17α-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione | 202062-87-1

• 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: 17α-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione
• 英文别名: 17α-hydroxy-13β-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione；17α-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione；17a-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione；(8S,13S,14S,17R)-17-acetyl-13-ethyl-17-hydroxy-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
• CAS: 202062-87-1
• 化学式: C₂₁H₂₈O₃
• 分子量: 328.452
• InChiKey: ZVJBJOUAHHOKAK-ANULTFPQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  17α-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione 在 disodium hydrogenphosphate 、 双氧水 、 碘 、 对甲苯磺酸 、 magnesium 、 原甲酸三乙酯 、 六氟丙酮 、 copper(l) chloride 、 二溴甲烷 作用下， 以 二氯甲烷 为溶剂， 反应 7.33h， 生成 3,20-bis-ethylenedioxy-13β-ethyl-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)phenyl]-18,19-dinorpregn-9-ene
  参考文献：
  名称：

  11β-Substituted 13β-ethyl gonane derivatives exhibit reversal of antiprogestational activity

  摘要：

  The syntheses of three 17 alpha-acetoxy-13 beta-ethyl-11 beta-aryl-18,19-dinorpregna-4,9-diene-3,20 diones from levonorgestrel are described Despite their close structural similarity To the antiprogesterone CDB-2914, one of the compounds exhibits agonistic progestational activity, and the other two compounds are totally inactive. (C) 1998 by Elsevier Science Inc.

  DOI：

  10.1016/s0039-128x(97)00119-0
• 作为产物：
  描述：

  (8S,13S,14S,17R)-13-Ethyl-17-ethynyl-17-nitrooxy-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta[a]phenanthren-3-one 在 mercury(II) diacetate 、 potassium hydrogencarbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 17α-hydroxy-13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione
  参考文献：
  名称：

  11β-Substituted 13β-ethyl gonane derivatives exhibit reversal of antiprogestational activity

  摘要：

  The syntheses of three 17 alpha-acetoxy-13 beta-ethyl-11 beta-aryl-18,19-dinorpregna-4,9-diene-3,20 diones from levonorgestrel are described Despite their close structural similarity To the antiprogesterone CDB-2914, one of the compounds exhibits agonistic progestational activity, and the other two compounds are totally inactive. (C) 1998 by Elsevier Science Inc.

  DOI：

  10.1016/s0039-128x(97)00119-0

文献信息

• INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17alpha-ACETOXY-11beta-[4-(N,N-DIMETHYL-AMINO)-PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS
  申请人：Dancsi Lajosne

  公开号：US20090187032A1

  公开（公告）日：2009-07-23

  The present invention relates to a new industrial process for the synthesis of solvate-free 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB-2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process. The process according to the invention is the following: i) 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) is reacted with potassium acetilyde formed in situ in dry tetrahydrofuran by known method, ii) the obtained 3-(ethylene-dioxy)-17α-ethynyl-17β-hydroxy-estra-5(10),9(11)-diene of formula (IX) is reacted with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid, iii) the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) is reacted first with sodium methoxide in methanol, then with trimethyl phosphite, iv) the obtained 3-(ethylene-dioxy)-17α-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) is reacted with hydrogen chloride in methanol, then v) the obtained 3-(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene-20-one of formula (VI) is reacted with ethylene glycol in dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid by known method, vi) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene of formula (V) is reacted with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone by known method, vii) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5α,10α- and 5β,10β-epoxides, is isolated from the solution and reacted with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran in the presence of copper(I) chloride catalyst without separation of the isomers by known method, viii) the obtained 3,3,20,20-bis(ethylene-dioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregn-9(11)-ene of formula (III) is reacted with potassium hydrogensulfate in water by known method, ix) the obtained 11β-[4-(N,N-dimethylamino)-phenyl]-17α-hydroxy-19-norpregn-4,9-diene-3,20-dione of formula (II) is acetylated with acetic anhydride in the presence of perchloric acid by known method, finally x) the solvate-free compound of formula (I) is liberated from the obtained solvate containing compound of formula (I) in a 1:1 mixture of ethanol and water at 70° C.

