DOCSLIB.ORG

United States Patent (19) 11) 4,122,254 Hill Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent (19) 11) 4,122,254 Hill Et Al United States Patent (19) 11) 4,122,254 Hill et al. 45 Oct. 24, 1978 54 PROCESS FOR PREPARING AURANOFIN 56) References Cited U.S. PATENT DOCUMENTS 75 Inventors: David T. Hill, North Wales, Pa.; Ivan Lantos, Blackwood, N.J.; Blaine M. 3,635,945 1/1972 Neneth et al. .......................... 536/4 Sutton, Hatboro, Pa. OTHER PUBLICATIONS 73) Assignee: SmithKline Corporation, Sutton et al., J. Med. Chem. 15, 1095 (1972). Philadelphia, Pa. Primary Examiner-Johnnie R. Brown Assistant Examiner-Blondel Hazel (21) Appl. No.: 811,670 Attorney, Agent, or Firm-William H. Edgerton 57 ABSTRACT 22 Filed: Jun. 30, 1977 Auranofin and its congeners are prepared by the reac tion of a S-substituted 2,3,4,6-tetra-O-acetyl-1-thio-g-D- 51) Int. Cl2 ... - O - C - O - B - O - - O C07.H. 23/00 glucopyranose with a tertiary phosphine gold ester or 52 U.S. C. ........................................ 536/121; 536/4; sulfide. 536/122; 424/180 58 Field of Search .................................... 536/121, 4 5 Claims, No Drawings 4,122,254 1. PROCESS FOR PREPARING AURANOFIN This invention comprises a new chemical method for the preparation of auranofin and its congeners which S-R + AgNO - G uses as the key starting material a 2,3,4,6-tetra-O-acetyl glucopyranosyl thioether or thioester whose aglycone portions (R) is a facile leaving group such as a stabilized carbonium ion or a facile displaceable group such as an 10 acyl group. This ether or ester starting material is re CHOAC acted with a reactive tertiary phosphine gold ester or O sulfide. Ac SAg II Ge Auranofin is an orally active antiarthritic agent which is useful in man J. Med. Chem. 15 1095 (1972); 15 U.S. Pat. No. 3,635,945). In these references auranofin is AcO Ac prepared by reacting an alkali metal salt of a 1-thio-g- III D-glucopyranose with a trialkyl phosphine gold halide. CHOAc The invention claimed here is believed to be quite dis 20 O tinct from such prior art processes and therefore patent able. AcO SAuP(CH) The process of this invention is illustrated by the following: AcO OAc 25 Auranofin CHAc A. This reaction can be carried out in one step or two. Also Aco S-R + (CH),P), AuX-G the reaction conditions for the reaction described in B 30 may vary from those described hereafter for example a lower alcohol such as methanol or ethanol or another AcO OAc solvent in which the reactants are soluble such as di methylformamide, dimethylacetamide, acetone or I II diethylcarbonate may be used. CHOAc 35 O In the process of this invention (A above) the thioe ther or thioester reagent (I) reacts very readily with the AcO SAuP(CH), tertiary phosphine gold reagent (II). Usually the reac tion proceeds at about room temperature but tempera tures up to the boiling point of the reaction mixture may AcO Ac be used. A preferred range of temperatures is from Auranofin (III) 25-75. The reaction time is until the reaction is com plete but may range from one-half hour up to several in which days depending on the temperature of the reaction and R is a displaceable group which forms either a rela 45 the reactivity of the reagents. Also the tertiary phos tively stable carbonium or ionic leaving group. phine gold halides are more reactive than the sulfides These may be a substituted or unsubstituted aryl and are less facile than are the bis tertiary phosphine methyl for example, a benzyl, benzhydryl or tri gold halides. phenylmethyl optionally substituted by one or Generally speaking any aprotic organic solvent in more methoxy groups or a methylenedioxy group; 50 which the reactants are soluble may be used such as a common halogentated hydrocarbon solvent such as an acyl group