Claims:We Claim:
1. A process for the preparation of alloy-amine and salt thereof represented by formula I

using a loop reactor geometry to moderate activity of reactive ingredients with built-in mixing and heat removal zones, said process comprising:
i) precooled solution of sodium nitrite and sodium bisulphite are added into the bulk of recycled mass and the reaction mass is intensely mixed wherein hot spot development is avoided owing to large reaction mass and intense stirring;
ii) SO2 dissolved in water is added, where the extraction of SO2 as an reactant to react with compound of Formual II from the aq. Solution is endothermic thus avoiding formation of hot spots and the aqueous medium assists in maintaining pH of the reaction mass to obtain compound of Formula III;
iii) an alkylating agent and NaOH solution is added to the reaction mass of step iii to obtain disodium disulphonate alkoxtamine; and
iv) disodium disulphonate alkoxtamine obtained in step iv is hydrolysed using mineral acid to give 98.2% pure in 72% yield alkoxyamine and salt thereof.

2. The process according to claim 1 wherein the improved reactor geometry ensures facile control of reaction mass temperature and pH eliminating formation of side reactions producing substantially pure product in good yield, reactor geometry for the said process as depicted in figure 1.

3. The process according to claim 1 wherein loop reactor geometry with built-in mixing and heat removal zones comprising recycling a large amount of the reacted mass thereby affording efficient and facile control of reaction mass pH, eliminating formation of difficult-to-remove impurities.

4. The process according to claim 1 wherein the said process comprises using aqueous solution of SO2 wherein endothermic de-solubilization of SO2 maintains the temperature and water medium maintains the pH of the reaction mass eliminating formation of difficult-to-remove impurities.

5. The process according to claim 1 wherein loop type reactor geometry maintains reactants in a sequential and distributed cascade leading to substantially reduced heat removal and pH maintenance duty in each constituent of the cascade by providing built-in mixing and heat removal zones in each cascade constituent and minimizing the localized acidic zones, wherein sulfurdioxide comes simultaneously in contact with combined solution of sodium nitrite and sodium bisulphite thereby minimizing hot spot formation and maintaining the pH resulting into disulphonate and its methylation followed by hydrolysis and distillation as represented below.

6. A process for preparing methoxy amine HCl (OCH3-NH2-HCl) comprising:
i) precooled solution of sodium nitrite and sodium bisulphite are added into the bulk of recycled mass and the reaction mass is intensely mixed wherein hot spot development is avoided owing to large reaction mass and intense stirring;
ii) SO2 dissolved in water is added, where the extraction of SO2 as an reactant to react with compound of Formual II from the aq. Solution is endothermic thus avoiding formation of hot spots and the aqueous medium assists in maintaining pH of the reaction mass to obtain compound of Formula III;
iii) Dimethyl sulphate and NaOH solution is added to the reaction mass of step iii to obtain disodium disulphonate alkoxtamine; and
iv) disodium disulphonate alkoxtamine obtained in step iv is hydrolysed using mineral acid to give 98.2% pure in 72% yield alkoxyamine and salt thereof.

Dated this 16th day of November, 2021

CHIRAG TANNA
of SEHGAL IPR SERVICES
APPLICANT’S PATENT AGENT

, Description:TECHNICAL FIELD OF THE INVENTION:
Disclosed herein is a techno modified improved process for the preparation of O- alkyl hydroxyl amine and its salts of formula I also referred as O-alkoxyamine,

Formula I
More particularly disclosed herein is an improved process for the preparation of this class of chemicals with special reference to methoxy hydroxylamine hydrochloride, commonly referred as O-Methyl hydroxylamine (herein after abbreviated as OMH) and its hydrochloride salt of formula IA (herein after abbreviated as OMAH)as an example.

Formula IA
Process disclosed in prior art results in low yield of product with undesired impurities. Inventors of the present invention have studied and perceived that the reason for such an adverse impact in the process is owing to tno control and effect of critical parameters like temperature and pH during the reactions involved therein. Inventors of the present invention based on exhaustive R&D and expertise opined that the best possible way to control such reaction parameters is to modifyi the design of the reactors and addition mode of reactants during the production of the compound of formulae I/IA.
