• 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:

    公开号:SU860708A1
    申请号:SU792718151
    申请日:1979-01-25
    公开日:1981-08-30
    发明作者:Даль Хельмут；Шеттле Эрнст；Виске Райнхольд；Вебер Альфред；Кеннеке Марио
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of steroids of general formula not described in the literature. :: v-BASIS 1 V I where dashed line indicates a possible double bond; X is hydrogen, fluorine or methyl; Y is hydrogen or lower alkanoyloxy, Z is hydrogen or methyl, V is methylene or ethylidene, R, is lower alkyl or an oxygen-interrupted alkyl group is hydrogen or lower alkyl, or Cc and R are three or tetramethylene groups if Y is alkanoyl-oxylate pharmacological activity. A known method for producing steroid-type acetals is that the alcohol is reacted with an aliphatic acetal in the presence of an acid catalyst l. The purpose of the invention is a method for producing new pharmacologically active steroids of general formula 1, based on the use of a known reaction. The objective is achieved by a method for producing steroids of the general formula I, in that the steroid of the general formula COCET; l-OH g, where V, X, y, Z are the above values, W is a carbonyl group, if the double bond is in position 4 , 5 and optionally 7,8, or W group of the formula D b and the alkanoyloxy group, if the double bond is in the 5.7 position, is reacted with acetal of the general formula III (RjCHCOR), where R and Kj have the above values or vinyl ester of general formula IV "4CH CHOR, where R- is as defined above, and R is water genus or lower alkyl or together with R - ethylene or trimethylene if Y alkanoyloxy, and in the resulting compound, if necessary oxidized 3 P- alkanoyloxy with simultaneous isomerisation of the double bond D followed by isolation of the desired product. The process is carried out in the presence of acid catalysts such as chloric acid, p-toluenesulfonic acid or phosphorus pentoxide, without a solvent or in an inert solvent, for example, chlorinated hydrocarbons, toluene, ether, tetrahydrofuran, dioxane. The temperature of the process is maintained between and + 50s using compounds of general formula III and from to. case of compounds of General formula IV. Steroids of General Formula I exhibit high anti-inflammatory activity. Example 1. a) 21.63 g of 3 / J21 -diacetoxy-17o-hydroxy-5-pregnen-20-one is dissolved in 150 ml of anhydrous methylene chloride and 100 ml of anhydrous formaldehyde dimethyl acetal. The solution is then cooled with water and added to a mixture of phosphorus pentoxide (21.6 g) and kieselguhr (43 g) and stirred for one hour at room temperature. The reaction mixture is then filtered and the residue is washed with methylene chloride, triethylamine is added to the filtrate until the pH has reached rffeT 9, and concentrated in vacuo. The residue was recrystallized from methanol-methylene chloride to obtain 22.68 g of 3p, 21-diacetoxy-17c-methoxymethoxy-5-pregnen-20-one with a melting point of 182-184c. b) An Erlenmeyer flask with a capacity of 2 with a sterile nutrient solution with a pH of 7 in an amount of 1 liter containing O, 3% yeast extract 0.3% Comsteep ilgour And 0.2% starch sugar is inoculated with dry culture FIavobacte Ium dehydrogenans ATCC 13930 and Shake for two days (175 rpm). In a 500 ml Erlenmeyer flask, 85 ml of the same nutrient medium are inoculated with 10 ml of the grown F1avobacte Ium dehydrogena culture and shaken at 7 ° C for 7 hours (175 rpm). Then, 5 ml of a sterile solution of 0.5 g of Zr, 21-diacetoxy-17c5fm-methoximethoxy-5-progen-20-ona in dimethylformamide is added to the culture in a dimethylformamide and shaken at 65 more hours (175 rpm). After the fermentation, the culture is extracted twice with 100 ml of ethylene chloride, the extract is concentrated under vacuum, the residue is purified by chromatography on alumina and 402 ml of 21-hydroxy-17s-methoxymethoxy-4-pregnen-3, 20-diode with a melting point of 152 is obtained 153 ° C. Example 2. a) 50 g of 3fi 