Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

• the present invention relates to chemical substances, and in particular to chemical substances having specific labels and to processes for making such substances. More particularly, the present invention relates to the labelling of organic molecules with isotopic hydrogen and optionally accompanied by reduction or deoxygenation of the chemical substance. Although the present invention will be described with particular reference to some types of organic molecules and to isotopic hydrogen exchange reactions, it is to be noted that labelling of any type of chemical species by isotopic hydrogen fall within the scope of the present invention.
• One aspect of the present invention is concerned with isotope exchange of chemical substances in which one or more hydrogen atoms of a molecule of a particular selected chemical substance are replaced by isotopic hydrogen atoms, i.e. deuterium or tritium, thereby labelling the molecule.
• the presence of a label may be used as a marker for the chemical substance i.e. as a means of always identifying the chemical substance, such as during or after subsequent reactions that the substance may undergo, by means of a suitable detector.
• it is necessary, at least in some cases to precisely identify the location of the isotopic marker within the molecule i «.e. the precise structural position within the molecule where the isotope exchange took place.
• Another aspect of the present invention is the reduction and/or deoxygenation of the chemical substance as well as the labelling of the substance by the isotopic atom.
• the present invention relates not only to labelling chemical substances but also to reducing and/or deoxygenating them as well.
• Raney nickel and its derivatives such as Raney Al alloy and the like
• the Raney-Ni catalyst has always been used in the presence of a reducing agent, such as for example hydrogen, and often at temperatures of about 100o-200oC and pressures of about 20 atmosphere. It was thought that in these processes the reduction was caused by the presence of the reducing agent, such as the hydrogen, with the Raney nickel acting as a catalyst. Further, it was thought that as the Raney-Ni was acting as a catalyst it required a hydrogen source, such as hydrogen or alcohol, to effect the reduction. Accordingly, the Raney-Ni had been used in catalytically small amounts of the order of about up to 1% by wt. of the total weight of reactants. In the case of isotopic hydrogen exchange reactions it has also been observed that deuteration of a chemical substance required the use of deuterium gas, and tritiation required the use of gaseous tritium.
• Raney-Ni by itself is sufficient to promote reduction of the chemical substance.
• the reactions may take place at convenient temperatures and pressures, such as between room temperature and 110°C, and at typically about 1 atmosphere, or at pressures less than about 5 atmospheres.
• the amount of Raney nickel required to promote the reduction and labelling may be considerably more than mere catalytical amounts previously used.
• the Raney-Ni may be present in an amount up to 1000% of the total amount of the reactants. It is thought that when large amounts of Raney nickel are used, it is the Raney nickel itself that supplies the hydrogen isotopes required for the reaction, and thus the co-presence of an additional reducing agent is not always required.
• labelled materials may be obtained in some examples.
• the reaction conditions are very mild relatively speaking and the labelled materials obtained are useful as marked biological substrates or solvents for n.m.r spectroscopy or for theoretical studies such as for example where comparison of the effect of hydrogen or deuterium on a molecule is desired.
• a process for isotopically labelling a chemical substance with a selected isotopic label comprising the steps of
• any chemical substance may be treated by the methods and processes of the present invention, however, the present invention finds particular application in treating chemical substances that can be hydrogenated.
• the chemical substances are organic molecules that can be reduced or deoxygenated. More preferably, the chemical substances are aromatic or aliphatic compounds such as alkenes, alkynes, ketones, aldehydes and the like.
• the label is deuterium or tritium.
• the material forming the label containing material is Raney nickel or the like such as nickel-aluminium, nickel-copper and nickel-copper aluminium alloys, and other precursors of Raney-Ni.
• suitable materials are finely divided platinum, rhodium, iridium, copper oxides, cobalt and the like.
• the hydrogen atoms on the surface of the Raney-Ni catalyst are exchanged with deuterium atoms by washing the catalyst with deuterium oxide (or tritium oxide).
• deuterium oxide or tritium oxide
• the selected substance to be labelled is dissolved in deuterium oxide (or tritium) or other suitable inert solvent and heated with the deuterated (or tritiated) Raney-Ni catalyst for periods ranging from 1 to 20 hours at temperatures ranging from room temperature to 100°C.
• the substance is insoluble in water, it is heated with the deuterated (or tritiated) Raney nickel i.e. one in which the hydrogen atoms have been replaced by deuterium (or tritium) atoms in a solution of tetrahydrofuran or dioxan or any other inert solvent.
• the present invention provides for the (1) exchange of activated aliphatic hydrogens for deuterium, (2) reduction (deuteration) of alkenes and carbonyl compounds, (3) aromatic hydrogen-deuterium exchange, and (4) reduction of aromatic rings to fully deuterated cyclohexanes. These reactions are performed under mild conditions and in the absence of deuterium gas or a deuterium donor. Similar reactions are possible with tritium.
• a stirred solution of the substrate (0.5 g) is refluxed for 18 hrs with deuterated Raney nickel (2 ml wet) .
• deuterated Raney nickel (2 ml wet)
• the temperature is kept around 70°.
• the solvent (5 ml) is tetrahydrofuran or heavy water (carboxylic acids and phenols are deuterated as sodium salts).
• the product is isolated in the usual manner after filtration to remove the Raney nickel. Yields are 70% or above.
• trans-stilbene gave 1,2-diphenyl-1,1,2,2-tetradeuteroethane.
• Sodium cinnamate in heavy water at 70°
• 2,2,3,3,2',3',4',5',6'-nonadeuterophenyl propanoic acid (I) The aromatic hydrogens were exchanged under these conditions.
• Cinnamaldehyde gave a deuterated material (i.r., n.m.r.) the mass spectrum of which showed that it was polymeric.
• Maleic acid (at 101°) gave 2,2,3 ,3-tetradeuterosuccinic acid.

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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1985
  • 1985-03-18 CA CA000476816A patent/CA1236483A/en not_active Expired
  • 1985-03-18 WO PCT/AU1985/000054 patent/WO1985004167A1/en unknown
  • 1985-03-18 EP EP19850901313 patent/EP0174962A1/de not_active Withdrawn

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