WO2019128154A1 - 甾体药物17位侧链的合成方法 - Google Patents

甾体药物17位侧链的合成方法 Download PDF

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WO2019128154A1
WO2019128154A1 PCT/CN2018/092378 CN2018092378W WO2019128154A1 WO 2019128154 A1 WO2019128154 A1 WO 2019128154A1 CN 2018092378 W CN2018092378 W CN 2018092378W WO 2019128154 A1 WO2019128154 A1 WO 2019128154A1
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reaction
compound
synthesizing
side chain
position side
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PCT/CN2018/092378
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杨坤
于传云
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广西万德药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of drug synthesis, in particular to a method for synthesizing a 17-position side chain of a steroid drug.
  • Steroid hormones refer to hormone drugs containing a steroid structure in the molecular structure. They are clinically important drugs, mainly including adrenal cortex hormones and sex hormones. As an important adrenocortical hormone drug, steroid hormone drugs are the isomers of dexamethasone, which acts on the same effect as ponisone and dexamethasone, and has anti-inflammatory, anti-rheumatic, anti-allergic and immunosuppressive effects. A variety of pharmacological effects, steroid hormone drugs and their analogues have become one of the most widely used drugs in clinical practice. Pharmacological studies have shown that the efficacy of steroid hormone drugs is closely related to the C 17 side chain, and the development of the C 17 side chain preparation method of steroid hormone drugs is of great significance. Its structural formula is as follows:
  • the cyanidation reaction inevitably uses highly toxic acetone cyanohydrin or sodium cyanide. Especially when R 16 is ⁇ or ⁇ -CH 3 , the purity and yield of cyanidation reaction are low, and the reaction waste Liquid treatment and reaction solvent recovery are difficult, and production safety accidents are prone to occur.
  • the object of the present invention is to provide a method for synthesizing the 17-position side chain of a steroidal drug with high safety, environmental protection, high yield and high purity, which has solved the above-mentioned prior art, has large safety hazards, is not environmentally friendly, and has low reaction yield.
  • the problem of high purity of the intermediate is to provide a method for synthesizing the 17-position side chain of a steroidal drug with high safety, environmental protection, high yield and high purity
  • the present invention proposes a method for synthesizing a 17-position side chain of a steroid drug, and the specific technical scheme is as follows:
  • R 16 is ⁇ or ⁇ -CH 3 , or -H 2 ;
  • R 16 is as defined above;
  • rings A and B represent the following groups:
  • R 3 represents a residue of an ether or an ester, and when R 3 represents a residue of an ether, R 3 is a C 1 -C 2 hydrocarbon group or a C 6 -C 8 aromatic hydrocarbon; and when R 3 represents an ester residue When it is -COR 3 ;
  • the method for synthesizing the 17-position side chain of the steroid drug, the polar aprotic solvent in the synthesis step S1 is diethyl ether or tetrahydrofuran, and the non-nucleophilic strong base is lithium diisopropylamide, two different One of lithium butylamide and lithium di-sec-butylaminoamide, the co-solvent is dichloromethane or chloroform.
  • the organic solvent in the step S3 is one or more of an organic weak base solvent such as pyridine, 4-methylpyridine or triethylamine;
  • the eliminator is one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride.
  • the method for synthesizing the 17-position side chain of the steroid drug, the step S4' ketal protection is: adding the orthoester in the organic solvent under the protection of an inert gas in the presence of a catalyst
  • the compound is prepared by reacting a mixed diol, a dithiol or a thiol of the formula HO-(CH 2 ) n -OH, HS-(CH 2 ) n -SH or HO-(CH 2 ) n -SH.
  • the method for synthesizing the 17-position side chain of the steroid drug is one of hydrochloric acid, hydrobromic acid and p-toluenesulfonic acid;
  • the organic solvent is dichloromethane, chloroform, benzene Or one or more of toluene;
  • the orthoester compound is one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate.
  • the molar ratio of the compound I, the 3-hydroxypropionitrile and the non-nucleophilic strong base in the step S1 is 1: (1.2 to 1.5): 2.4 ⁇ 3)
  • the reaction is kept at a reaction temperature of -80 to -20 °C for 2 to 5 hours.
  • the molar ratio of the compound II to the acetic anhydride in the step S2 is 1: (1.05 to 1.2); the reaction temperature is 0 to 50 ° C, and the reaction time is 1 to 4h.
  • the method for synthesizing the 17-position side chain of the steroid drug, the molar ratio of the compound III and the eliminator in the step S3 is 1: (1.1 to 1.5); the reaction temperature is -40 to 0 ° C, the reaction time It is 0.5 to 2 hours.
  • the method for synthesizing the 17-position side chain of the steroid drug, the molar ratio of the compound IV, the orthoester and the diol compound in the step S4' is 1: (1.2 to 1.5): (2 to 3)
  • the reaction temperature is 25 to 40 ° C, and if benzene or toluene is used as a solvent, the reaction temperature is 80 to 110 ° C; and the reaction time is 2 to 6 hours.
  • the method for synthesizing the 17-position side chain of the steroid drug, the oxidizing agent in the steps S4 and S5' is potassium permanganate, the organic solvent is a mixed solvent of acetone and ethylene glycol, and the reaction temperature is - 10 ⁇ 20°C, preferably 0 ⁇ 5°C, reaction time is 2-6h; if the oxidant is potassium citrate, the organic solvent is pyridine or triethylamine, the reaction temperature is 20-40 ° C, preferably 25-30 ° C; The reaction time is 18 to 24 hours.
