CN1223662A - 制备Drospirenon(6β,7β;15β,16β－二亚甲基－3－氧代－17α孕甾－4－烯－21,17－羰内酯,DRSP)的方法以及该方法的中间产物7α－(3－羟基－1－丙基)－6β,7β;15β,16β－二亚甲基－5β－雄甾烷－3β,5,17β－三醇(ZK92836)和6β,7β,15β,16β－二亚甲基－5β－羟基－3－氧代－17α－雄甾烷－21,17羰内酯 - Google Patents
制备Drospirenon(6β,7β;15β,16β－二亚甲基－3－氧代－17α孕甾－4－烯－21,17－羰内酯,DRSP)的方法以及该方法的中间产物7α－(3－羟基－1－丙基)－6β,7β;15β,16β－二亚甲基－5β－雄甾烷－3β,5,17β－三醇(ZK92836)和6β,7β,15β,16β－二亚甲基－5β－羟基－3－氧代－17α－雄甾烷－21,17羰内酯 Download PDFInfo
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- 101000605827 Homo sapiens Pinin Proteins 0.000 title abstract 2
- 102100038374 Pinin Human genes 0.000 title abstract 2
- METQSPRSQINEEU-OLKMEILKSA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3C3C4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-OLKMEILKSA-N 0.000 title abstract 2
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 title abstract 2
- 229960004845 drospirenone Drugs 0.000 title abstract 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
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- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical class [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
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- 239000002075 main ingredient Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RTXHNOBSQMHTSB-UHFFFAOYSA-N naphthalen-2-yl 2-hydroxypropanoate Chemical compound C1=CC=CC2=CC(OC(=O)C(O)C)=CC=C21 RTXHNOBSQMHTSB-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/007—3 membered carbocyclic rings in position 6-7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/008—3 membered carbocyclic rings in position 15/16
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Fats And Perfumes (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
本发明涉及制备Drospirenon(6β,7β;15β,16β－二亚甲基－3－氧代－17α－孕甾－4－烯－21,17－羰内酯,DRSP)的方法以及该方法的中间产物7α－(3－羟基－1－丙基)－6β,7β;15β,16β－二亚甲基－5β－雄甾烷－3β,5,17β－三醇(ZK92836)和6β,7β；15β,16β－二亚甲基－5β－羟基－3－氧代－17α－雄甾烷－21,17－羰内酯(ZK90965)。
Description
本发明涉及一种制备Drospirenon(6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羰内酯(Carbolactone),DRSP)的方法以及该方法的中间产物7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇(ZK92836)和6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯(ZK90965)。
长期以来，已知Drospirenon(6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羰内酯，DRSP,INN)可以作为甾族活性物质(DE26 52761 C2和DE30 22 337A1)和最后4步的制备以单釜法进行；在这种情况下，在二亚甲基丙炔醇ZK34506氢化之后，没有分离二亚甲基丙醇和5-β-OH-DRSP的后续中间步骤(参见下面的示意图)。
二亚甲基丙炔醇ZK34506在四氢呋喃中在钯炭上被氢化为二亚甲基丙醇ZK92836。这样获得的包括作为主要产物的丙醇ZK92836和含量波动的乳醇的氢化溶液在无分离和中间处理情况下转化为DrospiroenonZK30595(DRSP)。
