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WO2007069039A2 - Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués - Google Patents

Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués Download PDF

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Publication number
WO2007069039A2
WO2007069039A2 PCT/IB2006/003580 IB2006003580W WO2007069039A2 WO 2007069039 A2 WO2007069039 A2 WO 2007069039A2 IB 2006003580 W IB2006003580 W IB 2006003580W WO 2007069039 A2 WO2007069039 A2 WO 2007069039A2
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WO
WIPO (PCT)
Prior art keywords
process according
solvent
substituted
basic salt
triene
Prior art date
Application number
PCT/IB2006/003580
Other languages
English (en)
Other versions
WO2007069039A3 (fr
Inventor
Bruce Allen Pearlman
Chongsoo Lim
Original Assignee
Pfizer Products Inc.
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 Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007069039A2 publication Critical patent/WO2007069039A2/fr
Publication of WO2007069039A3 publication Critical patent/WO2007069039A3/fr

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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
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • 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
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C07J1/004—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0048—Alkynyl derivatives
    • 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
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • 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
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • This invention relates to a method for converting 17 substituted androsta-1 ,4,9(11)- triene-3-ones to 17 substituted 3-hydroxyestra-l,3,5(10),9(l l)-tetraenes ( ⁇ 9 -estra ⁇ es).
  • the 17 substituted ⁇ 9 -estranes are useful as intermediates in the synthesis of 19-nor steroids such as estradiol, estrone, estramustine, ethynylestradiol.
  • Magerlein J. Am. Chem. Soc, 80, 2220 (1958) formed methyl 3-hydroxy-19-nor-l, 3,5(10), 17(20)- ⁇ regnatetraen-21-oate from methyl 3-keto-l,4,17-(20)-[cis]-pregnatriene-21-oate in 15.3% yield by a pyrolysis method in a glass vessel.
  • Charpentier et al. (Steroids; 52; 1988; 609 - 621) removed the 19 methyl and aromatized the A ring of 7 ⁇ -methoxycarbonyl methyl-androsta-1 ,4,9( 11 )-triene-3, 17-dione using large excess of zinc (108 equivalents) in pyridine and water.
  • Tsuda et al. removed the 19 methyl and aromatized the A ring of androsta-1 ,4, 9-(the methyl expulsion does not work in the 1,4,6 case)triene-3,17-dione using large excess of zinc (96 equivalents) in pyridine (J. Org. Chem.; 1963, 26; 783-785) Harburn et al. discuss the use of zinc in pyridine for removing the 19 methyl from molecules similar to androsta-1 ,4,9(1 l)-triene-3,17-dione (J. Chem. Research (S); 1998; 424 - 425 and J. Chem. Research (M); 1998; 1872-1884).
  • elemental silicon in the presence of a basic salt, may be used to convert 17 substituted androsta-1 ,4,9(1 l)-triene-3-ones of Formula I to 17 substituted ⁇ 9 - estranes of Formula II.
  • the compound of Formula ⁇ are used in the synthesis of 39- ⁇ or-methyl steroids such as estradiol, estrone, estramustine, ethynylestradiol.
  • HPLC refers to high pressure liquid chromatography
  • TLC refers to thin layer chromatography
  • URMS refers to low resolution mass spectrum.
  • NMK refers io nuclear magnetic reonance spectroscopy.
  • THF refers to tetrahydroft-ran.
  • DMF N,N-dimethyIformaraide
  • DMA refers to N,N-dimelhylacetamide.
  • DMSO diroethylsulfoxide
  • sulf ⁇ lane refers to tetrahydrothiophene 1 ,3 -dioxide.
  • ATTD refers lo androsta-] ,4,9(3 ])-triene-3,17-dione.
  • MTBE refers to jnethyl-t-butylefher DESCRIPTION
  • elemental silicon in the presence of a basic salt, may be used to convert 17 substituted androata-l ,4,9(11 )-triene-3-ones of Formula I to 17 substituted ⁇ 9 - estranes of Formula II.
  • R 1 is OH
  • R 2 is H or — C- ⁇ CE
  • the 17 substituted androsta-3 ,4,903 >triene-3-ones of Formula I, the silicon,, and the basic salt ars mixed "* ⁇ ith a suitable solvent, and reacted at a temperature of 130 to 350 0 C.
  • a polar solvent with a boiling point of 130 "C or above fhat provides appreciable solubility for the basic salt is appropriate.
  • the solvent may have a boiling point well above 130 0 C, such as 1-decanol, which has a boiling point of 233 0 C, but the solvent should be a liquid at room temperature.
  • the alcohols boiling above 130 0 C 5 such as n-pentanol, the C 6 to C )0 saturated aliphatic alcohols, glycols and glycol mono-ethers such as ethylene glycol, diethylene glycol, ethylene glycol mono-ethyl ether, and diethylene glycol mono-ethyl ether, and mixtures thereof are suitable solvents.
  • high boiling polar aprotic solvents such as DMF, DMA, DMSO, and sulfolane may be mixed with the any of the polar solvents noted above to provide additional solubility for the basic salt.
  • Diethylene glycol mono-ethyl ether and a diethylene glycol mono-ethyl ether/ethylene glycol mixture are preferred solvents.
  • the solvents tend to be hygroscopic, and may contain a small percentage of water, such 1 to 2 percent water. It is not necessary to exclude water from this reaction, and it is often advantageous to add small quantities of water to enhance the reaction rate.
  • the amount of water that may be added is up to 25 volume percent of the total volume of the organic solvent components. The addition of water to the solvent accelerates the reaction when the basic salt is a carbonate or bicarbonate.
  • the basic salt is selected from alkali metal hydroxides, carbonates, and bicarbonates such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate; and soluble fluoride salts such as tetra(C] to C 4 )alkyl ammonium fluorides, sodium fluoride, potassium fluoride, and ((CH 3 ⁇ N) 3 SF 2 (CH 3 ) S .
  • the side products of the reaction, formed from the silicon are either silicates, or fluorosilicates. For example, when potassium hydroxide or carbonate is used as the basic salt, potassium silicate is formed, and when potassium fluoride is used as the basic salt, potassium fluorosilicate is formed during the reaction.
  • a preferred basic salt is potassium fluoride.
  • Two or more salts may be used in this reaction. After the 17 substituted androsta-1 ,4,9(11 )-triene-3-one, silicon, basic salt, and the appropriate solvent are mixed, the reaction mixture is heated at a temperature of 130 to 150 0 C until the reaction is complete. Depending upon the temperature, the solvent, and the basic salt, the reaction may take 2 hours or more. The reaction tends to come to completion more quickly if a soluble fluoride is selected as the basic salt. If a hydroxide, carbonate or bicarbonate is selected as the basic salt, the reaction rate may be increased by the addition of a small amount of water to the solvent.
  • TLC thin layer chromatography
  • the reaction mixture may be worked up, and the product isolated, by a number of methods that will be apparent to those skilled in the art.
  • a typical extractive work up the reaction mixture is cooled, and poured into a dilute aqueous solution of a mineral acid.
  • mineral acids include hydrochloric acid, sulfuric acid, and phosphoric acid.
  • the mixture is extracted several times with a water immiscible organic solvent, such as ethyl acetate, methylene chloride, methyl-t-butylether (MTBE), or 2-methyl THF.
  • Tetrahydrofuran may be used as an extracting solvent since the salts present in the water phase "salt out the THF into a separate layer.
  • the organic extract is washed with water and concentrated by evaporation.
  • the residue can be optionally purified by recrystaHization from solvents such as methylene chloride, benzene, or a 1:1 mixture of toluene and methylene chloride.
  • the ⁇ 9 -estrane residue may also be purified by extraction from an inert organic solvent, such as toluene, into a strong aqueous base such as aqueous KOH or NaOH. Upon acidification of the aqueous layer, the ⁇ 9 -estrane precipitates.
  • Androsta-],4,9(l l)-triene-3,17-dione ("ATD ; 0.5g, 1.77 mmol, 1 eq.), elemental silicon powder (325 mesh; 0.497g, 17.7 mmol, 10 eq.), K 2 CO 3 (2.45g, 17.7 mmol, 10 eq.), silica gel (as a filtration aid 0.5g) and diethylene glycol monoethyl ether (15 mL) were charged to a 50 mL, 2-necked round-bottomed flask equipped with condenser, magnetic stirring bar, nitrogen tee, and septum. The temperature of the reaction mixture was increased to 140 0 C, and was maintained for 2 hours.
  • Androsta-1 ,4,9(1 l)-triene-3,17-dione ("ATD (10.0 g, 35.4 mmol, 1 eq.), elemental silicon powder (325 mesh; 4.97 g, 177 mmol, 5 eq.), potassium fluoride (10.3 g, 177 mmol, 5 eq.), diethylene glycol monoethyl ether (140 mL) and ethylene glycol (70 mL) were charged to a 500 mL, 4-necked round-bottomed flask, equipped with a condenser, nitrogen tee, thermocouple, mechanical stirrer and a glass cap. The temperature of the reaction mixture was increased to 120 0 C.