  • the invention has the following advantages:
  • the present invention provides a novel method for synthesizing the key 17-position side chain of steroid hormone drugs, and the auxiliary materials used are non-toxic or low-toxic, which is environmentally friendly.
  • the cyano group on 3-hydroxypropionitrile is used instead of the highly toxic substances such as acetone-acetonitrile or sodium cyanide, which is safer and more environmentally friendly, and the reaction in each step is relatively easy to achieve.
  • the rate is high, the purity is high, the production is more economical and safe, and it is more suitable for industrial production.
  • the method for synthesizing the 17-position side chain of the present invention avoids the limitation of the reaction of the 1,4 double bond at the same time, and has high yield and low cost.
  • Figure 1 is a liquid phase spectrum of the oxidation product of Example 1;
  • Example 2 is a liquid phase spectrum of the oxidation product of Example 2.
  • the inert gas is helium, argon, nitrogen, helium, neon; polar aprotic solvent diethyl ether or tetrahydrofuran; non-nucleophilic strong base is lithium diisopropylamide, lithium diisobutylamide and di-second One of butylamino lithium; the co-solvent is dichloromethane or chloroform; the non-nucleophilic strong base is prepared by diisopropylamine, diisobutylamine or under the protection of an inert gas.
  • One of di-sec-butylamine, and n-butyllithium and n-hexane are reacted at a temperature of -80 to -40 ° C;
  • the molar ratio of compound III to the eliminator is 1: (1.1 ⁇ 1.5); the reaction temperature is -40 ⁇ 0 ° C, the reaction time is 0.5 ⁇ 2h; the inert gas is helium One of argon, nitrogen, helium and neon; the eliminator is one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride; the organic weak base solvent is pyridine, 4-methylpyridine, three One or more of ethylamine and the like;
  • the oxidant is potassium permanganate
  • the organic solvent is a mixed solvent of acetone and ethylene glycol
  • the reaction temperature is -10 to 20 ° C, preferably 0 to 5 ° C
  • the reaction time is 2 to 6 h
  • the oxidizing agent is potassium citrate
  • the organic solvent is pyridine or triethylamine
  • the reaction temperature is 20 to 40 ° C, preferably 25 to 30 ° C
  • the reaction time is 18 to 24 hours.
  • a method for synthesizing a 17-position side chain of a steroid drug is as follows:
  • the liquid funnel was mixed with 100 ml of dichloromethane and 250 ml of water, and the mixture was allowed to stand.
  • the organic phase was separated.
  • the aqueous phase was extracted with 50 ml of dichloromethane.
  • the organic phase was combined and washed twice with 100 ml of 0.5 eq.
  • the organic layer was dried over sodium sulfate, and concentrated to a small volume under reduced pressure at 40 ° C. EtOAc (EtOAc) . Yield: 86.8%, purity: 98.3%.
  • EtOAc EtOAc
  • EtOAc m EtOAc m.
  • the solid was dissolved in 150 ml of acetone, and 300 ml of water was slowly added dropwise, and the mixture was filtered under suction. The solid was dried at 50 ° C to obtain 18.4 g of a white solid compound V. Yield: 87.2%, purity: 98.6%.
  • Lithium / tetrahydrofuran solution about 15min drop, -45 ° C incubation reaction 0.5h, 5.46g of 3-hydroxypropionitrile and 39ml of ether mixed into the above non-nucleophilic strong base, 40min drop, keep the system
  • the temperature does not exceed -30 ° C, at this time the system is suspended, add 12 ml of dichloromethane to dissolve; the system is reduced to -60 ° C, take 20g of compound I, dissolved in 80ml of ether, drip into the above reaction system, about 2h
  • the reaction was terminated by adding 75 ml of a saturated aqueous solution of ammonium chloride and adjusted with 20% hydrochloric acid.
  • the organic phase was combined and extracted twice with water, 150 ml each time, and the organic phase was dried over anhydrous sodium sulfate Concentrate to near dryness, give a pale yellow solid crude, add the crude product to 50ml of dichloromethane, and filter. , 50 deg.] C and drying the solid to yield 23.1g fine white solid, compound II, weight yield: 115.5%, purity: 97.7%.
  • the reaction system was transferred to a separatory funnel, and 100 ml of dichloromethane and 250 ml of water were added and mixed well.
  • the organic phase was separated, and the aqueous phase was extracted with 50 ml of dichloromethane.
  • the organic phase was combined and washed twice with 100 ml of 0.5 equivalent of diluted hydrochloric acid.
  • the organic phase was dried over anhydrous sodium sulfate, and concentrated to a small volume under reduced pressure at 40 ° C., and then, the mixture was evaporated to dryness. Yellow solid, compound IV. Weight yield: 90.32%, purity: 98.7%.
  • the mixture was stirred and suction filtered, and the organic layer was separated, and the aqueous phase was extracted with 50 ml of ethyl acetate.
  • the organic phase was combined and washed twice with 100 ml of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 45 to 50 ° C.
  • the solid was dissolved in 150 ml of acetone, and 300 ml of water was slowly added dropwise to crystallize, suction filtered, and dried at 50 ° C to give 17.60 g of white solid. Weight yield: 88.98%, purity: 98.9%.
