WO1986000907A1 - Procede pour la production de steroides de 6alpha-methyle - Google Patents

Procede pour la production de steroides de 6alpha-methyle Download PDF

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Publication number
WO1986000907A1
WO1986000907A1 PCT/DE1985/000249 DE8500249W WO8600907A1 WO 1986000907 A1 WO1986000907 A1 WO 1986000907A1 DE 8500249 W DE8500249 W DE 8500249W WO 8600907 A1 WO8600907 A1 WO 8600907A1
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WO
WIPO (PCT)
Prior art keywords
methyl
dione
hydroxy
general formula
group
Prior art date
Application number
PCT/DE1985/000249
Other languages
German (de)
English (en)
Inventor
Klaus Annen
Helmut Hofmeister
Henry Laurent
Rudolf Wiechert
Original Assignee
Schering Aktiengesellschaft Berlin Und Bergkamen
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 Aktiengesellschaft Berlin Und Bergkamen filed Critical Schering Aktiengesellschaft Berlin Und Bergkamen
Publication of WO1986000907A1 publication Critical patent/WO1986000907A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16

Definitions

  • the invention relates to the object characterized in the claims.
  • the cyanohydrins of the general formula I required for the first reaction step of the process according to the invention preferably carry, as lower alkyl groups R 1 and R 2, those which have 1 to 4 carbon atoms.
  • Examples of cyanohydrins which may be mentioned are: 2-hydroxy-2-methyl-butanenitrile, 2-ethyl-2-hydroxy-butanenitrile, 1-hydroxycyclopentane carbonitrile, 1-hydroxy-cyclohexane carbonitrile and in particular 2-hydroxy-2-methyl nitrile propane nitrile.
  • the reaction step is carried out in the presence of an excess of cyanohydrin.
  • about 2 to 5 moles of cyanohydrin are used to convert one mole of steroid of the general formula I.
  • This reaction step is preferably carried out in water-containing lower alcohol (methanol, ethanol, isopropane ⁇ l etc.) as a solvent in the presence of basic catalysts (sodium hydroxide solution, potassium hydroxide solution etc.) at a pH of preferably 7.5 to 11 and a reaction temperature of preferably 10 to 60 ° C carried out, with the reaction mixture metered in as much water that only the desired process from the initially formed isomer mixture product crystallized.
  • the optimal reaction conditions are determined using the usual preliminary tests.
  • the subsequent reaction of the steroids of the general formula I a with the organometallic compounds of the general formula IV is carried out under conditions which are well known to the person skilled in the art. (See, for example, John Fried and John A. Edwards: Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Company, New York, 1972, Vol. II, page 132 ff).
  • the 3-oxo group and the hydroxy groups present are protected in a conventional manner before the reaction is carried out.
  • the 3-oxo group can be protected, for example, by ketalization with an alkanediol containing 2 to 6 carbon atoms (glycol, 2,2-dimethyl-1,3-propanediol, etc.) or o-diphenol.
  • the reaction is carried out by reacting the reactants in an inert solvent (for example chlorinated hydrocarbons such as dichloromethane, trichloroethane, 1,1,2,2 tetrachlorethylene etc.) in the presence of acids (p-toluenesulfonic acid, sulfuric acid, hydrochloric acid) etc.) and dehydrating agents (for example, trialkyl orthoformate such as trimethoxymethane or trieth ⁇ xymethane).
  • an inert solvent for example chlorinated hydrocarbons such as dichloromethane, trichloroethane, 1,1,2,2 tetrachlorethylene etc.
  • acids p-toluenesulfonic acid, sulfuric acid, hydrochloric acid
  • dehydrating agents for example, trialkyl orthoformate such as trimethoxymethane or trieth ⁇ xymethane.
  • the intermediate protection of the hydroxyl groups is expediently carried out by the compounds of the general formula I a with an alkyl vinyl ether with 2 to 8 carbon atoms in the alkyl radical, with 3,4-dihydro-2H-pyran with alkyl bromomethyl ether with 1 to 6 carbon atoms in the alkyl st or with dialkcxymethane with 1 to 6 carbon atoms in implement any alkoxy radical under the conditions of US Pat. No. 4,2 07,316.
  • the compound of general formula V thus obtained can be brominated in the 21-position in a manner known per se and the bromine atom can be exchanged for an acyloxy radical having 2 to 6 carbon atoms (preferably the acet ⁇ oxy radical) (see, for example, J. Fried and JA Edwards: Organic Reactions in Steroid Chemistry, vari Nostrand Reinhold Comp., New York, 1972, Vol 2, page 160 ff, 179 ff, 204 ff, 209 ff and 223 ff).
