• 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 preparing steroid intermediates of the formula …<CHEM>… in which pivaloyl chloride is added to a compound of the formula …<CHEM>… the resulting compound of the formula …<CHEM>… is reacted with a Grignard reagent of the formula …<CHEM>… wherein X is Cl or Br,… and the resulting compound of the formula …<CHEM>… is cyclized in the presence of a base. …<??>Compound I in turn may be readily converted by known methods to valuable steroids. …<??>Disclosed as a mixed anhydride steroid intermediate of formula III is 7a beta -methyl-2,3,3a alpha , 4, 5, 6, 7; 7a-octahydro-1H-inden-1,5-dione-4 alpha -(3-propionic acid) pivalic acid mixed anhydride.)
    公开号:SU999977A3
    申请号:SU792776318
    申请日:1979-06-18
    公开日:1983-02-23
    发明作者:Ф.Купер Генри；Р.Ван Хорн Альберт
    申请人:Синтекс (Ю.С.А.) Инк (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING 3,3-ETHYLENEDIOXN.-4,5-SECO-19-NOHORHDROST-9-EN-5,17-DIONA -. .-. I. - - The invention relates to / improved method of obtaining 3,3-ethylenedioxy-4,5-seco-19-norandrost-9-ene-5, 17-dione formula which finds use as an intermediate product in the synthesis of pharmacologically active steroids A method of obtaining 3,3-ethylenedioxy-4, 5-seco-19-noradrost-9-ene-5, 17-dione of formula (I) is known, which means that 3,3-ethylenedioxy-5-oxo- 17-oxy-4, 5-scooestte is oxidized with a solution of chromic anhydride in sulfuric acid in a further manner; , 3, 3-ethylenedioxy-17j-oxy-5-oxy-4, 5-secoestra-9-ene is obtained from 1-hydroxy-4- (2-carboxyethyl) -7a-methylhydrin-3-one, which by heating in acetic acid anhydride with sodium acetate is converted to rf-lactone 1-acetoxy-4- (2-carboxyethyl) -7a-methyl-3a, 4,7,7a-tetrahydroindane. The latter is reacted with an organomagnesium compound of the general formula (II) where X is chlorine or bromine, in ether at, and the substance obtained is treated with alkali in aqueous alcohol at the boiling point. The disadvantage of this method is relatively low. The purpose of the invention is to increase the yield of the target product. The goal is achieved by the fact that according to the method of obtaining 3, 3-zylenedioxy-4,5-seco-19-norandrost-9-ene-5, 17-dione of formula (I) 4- (2-carboxy-methyl) -7a-methyl hydridend 1, 5-dione is reacted with pivaloyl chloride in the presence of a tertiary amine and the resulting mixed anhydride of the formula is treated with an organomagnesium compound of the general formula (G1) in ether at -80 to -55c, followed by heating the resulting compound of the formula io in aqueous alcohol in the presence of bases neither at boiling point followed by isolation of the desired products. com famous method. Moreover, tritylamine is preferably used as a tertiary amide. Distinctive features of the method are the use of 4- (2-carboxyethyl) -7a-methylhydrindan-5-one 4- (2-carboxyethyl) -7a-methyl hydrindan-1,5-dione as a derivative, which is reacted with pivaloyl chloride in in the presence of a tertiary amine and the reaction of the resulting mixed anhydride of the formula (III) CO 2) 2 COCC () C with the organomagnesium compound of the formula (II) at -80 - -55 ° C to form the compound of the formula (ly) Preferably pivaloyl chloride and amine are used in approximately equimolar quantities. The acylation reaction is carried out in an inert organic solvent, for example ether, diethyl ether or tetrahydrofuran. Tetrahydrofuran is particularly preferred. The use of ether in this reaction step and the absence of a significant excess of acid chloride and amine allow the next stage of the addition of Grignard reagent to be added in the same solvent without the need to purify the mixed anhydride or remove the tertiary amine hydrochloride salt. The step of forming a mixed anhydride of formula (III) is carried out at a temperature of approximately -50 + 20 ° C, most preferably -30, for approximately 15 minutes to 2 hours. The progress of the reaction of formation of the mixed anhydride is controlled by precipitation from a reaction mixture of triethylamine hydrochloride The mixed anhydride is separated from the solvent by filtration and evaporation, however, it is preferable not to separate this