This techno modified improved process for the preparation of alkoxyamine or more commonly referred to as O-alkyl hydroxylamine and its salts comprises use of specific reactor geometry adopted for the different steps involving introduction of the streams of fresh reactant raw materials into a large stream of the reacted mass in a loop reactor with built-in mixing and heat removal zones.
Inventors of the present invention have made desired changes in the reactor dsugn comprising incorporating inventive modifications in the design of the reactors for said process that ensures efficient stirring/mixing of the reacting species thereby improving the thermo chemistry and kinetic theory of molecules in the reaction mass; thus providing an efficient and economically significant process by minimizing the hot spot formation and also said novel modification for said process controls the pockets of undesirable low pH thereby maintaining the appropriate pH and resulting into high purity product in high yield. As per the observations of the inventors, it has been found that control over these critical parameters viz temperature and pH play an important role in the process of preparing subject matter product in respect of purity and yield and also making the said process simple for industrial production.
The success for the subject matter product is influenced by rigid control of the process conditions viz. temperature and acid-alkali balance. The innovative reactor disclosed in the present disclosure ensures that the both the temperature control and acid-alkali balance made much easier while the intense mixing also improves the reaction kinetics by overcoming mass transfer resistance while minimizing onset of undesirable side reactions.
The process is further characterized by an important desired feature that controls the temperature of the reaction mass by minimizing/avoiding localized hot spot formation that reduces the decomposition of sodium nitrite thereby avoiding or minimizing the formation of harmful nitrogen oxides (NOx.). These oxides are not only hazardous but being acidic also contribute towards low pH of the reaction mass. Control over the pH for the said process is a dire need for high purity product in high yield and the present invention ensures this thus providing a solution to the existing problem in the process for making the subject matter product.

Reaction Scheme:

When R of the compound of formula I represents methyl group and X represent Cl it represents the compound of interest i.e, methoxyamine hydrochloride of formula IA.
Here it is important to note that side reactions taking place leads into the formation of trisulphonate of formula IV which on hydrolysis gets converted into ammonia and ammonium hydrogen sulphate as depicted herein below.
H+, ?
{Na(OSO2)}3 N + 3 H2O 3 NaHSO4 + NH3
IV
As per finding of the inventors these ammonia products are very difficult to remove once they are formed in the reaction products.
BACKGROUND OF THE INVENTION:Alkoxyamine and its salts, more specifically
Methoxyamine hydrochloride also referred as O-Methyl hydroxylamine hydrochloride, Methoxylamine hydrochloride, Methoxylamine, N-methoxyaminesare important chemicals and medicine drug intermediates and is also used for developing and printing of color photography and film as well. OMH and OMHH are widely used in the synthesis of drugs, active pharmaceutical ingredients, functional dyes, farm chemicals and herbicides having low mammalian toxicity.
OMHH is used as a reducing agent in organic synthesis industry for preparation of oximes. In the field of medicine: it can be used for the synthesis of second-generation cephalosporine antibiotics like cefuroxime (ester).
Raschig (Liebigs Ann. Chem., 241, p. 183 [1887]) discloses a process to synthesize hydroxylamine disulfonic acid potassium salt obtained from NaNO2 and NaHSO3 and subsequent precipitation with KCl with a yield of about 50%.
Traube, Ohlendorff and Zander (Ber. Der Deutschen(space)Gesellsch., 53, S. 1477 [1920]) reported methylation of potassium hydroxylamine disulphonate using CH3I followed by subsequent saponification and isolation of the desired product.
US6414191 discloses a process for the continuous preparation of OMHH by cleavage of acetone oxime methyl ether by means of hydrogen chloride and water, wherein the cleavage is carried out in a reaction column having less than 20 theoretical plates and the amount taken off at the top is said to be at-least 30% of the amount of feed.
