Cross-Reference To Related Application

This application claims priority to U.S. Provisional Application No. 61/909,541 , filed November 27, 2013, the disclosure of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The disclosure provides improved processes for preparing N-methylhydroxylamine and N-methylhydroxylamine hydrochloride.

Description of Related Art

N-alkylhydroxylamine, such as N-methylhydroxylamine (MHA), is a versatile starting material for the synthesis of a number of different compounds. N-alkylhydroxylamines are also used as valuable oxygen scavengers in boiler feed waters.

Various methods for synthesizing N-alkylhydroxylamines are known, but these methods have various disadvantages, especially when producing N-alkylhydroxylamines on an industrial scale. For example, N-alkylhydroxylamines may be obtained by catalytic hydrogenation of nitroalkanes, but that process usually results in low yields with substantial amounts of alkylamine that are formed and rapid loss of catalyst activity and selectivity.

There are also several methods for stabilizing the N-alkylhydroxylamines. For example, hydrogenation of nitromethane performed with Pd/C in the presence of sulfuric acid gave N-methylhydroxylamine sulfate salt. The sulfuric acid reacted with the N- methylhydroxylamine as it is formed to give the corresponding salt preventing over-reduction to methylamine. SUMMARY OF THE INVENTION

In a broad aspect, the disclosure provides a hydrogenation process for preparing N- methyl-hydroxylamine, where the process comprises treating a solution of nitromethane in a solvent with hydrogen in presence of a catalytic amount of a palladium catalyst and diethylene-triaminepentaacetic acid or a salt thereof.

In another aspect, the disclosure provides a hydrogenation process for preparing N- methyl-hydroxylamine hydrochloride comprising: treating a solution of nitromethane in a solvent with hydrogen in the presence of a catalytic amount of a palladium catalyst and diethylene-triaminepentaacetic acid or a salt thereof to yield N-methylhydroxylamine; and contacting the N-methylhydroxylamine with aqueous hydrochloric acid at a temperature of about 0 to about 50 °C.

The disclosure also provides a process for crystalizing N-methylhydroxylamine hydrochloride. For example, the disclosure provides a process comprising crystalizing the N- methylhydroxylamine hydrochloride obtained from the hydrogenation processes of the disclosure from a mixture comprising N-methylhydroxylamine hydrochloride and a polar solvent. The resulting N-methyl-hydroxylamine hydrochloride has high purity compared to commercially available products.

DETAILED DESCRIPTION OF THE INVENTION

Before the disclosed methods and materials are described, it is to be understood that the aspects described herein are not limited to specific embodiments, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

In view of the present disclosure, the methods and materials described herein can be configured by the person of ordinary skill in the art to meet the desired need. In general, the disclosed methods provide improvements in process for preparing N-methylhydroxylamine and N-methylhydroxylamine hydrochloride. For example, in certain aspect, the processes of the disclosure are unexpectedly suitable for producing N-methylhydroxylamine and its hydrochloride salt on an industrial scale in high yields and high purity.

Therefore, one aspect of the disclosure provides a hydrogenation process for preparing N-methylhydroxylamine comprising: treating a solution of nitromethane in a solvent with hydrogen in presence of a catalytic amount of a palladium catalyst and diethylenetriaminepentaacetic acid or a salt thereof.

Another aspect of the disclosure provides a hydrogenation process for preparing N- methyl-hydroxylamine hydrochloride comprising: treating a solution of nitromethane in a solvent with hydrogen in presence of a catalytic amount of a palladium catalyst and diethylene-triaminepentaacetic acid or a salt thereof to yield a mixture comprising N- methylhydroxylamine; and contacting the N-methylhydroxylamine with aqueous hydrochloric acid at a temperature of about 0 to about 50 °C.

The solvent suitable for use in the hydrogenation processes of the disclosure can be any liquid which is inert to hydrogenation and in which the nitromethane reactant, and preferably also the N-methylhydroxylamine product, is soluble. In one embodiment, the solvent may be a Ci-C ₅ alcohol. For example, in certain embodiments, the solvent may be methanol, ethanol, propanol, isopropanol, butanol, tertbutanol, or pentanol. In certain embodiments, the solvent may be a C-|-C ₃ alcohol. In other certain embodiments, the solvent is a mixture of two or more CrC ₅ alcohols. In another embodiment, the solvent employed in the processes as disclosed above may be a mixture of water and one or more Ci-C ₅ alcohols.

