• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds are disclosed of the formula wherein two of R1, R2 and R3 are hydrogen and the third group is hydrogen, lower alkyl, fluoro, chloro, bromo, lower alkoxy, lower alkenyloxy; and R5 is isopropyl or tertiary butyl. These compounds find use as .beta.-adrenergic blocking agents and vasodilators.
    公开号:SU862824A3
    申请号:SU782145553D
    申请日:1978-12-22
    公开日:1981-09-07
    发明作者:Джон Коутс Вильям；Мэйтлэнд Рое Энтони；Энтони Слэйтер Роберт；Майкл Тэйлор Эдвин
    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 pyrndazine derivatives, starting materials in the synthesis of adrenoblockers and vasodilators.
    The known reaction is alkylation of phenols with epichlorohydrin or epibromgndrin in the presence of base 1.
    The goal is to invent - to obtain new prsdazvodyh pnrndaznna possessing cevnshsh pharmacological properties.
    The goal is accomplished capable of obtaining common-language-wide formulas
    Kt
    u -OCH -CH-HIH ,,. Kcht J
    UH-lfH-A
    where two substituents from the number of RI, Rj, and B1 are alloys, and the third is hydrogen, fluorine or alkoxnl. with 1-4 atoms of Carbon A
    tert.buttshkmsssarbonilna or isoproshisenoza group.
    The method consists in the fact that the compound of the general formula
    5Si
    U
    TO
    II
    about
    yH-TfH-A
    sh
    where R, RJ, Yaz, and A are as defined above, they are reacted with zichlorohydrin or zymbybrindrin at 10-100 ° C in nI {without base.
    As osnshva.gi use gndrid
     sodium potassium carbonate and pssssess is carried out in a medium of dimethylformamide or butanone-2.
    The compounds obtained by the proposed method exist in the form of optical isomers. Racemic mixtures of compounds of the formula I are produced by well-known methods, such as salt formation 38 with optically active acids. Try a mixture of 6-chloro-3- (2-hydroxy-4. Methoxyphenyl) pyridazine, tert-butyl carbazate and 1,8-bis- (dimethylamsh {o) -nephthalene is heated and for 2 h, 6 (2-tert. Bootsloxyoxycarboiylhydraenoino) -3- (2-hydroxy-4-methoxyphenyl) shfidazin, i.e. ill. 193 194 ° C. A mixture of 6- (2-tert.butsyuksikarbonsh1gidrazino) -3- (2-hydroxy-4-methoxyphenyl) -pyrndazine, zlimbromgidrin and potassium carbonate and butanone-2 kip tit under reflux with stirring overnight. Evaporation of the filtered piscTBopa gives an oil, which is purified on a column of silica gel with elution with mixtures of dichloromethane and methanol, to obtain 6- (2-tert.-butyl-3-argonyl-phase) -3 2- (2,3-epoxy-propioxy) -4-methoxy-H1-shn1-shh1-shh1-shh-1-shh 2) T M a R 2. Hydrazine hydrate (1.2 ml) was added to a thinned suspension of 3- (2-hydroxybenzosch1) -propnonic acid (3.1 g) in water (20 mg) and the mixture was heated under reflux. within 45 min. The mixture was diluted with an equal volume of water, allowed to cool and filtered, to obtain 6- (2-oxfenyl) -4, 5-dagidro-3- (2E) -pyridazine (2.6 g), m.p. 211-212 ° The sodium salt of 3-nitrobenzenesulfonic acid (2.96 g) and 6- (2-hydroxyphenyl) -4,5-dihydrO3 (2H) -pyridaznon (2.5 g) is added to a solution of sodium hydroxide hydrate (1 , 31 in water (25 ml) and the mixture is boiled under reflux for 2.5 hours. Acetic acid is added to the warm stirred solution until further precipitation stops and the pH of the mixture becomes 9. The mixture is filtered , 6- (2-hydroxyphenyl) -3- (2H) -pyridazinone (2.05 g) is obtained, mp 295-299 ° C. Blend mixture of b- (2-hydroxyphenyl) -3 (2H) -sh1ridazinone (30 g), acetic anhydride (90 m l) and pyridine (0.3 ml) are heated on a boiling water bath for 85 minutes, the residue, obtained after evaporation under reduced pressure, is treated with methanol (30 ml) and after that with water (10 ml). and washed with aqueous methanol, 6- (2-acetoxyphenyl) -3 (2H) -pyridazione is obtained (30.5 g, yield: 83%), mp 179-180.5 C. A sample recrystallized from aqueous methanol zero. melts at 182.5-184 ,. A stirred mixture of -6- (2-acetoxyphenyl) 3 (2H-pyridazinone (9 g) and chloroxyphosphorus (36 ml) is heated in a water bath at 5–5 ° C in T e4eioie35 min and evaporated under reduced pressure. The residue is treated with ice and the solid collected and washed with 6d (, 3- (2-acetoxyphenyl) -6-chloropyridazine (9.27 g, yield 95%), mp. 133- is obtained. The sample recrystallized from the ethanol melts at 137-138 ° C. Mixed a mixture of 3- (2-acetoxyphensh1) 6-chloropyridazine (9 g) and hydrazine hydrate (45 m) is boiled "(refluxed for 30 minutes). The cooled solution is diluted with (Cf ohm water, the solid is filtered off and rinsed with water, obtained with a quantitative yield of 3-hydrazino6- (2-hydroxyfine {l) -part (dazin, mp 184-186 ° C. The sample, recirculating from ethanol, melts at 185-187 ° Melting point of hydrochloride 2.59-2b1 C (with decomposition). A mixture of 3-td {edzino-6- (2-hydroxyphenyl) -pyridazine (5.35 g), 2N hydrochloric acid (15 ml) and acetone (30 ml) is heated to a clear solution and then diluted with water (60 ml). A1 1 Bavl sodium carbonate solution to pH 8, and the resulting solid is collected and swirled with water to give 3- (2-hydroxyphenyl) -6- (isopropylidenehydrazino) pyridazine (5.87 g, yield 92%), m.p. . 230-231 ° C. npj6a, recrystallized from ethanol, melts at 234.5-235. . 3- (2-hydroxyphenyl) -6- (isoopi; shdenp1drchzino) -pyridazine (1.2 g) was added to a stirred mixture of nprc hydride (0.26 g, 50%, in oil) and dimethylformamide (5 ml). After 30 mins of ribavl epibromohydrin (1.7 ml), the mixture is stirred for 4.5 hours and then poured into water (20 ml). The product is extracted with dichloromethane and purified by the method of column chromatography to obtain 3- 2- (2,3-zpoxypropyoxy) phenyl} -6- (isopropylenehydrazino) -nidazine. EXAMPLE 3 A solution of M-methylsuquinimide (49.5 g, 0.44 mol) in anhydrous tetrahydrofuran (300 ml) was added to) dropwise T to a cold (-50 ° C) mixture of 2,6 difluorophenyl; within 1 hour. Lithium reagent Prepared from 1,3-dinfluorobenzene (50 g, 0.44 mol) in tetrahydrofuran (350 ml) and butyl lithium in hexane (254 ml, 0.38 mol). The mixture is brought to room temperature overnight, then cooled and then hydrolyzed with a cold 20% aqueous solution of ammonium chloride (200 ml). The aqueous phase is separated and extracted with chloroform. The combined organic solutions are thoroughly washed with water and evaporated to a small volume. After treatment with diethyl ether, a mixture of N-methyl-3- (2,6-difluorobenzosh1) propionamide tautomers, melting at 90--92 ° C and N-methyl-2- (2,6-difluorophenyl1) -2-hydroxy-pyrrolide 1 -5 as a white solid (25 g, 29%, mp 83-110 ° C), which is collected and washed with diethyl ether. By concentrating the mother liquor, an additional 6.4 g (7.5%) is obtained. Found %: C 57.99; H 4.94; N 6.18. C22, Ci, H ,, NF20j Calculated,%: C 58.15; H 4.88: N 6.17. M 22 Guide} Inverter (16 g, Oi32 mol) is added to a solution of the above product (24.2 OL1 mol) in 50% acetic acid (240m stirred mixture is boiled under reflux for 1 h to then "touibTpyioT precipitate is cooled, washed with water to obtain 6- (2,6-difluorophenyl) -4,5-dihydro-3 (2H) -pyri dazinone (17.2 g, 75% melted at 188-191 After recrystallization from ethanol pure pyridazinone is obtained, melting at 189 191 ° C. Found,%: C 56.91; H 3,%; N 13.30; M 21 p. C, oHeFjN, 0 Selected,%: C 57.14; H 3 , 84; N 13.33, 210. Bromine (4.8 ml, 0.09 mol) in acetic acid e (W ml) is added dropwise in those 90 m to a stirred low-boiling solution of b- (2.6; dinfluorophenyl) -4,5-dihydro-3 (2H) -pyr dazinone (19 g, 0.09 ml) in acetic acid (80 ml). boil under reflux, allow it to cool and then dilute with water. 