21-diacetoxy-17o-hydroxy-5-pregnen-20-one is mixed with 50 mg of anhydrous p-toluenesulfonic acid and 350 ml of anhydrous methylene chloride, cooled to 0, and after adding 10 g of methyl vinyl ether is stirred in for 4 h at 0 ° C. Triethylamine is then added until the pH reaches 9 and concentrated in vacuo to obtain 58 g of 3 p 21-diacetoxy-17c6- (1-methoxy-totoxy) -5-pregnen-20-one as a diastereomeric mixture with a melting point of 80-118 ° C (the sample recrystallized from methanol melts at 132-134 ° C). b) Under the conditions of Example 1c, a solution of 600 mg of 3 P 21-diacetoxy-17cl- (l-methacroxyethioxy) -5-inter1-20-one in the form of a diastereomeric mixture in 5 ml of dimethylformamide is treated with a culture of Flavobjterium dehvdroqenans ATCC 13CC 135 dimethylformamide and treated with Flavobjcterium dehvdroqenans ATCC 13CC 135 dimethylformamide and treated with Flavobjcterium dehvdroqenans ATCC 13CC 3 15 ml of dimethylformamide and treated with Flavobjcterium dehvdroqenans ATCC 13CC dimethylformamide and treated with Flavobjcterium dehvdroqenans ATCC 13CC 3 15 ml of dimethylformamide. 394 mg of 21-hydroxy-17o (.- (l-methoxyethoxy) -4-propene-3, 20-dione as a diastereomeric mixture with a melting point of 166-178s. Example 3. South 21-acetoxy-17c-hydroxy-4- pregnen-3, 20-dione is mixed with 13 mg of anhydrous p-toluenesulfonic acid and 130 ml of anhydrous methylene chloride, cooled before and after the addition of 2.3 g of methyl vinyl ether is stirred for 7 hours at P. The reaction mixture is worked up as in Example 2a, and 11.6 g of 21-acetoxy-17-c6 (1-methoxyethoxy) -4-pregnen-3,20-dione are obtained with a melting point of 135-150 ° C. South of 21-acetoxy-17c-hydroxy-4-pregnen-3, 20-dione with the conditions described in the example. Under the conditions, 2.5 g of ethyl vinyl ether is treated; 12.5 g of 21-acetoxy-17cC are obtained .- (1-ethoxyethoxy) -4-pregnen-3, 20-dione as an oily diastereomeric mixture. Example5. South of 21-acetoxy-177-hydroxy-4-pregnen-3, 20-dione with the conditions described in Example 4. 4 g of isobutylvinyl ether is treated with conditions to obtain 13.5 g of 21-acetoxy-17c3- (1-isobutyloxyethoxy) -4 - pregnen-3, 20-dione as an oily, diastereomeric mixture. Example 6. 1.95 g of 21-acetoxy-17o-hydroxy-4-pregnen-3, 20-dione is mixed with 5 mg of anhydrous p-toluenesulfonic acid, 25 ml of anhydrous methylene chloride and 3.5 dihydropyran and stirred for 13 hours at room temperature. temperature The reaction mixture is worked up as described in Example 3, and 2 g of 21-acetoxy-176-6 (2-tetrahydropyranyloxy) -4-pregnen-3, 20-dione are obtained as a diastereomeric mixture with a melting point of 185-200 ° C. Ex. 7. 7. 50 g of 21-acetoxy-17 -hydroxy-6ob1-methyl-4-pregnen-3, 20-dione, using the conditions described in the Example For example, are treated with 13.9 g of methylBINyl ether and get 59 g 21 -acetoxy-17c - {1-methoxyethoxy) -b, -methyl-4-pregnen-3, 20-dione in the form of an amorphous mass. Example 8. 2g of 21-acetoxy-17c6-hydroxy-1br-methyl-4-pregnen-3, 20-dione is mixed with 5 mg of anhydrous p-toluenesulfonic acid and 35 ml of anhydrous methylene chloride and cooled to. Then, with stirring, 0.5 g of methyl vinyl ether is added, stirred for 5 hours at approx. C, and for another 12 hours at room temperature, the reaction mixture is worked up, as described in Example 3A, and 2.1 g of 21-acetoxy-17-6 is obtained. (1-methoxyethoxy) -16f methyl-4-cinne-3,20-dione as an oily diastereomeric mixture. Example 9. 50 g of 17c hydroxy-4-pregnen-3, 20-dione, using the conditions described in the Example For example, are treated with 15 g of methyl vinyl ether and 51.2 g of 17c / g of (1-methoxyethoxy) -4-pregnane are obtained. 