DOCSLIB.ORG

United States Patent (19) 11 Patent Number: 4,585,591 Nitta Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent (19) 11 Patent Number: 4,585,591 Nitta Et Al United States Patent (19) 11 Patent Number: 4,585,591 Nitta et al. (45) Date of Patent: Apr. 29, 1986 (54) 17B-ETHYNYLSTEROIDs AND PROCESS 56) References Cited FOR PREPARNG SAME U.S. PATENT DOCUMENTS 75) Inventors: Issei Nitta, Machida; Shinichiro 3,023,206 2/1962 Burnet al. ..................... 260/239.55 Fujimori, Yokohama; Toshio Haruyama, Sagamihara; Shinya FOREIGN PATENT DOCUMENTS Inoue, Yamato, all of Japan 845441 8/1960 United Kingdom ............. 260/397.4 73 Assignee: Mitsubishi Chemical Industries, Ltd., OTHER PUBLICATIONS Tokyo, Japan L. A. van Dijck et al., "Synthesis and Reactions of 3-Methoxy-17-Hydroxy-17-Ethynyl-1,3,5(10)-Estra 21 Appl. No.: 325,026 triene', Recueil Journal of the Royal Netherlands Chemical Society, 96,7-8, Jul.-Aug., pp. 200-205 22 Filed: Nov. 25, 1981 (1977). Primary Examiner-Elbert L. Roberts 30 Foreign Application Priority Data Attorney, Agent, or Firm-Oblon, Fisher, Spivak, Dec. 10, 1980 JP Japan ................................ 55-174065 McClelland & Maier Dec. 10, 1980 JP Japan ... ... 55-174.066 Feb. 23, 1981 JP Japan .................................. 56-25307 (57) ABSTRACT Jul. 28, 1981 (JP) Japan ................................ 56-18343 This is disclosed novel intermediates, i.e. 1743-ethynyl steroids, which are useful for the preparation of corti 51) Int. Cl. .................................................. CO7J 1/00 coids such as hydrocortisone and prednisolone, and a 52 U.S. C. ............................ 260/3974; 260/397.45; process for preparing the same. 260/239.55 C, 260/397.5; 260/397.47 58) Field of Search ......................... 260/397.4, 397.45 4 Claims, No Drawings 4,585,591 1 2 17(3-ETHYNYLSTEROIDS AND PROCESS FOR -continued PREPARING SAME CECH BACKGROUND OF THE INVENTION This invention relates to a novel intermediate for use in the preparation of corticoids (adrenocortical hor mones) such as hydrocortisone, prednisolone and the MeO like. 10 Recently, androst-4-ene-3,17-dione and androsta-1,4- Thus, according to the reported process, estrone diene-3,17-dione have been produced in a large scale methyl ether is ethynylated to give mestranol, which is then esterified with methanesulfonyl chloride. The re and inexpensively from a sterol such as cholesterol or sulting methanesulfonate ester of mestranol is hydro sitosterol with the aid of bacteria of the Mycobacterium 15 lyzed in a hydrous tetrahydrofuran solvent in the pres genus whereby various steroidal drugs such as estrone, ence of silver nitrate to give epimestranol (the 1713 testosterone, spironolactone, etc. have been produced ethynyl isomer of mestranol) in an about 80% yield. from these starting compounds. This process, however, cannot be said to be advanta On the other hand, corticoids which comprises a 20 geous from a commercial viewpoint, since the methane major portion of the steroidal drugs are still prepared sulfonate ester of a tertiary alcohol such as nestranol methanesulfonic acid ester is extremely unstable and using as an intermediate progesterone which is pro can be synthesized only by limited procedures. For duced from stigmasterol, or 16-dehydropregnenolone example, according to the procedure described in the which is produced from diosgenin, or they are prepared 25 above-mentioned article, mestranol is dissolved in tetra from bile acids via a process comprising many steps. hydrofuran and cooled to - 60° C. To the cooled solu We have carried on investigations with attention to tion is added n-butyl lithium in an amount equimolar the fact that corticoids can be prepared through fewer with the mestranol. Subsequently methanesulfonyl steps from the aforementioned androst-4-ene-3,17 chloride is added also at - 60° C. Also regarding the dione, androsta-1,4-diene-3,17-dione or androsta-4,901)- 30 post-treatment, it is suggested in the article that the desired methanesulfonate cannot be obtained in good diene-3,17-dione which has recently be produced inex yield unless the reaction mixture is worked up carefully pensively and in a large scale from 9a-hydroxy-androst at a temperature of 0° C. or below. 