such as a substituted or unsubstituted chloroform, carbon tetrachloride, ethylene tetrachlo lower alkanoyl of 1-6 carbons for example acetyl, ride or methylene chloride, a benzenoid solvent such as propionyl, butanoyl, benzoyl, trifluoroacetyl, or a benzene, toluene or xylene, dimethylformamide, di lower alkyl of 1-6 carbons activated by a-substitu 55 methylacetamide, ethereal solvents such as diethyl tion such as by an oxygen atom for example me ether or dioxane, ethylacetate, ethyl carbonate, dimeth thoxymethyl; - ylsulfoxide, lower alkanols sucnh as methanol, ethanol X is a reactive halo for example, chloro, bromo or or isopropanol. The chloro lower hydrocarbons espe iodo or, only when R is an acyl group, triethyl 60 cially methylene chloride are preferred. phosphine goldthio (CH3)3PAuS-l; The reaction product, auranofin, is isolated by stan n is 1 or 2 and dard methods for example by evaporating the solvent in Ac is acetyl. vacuo if necessary to give crude auranofin which is then Also included in this reaction is a variation which purified by chromatography or fractional crystalliza comprises reaction of the thioether (I) with a heavy 65 tion. The starting materials are either known or are metal salt such as silver nitrate to give the silver salt of prepared by reactions detailed in the following illustra the sugar thiol (III) which is reacted with the tertiary tive examples. All temperatures are on the Centigrade phosphine gold reagent (II) to give auranofin scale. 4,122,254 3 4. glucopyranose and 1.44 g (4.1 mmoles) of chloro(trie EXAMPLE 1 thylphosphine) gold (I) was stirred at room temperature 2,3,4,6-Tetra-O-acetyl-L-S-trityl-L-thio-g-D- for 1 hour. The solution was filtered and the solvent glucopyranose removed at reduced pressure. Chromatography of the A pyridine solution (100 ml) of 35 g (0.096 mole) of 5 residue (silica gel/chloroform) followed by crystalliza 2,3,4,6-tetra-O-acetyl-L-thio-f3-D-glucopyranose tion from methanol-water gave auranofin, m.p. Methods in Carbohydrate Chemistry, Vol. 2, page 436 108-110; a)2 (1% methanol) = -55.8. (1967) and 28 g (0.10 mole) of triphenylmethyl chloride EXAMPLE 3 was stirred at room temperature for 12 hours. The solu tion was then filtered and the pyridine removed at re O A chloroform solution (25 ml) of 0.61 g (1.5 mmoles) duced pressure. The residue was dissolved in chloro of 2,3,4,6-tetra-O-acetyl-L-S-acetyl-L-thio-g-D- form (350 ml), washed with water (5 x 100 ml) and the glucopyranose and 1.0 g (1.5 mmoles) of bis(triethyl chloroform solution dried (magnesium sulfate). The phosphinegold)sulfide was refluxed overnight and the solvent was removed at reduced pressure and the resid solvent removed at reduced pressure. Chromatography ual oil dissolved in methanol and cooled to give 17 g 15 of the residue (silica gel, benzene-chloroform 0 to 100% (29%) of crystalline 2,3,4,6-tetra-O-acetyl-L-S-trityl-L- gives a yellow oil with the chloroform eluate. Prepara thio-g-D-glucopyranose, m.p. 177-179; ap (1% tive thin layer chromatography (silica gel, ether-2% methanol) = -37.8. acetone, followed by crystallization from methanol A chloroform solution (50 ml) of 3.0 g (4.9 mmoles) water gives auranofin, m.p. 110-111. of 2,3,4,6-tetra-O-acetyl-L-S-trityl-L-thio-g-D- EXAMPLE 4 glucopyranose and 1.95 g (4.9 mmoles) of bromo(trie thylphosphine)gold (I) Aust. J. Chem. 19, 539 (1966) A chloroform solution (25 ml) of 1.0 g (2.5 mmoles) was stirred at room temperature for 48 hours and then of pentaacetylthioglucose and 1.15 g (2.5 mmoles) of refluxed for 48 hours. The solvent was removed at bistriethylphosphine)gold chloride was stirred at room reduced pressure and the residue subjected to column 25 temperature for 72 hours and the solvent removed at chromatography (silica gel/5% ether-chloroform). reduced