Process

Details Process Process

2001-04-05

2004-02-10

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C562S058000, C564S299000

Reexamination Certificate

active

06689911

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel process for the preparation of &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone and pharmaceutically acceptable salts thereof. These compounds have previously been disclosed as being useful as medicaments. Such compounds are alternatively named as 4-[(tert-butylimino)methyl]benzene-1,3-disulfonic acid N-oxide derivatives.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,488,145 discloses &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone, pharmaceutically acceptable salts thereof and related pharmaceutical compositions. U.S. Pat. No. 5,475,032 discloses the use of such compositions in the treatment of stroke and of progressive central nervous system function loss conditions. And U.S. Pat. No. 5,508,305 discloses the use of such compositions for ameliorating the side effects caused by oxidative damage resulting from antineoplastic disease treatment. Similar disclosures are also made in WO 95/17876. U.S. Pat. No. 5,780,510 discloses the use of these same compounds in the treatment of concussion.
Various methods are available for the synthesis of nitrones. The most often used method involves the usually uncatalysed condensation reaction of a hydroxylamine derivative with an aldehyde or ketone (J. S. Roberts in D. H. R. Barton and W. D. Ollis,
Comprehensive Organic Chemistry
, Volume 2, pages 500-504, Pergamon Press, 1979; R. D. Hinton and E. G. Janzen,
J. Org. Chem
., 1992, 57, 2646-2651). The utility of this reaction is impaired by its susceptibility to steric hindrance, slow reaction rates, and, in certain cases, by the relative inaccessibility and/or instability of the hydroxylamine starting material. The latter problems can sometimes be overcome by in situ generation of the required hydroxylamine by reduction of a more readily available compound such as the corresponding nitro derivative. This general methodology is employed in the above-described patents where the preparation of &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone is described as involving the reaction of 4-formyl-1,3-benzenesulfonic acid with N-tert-butylhydroxylamine in refluxing methanol for approximately 18 hours.
&agr;-(2-Sulfophenyl)-N-tert-butylnitrone has been prepared by reaction of 2-formylbenzenesulfonic acid sodium salt with N-tert-butylhydroxylamine in refluxing ethanol for 2 days (E. G. Janzen and R. V. Shetty,
Tetrahedron Letters
, 1979, 3229-3232).
A modification of this type of methodology for the manufacture of &agr;-phenyl-N-methylnitrone has been described in French Patent 1,437,188 to E.I. DuPont de Nemours and Co.
We now disclose a novel process that possesses significant advantages for the preparation of &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone and salts thereof and is also particularly suited to large scale production.
DISCLOSURE OF THE INVENTION
This invention provides a process for the preparation of a compound of general formula (I)
wherein each R independently represents SO
3
H or a salt thereof.
This process involves reaction of an aldehyde of general formula (II)
wherein R is as defined above, with freshly prepared N-tert-butylhydroxylamine (III)
(CH
3
)
3
CNHOH  (III)
Thus, in one aspect this invention provides an integrated process in which: in a first step, N-tert-butylhydroxylamine (III) free base is prepared by neutralising N-tert-butylhydroxylamine acid addition salt in an organic reaction medium; in a second step the N-tert-butylhydroxylamine free base (III) formed in the first step is reacted under condensation conditions with an aldehyde of general formula (II), thereby forming the nitrone compound of general formula (I); and in a third step the compound (I) is isolated from the condensation reaction mixture.
In a second aspect, this invention provides an improvement in the condensation of N-tert-butylhydroxylamine (III) with an aldehyde of general formula (II) that comprises conducting the condensation in the presence of an acid catalyst.
In a third aspect, said acid catalyst is provided by incomplete neutralisation of the N-tert-butylhydroxylamine acid addition salt used as one of the starting materials.
DETAILED DESCRIPTION OF THE INVENTION
Starting Materials and Products
In this process, an aldehyde of general formula (II) is reacted with freshly generated N-tert-butylhydroxylamine to form an &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone compound of general formula (I). The compounds of formulae (I) and (II) may be acids or they may be salts.
Salts of compounds of formula (1) above may be formed by reacting the free acid (wherein R represents SO
3
H), or another salt thereof, with two or more equivalents of an appropriate base, using methods that are well known in the art.
The salts of compounds of formulae (I) and (II) referred to above will normally be those formed with pharmaceutically acceptable cations. The cation may be a monovalent material such as sodium, potassium, lithium, ammonium, alkylammonium or diethanolammonium. Alternatively, it may be a polyvalent cation such as calcium, magnesium, aluminium or zinc. It may also be a mixed salt formed with a polyvalent cation in combination with a pharmaceutically acceptable monovalent anion such as halide (for example, chloride), phosphate, sulphate, acetate, citrate or tartrate.
The two R's in those formulas are usually the same. However, they can be independently selected from the possibilities just enumerated.
It is preferred that the two R's in formulae (I) and (II) above be the same and each represents SO
3
−
Na
+
.
N-tert-Butylhydroxylamine is prepared from a commercially available acid addition salt such as N-tert-butylhydroxylammonium chloride as described below in the section entitled “The Premix Step”.
The aldehydes of general formula (II) are either commercially available or may be prepared from commercially available materials using methods that are well known in the art. Commercial 4-formyl-1,3-benzenedisulfonic acid disodium salt (II; R═SO
3
−
Na
+
) typically contains small but significant amounts of the corresponding benzyl alcohol and the corresponding benzoic acid derivatives, and of sodium chloride as impurities. It is preferable, but not essential, that such material is purified before use in the process of the present invention.
4-Formyl-1,3-benzenedisulfonic acid disodium salt (II; R═SO
3
−
Na
+
) is typically associated with varying amounts of water. The proportion of such water generally is not critical to the process of the present invention but generally may be taken into account when determining the overall composition of the compound (I)-forming reaction mixture.
The Premix Step
The free base form of N-tert-butylhydroxylamine is relatively unstable, tending in particular to undergo aerial oxidation. This is evidenced by the formation of blue colours, which indicate the presence of the oxidation product, 2-methyl-2-nitrosopropane. The free base of N-tert-butylhydroxylamine cannot therefore be stored as such but should be freshly generated immediately before use. In view of the instability of the free base of N-tert-butylhydroxylamine, it is advisable, particularly for large scale work, to generate the free base in solution and then to use this solution directly in the subsequent reaction rather than attempting to isolate the free base as such.
A preferred reaction for generating the free base of N-tert-butylhydroxylamine involves reacting in solution N-tert-butylhydroxylamine acid addition salt with a base. Typical acid addition salts include the hydrohalide acid addition salts, with the hydrochloride salt being preferred.
Bases include the simple inorganic bases such as the alkali metal hydroxides. However, these bases are less soluble in organic solvents. Thus, a preferred group of bases are those that are soluble in organic solvents and that do not yield water as a product of neutralisation. Such materials include alkali metal alkoxides such a sodium or potassium methoxide, ethoxide, isopropoxide and the like.
Typical solvents for generating the free base include lo

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