  • a method for synthesizing a 17-position side chain of a steroid drug is as follows:
  • the organic phase was combined and extracted twice with water, 150 ml each time, and the organic phase was dried over anhydrous sodium sulfate. Concentrate to near dryness at ⁇ 45°C under reduced pressure to give a crude yellow solid. Add the crude product to 50ml of chloroform. , Isolated by suction filtration, dried solid was 50 °C, to give fine white solid 23.5g, Compound II, Yield: 117.5%, purity: 98.1%.
  • the organic phase was separated, the aqueous phase was extracted with 50 ml of ethyl acetate, and the organic phase was combined and washed twice with 100 ml of water.
  • the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness at 45 ° C under reduced pressure. 300 ml of water was slowly added dropwise to the crystals, suction filtered, and the solid was dried at 50 ° C to obtain 17.82 g of a white solid. Yield: 88.44%, purity: 98.8%.
  • a method for synthesizing a 17-position side chain of a steroid drug is as follows:
  • the system was adjusted to pH 7.2 with 20% hydrochloric acid, and the organic phase was separated, and the aqueous phase was extracted twice with 50 ml of dichloromethane. The organic phase was combined and extracted twice with water, 150 ml each time. Dry, concentrated under reduced pressure at 40 ° C to near dryness to give a crude yellow solid. Beating, isolated by suction filtration, dried solid was 50 °C, to give fine white solid 23.4g, Compound II, Yield: 117%, purity: 98.5%.
  • the aqueous phase was extracted with 50 ml of ethyl acetate.
  • the organic phase was combined and washed twice with 100 ml of water.
  • the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness at 45 to 50 ° C.
  • 150 ml of acetone 300 ml of water was slowly added dropwise to the crystals, suction filtered, and the solid was dried at 50 ° C to obtain 18.30 g of a white solid. Yield: 88.26%, purity: 99.1%.

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Abstract

提供了一种甾体药物17位侧链的合成方法，其特征在于该甾体药物17位侧链的合成以化合物Ⅰ为起始原料，经亲核、酯化、消除、氧化反应等反应合成17位侧链，相较于传统工艺，采用3-羟基丙腈上氰基，而不使用丙酮腈醇或氰化钠等剧毒物，安全、环保性更高，而且各步反应相对容易实现，收率高，纯度高，生产更加经济、安全，更适合工业生产。

Description

甾体药物17位侧链的合成方法 技术领域
本发明涉及药物合成领域，特别是涉及一种甾体药物17位侧链的合成方法。
背景技术
甾体激素类药物(steroidhormonedrugs)是指分子结构中含有甾体结构的激素类药物，是临床上一类重要的药物，主要包括肾上腺皮质激素和性激素两大类。甾体类激素药物作为重要的肾上腺皮质激素类药物，为地塞米松的同分异构体，作用于波尼松龙和地塞米松相同，具有抗炎、抗风湿、抗过敏和抑制免疫等多种药理作用，甾体类激素药物及其类似物已成为临床使用最广泛的药物之一。药理研究表明，甾体类激素药物的药效与C 17侧链密切相关，开发甾体类激素药物C 17侧链制备方法具有十分重要的意义。其结构式如下所示：
Figure PCTCN2018092378-appb-000001
对于甾体激素类药物的合成，大部分难点集中在17位侧链的合成，特别是甾体类激素药物和地塞米松这两大甾体激素类药物；中国专利申请号为201310595026.0，公开号为CN103641878A的专利文献公开了一种甾体类激素药物17位侧链的制备方法，其合成路线如下所示：