6- (2,6-dfluorophenyl) -3 (2H) -pyridazinone is obtained (16.89 g, 90%), t. 208 ° C, recrystalline; shzovygayut from ethanol, get pure pyridazion, t. Pl. 210.5-213 ° C. Found,%: C 57.87; H 2.94; N 13.48; . CioHeFjNjO Calculated,%: C 57.68; And 2.91; N 13.46. M208. A stirred mixture of 6- (2-difluorophenyl) -3 (2H) -Sh1ridazknone (3.83 g, 0.018 mol) of sodium oxide salt (3.83 g, 0.0% mol) and digol (50 ml) is boiled in for 30 minutes The cold solution is acidified with hydrochloric acid and P1 (6) bicarbonate is added to pH 7. After up / m & taai under reduced pressure, the solid residue is dissolved in water, adjusted to pH 5 with acetic acid and extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution, dried, evaporated under reduced pressure, to obtain 6- (2-fluoro-6-hydroxyphenyl) -3 (2H) -pyridazinone, which after recrystallization from ethanol melts at 254-256 ° C. Found: C 58 , 04; H 3.46; N 13.45. SIRRING. Calculated,%: C 58.25; H 3.42; N 13.59. 6- (2-fluoro-6-hydroxyphenyl) -3 (2H) -pyridazinone (3.0 g, 0.015 mol) is poured with a layer of acetic anhydride containing traces of pyrischale, and the mixture is heated on a boiling water bath for 2 hours. After the evaporated solution of the prv under reduced pressure, a solid residue is obtained, which is triturated with diasrther, 6- (2-acetoxy-6-fluorofegai1l) -3 (2H) -pyridazinone (3 g, 83%) is taken into account, which, after distillation from ethanol melts at 179-180.5 ° C. Found,%: C 58.09; H 3.60; N 11.44. CiiHgFNjOa. Calculated,%: C 58.05; H 3.66; N 11.29. Pistilous phosphorus (3.4 g, 0.015 mol) is added to a solution of 6- (2-acetoxy-6-fluorophenyl) -3 (2H) -pyridazinone (2.5 g, 0.01 mol) in anhydrous pyridine (50 ml) The stirred mixture was boiled with cold water for 15 minutes and then poured into warm water (350 ml). The aqueous mixture is extracted with ethyl acetate, the extract is washed with 2N hydrochloric acid and water. After evaporation of the dried solution, a crude product (1.7 g) containing 6- (2-acetoxy-6-fluorophenyl) -3 (2H) -pyrndazinethion is obtained, melting at 178-181 ° C and 6- (2-fluoro-6 -oxiphenyl) -3 (2H) -pyrndazinthion. A mixture of two tions (1.1 g), methanol (100 ml) and 2N. A solution of sodium hydroxide (7 ml) is heated on a boiling water bath for 15 minutes and evaporated under reduced pressure. The residue is dissolved in water, treated with acetic acid to pH 4 and a precipitate is collected (0.8 g, melted at 174-178 ° C), which is washed with water. After recrystallization from addeton, 6- (2-fluoro-6-hydroxyfecyl) -3 (2E) -Sh1ridazinethion, melting at 182.5-184.5 ° C, is obtained. Mixed mixture 6- (2-fluoro-6-hydroxyphenyl) -3 (2H) -pyridazinethion n hydrazine hydrate is refluxed for 45 minutes. The mixture is diluted with water and the solid is filtered off and washed with water. After recrystallization from ethanol, 3- (2-fluoro-6-oxyfesh) -6-hydrazinopyridazine is obtained, melting at 221-222 ° C (with decomposition). The hydrochloride melts at 270-272 ° C (with decomposition). Excess acetone is added to a hot aqueous solution of 3- (2-fluoro-6-oxypheyl) -6-gdrazinopyridazone pshrochloride. The solution is aged for 30 minutes, neutralized with a solution of nati carbonate, the solid is filtered off and water is passed, and 3- (2-fluoro-6-oxyfs-w) -6-isoproshylidel Drazinoshyridazine is obtained, which after recrystallization from zethanol plits at 185-1 ° C A stirred mixture of 3- (2-ft (f 6-oxffesh1) -6-isopropylndesh-idrazyuk shridaz11na (1 g), potassium arbonate (3 g), zpibromhydricna (M ml.) Butanone-2 (30-ml) is boiled t with a reverse cold-chain for 3 hours. After evaporation of the filtered solution, an oil (2.1 g) is obtained, which is purified on a column