Title of Invention


Abstract A process for the preparation of a salt of N-tert-butylhydroxylamine which comprises reaction of N-tert-butylhydroxylamine, (CH3)3CNHOH, with a lower carboxylic acid, RCO2H wherein R represents hydrogen or C 1 to 4 alkyl.
Full Text FORM 2
(39 OF 1970]
[See Section 10]
ASTRAZENECA AB, a Swedish company, of S-151 85 Sodertalje, SWEDEN,
The following specification particularly describes the nature of the
invention and the manner in which it is to be performed:

Field of the Invention
i This invention relates to novel salts of -N-tert-butylhydroxylammc and processes fo.
their preparation. The salts are useful as intermediates in organic synthesis.
Background of the Invention
10 N-Alky! hydroxylamines, including N-tert-burylhydroxylamine, are important is
intermediates in organic synthesis, particularly in the preparation of nitrones, hydroxamic acids and C-nitroso compounds (J.S Roberts in D.H.R. Barton and W.D. Ollis, Comprehensive Organic Chemistry, Volume 2, pages 196 - 201, Pergamon Press, 1979).
is Mediods for the synthesis of N-alkyl hydro xylamines are well known in the art (J.S.
Roberts in D.H.R. Barton and W.D. Ollis, Comprehensive Organic Chemistry, Volume 2, pages 185 - 194, Pergamon Press, 1979). The most common method for die synmes:i oi such compounds involves the reduction of a corresponding nitrogen-containing compound which is at a higher oxidation level than the hydroxylamine itself. Thus, reductions of
:o nitro, nitroso and oxime derivatives have all been used.
W.D. Emmons (J Arr.er. Chem. Soc, 1957, 79, 5739 - 5754) describes the preparation of various oxaziridines by oxidation of the corresponding imine derivative with peracetic acid. Further hydrolysis of these oxaziridines with aqueous acid provides a useful 25 alternative route for the preparanon of /V-alkyl hydroxylamines.
In a related process, N-alkyl hydroxylamines such as N-tert-butylbydroxylarnine may be prepared by oxidation of an imino ether with peracid and subsequent hydrolysis of the resultant alkoxyoxaziridine (D. Thomas and D.H. Aue, Tetrahedron Letters, 1973, 30 1807-1810).

Hydroxylarnines are basic compounds and form salts with mineral acids, for example, hydrogen chloride and hydrogen bromide. Salts with strong organic acids, for example, oxalic acid and trifluoromethanesulphonic acid, are also known.
5 As the free bases N-alkyl hydroxybmines are not, in general, particularly stable, being prone, for example, to undergo aerial oxidation. For this reason, it is expedient to be able to prepare the generally more stable acid addition salts of such compounds. Such salts are particularly convenient as a means of storage of N-alkyl hydroxylamines.
10 Bayer (DE 35 35 451; EP 0 217 269) d-scribe a process for the preparation of N-alkyl-substituted hydroxylammonium chlorides by the reaction of certain arylaldimines with perpropionic acid and subsequent hydrolysis of the c caziridine formed thereby. Such hydrochloride salts are regarded as being particularly advantageous. Taus, it is stated that salts other than the hydrochlorides, for example, the corresponding sulphates or hydrogen
i s sulphates, often crystallise only poorly or not at all, a factor which considerably complicates their preparation, isolation and handling.
It has now surprisingly been found thatN-tert-butylhydroxylamine forms stable salts with lower carboxylic acids, for example, with acetic acid. Such salts display advantageous :o properties and are the subject of the present application.
Disclosure of the Invention
According to the invention we provide a salt of formula (I)
R represents hydrogen or C 1 to 4 alkyl.


In particular, it is preferred that R represents methyl such that the compound of formula (I) is N-tert-burylhydroxyiammonium acetate.
Unless otherwise indicated, the term "C I to 4 alky I" referred to herein denotes a straight or branched chain alky! group having from I to 4 carbon atoms. Examnies of such ground include methyl, ethyl, n-propyl, i-propyl, n-butyl. i-butyl and t-butyl.