In one embodiment, the solvent employed in the hydrogenation processes is methanol. Thus, one embodiment provides a process for preparing N-methylhydroxylamine comprising treating a solution of nitromethane in methanol with hydrogen in the presence of a catalytic amount of a palladium catalyst and diethylenetriaminepentaacetic acid or a salt thereof. Another embodiment provides a process for preparing N-methylhydroxylamine hydrochloride comprising: treating a solution of nitromethane in methanol with hydrogen in the presence of a catalytic amount of a palladium catalyst and diethylenetnaminepentaacetic acid or a salt thereof to yield a mixture containing N-methylhydroxylamine; and contacting the N-methylhydroxylamine with aqueous hydrochloric acid at a temperature of about 0 to about 50 °C.

The solvent for the hydrogenation may be present in a range of about 10 weight % to about 90 weight %, based on the weight of nitromethane. The weight ratio of the solvent to the nitromethane can be, for example, in the range of at least about 1 :5, at least about 1 :2, at least about 1 :1 , at least about 2:1 , at least about 3:1 , at least about 4:1 , or at least about 5:1 . For example, in certain embodiments, the weight ratio of the solvent to nitromethane is in the range of about 2:1 to about 1 :2, about 1 .5:1 to about 1 :1.5, about 2:1 to about 1 :1 , about 3:1 to about 1 :2, about 2:1 to about 1 :3, about 3:1 , about 2:1 , about 1.5:1 , about 1 :1 , about 1 :1 .5, or about 1 :2.

Known palladium catalysts may be used in the hydrogenation processes of the disclosure. In one embodiment, the palladium catalyst is palladium. In another embodiment, the palladium catalyst is palladium oxide. Such palladium catalysts can be present, for example, in a range of up to about 1 .5 weight %, up to about 1 weight %, up to about 0.5 weight %, up to about 0.2 weight %, up to about 0.1 weight %, or up to about 0.05 weight %, all calculated based on the weight of nitromethane. In certain embodiments, the palladium catalyst is used in an amount of about 0.0001 to about 1 .5 weight %, about 0.0001 to about 1.0 weight %, about 0.0005 to about 1 .0 weight %, about 0.001 to about 1 .0 weight %, about 0.0001 to about 0.5 weight %, about 0.01 to about 1 .0 weight %, about 0.001 to about 0.5 weight %, or about 0.0001 to about 0.01 weight %.

A wide variety of carrier materials can be used with the palladium catalyst described herein. For example, in certain embodiments, the carrier material includes one or more materials selected from the group consisting of carbon, alumina (aluminum oxide), silicon dioxide, magnesium aluminate (MgAI ₂ 0 ₄ ), and mixtures thereof. In one embodiment, the carrier support is selected from carbon, alumina, and mixtures thereof. In one embodiment, the palladium catalyst is palladium on a carrier support selected from carbon, alumina, and mixtures thereof. In one embodiment, the palladium catalyst is palladium on carbon.

The processes described herein can be performed at a variety of hydrogen pressures and temperatures. For example, in certain embodiments, the pressure of hydrogen gas is in the range of about 15 psi to about 1000 psi, about 50 psi to about 750 psi, about 100 psi to about 700 psi, about 100 psi to about 500 psi, about 100 psi to about 300 psi, about 100 psi, about 200 psi, about 300 psi, about 400 psi, about 450 psi, about 500 psi, or about 550 psi. In certain embodiments, the reaction temperature can remain in the range of about 10 °C to about 100 °C, in the range of about 20 °C to about 90 °C, in the range of about 40 °C to about 100 °C, in the range of about 50 °C to about 100 °C, in the range of about 40 °C to about 80 °C, or in the range of about 50 °C to about 750 °C. Of course, the person of ordinary skill in the art will understand that in certain embodiments and applications the temperatures and pressures may differ from those particularly described here.

In addition, in certain embodiments and applications the hydrogenation process components, e.g., nitromethane, palladium catalyst, diethylene-triaminepentaacetic acid, and hydrogen, may be added in any order. In one exemplary, non-limiting embodiment of the hydrogenation processes described herein, a solution of a palladium catalyst and diethylene- triaminepentaacetic acid or a salt thereof in a solvent are first added to the reactor under hydrogen, and then treated with a solution of nitromethane. In another exemplary, non- limiting embodiment of the hydrogenation processes described herein, a solution of nitromethane, a palladium catalyst, and diethylene-triaminepentaacetic acid or a salt thereof in a solvent are first added to the reactor, and then treated with hydrogen.

The level of diethylenetnaminepentaacetic acid or a salt thereof can vary. In certain embodiments of the processes as described herein, wherein diethylenetnaminepentaacetic acid or a salt thereof is present in an amount of about 0.0005 to about 0.5 weight % of nitromethane. In other embodiments, the diethylenetnaminepentaacetic acid or a salt thereof is present in the range of about 0.0005 to about 0.1 %, in the range of about 0.001 to about 0.5 %, in the range of about 0.001 to about 0.1 %, or in the range of about 0.0005 to about 0.05 %. One example of a suitable salt of diethylenetriaminepentaacetic acid is the sodium salt (e.g., diethylene-triaminepentaacetic acid pentasodium salt).

