Process for preparing...

Details Process for preparing... Process for preparing...

2001-07-05

2004-05-25

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06740761

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to an improved process for preparing 2-alkyl-3-aryl- and -heteroaryloxaziridines by oxidation of the corresponding aryl- or heteroarylaldimines using a peroxy compound.
2-tert-Butyl-3-phenyloxaziridine, for example, serves as starting material for preparing N-(tert-butyl)hydroxylamine, which is used for the synthesis of pharmaceutically active compounds.
It is already known (J. Am. Chem. Soc., 79, 5749 (1957)), that arylaldimines containing an unsubstituted or a nitro-substituted phenyl group can be covered with anhydrous peracetic acid into the corresponding oxaziridine which can be isolated by distillation and then hydrolyzed using aqueous-methanolic sulfuric acid, giving, after addition of alkali, the corresponding free N-alkylated hydroxylamine. The anhydrous peracetic acid required is prepared in situ from 90% strength aqueous hydrogen peroxide using excess acetic anhydride and catalytic amounts of sulfuric acid, in the solvent methylene chloride. The handling of such concentrated hydrogen peroxide solutions is associated with extremely high safety expenditure. Thus, if in any way possible, the preparation and handling of large amounts of such hydrogen peroxide solutions are avoided.
EP-B 217,269 discloses that N-alkyl-substituted aryloxaziridines are obtainable by reacting arylaldimines with perpropionic acid in benzene. To prevent hydrolysis of the arylaldimines and the aryloxaziridines under the acidic reaction conditions, the water content of the perpropionic acid has to be less than 0.1% by weight (“anhydrous perpropionic acid”). The preparation and handling of anhydrous perpropionic acid, too, is a process which requires high safety expenditure, in particular during the azeotropic distillation to remove the water.
Commercial m-chloroperbenzoic acid is a solid and, accordingly, easier to handle than peracetic acid or perpropionic acid. m-Chloroperbenzoic acid, too, has been used for oxidizing arylaldimines (J. Chem. Soc. Perkin Trans. 1 1990, 301 and 2390), the reaction being carried out in methylene chloride or methanol, i.e. a non-aqueous medium.
It is also known that benzylideneamino acid esters can be oxidized to the corresponding oxaziridines using monoperphthalic acids in the solvent diethyl ether (Tetrahedron Lett., 28, 2453 (1994)).
In general, the preparation and handling of percarboxylic acids is safer if water is present during their preparation and use, for example during oxidations. However, in the presence of acids and water, imines generally tend to hydrolyze. This is the reason why the presence of water has been substantially excluded in the known imine oxidations.
Furthermore, the presence of acid and water in the reaction medium used for preparing oxaziridines promotes hydrolytic cleavage of the oxaziridines formed into the corresponding aldehyde and the corresponding N-substituted hydroxylamine. The latter for its part is readily oxidized by the percarboxylic acid present to give the corresponding nitroso compound. Nitroso compounds are known to be substances which are highly carcinogenic. Accordingly, they have to be excluded in the preparation of intermediates for pharmaceutically active compounds.
According to WO 00/02848, the problem of the hydrolysis and the formation of undesirable subsequent products is solved by carrying out the oxidation with m-chloroperbenzoic acid in a two-phase system of toluene and an aqueous sodium carbonate solution. However, such a procedure is not recommended for realizing an industrial process, since two-phase reaction systems lead to upscaling problems which, if at all, can only be solved with great efforts.
None of the known methods for preparing aryloxaziridines by oxidizing arylamines with percarboxylic acids are satisfactory for industrial-scale processes. Accordingly, there is still a need for a simple, economical and low-risk process for preparing 2-alkyl-3-aryl- and heteroaryloxaziridines.
SUMMARY OF THE INVENTION