According to the invention, we further provide a process for the preparation of salts of formula (I) which comprises reaction of N'-tert-buryihydroxylamine, (CH3): CNHOH. with IO a lower ca-boxylic acid, RC02H, wherein R is as defined above.
In one aspect of this pro ess, a solution of N-tert-burymydroxylairiine, either formed by liberation of the free base from a salt such as the hydrochloride, or generated directly by synthesis, in a suitable solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, is diisopropyl ether, or methyl t-buryl ether is treated at a suitable temperature with an appropriate amount of 3 lower carboxylic acid such as acetic acid.
In a preferred aspect, ethyl acetate and sodium acetate, are added to a solution N-tert-butylhydroxylammonium chloride in water.
In another preferred aspect, ethyl acetate, acetic acid and sodium hydroxide, "are added to a solution of .N-tert-burylhydroxylamiiie hydrochloride in water.
In either way, N-tert-butylhydroxylammonium acetate is generated in situ, and may be 25 isolated by separation of the organic (ethyl acetate) layer, followed by evaporation.
It is particularly surprising and advantageous that the novel salt,
N-tert-butylhydroxylammonium acetate, can be partitioned from an aqueous phase into an organic phase.

The novel salts of formula (I) may, if necessary, be purified using techniques that are well known tn the art. Thus, they may be recrystallised from a suitable solvent such as toluene or ethyl acetate, or from a suitable solvent mixture.
5 However, most surprisingly and advantageously, the novel sa!r,
N-tert-butylhydroxylammonium acetate, may also be punfied by distillation under reduced pressure.
N-t'ert-butylhydroxy! imine, (CH})3CNHOF{, is well known in the literature and may be 10 preoarcd by methods that are known per se.
Thus, N-terr-buty'hydroxyl unine may be produced by reduction of 2-methyl-2-
nitropropane, (CH3)3CNO2, with, for example, zinc or aluminium amalgam (J. March,
Advanced Organic Chemistry, 1985 (3rt edition), pages 1103-1104; Organic Syntheses, is vol. 52, 77-82). For process scale work, such methods suffer from the disadvantages mat the 2-methyl-2-oitropropane required as a starting material is itself relatively expensive to prepare, and the reduction process requires careful concrc'. not least because fus potentially very exothermic nature.
zo N-tert-tiutylhydroxylarainc may also conveniently be prepared esing the general
methodology described by Emmons {vide infra) as summarised in Scheme 1. R' merein
may conveniently represent hydrogen, but may also represent one or more other suitable substituents. According to the Scheme, iV-ferr-butylamme (2) is reacted with a benzaldehyde (3) to give the imine (4) which in turn is oxidised with a peracid to afford the
25 oxazindine (5). The oxaziridine (5) may then either be hydrolysed directly using aqueous acid or alternatively may be first rearranged to the nitrone (6) which is then itself hydrolysed. [n either case the hydrolysis yields a mixture of N-tert-butylhydroxylamine (7), as a salt, and the benzaldehyde (3) which may be readily separated Advantages of this process are that both of the starting materials (2) and (3) are relatively inexpensive.
30 Furthermod the benzaldehyde (3) is regenerated in the course of the final hydrolysis and

may conveniently be separated and recycled. In addition, if a peracid such as meta-chloroperbenzoic acid is used for oxidation of the imine, the meta-chlorobenzoic acid generated therefrom may also be recovered and subsequently re-oxidised.
Scheme 1




10 The novel salts of formula (I) are, m general, crystalline compounds which, unlike the corresponding free base, N-tert butylhydroxylamirie, exhibit good stability upon storage, particularly towards aerial oxidation.
[f required, /V-rerf-butylhydroxylarrune may be liberated from the salts of formula (I) 15 simply by treatment with base.
When compared to N-tert-butylhydroxylarnmoniurn chloride, the novel salts of formula (0 have the particular advantage that they possess a surprisingly greater stability towards heat. Thus, investigation of N-tert-butylhydroxylammonium chloride using differential scanning calonmetry showed that tiiis salt undergoes an extremely exothermic process (AH ~ - 1312 J/g) at an onset temperature of + 136 °C. In contrast, A'-/err-butylhydroxylammoruum

