• 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:
    A process for the preparation of 15-hydroxyimino-E-homoeburnane derivatives of the formula (I), <IMAGE> (I) wherein X1 stands for hydrogen or halogen and R is a C1-6 alkyl group, or acid addition salts and optically active derivatives thereof. These compounds are valuable intermediates of the synthesis of compounds with outstanding biological effects. According to the invention a racemic or optically active 15-hydroxy-E-homoeburnane derivative of the formula (II), <IMAGE> (II) is treated, optionally after separating the 15-epimers and/or resolution, with a halogenating agent. The resulting 15-halo-E-homoeburnane derivative of the formula (III), <IMAGE> (III) wherein X2 stands for halogen, is reacted, optionally after separating the 15 epimers and/or resolution, with an alkali nitrite in the presence of an acid, and, if desired, the resulting 15-hydroxyimino-E-homoeburnane derivative of the formula (I) is converted into its acid addition salt and/or resolved. The compounds of the formula (III) formed as intermediates in the above process are new and biologically active.
    公开号:SU982541A3
    申请号:SU802949854
    申请日:1980-07-11
    公开日:1982-12-15
    发明作者:Сантаи Чаба；Сабо Лайош；Калауш Дьердь；Данчи Лайош；Кеве Тибор；Дрекслер Ференц
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    formula (I) or their salts or optical isomers based on 14-oxo-homoeburnan, the distinguishing feature of which is that the derivatives of 15-bc-e-homoeburnan of the general formula III) H to where R and X have the indicated values , in the form of a racemic mixture or their optical isomers, are treated with chlorine with phosphorus oxide in chlorobenzene (preferably at boiling) and the compounds of the formula are obtained in the form of a racemic mixture or their optic isomers where R and X have the indicated values, are reacted with alkali metal nitrite in attendance and acids, after which the target products are isolated in free H11de, in the form of salts and / or divided into optical isomers. The advantage of this method is the elimination of water adsorbing and toxic reagents, which simplifies the process. The invention also relates to a method for producing derivatives of the intermediate 15-chloro-E-homoeburn in the general formula (III), where R is ethyl x is a hydrogen or bromine atom or their salts or optical isomers based on the known hydroxyl to chlorine substitution reaction. 2, comprising the fact that the 15-hydroxy-E-homoeburnan derivatives of the general formula (II) where R and X have the indicated meanings, as a racemic mixture or optical isomers, are treated with phosphorus oxychloride in the medium chlorobene ash and the resulting compounds of formula (III) are isolated Yut in free view e, in the form of roles, or 15 epimers are separated and / or the racemates are divided into optical isomers. Example. 15-epimers of (+) - 3 (S) 17 (S) -oxo-15-chloro-E-go1 yeburnan 4.2 .g (13 mol) (+) -3 (3) 17 (S) -14- OKco-15-hydroxy-E-homoeburnan (mixture of 15-epimers) is boiled for 3 hours under reflux in 100 ml of chlorobenzene in the presence of 4.2 g of phosphorus oxychloride. The mixture is then cooled, diluted with stirring, 100 g of ice-cold water is adjusted to 5 with the help of 5%. an aqueous solution of sodium carbonate is 8.5 and shaken in a separatory funnel. The lower phase is drained, and the upper, aqueous phase is twice subjected to extraction with dichloromethane, in 50 ml portions. The organic phases are combined, dried with anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo to dryness. The residue after evaporation, which is a mixture of epimers, can be used without purification as a starting product in the next stage. Yield 3.50 g (81% of theoretical yield); m.p. 140-152s. The crude product obtained in this way can be separated by preparative thin-layer chromatography into two stereomeric chlorinated derivatives. Separation is carried out on KG-PF264fE5 brand silica gel using as the mobile phase a mixture of benzene and methanol, taken in a ratio of 14: 3. Elution is carried out with acetone. An isomer with a large H value melts at 155 ° C (after recrystallization from methanol). IR (in KBG):: 1700 cm (lactam - CO); mass spectroscopy m / e,%: 342 (M-t-, 100), 279 (26), 252 (37), 251 (21); 250 (17), 249 (48), 237 (13), 223 (13) 194 (16), 180 (27) 169 (27). j An isomer with a lower Rf melts at 142 ° C (after recrystallization from methanol). IR (Kvg): 1720 CM (lactam-CO); mass spectroscopy m / e,%: 342 (M, 71), 307 (63), 308 (100), 280 (22), 252 (45), 249 (34), 223 (18), 169 (20) . (c1), 3 (, 01, in chloroform). Example 2 (+) - 3 (S), 17 (S) -14-oxo-15-oxyimino-E-homoeburnan 0.20 g (0.058 mmol) mixture of epimers (+) - 3 (5) , 17 (S) -14-OXO-15-chloro-E-homoeburnan (prepared according to example 1) is dissolved in 4 ml of acetic acid, the solution is diluted with 1 ml of water and added to it with constant stirring at room temperature drop