This invention, accordingly, provides a process for preparing 2-alkyl-3-aryl- and heteroaryloxaziridines comprising oxidizing corresponding N-alkyl-aryl- or -heteroarylaldimines with an aromatic percarboxylic acid or a salt thereof in the presence of water, a water-soluble base, and a water-miscible solvent, at temperatures below 30° C.
DETAILED DESCRIPTION OF THE INVENTION
Suitable N-alkyl-aryl- and -heteroarylaldimines are, for example, those of the formula (I)
in which
R
1
, R
2
, and R
3
independently of one another each represent hydrogen, straight-chain or branched C
1
-C
20
-alkyl, C
3
-C
8
-cycloalkyl, straight-chain or branched C
2
-C
10
-alkenyl, or C
6
-C
10
-aryl, or the entire C(R
1
)(R
2
)(R
3
) group represents a C
3
-C
8
-cycloalkyl radical, and
X represents C
6
-C
12
-aryl or heteroaryl having 4 or 5 C atoms and 1 or 2 identical or different heteroatoms selected from the group consisting of N, O and S,
wherein all alkyl, cycloalkyl, alkenyl, aryl, and heteroaryl radicals may optionally be mono- or polysubstituted (alkyl radicals, for example, by saturated C
3
-C
12
-cycloalkyl, C
6
-C
10
-aryl, C
2
-C
8
-alkenyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1
-C
6
-alkoxy, C
6
-C
10
-aryloxy, carboxyl, C
1
-C
6
-alkoxycarbonyl, nitro, amido, nitrile, sulfonyl, or phosphate, and cycloalkyl, alkenyl, aryl, and heteroaryl radicals, for example, by C
1
-C
6
-alkyl, fluorine, chlorine, bromine, hydroxyl, C
1
-C
6
-alkoxy, carboxyl, C
1
-C
6
-alkoxycarbonyl, nitro, sulfonyl, or nitrile).
Preferred alkenyl radicals are those having electron-depleted double bonds, and preferred heteroaryl radicals are those which only contain the heteroatom(s) oxygen.
If N-alkyl-aryl- or -heteroarylaldimines of the formula (I) are used, the corresponding 2-alkyl-3-aryl- or -heteroaryloxaziridines of the formula (II)
in which the symbols used are as defined under formula (I), are obtained.
In the formulas (I) and (II), R
1
, R
2
, and R
3
, preferably independently of one another, each represent hydrogen, straight-chain or branched C
1
-C
10
-alkyl, C
3
-C
6
-cycloalkyl, straight-chain or branched C
2
-C
6
-alkenyl, or phenyl, or the entire C(R
1
)(R
2
)(R
3
) group represents C
3
-C
6
-cycloalkyl, the radicals mentioned not being substituted any further.
In the formulas (I) and (II), X preferably represents phenyl, naphthyl, or furyl, where the phenyl and naphthyl radicals may optionally be substituted by one or two identical or different radicals from the group consisting of C
1
-C
6
-alkyl, fluorine, chlorine, bromine, hydroxyl, C
1
-C
6
-alkoxy, C
1
-C
6
-alkoxycarbonyl, nitro, sulfonyl, and nitrile.
In the formulas (I) and (II), the entire C(R
1
)(R
2
)(R
3
) group particularly preferably represents unsubstituted n-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, cyclopropyl, cyclopentyl, or cyclohexyl, and X particularly preferably represents 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, or 4-nitrophenyl.
Particularly suitable aromatic percarboxylic acids and salts thereof are m-chloroperbenzoic acid and monoperoxyphthalic acid and their alkali metal and magnesium salts. Preference is given to using the magnesium salt of monoperoxyphthalic acid.
Suitable water-soluble bases are, for example, alkali metal and alkaline earth metal oxides, hydroxides, carbonates, bicarbonates, hydrogen phosphates, and dihydrogen phosphates. Preference is given to using sodium carbonate or sodium bicarbonate.
Suitable water-miscible solvents are, for example, water-miscible organic solvents that are inert under the reaction conditions, for example, mono- and polyhydric alcohols having up to 6 C atoms. Preference is given to using methanol or ethanol.
The process according to the invention can be carried out by initially preparing a mixture of the N-alkyl-aryl- or -heteroaryl aldimine and the water-miscible solvent. The aldimine content in the solvent can be varied within a relatively wide range. The concentration of the aldimine in the mixture with the solvent can, for example, be from 5 to 80% by weight, preferably from 20 to 50% by weight and in partic

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