为此，首先将四氢呋喃溶剂替换成二甲基甲酰胺，接着在40℃下用过量的3.7当量重铬酸吡啶鎓(PDC)将丙醇氧化为DRSP和5-β-OH-DRSP的混合物。在高的温度下氧化产物中5-β-OH-官能团对酸、路易斯酸和碱是不稳定的，因为在所有的情况下伴随着形成Drospirenon中的Δ-4,5-不饱和酮而得到热动力学稳定的产物。5-β-OH-DRSP中β-OH-官能团被消去，获得热动力学稳定的Drospirenon，并且该消去过程是无法抑制的。
通常，该混合物包括二种含量不固定的组分，其中作为主要组分的5-β-OH-DRSP以2-3∶1的比例存在。在一釜法的最后一步骤中，二种组分的混合物通过加入半浓盐酸被转化为粗的DRSP。
在下表中概括了最后四批操作物料。
从二亚甲基丙炔醇出发，以所有操作过程的沉积物的平均值计，获得粗的HPLC纯度是98.9％、产率是56％理论产率的DRSP。
| 物料 | 产率，粗的(％) | 纯度(100％-方法) |
| 537201 | 57.2 | 98.9 |
| 202 | 63.7 | 99.09 |
| 203 | 46.5 | 99.18 |
| 204 | 58.3 | 98.81 |
| 总计 | 平均产率：56.4 | 平均纯度：98.9 |
本发明的目的是提供一种制备Drospirenon的新方法，与现有技术相比其更具选择性和是更简单的，此外是生态学有利的；(省去三氧化铬的氧化反应)。
本发明的目的是根据权利要求书的教导解决的。
本发明包括制备Drospirenon(6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羰内酯，DRSP)
的方法，其中催化氢化17α-(3-羟基-1-丙炔基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇(ZK34506)
形成7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-
接着，借助于市购钌盐例如RuCl3、RuO2、KRuO4、K2RuO4，然而优选在催化量的RuCl3(1摩尔％)存在下，以及借助于常规的、简单的氧化剂例如叔丁基过氧氢、N-甲基-吗啉-N-氧化物、M2S2O8(M=Na、K)、MXOy(M=Li、Na、K；X=B、Cl、Br、I；y=1-4)，然而优选1至3当量的NaBrO3，在溶剂例如乙腈、氯仿、二氯甲烷、四氯化碳、水、四氢呋喃、叔丁醇、乙酸乙酯或它们的混合物，然而优选在乙腈-水混合物(组成乙腈∶水=1∶1)中进行氧化形成6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯(ZK90965)
并随后脱去水。
本发明在二步法中包括作为关键反应的将二亚甲基丙醇ZK92836转化为5-β-OH-DRSP ZK90965的钌催化氧化反应和随后转化为DrospirenonZK30595的消去水反应。
类似于现有技术中已知的方法，在本发明的方法中，在四氢呋喃中，在钯炭上用氢气氢化二亚甲基丙炔醇ZK34506。接着对氢化溶液进行溶剂交换，即用乙腈置换四氢呋喃。在40至60℃下用催化量的三氯化钌(1摩尔％)和3当量的溴酸钠将乙腈溶液有针对性地氧化为5-β-OH-DRSP。尽管在酸、路易斯酸例如在老的操作方法中的铬化合物、强碱或高温条件下5-β-OH-DRSP很不稳定，在所有的情况下这归因于高的形成热动力学稳定的Δ-4,5-不饱和酮的驱动力，但在所选择的反应条件下，获得了5-β-OH-DRSP的选择性合成，并且未观察到形成Drospiroenon。可以通过(操作)简单的水沉淀从反应溶液中分离出5-β-OH-DRSP。
在氢化和随后的氧化反应这二个步骤中产率是68％至75％。
由自身的试验已知，在酸的作用下Drospirenon按两条反应路线被分解。其一在酸性条件下Drospirenon易于转化为差向立体异构的异内酯ZK35096。
通过HCl在6,7-亚甲基基团上的进攻产生第二种副产物，其转化为开环产物ZK95673。
在新方法的反应条件下，这二种副产物被抑制，仅观察到＜0.2％数量级的副产物。
在消去反应中，产率是理论值的96％。因此，新方法的总产率是理论值的65至72％。
与现有技术相比，本发明另一非常重要的优点体现于生态学范围中。已经成功地通过催化量的金属代替迄今为止所使用的毒性铬化合物，至今其以重铬酸吡啶鎓盐的形式被用于氧化反应，然后必须处理以其溶液形式存在的重铬酸吡啶鎓盐。此外，可以通过共沸蒸馏循环使用乙腈-水混合物，这样同样可以获得对环境无任何危害的结果。
另外，本发明包括二种中间产物，7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇(ZK92836)和6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯(90965)。
实施例：
6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯
在1000毫升THF中在存在10克于炭上的钯(10％)和3毫升吡啶的情况下氢化50克17α-(3-羟基-1-丙炔基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇，直至吸收2当量氢气。接着，过滤出催化剂，并浓缩溶液至干燥，其中获得52.7克无需纯化可以进行进一步反应的7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇。