pressure. Chromatography of the residue (sil Crystallization of the resulting crude product from ica gel, benzene-chloroform 0 to 100%) gives an oil methanol-water gave auranofin as white crystals, m.p. which was purified further by preparative thin layer 109-113"; as (1% methanol) = -55.7. chromatography (silica gel, ether-2% acetone). Crystal Substituting stoichiometric quantities of p-methoxy 30 lization from methanol-water gives auranofin, m.p. benzyl chloride, benzyl chloride, op-dimethoxy-benzyl 98-101. chloride or p-bromobenzhydryl bromide for triphenyl What is claimed is: methyl(trityl) chloride in the above reactions gives 1. The method of preparing auranofin comprising auranofin. 35 reacting a compound of the structure: EXAMPLE 2 CHOAc 2,3,4,6-Tetra-O-acetyl-L-S-trityl-L-thio-g-D- O glucopyranose Ac S-R A pyridine solution (100 ml) of 35 g (0.096 mole) of 40 2,3,4,6 -tetra-O-acetyl-L-thio-fé-D-glucopyranose Methods in Carbohydrate Chemistry, Vol. 2, 436 AcO OAC (1963) and 28 g (0.10 mole) of triphenylmethyl chloride was stirred at room temperature for 12 hours. The solu in which Ac is acetyl and R is benzyl, p-methoxybenzyl, tion was filtered and the pyridine removed at reduced 45 op-dimethoxybenzyl, p-bromobenzhydryl, benzhydryl, pressure. The residue was dissolved in chloroform (350 triphenylmethyl, lower alkanoyl of i-6 carbons or me ml), washed with water (5 x 100 ml) and the chloro thoxymethyl; with a compound of the structure form solution dried over magnesium sulfate. The sol vent was removed at reduced pressure and the residue CH3)P, AuX dissolved in methanol and cooled to give 17 g (29%) of 50 crystalline 2,3,4,6-tetra-O-acetyl-D-S-trityl-L-thio-f3 in which n is 1 or 2 and X is Ci, I, Br or, only when R D-glucopyranose, m.p.
Load more

Recommended publications
  • 13C NMR Study of Co-Contamination of Clays with Carbon Tetrachloride
    Environ. Sci. Technol. 1998, 32, 350-357 13 sometimes make it the equal of solid acids like zeolites or C NMR Study of Co-Contamination silica-aluminas. Benesi (7-9) measured the Hammett acidity of Clays with Carbon Tetrachloride function H0 for a number of clays; these H0 values range from +1.5 to -8.2 (in comparison to H0 )-12 for 100% ) and Benzene sulfuric acid and H0 5 for pure acetic acid). Therefore, one can expect that certain chemical transformations might occur in/on clays that are similar to what are observed in zeolite TING TAO AND GARY E. MACIEL* systems. Thus, it is of interest to examine what happens Department of Chemistry, Colorado State University, when carbon tetrachloride and benzene are ªco-contami- Fort Collins, Colorado 80523 nantsº in a clay. This kind of information would be useful in a long-term view for understanding chemical transforma- tions of contaminants in soil at contaminated sites. Data on 13 these phenomena could also be useful for designing predic- Both solid-sample and liquid-sample C NMR experiments tive models and/or effective pollution remediation strategies. have been carried out to identify the species produced by Solid-state NMR results, based on 13C detection and line the reaction between carbon tetrachloride and benzene narrowing by magic angle spinning (MAS) and high-power when adsorbed on clays, kaolinite, and montmorillonite. Liquid- 1H decoupling (10), have been reported on a variety of organic sample 13C and 1H NMR spectra of perdeuteriobenzene soil components such as humic samples (11-13). Appar- extracts confirm the identities determined by solid-sample ently, there have been few NMR studies concerned directly 13C NMR and provide quantitative measures of the amounts with elucidating the interactions of organic compounds with of the products identifiedsbenzoic acid, benzophenone, and soil or its major components.
