WO2000078710A1

WO2000078710A1 - Method of making hydroxylamine salts

Info

Publication number: WO2000078710A1
Application number: PCT/US2000/017155
Authority: WO
Inventors: Xun Li; Indira Reddy; Mohammad Aslam; Baihua Wu
Original assignee: Alliedsignal Inc.
Priority date: 1999-06-23
Filing date: 2000-06-22
Publication date: 2000-12-28
Also published as: WO2000078710A8

Abstract

A method for producing hydroxylamine salts by using oximes as a principal reagent and which proceeds through the hydrolyzation of an oxime ether.

Description

METHOD OF MAKING HYDROXYLAMINE SALTS FIELD OF INVENTION

The present invention relates to methods for the production of hydroxylamine salts. BACKGROUND OF INVENTION

Hydroxylamine salts are of particular interest for use in the syntheses of numerous pharmaceutical drug candidates. For example, antihistaminic agents and other drugs used in the treatment of heart failure and hypertension may be synthesized using hydroxylamine salts.

Applicants believe that known methods for making hydroxylamine salts are highly inefficient, often using disfavored reaction ingredients and/or reaction conditions. For example, one known prior art processes for forming hydroxylamines comprises reacting an oxime and alkylating agent in the presence of sodium amide or sodium ethoxide in benzene or ethanol for extended periods of time (e.g. 12-24 hours), and then subjecting the reaction product to hydrolysis conditions for an additional extended period of time (e.g. 15 hours). Such processes are reported have produced yields of hydroxylamine salts of only about 23 % or less. See Bozdag, O. et al, "Synthesis of some novel oxime ether derivatives and their activity in the 'behavioral despair test'" Eur. J. Med. Chem., 33, 133-141 (1998).

The present inventors have come to appreciate that prior art processes of the type disclosed in Eur. J. Med. Chem., 33, 133-141 (1998) are disadvantageous for several reasons. In addition to long reaction times and low yields, another disadvantage of the prior art process is that benzene is a cancer suspect agent and thus may be dangerous to work with, especially in industrial scale conditions.

Recognizing these and other drawbacks of the prior art, the present inventors have perceived a need for a new, efficient and more desirable method for producing a wide range of hydroxylamine salts. These and other objects are achieved by the present invention as described below.

DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The present invention is directed to methods of producing a wide range of hydroxlamine salts, many of which find particular use in the syntheses of pharmaceutical drug candidates used as antihistaminic agents and/or in the treatment of heart failure and hypertension.

The present methods generally involve the steps of (a) reacting an oxime with an

alkylating agent to produce an oxime ether; and (b) reacting at least a portion of the oxime

ether with a hydrolizing agent to form a hydroxylamine salt. We have discovered that

unexpectedly beneficial results can be obtained by conducting the oxime reaction step (a) in

the presence of a solvent that enhances the relative speed and completeness of the reaction.

According to preferred embodiments of this aspect of the invention, the reaction (a) is

carried out in the presence of a solvent selected from the group consisting of l-methyl-2-

pyrrolidinone ("NMP"), acetonitrile and combinations of these

We have also discovered that the proper selection of the temperature and pressure

conditions for the hydrolization reaction is capable of producing unexpected and

surprisingly superior results. More particularly, it is preferred according to this aspect of

the invention that the hydrolization reaction step (b) comprises reacting the oxime ether at

the a temperature that is above about the boiling point of the hydrolyzing agent and below the decomposition temperature of the hydoxylamine salt and below the decomposition

temperature of the oxime ether.

In highly preferred embodiments, the present methods comprise (a) reacting an

oxime with an alkylating agent in the presence of a solvent selected from the group

consisting of NMP, acetonitrile and combinations of these, to produce an oxime ether; and

(b) reacting at least a portion of the oxime ether with a hydrolizing agent at a temperature

above about the boiling point of the hydrolyzing agent and below the decomposition

temperatures of the oximε ether and desired hydoxylamine salt to form said hydroxylamine

salt.

Numerous unexpected advantages are associated with the methods of the present

invention. For example, a significant and surprising increase in purity and yield is realized

by producing compounds in accordance with the present invention. By synthesizing

compounds according to the present invention, it is possible to obtain a hyroxylamine yield

that is at least about 40% (on a mole basis), more preferably at least about 45 % , and even

more preferably at least about 50% . It is believed that the present methods are capable of

achieving yields even as high as 65 % or greater. As used herein, the term "yield" refers

generally to the amount of product produced expressed as a percentage of the theoretical

amount of product that could be produced by the reactions. Furthermore, the methods of

the present invention produce the desired hydroxylamine salts in much shorter periods of

time as compared to the prior art processes.

