norelgestromin | 74183-55-4

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: norelgestromin
• 英文别名: d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one-3E-oxime；17α-hydroxy-13β-ethyl-18,19-dinorpregn-4-ene-20-yn-3-one oxime；13β-ethyl-17α-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one oxime；d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime；17-deacetyl-norgestimate；Ortho Evra；(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-ol
• CAS: 74183-55-4；53016-31-2
• 化学式: C₂₁H₂₉NO₂
• 分子量: 327.467
• InChiKey: ISHXLNHNDMZNMC-VTKCIJPMSA-N

物化性质

• 熔点：
  107-109°C
• 沸点：
  491.9±45.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：11mg/mL； DMSO：10mg/mL；乙醇：12mg/mL； PBS（pH 7.2）：0.25 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  52.8
• 氢给体数：
  2
• 氢受体数：
  3

制备方法与用途

概述

活性物质甲基孕酮（17-去酰诺孕酯；13-乙基-17-羟基-18,19-二去甲-17-α-孕甾-4-烯-20-炔-3-酮肟）属于孕激素类性激素。

用途

甲基孕酮能够抑制黄体生成素（LH）的释放，从而起到抑制排卵的作用。相比诺孕酯及其代谢产物如3-酮诺孕酯和左炔诺孕酮，甲基孕酮的一个显著优点是其较低的雄激素活性。

生物活性

Norelgestromin是Norgestimate的一种代谢物。

反应信息

• 作为产物：
  描述：

  左炔诺孕酮 在 盐酸羟胺 、 sodium acetate 作用下， 以 水 、 溶剂黄146 为溶剂， 反应 50.0h， 以86.7%的产率得到norelgestromin
  参考文献：
  名称：

  [EN] PURE D-(17alpha)-13-ETHYL-17-HYDROXY-18,19-DINORPREGN-4-ENE-20-YNE-3-ONE-3E- AND -3Z-OXIME ISOMERS, AS WELL AS PROCESS FOR THE SYNTHESIS OF THE MIXTURE OF ISOMERS AND THE PURE ISOMERS
  [FR] ISOMERES PURS DE D-(17 DOLLAR G(A))-13-ETHYL-17-HYDROXY-18,19-DINORPREGN-4-EN-20-YN-3-ONE-3E- ET -3Z-OXIME, ET PROCEDE POUR REALISER LA SYNTHESE DU MELANGE D'ISOMERES ET D'ISOMERES PURS

  摘要：

  该发明涉及公式（IA）的纯d-（17α）-13-乙基-17-羟基-18,19-二诺孕烷-4-烯-20-炔-3-酮-3E-肟异构体，以及公式（IB）的纯d-（17α）-13-乙基-17-羟基-18,19-二诺孕烷-4-烯-20-炔-3-酮-3Z-肟异构体，它们具有孕激素活性，以及合成上述异构体混合物和纯异构体的方法。该发明还涉及含有公式（IA）的纯异构体或公式（IB）的纯异构体作为活性成分的药物组合物，以及它们的合成方法，这些药物组合物可以单独使用或与其他活性成分（例如雌激素剂）一起使用，以及通常在实践中使用的药用辅料。

  公开号：

  WO2005000867A1

文献信息

• Process for the preparation of norelgestromin
  申请人：S.N.I.F.F. Italia S.P.A.

  公开号：EP1818338A1

  公开（公告）日：2007-08-15

  Process for the preparation of Norelgestromin or 17α-hydroxy-13β-ethyl-18,19-dinorpregn-4-ene-20-yn-3-one oxime, also in crystalline form, in particular with an E/Z isomer ratio of between 1.3 and 1.5.

  制备诺醇酮或17α-羟基-13β-乙基-18,19-二去甲孕酮-4-烯-20-炔-3-酮肟的过程，也可得到结晶形式，特别是其E/Z异构体比例在1.3至1.5之间。
• Process for obtaining norelgestromin in different relations of isomers E and Z
  申请人：——

  公开号：US20040266741A1

  公开（公告）日：2004-12-30

  The present invention is related to an oxime of the 13&bgr;-ethyl-17&agr;-hydroxi-18,19-dinorpregn-4-en-20-in-3-o (norelgestromin) of Formula I with a relation of isomers E/Z between 1.3 and 1.6 1 and the method of producing the oxime.

