• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:

    公开号:SU973025A3
    申请号:SU802989151
    申请日:1980-10-09
    公开日:1982-11-07
    发明作者:Вихерт Рудольф；Биттлер Дитер；Шлейзенер Аннерозе；Альбринг Манфред
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    Research institutes are esterified to produce ethers or esters, and the desired products are isolated by known methods.
    The reaction of the 17-keto compounds of the general formula I is carried out according to known methods with an organometallic compound (K | 2 -metal), in particular with α, 2-lithium, for example n-butyl lithium. The organometallic compound can also be prepared in a reaction solution from a haloalkane and an alkali metal, for example 1-bromopentane or 1-bromohexane and lithium. The reaction is carried out in an inert solvent {ether, tetrahydrofuran, hexane, etc.). The reaction temperature is 0-50 seconds, preferably the reaction is carried out at room temperature.
    In order to obtain 17 (-propyl compound (Ri-propyl), it is more expedient to first prepare 17c-allyl, a compound through the reaction of Grignard with allylmagnesium bromide and then hydrogenate it to 17c6-propyl compound. Hydrogenation is carried out using catalytically activated hydrogen. Catalysts are used for example, palladium on carbon and methanol or tris-triphenylphosphine-rhodium chloride in acetone. In a similar manner, a 17c-isobutyl compound is obtained through a 17c-isobutinyl compound.
    17 o6-ethyl compound (K.-ethyl can be obtained, for example, by a known method through 17c | {, - ethynyl compound. For this purpose, the 17-keto compound of general formula II, for example, with ethynylmagnesium bromide or lithium acetylide, is converted into 17a6-ethynyl compound and then hydrate to 17 ° j. -ethyl compound.
    Cleavage of the protective 3-keto group, which can be carried out before and after (under known conditions) also possible esterification (conversion to the 17-hydroxy ester or ester, is carried out by acid hydrolysis. Mineral acids (chloric, sulfuric acid) are used for cleavage of the protective group. , hydrochloric or organic acids (oxalic cleavage is carried out preferably in an alcohol solution or in other polar solvents (for example, acetone; at 20-100 o.
    For the subsequent conversion to the tertiary 17-hydroxy-ester ester, methods are used, usually used in the chemistry of steroids for esterification to the tertiary steroid alcohols. For example, you should specify the interaction with acids or acid anhydrides in the presence of strong acids (trifluoroacetic acid or p-toluenesulfonic acid) at 10-50 ° C, or interaction with an acid anhydride in the presence of a tertiary amine (pyridine or collidine at about 20-200 ° C If pyridine with 4- (dimethylamino-pyridine) is used as tertiary amines, esterification with the formation of a complex of the tertiary 17-hydroxy group can also be carried out at room temperature.
    To esterify to produce a 17-hydroxy group or hydroxyl groups in the 3- or 3- and 17-position are alkylating compounds, for example alkyl halides. Esterification to produce an ether is carried out using a known method in the presence of a strong base (caustic soda) using a polar solvent (hexamethylphosphorotriamide) at 0.33 ° C or In the presence of a strong base (sodium hydride) using ether (tetrahydrofuran) at 30 -.
    For the preparation of alkyl ethers, the carbon chain of which is interrupted by oxygen, and under certain conditions cyclized hydroxyl compound via digidropirina or alkylvinyl ethers, in the presence of a strong acid (p-tolug olsulfokislota or phosphorus oxychloride) is converted to the corresponding tetrahydropyranyl or alkoxyethyl ethers The reaction is preferably carried out in the presence of inert solvents (chloroform, dichloromethane, tetrahydrofuran, dioxane, etc., at a reaction temperature of -20 to. l preparation gidroksilnoe methoxymethyl ether compound is reacted, e.g., with formaldegidtsimetilatsetalem in anhydrous dichloromethane in the presence of phosphorus pentoxide at room temperature.
    The reduction of the keto group at the 3-position can be carried out by known methods by hydrogenation with a metal hydride. Suitable hydrogen donors are especially complex hydrides, e.g. sodium borohydride and tri- (tert-, butoxy-aluminum lithium hydride. Reduction with sodium borohydride is preferably carried out in a water-alcohol solution, dissolved with tri- (tert-, butoxy; -alum lithium hydride). - in ethereal solution. The reduction is carried out under mild conditions, preferably at 0-50 C.