  • the compound of the formula V is converted into the corresponding enamine salt in a lower alcohol (methanol, ethanol, propanol or isopropanol) using mineral acids (hydrochloric acid, sulfuric acid, perchloric acid etc.) and the latter is brominated using an alcoholic bromine solution.
  • An excess of bromine in the reaction mixture should be avoided as far as possible during this reaction.
  • the 21-bromine atom is exchanged directly for the 1-oxoalkyloxy radical by reaction with an alkali metal salt of an alkane carboxylic acid having 2 to 6 carbon atoms (preferably sodium acetate or potassium acetate).
  • the compounds of the general formula Ib can also be iodinated directly by means of iodine in the 21-position and this iodine exchanged for the 1-oxoalkyloxy radical.
  • the starting compounds for the process according to the invention can be synthesized as follows, for example:
  • a mixture of 1.0 g of phosphorus pentoxide and 7.5 g of silica gel is added in portions to 35 ml of anhydrous methylene chloride and 22.5 ml of methylal at room temperature. The mixture is stirred for 3 days at room temperature and a further 11 ml of methylal, 500 mg of phosphorus pentoxide and 3.75 g of silica gel are added. After a further 2 days, the reaction mixture is filtered off with suction, the residue is washed thoroughly with methylene chloride and concentrated to dryness in vacuo. The crude product is purified on 350 g of silica gel using a hexane-ethyl acetate gradient (0-50% ethyl acetate). This gives 3.6 g of 6-methylene-4,9-andr ⁇ stadien-3,17-dione. Melting point 166-167 ° C.
  • the crude product is purified on 1.5 kg of silica gel with a hexane-ethyl acetate: 12.0 g of 6 ⁇ -ethyl 1-4.9 (11) -androstadiene-3.17-dione are obtained. Melting point 197-197 ° C. a) 15 ml of trifluoroacetic anhydride are added dropwise at -10 ° C. to 25.0 g of 11 ⁇ -hydroxy-4-androstene-3,17-dione in 120 ml of pyridine. The reaction mixture is precipitated in ice-water, the precipitated product is suction filtered, dissolved in methylene chloride, washed with water and dried over sodium sulfate. The crude product is chromatographed on silica gel using an acetone-hexane gradient. 19.6 g of 11-trifluoroacetoxy-4-androsten-3,17-dione are obtained as a foam.
  • Tetrahydrofuran, 12.7 ml of butyl vinyl ether and then 20.0 g of 17ß-cyano-3,3- (2,2-dimethylpropan-1,3-dioxy) -6-methyl5,9 (11) -androstadien-17 ⁇ -ol are added.
  • the mixture is 20 min at room temp. stirred and 100 ml of methyl lithium (1 M) was added dropwise.
  • the reaction solution is stirred for 2 hours at room temperature, 80 ml of glacial acetic acid and 40 ml of water are added, and the mixture is heated to 110 ° C. for 2 hours. After stirring in a solution of 70.0 g of sodium carbonate in 2 l of water, the crystallization of 17-hydroxy-6 ⁇ -methyl-4,9 (11) -pregnadiene3,20-dione begins.
  • the product obtained is stirred in a mixture of 70 ml of acetone, 1 ml of water and 0.3 ml of glacial acetic acid with 30.0 g of potassium acetate under reflux.
  • the reaction product is placed in ice water after 2 h.
  • the precipitated product is filtered off, dissolved in methylene chloride, washed with water and dried over sodium sulfate.
  • 2.3 g of 21-acetoxy-11 ⁇ , 17-dihydroxy6 ⁇ -methyl-4-p rain -3, 20-dione are obtained.
  • 4-pregnen-3,20-dione is suspended in 120 ml of methanol and refluxed for 1 h with a mixture of 5 ml of 0.1 M aqueous sodium acetate solution and 4.3 ml of 0.1 N aqueous acetic acid. The mixture is concentrated until cloudy, poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and i. Vac. evaporated to dryness. The crude product is purified on silica gel using a hexane-acetone gradient. Yield 3.8 g of 17-butyryloxy-11 ⁇ , 21dihydroxy-6 ⁇ -methyl-4-pregnen-3,20-dione.

Landscapes

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

Abstract

Procédé pour la production de stéroïdes de 6alpha-méthyle possédant la formule (I) où X désigne un groupe hydroxyle et Y un atome d'hydrogène, ou bien X et Y désignent ensemble un lien carbone-carbone et R1 est un groupe cyanogène, un groupe acétyle ou un groupe alkanoyloxy-acétyle avec de 2 à 6 atomes de carbone dans l'acyle résiduel.
PCT/DE1985/000249 1984-07-23 1985-07-22 Procede pour la production de steroides de 6alpha-methyle WO1986000907A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19843427486 DE3427486A1 (de) 1984-07-23 1984-07-23 Verfahren zur herstellung von 6(alpha)-methylsteroiden
DEP3427486.3 1984-07-23

Publications (1)

Publication Number Publication Date
WO1986000907A1 true WO1986000907A1 (fr) 1986-02-13

Family

ID=6241571

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1985/000249 WO1986000907A1 (fr) 1984-07-23 1985-07-22 Procede pour la production de steroides de 6alpha-methyle