  本发明涉及一种与式I的13β-乙基-17α-羟基-18,19-二诺孕酮-4-烯-20-炔-3-醛（诺瑞格司特龙）的肟相关的异构体E/Z比例在1.3到1.61之间的肟化合物，以及制备该肟化合物的方法。
• [EN] PROCESS FOR THE SYNTHESIS OF HIGH PURITY D-(17ALPHA)-13-ETHYL-17­HYDROXY-18,19-DINORPRE:GN-4-ENE-20-YNE-3-ONE-OXIME<br/>[FR] PROCEDE DE SYNTHESE D'UNE D-(17ALPHA)-13-ETHYL-17-HYDROXY-18,19-DINOR-PREGN-4-ENE-20-YNE-3-ONE-OXIME TRES PURE
  申请人：RICHTER GEDEON VEGYESZET

  公开号：WO2005000868A1

  公开（公告）日：2005-01-06

  The invention relates to a process for the synthesis of high purity d-(17α)-13-ethyl-17­hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one-oxime (further on norelgestromine) via acetylation of d-norgestrel at position 17, oximation of the oxo group at position 3 of the obtained 17-acetoxy derivative, and finally hydrolyzing the acetoxy group at position 17 of the obtained 3-oxime derivative. The process according to our invention is as follows: the starting material, d-(17α-17-hydroxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3­one (d-norgestrel) - purity 93-94 % - is acetylated with acetic anhydride in acetic acid, in the presence of zinc chloride and hydrogen chloride, or 70 % perchloric acid in an inert gas atmosphere, and after completion of the reaction the excess of acetic anhydride and the 'enol acetate' by-product are decomposed with aqueous hydrochioric acid, then the formed d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one is isolated from the reaction mixture by addition of ice-water, the precipitated product is filtered off, washed with water, dried, dissolved in dichloromethane or acetone and clarified with silica gel or aluminum oxide and charcoal, after filtration of the clarifier the resulted solution is concentrated and the residue is recrystallized, the obtained d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one is reacted either with hydroxylammonium acetate or with hydroxylammonium chloride in the presence of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring for about 1 hour, after completion of the reaction water is added, the precipitated product is filtered off, washed with water, dried and recrystallized, the obtained d-(17α-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime is hydrolyzed with an equivalent amount of an alkali metal hydroxide in a C1-C4 alkanol solution, in nitrogen atmosphere between a temperature of about 5-38 °C, under vigorous stirring, after completion of the reaction the mixture is diluted with water and the pH of the resulted suspension is adjusted to 7,5-9 with acetic acid, the precipitated product is filtered off, washed with water, dried, the crude product is dissolved in ethanol, clarified with charcoal, and after filtration of the clarifier water is added to the obtained solution, the precipitated high purity d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime is filtered off, washed with water and in given case recrystallized from ethanol.

  该发明涉及一种合成高纯度d-(17α)-13-乙基-17-羟基-18,19-二诺孕烷-4-烯-20-炔-3-酮肟（后称诺尔酮）的过程，通过在17位对d-诺酮基进行乙酰化，在获得的17-乙酰氧衍生物的3位的酮基进行肟化，最后在获得的3-肟衍生物的17位处水解乙酰氧基。根据我们的发明，该过程如下：起始材料，d-(17α-17-羟基-13-乙基-18,19-二诺孕烷-4-烯-20-炔-3-酮（d-诺酮）-纯度93-94％-与乙酸酐在乙酸中，在锌氯化物和氢氯酸或70％高氯酸的惰性气氛中乙酰化，反应完成后，过量的乙酸酐和‘烯醇醋酸酯’副产物通过水盐酸分解，然后通过加入冰水将形成的d-(17α)-17-乙酰氧基-13-乙基-18,19-二诺孕烷-4-烯-20-炔-3-酮从反应混合物中分离，沉淀产物经过过滤、水洗、干燥，溶解于二氯甲烷或丙酮，并用二氧化硅胶或氧化铝和活性炭澄清，澄清剂过滤后浓缩溶液，残渣结晶，获得的d-(17α)-17-乙酰氧基-13-乙基-18,19-二诺孕烷-4-烯-20-炔-3-酮与羟胺醋酸盐或羟胺氯化物在乙酸中与钠醋酸存在下，在氮气氛中激烈搅拌约1小时反应，反应完成后加入水，沉淀产物过滤、水洗、干燥、结晶，获得的d-(17α-17-乙酰氧基-13-乙基-18,19-二诺孕烷-4-烯-20-炔-3-酮肟在C1-C4烷醇溶液中与等量的碱金属氢氧化物在氮气氛中在约5-38°C的温度下激烈搅拌水解，反应完成后用水稀释混合物，结果悬浮液的pH值用乙酸调至7.5-9，沉淀产物过滤、水洗、干燥，粗品溶于乙醇，用活性炭澄清，澄清剂过滤后加入水到获得的溶液，过滤、水洗高纯度d-(17α)-17-乙酰氧基-13-乙基-18,19-二诺孕烷-4-烯-20-炔-3-酮肟。
• Process for the preparation of 3-oximino steroids
  申请人：Villa Marco

