Process for preparing N-substituted hydroxylamines and salts...

Details Process for preparing N-substituted hydroxylamines and salts... Process for preparing N-substituted hydroxylamines and salts...

2001-12-07

2003-05-06

Davis, Brian J. (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S301000

Reexamination Certificate

active

06559340

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing N-substituted hydroxylamines from N-substituted aryl- or heteroaryloxaziridines by acid hydrolysis and also the isolation of the N-substituted hydroxylamines in the form of their salts.
N-Substituted hydroxylamines and in particular N-alkyl-hydroxylamines and salts thereof serve as starting materials and intermediates in the synthesis of pharmaceutically active compounds.
From J. Am. Chem. Soc. 79, 5739 (1957), it is already known that N-alkyl-oxaziridines can be converted into aldehydes and N-alkyl-hydroxylamines by acid hydrolysis. What is described is in particular the hydrolysis of 2-tert-butyl-3-phenyloxaziridine in the presence of 1.13 mol of sulfuric acid in methanol. After 20 hours at room temperature, the 2-tert-butyl-3-phenyloxaziridin is hydrolyzed to benzaldehyde and N-(tert-butyl)hydroxylamine. To isolate the hydroxylamine, the reaction mixture is initially mixed with water. The benzaldehyde is then removed by extraction with diethyl ether from the sulfuric-acid-containing medium. By addition of aqueous sodium hydroxide solution, the aqueous phase is made strongly alkaline, and the N-(tert-butyl)hydroxylamine is then extracted from the aqueous phase continuously for three days, using diethyl ether. The organic phase is dried and the solvent is removed, giving N-(tert-butyl)hydroxylamine in a yield of 82%. For an industrial process, an extraction time of three days is not particularly suitable, and this time can, if at all, only be reduced by using a special apparatus. Furthermore, our own examination of this extraction process has shown that, from a strongly alkaline medium (pH≧12), only 20% of the amount of product to be expected theoretically can be extracted with methylene chloride.
From EP-A 217,269 it is known that, in addition to sulfuric acid, hydrochloric acid is also suitable for hydrolyzing oxaziridines. In this case, the reaction is complete even after a reaction time of one hour. The aromatic aldehyde formed is extracted from the acidic aqueous phase using diethyl ether. The hydrochloride of the N-substituted hydroxylamine is then obtained in good yields by concentrating the aqueous phase and drying the residue. However, thermal tests have shown that the hydrochloride begins to decompose at temperatures above 50° C. The elevated temperatures that are usually required for distilling off the water are therefore unsuitable.
If N-alkyl-substituted hydroxylamines are to be used as inter-mediates and/or biologically active compounds, it is advantageous to provide them in a storage-stable form. In general, in particular the N-alkyl-substituted hydroxylamines are unsatisfactory with respect to their storage stability. In contrast, the salts of the N-alkyl-substituted hydroxylamines generally have a considerably better storage stability, and their isolation is therefore of greater interest. If the starting material required is the free hydroxylamine, it can be released immediately prior to use from the salts by adding base.
WO-A 00/02848 describes carboxylates of N-(tert-butyl)hydroxylamine. To prepare these carboxylates, initially 2-tert-butyl-3-phenyl oxaziridine is hydrolyzed using 1.5 equivalents of sulfuric acid. However, even after a reaction time of 20 hours, GC still shows 5.8 area per cent of starting material (Example 4). Complete conversion is observed only after two more days. The benzaldehyde formed is, as in the cases cited above, removed from the crude mixture by extraction. In contrast to other processes known from the literature, the further procedure comprises (1) adding a lower carboxylic acid RCOOH, where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, to the reaction mixture, (2) setting a pH of about 5.5 by adding aqueous sodium hydroxide