DE1112082B/GB930389A (hereinafter referred as “389) discloses a process for the preparation of Sodium hydroxylamine disulphonate HON (SO3Na)2 is prepared by the reaction in aqueous solution between SO2, NaNO2 and NaHSO3 (or Na2S2O5). “389 also discloses a process for O-Alkyhydroxylamines in wherein the alkyl group contains 1-4 carbon atoms and the said compounds are prepared by reacting NaNO2, SO2 and NaHSO3 (or Na2S2O5) in aqueous solution, to form sodium hydroxylamine disulponate, alkylating the latter without isolation, and hydrolysing off the sulphonate groups. The said prior art process yielded crude methoxyamine having a boiling point of 48-54OC. Which upon further purification via its hydrochloride gave pure methoxyamine in a yield of 60-65% without any mention of the purity. Drawback associated with this prior art process is that it involves steam distillation and fractionation of the distillate through a packed column about1metre in height.
Inventors of the present invention tried to reproduce the result by following the ditto procedure disclosed in the example 1 of ‘389 and observed that the distillation involved therein in the process was very difficult and unsafe in practice at industrial scalel.
SU721413A1 discloses the method for producing O-methylhydroxylamine, wherein O-methylhydroxylamine hydrochloride is reacted with ethylene diamine and O-methylhydroxylamine is isolated by distillation from the reaction mass when heated to 80°C in a water bath. .A distinctive feature of the method is the use of an organic base, ethylenediamine replacing strong alkali metal hydroxide, to neutralize O-methylhydroxylamine hydrochloride and release free base, OMH. This patent refers to DE1112082 disclosing sodium hydroxylamine disulphonate HON(SO3Na)2 prepared comprising the reaction in aqueous medium comprising reaction amongst SO2, NaNO2 and NaHSO3 (or Na2S2O5). Furthermore O-Alkyhydroxylamines in which the alkyl group with 1-4 carbon atoms were prepared by reacting NaNO2, SO2 and NaHSO3 (or Na2S2O5) in aqueous solution, to form sodium hydroxylamine disulponate, alkylating the latter without isolation followed by hydrolysis of the sulphonate groups. Reported yield for O-methylhydroxylamine is 73-76% without mentioning the purity of the desired product.
CN105330564A(hereinafter referred as “056) discloses the one pot reaction method comprising sulfur dioxide gas, sodium nitrite, sodium hydroxide, (Di)methyl-sulfate and methoxamine hydrochloride is obtained in aqueous phase. The method comprises waterin areaction vessel, into a required amount of sodium nitrite and sodium hydroxide are dropped. After stirring and dissolving, required amount of sulfur dioxide gas is passed. After having reacted, alternately adding a certain amount of sodium hydroxide and methyl-sulfate carries out reaction to termination, using sulfuric acid to adjust pH. This is followed by vacuum distillation to yield the free base product, OMH. The reported yield of O MH is 69.5% without mentioning the purity of the desired product.
Drawback associated with this prior art (‘056” is that there is no mention of the purity of the product. However, inventors of the present invention have repeated the example furnishing the yield of 69.5% comprising Sodium nitrite, Sodium hydroxide, Sulfur dioxide, Alkylating agent (DMS) in the molar ratio of 1:4:2:1.5 respectively found that the resulting product remains contaminated with ammonia to the extent to 3 to 4% and as per finding of the inventors these ammonia products are very difficult to remove once they are formed in the reaction products.
prior art processes disclosed herein above suffer from disadvantages which cab’t be overcome unless exothermic heat rapidly generated by the fast reactions between sodium nitrite sodium bisulphite as well as that of SO2 with mono sulphonate salt of formula II is not rapidly removed as there is bound to be an increase of temperature of the reaction mass resulting in the formation of undesired side products, such as hazardous oxides of nitrogen and/or trisulphonate, with consequent low yields and elaborate and expensive purification steps.The extensive purification steps also increase handling losses reducing the yield even further and making the process uneconomical.
TECHNICAL PROBLEMS ASSOCIATED WITH PRIOR ART:
The reaction of sodium nitrite with sodium bisulphite is both fast and exothermic. Consequently, if the heat generated is not rapidly removed, the temperature of the reaction mass rises, leading to side reactions and results into lowering of yield with inferior product quality. This is a problem associated with the processes disclosed in the prior art for the preparation of subject matter product.