3.20-dione with a melting point of 115-152 ° C. Example 10. a) 50 g of 3 P21-diacetoxy-17c) 6-hydroxy-5-pregnen-20-one, under the conditions described in Example 1a, in 150 ml of methylene chloride are treated with 380 g of formaldehyde-hydroxy glycol monomethyl ether, 50 g half-thiocarboxylic phosphorus and 100 g of kieselgur, 45.8 g of 3 p21-diacetoxy-17ot - (2-methoxyethoxy-methoxy) -5-pregnen-20-one with a melting point of 160-161 C are obtained. b) As described in example 1b Use 0.5 g of 3 j 21-diacetoxy-17o - (2-methoxyethoxy-methoxy) -4-pregne 720-it is treated with Flav bacterium debydrogenans ATCC 13930 and get 390 mg of 21-hydroxy-176 -6- (.2- methoxyethoxy-methoxy-4-pregn nz, 20-dione in the form of a glassy mass. Example 11. Zg 17o (.- hydrox-19-nor-4-pregnen-3,20-dione is suspended in 75 ml formaldehyde dimethyl acetal, cooled in an ice bath and mixed in portions with a mixture of 7.5 g of kieselguhr and 4.5 g of phosphorus semi-thioxy. After 3 h, the mixture is filtered and the pH of the filtrate is adjusted to 9 using triethylamine. acetate, get 1.48 g of 17a1-methoxymethoxy-19-nor-4-pregnen-3, 20-dione, which after recrystallization of methanol by melting its at 120s. Example 12. 5 g of 17 ° (goxy-19-nor-4-pregnen-3, 20-dione under the conditions described in example 1a, are subjected to the reaction of fusion with formaldehyde and get 17c-ethoxymethoxy-19-nor-4-pregnane- 3, 20-dione with a melting point of 69-71 ° C. Example 13. 5 g of 17c6-oxy-19-nor-4-pregnen-3, 20-dione under the conditions described in example 1a are subjected to an exchange reaction with formaldehyde dipropylacetate, 17c1-propoxymethoxy-19-nor-4-pregnen-3, 20-dione with a melting point of 97-99 ° C are obtained and obtained. Example 14. 50 g of 21-ethoxy-17o-oxy-4-pregnen-3, 20-dione suspended with 600 ml of formaldehyde diethyl etata and 600 ml of methylene chloride and cooled to a temperature of minus minus 40 C. While stirring, a mixture of 75 g of phosphorus pentoxide and 150 g of kieselguhr is added, then stirred for 30 hours at minus. The solution is filtered and neutralized with triethylamine. and the residue is recrystallized from methanol to obtain 35.9 g of 21-acetoxy-17c-ethoxymethoxy-4-pregnen-3, 20-dione, which, after repeated recrystallization, has a melting point of 137-139s. Example 15. 25 g of 21-acetoxy-17-hydroxy-4-pregnen-3,20-dione are suspended with 200 ml of formaldehyde dipropylacetate and 320 ml of methylene chloride, then cooled to minus. While stirring, a mixture of 49.3 g of phosphorus pentoxide and 97 g of kieselguhr is added, followed by stirring for 22 hours at minus. The solution is filtered and neutralized with triethylamine. Methylene chloride is distilled off in vacuo and the phase containing formaldehyde dipropyl acetate is drained from the separated oil. After distilling off an additional amount of the solvent in vacuo, 19 g of crystalline 21-acetoxy-1b-propoxymethoxy-4-stragene-3, 20-dione with melting point 145-14 ° C are obtained. Example 16. 50 g of 21-acetoxy-17c6-hydroxy-: 4-pregnen-3-, 20-dione are suspended with 500 ml of formaldehyde dibutyl acetal and 500 ml of methylene chloride, then cooled to minus. While stirring, a mixture of 74 g of phosphorus pentoxide and 150 g of kieselguhr is added, followed by stirring for 30 hours at minus. The solution is filtered and neutralized with triethylamine. Methylene chloride is distilled off in vacuo and the phase containing formaldehyde cycloacetal is removed from
    oil released. After distillation of an additional amount of the solvent in vacuo, 38.7 g of crystalline 21-acetoxy-1 lai-butythoxymethoxy-4-pregnen-3, 20-dione with a melting point of 123.5124, are obtained.
    Example 17. 10.6 g of 21-acetoxy-6o1-fluoro-17o, -oxy-4-pregnen-3, 20-dione are dissolved in 265 ml of methylene chloride and 47.7 ml of formaldehyde dimethyl acetal, a mixture of 7.95 is added in portions g of phosphorus pentoxide and 15 g of kieselgur and stir the mixture for 90 minutes in a nitrogen atmosphere at room temperature. The solution is filtered and mixed with 2.1 ml of triethylamine. The solvent was distilled off and the residue was recrystallized from methanol to obtain 7.6 g of 21-acetoxy-6o-fluoro-177-methoxymethoxy-4-pregene-3, 20-dione with a melting point of 161-167 s.