    For subsequent esterification to obtain the ester of the hydroxyl group at the 3-position, for example, the reaction with an acid anhydride or acid halide in the presence of a tertiary amine (pyridine, collidine, or triethylamine at room temperature. 3-hydroxy can also be esterified to give ester using acid anhydride when using strong acid Sp-toluenesulfonic acid or with the help of the corresponding acid and trifluoroacetic acid anhydride at room temperature. and esterification to produce an ester in the presence of an acid catalyst at room temperature or in the presence of a basic catalyst at elevated temperature (20–200 C 7 can also be esterified at the same time to form a complex group of hydroxyl groups in the 3- and 17-positions. If Pyridine and 4- (dimethylamino-pyridine) are used as the main catalysts; roxyl groups can also be esterified to form ester groups in the basic medium at room temperature. About 17-ketosteroid of general formulas II used as starting materials is obtained by a known method from 1c methyl-5-6-androstan-17p-ol-3-one by introducing a protecting group in and oxidation in the 17-position. The preparation of compounds of general formula II can be shown, for example, in the preparation of 3, 3-ethylenedioxy-lob-methyl-5-6-androstan-17-one. 20 g of 17p-oxy-1oC-methyl-5v6-androe stan-3-one in 500 ml of benzene together with 60 ml of ethylene glycol and 600 mg of n-loulesulfonic acid are stirred for 5.5 h at boiling temperature with a fridge when using a water separator. After cooling, the reaction solution was diluted with ether, washed with sodium bicarbonate solution and water, and dried. After evaporation, 23 g of crude 3, α-ethylenedioxy-loL -methyl-5-6-androst -17fb-it is obtained. 23 g of 3,3-ethylenedioxy-1O6-methyl-5O1.-Androstan-17 | b-it in 230 ml of dichloromethane along with 20 g of pyridinium chlorochromate in the presence of 20 g of sodium acetate is stirred for 1 h at a carbonate temperature. The reaction solution is then diluted with ether, filtered off insolubles, and the filtrate is washed with water. After drying and evaporation, 21.5 g of 3,3-ethylenedioxy-1vC-methyl-5cA-androstan-17-one are obtained as a crude product. Example 1. 800 g of magnesium shavings in 20 ml of absolute ether are reacted with 2 g of allyl bromide in 5 ml of absolute ether to produce allyl magnesium bromide. To this solution, at room temperature, 2 g of 3,3-ethylenedioxy-1o. -Methyl-5a-androstan-17-one in 5 ml of dichloromethane are added and stirred for 3 hours. The ice-cooled reaction solution is then slowly mixed with saturated milk. A saturated solution of ammonium chloride is diluted with ether and washed with a saturated solution of ammonium chloride and water. After drying and evaporation, 2.1 g of 3,3-ethylenedixy-loL-methyl-17c are obtained. - (2-propenyl-5 ° -androstan-17 ol as a crude product. 2.1 g 3, 3-ethylenedioxy-lQi-methyl 17Y - (2-propenyl-5 o-androstan-17E-ol in 106 ml of methanol is hydrogenated in the presence of 210 mg of 10% palladium on carbon until the equivalent of hydrogen is taken in. The catalyst is filtered off and the filtrate is evaporated in vacuo to give 2.1 g of 3,3-ethylenedioxy-loi-methyl-17-6-n-propyl-5-o - -androstan-17-ol as a crude product. A sample recrystallized from diisopropyl ether melts at 150-150. 1.5 g of 3,3-ethylenedioxy-1e6-methyl-17 o -n-propyl-5-6-androstane 17 to 30 ml of methanol 3 ml of water together with 1.5 g of oxalic acid is stirred for 2 hours at room temperature, then diluted with ether, rotted with water and dried. After evaporation, the residue is chromatographed on silica gel and 1.1 g of 17 / -oxy-1o-ketil- are obtained. 17o-n-propyl-5 s - ndrostan-E-it in the form of oil, 5 (SCHEZ). O Example 2. 1.25 g 3,3-ethylenedioxy-1 OC, -methyl-5 cL-androstan-17on in 12.5 ml of absolute tetrahydrofuran, while cooling with ice and passing argon, is mixed with 3.5 ml of butyl lithium solution (15% in hexane) and stirred for 22 hours at room temperature. An excess amount of the reagent is then decomposed with water, the reaction solution is diluted with ether, and treated with water. After drying and evaporation, the residue on silica gel chromatographs yields 950 mg of 17 o-n-butyl-3,3-ethylenedioxy-1 cL-methyl-5 in 6-androstan-17 B -ola as a crude product 950 ml of 17od-n- butyl-3,3-ethylenedioxy-lo6-methyl-5at-andprostan-17-ola in 10 ml of methanol is stirred with 1 MP of 8% sulfuric acid for 30 minutes at room temperature. Dilute with ether, wash with water and dry. The residue obtained after evaporation is chromatographed on fa silica gel and 620 mg of 17 C1 / -n-butyl-17r-hydroxy-1 0 -methyl-5o-Andrstan-3-one are obtained in the form of an oil, TrfJ | +5, b (chloroform).
