimethylaminomethyl-2-barylmethylthio) ethylamino-5 (6-methoxy-3-pyridylmethyl) -4-pyrI1 "medone (0.81 g) and a solution of hydrogen chloride in ethyl alcohol (2 and; 26 ml) is refluxed for 25 hours and evaporated to dryness. The residue is recrystallized from ethanol and a mixture of ethanol and methanol to obtain (5-dimethylaminomethyl-2-furylmethylthio) ethylamino-5- (6-oxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride (0.68 g; 69%), t. square 174-177.5 ° C. Example 15. A solution of 2- (5-dimethylaminomethyl-2-thienylmethylphenyl) ethipamine amine (2.76 g; 12 mmol) and 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) - . 4-Pyrimidone (2.77 g) 10 mmol) in ethanol (15 ml) is refluxed for 19 h and evaporated to dryness. Pyridine (15 ml), ki mixture was added. The mixture is evaporated to dryness for 4 hours and the residue is washed with water to give 2- (5-dimethylamines metsh1-2-thienylmethylthio) ethylamino-5 (2-methoxy-4-pyridylmethyl) -4-pyrimidon (3.95 d) in a willow of a gummy substance, it is boiled under reflux for 27 hours in a solution of hydrogen chloride in ethanol (1.5 to 75 ml). The mixture is evaporated to dryness and the residue is recrystallized twice from dimethyl ether to give 2- (dimethylaminomethyl-2-thienylmethylthio) ethylamino-5- (2-hydroxy-4-pyridylmethyl) 4-pyrimidone (3.08 g; 63%), t. square 147 150С. Example 16. A mixture of (2furylmethylthio) ethylamino1 | -5- (6-methyl3-pyridylmethyl) -4-pyrimidone (3.0 g) pyrrolidine (1.79 g) (Warmalin (37%; 0.75 g) and acetic acids (10 ml) are boiled in a water bath for 2.5 hours, diluted with water, adjusted to pH 8-9 with sodium bicarbonate and extracted with ethyl acetate. Organic extracts are evaporated to dryness and recrystallized from ethyl acetate to give 2-p - (5-pyrillidinomethyl-2-furylmethylthio) ethylaminoJ-5- (b-methyl 3-pyridylmethyl) -4-pyrimidone (1.64 g) t. M.P.Rm and D 17. 1. Ethyl-3- (2-Pyridyl) propionate is reacted with ethyl formate and a solution of sodium hydride in 1,2-dimethoxyethane, ethyl-2-Lormyl-3- (2-pyridyl) propionate is obtained. This substance is reacted with nitroguanidine and a solution of sodium methylate in methanol is obtained 2-nitroamino-5- (2-pyridylmea- or) 4-pyrimidone, m.p., 207.5218 C (decomp.). 2, A mixture of 2- (5-dimethylaminomethyl2-furylmethylthio) ethylamine (2.17 g), 2-nitroamino-5- (2-pyridyl The "ethyl) -4pyrimidone (1.50 g) and dry pyridine (15 ml) are refluxed for 20 hours and evaporated to dryness. The residue is washed with water to give crude 2-f2- (5-dimethylaminomethyl-2-pyrylmethyl-thio) ethylamino -5- (2-pyridylmethyl) -4-pyrimidone, which is treated with a solution of hydrogen chloride in ethanol and recrystallized, to give trihydrochloride-trihydrochloride. St. Plate 207-210 0 (from 2-propanol). Example 18. A mixture of 2- (5-methylmethylaminomethyl-2-furylmethylthio) ethyl amine (1.71 g), 5- (4-pyridylmethyl-2methylthio) -4 -pyrimidone (1.5 g) and pyridine are boiled under reflux with NIKOM for 24 hours, evaporated to dryness, the residue is washed with water, and crude (5-dimethylaminomethyl-2-furyl- / methylthio) ethylamino3-5- (4-pi) is obtained lmethyl) -4-pyrimidone, This substance is treated with a solution of hydrogen chloride in ethanol and recrystallized from 2-propanol and methanol and from ethanol and methanol, to obtain trihydrochloride (1.29 g), mp 194.7 ° C. derivatization of pyrimidone-4 with the general formula I -cho.CHjB CHj SCH CHgMH - hydrogen, dimethylaminomethyl, piperidinomethyl, or pyrrolidinomethyl; X - oxygen or sulfur; B - imperceptible pyridyl or substituted by hydroxy, alkoxy group with 1-4 carbon atoms of the genus, one or two alkyls with 1-4 carbon atoms; N is hydroxypyridyl, 5- (1,3-benzodioxolyl), thienyl ,, quinolyl f naphthyl or furyl, or their acid addition salts, characterized in that pyrimidone-4 - of the general formula II I HN: rJA and O, where 8 has the same meaning as B or B having a protecting group; Q.- Nitroamino- or alcthio group with carbon atoms, is reacted with an amine of the general Formula I I .. JP. SCH CHgNHg where D and X have the indicated meanings, followed by isolating the target product as a base or acid addition salt, or removing the protecting group and isolating the desired product as a base or acid addition salt, or in the case where ID is hydrogen, and B is not Furil or thienyl, aminomethylate with a mixture of formaldehyde and dimethylamine, or formaldehyde and piperidine, dimethyl (methylene) ammonium salt or (bis-dimethylamino) methane, followed by isolation of the target product as a base or acid o-additive salt, Priority on the basis of: 13.02.78 with D - dimethylaminomethyl or piperidinomethyl; X - oxygen; 3 - unsubstituted pyridyl or substituted by an oxy group, one or two alkyls with 1-4 carbon atoms, N is oxypyridyl, 5- (1,3-benzo17 999971 e
    dioxolyl), thienyl, naphthyl, furyl, prenod, and B has the meanings excellent
    or B - have a protective group, against furyl and thienyl. ..
    Q is an alkythio group with 1–4 carbon atoms — 12.02.79 at O g hydrogen) B – xi;
    kind of. zero
    05/25/78 with (I - nitroaminogroup-Sources of information,
    na 5 taken into account in the examination
    11/13/78 with X - sulfur; aminometyp1. Patent 1 of the campaign 2336935
    Compound 1, where D is A 61 K 31/505, published. 1977.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB574078|1978-02-13|
    GB2283478|1978-05-25|
    GB7844259|1978-11-13|
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