  本发明涉及一种新的工业合成过程，用于合成无溶剂17α-乙酰氧基-11β-[4-(N,N-二甲基氨基)-苯基]-19-去孕烷-4,9-二烯-3,20-二酮[CDB-2914]，其化学式为(I)，该化合物是一种强抗孕激素和抗糖皮质激素剂。本发明还涉及用作该过程中间体的化合物的化学式(VII)和(VIII)。本发明的工艺如下：i)使用已知方法，在干四氢呋喃中与现场形成的乙酰乙炔钾反应，得到化学式(X)的3-(乙二氧基)-麦角甾-5(10)，9(11)-二烯-17-酮，ii)在三乙胺和乙酸存在下，使用二氯甲烷中的苯基磺酰氯与上述得到的3-(乙二氧基)-17α-乙炔基-17β-羟基-麦角甾-5(10)，9(11)-二烯反应，得到化学式(IX)的产物，iii)使用甲醇中的甲酸钠和三甲基膦酸三甲酯，先后与上述得到的3-(乙二氧基)-21-(苯基磺酰基)-19-去孕烷-5(10)，9(11)，17(20)，20-四烯反应，得到化学式(VIII)的异构混合物，iv)使用甲醇中的氢氯酸与上述得到的3-(乙二氧基)-17α-羟基-20-甲氧基-19-去孕烷-5(10)，9(11)，20-三烯反应，得到化学式(VII)的产物，v)使用三甲基正酯和对甲苯磺酸在二氯甲烷中与上述得到的3-(乙二氧基)-17α-羟基-19-去孕烷-5(10)，9(11)-二烯-20-酮反应，得到化学式(VI)的产物，vi)使用已知方法，在吡啶和二氯甲烷的混合物中，使用六氯代丙酮，与上述得到的3,3,20,20-双(乙二氧基)-17α-羟基-19-去孕烷-5(10)，9(11)-二烯反应，得到化学式(V)的产物，vii)从溶液中分离出含有大约1:1的5α,10α-和5β,10β-环氧化物的化学式(IV)的产物，并使用已知方法，在四氢呋喃中与从4-溴-N,N-二甲基苯胺中获得的格氏试剂和氯化铜(I)催化剂反应，而不分离异构体，得到化学式(III)的产物，viii)使用已知方法，在水中使用硫酸氢钾与上述得到的3,3,20,20-双(乙二氧基)-5α,17α-二羟基-11β-[4-(N,N-二甲基氨基)-苯基]-19-去孕烷-9(11)-二烯反应，得到化学式(II)的产物，ix)使用已知方法，在高氯酸存在下，使用乙酸酐对上述得到的化学式(II)的11β-[4-(N,N-二甲基氨基)-苯基]-17α-羟基-19-去孕烷-4,9-二烯-3,20-二酮进行乙酰化，最后在70°C的乙醇和水的1:1混合物中从得到的含溶剂化合物中解放出化学式(I)的无溶剂化合物。
• INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17 ALPHA -ACETOXY-11 BETA -[4-(N,N-DIMETHYL-AMINO)- PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS
  申请人：Richter Gedeon NYRT

  公开号：EP2027140B1

  公开（公告）日：2013-03-13
• US8110691B2
  申请人：——

  公开号：US8110691B2

  公开（公告）日：2012-02-07
• [EN] INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17a-ACETOXY-11ß-[4-(N,N-DIMETHYL-AMINO)- PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS<br/>[FR] PROCÉDÉ INDUSTRIEL POUR LA SYNTHÈSE DE 17a-ACÉTOXY-11ß-[4-(N,N-DIMÉTHYLAMINO)PHÉNYL]-19-NORPREGNA-4,9-DIÈNE-3,20-DIONE ET NOUVEAUX INTERMÉDIAIRES DU PROCÉDÉ
  申请人：RICHTER GEDEON NYRT