THE OXIME REACTION STEP

It is contemplated that any oxime reactant known in the art can be adapted for use in accordance with the present invention. A large number of oximes are commercially

available and/or are known in the literature to be obtainable by art-recognized procedures.

Although it is contemplated that oximes in general can be used to advantage in the

methods of the present invention, it is particularly preferred to use oximes as illustrated in

Formula I below:

R,(R₂)-C=N-OH (I)

wherein R, and R₂ are independently selected from the group consisting of hydrogen,

unsubstituted or substituted alkyl groups, unsubstituted or substituted cycloalkyl groups,

unsubstituted or substituted aryl groups and unsubstituted or substituted aralkyl groups.

R, or R₂ as an unsubstituted or substituted alkyl group may be straight-chained or

branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl,

octyl, or decyl. Preferably, R, or R₂ as an unsubstituted or substituted alkyl group is an

alkyl having about 1 to about 12 carbons, for example, methyl, ethyl, propyl, isopropyl,

butyl, isobutyl, pentyl or hexyl. More preferably, R, or R₂ as an unsubstituted or

substituted alkyl group is either methyl or ethyl.

R, or R₂ as an unsubstituted or substituted cycloalkyl may be, for example,

cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, methylcyclopentyl, cyclohexyl,

methylcyclohexyl, dimethylcyclohexyl, cycloheptyl, and cyclohexyl. Preferably, R, or R₂

as an unsubstituted or substituted cycloalkyl is cyclopentyl, cyclopentadienyl or cyclohexyl.

R, or R₂ as an unsubstituted or substituted aryl group may be, for example, phenyl,

o-tolyl, -m-tolyl, -p-tolyl, -o-xylyl, -m-xylyl, -p-xylyl or napthyl. Preferably, R, or R₂ as

an unsubstituted or substituted aryl group is an aryl group having about 6 to about 10 carbons, such as, phenyl or napthyl.

R, or R₂ as an unsubstituted or substituted aralkyl group may be, for example,

benzyl, methylbenzyl, methoxybenzyl, diphenylmethyl, phenylethyl, or phenylpropyl.

Preferably, R, or R₂ as an unsubstituted or substituted aralkyl group is an aralkyl having

about 7 to about 9 carbons, especially, benzyl.

Particularly preferred oximes include acetoxime, benzaldehyde oxime, and methyl

ethyl ketone oxime.

As mentioned above, the present invention involves reacting an oxime with "alkylating agent". As used herein, the term "alkylating agent" refers to any material capable of providing to the reaction a nucleophilic alkyl, aryl, aralkyl or cycloalkyl group capable of reacting with the oxime to form an oxime ether. The nucleophilic group provided by the alkylating agent or agents may be unsubstituted or subtituted and may contain heteroatoms. Examples of suitable alkylating agents include: 2-(N,N-Dimethylamino)ethyl chloride

hydrochloride, methyl chloride, ethyl chloride, propanyl chloride, isopropanyl chloride,

butyl chloride, benzyl chloride, benzyl bromide, phenyl chloride and phenyl bromide.

Preferred alkylating agents include: 2-(N,N-Dimethylamino)ethyl chloride hydrochloride,

methyl chloride and ethyl chloride. In a particularly preferred embodiment, the alkylating

agent comprises 2-(N,N-Dimethylamino)ethyl chloride hydrochloride.

The oxime alkylation reaction of the present invention is conducted under conditions effective to convert at least a portion of the oxime starting material, and preferably at least about 45 % (on a mole basis) of the oxime to oxime ether. In general, it is contemplated that the particular temperatures, pressures and other reaction conditions can vary widely within the scope of the present invention, depending on factors such as the particular starting material being used, the process equipment available and the particular hydroxylamine salt

that is desired.

It is highly preferred that the oxime alkylation reaction take place in an inert solvent. Generally, any known inert solvent can be used with some degree of effectiveness in accordance with the present invention. However, it is preferred that the oxime reaction is

effective to provide an oxime ether yield of at least about at least about 40% (on a mole

basis), more preferably at least about 45%, and even more preferably at least about 50% .