Figure PCTCN2018092378-appb-000002
该合成路线，氰化反应不可避免的用到剧毒的丙酮氰醇或氰化钠，特别是 R 16为α或β-CH 3时，其氰化反应纯度和收率都较低，反应废液处理、反应溶剂回收都较困难，易出现生产安全事故。
以上背景技术内容的公开仅用于辅助理解本发明的发明构思及技术方案，其并不必然属于本专利申请的现有技术，在没有明确的证据表明上述内容在本专利申请的申请日已经公开的情况下，上述背景技术不应当用于评价本申请的新颖性和创造性。
发明内容
本发明的目的在于提出一种安全、环保、收率高、纯度高的甾体药物17位侧链的合成方法，已解决上述现有技术存在的安全隐患大、不环保、反应收率低、中间体纯度高的问题。
为此，本发明提出一种甾体药物17位侧链的合成方法，具体技术方案如下：
一种甾体药物17位侧链的合成方法，所述甾体激素类药物中间体的结构式如下所示：
Figure PCTCN2018092378-appb-000003
式中，R 16为α或β-CH 3，或者-H 2；
S1：亲核反应，在惰性气体保护下，3-羟基丙腈和极性非质子溶剂混合，用非亲核性强碱处理后加入助溶剂，再与化合物Ⅰ反应，制得化合物Ⅱ；
Figure PCTCN2018092378-appb-000004
式中，R 16定义同上；
式中，环A和B代表以下基团：
Figure PCTCN2018092378-appb-000005
式中，R 3代表醚或酯的残基，当R 3代表醚的残基时，R 3为C 1～C 2的烃基或C 6～C 8的芳烃；当R 3代表酯的残基时，其为-COR 3；
S2：酯化反应，用吡啶和乙酸酐对化合物Ⅱ进行处理，得化合物Ⅲ；
Figure PCTCN2018092378-appb-000006
S3：消除反应，在惰性气体保护下，化合物Ⅲ溶于有机溶剂中，与消除剂反应制得化合物Ⅳ；
Figure PCTCN2018092378-appb-000007
S4：氧化反应，若起始原料环A和B为Ⅰ a，化合物Ⅳ直接经氧化反应制得化合物Ⅴ a；
Figure PCTCN2018092378-appb-000008
S4’：缩酮保护，若起始原料环A和B为Ⅰb，化合物Ⅳ需对3-羰基进行缩 酮保护制得化合物Ⅴ b；
Figure PCTCN2018092378-appb-000009
S5’：氧化反应，化合物Ⅴ b经氧化反应制得化合物Ⅵ。
Figure PCTCN2018092378-appb-000010
优选地，所述的甾体药物17位侧链的合成方法，所述合成步骤S1中的极性非质子溶剂为乙醚或四氢呋喃，非亲核性强碱为二异丙基氨基锂、二异丁基氨基锂和二仲丁基氨基锂中的一种，助溶剂为二氯甲烷或三氯甲烷。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S3中的有机溶剂为吡啶、4-甲基吡啶、三乙胺等有机弱碱溶剂的一种或多种；所述消除剂为二氯亚砜、三氯氧磷和五氯化磷中的一种。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S4’缩酮保护为，在惰性气体保护下，在催化剂存在下，化合物Ⅳ在有机溶剂中，加入原酸酯类化合物，和化学式为HO-(CH 2) n-OH、HS-(CH 2) n-SH或HO-(CH 2) n-SH的混合二醇、二硫醇或硫醇反应制得。
优选地，所述的甾体药物17位侧链的合成方法，所述所述催化剂为盐酸、氢溴酸及对甲苯磺酸中的一种；所述有机溶剂为二氯甲烷、氯仿、苯或甲苯中的一种或多种；所述原酸酯类化合物为原甲酸三甲酯、原甲酸三乙酯、原乙酸三甲酯和原乙酸三乙酯中的一种。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S1中化合物Ⅰ、3-羟基丙腈和非亲核性强碱的摩尔比为1:(1.2～1.5):(2.4～3)，在反应温度为-80～-20℃条件下保温反应2～5h。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S2中化合物Ⅱ和乙酸酐的摩尔比为1：(1.05～1.2)；反应温度为0～50℃，反应时间为1～4h。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S3中化合物Ⅲ和消除剂的摩尔比为1:(1.1～1.5)；反应温度为-40～0℃，反应时间为0.5～2h。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S4’中化合物Ⅳ、原酸酯和二醇类化合物的摩尔比为1：(1.2～1.5):(2～3)；若用二氯甲烷或氯仿作溶剂，反应温度为25～40℃，若用苯或甲苯作溶剂，反应温度为80～110℃；反应时间为2～6h。
优选地，所述的甾体药物17位侧链的合成方法，所述步骤S4和S5’中的若氧化剂为高锰酸钾，有机溶剂为丙酮和乙二醇的混合溶剂，反应温度为-10～20℃，优选为0～5℃，反应时间为2～6h；若氧化剂为锇酸钾，有机溶剂为吡啶或三乙胺，反应温度为20～40℃，优选为25～30℃；反应时间为18～24h。
本发明与现有技术相比，优势有以下：
(1)本发明提供了一种合成甾体类激素药物关键17位侧链的新方法，所用辅料无毒或低毒，利于环保。
(2)相较于传统工艺，采用3-羟基丙腈上氰基，而不使用丙酮腈醇或氰化钠等剧毒物，安全、环保性更高，而且各步反应相对容易实现，收率高，纯度高，生产更加经济、安全，更适合工业生产。
(3)本发明合成17位侧链的方式，避免了1,4双键同时存在对反应的限制，收率高、成本低。
附图说明
图1是实施例1的氧化产物的液相图谱；
图2是实施例2的氧化产物的液相图谱。
具体实施方式
一种甾体药物17位侧链的合成方法，具体实验操作如下：
S1亲核反应：在惰性气体保护下，化合物Ⅰ、3-羟基丙腈和非亲核性强碱的摩尔比为1:(1.2～1.5):(2.4～3)，在反应温度为-80～-20℃条件下保温反应2～5h；
所述惰性气体为氦气、氩气、氮气、氖气、氙气；极性非质子溶剂乙醚或四氢呋喃；非亲核性强碱为二异丙基氨基锂、二异丁基氨基锂和二仲丁基氨基锂中的一种；助溶剂为二氯甲烷或三氯甲烷；所述的非亲核性强碱的制备过程为，在惰性气体保护下，由二异丙胺、二异丁胺或二仲丁胺中的一种，和正丁基锂、正己烷于-80～-40℃温度下反应制得；