    Example 3. 400 ml of lithium are squeezed out with ice-cold absolute tetrahydrofuran (20 ml) and then 7.8 ml of 1-rootutane is added dropwise. At the end of the reaction, 1.6 g of 3, 3-ethylenedioxy-1 o6-methyl-5a.-androstan-17-one is added dissolved in 8 ml of absolute tetrahydrofuran and stirred 48 hours at room temperature under argon atmosphere. After chromatography on silica gel, 1.1 g of 3,3-ethylenedioxy-1, o-methyl-17Ob-n-amyl-5 ci-androstan-17 fi-ol, are obtained in the form of an oil,
    1.0 g of 3, 3-ethylenedioxy-1, o4.-m "tyl17" with 1-n-pmil-5o-androstan-17 -ola is used as in Example 2 for cleavage of the ketal and treated as in Example 2.:. After chromatography on silica gel, 720 J-hydroxy-1 ot-methyl17 o1-n-amyl-5 b6-androstan-3-one is obtained in the form of an oil.
    Example 4 “Isovom of ice-cold absolute tetrahydrofuran squeeze out 500 mg of lithium and then 11.3 ml of 1-bromhexane is added dropwise. At the end of the reaction, 2.0 g 3 is added dropwise. The 3-ethylenedioxy-1 has noted –5 with –androstan-17-one in 10 gl of absolute tetrahydrofuran and stirred for 48 hours at room temperature in an argon atmosphere. Processed as described in Example 2 and chromatographed on silica gel. 950 mg of 3, 3-ethylenedioxy-1 et-n-hesyl-lot-methyl-5cC-androstan-17-ol are obtained in the form of an oil.
    850 mg of 3,3-ethylenedioxy-17 ° C-n-hesyl-1 with methyl-5 oi-androstan-17 / i-ol are converted as in Example 2 to the ketal cleavage conditions and treated as in Example 2. After chromatography on silica gel, 630 mg of 17 ° C-n-hexyl-17 p-hydroxy-1o-methyl-5 db-androstan-3-one are obtained in the form of an oil.
    Example 5 1.5 g of magnesium shavings in 40 ml of absolute tetrahydrofuran are brought into contact with 4.9 t – m of ethyl bromide to give ethyl magnesium bromide. This solution is added dropwise in 40 MP of absolute tetrahydrofuran, and acetylene is passed through the ink. 3 g of 3,3-ethylenedioxy-1o-methyl-5o-androstan-17-one to a solution of acetylene magnesium bromide drbavl Fri 3 g and stirred for 23 hours at room temperature. Under ice cooling, the excess reagent is decomposed with a saturated solution of ammonium chloride, then diluted with ether and washed with water. After drying and evaporation, the residue is chromatographed on silica gel, and 2.65 g of 17 revinyl 3, 3-ethylenedioxy-1 pC-methyl-5 o-androstan-17 are obtained (in the form of crude product
    1.4 g of 17o-ethynyl-3,3-ethylenedioxy-1o (-methyl-5 O.-androstan-17p -ea in 70 ml of methanol is hydrogenated in the presence of 200 mg of 5% palladium on carbon to absorb two equivalents of hydrogen The catalyst is then filtered and evaporated in vacuo.
    1.4 g of 17 ° -ethyl-3, 3-ethylenedioxy-1 o -methyl-5 with b-androstan-17 p ol are obtained in the form of an oil.
    1.4 g 17 ° C-ethyl-3,3-zylenedioxy-:.-Methyl-5 ° C-androstan-17th jol
    used as in example 2 for the cleavage of ketal and treated as in example 2. After chromatography on silica gel and recrystallization from diisopropyl
    1.1 g of 17; 6-ethyl-17-oxy-lot-methyl-5 ot-androstan-3-one with m.p. 151.5-152 ,.