acetate undergoes no significantly exothermic processes when treated under the same conditions.
In addition, A^-ferf-butylhydroxylarnmonium chloride is rather hygroscopic, readily taking 5 up water from the surroundings. This disadvantage is much less apparent with N-tert-butyfhydroxyfammoruum acetate.
The invention is illustrated by the following non-limiting examples.
NMR. spectra were recorded on a Bruker in;.trumem at 200 MHz for 'H and 50 MHz for ,JC. Chemical shift data are given in ppm downfield from tetramethyfsilane (TMS).
Example 1
is N-tert-ButylhydroxylammQnium Acetate
N-tert-Butylhydroxylamuie hydrochloride (5 6 g, 0.43 mol, 97%) was dissolved in water (226 g) and charged to a 1 L three-nerlced glass bottle under argon gas Ethvl acetate (246 g) and potassium carbonate (79 g, 0.57 mol, 1.3 equiv ) were added and the mixture was stirred vigorously for 1 h at + 20 °C. Both phases were siphoned to a separating
20 funnel. The water phase was separated off and extracted once more with ethyl acetate (100 ml). The organic phases were pooled and acetic acid (28.1 g, 0.47 mol, i .09 equiv) was added. The solvent was evaporated off. The resulting clear, yellow-green oil was treated with additional ethyl acetate (203 g) and concentrated again. The bottle was piaced in the refrigerator and after 2 h the product had turned crystallme. The substance was easily
25 crushed giving a slightly yellowish powder (63.4 g, 90%). This material could be recrystalhsed using either toluene or ethyl acetate as solvent
DirTerennaf scanning cai'orimetry showed an endothermic meeting point at - 67 7 °C Powder X-ray diffraction analysis showed a high degree of crystalliruty. 1H NMR (d,-acetonitriIe) 6 8.33 (s, 2H), 1.92 (s. 3H) and 1.21 (s, 9H).
30 13CNMR(d,-acetonitrile)& 177.5, 57.0, 23.1 and 21.3.

Example 2
N-terrt-Butylhydroxylammonium Acetate 5 N-tert-Butylhydroxylarr.ine hydrochlonde (19.7 g, 98%, 0. [ 5 mol) was dissolved in water (40 g) at + 20 °C. Ethyl acetate (118 g) and sodium acetate (19.3 g, 0.24 mol, 1.5 equiv.) were added. A slurry was formed initially but then dissolved. After 2 h the bluish organic phase was separated and concentrated giving an opaque, yellow oil (20.6 g, 88%) that solidified upon standing in the r .frigerator. IO Chromatog^phic punty (GC): 97.0 area%.
Example 3
a) N-Benzyhdene-tert-butylarrane
15 Toluene (330 g), benzaldehyde (66.0 g, 0.62 mol) and ferr-butylamine (50.0 g, 0 6& mol, 11 eq-,:v.) were added to .- 1L reaction bottL :onnectsd to a D-Siark: trap. II..: \,MUC was heated in a PEG 400 oil bath maintained at 130 °C. .After 7 h at reflux, GC indicated that 99.7% conversion had been achieved. The reaction mixture was cooled and used directly in the subsequent step.
20 In a separate experiment the product was isolated by evaporation and was characterized as follows:
Chromatographic punty (GC): 0 2 area% benzaldehyde; 99.S area% A'-benzylidene-ror.'-butylamine. 'HNMR(CDCl3)5 l.29(s,9H), 7.37 (m, 3H), 7.73 (s. 2H) and 8.26 (s, IH).
25 nCNMR(CDCl3)5 29.6, 57 I, 127.8, 128.4, 130.0, 137 I and 155.0. MS m/z 146 (MM 5, 100%), 161 (M*. 6%).


b) 2-tert-Butyl-3-phenyloxaziridine
Sodium carbonate (65.6 g, 0.62 mol, I equiv.) was dissolved in water (400 g) and cooled t + 20 °C. Meta-Chloroperbenzoic acid (149.8 g, 75%, 0.65 mol, 1.05 equiv.) was dissolved in toluene (300 g) and ethanol (150 g) and heated gently to - 20 °C. The aqueous sodium carbonate solution was then added to the toluene solution of N-benzylidene-terf-butylarnine prepared in (a) above in a 2 L reaction bottle which was immersed in a cold water bath (temperature lH NMR(CDC13)5 1.17 (s, 9H). 4.68 (s, lH)and 7.33-7.46 (m. 5H). "CNMR(CDC13)6 25.2, 58.3. 73.5, 127.4. t2S.3. 129.6. 133.2 and 135.5. MS m/z 57 ((00%), 1 77 (M', 1%).