S2酯化反应：化合物Ⅱ和乙酸酐的摩尔比为1:(1.05～1.2)；反应温度为0～50℃，反应时间为1～4h；
S3消除反应：在惰性气体保护下，化合物Ⅲ和消除剂的摩尔比为1:(1.1～1.5)；反应温度为-40～0℃，反应时间为0.5～2h；所述惰性气体为氦气、氩气、氮气、氖气、氙气的一种；消除剂为二氯亚砜、三氯氧磷和五氯化磷中的一种；有机弱碱溶剂为吡啶、4-甲基吡啶、三乙胺等中的一种或多种；
S4’缩酮反应：若起始原料环A和B为Ⅰb，化合物Ⅳ需对3-羰基进行缩酮保护制得化合物Ⅴ b；其中，化合物Ⅳ、原酸酯和二醇类化合物的摩尔比为1：(1.2～1.5):(2～3)；若用二氯甲烷或氯仿作溶剂，反应温度为25～40℃，若用苯或甲苯作溶剂，反应温度为80～110℃；反应时间为2～6h；
S4和S5’氧化反应：若氧化剂为高锰酸钾，有机溶剂为丙酮和乙二醇的混合溶剂，反应温度为-10～20℃，优选为0～5℃，反应时间为2～6h；若氧化剂为锇酸钾，有机溶剂为吡啶或三乙胺，反应温度为20～40℃，优选为25～30℃；反应时间为18～24h。
下面列举几个具体的实施例进行详细解释：
实施例1
一种甾体药物17位侧链的合成方法，工艺流程如下：
Figure PCTCN2018092378-appb-000011
具体实验步骤如下：
室温、氮气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入34.74ml二仲丁胺，降至-50℃，滴加125ml浓度为1.6mol/L的正丁基锂/正己烷溶液，约15min滴完，-80℃保温反应0.5h，将5.75g的3-羟基丙腈和39ml的四氢呋喃混合液滴入上述非亲核性强碱中，0.5h滴完，保持体系温度不超过-30℃，此时体系为悬浊态，加12ml二氯甲烷溶清；体系降至-60℃，取20g化合物Ⅰ，溶于80ml四氢呋喃中，滴入上述反应体系，约1h滴完，-80℃保温反应2h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至5℃，加入75ml饱和氯化铵水溶液终止反应，用20％的盐酸调节体系PH＝7，静置分出有机相，水相用50ml二氯甲烷萃取2次，合并有机相并用水萃取2次，每次用水150ml，有机相用无水硫酸钠干燥，40+℃减压浓缩至近干，得淡黄色固体粗品，将粗品加入50ml二氯甲烷打浆，抽滤分离，固体50℃烘干，得22.7g类白色固体精品，为化合物Ⅱ，收率：113.5％，纯度：97.6％。
S2：酯化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入68ml吡啶、22.7g上述化合物Ⅱ，搅拌溶清，加入6.13ml乙酸酐，升至0～5℃保温反应4h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入100ml水 和150ml二氯甲烷终止反应，分出有机相，水相用60ml二氯甲烷萃取，合并有机相并用100ml 1当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40～45℃减压浓至小体积，加30ml异丙醚带两次真空减压回收2次，并用异丙醚搅散抽滤，固体45℃烘干，得24.3g白色固体，为化合物Ⅲ。收率：107.0％，纯度：97.8％。
S3：消除反应
室温、氮气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入145ml吡啶、24.3g上述化合物Ⅲ，搅拌溶清，降至-40℃，滴加7.77g二氯亚砜，滴完后-40℃保温反应1h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至0℃，加入30ml水淬灭反应，将反应体系转至分液漏斗，加100ml二氯甲烷和250ml水充分混合均匀，静置，分出有机相，水相用50ml二氯甲烷萃取，合并有机相并用100ml 0.5当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40℃减压浓至小体积，加20ml乙酸乙酯真空减压回收2次，并用乙酸乙酯打浆，抽滤，固体45℃烘干，得21.1g淡黄色固体，为化合物Ⅳ。收率：86.8％，纯度：98.3％。
S4：氧化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入21.1g上述化合物Ⅳ，溶于60ml丙酮和10.5ml乙二醇中，降至-10℃，分批加入8.94g高锰酸钾，加完后-10℃保温反应6h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入150ml饱和的亚硫酸钠水溶液淬灭反应，加100ml乙酸乙酯和120ml水搅拌，抽滤，滤液静置分出有机相，水相用50ml乙酸乙酯萃取，合并有机相并用100ml水洗2次，有机相用无水硫酸钠干燥，45℃减压浓至近干，将该固体溶于150ml丙酮中，缓慢滴加300ml水析晶，抽滤，固体50℃烘干，得18.4g类白色固体化合物Ⅴ，收率：87.2％，纯度：98.6％。
实施例2
一种甾体药物17位侧链的合成方法，工艺流程如下：具体实验步骤如下：
Figure PCTCN2018092378-appb-000012
S1：亲核反应
室温、氦气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入21.66ml二异丙胺，降至-50℃，滴加125ml浓度为1.6mol/L的正丁基锂/四氢呋喃溶液，约15min滴完，-45℃保温反应0.5h，将5.46g的3-羟基丙腈和39ml的乙醚混合液滴入上述非亲核性强碱中，40min滴完，保持体系温度不超过-30℃，此时体系为悬浊态，加12ml二氯甲烷溶清；体系降至-60℃，取20g化合物Ⅰ，溶于80ml乙醚中，滴入上述反应体系，约2h滴完，-60℃保温反应5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至5℃，加入75ml饱和氯化铵水溶液终止反应，用20％的盐酸调节体系PH＝7，静置分出有机相，水相用50ml二氯甲烷萃取2次，合并有机相并用水萃取2次，每次用水150ml，有机相用无水硫酸钠干燥，45℃减压浓缩至近干，得淡黄色固体粗品，将粗品加入50ml二氯甲烷打浆，抽滤分离，固体50℃烘干，得23.1g类白色固体精品，为化合物Ⅱ，重量收率：115.5％，纯度：97.7％。