by drop a solution of 1.2 g of sodium nitrite and 4 ml of water. The mixture was left to stand at room temperature for 24 hours, basified, before -. An aqueous solution of ammonium hydroxide is concentrated to pH: 9 and extraction is carried out three times with dichloromethane, in 5 ml portions. the combined dichloromethane extracts were dried with anhydrous magnesium sulphate, which was then filtered, and the filtrate was evaporated to dryness in vacuo. The resulting oily liquid (0.19 g) was purified by preparative thin layer chromatography (KG-PF2.56 + 366 mobile phase benzene-methanol in a ratio of 14: 3, eluant mixture of dichloromethane and methanol in a ratio of 20: 5); The unreacted starting compound R is higher than the target product. After removing the solvent from the eluate, 0.13 g of (+) - 3 (5) -14-oxo-15-oxyimino-E-homoeburnan (68% of the theoretical yield) is obtained; t.il. i90 ° C (after recrystallization from ether); (c) + 6l (, in dichloromethane). IR (in KBr): 3200 (OH), 1705 CNf (lactam-CO) / 1642 cm- ()., Results of the analysis (based on C pH-y-jOj mol.v. 337.4): Calculated ,%: C 71.19, H 6, 12.45; Found%: C 71.30, H 6.60, N 12.65 To obtain the hydrochloride salt, 0.13 g of the product obtained is dissolved in 1 ml of methanol, the solution is acidified with methanolic hydrochloric acid to pH 5, precipitated the precipitating hydrochloride is filtered off and dried. The resulting hydrochloride salt melts at 256-257 s after recrystallization from methanol). Take p3. (+) -3 (S), 17 (S) -11-bromo-14-oxo-15-chloro-E-homoeburnan (mixture of 15-epimers). 1.00 g (2.48 mmol) of a mixture of 15-epimers of (+) - 3 (S), 17 (S) -ll-bromo-1 4 -oxy-15-hydroxy-E-homoeburnan is dissolved in A9 ml of chlorobenzene, The resulting solution is mixed under constant stirring with a solution of 0.85 g of phosphorus oxychloride in 1 ml of chlorobenzene and heated under reflux for 1 h. After cooling, the reaction mixture is shaken in a separating funnel under ice-cooling with 15 ml of a 15% aqueous solution of sodium carbonate and the lower organic phase is separated. From the alkaline aqueous phase, extraction is carried out three times with dichloromethane containing 1% methanol (10 ml portions). The organic extracts are combined, dried with anhydrous magnesium sulphate, which is then filtered, and the filtrates are evaporated in vacuo to dryness; The resulting oily liquid (1.00 g) is a mixture of 15-epimers of the desired product, which can be used as a starting product in the next step without further purification. If desired, 15-epimers can be separated by preparative thin layer chromatography (KG benzene / methanol 14: 3 mobile phase; acetone (dichloromethane: 2: 1)). Separation yields 0.32 g ( 30.5% of the theoretical yield of the isomer (a) with a lower R value, mp 215-216 ° C (after recrystallization from acetone); (o) +55.6 (with 1.024, in CHCl3). IR (in KBG) 1705 cm (lactam-CO). Analysis results (based on C, H, BrCl; 1AP, H 421.77). G Calculated,%: C 56.95, H 5.25, N 6 , 64; Found,% C 56.70, H 5.35, N 6.45. Isomer (c) with a higher R value {sex as a result of separation in the form of an oily liquid in an amount of 0.45 g (43% of the theoretical yield), by reaction with a methanolic hydrochloric acid solution, it is converted into the hydrochloride salt; mp. 269 ° C (with decomposition, after recrystallization from acetone )} (L) (s-1.05, in dichloromethane). IC (in KBr): 1705 cm- (lactam-CO). Analysis results (based on C oH jjNOBCl-i; mol.ves 458.23). Calculated. %: C 52.41, H 5.05, N 6.11; Found,%: C, 52.34; H, 5.27; N6.20. Example 4. (1) -3 (S), 17 (S) -1,1-bromo-14-oxo-15-OXYIMINO-E-HOMO-: zburnan. 0.50 g (1.18 mmol) of (+) - 3 (8), 17 (3) -11-bromo-14-oxo-15-chloro-E-homoeburnan (a mixture of 15-zpimers) prepared according to the method of with example 3, dissolved in 11 ml of glacial acetic acid, to the resulting solution with constant stirring, a solution of 2.70 g of sodium nitrite in 9 MP of water is added dropwise at room temperature and left to stand for 30 hours The reaction mixture is then poured into 20 g of ice-iodine, alkalized by adding a concentrated solution of ammonium hydroxide to pH 9, and extraction is carried out three times with dichloromethane, 10 ml. The combined organic layers were dried with anhydrous magnesium sulphate, which was then filtered and the filtrate was evaporated to dryness. The resulting oily liquid (0.50 g) is purified by preparative thin layer chromatography (KG-RF2. Mobile phase: a mixture of benzene and methanol in a ratio of 14: 3; eluent: dichloromethane). The unreacted R value of the starting compound is higher than Cg of the target product. 0.32 g of an oily desired product is obtained (60.5% of the theoretical yield). Obtained in the described manner as an oily liquid (+) - 3 (S), 17 (3) -11-bromo-14-oxo-15-oxyimino-E-homoeburnan is converted in the usual way by reacting with a methanolic hydrochloric acid solution, to crystalline hydrochloride salt.