Similarly, the reaction of sulfur dioxide with monosulphonate of formula II salt is also fast and exothermic.The problem associated with the processes disclosed it the prior art is exotherm causing the heat release and consequent rise in temperature thereby forming the undesired impurity products, which cannot be sorted out, unless suitable arrangements are made for a rapid removal of heat to attain desired temperature
Further, even a slight excess of SO2 leads to a sudden reduction of pH locally in the reaction mass leading to undesirable side reactions and consequent loss of the nitrite raw material and significantly reducing yields and purity
Rise in temperature due to the exothermic nature of the reactions of synthesis as discussed herein above and also the fluctuations in pH of the reaction mass causes the formation of hazardous oxides of nitrogen and undesirable side products.
Formation of undesirable side products affects yield and purity of the subject matter product. Processes disclosed in the prior art have a common shortcoming which is potential formation of micro zones of high acidity and / or thermal hot spots when SO2, (whether as a gas, or, in its condensed liquid form), reacts with the aqueous solution of sodium nitrite in the presence of sodium bisulphite or sodium acetate. High acidity and high temperature which are detrimental to the desired reaction in the process disclosed in the prior art for the desired product always results in the formation of undesirable impurities thus impacting purity and yield of desired product adversely making the said process uneconomical.
Another drawback associated with processes disclosed in the prior art is the onset formation of side reaction products resulting from the reactions occurring at temperature higher than desired, which leads to generation of hazardous NOx gases from decomposition of NaNO2. On the other hand low pH of the reaction mass leads to a competitive side reaction resulting into formation of nitrilo trisulphonic acid disodium salt (to be referred herein after as disodium NTS represented by formula IV as an impurity. The formation of by-product not only reduces yield but in the subsequent hydrolysis step also leads to generation of a difficult-to-separate ammonia / ammonium salts as impurities. None of the processes disclosed in the prior art talks about the purity of the desired product.
CONTRIBUTING FACTORS TOWARDS LOW PURITY:
i. Limitations of the conventional mode of mixing of the reactants
ii. Possibility of generation of localised hot spot formation as a consequence
iii. Limitations of controlling instantaneous localized pH drops as also that of the pH of the reaction mass
iv. Limitations of controlling instantaneous localized hot spots as also overall control of the temperature of the reaction mass
v. Unsafe distillation of the product
TECHNICAL SOLUTION TO THE PROBLEMS ASSOCIATED WITH PRIOR ART PROCESSES:
Inventors of the present invention have made favorable changes by incorporating innovative modifications in the design of the reactor that ensures intense and efficient mixing of the reacting species. The intense mixing minimizes/eliminates the hot spot formation and also controls the pockets of undesirable low pH thereby maintaining the reaction critical parameters viz temperature and pH avoiding side reactions and formation of undesired impurities. As per the observations of inventors of the present invention, process yield and the purity is strongly dependent on critical parameters viz. temperature and pH of the reaction mass and same is supported by the results obtained by the inventive process disclosed herein.
One of the key features of the invention is the introduction of the streams of fresh reactant raw materials into a large stream of the reacted mass in a loop reactor with built-in mixing and heat removal zones.
The reactor geometry adopted for the process also involves recycling a large amount of the reacted mass in a loop reactor with built-in mixing and heat removal zones. Typically, the quantum of reacted mass recycled is about 50 to 100 times the amount of introduction of fresh input. This arrangement ensures that the heat generated by the exothermic reactions is distributed over a much larger mass which precludes the formation of local hot spots. The recycling mass also acts as a pH buffer preventing local pockets of high acidity due to rapid dissipation of the reacting species into the bulk of the recycled mass thereby permitting maintenance of a rigid control of the critical process parameters viz. temperatureand pH within the desired range.
The problem of rapid heat transfer to maintain the reaction mass temperature within the desired limits is further aided by splitting the overall reaction between Bisulphite, Nitrite and Sulphur Dioxide over two reactor modules: the first carries out mixing Bisulphite and Nitrite with its own heat removal apparatus. The product of this reactor module feeds into the next module where Sulphur dioxide aqueous solution is reacted with the mixture of Nitrite and Bisulphite to yield the desired Bisulphonate product. Thus, such an arrangement allows tackling of the two exothermic heat loads separately thereby allowing a much better temperature control that ensures high purity product in high yield avoiding formation of undesired impurities.