solution, (3) then extracting the carboxylates of the N-(tert-butyl)hydroxylamine from the weakly acidic medium using ethyl acetate, and (4) isolating the carboxylates by crystallization from ethyl acetate or toluene or by distillation. However, in the preparation of N-(tert-butyl)hydroxylammonium acetate from 2-tert-butyl-3-phenyloxaziridine, this route gives, after distillation and subsequent crystallization, only 45% of the desired product. As shown by differential thermoanalysis of, for example, N-(tert-butyl)-hydroxylammonium acetate, the salt begins to decompose even at 70° C., with a heat production rate of 1 W/kg. The ethyl acetate should therefore be removed under reduced pressure. Additional thermal stress for distilling the N-(tert-butyl)hydroxylammonium acetate to purity is therefore not to be recommended.
All known methods for preparing N-substituted hydroxylamines and in particular N-alkyl-hydroxylamines and salts thereof by acid hydrolysis of aryloxaziridines in aqueous medium are unsatisfactory for implementation on an industrial scale, with respect to reaction time, isolation method, extraction times, and the solvents used. There is therefore a need for an economical and safe process for producing N-substituted hydroxylamines and salts thereof.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing N-substituted hydroxylamines of the general formula (I) and salts thereof
where
R may represent
(i) a radical of the general formula (II)
 in which
R
1
, R
2
, and R
3
independently of one another 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
(ii) a C
3
-C
8
-cycloalkyl radical, comprising
(1) acidically hydrolyzing aryl- or heteroaryloxaziridines of the general formula (III)
 in which
R has the meaning given above for formula (I), and
X represents a C
6
-C
12
-aryl radical or a C
3
- or C
5
-heteroaryl radical, using at least two equivalents of an acid and a water-miscible solvent, and
(2) isolating the N-substituted hydroxylamines in the form of their salts of the general formula (IV)
 where R has the meaning given above and R′ represents hydrogen or C
1
-C
3
-alkyl, by subjecting the resulting hydrolyzed reaction mixture to the following steps:
(a) removal of the aromatic or heteroaromatic aldehyde of the formula XCHO that is also formed during the acid hydrolysis,
(b) adjustment of the reaction mixture to a pH in the range of 7 to 11,
(c) removal of the N-substituted hydroxylamine of the general formula (I) from the reaction mixture,
(d) addition of an acid R′COOH to the N-substituted hydroxylamine, and
(e) isolation of the salt of the general formula (IV).
DETAILED DESCRIPTION OF THE INVENTION
In the process according to the invention, the aryl- or heteroaryl-oxaziridines of the general formula (III) are initially cleaved hydrolytically.
Preferred acids for the acid hydrolysis are strong acids, particularly hydrochloric acid, phosphoric acid, sulfuric acid, and trifluoroacetic acid. Sulfuric acid has been found to be especially useful.
Suitable water-miscible solvents are all water-miscible organic solvents that are inert under the reaction conditions, for example, mono- and polyhydric alcohols having up to 6 carbon atoms. Preference is given to using methanol or ethanol.
If the radicals R
1
, R
2
, and/or R
3
in the radical R are alkyl radicals, these can in turn be substituted by saturated cycloalkyl radicals, aryl radicals, alkinyl radicals, and/or radicals that contain heteroatoms, such as halogen, oxygen, sulfur, nitrogen, and/or phosphorus atoms. Such saturated cycloalkyl radicals can, for example, contain 3 to 12 carbon atoms, such aryl radicals can, for example, contain 6 to 10 carbon atoms, and such alkinyl radicals can, for example, contain 2 to 6 carbon atoms. Suitable heteroatom-containing radicals are, for example, fluoro, chloro, bromo, iodo, hydroxyl, C
1
-C
6
-alkoxy, C
6
-C
10
-phenoxy, carboxyl, C
1
-C
6
-alkoxycarbonyl, nitro, amide, nitrile, mercapto, sulfonyl, phosphite, and phosphate groups.
If the radical R is a cycloalkyl radical or the radicals R
1
, R
2
, and/or R
3
in the radica

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