    [Show full text]
  • Efficient Synthesis of Chelators for Nuclear
    (19) TZZ Z_T (11) EP 2 079 486 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 49/00 (2006.01) A61K 51/04 (2006.01) 04.04.2018 Bulletin 2018/14 A61P 9/00 (2006.01) A61P 9/10 (2006.01) A61P 9/06 (2006.01) A61P 35/00 (2006.01) (2006.01) (21) Application number: 07799253.5 A61P 35/02 (22) Date of filing: 02.07.2007 (86) International application number: PCT/US2007/072669 (87) International publication number: WO 2008/045604 (17.04.2008 Gazette 2008/16) (54) EFFICIENT SYNTHESIS OF CHELATORS FOR NUCLEAR IMAGING AND RADIOTHERAPY: COMPOSITIONS AND APPLICATIONS EFFIZIENTE SYNTHESE VON CHELATOREN FÜR NUKLEARBILDGEBUNG UND RADIOTHERAPIE: ZUSAMMENSETZUNGEN UND ANWENDUNGEN SYNTHÈSE EFFICACE DE CHÉLATEURS DESTINÉS À L’IMAGERIE NUCLÉAIRE ET À LA RADIOTHÉRAPIE : COMPOSITIONS ET APPLICATIONS (84) Designated Contracting States: (74) Representative: Dehmel, Albrecht AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Dehmel & Bettenhausen HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE Patentanwälte PartmbB SI SK TR Herzogspitalstraße 11 Designated Extension States: 80331 München (DE) AL BA HR MK RS (56) References cited: (30) Priority: 05.10.2006 US 828347 P US-A1- 2005 079 133 US-A1- 2006 182 687 28.06.2007 US 770395 • G. BORMANS, B. CLEYNHENS, T. J. DE GROOT, (43) Date of publication of application: L. MORTELMANS, J.-L. MORETTI, A. 22.07.2009 Bulletin 2009/30 VERBRUGGEN: "Synthesis, radio-LC-MS analysis and biodistribution in mice of (73) Proprietors: 99mTc-NIM-BAT" JOURNAL OF LABELLED • The Board of Regents of The University of Texas COMPOUNDS AND RADIOPHARMACEUTICALS, System vol.
    [Show full text]
  • WO 2017/205880 Al 30 November 2017 (30.11.2017) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/205880 Al 30 November 2017 (30.11.2017) W !P O PCT (51) International Patent Classification: Published: A61K 31/496 (2006.01) C07D 265/30 (2006.01) — with international search report (Art. 21(3)) A61K 31/5377 (2006.01) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/US20 17/0403 18 amendments (Rule 48.2(h)) — with information concerning request for restoration of the (22) International Filing Date: right of priority in respect of one or more priority claims 30 June 2017 (30.06.2017) (Rules 26bis.3 and 48.2(b)(vii)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/341,049 24 May 2016 (24.05.2016) US 62/340,953 24 May 2016 (24.05.2016) US 62/357,134 30 June 2016 (30.06.2016) us 62/357,166 30 June 2016 (30.06.2016) us 62/508,256 18 May 2017 (18.05.2017) us (71) Applicant: SAREPTA THERAPEUTICS, INC. [US/US]; 215 First Street, Cambridge, MA 02139 (US). = (72) Inventors: CAI, Bao; c/o Sarepta Therapeutics, Inc., 215 = First Street, Cambridge, MA 02142 (US). MARTINI, — Mitchell; c/o Sarepta Therapeutics, Inc., 215 First Street, = Cambridge, MA 02142 (US). THOMAS, Katie; c/o Sarep- = ta Therapeutics, Inc., 215 First Street, Cambridge, MA = 02142 (US). SHIMABUKU, Ross; c/o Sarepta Therapeu- tics, Inc., 215 First Street, Cambridge, MA 02142 (US).