The inventors of the present invention have used an aqueous solution of SO2 for carrying out the second stage of reacting with the mixture of sodium nitrite and sodium bisulphite. The dilution of the SO2 reactant along with additional mass of water the aqueous solution allows a superior control of both the two critical parameters viz. pH and temperature thereby boosting the yield with better purity profile.
After implementing this change, it has been observed by the inventors that this innovative method of introducing the reactant SO2 affords a superior control over the pH thus minimizing the extent of side reaction to form di sodium NTS along with the uniformity in temperature by preventing local over-heating thereby improving Q2 (Quantity and quality) of di sodium HDS the desired intermediate. These innovative modifications contribute significantly towards achieving improved yield due to better conversion to the desired intermediate and suppression of side reactions producing undesirable impurities which, in turn, improve yield and quality of the target molecule, hydroxyl methylamine and salt thereof both to be referred interchangeably as desired product herein after, by reducing handling losses due to much less extensive purification.
OBJECT OF THE PRESENT INVENTION:
The present invention relates to a method for producing alkoxyamines as a class of chemicals and more specifically, an O-methyl hydroxylamine useful as a synthetic intermediate for manufacture of drugs and agro-chemicals.
One aspect of the present invention is to provide proactive, scientific and risk mitigation based systematic approach to improve the quality standard of the product an alkoxyamine.
Another aspect of the present invention is to adopt the reactor geometry for all the three stages of process including the stages involving the formation of mono and di sodium hydroxylamine sulphonate salt as also the alkylation stage, wherein recycling a large amount of the reacted mass in a loop reactor with built-in mixing and heat removal / addition zones takes place.
More specifically, it is an object of the present invention to provide an efficient, economical, continuous and eco-friendly process for producing an alkoxyamine.
Further, it is an object of the present invention to utilize the present concept of quality by modifying the design to achieve critical process parameters involved therein.
It is also an object of the present invention to overcome the commonly encountered problems in the prior art processes which lead to low yields and impure product contaminated with difficult-to-remove impurities.
It is also an object of the present invention to have the adoption and implementation of the said concept of quality by design by the inventors of the present invention to reduce the risk associated product development during the scale-up manufacturing and commercialization.
The term “first”, “second” and the like, herein do not denote any order, quantity or importance, but rather are used to distinguish one element from another, and the terms “a” and “an” hereinafter do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items.
First object of the present invention is to overcome the disadvantages associated with the conventional process for the production of O-alkyl hydroxylamine preferably and as an example, O-methyl hydroxylamine and its salts as discussed herein and to maximize the yield while simultaneously minimizing impurity generation through undesirable side reactions.
Second object of the present invention is to provide a method for the production of high purity O-alkyl hydroxylamine and its salts, in good yields with high purity by a continuous process thus avoiding batch to batch variations through a choice of suitable reactor geometry while permitting easy scale up of production capacity.
Third aspect of the present invention is to incorporate some modifications in the required equipment that facilitates easy maintenance of the vital process parameters for good yields and minimizing side reactions thereby resulting into quality product with improved / better impurity profile.
Fourth aspect of the invention is to recycle the quantum of reacted mass to the extent of50 to 100 times the mass amount of fresh input introduced, which helps to maintain the temperature of the reaction mass and eliminates the local hot spot formation thereby maintaining throughout the reactor within the desired range of temperature.
Fifth aspect of the present invention is to provide the control over the critical parameters like pH and temperature not merely through controlled addition of reactants but by providing in-built pH buffer and heat sink through dominant recycle of reacted product stream.
Sixth objective of the invention is to avoid the formation of hot spots thereby avoiding the rise in temperature that results into the formation of undesired products through suitable choice of reactor geometry as stated herein above.
Yet another objective of the present invention is to have control over temperature rise due to release of exothermic heat of reaction as discussed herein above to avoid formation of hazardous oxides of nitrogen represented by (NOx) during reaction due to undesirable high temperature and / or uncontrolled pH variation.
Yet another objective of the present invention is to maintain the appropriate and most desirable pH (in the range of 3.9 to 5.0) of the reaction mass, as very acidic pH causes decomposition of monosulfonate as well as disulfonate salts of formulae II and III respectively thereby adversely impacting the yield and the quality of the desired product.