The aqueous hydrochloride acid used in the process for preparing N-methyl- hydroxylamine hydrochloride may be present in a range of concentrations. For example, in one embodiment, the aqueous hydrochloride acid is added in an amount of about 0.5 to about 3 molar equivalents based on the amount of N-methylhydroxylamine. In other embodiments, the aqueous hydrochloride acid is added in an amount of about 0.5 to about 2, or about 0.5 to about 1 .5, or about 0.5 to about 1 , or about 0.75 to about 2, or about 0.75 to about 1.5, or about 0.75 to about 1 , or about 1 to about 2, or about 1 to about 1 .75, or about 1 to about 1 .5, or about 1 to about 1 .25, or about 0.5, or about 0.75, or about 1 , or about 1.25, or about 1.5, or about 2, all molar equivalents of N-methylhydroxylamine. In particular embodiment, the aqueous hydrochloride acid is added in an amount of about 1 to about 1 .5 molar equivalents based on the amount of N-methylhydroxylamine.

In one embodiment, the aqueous hydrochloride acid further comprises the hydrogenation solvent as described above. For example, in a particular embodiment, the aqueous hydrochloride acid further comprises methanol.

Contacting N-methylhydroxylamine with aqueous hydrochloric acid as described herein can be performed at a variety of temperatures. In certain embodiments, the temperature can remain in the range of about 0 °C to about 50 °C, in the range of about 0 °C to about 40 °C, in the range of about 0 °C to about 30 °C, in the range of about 0 °C to about 25 °C, in the range of about 5 °C to about 30 °C, in the range of about 10 °C to about 30 °C, in the range of about 15 °C to about 30 °C, in the range of about 10 °C to about 25 °C, or in the range of about 15 °C to about 25 °C. In particular embodiments, the contacting N- methylhydroxylamine with aqueous hydrochloric acid as described herein is conducted at a temperature of between about 0 to about 25 °C. In other embodiments, the contacting N- methylhydroxylamine with aqueous hydrochloric acid is carried out at a temperature of between about 15 to about 23 °C.

Another aspect of the disclosure provides a process for crystalizing N- methylhydroxylamine hydrochloride. For example, the disclosure provides crystalizing N- methylhydroxylamine hydrochloride obtained from the hydrogenation processes described herein from a mixture comprising about 1 to about 2 parts of N-methylhydroxylamine hydrochloride to about 1 part of a polar solvent. The resulting N-methyl-hydroxylamine hydrochloride has high purity compared to commercially available products.

The amount N-methylhydroxylamine hydrochloride to the polar solvent may vary. For example, in one embodiment, the mixture comprises about 2 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1.8 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1.75 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1.6 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1.5 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1 .4 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1.25 parts of N-methylhydroxylamine HCI to about 1 part of a polar solvent, or about 1 part of N-methylhydroxylamine HCI to about 1 part of a polar solvent. In another embodiment, the mixture comprises about 1 .3 to about 1 .7 parts of N-methylhydroxylamine hydrochloride to about 1 part of a polar solvent. In yet another embodiment, the mixture comprising about 1 .4 to about 1.6 parts of N-methylhydroxylamine hydrochloride to about 1 part of a polar solvent. In a particular embodiment, the mixture comprising about 1 .5 parts of N-methylhydroxylamine hydrochloride to about 1 part of a polar solvent.

The polar solvent suitable for use in the crystallization processes described herein may be one or more Ci-C ₅ alcohols. For example, in certain embodiments, the solvent may be methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or pentanol. In certain embodiments, the solvent may be a C ₂ -C ₄ alcohol. In other certain embodiments, the solvent is a mixture of two or more CrC ₅ alcohols. In another embodiment, the solvent is a mixture of two or more C ₂ -C ₄ alcohols. In particular embodiments, the polar solvent used for the crystallization is methanol, ethanol, isopropanol, tertbutyl alcohol, or a mixture thereof. In other particular embodiments, the polar solvent is a single solvent (i.e., not a mixture). One embodiment of the disclosure provides crystallization of N-methylhydroxylamine hydrochloride as described herein in isopropanol.

