17α-acetoxy-3,3[1,2-ethanediylbis(oxy)]-19-norpregna-5(10),9(11)-diene-20-one | 240806-31-9

• 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-acetoxy-3,3[1,2-ethanediylbis(oxy)]-19-norpregna-5(10),9(11)-diene-20-one
• 英文别名: 3,3-ethylenedioxy-17α-acetoxy-19-norpregna-5(10),9(11)-diene-20-one；17α-acetoxy-3,3-[1,2-ethanediylbis(oxy)]-19-norpregna-5(10),9(11)-dien-20-one；19-Norpregna-5(10),9(11)-diene-3,20-dione, 17-(acetyloxy)-, cyclic 3-(1,2-ethanediyl acetal)；[(8S,13S,14S,17R)-17-acetyl-13-methylspiro[1,2,4,6,7,8,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,2'-1,3-dioxolane]-17-yl] acetate
• CAS: 240806-31-9
• 化学式: C₂₄H₃₂O₅
• 分子量: 400.515
• InChiKey: ZGGAHACLOAUQSQ-VCHRRKICSA-N

物化性质

• 熔点：
  232 °C(Solv: dichloromethane (75-09-2); ethyl acetate (141-78-6))
• 沸点：
  537.7±50.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  17α-acetoxy-3,3[1,2-ethanediylbis(oxy)]-19-norpregna-5(10),9(11)-diene-20-one 在 disodium hydrogenphosphate 、 六氟-2-丙酮单水合物 、 水 、 双氧水 、 magnesium 、 1,2-二溴乙烷 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 13.75h， 生成 17α-acetoxy-11β-[4-(N-piperidino)phenyl]-19-norpregna-4,9-diene-3,20-dione
  参考文献：
  名称：

  JP5770235

  摘要：

  公开号：
• 作为产物：
  描述：

  17-羟基-19-去甲孕甾-4,9-二烯-3,20-二酮乙酸酯 在 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 生成 17α-acetoxy-3,3[1,2-ethanediylbis(oxy)]-19-norpregna-5(10),9(11)-diene-20-one
  参考文献：
  名称：

  17&bgr;-acyl-17&agr;-propynyl-11&bgr;-(cyclic amino) aryl steroids and their derivatives having antagonist hormonal properties

  摘要：

  这项发明涉及一种新型的17β-酰基-17α-丙炔基类固醇，具有强效的抗孕激素活性。

  公开号：

  US06740645B1

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。
• Process for obtaining 17alfa-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione
  申请人：Crystal Pharma, S.L.U.

  公开号：EP2348033A2

  公开（公告）日：2011-07-27

  The process comprises (a) forming 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (VA-2914) isopropanol hemisolvate crystals by dissolving in isopropanol and subsequently crystallising; (b) separating the VA-2914 isopropanol hemisolvate crystals; and (c) converting said VA-2914 isopropanol hemisolvate into VA-2914. The VA-2914 compound is a steroid with anti-progestational and anti-glucocorticoid activity, useful in therapeutic and contraceptive gynaecological indications and in treating Cushing's syndrome and glaucoma.

  该工艺包括：(a) 将 17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮 (VA-2914)溶解于异丙醇并随后结晶，形成异丙醇血异溶物晶体；(b) 分离 VA-2914 异丙醇血异溶物晶体；以及 (c) 将所述 VA-2914 异丙醇血异溶物转化为 VA-2914。VA-2914 复合物是一种具有抗孕激素和抗糖皮质激素活性的类固醇，可用于妇科治疗和避孕，以及治疗库欣综合征和青光眼。
• Method for preparing 17 alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione, intermediates thereof, and methods for the preparation of such intermediates
  申请人：Kim K. Hyun

  公开号：US20060111577A1

  公开（公告）日：2006-05-25

  Methods for the preparation of the 19-norprogesterone of formula I and its intermediates, in crystalline and amorphous forms.

  式 I 的 19-去甲孕酮及其结晶和无定形中间体的制备方法。
• Method for obtaining 17sg(a)-acetoxy-11$g(b)-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione
  申请人：Guisasola Silva Luis Octavio

  公开号：US20060247452A1

  公开（公告）日：2006-11-02

  The process comprises (a) forming 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (VA-2914) isopropanol hemisolvate crystals by dissolving in isopropanol and subsequently crystallising; (b) separating the VA-2914 isopropanol hemisolvate crystals; and (c) converting said VA-2914 isopropanol hemisolvate into VA-2914. The VA-2914 compound is a steroid with anti-progestational and anti-glucocorticoid activity, useful in therapeutic and contraceptive gynaecological indications and in treating Cushing's syndrome and glaucoma.

  该工艺包括：(a) 将 17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮 (VA-2914)溶解于异丙醇并随后结晶，形成异丙醇血异溶物晶体；(b) 分离 VA-2914 异丙醇血异溶物晶体；以及 (c) 将所述 VA-2914 异丙醇血异溶物转化为 VA-2914。VA-2914 复合物是一种具有抗孕激素和抗糖皮质激素活性的类固醇，可用于妇科治疗和避孕，以及治疗库欣综合征和青光眼。
• [EN] METHOD FOR PREPARING 17 alpha-ACETOXY-11beta-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES<br/>[FR] PROCEDE DE PREPARATION DE 17 DOLLAR G(A)-ACETOXY-11 DOLLAR G(B)-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, D'INTERMEDIAIRES DE CEUX-CI ET PROCEDES DE PREPARATION DESDITS INTERMEDIAIRES
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2004078709A3

  公开（公告）日：2005-02-24