4ene-3,17-dione which has also recently be produced by In addition, in order to prepare 17(3-ethynyl-17a a fermentative process. 35 hydroxyandrost-4-en-3-one Ot 17p-ethynyl-17a hydroxyandrosta-1,4-dien-3-one which is useful as an BRIEF DESCRIPTION OF THE PRIOR ART intermediates for the preparation of hydrocortisone or A novel technique of isomerization of 17a-ethynyl prednisolone, it is necessary to synthesize ethisterone group into 17a-ethynyl group has recently been re methanesulfonic acid ester or 17a-ethynyl-17A-hydrox ported Tetrahedron Letters, 21, 2665 (1980). 40 yandrosta-1,4-dien-3-one 176-methanesulfonic acid es ter. However, in contrast with mestranol, these steroids have a 3-carbonyl group on the ring A of the steroid skeleton, said carbonyl group being sensitive to and reactive with n-butyl lithium. Therefore, the above 45 mentioned process cannot be employed to synthesize the desired methanesulfonate of such a 3-carbonyl-con taining steroid in good yield. Thus, the above prior art process is considered to be far from satisfactory as a commercial process for the 50 preparation of steroids in that it requires an extremely low temperature of -60 C. and that it is applicable only to those steriods which are free from n-butyl lithi um-labile structural element. (1) BuLi 55 (2) MeSO2Cl SUMMARY OF THE INVENTION - a Ge. The present invention relates to novel intermediates, i.e., 1713-ethynylsteroids such as, e.g., 1713-ethynyl 17ahydroxyandrost-4-en-3one, 17B-ethynyl-17a hydroxyandrosta-1,4-dien-3-one, 176-ethynyl-17a acetoxyandrosta-1,4-dien-3-one, etc., which are useful for the preparation of corticoids such as hydrocortisone and prednisolone, and a process for preparing the same. DESCRIPTION OF THE PREFERRED EMBODIMENTS MeO In one aspect, the present invention provides a 17(3- ethynylsteroid of the formula: 4,585,591 4. carbon atoms, and the aryl for R usually contains 6 to (I) about 10 carbon atoms. The steroid having the partial structural formula (II) which is used as a starting compound in this method includes sulfonic acid esters such as 3,3-ethylenedioxy 17aethynyl-17 (3-hydroxyandrost-5ene 1713-methanesul fonic acid ester, and 3,3-ethylenedioxy-17a-ethynyl 17(3-hydroxyandrosta-5,901)-diene 17(3-methanesul fonic acid ester; nitric acid esters such as 17a-ethynyl 10 1713-hydroxyandrost-4-en-3-one 1713-nitric acid ester, wherein the dotted lines represented either a single or 17a-ethynyl-17 (3-hydroxyandrosta-1,4-dien-3-one double bond, and X is hydroxyl or an acyloxy. 1713nitric acid ester and 17a-ethynyl-1713-hydroxyan The acyloxy group for X contains an acyl moiety drosta-4,901)-dien-3-one 1713-nitric acid ester, and ni having 2 to about 13 carbon atoms, usually 2 to 7 carbon trous acid esters such as 17a-ethynyl-17A-hydroxyan atoms and preferably 2 to 4 carbon atoms. 15 drost-4-en-3-one 17f8-nitrous acid ester, 17a-ethynyl The compounds of the foregoing formula (I) include 1713-hydroxyandrosta-1,4-dien-3-one 1713-nitrous acid 17(3-ethynyl-17a-hydroxyandrost-4-en-3-one, 17(3- ester and 17a-ethynyl-17(3-hydroxyandrosta-4,901). ethynyl-17a-hydroxyandrosta-1,4-dien-3-one, 17(3ethy dien-3-one 1713-nitrous acid ester. The steroid skeleton nyl-17a-hydroxyandrosta-4,901)-dien-3-one, 17(3-ethy 20 may be a 19-norsteroid such as 19-norethisterone or a nyl-17a-hydroxyandrosta-1,4,9(I)-trien-3-one, etc., as steriod the ring A of which comprises an aromatic nu well as esters of