It is believed that the present methods are capable of achieving yields even as high as 65 %

or greater. The present inventors have surprisingly found that this desirable yield can be

achieved by selecting as the inert solvent either NMP, acetontrile, or combinations of these. It has been discovered that the use of these solvents affords a significant and substantial

increase in yields in the production of oxime ether in comparison to the solvents used in the

prior art. Although the applicants do not wish to be bound by or to any theory of

operation, it is believed that the solvents specified herein contribute to the surprising

increase in yield because the oxime reactants and the oxime salt intermediate formed are all

independently soluble to a highly favorable degree in the specified solvents. Furthermore,

undesirable halide salt side products formed in the oxime reaction (a) are generally

insoluble in the preferred solvents and precipitate out of the reaction solution. It is believed

that this in turn aids in the achieving a high degree of reaction completion in relatively short

reaction times.

It is contemplated that the other conditions for conducting the oxime reaction can be selected as required for each individual application in view of the description of the invention contained herein. With respect to the relative amounts of the oxime and alkylating agent to be used in the practice of the present invention, it is believed that this can vary widely depending on the particulars of each application, including the particular oxime starting material and the desired yield from the oxime reaction step (a). Preferably, the relative amount of starting materials used, together with the other process condition, as described herein, are effective to achieve a greater than 50% yield (on a mole basis) of oxime ether. For example, for preferred processes in which the oxime starting material comprises acetoxime and the alkylating agent is 2-(N,N-Dimethylamino)ethyl chloride hydrochloride,

the mole ratio of oxime to alkylating agent is preferably at least about 1:2, more preferably

at least about 1 : 1.5, and even more preferably at least about 1: 1.

According to certain preferred embodiments, the oxime reaction (a) comprises

reacting the oxime, the alkylating and a base in the presence of an inert solvent. Any

suitable base soluble in the solvent can be used. Examples of bases adaptable for use in

the present invention include: sodium hydroxide, potassium hydroxide, sodium carbonate,

potassium carbonate, and the like. In a preferred embodiment, the base comprises sodium

hydroxide or potassium hydroxide. Furthermore, applicants have discovered that bases

such as sodium hydroxide and potassium hydroxide are especially useful in the form of a

fine powder flake. Although applicants do not wish to be bound by or to any particular

theory of operation, it is believed that fine powder flakes more readily dissolve in the

reaction solvent and increase the reaction surface between the base, the alkylating agent and

oxime starting material, resulting in a shorter completion time for the reaction Accordingly, in a particularly preferred embodiment of the present invention, the base comprises a fine powder of sodium hydroxide or potassium hydroxide.

The relative amount of base to be used in the preferred practice of the present invention can also vary widely within the scope hereof. However, for preferred processes in which the oxime starting material comprises acetoxime and the alkylating agent is 2-(N,N-

Dimethylamino)ethyl chloride hydrochloride, the mole ratio of oxime to base is preferably

at least about 1 :4, preferably at least about 1 :3.25, and even more preferably at least about

1 :2.5.

Those skilled in the art will appreciate that the conditions under which the alkylation reaction occurs, including the pressure, temperature and period of reaction can vary widely within the scope hereof, depending on numerous factors, including the particular starting materials used. However, in general, it is believed oxime reactions of the present invention will require shorter periods of time to complete than prior art processes. For preferred processes in which the oxime starting material comprises acetoxime and the alkylating agent is 2-(N,N-Dimethylamino)ethyl chloride hydrochloride, it is preferred that the reaction time

of the alkylation reaction be about 10 hours or less. More preferably, the reaction time is about 8 hours or less, and even more preferably 6 hours or less. In view of the teachings contained herein, those skilled in the art will be able to select the appropriate reaction conditions to achieve the particular desired result. For preferred embodiments in which the oxime starting material is acetone oxime and the alkylating agent is 2-(N,N- Dimethylamino)ethyl chloride hydrochloride, the alkylating reaction is preferably carried

out at temperatures of from about 30 °C to about 150°C, more preferably from about 45 ^CC

to about 130°C, and even more preferably from about 60°C to about 75°C. Furthermore, the alkylating reaction is preferably carried out at pressures of from about 1 to about 3

atmospheres ("atm."), more preferably from about 1 to about 2 atm. and even more

preferably at about 1 atm.