    [Show full text]
  • A Carbocation Substituted Clay and Its Styrene Nanocomposite Jinguo Zhang Marquette University
    Marquette University e-Publications@Marquette Chemistry Faculty Research and Publications Chemistry, Department of 2-1-2004 A Carbocation Substituted Clay and its Styrene nanocomposite Jinguo Zhang Marquette University Charles A. Wilkie Marquette University, [email protected] Accepted version. Polymer Degradation and Stability, Vol. 83, No. 2 (February 2004): 301-307. DOI. © 2003 Elsevier Ltd. Used with permission. Marquette University e-Publications@Marquette Chemistry Faculty Research and Publications/College of Arts and Sciences This paper is NOT THE PUBLISHED VERSION; but the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in th citation below. Polymer Degradatopm and Stability, Vol. 83, No. 2 (February 2004): 301-307. DOI. This article is © Elsevier and permission has been granted for this version to appear in e-Publications@Marquette. Elsevier does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from Elsevier. A carbocation substituted clay and its styrene nanocomposite Jinguo Zhang Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI Charles A. Wilkie Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI Abstract A substituted tropylium ion can be ion-exchanged onto montmorillonite to give a novel organically- modified clay. One can prepare a polystyrene nanocomposite of this clay by emulsion, but not bulk, polymerization. This is the first example of a clay that contains a carbocation and its use to prepare a polymer- clay nanocomposite. Both the clay and its nanocomposites exhibit outstanding thermal stability. Characterization by X-ray diffraction, transmission electron microscopy, cone calorimetry, thermogravimetric analysis and the evaluation of mechanical properties shows that a mixed intercalated-exfoliated nanocomposite is obtained.
    [Show full text]
  • An Investigation Into Synthetic Routes to Optically Active Trityl Systems
    University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 1-1-1964 An investigation into synthetic routes to optically active trityl systems. Joseph M. Prokipcak University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Prokipcak, Joseph M., "An investigation into synthetic routes to optically active trityl systems." (1964). Electronic Theses and Dissertations. 6037. https://scholar.uwindsor.ca/etd/6037 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. AN INVESTIGATION INTO SYNTHETIC ROUTES TO I OPTICALLY ACTIVE TRITYL SYSTEMS BY JOSEPH M. PROKIPCAK A Thesis Submitted to the Faculty of Graduate Studies through the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Windsor Windsor, Ontario 1964 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
    [Show full text]
  • Direct Chemical Reduction of Triphenylcarbinol to Triphenylmethane Maurice M
    CR 0 AT IC A CHEMIC!-.. ACT A 45 (1973) 511 CCA-791 547.63 Original Scientific Paper Direct Chemical Reduction of Triphenylcarbinol to Triphenylmethane Maurice M. Kreevoy and David C. Johnston* Chemical Dynamics Laboratory, University of Minnesota, Minneapol-is, Minnesota, U .S.A. BH3cN- has been found to be a moderately efficient trapping agent for triphenylmethyl cations, roughly comparable to chloride ion. Since BH3CN- is moderately resistant to acid hydrolysis, it can trap triphenylmethyl cations generated by treatment of triphenyl­ carbinol with HCl in 25% water - 750/o tetrahydrofuran. A quanti­ tative yield of triphenylmetharie, based on unrecovered tripheny~­ carbinol, can be obtained, but the process is inefficient in its use of BH3CN- because of the competing hydrolysis. In the last few years cyanotrihydridoborate ion, BH3 CN-, has found wide use as a borohydride type reducing agent which will tolerate moderate con­ 2 centrations of acid. •3 Because of this property we thought it might be used to reduce tertiary alcohols to the corresponding hydrocarbons in acidic medium (eq. 1). Some further utilization of the remaining two (1) 2 hydridic hydrogens of BH2CN might also be expected. These expectations have been realized for triphenylcarbinol, but under conditions which suggest that the procedure cannot be extended to alcohols which lead to less stable carbonium ions. For highly stabilized carbonium ions the method may some­ times provide a useful trap, especially since the hydrocarbons do not undergo further solvolysis, as do many other derivatives. It may also sometimes be a synthetically useful reduction, leading directly to the hydrocarbon. The unsub­ stituted anion, BH, -, is capable of directly reducing alkyl halides and sulfonate esters,4•5 but not alcohols because of its sensitivity to acid.