these 1713-ethynyl-17a-hydroxysteroids cleus such as mestranol. In those steriods having a car with a carboxylic acid such as acetic acid, propionic bonyl group at the 3-position, the carbonyl group may acid or benzoic acid. be protected with an acetal-, enol- or enamine-type Thus, the compounds of the formula: 25 protective group. In addition, the steroid may contain one or more substituents such as hydroxyl at the 1-, 6- or 11-position, keto at the 11-position, fluorine at the 6- or CECH (I") 9-position and methyl at the 1-, 6- or 16-position. The method (Method A) may be carried out by react 30 ing a steroid having the partial structural formula (II) with water in the presence of a catalytic amount of cuprous (i.e. monovalent copper) salt. The cuprous salt includes cuprous halides such as cuprous chloride, cuprous bromide and cuprous iodide, 35 cuprous cyanide, cuprous oxide, cuprous phosphate, cuprous acetate and the like. Usually cuprous chloride is preferably used because of its inexpensiveness. The cuprous salt is usually used in an amount of 0.01 (I") to 1.0 mole, preferably 0.05 to 0.4 mole per mole of the starting steroid. The use of much less cuprous salt than above requires a prolonged period of time to attain an adequate conversion of the starting steroid, while the use of much more cuprous salt offers no particular prob lem. 45 The reaction is conducted in a solvent which is desir ably compatible with water and which desirably has no are both included in the compounds (I) of this inven or little nucleophilicity. Suitable solvents include ethers tion. In the above formulas (I) and (I'), the dotted lines such as tetrahydrofuran, dioxane and ethylene glycol are as defined above and Z is an acyloxy group. dimethyl ether, esters such as ethyl acetate, ketones The 1713-ethynyl-17a-hydroxysteroids of formula (I) 50 such as acetone, and other highly polar aprotic solvents may be prepared by either the following method A or such as dimethylformamide, and dimethyl sulfoxide.
Load more

Recommended publications
  • Seco-Steroids C07C)
    CPC - C07J - 2021.08 C07J STEROIDS (seco-steroids C07C) Definition statement This place covers: Compounds containing a cyclopenta[a]hydrophenanthrene skeleton (see below) or a ring structure derived therefrom: • by contraction or expansion of one ring by one or two atoms; • by contraction or expansion of two rings each by one atom; • by contraction of one ring by one atom and expansion of one ring by one atom; • by substitution of one or two carbon atoms of the cyclopenta[a]hydrophenanthrene skeleton, which are not shared by rings, by hetero atoms, in combination with the above defined contraction or expansion or not, or; • by condensation with carbocyclic or heterocyclic rings in combination with one or more of the foregoing alterations or not. Preparation of steroids including purification, separation, stabilisation or use of additives unless provided for elsewhere, as specified below. Treatment and modification of steroids provided that • the treatment is not provided for elsewhere and • the resultant product is a compound under the subclass definition. Relationships with other classification places In class C07, in the absence of an indication to the contrary, a compound is classified in the last appropriate place, i.e. in the last appropriate subclass. For example cyclopenta [a] hydrophenantrenes are classified in subclass C07J as steroids and not in subclasses C07C or C07D as carbocyclic or heterocyclic compounds. Subclass C07J is a function-oriented entry for the compounds themselves and does not cover the application or use of the compounds under the subclass definition. For classifying such information other entries in the IPC exist, for example: Subclass A01N: Preservation of bodies of humans or animals or plants or parts thereof; biocides, e.g.