The oxime ether compounds obtained from the aforementioned reaction may be

purified by conventional methods known to those skilled in the art. For example, aqueous

washes, drying, concentrating under reduced pressure, distillation, and the like may be

used to purify the oxime ether. In preferred embodiments, the products of reaction step (a)

of the present invention are purified using fractional distillation. In general, large amounts

of solvent, including up to about 95 % or more can be recovered during distillation and

recycled. In this manner the solvent cost is significantly reduced.

THE HYDROLYSIS REACTION

The second step of the present methods comprises reacting the oxime ether with a hydrolyzing agent to form the desired hydoxylamine salts. The preferred hyrolyzing agents according to the present invention comprise a liquid, and even more preferably an acid dissolved in a liquid solvent. In such embodiments, it is generally preferred that the step (b) comprises dissolving the oxime ether in the hydrolyzing agent and exposing the reactants to conditions effective to produce the desired hydroxlamine salt.

Any known acid and solvent used conventionally in acid-catalyzed hydrolysis reactions can be used in the present invention. Examples of acids suitable for use in the present invention include hydrochloric acid and sulfuric acid. For example, in a preferred embodiment wherein the oxime ether is 2-(N,N-Dimethylamino)ethyl acetoxime ether, the hydrolyzing agent comprises a 20% solution of hydrochloric acid in water. Those of skill in the art will be readily able, without undue experimentation, to select acids and solvents for

use in the hydrolysis step of the present invention.

Applicants have surprisingly found that vastly superior results can be achieved by utilizing a hydrolysis reaction temperature within a defined range. Thus, although the hydrolysis reaction may be conducted generally at temperatures used in prior art hydrolyses, applicants have discovered that by conducting the hydrolysis reaction at a temperature above the boiling point of the hydrolyzing agent, but below the decomposition temperatures of the oxime ether and the hydroxylamine salts, a significantly higher yield of product can be formed in a significantly shorter time than had been available with prior art processes. As used herein the term "decomposition temperature" of a compound refers generally to the temperature at which, under the reaction pressure, the compound breaks down into smaller constituents. Furthermore, the term "boiling point" as used herein means the initial boiling point of the hydrolyzing agent at the pressure of the reaction.

Although the applicants do not wish to be bound by or to any particular theory of operation, it is believed that at temperatures below the boiling point of the hydrolyzing agent, the reaction mixture will develop an undesirably high concentration of the ketone or aldehyde side-products, which are formed by hydrolyzing the carbon-nitrogen imine bond of the oxime ether. It is believed that the presence of these side products inhibits the formation of the desired hydroxylamine salts. As illustrated in the reaction equation below, the hydrolysis reaction is an equilibrium reaction.

oxime ether + acid + water .., - hydroxylamine salt + ketone/aldehyde Accordingly, the formation of the ketone or aldehyde side-product on the right side of the equation increases the concentration of side-product present and tends to drive the reaction towards the left, thus hindering formation of the desired product.

However, applicants believe that by conducting the hydrolysis reaction at a temperature sufficient to cause accelerated vaporization of the solvent in the hydrolyzing agent, the disfavored side-product is preferentially removed from the reaction mixture. In this manner, the conversion of oxime ether to hydroxylamine salt is much less hindered, and oxime ether can be converted to hydroxylamine salt at a faster rate and to a greater degree of completion.

It is also important to note that conducting the hydrolysis reaction at a temperature above the decomposition point of the oxime ether or the hydroxylamine salt product can be detrimental for a number of reasons. For instance, heating the reaction mixture above either decomposition point will break down the oxime ether starting material or the desired reaction product and significantly lower the reaction yield. Moreover, the decomposition of oxime ethers and/or hydroxylamine salts results often in the quick release of large quantities of ammonia gas, causing violent explosions. Accordingly, in preferred embodiments of the present invention, the temperature at which the hydrolysis reaction is conducted is maintained below the decomposition points of the oxime ether and the desired hydroxylamine salt.

To further ensure the safety and efficiency of the hydrolysis reaction, it is preferred

that the reflux temperature at which the reaction is conducted be at least 30 °C below the

lower of the decomposition points of the oxime ether and the desired hydroxylamine salt.

More preferably, the reflux temperature is at least 45 °C below the lower decomposition point, and even more preferably, 60 °C below. For example, for preferred processes in

which the oxime ether is 2-(N,N-Dimethylamino)ethyl acetoxime ether and the desired

hydroxylamine salt is O-[2-N,N-dimethylamino)ethyl]-hydroxylamine dihydrochloride, the

reaction temperature is preferably from about 105°C to about 120°C. More preferably, the

reaction temperature of the preferred processes is from about 108°C to about 115°C, and

even more preferably from about 110°C and 113°C.