将50.2克7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇悬浮在250毫升乙腈中，并加热至45℃。在其中滴加溶解在10毫升水中的0.52克三氯化钌和溶解在250毫升水中的62.46克的溴酸钠。在50℃继续搅拌2小时，接着通过加入1000毫升水使该溶液停止反应。加入200毫升乙酸乙酯，分离各相，接着用600毫升乙酸乙酯萃取含水相。经硫酸钠干燥合并的有机相，并接着浓缩至干燥。这里获得43.44克的6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯作为粗产物。通过重结晶从丙酮-异醚中获得35.7克熔点是216至218℃的6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯。旋光值(Drehwert)是65.6°(钠线，CHCl3中c=1.02)。
6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羰内酯
将28克6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯悬浮在280毫升THF中，接着与10摩尔％的1.5克对甲苯磺酸混合。在30分钟之后，加入125毫升饱和NaCl溶液和8.2毫升1NNaOH溶液。在相分离之后，经硫酸钠干燥有机相，并浓缩至干燥，这里获得25.67克6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羰内酯作为粗产物，根据HPLC测定的纯度是93％。
可以通过色谱分离法进行进一步纯化。
色谱分离物质的熔点是197.5-200℃。
Claims (3)
1、制备Drospirenon(6β,7β；15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-
其中催化氢化17α-(3-羟基-1-丙炔基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-三醇(ZK34506)
形成7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-
接着，在钌盐存在下氧化形成6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯(ZK90965)
并随后脱去水。
2、7α-(3-羟基-1-丙基)-6β,7β；15β,16β-二亚甲基-5β-雄甾烷-3β,5,17β-
3、6β,7β；15β,16β-二亚甲基-5β-羟基-3-氧代-17α-雄甾烷-21,17-羰内酯(ZK90965)。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19633685A DE19633685C1 (de) | 1996-08-12 | 1996-08-12 | Verfahren zur Herstellung von Drospirenon (6beta,7beta;15 beta,16beta-Dimethyl-en-3-oxo-17alpha-pregn-4-en-21,17-carbolacton, DRSP) sowie 7alpha-(3-Hydroxy-1-propyl)-6beta,7beta;15beta, 16beta-dimethylen-5beta-androstan-3beta,5,17beta-triol (ZK 92836) und 6beta,7beta;15beta,16beta-dimethylen-5beta-hydroxy-3-oxo-17alpha-androstan-21,17-carbolacton (90965) als Zwischenprodukte des Verfahrens |
| DE19633685.6 | 1996-08-12 |
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| CN1223662A true CN1223662A (zh) | 1999-07-21 |
| CN1158300C CN1158300C (zh) | 2004-07-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101223186B (zh) * | 2005-07-21 | 2012-09-05 | 拜耳医药股份有限公司 | 通过无金属氧化17-(3-羟基丙基)-3,17-二羟基雄甾烷制备3-氧代-孕甾-4-烯-21,17-内酯的方法 |
| WO2011113196A1 (zh) * | 2010-03-16 | 2011-09-22 | 台州太法药业有限公司 | 屈螺酮制备方法 |
| US8921346B2 (en) | 2010-03-16 | 2014-12-30 | Taizhou Taifa Pharmaceuticals Co., Ltd. | Preparation method of drospirenone |
| CN101830959A (zh) * | 2010-05-27 | 2010-09-15 | 杭州龙山化工有限公司 | 一种曲螺酮的合成方法 |
| CN101830959B (zh) * | 2010-05-27 | 2012-07-18 | 杭州龙山化工有限公司 | 一种曲螺酮的合成方法 |
| CN105164144A (zh) * | 2013-04-12 | 2015-12-16 | 工业化学有限公司 | 用于制备屈螺酮的工艺 |
| CN105164144B (zh) * | 2013-04-12 | 2017-03-08 | 工业化学有限公司 | 用于制备屈螺酮的工艺 |
| CN113387993A (zh) * | 2021-07-06 | 2021-09-14 | 江西百思康瑞药业有限公司 | 一种屈螺酮的合成方法 |
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