    [Show full text]
  • GC/C/IRMS) Als Potentielle Untersuchungsmethode Zum Nachweis Einer Illegalen Anwendung Von 19-17 Βββ-Nortestosteron in Der Ebermast
    Einsatz der Stabilisotopen-Massenspektrometrie (GC/C/IRMS) als potentielle Untersuchungsmethode zum Nachweis einer illegalen Anwendung von 19-17 βββ-Nortestosteron in der Ebermast Dissertation zur Erlangung des akademischen Doktorgrades der Naturwissenschaften an der Bergischen Universität im Fachbereich Mathematik und Naturwissenschaften Die Arbeit wurde in der Zeit vom 15. Mai 2003 bis 31.Dezember 2006 am Chemischen und Veterinäruntersuchungsamt in Freiburg angefertigt vorgelegt von Annette Mertineit-Heinz Wuppertal 2007 Diese Dissertation kann wie folgt zitiert werden: urn:nbn:de:hbz:468-20070870 [http://nbn-resolving.de/urn/resolver.pl?urn=urn%3Anbn%3Ade%3Ahbz%3A468-20070870] dem Allmächtigen Gott Das Geheimnis Gottes ist Jesus Christus, in dem alle Schätze der Weisheit und Erkenntnis verborgen sind. Die Bibel , Kolosser 2, 3 Dank Mein besonderer Dank gilt Herrn Prof. Dr. Michael Petz, der es mir ermöglichte, an der Universität Wuppertal diese Dissertation anzufertigen. Für seine Hilfsbereitschaft und Ermutigungen bin ich ihm sehr dankbar. Bedanken möchte ich mich beim Amtsleiter des CVUA Herrn Dr. Roland Renner sowie Laborleiter Herrn Dr. Martin Metschies, dass ich die Untersuchungen für diese Arbeit am CVUA durchführen durfte. Bei Laborleiterin Frau Dr. Eva Annweiler möchte ich mich für ihre vielseitige Unterstützung in analytischen Fragen und ihre Hilfe bei der Durchsicht der Arbeit bedanken. Den Labormitarbeitern Herrn Thomas Huber danke ich für die Unterstützung bei den EA/IRMS-Messungen, Frau Sylvia Scanlan-Sierra bei den GC/MS-Messung und Herrn Manfred Grosse bei den GC/FID-Messungen. Herr Grosse hat sich immer Zeit genommen, mich zu unterstützen, ohne dabei seine tägliche Arbeit zu vernach- lässigen. Für die Unterstützung der Aufarbeitung der Eberurine gilt mein Dank Laborleiter Herr Lippold und den Mitarbeitern Frau Annabarbara Fies, Herrn Markus Roth und Frau Maria Schmidt.
    [Show full text]
  • United States Patent Office Patented Jan
    3,231,567 United States Patent Office Patented Jan. 25, 1966 2 droxy ethylene, hydroxy propylene, hydroxybutylene and 3,231,567 PROCESS FOR THE PREPARATION OF 3-HY the like; a saturated or unsaturated cycloaliphatic moiety, DROXY. AND 3-ALKOXY-ESTRATRIENES such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, AND INTERMEDIATES THEREFOR cyclopentenyl, cyclohexenyl, cyclopentylpropyl, cyclo Alberto Ercoli and Rinaldo Gardi, Milan, and Cesare 5 heptyl, cyclooctyl radical; or an araliphatic moiety, such Pedrai, Bergamo, Italy, assignors to Francesco Wismara as benzyl, phenetyl, cynnamyl radical. Preferred hydro S.p.A., Casadenovo, Italy carbon radicals are aliphatic moieties containing from 1 No Drawing. Fied Dec. 16, 1963, Ser. No. 330,584 to 8 carbon atoms, inclusive, cycloaliphatic moieties con Claims priority, application Italy, Dec. 19, 1962, taining from 5 to 6 carbon atoms in the ring and the Patent 24,856/62 benzyl radical. 20 Claims. (C. 260-239.55) 10 Methods for the aromatization of the ring A of 19-nor This invention relates to an improved process for con steroids are already known in the literature and the prior verting steroids of the 19-nor-androstane and 19-nor-preg art teaches the conversion of a 3-keto-19-norsteroid of name series into derivatives of the estrogenic series. The the androstane series into a derivative of the estrogenic invention also relates to certain new 19-norsteroid deriva 5 series. This conversion may be accomplished by first tives useful as intermediates in said conversion. preparing a 5,10-epoxy-estren-3-one or a 3-ketal thereof More particularly, this invention is concerned with a by epoxiding a 5 (10)-estrene-3-one or A-3-keto-19-nor amethod for the aromatization of the ring A to produce steroid 3-ketal, respectively, with a peracid.