Crystallization of N-methylhydroxylamine hydrochloride as described herein can be performed at a variety of temperatures. In certain embodiments, the crystallization temperature is in the range of about 0 °C to about 35 °C, in the range of about 10 °C to about 35 °C, in the range of about 0 °C to about 25 °C, in the range of about 0 °C to about 23 °C, in the range of about 5 °C to about 30 °C, in the range of about 5 °C to about 25 °C, in the range of about 10 °C to about 30 °C, in the range of about 10 °C to about 30 °C, in the range of about 10 °C to about 25 °C, or in the range of about 15 °C to about 20 °C. In particular embodiments, the crystallization of the N-methylhydroxylamine hydrochloride is conducted at a temperature of between about 10 to about 20 °C. In other embodiments, the crystallization of the N-methylhydroxylamine hydrochloride is conducted at a temperature of between about 15 to about 25 °C. In other embodiments, the crystallization of the N-methylhydroxylamine hydrochloride is carried out at a temperature of between about 15 to about 20 °C. Of course, the person of ordinary skill in the art will understand that in certain embodiments, the temperatures may differ from those particularly described here. Definitions

The following terms and expressions used have the indicated meanings.

Throughout this specification, unless the context requires otherwise, the word "comprise" and "include" and variations (e.g., "comprises," "comprising," "includes," "including") will be understood to imply the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein the term "contacting" includes the physical contact of at least one substance to another substance.

Ranges can be expressed herein as from "about" one particular value, and/or to

"about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

All percentages, ratios and proportions herein are by weight, unless otherwise specified. A weight percent (weight %, also as wt %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included (e.g., on the total amount of the shift catalyst). All mol% values are based on the moles of nitromethane.

EXAMPLES

The methods of the disclosure are illustrated further by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and in them.

Example 1

To 2-liter stirred Parr, stainless steel autoclave; was charged 2.02 g 5% palladium on carbon catalyst (Pd/C), 1.01 g Chel DTPA-41 (40% aqueous diethylenetriaminepentaacetic acid pentasodium salt, DTPA ^« Na ₅ ), and 240 g methanol (MeOH). The autoclave was sealed, pressure purged 3 times with nitrogen (N ₂ ), 3 times with hydrogen (H ₂ ), and then pressured to about 500 psig H ₂ . Agitation was begun and set at 600 rpm. The Parr controller was set to warm the reactor to the reaction temperature (55 °C). During this time, 480 g MeOH and 320 g nitromethane were-premixed and added to the feed pump addition funnel. The Eldex high pressure feed pump was primed with the nitromethane-MeOH solution and the pump setting adjusted to 6 ml/min. When the autoclave temperature stabilized at 55 °C, the hydrogen feed valve was opened to the regulated H ₂ at 600 psig. The pump was started and the pump feed valve was opened and the nitromethane-MeOH solution was fed to the autoclave in 3 hours and 4 minutes. During the feed period, the autoclave temperature was maintained at 55-56 °C and the pressure ranged from 594-615 psig H ₂ . Once all the nitromethane-MeOH solution had been pumped into the autoclave, the feed lines were flushed with 45.1 g MeOH and the temperature was held at 55 °C for 15 minutes. The reaction mass was cooled to 25°C and the autoclave was vented and purged with N ₂ . The reaction product was filtered through a glass microfiber filter to remove catalyst and stored under N ₂ . A sample was analyzed by titration and found to contain 20.98 wt% N-methylhydroxylamine (93% molar yield) and 0.27 wt% methylamine.

Example 2

To a 500 ml flask equipped with a magnetic stirrer, thermocouple, and ice water bath was charged 224.0 g of the crude N-methylhydroxylamine product of Example 1 . To this was slowly added 1 10.3 g aqueous HCI (-37%, 10% molar excess) while keeping the temperature below 25 °C, resulting in 333.4 g of N-methylhydroxylamine hydrochloride / methanol / water solution. Example 3

Methanol and water were removed from N-methylhydroxylamine hydrochloride / methanol / water solution of Example 2 on a rotary evaporator at ~5 mm Hg and 45 °C, resulting in 85.8 g viscous material (theoretical = 83.5 g, Karl Fischer analysis showed 0.6 % water). To this was added 58.3 g isopropanol. While stirring with ambient cooling, the material crystallized. The liquid was removed by filtration resulting in off white crystals. To the crystals was added 59.9 g isopropanol and the mixture was swirled to rinse the crystals prior to another filtration, generating 75.7 g of wet crystals. The crystals were dried at 5 mm Hg and 45 °C, giving 66.2 g dry crystals. The rinse mother liquor was re-filtered and the crystals recovered were dried at the same conditions giving another 1 .7 g of dry crystals, totaling 67.9 g dry crystals of N-methylhydroxylamine hydrochloride (an 81.3% isolated molar yield from N-methylhydroxylamine).

N-methylhydroxylamine hydrochloride (MHA ^« HCI) purity was assessed by melting point and compared to melting point of MHA ^« HCI purchased from Sigma-Aldrich, St. Louis, MO. Note: higher melting point is indicative of higher purity.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.