Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonic acids or salts thereof
Reexamination Certificate
2001-04-05
2002-11-12
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonic acids or salts thereof
C564S282000, C564S300000, C564S396000
Reexamination Certificate
active
06479697
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. 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, pp. 500-504, Pergamon Press, 1979; R. D. Hinton and E. G. Janzen,
J. Org. Chem.,
1992, 57, pp. 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, pages 3229 to 3232).
A modification of this type of methodology for the manufacture &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
In one aspect, 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 N-tert-butylhydroxylammonium acetate (III)
(CH
3
)
3
CNHOH CH
3
CO
2
H (III)
In a second aspect, this invention provides a method for preparing and recovering a compound of general formula (I). In the first step of this process, the compound is prepared as just described. In a subsequent step, the compound is isolated.
DETAILED DESCRIPTION OF THE INVENTION
Products and Starting Materials
In this process, an aldehyde of general formula (II) is reacted with N-tert-butylhydroxylammonium acetate to form an &agr;-(2,4-disulfophenyl)-N-tert-butylnitrone compound of general formula (I). The compounds of general 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 such as calcium or magnesium in combination with a pharmaceutically acceptable anion such as halide (for example chloride), phosphate, sulphate, acetate, citrate or tartrate.
The two R's in these formulae 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-Butylhydroxylammonium acetate is disclosed in co-pending PCT patent application WO 00/02848.
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 Process
The first step is the condensation of the N-tert-butylhydroxylammonium acetate (III) with the aldehyde (II). This reaction is typically conducted in a batch mode with agitation. It could, if desired, be carried out continuously in a flow reaction system.
In this process it is preferred that in general about 1.25 to 2.5 equivalents of N-tert-butylhydroxylammonium acetate (III) is used for each equivalent of the aldehyde (II). It is particularly preferred that about 1.6 to 2.0 equivalents of N-tert-butylhydroxylammonium acetate (III) is used.
The condensation of the present invention is carried out in solution, using a suitable inert solvent in which the starting materials are sufficiently soluble. It is preferred that a suitable polar organic solvent such as an alcohol, or mixture of alcohols, is used as solvent. It is particularly preferred that the solvent is methanol. It is further preferred that the reaction mixture contains a suitable percentage of water, generally less than 10% by volume, such as from about 2% to 10% by volume. It is particularly preferred that the solvent contains about 5% by volume of water. It has been found that the presence of a suitable amount of water provides significant advantages, particularly with regards to inhibiting the conversion of the aldehyde (II) into the undesirable acetal side product (IV)
by reaction with the solvent R
1
OH.
The presence of a suitable amount of water in the solvent also increases the solubility of the 4-formyl-1,3-benzenedisulfonic acid disodium salt (II; R═SO
3
−
Na
+
) starting material and thereby significantly improves the kinetics of the process and enables the use of a more concentrated system.
The proportion of reaction solvent is typically maintained at about 2 to 8 mL of solvent per gram of nitrone product or greater, with proportions of from 2 to 6 and especially 3 to 4 mL/g being preferred.
The condensation is conducted at a temperature from about ambient temperature to about 150° C., good results being achieved at temperatures of from about ambient to about 125° C., with temperatures of from about 40° C. to about 100° C. being preferred.
The condensation reaction is rel
Blixt Jörgen
Kruk Henry
McGinley John
Pouhov Sergei
Vajda John
AstraZeneca AB
Nixon & Vanderhye
Padmanabhan Sreeni
Witherspoon Sikarl A.
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