  公开号：WO2007144674A1

  公开（公告）日：2007-12-21

  [EN] The present invention relates to a new industrial process for the synthesis of solvate- free 17a-acetoxy-11ß-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB -2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process. The process according to the invention is the following: i) 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) is reacted with potassium acetilyde formed in situ in dry tetrahydrofuran by known method, ii) the obtained 3-(ethylene-dioxy)-17a-ethynyl-17ß-hydroxy-estra-5(10),9(11)-diene of formula (IX) is reacted with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid, iii) the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) is reacted first with sodium methoxide in methanol, then with trimethyl phosphite, iv) the obtained 3-(ethylene-dioxy)-17a-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) is reacted with hydrogen chloride in methanol, then v) the obtained 3-(ethylene-dioxy)-17a-hydroxy-19-norpregna-5(10),9(11l)-diene-20- one of formula (VI) is reacted with ethylene glycol hi dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid by known method, vi) the obtained 3,3,20,20-bis(ethylene-dioxy)-17a-hydroxy-19-norpregna- 5(10),9(11)-diene of formula (V) is reacted with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone by known method, vii) the obtained 3,3,20,20-bis(ethylene-dioxy)-17a-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5a,10a- and 5ß,10ß-epoxides, is isolated from the solution and reacted with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran in the presence of copper(I) chloride catalyst without separation of the isomers by known method, viii) the obtained 3,3,20,20-bis(ethylene-dioxy)-5a,17a-dihydroxy-11ß-[4-(N,N-dimethylamino)-phenyl]-19-norpregn-9(11)-ene of formula (III) is reacted with potassium hydrogensulfate in water by known method, ix) the obtained 11ß-[4-(N,N-dimethylamino)-phenyl]-17a-hydroxy-19-norpregn-4,9-diene-3,20-dione of formula (II) is acetylated with acetic anhydride in the presence of perchloric acid by known method, finally x) the solvate-free compound of formula (I) is liberated from the obtained solvate containing compound of formula (I) in a 1 : 1 mixture of ethanol and water at 70° C.
  [FR] La présente invention concerne un nouveau procédé industriel pour la synthèse de 17a-acétoxy-11ß-[4-(N,N-diméthylamino)phényl]-19-norpregna-4,9-diène-3,20-dione [CDB-2914] de formule (I) sans solvate, laquelle est un puissant agent antiprogestogène et antiglucocorticoïde. L'invention concerne également des composés de formule (VII) et (VIII) utilisés en tant qu'intermédiaires dans le procédé. Le procédé selon l'invention consiste à : i) faire réagir par un procédé connu de la 3-(éthylènedioxy)-estra-5(10),9(11)-diène-17-one de formule (X) avec de l'acétylure de potassium formé in situ dans du tétrahydrofurane sec, ii) faire réagir le 3-(éthylènedioxy)-17a-éthynyl-17ß-hydroxyestra-5(10),9(11)-diène de formule (IX) obtenu avec du chlorure de phénylsulfinyle dans du dichlorométhane en présence de triéthylamine et d'acide acétique, iii) faire réagir le mélange isomérique de 3-(éthylènedioxy)-21-(phénylsulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraène de formule (VIII) obtenu, d'abord avec du méthylate de sodium dans du méthanol, ensuite avec du phosphite de triméthyle, iv) faire réagir le 3-(éthylènedioxy)-17a-hydroxy-20-méthoxy-19-norpregna-5(10),9(11),20-triène de formule (VII) obtenu avec du chlorure d'hydrogène dans du méthanol, ensuite v) faire réagir par un procédé connu la 3-(éthylènedioxy)-17a-hydroxy-19-norpregna-5(10),9(11)-diène-20-one de formule (VI) obtenue avec de l'éthylèneglycol dans du dichlorométhane en présence d'ortho-formiate de triméthyle et d'acide p-toluènesulfonique, vi) faire réagir par un procédé connu le 3,3,20,20-bis(éthylènedioxy)-17a-hydroxy-19-norpregna-5(10),9(11)-diène de formule (V) obtenu avec du peroxyde d'hydrogène dans un mélange de pyridine et de dichlorométhane en présence d'hexachloroacétone, vii) isoler à partir de la solution le 3,3,20,20-bis(éthylènedioxy)-17a-hydroxy-5,10-époxy-19-norpregn-9(11)-ène de formule (IV) obtenu, contenant à peu près un mélange à 1:1 du 5a,10a-époxyde et du 5ß,10ß-epoxyde, et faire réagir celui-ci par un procédé connu avec un réactif de Grignard, obtenu à partir de 4-bromo-N,N-diméthylaniline, dans du tétrahydrofurane en présence d'un catalyseur en chlorure de cuivre(I) sans séparer les isomères, viii) faire réagir par un procédé connu le 3,3,20,20-bis(éthylènedioxy)-5a,17a-dihydroxy-11ß-[4-(N,N-diméthylamino)phényl]-19-norpregn-9(11)-ène de formule (III) obtenu avec de l'hydrogénosulfate de potassium dans de l'eau, ix) acétyler la 11ß-[4-(N,N-diméthylamino)phényl]-17a-hydroxy-19-norpregn-4,9-diène-3,20-dione de formule (II) obtenue avec de l'anhydride acétique en présence d'acide perchlorique par un procédé connu, enfin x) libérer le composé de formule (I) sans solvate du composé de formule (I) contenant du solvate dans un mélange à 1:1 d'éthanol et d'eau à 70°C.