    [Show full text]
  • United States Patent (19) (11) Patent Number: 4,874,867 Aldrich Et Al
    United States Patent (19) (11) Patent Number: 4,874,867 Aldrich et al. 45) Date of Patent: Oct. 17, 1989 54 TETRAZOLE INTERMEDIATESTO FOREIGN PATENT DOCUMENTS ANTHYPERTENSIVE COMPOUNDS 2026286 2/1987 Japan ................................... 548/101 75 Inventors: Paul E. Aldrich, Wilmington; John Jonas V. Duncia, Newark; Michael E. Primary Examiner-David B. Springer Pierce, Wilmington, all of Del. Attorney, Agent, or Firm-Black & Sutherland (73) Assignee: E. I. Du Pont De Nemours and 57 ABSTRACT Company, Wilmington, Del. Tetrazole intermediates useful to prepare antihyperten 21 Appl. No.: 275,583 sive compounds described in coassigned application 22 Filed: Nov. 23, 1988 U.S. Ser. No. 884,920, filed July 11, 1986, are described, these tetrazoles have the formula: Related U.S. Application Data CH2X2 62) Division of Ser. No. 53,198, May 22, 1987, Pat. No. 4,820,843. 51 Int. Cl. .... OO CO7D 257/04; C07F 7/22 (52) U.S. C. ...................................... 548/101; 54.6/11; GO) N 544/64; 544/225 (58) Field of Search .................... 544/64, 225; 54.6/11; O-x 548/101 56) References Cited U.S. PATENT DOCUMENTS wherein X1 and X2 are as described in the specification. 4,454,135 6/1984 Lepone ... - O do a 0 m 544/64 4,486,424 12/1984 Wehner .................... ... 548/101 10 Claims, No Drawings 4,874,867 1. TETRAZOLE INTERMEDIATESTO ANTHYPERTENSIVE COMPOUNDS This is a division of application Serial No. 5 07/053,198, filed May 22, 1987, now U.S. Pat. 4,820,843. BACKGROUND OF THE INVENTION 1. Field of the Invention R is alkyl of 1-6 carbon atoms, phenyl or cyclohexyl; This invention relates to substituted tetrazoles useful" R1 is alkyl of 3-10 carbon atoms, alkenyl of 3 to 10 as intermediates in the preparation of antihypertensive carbon atoms, alkynyl of 3 to 10 carbon atoms, and compounds described in copending U.S.
    [Show full text]
  • Kinetics of the Alkylation and Acylation of Nickel Dipivaloyimethide Kenneth Eugene Johnson Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1959 Kinetics of the alkylation and acylation of nickel dipivaloyimethide Kenneth Eugene Johnson Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Johnson, Kenneth Eugene, "Kinetics of the alkylation and acylation of nickel dipivaloyimethide " (1959). Retrospective Theses and Dissertations. 2181. https://lib.dr.iastate.edu/rtd/2181 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. KINETICS OF THE ALKYLATION AND ACYLATION OF NICKEL DIPIVALOYmETHIDE Kenneth migene Johnson A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment The Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Subject: Organic Chemistry Approved: Signature was redacted for privacy. In Change of Major Work Signature was redacted for privacy. Head of Major Department Signature was redacted for privacy. Dean ui vrx-fciuuEi ue v uj-lege Iowa State University Of Science and Technology Ames, Iowa 1959 il TABLE OF CONTENTS Page INTRODUCTION 1 HISTORICAL 3 EXPERIMENTAL ll| RESULTS AND DISCUSSION 3^ SUMMARY 62 ACKNOWLEDGMENT 6%. 1 INThO LOTION The present knowledge of the chemistry of metal ion complexes has emanated principally from, two general areas of study. The first of these includes investigations of the thermodynamic and chemical properties of metal complexes with common inorganic nucleophilic ligands.
