WO1991001319A1 - Synthese des derives de cyclopentene - Google Patents

Synthese des derives de cyclopentene Download PDF

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Publication number
WO1991001319A1
WO1991001319A1 PCT/EP1990/001200 EP9001200W WO9101319A1 WO 1991001319 A1 WO1991001319 A1 WO 1991001319A1 EP 9001200 W EP9001200 W EP 9001200W WO 9101319 A1 WO9101319 A1 WO 9101319A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
iii
effected
protecting group
Prior art date
Application number
PCT/EP1990/001200
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English (en)
Inventor
Peter Leslie Myers
Richard Storer
Christopher Williamson
Martin Francis Jones
Ian Leonard Paternoster
Keith Biggadyke
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO1991001319A1 publication Critical patent/WO1991001319A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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

  • This invention relates to a new process for the preparation of certain optically active purine substituted cyclopentene derivatives and novel intermediates used in this process.
  • the invention describes the synthesis of the IR-cis isomer of carbovir, [l'R ⁇ 'Sl- ⁇ -amino ⁇ -CA- ⁇ ydroxymethylJ- ⁇ -cyclopenten-l-ylj-l ⁇ -dihydro -6H-purin-6-one, an antiviral agent.
  • GB-A-2217320 discloses a group of antiviral purine substituted cyclopentene derivatives including the IR-cis isomer of carbovir, [l'R, I S]-2-amino-9-[4-(hydroxymethyl)-2-cyclopenten-l-yl]-l,9- dihydro-6H-purin-6-one, a compound of the formula (I)
  • the compound of formula (I) (also referred to hereinafter as (-)-carbovir) has been found to have potent activity against human immunodeficiency virus (HIV) associated with acquired immune deficiency syndrome (AIDS) [see Vince, R., et al. , Biochem. Biophys.
  • (-)carbovir may conveniently be prepared from an optically pure 6-oxabicyclo[3.1.0]hex-3-ene derivative of formula (II)
  • the present invention thus provides in one aspect a process for the preparation of a compound of formula (I) and physiologically acceptble salts thereof which comprises the steps of (a) reacting a compound of formula (II) with 2,6-diaminopurine to produce a 1-OH 0 compound of formula (III) below (b) reacting the said compound of formula (III) to replace the 1-OH group by hydrogen to form a compound of formula (V) below and (c) reacting said compound of formula (V) to convert the 2,6-diamino purine base therein to the desired guanine base with removal of the R protecting group after step (b) or at a suitable stage in step (c) to produce (-)carbovir, with salt formation *-_5 as an optional subsequent step.
  • step (a) above may conveniently be effected by reacting a compound of formula (II) with 2,6-diaminopurine in the presence of a suitable base to give a compound of formula (III)
  • Bases which may be used include alkali metal hydrides, such as sodium hydride, and the reaction may be effected in the presence of a suitable solvent, conveniently dimethylformamide when sodium hydride is the base. It may be
  • step (b) above may conveniently be effected by (i) reacting the compound of formula (III) to convert the 1-OH group to a leaving group removable by reduction (e.g. by homolytic reduction) and (ii) reducing said compound to replace the leaving group by a hydrogen atom.
  • reaction of a compound (III) to"introduce the R J group in the compound (IV) may be effected in the presence of a suitable base such as an amine (e.g. pyridine or 4-dimethylaminopyridine) and in a solvent such as a halogenated hydrocarbon (e.g. dichloromethane), conveniently at a reduced temperature (e.g. about ⁇ 30 to -10 U C).
  • a suitable base such as an amine (e.g. pyridine or 4-dimethylaminopyridine)
  • a solvent such as a halogenated hydrocarbon (e.g. dichloromethane)
  • the reduction reaction to provide a compound of formula (V) may conveniently be carried out in a suitable solvent, such as pyridine when an alkyltin hydride is the reducing agent.
  • step (c) above may conveniently be effected by a series of reactions (l)-(6) as illustrated in the following Scheme.
  • Reaction (1) may be effected, for example, by treating the compound of formula (V) with a suitable acylating agent such as acetic anhydride, under conditions whereby the R 1 protecting group is removed, for example in the presence of a Lewis acid catalyst such as boron trifluoride etherate.
  • a suitable acylating agent such as acetic anhydride
  • Reaction (2) may be effected under conditions suitable for the removal of the protecting group R 1 without affecting the rest of the molecule.
  • the group R 1 and conditions for the removal of R 1 are defined below.
  • Reaction (3) may be effected, for example, by treating (15,4R)- 4-[2,6-diamino-9H-purin-9-yl]-2-cyclopentenemethanol with a suitable acylating agent such as acetic anhydride.