Yet another objective of the present invention is to use the appropriate stoichiometry of sulfur dioxide to avoid the formation of undesirable trisulphonate salt of the formulaIV{Na(OSO2)}3N which on hydrolysis generates sodium bisulphate and ammonia/ ammonium hydrogen salt as represented herein below which is difficult for its removal thereby making the process non feasible.
{Na(OSO2)}3 N + 3 H2O 3 NaHSO4 + NH3
It is yet a further objective of the present invention to provide a continuous process production which is suitable for a large-scale industrial manufacture of O-alkyl hydroxylamines and its salts by eliminating/ minimizing the risks associated with batch-to-batch variations associated with batch operations, and one method which is suitable for a large-scale industrial production of such compounds.
These and other objects and advantages of the present invention will become evident from the description which follows.
SUMMARY OF THE INVENTION:
Disclosed herein is a novel and innovative process which ensures control of the critical reaction parameters such as temperature and pH of the reaction mass, for synthesizing high purity O-alkyl hydroxylamine and the salts thereof in high yield while lending itself for facile transformation into a scalable continuous manufacturing process.
The present invention is to adopt the reactor geometry for all the three stages of process including the stages involving the formation of mono and di sodium hydroxylamine sulphonate salt as also the alkylation stage, wherein recycling a large amount of the reacted mass in a loop reactor with built-in mixing and heat removal / addition zones takes place.
This present invention discloses an efficient process that provides and enables easier control over the critical process parameters viz. temperature and pH of the reaction mass comprising effective mixing with a recycled stream of reacted material that results simultaneously in eliminating the local hotspots by distributing the heat of reaction mass over a larger mass and also maintaining the desired pH thereby avoiding the formation of side products thus resulting in improving both the high yield and high purity of the desired product.
The technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies of prior art. The method that is described in the present invention avoids yield loss from wastage of reactants through side reactions that produce impurities which are difficult-to-separate and / or avoids the formation of toxic substances such as oxides of nitrogen produced by the decomposition of sodium nitrite through a modified reactant state and a suitable choice of reactor geometry.
The present invention particularly relates to an improved process for the preparation of OMH and OMHH, the basic principles employed can be used for synthesis of O-alkyl hydroxylamine analogues and their salts by adopting suitable alkylating agents such as appropriate alkyl bromides instead of Dimethyl Sulphate referred to in the present invention for synthesizing OMH.
The present invention describes an improved process that affords superior control over the critical parameters like temperature and pH of the reaction mixture by incorporating use of aqueous solution of SO2 with tempered reactivity, effective, vigorous mixing that results in eliminating formation of local thermal hot spots as also of pockets of high acidity. This invention thus achieves rigid maintenance of the appropriate pH levels throughout the reaction mass thereby avoiding the formation of side products with resultant significant improvement in both yield and purity of the product.
Inventors of the present invention have made favorable and innovative changes in the design of the reactors that result in vigorous and efficient mixing thus minimizing the hot spot formation and maintaining the appropriate pH.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The invention will now be described in relation to the accompanying drawings, in which:
FIGURE 1 illustrates the reactor process design which facilitates this invention.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The preferred embodiments described herein detail for illustrative purposes only and are by no means limiting and can be further enhanced by many variations. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient but are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
Along with the main aspect of the invention as discussed below and above; all other aspects of the present invention are discussed herein after in detail via different embodiments.
Impurities discussed herein after or before once formed, are difficult to remove from desired product except through elaborate and expensive post synthesis operations.
CHARACERISTIC FEATURES OF THE PRESENT INVENTION:
• Modifying the design of the reactor as given herein below has played a vital role in controlling the critical process parameters like pH and the temperature thereby improving the quantity and quality of the desired product. FIGURE 1 illustrates the reactor process design which facilitates this invention.