    [Show full text]
  • Anabolic Steroids Detected in Bodybuilding Dietary Supplements– a Significant Risk to Public Health V
    Drug Testing 1esearch article and Analysis Received; ,. June ,01$ Revised; 1 September ,01$ <ccepted: $ September ,01$ =ublished online in 7iley Online Library 3!!!.drugtestinganalysis.com4 >%I 1..1..,?dta.17,@ Anabolic steroids detected in bodybuilding dietary supplements– a significant risk to public health V. Abbate,a A. T. Kicman,b M. Evans-Brown,c J. McVeigh,d D. A. #owan,b #. Wilson,e S. J. #olese and C. J. $alkerb& Twenty-four products suspected of containing anabolic steroids and sold in fitness equipment shops in the (nited Kingdom )(K) ere analyzed for their qualitative and semi-quantitative content using full scan gas chromatography-mass spectrometry ),#-M%*, accurate mass li'uid chromatography-mass spectrometry )-#-M%*, high pressure liquid chromatography ith diode array detection )./-#-"A"*, (V-Vis, and nuclear magnetic resonance )0M1* spectroscopy. 2n addition, 3-ray crystallography enabled the identification of one of the compounds, here reference standard as not available. 4f the 56 products tested, 57 contained steroids including kno n anabolic agents8 9: of these contained steroids that ere different to those indicated on the packaging and one product contained no steroid at all. 4verall, 97 different steroids ere identified8 95 of these are controlled in the (K under the Misuse of "rugs Act 9;<9. %everal of the products contained steroids that may be considered to have considerable pharmaco- logical activity, based on their chemical structures and the amounts present. This could un ittingly e=pose users to a significant risk to their health, hich is of particular concern for na>ve users. #opyright ? 5@96 !ohn $iley A %ons, -td.
    [Show full text]
  • Biological Efficacy and Plasma Norethisterone Levels of Orally Administered Norethisterone Enanthate in Rat and Hamster
    Indian J Physiol Pharmacol 1998; 42 (4) : 485-490 BIOLOGICAL EFFICACY AND PLASMA NORETHISTERONE LEVELS OF ORALLY ADMINISTERED NORETHISTERONE ENANTHATE IN RAT AND HAMSTER P. RAVINDER, K. MADHAVAN NAIR AND B. SIVAKUMAR* Division of Biophysics. National Institute of Nutrition. (Indian Council of Medical Research) Jamai-Osmania, Hyderabad - 500 007 (Received on September 11, 1997) Abstract: Norethisterone enanthate (NET-En) is a well known intramuscular contraceptive drug. The long acting nature of this prep~ration when administered orally was evalu~ted in female rats and hamsters using fertility inhibition test and from the plasma levels of norethisterone (NET). An oral dose of 20-60 mg NET-En was administered to random groups of six female rats and hamsters and were mated after five and ten days with males of proven fertility. The fertility inhibition rate was determined from vaginal delivery. A dose-dependent reduction in fertility was seen in rats 5 days after oral administration of NET-En. This effect was found to be less pronounced and not significant 10 days after administration of similar doses of NET-En. In hamsters, a similar but less pronounced effect was noted. The decrease in fertility was significant only at the 60 mg dose. The plasma levels of NET estimated by RIA over a period of 15 days, in a different set of treated rats, suggested rapid absorption of NET-En within a day, and drug concentration decreased slowly, the levels on the 4th day ranged from 0.9-2.3 with the 10 mg and 1.0-4.0 ng/ml with the 20 mg dose.