  • Reaction (4) may be effected, for example, by treating the compound of formula (VI) with methanolic ammonia, conveniently at ambient temperature.
  • Reaction (5) may be effected, for example, by hydrolysis, and conveniently by treating the compound of formula (VII) with a suitable acid, for example nitrous acid (conveniently prepared in situ from acetic acid and sodium nitrite).
  • a suitable acid for example nitrous acid (conveniently prepared in situ from acetic acid and sodium nitrite).
  • Reaction (6) may be effected, for example, by treating the compound of formula (VIII) with methanolic ammonia, conveniently at ambient temperature.
  • R L may represent any suitable hydroxyl protecting group which can be removed utilising conventional reagents and without adversely affecting the rest of the molecule. Suitable readily removable hydroxyl protecting groups will be familiar to those skilled in the art. Such groups are disclosed in, for example, 'Protective Groups in Organic Chemistry' , Ed. 3. F. W. McOmie (Plenum Press, 1973) and 'Protective Groups in Organic Synthesis' by Theodora W. Greene (3ohn Wiley and Sons, 1981).
  • Suitable hydroxyl protecting groups include aralkyl groups such as p-methoxybenzyl or benzyl which may conveniently be removed under mild acid conditions, for example using a Lewis acid such as boron tribromide at low temperature (e.g. ⁇ 78 ⁇ C).
  • (-)Carbovir may be prepared according to the present multistep process as an optically and chemically pure product.
  • the present process provides a particularly convenient method for preparing (-)carbovir for use on a laboratory or an industrial scale.
  • Compounds of formula (II ) may be prepared by reacting a compound of formula (IX)
  • Suitable leaving groups will be within the knowledge of persons skilled in the art.
  • Particular examples of the atom or group L included 0H,0S02R S (where R 5 represents alkyl, for example C j ,_ 6 alkyl such as methyl, aryl, for example phenyl or tolyl, or trifluoromethyl) or halogen (e.g. bromine or iodine).
  • Suitable conditions for the conversion of compounds of formula (IX) to compounds of formula (II) will of course depend upon the nature of the leaving group L.
  • L represents OH
  • the elimination reaction may be effected by methods such as those referred to in "Compendium of Organic Synthetic Methods", Eds. I. T. Harrison and S. Harrison, Wiley-Interscience, 1971, pp. 484-488.
  • L represents a halogen atom
  • the elimination reaction may be effected by methods such as those referred to in "Compendium of Organic Synthetic Methods, Eds. I. T. Harrison and S. Harrison, Wiley-Interscience, 1971, pp. 507-510.
  • compounds of formula (IX) in which L represents 0S0 R 5 (where R 5 is as defined previously) are particularly convenient precusors to the compounds of formula (II).
  • Such compounds may be converted to compounds of formula (II) by treating the appropriate compound of formula (IX) with a base, for example an alkali metal alkoxide (e.g. sodium methoxide) in an alcoholic solvent such as methanol or a quaternary ammonium salt in a solvent such as an ether (e.g. tetrahydrofuran) .
  • a base for example an alkali metal alkoxide (e.g. sodium methoxide) in an alcoholic solvent such as methanol or a quaternary ammonium salt in a solvent such as an ether (e.g. tetrahydrofuran) .
  • a base for example an alkali metal alkoxide (e.g. sodium methoxide) in an alcoholic solvent such as methanol or
  • a quaternary ammonium salt when used this is conveniently a tetraalkylammonium halide, for example a tetrabutylammoniu halide such as tetrabutylammonium fluoride.
  • the elimination reaction may be carried out at any suitable temperature and conveniently at ambient temperature.
  • Salts (e.g. physiologically acceptable salts) of the compound of formula (I) may be prepared from the corresponding free base according to the methods described in GB-A-2217320.
  • the following examples illustrate the present invention but should not be construed as a limitation of the invention. All temperatures are in °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit un procédé de préparation de l'isomère 1R-cis de carbovire, le [1'R,4'S]-2-amino-9-[4-(hydroxyméthyl)-2-cyclopentène-1-yle-1,9-dihydro-6H-purin-6-one et ses sels physiologiquement acceptables, à partir d'un composé dont la formule est (II), (où R1 est un groupe protecteur d'hydroxyle) par l'intermédiaire d'un composé dont la formule est (III), (où R1 est un groupe protecteur d'hydroxyle). L'isomère 1R-cis de carbovire est un agent antiviral à activité puissante contre le virus de l'immunodéficience humaine (HIV).
PCT/EP1990/001200 1989-07-19 1990-07-18 Synthese des derives de cyclopentene WO1991001319A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898916479A GB8916479D0 (en) 1989-07-19 1989-07-19 Chemical process
GB8916479.2 1989-07-19