The period of reaction can vary widely within the scope hereof, depending on numerous factors, including the particular starting materials used. However, in general, it is believed oxime ether reactions of the present invention will require shorter periods of time to complete than prior art processes. For preferred processes in which the oxime ether starting material comprises 2-(N,N-Dimethylamino)ethyl acetoxime, it is preferred that the reaction

time of the alkylation reaction be about 12 hours or less. More preferably, the reaction time is about 10 hours or less, and even more preferably 8 hours or less. In view of the teachings contained herein, those skilled in the art will be able to select the appropriate reaction conditions to achieve the particular desired result.

It is preferred that the hydrolysis reaction of the present invention be conducted according to the teachings hereof so as to provide an hydroxylamine salt yield of at least

about at least about 40% (on a mole basis), more preferably at least about 45 % , and even

achieving yields even as high as 65 % or greater for the hydrolysis step.

The hydroxylamine salt compounds obtained from the aforementioned reaction may

be purified by conventional methods known to those skilled in the art. For example, aqueous washes, drying, concentrating under reduced pressure, distillation, and the like

may be used. In preferred embodiments, the hydrolysis reaction is carried out in a vessel

which is connected to or comprises distillation apparatus. Those of ordinary skill in the art

will be readily able to discern appropriate apparatus for removing distillate from the

hydrolysis reaction without undue experimentation.

In preferred embodiments, the hydroxylamine salt products of the present invention

are purified using recrystallization techniques. Techniques for recrystallizing compounds

within a variety of solvents are well-known in the art, and those of ordinary skill in the art

will readily be able to optimize known techniques to recrystallize and recover compounds

according to the present invention. Examples of recrystallization are disclosed in Perrin,

D.D; Armarego W.L.F., Purification of Laboratory Chemicals (3rd edition, Peragamon

Press 1988) (pp.12-16)., which is incorporated herein by reference. A particularly

preferred solvent for use in recrystallization of hydroxylamine salts is methanol.

Examples

In order to illustrate, in a non-limiting manner, the present invention is described in

connection with the following examples.

Example 1

This example illustrates the synthesis of 2-(N,N-Dimethylamino)ethyl acetoxime

ether (DMAE-AO) from acetoxime (AO) and 2-(N,N-Dimethylamino)ethyl chloride

hydrochloride.

To a jacketed 3-necked round-bottom flask (12L), equipped with a mechanical stirrer, a thermocouple and a condenser fixed with a nitrogen inlet/outlet, was charged 2.9

liters of acetonitrile (CH₃CN). The acetonitrile was agitated using the mechanical stirrer.

Acetone oxime (511.6 g, 7.0 mol) was charged as one portion and the resulting mixture

was stirred at room temperature (25 °C) for 10 min. Sodium hydroxide flake (644.0 g,

16.4 mol) was added to the solution and the reaction was heated to 45 °C and agitated for

30 min. 2-(N,N-dimethylamino)ethyl chloride hydrochloride (1109.2 g, 7.7 mol) was

added in five portions (220 g/220mL CH₃CN/10.0 min/per portion) over 50 min. After the

addition, the reaction was agitated at 65-70 °C for 1.5 hours and was then monitored by

gas chromatography (GC) to determine the disappearance of AO. The reaction was cooled to 25 °C, and the salt was filtered off under slight vacuum. The resulting cake was washed

once with CH₃CN (0.2 L) and dried under vacuum. The combined filtrate of 2-(N,N-

dimethylamino)ethyl acetoxime ether product was held in a cold chamber prior to

distillation.

Next, to a fractional distillation unit comprising: a 3-necked round-bottom flask (5.0

L) equipped with a magnetic stirrer, a thermocouple, a fractional distillation column (10

theoretical plates) connected to a splitter and a timer, a condenser with vacuum line and

receivers, was added the aforementioned filtrate (3.0 L). The reflux rate was set as 1 : 1 and

the cooling fluid temperature was set at 0°C. The solution was heated to gentle reflux

(82°C) for 5 min, then the system pressure was gradually reduced from 756 to 600 rnmHg.