    Example 6. 5.0 g of 17 | b-hydroxy-1c -methyl-17 o - n-propyl-5 ot-androstan-3-one in 5 ml of absolute tetrahydrofuran together with 5.0 g of tri-tert-butoxyl lithium hydride stirred for 3 hours at room temperature. The mixture is diluted with ether, washed with dilute sulfuric acid and water, evaporated and evaporated. After chromatography on silica gel and review by circumstances, recrystallization from diisopropyl ether gives 860 ml of 1 ° C methyl 17 {-n-propyl-5 o4 - androstan-3 / 3-17 diol with m.p. 117-118 with and 3,3 g 3 about isomer with. 143-144 seconds
    Example 7. 1.5 g17 --OKCH1 o -methyl-17 ° C-n-propyl-5cC-androstan-3-one in 6 ml of pyridine together with 3 ml of acetic anhydride after the addition of 75 mg of 4-dimethyl1 "non-pyridine) is left to stand 16 h at room temperature. After precipitation with ice water and recrystallization from hexane, 1.3 g of 17 (-acetoxy-lci-methyl-17oi-H-napropyl-5c-androstan-3-one with mp 128-129 ° C.) are obtained.
    Example B 1.0g 17} 3-acethyxy-lai-methyl-17o6-n-propyl-5 oLandrostan-3-one is reacted with tri-tert-butoxyalkyl lithium and treated as in Example 6. After chromatography on silica gel, 650 mg of 17/3-acetoxy-1 o -methyl-17 oL-n-propyl-5c6-androstan-3 p-ol are obtained in the form of an oil. Example 9 250 mg of 17p-acetoxy-1o. Methyl-17O1-n-propyl-5 oLandrostan-3 in 1 ml of pyridine together with 0.5 ml of anhydrous oil anhydride settle for 48 hours at room temperature. The mixture is diluted with ether and washed several times with water.
    dried and evaporated. The residue is chromatographed on silica gel. 270 mg of 17p-acetoxy-3-butyry of riloxy-1o-methyl-17cC-n-propyl-5o (.-Androst on oil is obtained.
    Example 10. 400 mg of 17 / -acetoxy-1 with / -methyl-17e / .- n-propyl-5-androstan-3, -ola in 2.8 ml of absolute di: alormethane and 1.8 ml of dimethyl formaldehyde are mixed with a mixture of 600 mg of W20 diatomaceous earth and 300 mg of phosphorus pentoxide is stirred for 45 min at room temperature. Sucked off insoluble parts and washed with dichloromethane, which contains 3-5% triethylamine. The crude product obtained after evaporation is chromatographed on silica gel. 280 mg of 17p-acetoxy-3-methoxy-1c -methyl-17o (-n-propyl-5c-androst is obtained.
    Elemental analysis:
    Calculated,%: H 10.99 / 0 10.4b; C 78.5
    Found,%: H ll, 2i; o 10, 78.38
    Example 11. 400 mg of 17 p -oxy1 "A-methyl-17o1-n-propyl-5o-androst-3-one in 1.6% pyridine and 0.8 ml of enanthic anhydride with the addition of 40 mg of 4-dimethylaminopyridine are mixed 42 h at room temperature. It is diluted with ether, rolled through with water, dried and evaporated. The residue is chromatographed on silica gel. Get 370 yg 17 / J-heptanoyl hydroxy-lot-methyl-17 sL-and-propyl-5 ° C-androstan-3-one in the form of oil.
    Example 12. 7, O g 3,3-ethyldioxy-1 aC-methyl-5 o1 - androstan-17-one in 70 ml of tetrahydrofuran mixture. with 2.8 g of magnesium shavings, then 14.35 ml of crotyl bromide in 15 ml of tetrahydrofuran is slowly added dropwise and then further stirred for 45 minutes at room temperature. The excess reagent is decomposed under ice-cooling with ammonium chloride solution, then the reaction solution is diluted with ether, washed with water, dried and evaporated. The residue is chromatographed on silica gel to obtain 1.95 g of 3.3 ethylene dioxy-1 A-methyl-17 dt- (1-methyl-2-propenyl-5 oi-androstan-17 fi-ol as a crude product.
