US3415853A - Process for the preparation of delta1,3,5(10)-3,17-dihydroxy steroids - Google Patents

Process for the preparation of delta1,3,5(10)-3,17-dihydroxy steroids Download PDF

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Publication number
US3415853A
US3415853A US543814A US54381466A US3415853A US 3415853 A US3415853 A US 3415853A US 543814 A US543814 A US 543814A US 54381466 A US54381466 A US 54381466A US 3415853 A US3415853 A US 3415853A
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US
United States
Prior art keywords
hydroxy
keto
oestradiol
ether
androstadiene
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.)
Expired - Lifetime
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US543814A
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English (en)
Inventor
Modderman Pieter
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Organon NV
Organon Inc
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Organon NV
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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • a -3,17-dihydroxy steroids are prepared by treatment of a A -3'keto-1O-methyl-IZB-hydroxy steroid with an alkali metal in presence of a polycyclic aromatic compound and an ethereal solvent, followed by acid conversion of the alkali metal salt of the corresponding steroid, including the step of converting the 17B-hydroxy group to a mixed acetal and ketal.
  • the process enables the preparation of A -3-keto-17/3-hydroxy-androstadiene having an ether structure at the 17-position.
  • the invention relates to an improved process for the preparation of A -3-hydroxy-steroids by treatment of a A -3-keto-10-methyl-steroid with an alkali metal in the presence of a polycyclic aromatic compound and an ethereal solvent, followed by acid con-version of the alkali metal salt of the relative steroid.
  • the starting products may possess all kinds of substituents elsewhere in the preferably ketalised, or a 1 7fi-hydroxyl group, possibly converted into the tetrahydropyranyl-ether.
  • R R and R hydrogen or an alkyl group with 1-6 carbon atoms.
  • Y an alkyl group with 1-4 carbon atoms.
  • the desired oestradiol is obtained in a yield of at least calculated on the free A -3-ketol7/3-hydroxy-androstadiene after conversion of this compound into the acetal or ketal described before.
  • the present process has a few more advantages over the known process. Firstly the vinylalkyl-ethers to be used in the formation of the acetal or ketal are much cheaper than the dihydropyran to be used in the preparation of tetrahydropyranyl-ethers. Secondly the IZB-hydroxyl acetals or kefials derive-d from the above-mentioned vinylalkyl-others are generally obtained in a higher yield than the tetrahydropyranyl-ethers; and thirdly the final products can be isolated more easily in a pure condition than those obtained if tetrahydropyranyl-ethers are applied.
  • the prepa-ra ion of the 17fi-h-ydroxy derivatives according to the invention takes place by reacting the relative l7-hydroxy-steroid with a vinylalkyl-ether in the presence of an acid catalyst, such as paratoluene sulphonic acid, benzene sulphonic acid, dinitro benzene sulphonic acid, hydrochloric acid or a Lewis acid, such as borotrifluoride or the etherate thereof.
  • an acid catalyst such as paratoluene sulphonic acid, benzene sulphonic acid, dinitro benzene sulphonic acid, hydrochloric acid or a Lewis acid, such as borotrifluoride or the etherate thereof.
  • the reaction may be performed in the presence of a solvent, such as an aromatic hydrocarbon, for instance benzene or toluene, an ether, a halogenated hydrocarbon, such as chloroform or carbon tetrachloride, or petroleumether.
  • a solvent such as an aromatic hydrocarbon, for instance benzene or toluene, an ether, a halogenated hydrocarbon, such as chloroform or carbon tetrachloride, or petroleumether.
  • an inhibitor such as hydroquinone, may be added to avoid polymerisation of the vinyl-ether.
  • the present process also relates to the new derivatives of a A -3-kcto-l7B-hydroxy-androstadiene compound, of which the structure at carbon atom 17 is given below:
  • the 17-derivatives of A -3-keto-10methyl-17/8- hydroxy-steroids to be used as starting products in the present process may possess yet other substituents elsewhere in the molecule and/or double bonds insofar as these groups are not sensitive to the present reductive aromatisation.
  • the aromatisation of the starting products of the present invention takes place by the known method, consisting in the reaction of such a starting product with at least two atomic equivalents of an alkali metal, and a polycyclic aromatic compound capable of serving as a radical anion precursor, e.g. biphenyl, naphthalene, methylnaphthalene, phenanthrene or anthracene, in the presence of an ethereal solvent, followed by acidification of the resulting steroidal alkali metal salt, as more fully described in the above cited British patent.
  • a radical anion precursor e.g. biphenyl, naphthalene, methylnaphthalene, phenanthrene or anthracene
  • EXAMPLE I Thirty grams of A -3-keto-l7fl-hydroxy-androstadiene are suspended in 300 ml. of ethylvinyl-ether, after which slowly, in small portions, 100 mg. of p-toluene sulphonic acid are added. While the substance dissolves the temperature rises to about 25 C. After that the solution is stirred for minutes. Next the reaction mixture is washed with 50 ml. of a 10% potassium carbonate solution, after that with water until neutral and finally evaporated to dryness.
  • the aqueous mixtures are extracted with 50 ml. of benzene and the total organic layer evaporated to dryness.
  • the residue is boiled twice with 300 ml. of hexane and after cooling down to room temperature filtered off.
  • the residue is dissolved in 500 ml. of boiling benzene, filtered over hyflo, and crystallised.
  • the mother liquor is chromatographed over silicagel in benzene.
  • EXAMPLE IV Five grams of A -3-ket0-17,8-hydroxy-l7a-mcthylandrostadiene are dissolved in ml. of ethylvinyl-ether, after which 25 mg. of p-toluene sulphonic acid are added. After slightly heating the mixture is maintained at room temperature for 45 minutes, after which 10 mg. of ptoluene sulphonic acid are added. If no noticeable reaction occurs, a bicarbonate solution is added, the mixture extracted with ether, washed and evaporated to dryness.
  • Y--OCH CH in which Y is alkyl with l-4 carbon atoms.
  • R is selected LEWIS GOTTS, Primary Examiner.
  • T M MESHBESHER Assistant Examiner and R R and R are selected from the group consisting of hydrogen and lower alkyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US543814A 1965-04-28 1966-04-20 Process for the preparation of delta1,3,5(10)-3,17-dihydroxy steroids Expired - Lifetime US3415853A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
NL6505397A NL6505397A (Direct) 1965-04-28 1965-04-28