Publications (1)

Publication Number Publication Date
WO1991001319A1 true WO1991001319A1 (fr) 1991-02-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/001200 WO1991001319A1 (fr) 1989-07-19 1990-07-18 Synthese des derives de cyclopentene

Country Status (2)

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GB (1) GB8916479D0 (fr)
WO (1) WO1991001319A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045529A1 (fr) * 1996-05-30 1997-12-04 Lonza Ag Procede de production d'aminoalcools et de leurs derives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605659A (en) * 1985-04-30 1986-08-12 Syntex (U.S.A.) Inc. Purinyl or pyrimidinyl substituted hydroxycyclopentane compounds useful as antivirals
EP0236935A2 (fr) * 1986-03-06 1987-09-16 Takeda Chemical Industries, Ltd. Purine-nucléosides carboxyliques, leur production et utilisation
EP0267878A1 (fr) * 1986-11-14 1988-05-18 Ciba-Geigy Ag Dérivés de l'adénine N9-substitués par le groupement cyclopentyle
FR2626002A1 (fr) * 1988-01-20 1989-07-21 Univ Minnesota Nucleosides dideoxydidehydrocarbocycliques et composition pharmaceutique les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605659A (en) * 1985-04-30 1986-08-12 Syntex (U.S.A.) Inc. Purinyl or pyrimidinyl substituted hydroxycyclopentane compounds useful as antivirals
EP0236935A2 (fr) * 1986-03-06 1987-09-16 Takeda Chemical Industries, Ltd. Purine-nucléosides carboxyliques, leur production et utilisation
EP0267878A1 (fr) * 1986-11-14 1988-05-18 Ciba-Geigy Ag Dérivés de l'adénine N9-substitués par le groupement cyclopentyle
FR2626002A1 (fr) * 1988-01-20 1989-07-21 Univ Minnesota Nucleosides dideoxydidehydrocarbocycliques et composition pharmaceutique les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of the American Chemical Society, Volume 110, No. 2, 20 January 1988, American Chemical Society, (US), B.M. TROST et al.: "A Transitionmetal-Controlled Synthesis of (+)-Aristeromycin and (+)-2', 3' -Diepi-Aristeromycin. An Unusual Directive Effect in Hydroxylations", pages 621-622 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045529A1 (fr) * 1996-05-30 1997-12-04 Lonza Ag Procede de production d'aminoalcools et de leurs derives
US6368850B1 (en) 1996-05-30 2002-04-09 Lonza Ag Process for the preparation of amino alcohols and derivatives thereof
US7405065B2 (en) 1996-05-30 2008-07-29 Lonza Ag Enzyme for the preparation of 1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives

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Publication number Publication date
GB8916479D0 (en) 1989-09-06

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