    [Show full text]
  • Sports Drug Testing and Toxicology TOP ARTICLES SUPPLEMENT
    Powered by Sports drug testing and toxicology TOP ARTICLES SUPPLEMENT CONTENTS REVIEW: Applications and challenges in using LC–MS/MS assays for quantitative doping analysis Bioanalysis Vol. 8 Issue 12 REVIEW: Current status and recent advantages in derivatization procedures in human doping control Bioanalysis Vol. 7 Issue 19 REVIEW: Advances in the detection of designer steroids in anti-doping Bioanalysis Vol. 6 Issue 6 Review For reprint orders, please contact [email protected] 8 Review 2016/05/28 Applications and challenges in using LC–MS/MS assays for quantitative doping analysis Bioanalysis LC–MS/MS is useful for qualitative and quantitative analysis of ‘doped’ biological Zhanliang Wang‡,1, samples from athletes. LC–MS/MS-based assays at low-mass resolution allow fast Jianghai Lu*,‡,2, and sensitive screening and quantification of targeted analytes that are based on Yinong Zhang1, Ye Tian2, 2 ,2 preselected diagnostic precursor–product ion pairs. Whereas LC coupled with high- Hong Yuan & Youxuan Xu** 1Food & Drug Anti-doping Laboratory, resolution/high-accuracy MS can be used for identification and quantification, both China Anti-Doping Agency, 1st Anding have advantages and challenges for routine analysis. Here, we review the literature Road, ChaoYang District, Beijing 100029, regarding various quantification methods for measuring prohibited substances in PR China athletes as they pertain to World Anti-Doping Agency regulations. 2National Anti-doping Laboratory, China Anti-Doping Agency, 1st Anding Road, First draft submitted:
    [Show full text]
  • Microbial Transformation of Bile Acids. a Unified Scheme for Bile Acid Degradation and Hydroxylation of Bile Acids
    SR P T03 Form 3 CONDITIONAL THE UNIVERSITY OF NEW SOUTH WALES DECLARATION RELATING TO DISPOSITION OF PROJECT REPORT/THESIS This is to certify that I d?..^ ...being a candidate for the degree of am fully aware of the policy of the University relating to the retention and use of higher degree project reports and theses, namely that the University retains the copies submitted for examination and is free to allow them to be consulted or borrowed. Subject to the provisions of the Copyright Act, 1968, the University may issue a project report or thesis in whole or in part, in photostat or microfilm or other copying medium. I wish the following condition to attach to the use of my project f^pert/thesis: . \ ^-ri pi^^fM-i oA ...-to. .m.P^^.E d .v ^y ^ Ci^^k ^ S.t 01- ^ ^sos-. ^ .TTlk^.f^ u QMIT^. ^L.J^ I also authorize the publication by University Microfilms of a 350 word abstract in Dissertation Abstracts International (applicable to doctorates only). Witness... ..e GENETIC MANIPULATION OF PSEUDOMONADS TO PRODUCE STEROID CATABOLITES FROM BILE ACIDS. A THESIS SUBMriTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF NEW SOUTH WALES AUSTRALIA BY JOHN ALTON IDE SCHOOL OF BIOTECHNOLOGY MAY, 1989. UNIVERSITY OF N.S.W. 16 MAY 1990 CONTENTS Page ABSTRACT i DECLARATION iii ACKNOWLEDGEMENTS iv LIST OF PUBLICATIONS v LIST OF TABLES vi LIST OF FIGURES viii ABBREVIATIONS xi 1 INTRODUCTION 1 LI INTRODUCTION TO STEROID PRODUCTION. 1 L2. EARLY SYNTHETIC PROCESSES FOR THE MANUFACTURE OF STEROID DRUGS. 4 L3. CURRENT PROCESSES 8 L4.