The remaining 2.0 L of filtrate was added to the distillation unit after 2.0 L of distillate

CH_jCN was collected. The distillation was then continued until a total amount of 4.0 L of

distillate was gathered. The pot temperature was raised to 105°C and the vacuum was gradually decreased to 90 mmHg. The distillates (50mL/per cut) were checked carefully by

GC until the desired hydroxylamine salt product comprised 92% of the distillate. The

receiver was changed and the distillate was collected until the overhead temperature

dropped to 90° C. Then, the receiver was changed again and the vacuum was gradually

increased to 15 mmHg and several more cuts of distillates were collected, which were

sequentially checked by GC. Those cuts containing 97% or higher of DMAE-AO were

combined. A total of 632 g (56% yield) of DMAE-AO was obtained in>98% purity. The

fractions containing 75-92% DMAE-AO were combined and added to the next batch

distillation.

Example 2

This example illustrates the synthesis of O-[2-N,N-dimethylamino)ethyl]-

hydroxylamine dihydrochloride ("DMAEHA-2HC1") via the hydrolysis of DMAE-AO.

To a 3-necked round bottom flask (5.0L) equipped with a mechanical stirrer, a

thermocouple, a dropping funnel and a condenser connected to both a receiver and a caustic

scrubber (loaded with 25 % of aqueous NaOH solution), was added cooled (5°C) 20% HCl

solution (2795 g, 15.09 mol). The reaction mixture was cooled to 0°C and agitated.

DMAE-AO (750 g, 5.03 mol) was added slowly into the HCl solution and the jacket

temperature was controlled below 50° C. After the addition, the reaction jacket temperature

was set to 110-1 13 °C and the reaction was heated to boil. A distillate (2990 g) was

collected while 2810 g of 20% HCl was added to the reaction over 5-8 hours. The reaction was monitored by GC to determine the disappearance of DMAE-AO. After completion of

the hydrolysis, most of the water in the reaction distilled out (pot 113°C, overhead 113°C,

1350 g of water was collected). Then the reaction mixture was cooled to 100°C and n-

butanol (1.8L, b.p. 118°C) was added. The mixture was heated to reflux (jacket

temperature 118°C) for azeotropic distillation. Water (660 g) was collected from a Dean-

Stark trap while a homogeneous phase was formed. With mild agitation, the reaction was

cooled to 25 °C. The resulting pale-yellow crystals were filtered and dried under nitrogen

flow in a vacuum oven at 50°C for 16 hours to afford 865.5 g of crude product in 97.3 %

yield.

A portion of the aforementioned crystals (500 g) was placed in a 3-necked round-

bottom flask (5.0 L) equipped with a mechanical stirrer, a thermocouple and a condenser

connected to nitrogen inlet/outlet lines. Methanol (3.2 L) was added to the flask and the

resulting suspension was heated to 65 °C and refluxed for 20 min with mild agitation. A

portion of methanol (1.31 L, 41 % of total volume) was distilled out and the solution was

gradually cooled and seeded with high pure DMAEHA-2HC1 crystal at 60°C. The solution

was agitated at a moderate rate at 25 °C for 12 hours. The resulting crystals were filtered

off and dried under nitrogen flow in a vacuum oven at 50 °C for 12 hours to afford 410 g of

DMAEHA-2HC1 (68% yield) with 98.3 % purity. The mother liqueur was placed in cold

chamber (5°C) for 18 hours and 50.5 g of the second corps was obtained in 95.4% purity.

Having thus described a few particular embodiments of the invention, various alterations, modifications and improvements will readily occur to those skilled in the art. Such alterations, modifications and improvements as are made obvious by this disclosure are intended to be part of this description though not expressly stated herein, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description is by way of example only, and not limiting. The invention is limited only as defined in the following claims and equivalents thereto.

Claims

CLAIMSWhat is claimed is:

1. A method for producing hydroxylamine salt comprising alkylating an oxime to produce an oxime ether and hydrolyzing said oxime ether to produce hydroxylamine salt, said alkylating and hydrolyzing steps being carried out under conditions effective to produce a hydroxylamine salt yield of at least about 40 % (on a mole basis).

2. The method of claim 1 wherein said oxime is of the formula:

R,(R₂)-C =N-OH

wherein R_{ and R₂ are independently selected from the group consisting of hydrogen,

3. The method of claim 1 wherein said alkylating step comprises reacting said

oxime

with an alkylating agent in the presence of a solvent.

4. The method of claim 3 wherein said solvent is selected from the group consisting of acetonitrile, l-methyl-2-pyrrolidinone ("NMP") and combinations thereof.

