Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-20
1999-01-12
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546108, 546122, 546180, C07D21172, C07D21184, C07D21361, C07D22112
Patent
active
058592555
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the preparation of halogenated compounds, in particular, halogenated heterocyclic compounds. More particularly, the invention relates to the fluorination of heterocyclic compounds.
The preparation of halogenated heterocycles has received a great deal of attention due to the many synthetic and industrial processes in which such substrates are employed, for example, in the pharmaceutical, plant protection and dye industries.
Few methods are available for the introduction of a fluorine atom at the 2- and/or 6-positions of pyridine. Traditionally, routes to 2-fluoropyridines have been based on multi-step BalzSchieman type decompositions of pyridine diazonium tetrafluoroborate salts. Halogen exchange processes involving the reaction of a fluoride ion source, such as SbF.sub.5, KF, HF, etc, with a chlorinated pyridine at elevated temperatures have frequently been used to prepare fluoropyridines. The electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in only 22% yield. With xenon difluoride, pyridine gave a mixture of fluoropyridines and, also, cesium fluorooxysulfate reacts with pyridine at room temperature in ether to give 2-fluoropyridine in 61% yield.
The preparation of related fluorine-containing heterocycles such as 2-fluoroquinoline may be accomplished by similar methodology, ie halogen exchange processes, fluorodediazotisation. etc.
A method for the direct fluorination of organic compounds is disclosed in U.S. Pat. No. 2013030. However, the technique is primarily directed towards non-heterocyclic derivatives and, in any event, is subject to unwanted side reactions and, as a consequence, yields of desired products are generally poor, and the material obtained is in a low state of purity. Preparations of 2-fluoropyridines by direct reaction with elemental fluorine have also been reported in U.S. Pat. No. 4786733. In this case, the reactions are kinetically competitive with side chain fluorination and, therefore, yields of the desired 2-fluoropyridines are again low. In addition, the reported reaction of elemental fluorine with quinoline results in predominant fluorination of the annulated aromatic ring and extensive fragmentation of the hetero ring. Surprisingly, it has now been found that heterocyclic compounds can be selectively fluorinated by elemental fluorine when another halogen is present in the reaction medium.
According to the present invention, there is provided a method of preparing a heterocyclic organic compound having at least one fluorine substituent in the heterocyclic ring, the method comprising the step of reacting a heterocyclic compound with elemental fluorine in the presence of at least one of chlorine, bromine, iodine and an interhalogen compound.
Examples of interhalogen compounds are iodine monobromide and iodine monochloride.
The heterocyclic compound which is fluorinated by the method of the present invention may be a nitrogen-containing heterocyclic compound. The heterocyclic compound may include a five- or six-membered ring which may contain optional sustituents. The ring may be attached or fused to another one or more rings which may or may not be heterocyclic.
The heterocyclic compound preferably includes a six-membered aromatic ring containing one or more nitrogen atoms such as pyridine or a related heterocycle such as pyrimidine, pyridazine or triazine, or a related benzo-fused heterocycle such as quinoline, isoquinoline, quinoxaline or quinoazoline, or a bi-or poly-cyclic compound such as bipyridine.
The positions of the ring or rings of the heterocyclic compound fluorinated by the method according to the present invention which are not occupied by heteroatoms may carry substituents. Thus, where the heterocycle is pyridine it may carry substituents at from one to five ring positions. Where the heterocycle is a pyrimidine it may carry substituents at from one to four ring positions. Where the heterocycle is quinoline or isoquinoline it may carry substituents at from one to six ring positi
REFERENCES:
patent: 2013030 (1935-09-01), Calcott
patent: 4786733 (1988-11-01), Van Der Puy
patent: 5455373 (1995-10-01), Kawa
Chemical Abstracts #124:55893, abstract of Tetrahedron Lett, vol.36(37), pp. 6705-6708, 1995.
Chemical Abstracts #110:154118, abstract of J Org Chem, vol. 54(7), pp. 1726-1731, 1989.
Chemical Abstracts #116:234035, abstract of EP 499930, 1992.
March J., Advanced Organic Chemistry, John Wiley & Sons, New York (1992), pp. 534 & 671.
Rozen et al., A Novel Aromatic Iodination Method Using F.sub.2, Journal of Organic Chemistry 55:3552-3555 (1990).
Chambers Richard Dickinson
Sandford Graham
F2 Chemicals Ltd.
Kight John
M. Mach D. Margaret
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