EP0591268A1 - Procede de preparation de steroides 6-methyleniques - Google Patents

Procede de preparation de steroides 6-methyleniques

Info

Publication number
EP0591268A1
EP0591268A1 EP92911939A EP92911939A EP0591268A1 EP 0591268 A1 EP0591268 A1 EP 0591268A1 EP 92911939 A EP92911939 A EP 92911939A EP 92911939 A EP92911939 A EP 92911939A EP 0591268 A1 EP0591268 A1 EP 0591268A1
Authority
EP
European Patent Office
Prior art keywords
steroids
group
hydrogen atom
methylene
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92911939A
Other languages
German (de)
English (en)
Inventor
Rolf Bohlmann
Henry Laurent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0591268A1 publication Critical patent/EP0591268A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the invention relates to a process for the preparation of 6-methylene steroids of the general sub-formula I.
  • wo ⁇ n X symbolizes the CD ring system of steroids of the androstane series or Pregnan series from steroids of the general sub-formula II
  • wo ⁇ n X has the meaning given above, or the 3-enol ethers of these steroids and formaldehyde, which is characterized in that the reaction is carried out in the presence of primary or secondary amines.
  • EP-B 0034115 already describes a process for the preparation of 6-methylene steroids of the general sub-formula I from steroids of the general sub-formula II and formaldehyde.
  • This known method is preferably carried out using phosphoric acid derivatives such as phosphorus pentoxide, phosphorus oxychloride or phosphorus oxybromide as the condensing agent.
  • phosphoric acid derivatives such as phosphorus pentoxide, phosphorus oxychloride or phosphorus oxybromide
  • phosphate-containing wastewater is produced in the preparation of the reaction mixture, the disposal of which is economical portable conditions is known to be quite problematic.
  • Another serious disadvantage of the previously known process is that it gives only very unsatisfactory yields of the desired process product in the reaction of steroids with a free IIß-hydroxy group (SYNTHESIS, 1982, p 34-40, especially Table 1, No. 6n).
  • the method according to the invention has the advantage that such environmentally harmful wastewater does not occur. Furthermore, it has the advantage that it is also in the
  • the starting compounds for the process according to the invention can contain the same substituents in the CD ring system X as the previously known process.
  • the process according to the invention is of particular importance in the context of the synthesis of highly effective 6 ⁇ -methyl corticoids.
  • the process according to the invention can also be carried out with steroids as the starting substance which have a free hydroxyl group in the 11 ⁇ position, since substances of this type, such as hydrocortisone, are often commercially available preparations.
  • steroids In the previously known processes, one must either start from steroids with a protected II ⁇ -hydroxyl group, the elimination of which is usually not unproblematic or introduce the II ⁇ -hydroxyl group subsequently by microbiological means, which is very complex and requires considerable know-how.
  • steroids of the general sub-formula II are particularly preferred, those as CD ring system X those of the general sub-formula III
  • wo ⁇ n n are the numbers 1 or 2
  • Alkylidendioxy distru with up to 6 carbon atoms mean or wherein R2 symbolizes a hydrogen atom, a hydroxy group or an acyloxy group with up to 8 carbon atoms and R3 represents a hydrogen atom or a methyl group.
  • the starting compounds can contain, for example, the same protective groups as those in the previously known process. However, it has already been mentioned that protective groups of this type are not necessary for carrying out the process according to the invention.
  • acyloxy groups R- and R2 of these substances are the benzoyloxy group or straight-chain or branched alkanoyloxy groups such as the acetoxy group, the propionyloxy group, the butyryloxy group, the 1-methylpropionyloxy group, the 1,1-dimethylpropionyloxy group or the hexanoyloxy group.
  • the isopropylidenedioxy group may be mentioned as the alkylidenedioxy group.
  • R4 represents an alkyl group with 1 to 4 carbon atoms, to be converted and then converted into the 6-methylene steroids of the general sub-formula I.
  • the method according to the invention can also be used using aqueous formaldehyde solution or using condensation products of formaldehyde, such as 1,3,5-trioxane or paraformaldehyde, from which formaldehyde is formed in the course of the reaction.
  • the process is carried out in the presence of primary or secondary amines. It corresponds to the type of reaction known under the name aminomethylation or Mannich reaction.
  • Suitable amines are, for example, those of the general sub-formula V *
  • R5 and Rg together represent the grouping - (CH2) 2-Q- (CH2) 2 ⁇ with Q in the meaning of a carbon-carbon bond, a methylene group or an oxygen atom or in which
  • R5 is an alkyl group with up to 8 carbon atoms, a benzyl group or an alkyl group optionally containing up to 4 carbon atoms or
  • Alkoxy groups and / or fluorine atoms or chlorine atoms substituted phenyl radical and Rg has the same meaning as R5 or symbolizes a hydrogen atom.
  • N-methylaniline has been used as the amine component, but it can be considered certain that other amines, such as, for example, pyrrolidine, piperidine, morpholine, diethylamine, diisopropylamine or N-methylbenzylamine, are also used Implementation of the method according to the invention are suitable.
  • the components are in an inert solvent (for example an ether, such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) or a chlorinated hydrocarbon (such as dichloromethane, trichloromethane, tetrachloromethane, 1 , 1,2,2-tetrachloroethane etc.) dissolved or suspended.
  • an inert solvent for example an ether, such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
  • a chlorinated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, 1 , 1,2,2-tetrachloroethane etc.
  • the reaction is preferably carried out in the presence of acids as catalysts (for example mineral acids such as hydrogen chloride, sulfuric acid or phosphoric acid or preferably strong organic acids such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid).
  • acids for example mineral acids such as hydrogen chloride, sulfuric acid or phosphoric acid or preferably strong organic acids such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
  • the reaction temperature is usually 0 ° C to 120 ° C.
  • reaction parameters are the same that are usually used in Mannich reactions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Selon un procédé de préparation de stéroïdes 6-méthyléniques répondant à la formule générale (I), dans laquelle X représente le système cyclique CD des stéroïdes de la série des androstanes oou de la série des pregnanes, à partir de stéroïdes répondant à la formule générale (II), dans laquelle X a la signification susmentionnée, ou à partir des éthers 3-énoliques de ces stéroïdes et de formaldéhyde, la réaction se fait en présence d'amines primaires ou secondaires.
EP92911939A 1991-06-26 1992-06-15 Procede de preparation de steroides 6-methyleniques Withdrawn EP0591268A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19914121484 DE4121484A1 (de) 1991-06-26 1991-06-26 Verfahren zur herstellung von 6-methylensteroiden
DE4121484 1991-06-26
PCT/EP1992/001366 WO1993000354A1 (fr) 1991-06-26 1992-06-15 Procede de preparation de steroides 6-methyleniques