    [Show full text]
  • Epidemiology of Abnormal Uterine Bleeding 25 Michael Zinger 5
    Modern Management…Uterine Bleeding rev2:Modern Management…Uterine Bleeding rev2 9/1/08 10:24 Page 1 Modern Management of O’Donovan O’Donovan ABNORMAL • UTERINE BLEEDING Miller Modern Management of Modern Management of Abnormal Uterine Bleeding is written by an internationally recognized team of experts – many of whom are at the forefront of developing 'second-generation' endometrial ablation techniques as well as ABNORMAL UTERINE BLEEDING Modern Management of standard practice. The book covers the full range of surgical and medical treatments, including the background, diagnosis and treatment. ABNORMAL This must have book will help gynecologists refine their operative techniques and consider new approaches to this highly challenging condition. UTERINE BLEEDING Edited by Peter Joseph O`Donovan FRCOG FRCS (ENG) Consultant Gynaecologist and Gynaecological Cancer Lead Director MERIT Centre, Bradford Teaching Hospitals NHS Trust, Bradford and Professor of Medical Innovation, Bradford University, Bradford,UK Charles E Miller MD FACOG Director of Minimally Invasive Gynecologic Surgery, Lutheran General Hospital, Park Ridge, and Clinical Associate Professor, Department of Obstetrics and Gynecology, University of Chicago, and Clinical Associate Professor, Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL, USA Cover illustration: ‘The Uterine’ by Elizabeth Gray © UK 2008 Edited by ISBN 978-0-415-45479-7 Peter Joseph O’Donovan www.informahealthcare.com 9 78041 5 454797 Charles Miller MODERN MANAGEMENT OF ABNORMAL
    [Show full text]
  • Bismuth(III) Reagents in Steroid and Terpene Chemistry
    Molecules 2011, 16, 2884-2913; doi:10.3390/molecules16042884 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Bismuth(III) Reagents in Steroid and Terpene Chemistry Jorge A. R. Salvador 1,*, Samuel M. Silvestre 2 and Rui M. A. Pinto 1 1 Laboratório de Química Farmacêutica, Faculdade de Farmácia da Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal 2 Health Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +351 239488479; Fax: +351 239827126. Received: 10 February 2011; in revised form: 14 March 2011 / Accepted: 29 March 2011 / Published: 4 April 2011 Abstract: Steroid and terpene chemistry still have a great impact on medicinal chemistry. Therefore, the development of new reactions or “greener” processes in this field is a contemporaneous issue. In this review, the use of bismuth(III) salts, as “ecofriendly” reagents/catalysts, on new chemical processes involving steroids and terpenes as substrates will be focused. Special attention will be given to some mechanistic considerations concerning selected reactions. Keywords: bismuth(III) salts; catalysis; steroids; terpenes; triterpenoids 1. Introduction Steroids [1] and terpenes [2] constitute a large and structurally diverse family of natural products and are considered important scaffolds for the synthesis of molecules of pharmaceutical interest. Different contributions ranging from natural product isolation and characterization to the synthesis of new compounds and their biological evaluation are reported every day. These investigations are justified by the well known biological properties of steroids and terpenes that make them useful molecules in pharmacy and medicine.
    [Show full text]
  • Recent Advances of Bismuth(III) Salts in Organic Chemistry: Application To
    Mini-Reviews in Organic Chemistry, 2009, 6, 241-274 241 Recent Advances of Bismuth(III) Salts in Organic Chemistry: Application to the Syn- thesis of Aliphatics, Alicyclics, Aromatics, Amino Acids and Peptides, Terpenes and Steroids of Pharmaceutical Interest Jorge A.R. Salvador a,*, Rui M.A. Ppinto a and Samuel M. Silvestreb a Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra b Centro de Investigação em Ciências da Saúde, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal Abstract: In this review recent uses of the inexpensive and commercially available bismuth(III) salts in organic chemistry will be high- lighted. Their application to the development of new processes or synthetic routes that lead to compounds of pharmaceutical interest will be matter of discussion. It will focus on bismuth(III) salt-mediated reactions involving the preparation of non-heterocyclic compounds such as aliphatics and alicyclics, monocyclic and polycyclic aromatics, amino acids and peptides, terpenes and steroids. Keywords: Bismuth(III) salts, aliphatics, alicyclics, aromatics, amino acids, peptides, terpenes, steroids, pharmaceutical interest. 1. INTRODUCTION try point of view [4]. This review focuses on the use of bismuth(III) The increasing concern about the environment and the need for salts for the synthesis of the following groups of non-heterocyclic “green reagents” has placed bismuth and its compounds into focus compounds: aliphatics and alicyclics, monocyclic and polycyclic over the last decade. Despite the fact that bismuth is a heavy metal, aromatics, amino acids and peptides, terpenes and steroids, and has bismuth and bismuth(III) salts are considered safe, non-toxic and been organized according to the nature of the reaction products.