S2：酯化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入68ml吡啶、23.1g上述化合物Ⅱ，搅拌溶清，加入6.21ml乙酸酐，升至10℃ 保温反应2h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入100ml水和150ml二氯甲烷终止反应，分出有机相，水相用60ml二氯甲烷萃取，合并有机相并用100ml 1当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40℃减压浓至小体积，加30ml异丙醚带两次真空减压回收2次，并用异丙醚搅散抽滤，固体45℃烘干，得24.8g白色固体，为化合物Ⅲ。重量收率：107.36％，纯度：97.9％。
S3：消除反应
室温、氦气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入145ml 4-甲基吡啶、24.8g上述化合物Ⅳ，搅拌溶清，降至-40℃，滴加7.89g二氯亚砜，滴完后-35℃保温反应1.5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至0℃，加入30ml水淬灭反应，将反应体系转至分液漏斗，加100ml二氯甲烷和250ml水充分混合均匀，静置，分出有机相，水相用50ml二氯甲烷萃取，合并有机相并用100ml 0.5当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40℃减压浓至小体积，加20ml乙酸乙酯真空减压回收2次，并用乙酸乙酯打浆，抽滤，固体45℃烘干，得22.4g淡黄色固体，为化合物Ⅳ。重量收率：90.32％，纯度：98.7％。
S4’：缩酮反应
将7.07g乙二醇、15.82g原甲酸三乙酯、70ml二氯甲烷分别加入到反应烧瓶中，搅拌，加入0.24g对甲苯磺酸。加入22.4g上述化合物Ⅳ。35℃搅拌6h，取样做TLC分析，反应完全后，加入100g 10％碳酸钠水溶液终止反应，搅拌20min后静置分层，水层用30ml二氯甲烷萃取干净，合并有机层并用100ml水萃取2次，无水硫酸钠干燥有机层后，40℃浓缩近干，异丙醚带两次并用异丙醚搅散抽滤，干燥，得干燥化合物Ⅴb 19.78g，收率88.30％。
S5’：氧化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入19.78g上述化合物Ⅴb，溶于60ml丙酮和10.5ml乙二醇中，降至0℃，分批加入7.5g高锰酸钾，加完后0℃保温反应5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入150ml饱和的亚硫酸钠水溶液淬灭反应，加100ml乙酸 乙酯和120ml水搅拌，抽滤，滤液静置分出有机相，水相用50ml乙酸乙酯萃取，合并有机相并用100ml水洗2次，有机相用无水硫酸钠干燥，45～50℃减压浓至近干，将该固体溶于150ml丙酮中，缓慢滴加300ml水析晶，抽滤，固体50℃烘干，得17.60g类白色固体。重量收率：88.98％，纯度：98.9％。
实施例3
一种甾体药物17位侧链的合成方法，工艺流程如下：
Figure PCTCN2018092378-appb-000013
具体实验步骤如下：
室温、氩气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入29.10ml二异丁胺，降至-50℃，滴加125ml浓度为1.6mol/L的正丁基锂/正己烷溶液，约30min滴完，-70℃保温反应0.5h，将11.83g的3-羟基丙腈和39ml的四氢呋喃混合液滴入上述非亲核性强碱中，1h滴完，保持体系温度不超过-30℃，此时体系为悬浊态，加12ml三氯甲烷溶清；体系降至-60℃，取20g化合物Ⅰ，溶于80ml四氢呋喃中，滴入上述反应体系，约2h滴完，-60℃保温反应2.5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至5℃，加入75ml饱和氯化铵水溶液终止反应，用20％的盐酸调节体系PH＝7，静置分出有机相，水相用50ml三氯甲烷萃取2次，合并有机相并用水萃取2次，每次用水150ml，有机相用无水硫酸钠干燥，40～45℃减压浓缩至近干，得淡黄色固体粗品，将粗品加入50ml三氯甲烷打浆，抽滤分离，固体50℃烘干，得23.5g 类白色固体精品，为化合物Ⅱ，收率：117.5％，纯度：98.1％。
S2：酯化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入68ml吡啶、23.5g上述化合物Ⅱ，搅拌溶清，加入7.19ml乙酸酐，升至20℃保温反应1.5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入100ml水和150ml二氯甲烷终止反应，分出有机相，水相用60ml二氯甲烷萃取，合并有机相并用100ml 1当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40℃减压浓至小体积，加30ml异丙醚带两次真空减压回收2次，并用异丙醚搅散抽滤，固体45℃烘干，得25.3g白色固体，为化合物Ⅲ。收率：107.66％，纯度：98.2％。
S3：消除反应