• The reactor geometry adopted for both the process stages viz., mixing of sodium nitrite and sodium bisulphite and reacting aqueous solution of SO2 with the previously mixed nitrite-bisulphite solutions, comprising each instance, of insertion of fresh lot of reactants into a pre-cooled recycling a large stream of the reacted mass in a loop reactor with built-in mixing and heat removal / addition zones. Typically, the quantum of reacted mass recycled is about 50 to 100 times the amount of introduction of fresh input. The intense, rapid mixing of the recycled mass and fresh input is carried out in a dynamic inline mixer.
• This arrangement of a loop type reactor with a large recycle of reacted mass simultaneously permits the distribution of the generated heat during the exothermic reaction during mixing of the aqueous solutions of sodium nitrite and sodium bisulphite as well as due to the exothermic reaction between SO2 and the aqueous solution comprising sodium nitrite and sodium bisulphite or sodium acetate over a much larger mass (fresh input mass + 50-100 times fresh input mass from recycle = 51 – 101 times the fresh input mass) thus restricting the temperature rise, so detrimental to the reaction yields, to a minimum.
• Further, possibility of cooling the reacted mass exiting, the dynamic inline mixer in an external heat exchanger built in the loop and bleeding out a portion of the reacted mass equivalent to the fresh feed while returning the remaining substantial portion of the cooled reacted mass back to the dynamic inline mixer, its dominant mass providing, at once, both a pH buffer and a heat sink for the reaction of the fresh input reactants.
• Carrying out the synthesis in an environment of substantially stable and desirable pH and the temperature levels improve the Q2 i.e. quality and quantity.
• Use of suitable concentration aqueous solution of SO2 and vigorous mixing in process of the present invention allows a rigid control over the pH thereby minimizing the extent of side reaction to nitrilo tri sulphonic acid disodium salt (abbreviated as NTS, specie designated as IV in reaction scheme presented earlier), thereby increasing the yield and quality of the desired product.
• The suppression of generation of the undesirable by-product simultaneously results in better yields while reducing associated losses in working up due to less generation of undesirable and difficult-to-remove ammonia. The latter is difficult to remove due to its tendency to form an azeotrope with the desired free base product molecule viz. OMH.
• Reacting the pre-cooled aqueous mixture /solution comprising NaNO2 and NaHSO3 with aqueous solution of SO2 in requisite proportions in a substantially constant temperature level environment notwithstanding the exothermic nature of the reaction helps minimizing nitrite decomposition to a minimum allowing more conversion to specie III in the reaction scheme presented earlier.
• The large recycle of reacted mass acting as a “mass” buffer through quick and thorough dispersal of the introduced aqueous solution of SO2 thus maintaining a substantially uniform pH at the desirable level and allowing no pockets / zones of increased acidity.
• The use of high-speed dynamic inline mixer ensures that the mixing of the streams is sufficiently intense and uniform to prevent any “hot spots” and also any “high acidity pockets”. Such a rigidly controlled reaction environment in terms of two critical parameters viz. reaction temperature and reaction mass pH leads to good yields and considerably small quantity of troublesome ammonia impurity.
• Aqueous solution of SO2 with appropriate concentration instead of gaseous / liquefied SO2 allows a superior control over the temperature, due to a tempered concentration of this highly reactive specie.
• Since dissolution of SO2 in water is highly exothermic, the extraction of SO2 for reacting with the nitrite-bisulphite mixture through reaction mass is necessarily endothermic in nature. Thus, the use of this pre-cooled aqueous solution of SO2 instead of gaseous / liquid SO2 provides at once, a more dilute and tempered form of the reactive SO2 species along with attendant
? Easier and better pH control
? Accompanying water acting as adding to the dominant mass for heat distribution and pH stabilizing buffer
? Extraction and consumption of SO2 by reaction from its aqueous solution being endothermic, the reaction mass has a built-in heat sink which partially absorbs the exothermic heat of reaction, water thus acts as a diluent leading to a better control of pH even at micro level.
• A built-in heat sink allowing a much better control of the reaction mass minimizing the hot spot formation thereby avoiding rise in temperature avoiding formation of undesired impurities and enhancing the yields.
The inventors of the present inventors have observed that the generation of undesirable byproducts is strongly dependent on both unacceptable variations of temperature and pH outside a very narrow range, and if these two are not accurately controlled within the desired range, the irrevocable end result is an inferior quality and yield of the desired product.