    The hydrochloride crystallized from methanol melts at 235-236 C, (o) +44.9 (, 10 in dimethylformamide). IR {in KBG): 3460 cm-Mon), 1710 cm- (lactam-CO), 1622 CM (). Mass spectroscopy M / e,%: 415 (M, 62).
    权利要求:
    Claims (2)
    [1]
    1. A method of producing derivatives of 15-oximes, but-E-homoeburnan of general formula I:
    , -1 Г rt-r 1Г l /,
    YAO-1G
    /
    where R is ethyl;
    X is a hydrogen atom or bromine, or their salts, or their optical isomers based on 14-oxo-homoeburnan derivatives, characterized in that, in order to simplify the process, 15-hydroxy-E-homoeburnan derivatives of general formula II
     (AND)
    n
    where R and X have the indicated meanings, in the form of a racemic mixture or their optical isomers, are treated with phosphorus oxychloride in chlorobenzene and the resulting compounds of formula III
    Jii)
    where R and X have the indicated meanings, in the form of a racemic mixture or their optical isomers, are reacted with an alkali metal nitrite in the presence of an acid, followed by. The desired products are isolated in free form, in the form of salts, and / or divided into optical isomers.
    [2]
    2. A method for preparing 15-chloro-E-homoeburnan derivatives of general formula III:
    (Where K is ethyl;
    X is a hydrogen atom or bromine, or their salts or their optical isomers,
    characterized in that
    15-hydroxy-E-homoeburnan derivatives
    General formula II:
    25
    thirty
    where Them has the indicated values, in the form of a racemic mixture or optical isomers are treated with chlorine oxide
    35 phosphorus in chlorobenzene and the resulting compounds of formula (III) are isolated in free form, in the form of salts and / or 15-epimers are separated and / or the racemates are separated into optical isomers
    40 Sources of information
    taken into account in the examination
    1. The patent of the People’s Republic of Hungary No. 163769, cl. C 07 d 57/06, published 1974 (prototype).
    类似技术:
    公开号 | 公开日 | 专利标题
    DK173703B1|2001-07-09|Methods for preparing D, L- | and D- | -1-aryl-2-acylamido-3-fluoro-1-propanols, respectively
    SU776557A3|1980-10-30|Method of preparing optically active anthracyclinones
    SU613724A3|1978-06-30|Method of obtaining 8-thiomethyl-ergolines or salts thereof
    SU982541A3|1982-12-15|Process for producing derivatives of 15-hydrohymino-homoeburane or their salts, ortheir optical isomers and derivatives of intermideate 15-chloro-e-homoeburane or optical isomers
    US4228079A|1980-10-14|Dialkoxy monorden derivatives
    DK149155B|1986-02-17|METHOD FOR PREPARING ISOSORBID-2 NITRATE
    SU910118A3|1982-02-28|Process for producing n -glucofuranozid-6-yl-n -nitrosocarbamide
    HU194272B|1988-01-28|Process for producing 7,16-dioxa-2-aza-10-0-kladinosyl-12-0-dezozaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethyl-bicyclo-square bracket opened-11,2,1-square bracket closed-hexadeca-1/2/-en-8-one
    GB2036744A|1980-07-02|Eburnane derivatives
    SU1556538A3|1990-04-07|Method of producing pyrimidine derivatives
    US4560764A|1985-12-24|Synthesis of an imidazolyl isothiourea
    US4521616A|1985-06-04|Method for the preparation of fluoroanthranilic acids
    US4499294A|1985-02-12|Process for production of methyl 2-tetradecylgycidate
    HU194857B|1988-03-28|Process for production of 4-amin-6-fluor-cromane-4-carbonic acid and its 2/r/ methilesther
    US4468518A|1984-08-28|Imidazole guanidine compounds and method of making same