    1.92 g of 3,3-ethylenedioxy-l (-methyl-l 7 oL - (1-methyl-2-propenyl) -5 ° C-androstan-17 p-ol in 19.2 ml of methanol and together with 1, U2 ml of 8% sulfuric acid is stirred for 15 minutes at room temperature, then diluted with ether, washed with water until the reaction is neutral, dried and evaporated. The residue is chromatographed on silica gel and recrystallized from diisopropyl ether to obtain 780 ml of 17 f) -oxy-1 C-methyl-17c - (1-methyl-2-propenyl) -5 € /.- androstan-3-one with m.p. 148.5-150s.
    770 mg of 17 / L-hydroxy-lci-methyl-17o (1-methyl-2-propenyl) -5 with 1-androstan-3-one in 5 ml of tetrahydrofuran and 15 ml of methanol in the presence of 150 mg of 10% palladium. carbon is hydrogenated until the equivalent of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo. Remainder
    chromatographic on silica gel. After recrystallization from diisopropyl ether, 440 mg of 17 / -oxy1 o (- methyl-17cc - (1-methyl-n-propyl) -5 cz - androstan-3-one with mp. 172.5 173,.
    Elemental analysis:
    Calculated,%: C 76, 87; n 10.84, O 12.20. Found,%: C 76.79; n 10.62, o. 1,1,47. Example 13. 70.0 mg 1 ot-methyl-17 o.n.-propyl-5 ot-androstan-Zo 17 (-diol (prepared according to Example 6, mp. 143-144 s, 2.8 ml of pyridine and 1.4 ml of acetic acid anhydride are settled for 22 hours at com-.
    natnoy.temperatura. After precipitating with ice water, the resulting crude product is chromatographed on silica gel to obtain 760 mg of BN-acetoxy-1 oL-methyl-17c | L-n-propyl-5 androstan-17 / B ol as an oil.
    Example 14, 1.5 g of 1o -methyl-. -17c / -n-propyl-5 ° C-androstan-3 oi - 17f -diol in 6 ml of triethylamine and 1.5 mg of acetic anhydride together with 50 mg of 4-dimethylaminopyridine are defended
    for 6 days at room temperature. After precipitating with ice water, the resulting crude product was chromatographed on silica gel to obtain 1.08 g of 17 p-diacetoxy-1 or 1 methyl-17c (.- n-propyl-5 oL-androstg with a mp of 99 ° C.
    1 Approx 15. 1g 3,3-ethylenedioxy-1 / - methyl-17 jL- (2-propenyl 5 ° C-androstan-17 / -ol (prepared according to example 1 in 10 ml of methanol together with 1 ml of 8% - sulfuric acid is stirred for 15 min at room temperature and rubbed as in Example 12. After over
    710 mg of 17 / L-hydroxy-1 "-methyl-17at- (2-propenyl-5 ct.-an; Drostan-3-one with mp 115-11 bs) are obtained from crystallization from diisopropyl ether.
    权利要求:
    Claims (2)
    [1]
    1. A method for preparing 17c6 alkyl steroids of the general formula
    Obl
    "ABOUT
    dt
    -Wg
    I
    n
    65
    Rjj - this is hydrogen, acyl
    .-Su-group;
    R is an alkyl C ,, - C5 group j X is an oxygen atom or a group
    H orjl where
    Rj is a hydrogen atom, acyl, or methyl group,
    characterized in that the etosteroid of the general formula
    ABOUT
    I5
    H
    where V is the protection of an ethylenedioxy group, is brought into contact with the host.
    the remainder. with an organometallic compound, the protective group is cleaved at the 3-position and, depending on the desired R value and in general, the 17-hydroxy group is esterified to form an ester group before or after cleavage of the protective group in the 3-position, the 3-keto group is reduced, after whereupon the free hydroxyl groups at the 3-position are esterified to produce ethers or esters and the desired products are isolated.
    Sources of information taken into account in the examination
    1. German patent 1152100, cl. 12 About 25/02, published. 1974.
    [2]
    2. Fizer L. and Fizer M. Reagents for organic synthesis. M., Mir, t. 1, p. 236-237, 1970.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR1382468A|1964-01-28|1964-12-18|Spofa Vereinigte Pharma Werke|Process for the preparation of 1-methyl-substituted 3-keto-androstane compounds, and products according to those obtained by the present or similar process|
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    申请号 | 申请日 | 专利标题
    DE19792943776|DE2943776A1|1979-10-26|1979-10-26|17ALKYLSTEROIDS, THE PREPARATIONS CONTAINING THE SAME, AND METHOD FOR THE PRODUCTION THEREOF|
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