    [Show full text]
  • United States Patent Office Patented May 5, 1970
    3,510,477 United States Patent Office Patented May 5, 1970. 1. 2 3,510,477 a carboxylic acyl group having from one to about twelve 22-ETHYLENE-3-OXO-STEROIDS carbon atoms. AND INTERMEDIATES When the 4'-hydroxyspirosteroid-2,4'-m-dioxan-3-one Andrew John Manson, Beaconsfield, Quebec, Canada, as or ester thereof is subjected to mild alkaline conditions signor to Sterling Drug Inc., New York, N.Y., a cor the dioxane ring is cleaved to produce a 2-methylene-3- poration of Delaware oxo-steroid (III). The mild alkaline conditions are pro No Drawing. Continuation-in-part of application Ser. No. duced by contacting the steroid with a weak inorganic 502,394, Oct. 22, 1965. This application Oct. 4, 1967, Ser. No. 672,713 base, for example, an alkali metal carbonate or aluminum Claims priority, application Great Britain, Oct. 17, 1966, oxide. 46,383/66 0 The 2-methylene-3-oxo-steroid reacts with diazometh Int. C. C07c 173/10, 169/22, 169/12 ane to give a spirosteroid-2,3'(2'o)-1-pyrazolin-3-one U.S. C. 260-239.5 39 Claims (IV-A). The latter may in part rearrange to the isomeric spirosteroid-2,3’ (2'oz) - 5 - pyrazolin - 3 - one (IV-B) under the reaction conditions and work-up procedures ABSTRACT OF THE DISCLOSURE 5 used. The pyrazolines (IV-A and IV-B) in acid medium, or by simple pyrolysis, lose nitrogen and are converted to 2,2-ethylene-3-oxo-steroids are prepared starting from a 2,2-ethylene-3-oxo-steroid (V).
    [Show full text]
  • United State S Patent Office Patented Dec
    3,014,931 United State s Patent Office Patented Dec. 26, 1961 2. of 19-nor-4-pregnene-3,20-dione; the yields of the prod 3,0i4,931 10-CARBOXY.A4ANCROSTENES AND PROCESS ucts are no more than 6.2% and 3.3% relative to the FOR THE PRODUCTiON THEREOF starting steroids, respectively. Thus this process is not Masamoto Nishikawa, Nishinomiya, and Hikoichi Hagi suited for any practical purpose. wara, Oyodo-ku, Osaka, Japan, assigaors to Takeda The present invention is directed to the embodiment Pharmaceutical industries, Ltd., Osaka, Japaa of practical means for the preparation, on an industrial No Drawing. Filled Mar. , 1960, Ser. No. 12,001 scale, of the A4-3-oxo-19-norsteroid compounds. Briefly Claims priority, application Japan Sept. 30, i958 stated, this means-according to the invention- involves 16 Claims. (C. 260-397.) essentially the conversion of initial A-3-oxo-19-oxo (or 0 hydroxy)-steroid compounds into the desired A-3-oxo The present application is a continuation-in-part of co 19-norsteroid compounds. A feature of the invention is pending application, Serial No. 841,953, filed September that the starting steroid compounds can themselves be 24, 1959, now abandoned. prepared on an industrial scale and in good yield by The present invention relates to the preparation of subjecting the corresponding 19-unsubstituted A-3-oxo A-3-oxo-19-norsteroid compounds. Features of the pres steroid compound to biological oxidation with a micro ent invention which contribute to its feasibility for use in organism of the genus Corticium (after the manner de the industrial production of A-3-oxo-19-norsteroid com scribed in “Chemical and Pharmaceutical Bulletin,' vol.
    [Show full text]