Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-25
2003-03-11
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S295000, C562S828000, C562S830000, C562S834000
Reexamination Certificate
active
06531605
ABSTRACT:
This invention concerns a novel chemical process and, more particularly, it concerns a novel chemical process for the manufacture of pyridinesulfonyl chlorides and certain benzenesulfonyl chlorides.
Pyridinesulfonyl chlorides and benzenesulfonyl chlorides are useful in the manufacture of compounds having a variety of uses, such as in the manufacture of pharmaceuticals or herbicides. For example 2-chloropyridine-3-sulfonyl chloride is particularly useful in the production of the endothelin antagonists described in International Patent Application, Publication No. WO 96/40681.
A number of methods are known for preparing pyridinesulfonyl chlorides (such as 2-chloropyridine-3-sulfonyl chloride) and benzenesulfonyl chlorides. One such method involves reaction of the diazonium salt of the corresponding aminopyridine (such as 3-amino-2-chloropyridine) or aromatic amine with sulfur dioxide in the presence of acetic acid and using CuCl or CuCl
2
as catalyst, followed by isolation of the product by solvent extraction. Such a method is disclosed in WO 96/40681 and European Patent Application, Publication Nos. 733629 and 618209. Similar methods are disclosed in
Synthesis
, (1969), 6, No. 1, pages 3-10 and
Rec. Trav. Chim
., (1965), 84, pages 24-29.
A disadvantage with carrying out this process on a large scale is the difficulty associated with the isolation of the product free of impurities at the end of the reaction. In particular it is often difficult on a large scale to obtain the product free of acetic acid or prevent hydrolysis of the product to the corresponding sulfonic acid on work-up. A further disadvantage of carrying out this process on a large scale is the use of the gaseous reagent, sulfur dioxide. These disadvantages make this process unattractive for operation on a commercial scale.
Surprisingly, a process has now been discovered for the manufacture of pyridine sulfonyl chlorides and certain benzenesulfonyl chlorides which avoids the use of both acetic acid and sulfur dioxide gas and which overcomes the isolation problems encountered with the known process.
According to the invention there is provided a process for the manufacture of a pyridinesulfonyl chloride or a benzenesulfonyl chloride in which the benzene ring bears one or more electron-withdrawing groups which comprises reaction of the diazonium salt of an aminopyridine or aminobenzene in which the benzene ring bears one or more electron-withdrawing groups with a mixture of thionyl chloride in water, in the presence of an electron transfer catalyst.
A particular aspect of the present invention is a process for the manufacture of a pyridinesulfonyl chloride which comprises reaction of the diazonium salt of an aminopyridine with a mixture of thionyl chloride in water, in the presence of an electron transfer catalyst.
A further particular aspect of the present invention is a process for the manufacture of a benzenesulfonyl chloride in which the benzene ring bears one or more electron-withdrawing groups (more particularly one or two electron-withdrawing groups) which comprises reaction of the diazonium salt of an aminobenzene, in which the benzene ring bears one or more electron-withdrawing groups, with a mixture of thionyl chloride in water, in the presence of an electron transfer catalyst.
It will be appreciated that, where a pyridinesulfonyl chloride or an aminopyridine is referred to, the pyridine ring may be unsubstituted or may bear one or more substituents. A particular substituent includes, for example, an electron-withdrawing substituent.
A preferred electron transfer catalyst includes, for example, cupric chloride (CuCl
2
) and cuprous chloride (CuCl), especially the latter. Preferably 0.012 to 0.05 equivalents of catalyst (per equivalent of amino compound) are used.
It is well known that functional groups or substituents can be classified as electron-withdrawing (−I) or electron-donating (+I) groups relative to hydrogen, as disclosed by J. March in Advanced Organic Chemistry, Fourth Edition, Wiley & Sons. Typical electron-withdrawing groups are referred to or listed in the above publication and disclosure of these are incorporated herein by reference. Particular electron-withdrawing groups include, for example, chloro, bromo, cyano, nitro and carboxy.
The preparation of the diazonium salt of a primary aromatic or heteroaromatic amine is well known in the art of organic chemistry, by reaction of the amine with nitrous acid. For the process of the present invention it is convenient to generate the nitrous acid in situ by the conventional method of reacting an alkali metal nitrite, especially sodium nitrite, with a mineral acid, especially hydrochloric acid, in the presence of the amino compound. The diazotisation reaction is generally carried out at a temperature in the range of about +5 to −10° C., and preferably at about +1 to −4° C. It is preferred to use about 1 to 1.2 equivalents of alkali metal nitrite and 3 to 20 (more preferably 11 to 13) equivalents of concentrated (approximately 36%) hydrochloric acid (per equivalent of amino compound). When the starting material is an aminobenzene bearing one or more electron-withdrawing groups, it is preferred that the amine is added to the mineral acid and this mixture heated at 30 to 50° C. for 10 to 60 minutes (to ensure complete salt formation) prior to cooling and addition of the aqueous sodium nitrite solution. The water charge to dissolve the sodium nitrite is generally between 1 to 5 volumes based on the input weight of amino compound, although solid nitrite may alternatively be added portionwise to the mixture of the amine in hydrochloric acid. It is preferable to use the diazonium salt solution or slurry so generated immediately after preparation because of the instability of the diazoniun salt, maintaining the temperature of the solution or slurry at about +1 to −4° C. during the addition.
It is preferred that 2 to 12 equivalents of thionyl chloride are used per equivalent of amino compound, and especially 4 to 5 equivalents.
It is preferred that the water charge for thionyl chloride dissolution is between 5 to 30 volumes (and more preferably 10 to 20 volumes) of water, based on the input weight of amino compound.
It is preferred that the thionyl chloride and water mixture is maintained at 18-25° C., and conveniently at about ambient temperature, for 1 to 48 hours, and conveniently 15 to 20 hours (for example overnight), prior to reaction with the diazonium salt.
It is preferred that the solution of the diazonium salt is added over as short a time as possible consistent with maintaining the exothermic reaction at a temperature between −10 and +5° C., and preferably between −4 and +1° C. After addition it is preferred that the reaction is maintained at about this temperature for 15 to 90 minutes.
The product may be isolated by extraction into a suitable solvent, such as a hydrocarbon, chlorinated hydrocarbon or ether solvent immiscible with water, such as dichloromethane, diethyl ether or preferably toluene. The absence of acetic acid in the reaction mixture means that difficulties associated with the presence of acetic acid in the solvent extract (and its subsequent removal) are avoided. The advantage of using toluene as the extraction solvent is that the extract can be washed with water and any residual traces of water and entrained HCl removed by azeotropic distillation to give the product as a solution in toluene, which can then be used directly in a subsequent reaction or the toluene can be removed under vacuum to give the product which may be recrystallised in high purity, for example from a non-polar solvent such as n-hexane, isohexane or cyclohexane.
Alternatively, where the product is a solid sulfonyl chloride, it may precipitate from the reaction mixture and be collected by filtration instead of by solvent extraction.
The process of the invention is particularly suitable for preparing 2-halogenopyridine-3-sulfonyl chlorides such as 2-chloropyridine-3-sulfonyl chloride.
A further
McKenzie Thomas C
Rothwell Figg Ernst & Manbeck
Shah Mukund J.
Zeneca Limited
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