intermediate compound, but directly use the tetrahydrofuran solution of the mixed anhydride in the next, stage ssov. Preferably, the Grignard reagent of general formula (II) is used in the form of a solution in tetrahydrofuran with a concentration of 0.5-2.0 M, preferably about 1.0 M. The Grignard reagent is added to the mixed anhydride solution at -70 - -65. The compound of formula (IV) is cyclized to the tricyclic compound of formula (I) in the presence of a base. The cyclization in an alkaline medium is carried out using sodium hydroxide or potassium hydroxide in an aqueous solvent medium, preferably in an aqueous alcoholic solvent medium, for example, an aqueous solution of methanol. Although the amount of alkali with respect to compound (IV) is not critical, it is preferable to use a base in 210-fold molar excess. The cyclization reaction is carried out at 40-80 ° C, best of all at the boiling point of a water-alcohol solution. The reaction is carried out in an atmosphere of inert gas, for example nitrogen. Applying the invention without separating or purifying the intermediates results in approximately 80% yield of the tricyclic compound of formula (I). Example. A solution of 5 g of (+) 7a L-methyl-2, 3, Sad, 4, 5, b, 7,7a-octahydro-lH-indene-l, 5-dione-4cC- (3-propionic acid) with t. square 108-109C in 48 ml of anhydrous tetrahydrofuran (THF) and 2.12 g of triethylamine are cooled under nitrogen to. After stirring for 5 minutes at -30, 2.56 g of trimethylacetyl chloride was injected with a syringe. The mixture was left Harpei until -20 and stirred at this temperature for 30 minutes. The aliquot was filtered and evaporated to dryness. The resulting mixed anhydride (+) -7a | -methyl-2,3, 4,5, 6,7, 7a-octahydro-1H-inden-1,5-dione-4O1 .- (3-propionic acid) and pivalic acid shows the following characteristic peaks in the IR spectrum : 1820, 1745, 1710, 1010, and 1040 cm. The reaction mixture is cooled before and 22.1 ml of 0.95 m Grignard reagent is added in 40 min.
    权利要求:
    Claims (1)
    [1]
    / Claims 1. A method for producing 3,3-ethylenedioxy-4,5-seco-19-norandrost-9-en-5,17-, dione of the formula
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    同族专利:
    公开号 | 公开日
    DD144269A5|1980-10-08|
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    DK246479A|1979-12-20|
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    PL123780B1|1982-11-30|
    AT7600T|1984-06-15|
    JPH0129792B2|1989-06-14|
    CS212221B2|1982-03-26|
    HU181503B|1983-10-28|
    YU142779A|1983-02-28|
    CS212220B2|1982-03-26|
    EP0006355A1|1980-01-09|
    JPH0316333B2|1991-03-05|
    JPS6425747A|1989-01-27|
    SG38287G|1987-07-24|
    HK96787A|1987-12-24|
    DK129491D0|1991-07-02|
    JPS552675A|1980-01-10|
    PL216413A1|1980-03-24|
    JPS645034B2|1989-01-27|
    ES481650A1|1980-04-16|
    PL118827B1|1981-10-31|
    HU186974B|1985-10-28|
    DE2967004D1|1984-06-28|
    EP0006355B1|1984-05-23|
    DK129491A|1991-07-02|
    JPS6425772A|1989-01-27|
    引用文献:
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    US3117979A|1960-01-22|1964-01-14|Roussel Uclaf|Esters of 10beta-substituted 4, 5-seco-delta9-19-nor-androstene-17beta-ol-3, 5-dines, intermediates and process|
    FR1255101A|1960-01-22|1961-03-03|Chimiotherapie Lab Franc|Process for alkylating intermediates in the synthesis of 10-alkyl 19-nor steroids|
    BE657261A|1962-03-06|
    NL130550C|1966-05-26|
    US3984473A|1968-10-04|1976-10-05|Hoffmann-La Roche Inc.|Stereospecific total steroidal synthesis via substituted C/D-trans indanones|
    US3686215A|1969-03-27|1972-08-22|Syntex Corp|Production of 5,6,7,7a-tetrahydroindan-5-ones|
    SE367181B|1969-05-14|1974-05-20|Takeda Chemical Industries Ltd|
    US3813417A|1970-08-26|1974-05-28|Hoffmann La Roche|Cycloalkylbenzopyrans|
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    JPS58134577A|1982-02-05|1983-08-10|Nippon Kogaku Kk <Nikon>|Electrooptic optical control element|
    NL8602767A|1986-10-31|1988-05-16|Gantax Nv|ORGANIC ACID ANHYDRIDE, AND A PHARMACEUTICAL PREPARATION BASED ON A PRODRUG.|
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    法律状态:
    优先权:
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