    [Show full text]
  • Aldrich Hydrocarbons
    Aldrich Hydrocarbons Library Listing – 1,199 spectra Subset of Aldrich FT-IR Library related to hydrocarbons. The Aldrich Material-Specific FT-IR Library collection represents a wide variety of the Aldrich Handbook of Fine Chemicals' most common chemicals divided by similar functional groups. These spectra were assembled from the Aldrich Collection of FT-IR Spectra and the data has been carefully examined and processed by Thermo. The molecular formula, CAS (Chemical Abstracts Services) registry number, when known, and the location number of the printed spectrum in The Aldrich Library of FT-IR Spectra are available. Aldrich Hydrocarbons Index Compound Name Index Compound Name 304 (+)-BETA-PINENE, 98% 483 1,1,2,2-TETRABROMOETHANE, 98% 306 (+)-CAMPHENE, TECH., 80% 481 1,1,2,2-TETRACHLOROETHANE, 235 (+)-CYCLOSATIVENE, 99% 97% 308 (+)-LONGIFOLENE, 98+% 591 1,1,2-TRICHLORO-2,3,3- 289 (-)-ALPHA-CUBEBENE, 97% TRIFLUOROCYCLOBUTANE, 97% 307 (-)-CAMPHENE, 95% 464 1,1,2-TRICHLOROETHANE, 98% 314 (-)-ISOCARYOPHYLLENE, 98% 494 1,1,2- 597 (-)-MENTHYL CHLORIDE, 99+% TRICHLOROTRIFLUOROETHANE, 843 (1,2-DIBROMOETHYL)BENZENE, 99% 99% 566 1,1,3-TRICHLOROPROPENE, 95% 840 (1-BROMOETHYL)BENZENE, 97% 744 1,1,4,4-TETRAPHENYL-1,3- 291 (1R)-(+)-ALPHA-PINENE, 98% (91+% BUTADIENE, SCINTIL-LATION EE/GLC) GRADE, 99+% 287 (1S)-(+)-3-CARENE, 99% 675 1,1-BIS(3,4- 292 (1S)-(-)-ALPHA-PINENE, 98% (81+% DIMETHYLPHENYL)ETHANE, EE/GLC) TECH., 90+% 305 (1S)-(-)-BETA-PINENE, 99% 1156 1,1-BIS(4-CHLOROPHENYL)-2,2,2- 850 (2,2-DICHLORO-1- TRICHLOROETHANE, 99+% METHYLCYCLOPROPYL)BENZENE
    [Show full text]
  • Design, Synthesis and Evaluation of Novel Small Molecule Inhibitors of the Histone Methyltransferase DOT1L and the Ubiquitination Facilitator Keap1
    Design, Synthesis and Evaluation of Novel Small Molecule Inhibitors of the Histone Methyltransferase DOT1L and Ubiquitination Facilitator Keap1 Sophie S. Spurr A thesis submitted for the award of doctor of philosophy School of Pharmacy, University College London 2017 Declaration I, Sophie S. Spurr confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Sophie S. Spurr i Abstract This thesis details the design, synthesis and evaluation of novel small molecule inhibitors of the histone methyltransferase DOT1L and the ubiquitination facilitator Keap1. The thesis is in two parts as outlined below. Part 1: The first part of this thesis details efforts towards identification of novel small molecule inhibitors of DOT1L, a histone methyltransferase which has been implicated in the development and proliferation of mixed lineage leukaemias (MLL). This work aims to optimise the drug-like properties of published DOT1L inhibitors while retaining potency, through further exploration of the nucleobase template. Structure-activity relationships (SARs) identified polar substituents and small heterocycles as favourable replacements for the halogen in 5-ITC, a small molecule inhibitor of DOT1L. Alternative nucleobase templates also demonstrated comparable DOT1L inhibition. To demonstrate proof of concept, a polar nitrile substituent was translated into the inhibitor Br-SAH as a direct replacement of the bromide. Activity was retained and a crystal structure obtained which demonstrated the nitrile occupied the same hydrophobic pocket. This work also demonstrated the use of a nitrile as a non-traditional replacement for heavy halogen atoms. Part 2: The second part of this thesis details identification of novel inhibitors of the Keap1-Nrf2 protein-protein interactions (PPI) using an approach based on kinetic target-guided synthesis (kTGS).