of silica gel by elution of a mixture of methanol and chloroform to obtain 3- ((2,3-epoxy-nptHraoKCH) -6-fluorophenyl) -6-eopropylidene hydrazinopyridazine. The formula was invented and the method for producing phenylhydrosine pyrididine of the general formula XB (-JJJ-CHF-CHF-CH). the substituent from among Rj, R2, RS is hydrogen; and the third is hydrogen, fluorine or alkoxy with 1-4 carbon atoms A is a tert-butyloxycarboxylic or isoproshiochene group, distinguished by the fact that the compound of the general formula Sh-Sh- Where are RI, B}, Jaz A, and the aforementioned sources laugh, iju zpibromgidriiom or with epichlorohydrin at 10-100 C in the presence of wasps syuash. 2. The way Rp. 1, that is, the fact that sodium hydride, potassium carbonate, is used as the base as the base and the process is carried out in vimethylformamide or butaion-2. Priority signs: 18.06.74- tsholstanme as a reagent gahlorg ja ka; 01/02/75 - use as an epibromoscount reagent. Sources of information used in the collection during the examination 1. Wageshd-Hilgetag. Experimental methods in organic hichi. M., Himi, 1968, p. ZZZ;
    权利要求:
    Claims (2)
    [1]
    Claim
    The method of obtaining phenylhydrosinopyridazines of the General formula
    ЯН-МН-А where two substituents from among R t , R 2 , R 3 are hydrogens; and the third is hydrogen, fluorine or alkoxyl with 1-4 carbon atoms, A is a tert-butyloxycarboxyl or isopropylidene group, characterized in that the compound of the general formula
    JTH-BH-A where Rt, Rj, R 3 and A have the above meanings. values, are subjected to interaction with epibrom * hydrin or epichlorohydrin at 10-100 in C 15 in the presence of a base.
    [2]
    2. The method of pr and. 1, due to the fact that sodium hydride or potassium carbonate is used as the base and the process is carried out in a medium of dimethylformamide or buta 20 non-2.
    Priority by signs:
    06/18/74 the use of epichlorohydrin as a reagent;
    01/02/75 - use of 25 epibromohydrin as a reagent.
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    同族专利:
    公开号 | 公开日
    DK145099B|1982-08-30|
    FI62532B|1982-09-30|
    SE416650B|1981-01-26|
    AU8158175A|1976-12-02|
    CA1067078A|1979-11-27|
    JPS5113782A|1976-02-03|
    DE2527066A1|1976-01-08|
    DK145099C|1983-01-31|
    LU72739A1|1975-10-08|
    DK245275A|1975-12-19|
    IL47351D0|1975-07-28|
    FI751790A|1975-12-19|
    NL7507267A|1975-12-22|
    SE7506947L|1975-12-19|
    ES438685A1|1977-05-16|
    FR2275213B1|1979-08-10|
    US4053601A|1977-10-11|
    FI62532C|1983-01-10|
    IE42214L|1975-12-18|
    FR2275213A1|1976-01-16|
    IE42214B1|1980-07-02|
    CH617429A5|1980-05-30|
    IL47351A|1980-02-29|
    引用文献:
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    BE758146A|1969-10-29|1971-04-28|Smith Kline French Lab|AMIDINE DERIVATIVES|
    US3818097A|1969-10-29|1974-06-18|Smith Kline French Lab|Method of inhibiting histamine activity with isothioureas|
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    DE3302442A1|1983-01-26|1984-07-26|Basf Ag, 6700 Ludwigshafen|NEW PYRIDAZINONE, METHOD FOR THE PRODUCTION THEREOF, THERAPEUTICAL AGENTS CONTAINING THESE COMPOUNDS AND THE USE THEREOF|
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    JPH0629254B2|1986-09-08|1994-04-20|帝国臓器製薬株式会社|Pyridazinone derivative|
    CN101444496B|2001-06-12|2011-04-13|维尔斯达医疗公司|Compounds for the treatment of metabolic disorders|
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    WO2021260609A1|2020-06-25|2021-12-30|Novartis Ag|Process for the manufacture of 1,4-disubstituted pyridazine compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB26864/74A|GB1527712A|1974-06-18|1974-06-18|Hydrazinopyridazines|
    GB2075|1975-01-02|
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