Publications (1)

Publication Number Publication Date
EP0591268A1 true EP0591268A1 (fr) 1994-04-13

Family

ID=6435018

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92911939A Withdrawn EP0591268A1 (fr) 1991-06-26 1992-06-15 Procede de preparation de steroides 6-methyleniques

Country Status (4)

Country Link
EP (1) EP0591268A1 (fr)
JP (1) JPH07500086A (fr)
DE (1) DE4121484A1 (fr)
WO (1) WO1993000354A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2246359A1 (fr) * 2009-04-23 2010-11-03 Crystal Pharma, S.L.U. Procédé pour la préparation de fluorométholone et intermédiaires
FR3012452A1 (fr) 2013-10-28 2015-05-01 Sanofi Sa Procede de preparation de derives steroidiens
EP3006453A1 (fr) 2014-10-08 2016-04-13 Cosmo Technologies Ltd. 17alpha-monoesters et 17alpha, 21-diesters de cortexolone pour utilisation dans le traitement de tumeurs
RU2663484C1 (ru) * 2017-05-18 2018-08-06 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) СПОСОБ ПОЛУЧЕНИЯ 6α-МЕТИЛГИДРОКОРТИЗОНА ИЛИ ЕГО ЭФИРОВ ИЗ 21-АЦЕТАТА ГИДРОКОРТИЗОНА
RU2664101C1 (ru) * 2017-06-30 2018-08-15 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Способ получения 6-метиленгидрокортизона или его эфиров из 21-ацетата гидрокортизона
RU2663483C1 (ru) * 2017-12-29 2018-08-06 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Способ получения 6-(n-метил-n-фенил)аминометил-гидрокортизона или его эфиров из 21-ацетата гидрокортизона
CN110655549B (zh) * 2018-06-29 2022-06-14 天津药业研究院股份有限公司 6β-甲泼尼龙的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8801697D0 (en) * 1988-01-26 1988-02-24 Erba Farmitalia Improvements in synthesis of 6-methylene derivatives of androsta-1 4-diene-3 17-dione

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9300354A1 *

Also Published As

Publication number Publication date
JPH07500086A (ja) 1995-01-05
WO1993000354A1 (fr) 1993-01-07
DE4121484A1 (de) 1993-01-07

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