室温、氩气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入145ml三乙胺、25.3g上述化合物Ⅲ，搅拌溶清，降至-40℃，滴加14.64g三氯氧磷，滴完后-30℃保温反应1h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至0℃，加入30ml水淬灭反应，将反应体系转至分液漏斗，加100ml二氯甲烷和250ml水充分混合均匀，静置，分出有机相，水相用50ml二氯甲烷萃取，合并有机相并用100ml 0.5当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40℃减压浓至小体积，加20ml乙酸乙酯真空减压回收2次，并用乙酸乙酯打浆，抽滤，固体45℃烘干，得22.5g淡黄色固体，为化合物Ⅳ。收率：88.93％，纯度：98.7％。
S4’：缩酮反应
将10.93g 3-巯基丙醇、7.55g原甲酸三甲酯、50ml苯分别加入到反应烧瓶中，搅拌，加入0.24g 30％盐酸，加入22.5g上述化合物Ⅳ，80℃搅拌3h，取样做TLC分析，反应完全后，搅拌下，把反应液倒入73ml苯，冷却到0℃。搅拌1h，过滤。干燥，得干燥化合物Ⅴb，20.14g，收率89.53％。
S5’：氧化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入20.14g上述化合物Ⅳ，溶于70ml吡啶中，降至0℃，分批加入17.17g锇酸钾， 加完后25℃保温反应18h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入150ml饱和的亚硫酸钠水溶液淬灭反应，加100ml乙酸乙酯和120ml水搅拌，抽滤，滤液静置分出有机相，水相用50ml乙酸乙酯萃取，合并有机相并用100ml水洗2次，有机相用无水硫酸钠干燥，45℃减压浓至近干，将该固体溶于150ml丙酮中，缓慢滴加300ml水析晶，抽滤，固体50℃烘干，得17.82g类白色固体。收率：88.44％，纯度：98.8％。
实施例4
一种甾体药物17位侧链的合成方法，工艺流程如下：
Figure PCTCN2018092378-appb-000014
具体实验步骤如下：
S1：亲核反应
室温、氩气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入27.20ml二仲丁胺，降至-50℃，滴加125ml浓度为1.6mol/L的正丁基锂/正己烷溶液，约45min滴完，-50℃保温反应0.5h，将6.26g的3-羟基丙腈和39ml的四氢呋喃混合液滴入上述非亲核性强碱中，40min滴完，保持体系温度不超过-30℃，此时体系为悬浊态，加12ml二氯甲烷溶清；体系降至-60℃，取20g化合物Ⅰ，溶于80ml四氢呋喃中，滴入上述反应体系，约1.5h滴完，-30℃保温反应2.5h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至5～10℃， 加入75ml饱和氯化铵水溶液终止反应，用20％的盐酸调节体系PH＝7.2，静置分出有机相，水相用50ml二氯甲烷萃取2次，合并有机相并用水萃取2次，每次用水150ml，有机相用无水硫酸钠干燥，40℃减压浓缩至近干，得淡黄色固体粗品，将粗品加入50ml二氯甲烷打浆，抽滤分离，固体50℃烘干，得23.4g类白色固体精品，为化合物Ⅱ，收率：117％，纯度：98.5％。
S2：酯化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入68ml吡啶、23.4g上述化合物Ⅱ，搅拌溶清，加入6.29ml乙酸酐，升至35℃保温反应3h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入100ml水和150ml二氯甲烷终止反应，分出有机相，水相用60ml二氯甲烷萃取，合并有机相并用100ml 1当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，45℃减压浓至小体积，加30ml异丙醚带两次真空减压回收2次，并用异丙醚搅散抽滤，固体45℃烘干，得25.6g白色固体，为化合物Ⅲ。收率：109.4％，纯度：98.5％。
S3：消除反应
室温、氩气保护下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入145ml吡啶、25.6g上述化合物Ⅲ，搅拌溶清，降至-40℃，滴加14.25g五氯化磷，滴完后-20℃保温反应2h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，回温至0℃，加入30ml水淬灭反应，将反应体系转至分液漏斗，加100ml二氯甲烷和250ml水充分混合均匀，静置，分出有机相，水相用50ml二氯甲烷萃取，合并有机相并用100ml 0.5当量稀盐酸水洗2次，有机相用无水硫酸钠干燥，40～45℃减压浓至小体积，加20ml乙酸乙酯真空减压回收2次，并用乙酸乙酯打浆，抽滤，固体45℃烘干，得23.0g淡黄色固体，为化合物Ⅳ。收率：89.84％，纯度：98.5％。
S4’：缩酮反应
将21.44g 1,4-丁二硫醇、10.53g原乙酸三甲酯、60ml甲苯分别加入到反应烧瓶中，搅拌，加入0.24g 5％氢溴酸。加入23.0g上述化合物Ⅳ。110℃搅拌6h，取样做TLC分析，反应完全后，搅拌下，把反应液倒入73ml甲苯，冷却到0℃， 搅拌1h，过滤。干燥，得干燥化合物Ⅴb 20.73g，收率90.15％。
S5’：氧化反应
室温下，往一洁净干燥的装配温度计、机械搅拌的500ml三口圆底烧瓶中加入20.73g上述化合物Ⅳ，溶于80ml三乙胺中，降至0℃，分批加入17.65g锇酸钾，加完后30℃保温反应24h，TLC中控反应完全(展开剂：丙酮/石油醚＝1:2)，加入150ml饱和的亚硫酸钠水溶液淬灭反应，加100ml乙酸乙酯和120ml水搅拌，抽滤，滤液静置分出有机相，水相用50ml乙酸乙酯萃取，合并有机相并用100ml水洗2次，有机相用无水硫酸钠干燥，45～50℃减压浓至近干，将该固体溶于150ml丙酮中，缓慢滴加300ml水析晶，抽滤，固体50℃烘干，得18.30g类白色固体。收率：88.26％，纯度：99.1％。
以上内容是结合具体的/优选的实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，其还可以对这些已描述的实施例做出若干替代或变型，而这些替代或变型方式都应当视为属于本发明的保护范围。