Country Status (5)

Country Link
EP (1) EP0187847A1 (fr)
JP (1) JPS61502960A (fr)
DE (1) DE3427486A1 (fr)
PL (1) PL254621A1 (fr)
WO (1) WO1986000907A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003534A1 (fr) * 1986-11-05 1988-05-19 The Upjohn Company ETHERS STEROIDES SILYL-17alpha ET PROCEDE DE PREPARATION DE CORTICOIDES ET DE PROGESTERONES
WO1995030684A1 (fr) * 1994-05-09 1995-11-16 Pharmacia & Upjohn Company SYNTHESE DU 17β-CYANO-3-ETHOXY-17α-HYDROXY-6-METHYLANDROSTA-3,5,9(11)-TRIENE
US5972922A (en) * 1990-06-11 1999-10-26 Alcon Laboratories, Inc. Steroids which inhibit angiogenesis
WO2011130877A1 (fr) * 2010-04-21 2011-10-27 天津金耀集团有限公司 Forme cristalline de monohydrate d'acéponate de méthylprednisolone et procédés de préparation associés
CN103601786A (zh) * 2013-11-22 2014-02-26 湖南新合新生物医药有限公司 甲基泼尼松龙关键中间体的制备方法
CN105017364A (zh) * 2015-07-06 2015-11-04 湖南新合新生物医药有限公司 甲基泼尼松龙中间体及其制备方法和应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3931064A1 (de) * 1989-09-14 1991-03-28 Schering Ag Verfahren zur herstellung von progesteron-derivaten
CN111748010B (zh) * 2019-03-29 2023-12-08 天津药业研究院股份有限公司 一种醋丙甲泼尼龙无水晶型及其组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054786A1 (fr) * 1980-12-23 1982-06-30 Schering Aktiengesellschaft Dérivés de la 6-alpha-méthyl hydrocortisone, leur préparation et leur utilisation
EP0153001A2 (fr) * 1984-02-03 1985-08-28 The Upjohn Company Stéroides porteurs d'un groupe énamide ou énimide et leur préparation
JPH08262296A (ja) * 1995-03-23 1996-10-11 Mitsubishi Cable Ind Ltd 光ファイバケーブル

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054786A1 (fr) * 1980-12-23 1982-06-30 Schering Aktiengesellschaft Dérivés de la 6-alpha-méthyl hydrocortisone, leur préparation et leur utilisation
EP0153001A2 (fr) * 1984-02-03 1985-08-28 The Upjohn Company Stéroides porteurs d'un groupe énamide ou énimide et leur préparation
JPH08262296A (ja) * 1995-03-23 1996-10-11 Mitsubishi Cable Ind Ltd 光ファイバケーブル

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 97, No. 17, 25 October 1982, Columbus, Ohio (US) see page 719, Abstract 145148s, & JP, A, 8262296 (Mitsubishi) 15 April 1982 *
JOHN FRIED, JOHN A. EDWARDS, Organic Reactions in Steroid Chemistry, Vol. II, published in 1972 Van Nostrand Reinhold Company, New York (US), see page 223 (cited in the application) *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003534A1 (fr) * 1986-11-05 1988-05-19 The Upjohn Company ETHERS STEROIDES SILYL-17alpha ET PROCEDE DE PREPARATION DE CORTICOIDES ET DE PROGESTERONES
EP0268400A1 (fr) * 1986-11-05 1988-05-25 The Upjohn Company 17 alpha silyléthers de stéroides et procédé de préparation de corticoides et de progestérones
US5972922A (en) * 1990-06-11 1999-10-26 Alcon Laboratories, Inc. Steroids which inhibit angiogenesis
WO1995030684A1 (fr) * 1994-05-09 1995-11-16 Pharmacia & Upjohn Company SYNTHESE DU 17β-CYANO-3-ETHOXY-17α-HYDROXY-6-METHYLANDROSTA-3,5,9(11)-TRIENE
AU684946B2 (en) * 1994-05-09 1998-01-08 Pharmacia & Upjohn Company SYNTHESIS OF 17B CYANO-3-ETHOXY-17a-HYDROXY-6-METHYLANDROSTA-3,5,9-(11)-TRIEN 9(11)-triene
WO2011130877A1 (fr) * 2010-04-21 2011-10-27 天津金耀集团有限公司 Forme cristalline de monohydrate d'acéponate de méthylprednisolone et procédés de préparation associés
CN103601786A (zh) * 2013-11-22 2014-02-26 湖南新合新生物医药有限公司 甲基泼尼松龙关键中间体的制备方法
CN105017364A (zh) * 2015-07-06 2015-11-04 湖南新合新生物医药有限公司 甲基泼尼松龙中间体及其制备方法和应用

Also Published As

Publication number Publication date
PL254621A1 (en) 1986-06-17
DE3427486A1 (de) 1986-01-30
EP0187847A1 (fr) 1986-07-23
JPS61502960A (ja) 1986-12-18

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