• 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:
    The invention relates to a new process for the preparation of known aromatase inhibitors of the following formula <CHEM> wherein each of R1 and R3, independently, is hydrogen or C1-C6 alkyl; R2 is hydrogen, halogen or C1-C6 alkyl and R4 is hydrogen or fluorine; the process comprising subjecting to Mannich reaction a compound of formula <CHEM> wherein R1,R2,R3 and R4 are as defined above, and then oxidizing the respective 6-methylene derivative thus obtained.
    公开号:SU1681731A3
    申请号:SU884356486
    申请日:1988-09-09
    公开日:1991-09-30
    发明作者:Лонго Антонио；Ломбарди Паоло
    申请人:Фармиталиа Карло Эрба С.Р.Л.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dione of the general formula
    H °
    Df
     T1
    O T T C
    "2 SNT
    where RI and Ra are each independently hydrogen or C1-C4-alkyl;
    Ra is hydrogen, chlorine, fluorine or bromine;
    R is hydrogen or fluorine, known aromatase inhibitors used in the treatment of hormone tumors
    The purpose of the invention is to simplify the process of obtaining the desired products by eliminating a reagent such as dichlorodicyanobenzoquinone and double purification by column chromatography.
    Example 1. 6-Methylenandrost-1,4-diene-17/3-ol-3-one (compound (IV): RI R2
    Ra - R4 H).
    A stirred mixture of 106.2 g (3.54 mol) of paraformaldehyde and 346.4 g (4.248 mol) of dimethylamine hydrochloride in 3.6 l of isopentanol is heated (temperature about 131 ° C) under a nitrogen atmosphere in a reflux flask equipped with a trap Dean-stark. About 900 ml of a mixture of isopentanol and the separated water is collected and removed. Intramolecular temperature
    the reactions are lowered to 10-15 ° C and 90 g (0.314 mol) of boldenone (i.e. androsta-1,4-diene-17/3-olone) are added to the reaction mixture, after which the mixture is again heated in a flask for 15 hours. After cooling, the mixture is treated with 1.2 liters of 0.1N IMaOH solution and stirred for 30 minutes. The organic phase is separated, washed with water and evaporated in vacuo (external temperature 80 ° C), thus obtaining 1.6 L of suspension. The supernatant is separated, the precipitate is washed twice with 100 ml of hexane in portions and then crystallized from 500 ml of a mixture of ethanol and water (70:30). The filtered white precipitate was dried under vacuum at 40 ° C, giving 28.7 g (0.963 mol, yield 30.7%) of this product. T, pl. 135-137 ° C.
    NMR (CDCIa, 5): 0.82 (3N, s); 1.15 (ЗН, s); 3.67 (1H, m); 4.97 (2H, m); 6.23 (2H, m); 7.08 (1H, d).
    Example 2. b-Methylenandrost-1,4-diene-3,17-dione (compound (I): Ri Ra Ps R4 H).
    To a stirred solution of 2.8 g (0.963 mol) of 6-methylene-androst-1,4-diene-17 / -ols-3-one in 700 ml of acetone at -10 ° C is added dropwise 35 ml of Jones reagent. After that, the reaction mixture is stirred for 10 minutes and then thoroughly treated with 50 ml of isopropanol. After further stirring for one hour, the resulting precipitate is filtered and washed thoroughly with acetone. The combined filtrate and washing solution was mixed with 100 g of sodium bicarbonate for 1 hour, filtered and evaporated in vacuo. The resulting solid is combined with 500 ml of water, filtered, washed with water, and then dried under vacuum at a temperature of about 40 ° C, and 25 g of a solid are formed. Further purification by crystallization from 300 ml of a mixture of 65:35 ethanol and water gives 22.4 g (0.76 mol, 79% yield) of the compound. T. pl. 192-195 ° C.