    Example 18. a) 43 g 3} b, 21-diacetoxy-17c "oxy-16 | -methyl-5-pregnen-20-it is dissolved in 800 ml of formaldehyde-dimethyl acetal and cooled to minus. Add in separate portions a mixture of 43 g of phosphorus pentaoxide and 86 g of kieselguhr and stir the mixture for 15 hours at a temperature of about minus. The solution is filtered, neutralized with triethylamine and the solvent is distilled off in vacuo. The residue is recrystallized from methanol to obtain 31.5 g of 3 |, 21-diacetoxy-17c1-methoxymethoxy-16p-methyl-5-Pregnen-20-one with a melting point of 1 17-118 ° C.
    b) F1avobacterigm dehydrogenans ATCC 13930 is extracted, as indicated in Example 1b, and fermented. After 6 hours, 4 ml of a sterile solution of 0.2 g Pp, 21-diacetoxy-17e-methoxymethoxy-16 P-methyl-5-pregnen-20-one in dimethylformamide is added to the culture and shaken for an additional 6 to 5 hours.
    . After subsequent fermentation. the culture is treated as described in Example 16, and 163 mg of 21-hydroxy-17c6-methoxy-methoxy-1b -methyl-4-pregnen-3, 20-dione with melting point 126 / 128-129 C are obtained.
    Example 19. 29.1 g of 21-acetoxy-b-chloro-17c-oxy-4, 6-pregnadien-3, 20-dione are dissolved in 730 ml of methyl enchloride and 131 ml of formaldehyde dimethyl acetal. 22.12 g of phosphorus pentoxide and 44 g of kieselgur are added in portions of the mixture) and the mixture is stirred for 2.5 hours under nitrogen at room temperature. The solution is filtered and mixed with 5.8 ml of triethylamine. The solvent is distilled off and the residue is recrystallized from methanol with the addition of activated carbon and 1% triethylmino to obtain 15.6 g of 21-acetoxy-6-chloro-17 ° -methoxymethoxy-4, b-pregnadiene-3,20-dione with a melting point 183-1.8bs.
    Example 20. a) 38.85 g of 21-acetoxy-17c-oxy-4-pregnen-3, 20-dione are mixed with 235 g of formaldeld 5 hyddiisopropyl acetal and 500 ml of methylene chloride and cooled to minus 20c. With stirring, a mixture of 75 g of phosphorus pentoxide and 150 g of kieselguhr is added and stirred for 20 hours at minus 20 ° C.
    The mixture is filtered, washed with methylene chloride and the pH is adjusted to 9 by the addition of triethylamine. The solvent is distilled off in vacuo and the residue is taken up in methylene chloride. The solution is washed with half the sodium chloride solution, dried with sodium sulfate, treated with activated carbon, sucked off through kieselgur and concentrated in vacuo. The residue is chromatographed on kieselgur with a mixture of toluene and ethyl acetate, to obtain 35.8 g of 21-acetoxy-17o1. Isopropoxymethoxy-4-pregnanei-3, 20-dione, which after -crystallization with pentane has
    5, melting point 111-117 °.
    权利要求:
    Claims (1)
    [1]
    1. Fizer L., Fizer M.
    Steroids. M., 1974, p. 322-323,
    类似技术:
    公开号 | 公开日 | 专利标题
    US4611067A|1986-09-09|Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein
    EP0606044A1|1994-07-13|Lactones compounds useful as pharmaceuticals
    EP0044158B1|1984-08-15|Novel optically active imidazolidin-2-one derivatives and their production
    SU860708A1|1981-08-30|Method of preparing steroids
    Mukaiyama et al.1992|An efficient method for the preparation of carboxylic esters via mixed anhydrides by the promotion of a catalytic amount of Lewis acid
    CH651005A5|1985-08-30|TERPENOIDS CONTAINING TWO FUNCTIONAL GROUPS AND PROCESS FOR THEIR PREPARATION.