Claims (10)

  1. 一种甾体药物17位侧链的合成方法，所述甾体激素类药物中间体的结构式如下所示：
    Figure PCTCN2018092378-appb-100001
    式中，R 16为α或β-CH 3，或者-H 2；
    其特征在于：
    S1：亲核反应，在惰性气体保护下，3-羟基丙腈和极性非质子溶剂混合，用非亲核性强碱处理后加入助溶剂，再与化合物Ⅰ反应，制得化合物Ⅱ；
    Figure PCTCN2018092378-appb-100002
    式中，R 16定义同上；
    式中，环A和B代表以下基团：
    Figure PCTCN2018092378-appb-100003
    式中，R 3代表醚或酯的残基，当R 3代表醚的残基时，R 3为C 1～C 2的烃基或C 6～C 8的芳烃；当R 3代表酯的残基时，其为-COR 3；
    S2：酯化反应，用吡啶和乙酸酐对化合物Ⅱ进行处理，得化合物Ⅲ；
    Figure PCTCN2018092378-appb-100004
    S3：消除反应，在惰性气体保护下，化合物Ⅲ溶于有机溶剂中，与消除剂反 应制得化合物Ⅳ；
    Figure PCTCN2018092378-appb-100005
    S4：氧化反应，若起始原料环A和B为Ⅰ a，化合物Ⅳ直接经氧化反应制得化合物Ⅴ a；
    Figure PCTCN2018092378-appb-100006
    S4’：缩酮保护，若起始原料环A和B为Ⅰ b，化合物Ⅳ需对3-羰基进行缩酮保护制得化合物Ⅴ b；
    Figure PCTCN2018092378-appb-100007
    S5’：氧化反应，CH 3化合物Ⅴ b经氧化反应制得化合物Ⅵ。
    Figure PCTCN2018092378-appb-100008
  2. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述合成步骤S1中的极性非质子溶剂为乙醚或四氢呋喃，非亲核性强碱为二异丙基氨基锂、二异丁基氨基锂和二仲丁基氨基锂中的一种，助溶剂为二氯甲烷或三氯甲烷。
  3. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S3中的有机溶剂为吡啶、4-甲基吡啶、三乙胺等有机弱碱溶剂的一种或多种；所述消除剂为二氯亚砜、三氯氧磷和五氯化磷中的一种。
  4. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S4’缩酮保护为，在惰性气体保护下，在催化剂存在下，化合物Ⅳ在有机溶剂中，加入原酸酯类化合物，和化学式为HO-(CH 2) n-OH、HS-(CH 2) n-SH或HO-(CH 2) n-SH的混合二醇、二硫醇或硫醇反应制得。
  5. 如权利要求4所述的甾体药物17位侧链的合成方法，其特征在于：所述所述催化剂为盐酸、氢溴酸及对甲苯磺酸中的一种；所述有机溶剂为二氯甲烷、氯仿、苯或甲苯中的一种或多种；所述原酸酯类化合物为原甲酸三甲酯、原甲酸三乙酯、原乙酸三甲酯和原乙酸三乙酯中的一种。
  6. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S1中化合物Ⅰ、3-羟基丙腈和非亲核性强碱的摩尔比为1:(1.2～1.5):(2.4～3)，在反应温度为-80～-20℃条件下保温反应2～5h。
  7. 如权利要求4所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S2中化合物Ⅱ和乙酸酐的摩尔比为1：(1.05～1.2)；反应温度为0～50℃，反 应时间为1～4h。
  8. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S3中化合物Ⅲ和消除剂的摩尔比为1:(1.1～1.5)；反应温度为-40～0℃，反应时间为0.5～2h。
  9. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S4’中化合物Ⅳ、原酸酯和二醇类化合物的摩尔比为1：(1.2～1.5):(2～3)；若用二氯甲烷或氯仿作溶剂，反应温度为25～40℃，若用苯或甲苯作溶剂，反应温度为80～110℃；反应时间为2～6h。
  10. 如权利要求1所述的甾体药物17位侧链的合成方法，其特征在于：所述步骤S4和S5’中的若氧化剂为高锰酸钾，有机溶剂为丙酮和乙二醇的混合溶剂，反应温度为-10～20℃，反应时间为2～6h；若氧化剂为锇酸钾，有机溶剂为吡啶或三乙胺，反应温度为20～40℃，反应时间为18～24h。
PCT/CN2018/092378 2017-12-25 2018-06-22 甾体药物17位侧链的合成方法 WO2019128154A1 (zh)

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CN106866768A (zh) * 2017-04-25 2017-06-20 广西万德药业有限公司 一种诺美孕酮中间体的合成方法
CN108101950A (zh) * 2017-12-25 2018-06-01 广西万德药业有限公司 甾体药物17位侧链的合成方法

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US4600538A (en) * 1984-08-02 1986-07-15 The Upjohn Company Corticosteroids from 17-keto steroids via 20-cyano-Δ17 (20)-pregnanes
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CN108101950A (zh) * 2017-12-25 2018-06-01 广西万德药业有限公司 甾体药物17位侧链的合成方法

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