  公开号：US20060035872A1

  公开（公告）日：2006-02-16

  The present invention provides a method of preparing norelgestromin or norgestimate by reacting the corresponding 3-oxosteroid precursor with hydroxylamine HCl and a base to obtain a reaction mixture forming norelgestromin or norgestimate; monitoring the anti/syn ratio of the norelgestromin or norgestimate produced in the reaction mixture; adding a base to the reaction mixture to neutralize acidity in the reaction mixture when a desired anti/syn ratio is detected; and isolating the norelgestromin or norgestimate. The present invention also provides a process allowing a control of the formation of the anti isomer and syn isomer of norelgestromin or norgestimate by reacting the corresponding 3-oxosteroid precursor with hydroxylamine HCl and a base to obtain a reaction mixture forming norelgestromin or norgestimate; regulating the acidity of the reaction mixture to adjust the anti/syn ratio of the norelgestromin or norgestimate produced in the reaction mixture; adding a base to the reaction mixture to neutralize acidity in the reaction mixture when a desired anti/syn ratio is detected; and isolating the norelgestromin or norgestimate.

  本发明提供了一种通过将相应的3-氧代类固醇前体与羟胺盐酸和碱反应以获得形成诺酮炔酮或诺酮炔酮的反应混合物的方法；监测在反应混合物中产生的诺酮炔酮或诺酮炔酮的反式/顺式比例；当检测到所需的反式/顺式比例时，向反应混合物中添加碱以中和反应混合物中的酸性；并分离诺酮炔酮或诺酮炔酮。本发明还提供了一种允许控制诺酮炔酮或诺酮炔酮的反式异构体和顺式异构体形成的过程，该过程包括通过将相应的3-氧代类固醇前体与羟胺盐酸和碱反应以获得形成诺酮炔酮或诺酮炔酮的反应混合物；调节反应混合物的酸性以调整在反应混合物中产生的诺酮炔酮或诺酮炔酮的反式/顺式比例；当检测到所需的反式/顺式比例时，向反应混合物中添加碱以中和反应混合物中的酸性；并分离诺酮炔酮或诺酮炔酮。
• Process for the synthesis of high purity D-(17a)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one oxime
  申请人：Tuba Zoltan

  公开号：US20050032763A1

  公开（公告）日：2005-02-10

  The invention relates to a process for the synthesis of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime (also known as norelgestromin) via acetylation of d-norgestrel at position 17; oximation of the oxo group at position 3 of the obtained d-(17α)-13-ethyl-17-(acetyloxy)-18,19-dinorpregn-4-ene-20-yn-3-one; and then hydrolyzing the acetyloxy group at position 17 of the obtained d-(17α)-13-ethyl-17-(acetyloxy)-18,19-dinorpregn-4-ene-20-yn-3-oxime derivative, thereby obtaining norelgestromin.

  该发明涉及一种合成d-(17α)-13-乙基-17-羟基-18,19-二诺孕烷-4-烯-20-炔-3-酮肟（也称为诺莫酮）的方法，通过在17位对d-诺鲁孕酮进行乙酰化；在得到的d-(17α)-13-乙基-17-(乙酰氧基)-18,19-二诺孕烷-4-烯-20-炔-3-酮的3位的酮基进行氧化反应；然后水解所得的d-(17α)-13-乙基-17-(乙酰氧基)-18,19-二诺孕烷-4-烯-20-炔-3-酮肟衍生物的17位的乙酰氧基，从而获得诺莫酮。