    SU931107A3|1982-05-23|Process for producing racemic or optically active bromoderivatives of 14-oxo-15-hydroxy-e-homoeburnanes
    KR0132188B1|1998-04-17|Preparation process of pyridobenzoxazine carboxylic acid derivatives
    Nagarajan et al.1982|Nitroimidazoles: Part IX. Addition of diazomethane to 1-methyl-5-nitro-2-acylamino-& 2-Sulphonamidoimidazoles & to 2-Dichloracetamido-5-nitrothiazole
    US4520201A|1985-05-28|Synthesis of cimetidine and analogs thereof
    SU922108A1|1982-04-23|Process for producing derivatives of 6-methyl-8-beta-hydrazinomethylergolin or their salts
    US5663411A|1997-09-02|2-benzoyl-3-[|-yl)amino]acrylate derivatives and a method for the preparation of the same
    Müller et al.1983|The Synthesis of n, n‐Dimethyl‐2‐|‐ethylamine and of Mesembrine‐Like Metabolites of this Potential Analgesic
    SU986295A3|1982-12-30|Method of producing quinoline 6-oxoderivatives
    SU753360A3|1980-07-30|Method of preparing 6,7-dimethoxy-4-amino-2/4-|-1-piperazinyl/-quinazoline
    SU1752734A1|1992-08-07|3,4-dihydroxyfurazane as an intermediate product for synthesis of compound, containing dioxafurazanyl moiety, reagents, used in analytical chemistry, and method of its synthesis
    同族专利:
    公开号 | 公开日
    NZ194316A|1982-12-07|
    FI70020B|1986-01-31|
    NL8003822A|1981-01-15|
    DE3026602A1|1981-02-05|
    JPS595595B2|1984-02-06|
    DE3026602C2|1990-05-03|
    DK302280A|1981-01-14|
    PH15654A|1983-03-11|
    GB2055368B|1983-10-19|
    DK156574C|1990-01-29|
    JPS59116285A|1984-07-05|
    BE884228A|1981-01-09|
    FR2460951B1|1983-08-26|
    FI802175A|1981-01-14|
    IL60445A|1984-05-31|
    AU6035080A|1981-01-15|
    CA1137083A|1982-12-07|
    AU534308B2|1984-01-19|
    FR2460951A1|1981-01-30|
    FI70020C|1986-09-12|
    US4314939A|1982-02-09|
    ATA358880A|1984-02-15|
    JPH0227994B2|1990-06-20|
    ZA803952B|1981-07-29|
    SE8005127L|1981-01-14|
    IT8023404D0|1980-07-11|
    SE438504B|1985-04-22|
    ES8106727A1|1981-09-01|
    AT375939B|1984-09-25|
    CH644122A5|1984-07-13|
    GB2055368A|1981-03-04|
    ES493336A0|1981-09-01|
    DK156574B|1989-09-11|
    JPS5632476A|1981-04-01|
    HU180927B|1983-05-30|
    IT1132528B|1986-07-02|
    IL60445D0|1980-09-16|
    NO802101L|1981-01-14|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    HU180514B|1977-05-26|1983-03-28|Richter Gedeon Vegyeszet|Process for producing apovinca inic esters,or esters of vicaminic and apovincaminic acids at the same time|
    HU180928B|1979-08-06|1983-05-30|Richter Gedeon Vegyeszet|Process for preparing new brominated 15-hydroxy-e-homo-eburane derivatives|
    HU181496B|1979-08-13|1983-07-28|Richter Gedeon Vegyeszet|Process for preparing 10-bromo-15-hydroxy-e-homo-eburnanes|HU181496B|1979-08-13|1983-07-28|Richter Gedeon Vegyeszet|Process for preparing 10-bromo-15-hydroxy-e-homo-eburnanes|
    HU186891B|1981-06-12|1985-10-28|Richter Gedeon Vegyeszet|Process for producing esters of apovincaminic acid|
    HU182380B|1981-09-30|1983-12-28|Richter Gedeon Vegyeszet|Process for producing esters of vincaminic acid|
    HU182411B|1981-11-03|1984-01-30|Richter Gedeon Vegyeszet|Process for preparing eburnamonine derivatives|
    HU185172B|1981-12-30|1984-12-28|Richter Gedeon Vegyeszet|Process for the preparation of hydroxy-imino-e-homo-eburnanes|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU79RI719A|HU180927B|1979-07-13|1979-07-13|Process for producing 1k-hydroximino-e-homoe-eburane de rivatives|
    [返回顶部]