5. The method of claim 1, wherein the oxime is selected from the group consisting of acetone oxime, benzaldehyde oxime, methyl ethyl ketone oxime and combinations of two or more of these.

6. The method of claim 3 wherein the alkylating agent is selected from the group consisting of 2-(N,N-Dimethylamino)ethyl chloride hydrochloride, methyl chloride, ethyl chloride and combinations of two or more of these.

7. The method of claim 3 wherein said alkylating step comprises reacting said alkylating agent with said oxime in the presence of a base dissolved in said solvent.

8. The method of claim 7 wherein said base used is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and combinations of two or more of these.

9. The method of claim 7 wherein said base comprised a fine powder flake prior to dissolution in said solvent.

10. The method of claim 1 further comprising the step of purifying said hydroxylamine salt by recrystallization.

11. The method of claim 1 wherein said alkylation step produces an oxime ether yield of at least about 45%> (on a mole basis) in a reaction time of no greater than about 6 hours.

12. The method of claim 11 wherein said alkylating step comprises reacting said

consisting of acetonitrile, 1 -methyl-2-pyrrolidinone ("NMP") and combinations thereof.

13. The method of claim 1 wherein said wherein said hydro lyzation produces an hydroxylamine salt yield of at least about 45% (on a mole basis) in a reaction time of no greater than about 8 hours.

14. The method of claim 13 wherein said hydrolyzation step comprises reacting said oxime ether with a liquid hydrolyzing agent at a temperature above about the boiling temperature of the hydrolyzing agent and below about the lower of the decomposition temperatures of said hydroxylamine salt and said oxime ether.

15. The method of claim 14, wherein said temperature is at least about 30 degrees below the decomposition temperature of said oxime ether.

16. The method of claim 14, wherein said temperature is at least about 30 degrees below the decomposition temperature of said hydroxylamine salt.

17. The method of claim 13 wherein the hydrolyzing agent comprises a solution of HCl in water and said hydrolyzation temperature is from about 105°C to about 120°C.

18. The method of claim 17 wherein said hydrolyzation step forms said hydroxylamine salt and a side product of the formula R,(R₂)-C=O and wherein said

hydrolysis step comprises removing said side product from the reaction mixture by distillation.

19. A method for producing a hydroxylamine salt comprising alkylating an oxime

in the presence of a solvent selected from the group consisting of acetonitrile, l-methyl-2- pyrrolidinone and mixtures thereof, to form an oxime ether and reacting said oxime ether with a hydrolyzing agent at a temperature above about the boiling temperature of the hydrolyzing agent and below about the decomposition temperatures of said hydroxylamine salt and said oxime ether to produce a hydroxylamine salt.

20. The method of claim 19 wherein said oxime is of the formula:

R,(R₂)-C=N-OH

21. The method of claim 20 wherein the oxime is selected from the group consisting of acetone oxime, benzaldehyde oxime, methyl ethyl ketone oxime and combinations of two or more of these.

22. The method of claim 19 wherein said alkylating step comprises reacting said

oxime with an alkylating agent in said solvent, said alkylating agent being selected from the

group consisting of 2-(N,N-Dimethylamino)ethyl chloride hydrochloride, methyl chloride, ethyl chloride and combinations of two or more of these.

23. The method of claim 22 wherein said alkylating step comprises reacting said alkylating agent with said oxime in the presence of a base dissolved in said solvent.

24. The method of claim 19 wherein said alkylation step produces an oxime ether yield of at least about 50% (on a mole basis) in a reaction time of no greater than about 6 hours.

25. The method of claim 19 wherein said wherein said hydrolyzation produces an hydroxylamine salt yield of at least about 50% (on a mole basis) in a reaction time of no greater than about 8 hours.

26. The method of claim 19 wherein the hydrolyzing agent comprises a solution of HCl in water and said hydrolyzation temperature is from about 105°C to about 120°C.

27. A method for producing a hydroxylamine salt comprising alkylating an oxime

in the presence of a solvent selected from the group consisting of acetonitrile, l-methyl-2- pyrrolidinone and mixtures thereof, to form an oxime ether and hydrolyzing said oxime ether to produce hydroxylamine salt.

28. A method for producing a hydroxylamine salt comprising alkylating an oxime to produce an oxime ether and reacting said oxime ether with a hydrolyzing agent at a temperature above about the boiling temperature of the hydrolyzing agent and below about the decomposition temperatures of said hydroxylamine salt and said oxime ether to produce a hydroxylamine salt.