    [Show full text]
  • SYNTHESIS and REACTIONS Or ; DERIVATIVES
    PART 1 DIPOSITIVE CARBONIUM IONS PART 11 SYNTHESIS AND REACTIONS or ; TETRAMETHYLBENZOCYCLOBUTENE_ DERIVATIVES T3931: "for “10 Damn of DI}, D; MICHIGAN STATE UNIVERSITY Richard Wayne Fish 1960 THEb‘ta 1.1 BRA R Y Michigan Sm: ”,3 Unirfrsity Z<grozz .0252”: Hmfi '8 iamflis; ”Saw “29:05 PART I DIPOSITIVE CARBONIUM IONS PART II SYNTHESIS AND REACTIONS OF TETRAMETHYLBENZOCYCLOBUTENE DERIVATIVES BY Richard Wayne Fish AN ABSTRACT Submitted to the School of Advanced Graduate Studies of Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1960 Approved ABSTRACT The primary purpose of this investigation was to determine the structure of the speciesre3ponsib1e for the intense red color observed when trichloromethylpentamethylbenzene was added to 100% sulfuric acid. Cryosc0pic measurements showed that five particles were pro- duced in the reaction. _ Two of these, swept from the solution with dry nitrogen, were hydrogen chloride. Conductance measurements on the original and the hydrogen chloride-free solutions showed that two bisulfate ions were produced. Hydrolysis of the original solution gave a nearly quantitative yield of pentamethylbenzoic acid. The hydrogen chloride-free solution gave a nearly quantitative yield of pentamethyl- benzoic acid and approximately one mole of chloride ion per mole of trichloromethylpentamethylbenzene when hydrolyzed. The best explana- tion for these data is that the fifth particle must be a stable dipositively charged carboniuxn ion (11). CH3 CH3 CH3 H3 (1) CH3 cc13 + 2sto4——> CH Q é-c1 + mm + ZHSO4' CH3 H3 CH3 CH3 I 11 This is believed to be the first reported example of a dipositive carboniurn ion.
    [Show full text]
  • WO 2017/205513 Al 30 November 2017 (30.11.2017) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/205513 Al 30 November 2017 (30.11.2017) W !P O PCT (51) International Patent Classification: C07F 9/6558 (2006.01) C07F 9/6561 (2006.01) (21) International Application Number: PCT/US20 17/034284 (22) International Filing Date: 24 May 2017 (24.05.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/340,953 24 May 2016 (24.05.2016) US 62/357,134 30 June 2016 (30.06.2016) US (71) Applicant: SAREPTA THERAPEUTICS, INC. [US/US]; 215 First Street, Cambridge, MA 02142 (US). (72) Inventors: CAI, Bao; c/o Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142 (US). MARTINI, Mitchell; c/o Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142 (US). SHIMABUKU, Ross; c/o Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142 (US). THOMAS, Katie; c/o Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142 (US). (74) Agent: TRINQUE, Brian, C. et al; Lathrop & Gage, LLP, 28 State Street, Boston, MA 02109 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY,MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]