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

Abstract

La présente invention a pour objet un procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-l,3,5(10),9(11)-tétraènes 17-substitués.
PCT/IB2006/003580 2005-12-13 2006-12-12 Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués WO2007069039A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74970605P 2005-12-13 2005-12-13
US60/749,706 2005-12-13

Publications (2)

Publication Number Publication Date
WO2007069039A2 true WO2007069039A2 (fr) 2007-06-21
WO2007069039A3 WO2007069039A3 (fr) 2007-10-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/003580 WO2007069039A2 (fr) 2005-12-13 2006-12-12 Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués

Country Status (1)

Country Link
WO (1) WO2007069039A2 (fr)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHARPENTIER ET AL.: "SYNTHESIS OF 7-ALPHA- AND 7-BETA-CARBOXYMETHYL-9(11)-ENE DERIVATIVES OF ESTRONE AND ESTRADIOL" STEROID, vol. 52, no. 5-6, 1988, pages 609-621, XP002439115 cited in the application *
LIM ET AL: "An environmentally friendly and cost effective synthesis of estradiol featuring two novel reagents: Si(0)/KF and PMHS/hexamethyldisiloxane/pTS" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 47, no. 36, 4 September 2006 (2006-09-04), pages 6417-6420, XP005589978 ISSN: 0040-4039 *
MAGERLEIN B J ET AL: "Preparation and Reactions of 11-Substituted 1,3,5(10)-Estratrienes. I. 11-Oxygenated Estrones and Estradiols" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 80, 5 May 1958 (1958-05-05), pages 2220-2225, XP002177431 ISSN: 0002-7863 cited in the application *
TSUDA ET AL.: "AN AROMATIZATION OF A CROSS-CONJGATED DIENONE SYSTEM WITH ZINC" JOURNAL OF ORGANIC CHEMISTRY, vol. 26, 1963, pages 783-785, XP002439114 cited in the application *

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Publication number Publication date
WO2007069039A3 (fr) 2007-10-04

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