    US3900512A|1975-08-19|2-|-4|-hydroxy-2-cyclopenten-1-one and method for preparing same
    EP0501310A1|1992-09-02|Method for optical resolution of corey lactone diols
    US4415501A|1983-11-15|Alkenylzirconium reagents useful for prostaglandin analog synthesis
    US7153983B2|2006-12-26|Chemo-enzymatic process for the preparation of opticaly enriched β-benzyl-γ-butyrolactones
    Ohta et al.1993|Total synthesis of grahamimycin A1
    US4158012A|1979-06-12|Steroid synthesis process using mixed anhydride
    US4940797A|1990-07-10|Process for synthesis of FK-506 C10-C18 intermediates
    US4618690A|1986-10-21|Process for the preparation of |-4-hydroxy-2-cyclopentenyl esters
    US4225524A|1980-09-30|Steroid derivatives and process for preparing the same
    JPH06256278A|1994-09-13|Optically active alpha-carbamoylalkanoic acid derivative and its production
    DeCamp et al.1989|Synthesis of |-dihydromevinolin by selective reduction of mevinolin
    US4914220A|1990-04-03|Process for synthesis of E-2-methyl-α,β-unsaturated aldehydes
    CA1131238A|1982-09-07|Process for the preparation of bicycliclactone diol derivatives
    US4603013A|1986-07-29|Estrane derivatives
    US4603213A|1986-07-29|Total synthesis of 1RS,4SR,5RS-4-|-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid
    Izawa et al.1992|A facile enantioselective synthesis of |-1-amino-2, 3-bishydroxymethylcyclobutane derivatives, a key synthetic intermediate of carbocyclic oxetanocins
    US5136112A|1992-08-04|Process for preparing 2-hydroxy-2 5, 5, 9-tetramethyldecalyl ethanol
    KR100543172B1|2006-01-20|A Process for Preparing Terrein Compounds
    US4672132A|1987-06-09|Process for producing an aldehydelactone
    同族专利:
    公开号 | 公开日
    AU4366579A|1979-08-02|
    DD141524A5|1980-05-07|
    AT371824B|1983-08-10|
    IE790135L|1979-07-25|
    GB2013685A|1979-08-15|
    JPS54145649A|1979-11-14|
    DD150223A5|1981-08-19|
    US4224320A|1980-09-23|
    ES477161A1|1979-07-01|
    HU184189B|1984-07-30|
    ATA50379A|1982-12-15|
    GR73667B|1984-03-28|
    CA1139743A|1983-01-18|
    AU529413B2|1983-06-09|
    CS212218B2|1982-03-26|
    EP0003519A1|1979-08-22|
    DK28679A|1979-07-26|
    IL56495D0|1979-03-12|
    DE2803660A1|1979-07-26|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2924597A|1958-04-08|1960-02-09|Ormonaterapia Richter S P A|Process for the preparation of 17alpha hydroxy-progesterone, esters thereof, and intermediates therefor|
    US3187025A|1963-06-11|1965-06-01|Smith Kline French Lab|Process for preparing compound s|
    DE1543245C3|1965-11-26|1974-07-18|Merck Patent Gmbh, 6100 Darmstadt|16-Methy len-19-norprogesterone derivatives, processes for their production and pharmaceutical preparations containing them|
    NL6605514A|1966-04-25|1967-10-26|
    US3530117A|1969-01-09|1970-09-22|Merck & Co Inc|Delta4 and delta4,6 - 17 - hydroxy - steroidal pyrazoles of the pregnane series|DE2952003A1|1979-12-21|1981-07-02|Schering Ag Berlin Und Bergkamen, 1000 Berlin|NEW KORTIKOID-17-THIOACETALE, THEIR PRODUCTION AND USE|
    FR2552766B1|1983-10-04|1987-06-26|Theramex|NEW PROCESS FOR THE PREPARATION OF DERIVATIVES FROM THE 17 A-HYDROXY 19-NOR PROGESTERONE SERIES|
    US4588683A|1984-02-06|1986-05-13|Eastman Kodak Company|Method of preparing 11β, 17α, 20, 21-tetrahydroxy steroids and corresponding 11β, 17α, 21-trihydroxy-20-oxo steroids|
    US4588525A|1984-02-27|1986-05-13|Molecular Biosystems, Inc.|Prodrug compounds for dermal application|
    JP2562134B2|1986-09-19|1996-12-11|喜徳 喜谷|Novel platinum-steroid complex|
    PL178307B1|1993-01-08|2000-04-28|Astra Ab|Novel ileum and colon specific steroid derivatives|
    US5710293A|1995-10-13|1998-01-20|The Population Council, Center For Biomedical Research|Method of preparation of ester derivatives of steroids|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782803660|DE2803660A1|1978-01-25|1978-01-25|NEW IN 17-POSITION SUBSTITUTED STEROIDS OF THE PREGN SERIES, THEIR PRODUCTION AND USE|
    [返回顶部]