d) N-fert-Butythydroxytammonium Acetate
N-tert-butylphenylnitrone (44.8 g. 0.25 mol) was dissolved in toluene (1 34 g) in a 500 m! bottle. Sulphuric acid (27.5 g, 95 to 97%, 0.27 mol, 1.1 equiv.) was diluted in water (134 g) 5 and added to the reaction bottle. The two-phase mixture was then heated to + 50 °C and stirred vigorously for approximately 2 h. At that time, GC indicated that only 0.2 area% of N-terf-butylphenylnitrone remained. After cooling to + 20 °C, the dark red organic phase was discarded and the clear, yellow water phase was extracted once with toluene (46 g). To the remaining water phase was then added acetic acid (14.8 g, 0.25 mol, 1.0 equiv.)
10 followed by sodium hydroxide (45% aqueous solution' until the pH of the water phase was approximately 5.5. Ethyl acetate (224 g) was then added and the mixture was st rred vigorously. The organic phase was then separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic fractions were then evaporated to leave an oil (35.2 g). This material was purified by distillation under reduced pressure. A
15 stable distillation point was achieved at 19 mbar/ + 7S °C. Fraction 1, reuuved below
70 °C, contained 2."' g and fraction 2, -collected between 7 J DC and ~ SO L., contained a highly viscous oil (28.7 g, 76%) that crystallized as a white solid upon standing. pKa 6.4 Chromatographic purity (GC): 99.4 area%
20 'HNMR(d4-methanol)5 1.27 (s, 9H), 1.95 (s, 3H) and 5.51 (s. NO-H). nC NMR (d4-methanol) 5 22.9, 24.1, 59.0 and 180.2.
Example 4 25 N-tert-Butylhydroxylammoruum Acetate
2-tert-Butyl-3-phenyloxazindine (30.3 g, 98.2area%, 0.17 mol) was dissolved in edianol (90 g). Sulphuric acid (25.7 g, 95 to 97%, 0.25 mol, 1.5 equiv.) was diluted in water (90 g) and added to the 500 ml reaction bottle. The reaction mixture was stirred at + 20 °C for

20 h at which time analysis by GC showed that 5.8 area% oxazindine remained. Leaving the reaction stirring over the weekend gave complete conversion. The solvents were evaporated and the concentrate was partitioned between water (90 g) and ethyl acetate (90 g). The organic phase was discarded and fresh ethyl acetate (150 g) and acetic acid
5 (10.8 g, 0 18 mo!, 1.1 equiv 1 were added, followed by sodium hydroxide (45% aquris solution) until the aqueous phase had approximately pH 5.5. The orgaruc phase was then separated, filtered through 000 filter paper and concentrated giving an oil (17.3 g) This material was distilled at 20 mbar and the fractions distilling above + 72 °C were collected giving a clear oil (11.5 g, 45%) that crystallized immediately.
10 Chromatographic purity (GC): 99.5 area%

1. A process for the preparation of a salt of N-tert-butylhydroxylamine which comprises reaction of N-tert-butylhydroxylamine, (CH3)3CNHOH, with a lower carboxylic acid, RCO2H wherein R represents hydrogen or C 1 to 4 alkyl.
2. The process as claimed in claim 1 which comprises reaction of a solution of N-tert-butylhydroxylamine, (CH3)3CNHOH, in a suitable solvent with acetic acid
3. A process for the preparation of a salt of N-tert-butylhydroxylamine which comprises treatment of an solution of N-tert-butylhydroxylammonium chloride in water with sodium acetate in the presence of ethyl acetate.
4. A process for the preparation of a salt of N-tert-butylhydroxylamine which comprises treatment of a solution of N-tert-butylhydroxylammonium chloride in water with acetic acid and sodium hydroxide in the presence of ethyl acetate.
5. The process for the isolation of N-tert-butylhydroxylamine acetate prepared by the process as claimed in claim 3 or claim 4 which comprises separation of the ethyl acetate layer followed by removal of the ethyl acetate by evaporation.
6. A process for the purification of N-tert-butylhydroxylamine acetate which comprises distillation under reduced pressure.
Dated this 22nd day of December, 2000.



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Patent Number 206893
Indian Patent Application Number IN/PCT/2000/00775/MUM
PG Journal Number 30/2007
Publication Date 27-Jul-2007
Grant Date 15-May-2007
Date of Filing 22-Dec-2000
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN.
# Inventor's Name Inventor's Address
PCT International Classification Number C07C 83/00
PCT International Application Number PCT/SE99/01228
PCT International Filing date 1999-07-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9802507-5 1998-07-10 Sweden