    Found: C 81.01; H 8.16
    C20H2402
    Calculated: C 81.04; H 8.05
    UV (USN, m / 0: 247 (e 13750).
    NMR (CDCI3, 5): 0.94 (3N, s); 1.17 (ЗН, s); 5.04 (2H, m); 6.18 (1H, brs); 6.25 (1H, dd); 7.09 (1N.d).
    Using the same procedure and starting with the corresponding compound of formula (IV), the following final compounds can be obtained:
    1-methyl-6-methylenandrost-1,4-di- -3,17-dione, m.p. 178-180 ° C; Found: C 81.18; H 8.37
    C21H2602
    Calculated: C, 81.25; H 8.44
    1-Ethyl-6-methylenandrost-1,4-diene-3,17-dione: Found: C, 81.32; H 8.62
    C22H2802
    Calculated: C, 81.44; H 8.70
    4-Methyl-6-methylenandrost-1.4-diene-3,17-diene:
    Found: C, 81.15; H 8.32
    C21H2602
    Calculated: C, 81.25; H 8.44
    4-Chloro-6-methylenandrost-1,4-diene-3, 17-dione. T. pl. 148-150 ° C:
    Found: C, 72.40; H, 6.91; CI 10.53
    C20H23C102
    Calculated: C, 72.61: H, 7.01; CI 10.72
    NMR (CDCI3, 5): 0.84 (3N, s); 1.24 (3N, s); 5.13 (1 N. s); 6.37 (1 N. d); 7.08 (1 H, d);
    mass spectrometry (m / z): 330;
    4-bromo-6-methylenandrost-1,4-diene-3, 17-dione
    Found: C, 63.90; H 6.03; Vr 21.15
    С2оН2зВг02
    Calculated: C, 64.00; H 6.18; Wg 21,29
    4-fluoro-6-methylenandrost-1,4-diene-3, 17-dione
    Found: C, 76.35; H 7.34; F 6.01
    C20H23F02
    Calculated: C 76.41; H 7.37; F 6.04 4-chloro-1-methyl-6-methyl e n androsta-1,4-dien-3., 17-dione;
    4-bromo-1-methyl-6-methyleneandrosta-1,4 -diene-3,17-dione
    Found: C, 76.75; H 7.62; F 5.71
    C21H25F02
    Calculated: C, 76.80; H 7.67; F 5.79
    Similarly, the following 7- and / or 16-substituted derivatives can be obtained in the form of simple epimers or in the form of their mixture:
    1,7-dimethyl-15-fluoro-6-methylenandros-α-1,4-diene-3,17-dione
    Found: C, 77.05; H, 7.80; F 5.45
    C22H27F02
    Calculated: C, 77.16; H 7.95; F 5,55 16-fluoro-4-chloro-1,7-dimethyl-6-methylene androsta-1,4-diene-3,17-dione
    Found: C, 70.05; H 6.89; CI 9.32; F 4.99
    C22H26CIF02
    Calculated: C, 70.11; H 6.95; CI 9.41; F5.04
    权利要求:
    Claims (1)
    [1]
    The invention The method of producing methylene derivatives of androsta-1,4-diene-3,17-dione of the general formula
    (I)
    where Ri and Rs are each independently hydrogen or C 1 -C 4 alkyl;
    R2 is hydrogen, chlorine, fluorine or bromine;
    R4 is hydrogen or fluorine, characterized in that, in order to simplify the process, the compound is
    QTT formulas
    Ri „K
    R,.
    00
    where Ri - R4 have the indicated meanings,
    interact with paraformaldehyde and hydrogen halide amine of the general formula
    R,
    R
    /
    Yang
    HE)
    where each of R is the same or different - lower C1-C4-alkyl, in isopentanole at reflux temperature (reflux) to give a compound of the general formula
    Ri
    20
    (Iv)
    II
    Zchl
    where RI - R4 have the indicated meanings, the hydroxy group of which is then oxidized.
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    引用文献:
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