Publications (1)

Publication Number Publication Date
US3415853A true US3415853A (en) 1968-12-10

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US543814A Expired - Lifetime US3415853A (en) 1965-04-28 1966-04-20 Process for the preparation of delta1,3,5(10)-3,17-dihydroxy steroids

Country Status (5)

Country Link
US (1) US3415853A (Direct)
CH (1) CH478109A (Direct)
DE (1) DE1593150A1 (Direct)
GB (1) GB1139326A (Direct)
NL (1) NL6505397A (Direct)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3128291A (en) * 1960-06-23 1964-04-07 Leo Pharm Prod Ltd New hemiacetals and hemicaetal esters of the androstane series and a method for their production
US3274182A (en) * 1963-12-28 1966-09-20 Searle & Co Process for reducing 19-methyl-1, 4-dien-3-ones to corresponding 19-nor-3-oxy-1, 3, 5(10)-trienes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3128291A (en) * 1960-06-23 1964-04-07 Leo Pharm Prod Ltd New hemiacetals and hemicaetal esters of the androstane series and a method for their production
US3274182A (en) * 1963-12-28 1966-09-20 Searle & Co Process for reducing 19-methyl-1, 4-dien-3-ones to corresponding 19-nor-3-oxy-1, 3, 5(10)-trienes

Also Published As

Publication number Publication date
NL6505397A (Direct) 1966-10-31
DE1593150A1 (de) 1970-07-16
GB1139326A (en) 1969-01-08
CH478109A (de) 1969-09-15

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