Consequently, inventors of the present invention have made innovative and favorable changes by incorporating some beneficial modifications in the design of the reactors that ensures vigorous and efficient mixing of the reacting species thereby minimizing the hot spot formation and also controlling the pockets of undesirable low pH with consequent adherence to the desired narrow range of pH and temperature.
As mentioned earlier, the reactor geometry adopted for both the process stages involves recycling a large amount of the reacted mass in a loop reactor with built-in mixing and heat removal zones. Typically, the quantum of reacted mass recycled is about 50 to 100 times the amount of introduction of fresh input.
The process is further characterized by the distinguishing feature that by controlling the temperature of the reaction mass as desired thus preventing local high temperature significantly reduces the decomposition of sodium nitrite thereby avoiding or minimizing the formation of harmful nitrogen oxides (NOx.).These oxides are not only hazardous but also impact the yield further by reducing pH of the reaction mass.
Furthermore; maintenance of appropriate pH minimizes competitive side reactions thereby improving the yield and purity of the desired product.
Inventors of the present invention have thus provided a solution to the problems associated with the synthesis using conventional process by incorporating the modification in the reactors based on concept of the simple chemical engineering thereby ensuring maximum propagation of desired reaction while suppressing/avoiding/minimizing side reactions leading to impurities therebydelivering the desired product in high yield and high purity.
The use of conventional reactors with agitators is in most instances are not capable to deliver the required intense and micro-level mixing. The consequence of this is evident from the reported prior art literature where yields range upto 60-65% at the best without any mention of purity. The most desirable reaction parameters for best results are observed. In the present invention, the use of high-speed dynamic inline mixer ensures that the mixing of the streams is sufficiently intense and uniform to prevent any “hot spots” and also any “high acidity pockets “such as a rigidly controlled reaction environment in terms of two critical parameters viz. reaction temperature and pH of the reaction mass leads to good yields with improved impurity profile specifically considerably small quantity of troublesome and hard-to-eliminate ammonia impurity.
In view of the above observations, there is need for an improved process for the preparation of alkoxyamine and salts thereof which is free of above-mentioned drawbacks.
None of the prior art cited herein above teaches or motivates a skilled person in the art to consider modified process as disclosed herein for the preparation of alkoxy amine and salts thereof. This could be achieved by the inventors of the present invention by analyzing and understanding the issues responsible for poor yield and low purity product obtained based on prior art processes disclosed in the prior art. Inventors of present invention without any teaching or indication from the prior art based on exhaustive R&D efforts have been able to understand the shortcomings in the prior art process and have provided a solution by inventing an efficient process by incorporating the concept of quality by reactor design which not only ensures control over responsible reaction parameters viz temperature and pH but also provides a quality product and thereby making the said process novel and inventive as disclosed herein.
In accordance with one of the general embodiment, the present invention for the preparation of alkoxy amine and salts thereof of formula I discloses a process comprising contacting the pre-cooled mixed and reacted aqueous solutions of NaNO2 and NaHSO3(as shown in first stage as represented herein above) with aqueous solution of SO2 in requisite proportions The molar proportion of NaNO2 : NaHSO3 : SO2is 1 : 1.1 : 0.85 in a substantially constant temperature , wherein arrangement of a loop type reactor with a large recycle of reacted mass simultaneously permitting the distribution of the heat generated during the exothermic mixing and reaction between the aqueous solutions of sodium nitrite and sodium bisulphite as well as due to the exothermic reaction between SO2 and the said reacted aqueous solution comprising sodium nitrite and sodium bisulphite or sodium acetate over a very large mass thus restricting the temperature rise and pH thereby restricting the formation of undesirable by product of the reaction. Next stage comprises alkylation of the compound of formula III using dialkyl sulphate in presence of an alkali at a temperature ~ 600C preferably and pH 7 – 9.5thereby resulting in the desired product “as a base” of formula I followed by its conversion into salts of formula I.
Reaction

In accordance with one of the general embodiment, in the present invention for the preparation of alkoxy amine and salts thereof of formula I comprises reacting the pre-cooled aqueous mixture /solution comprising alkali metal nitrite and alkali metal bisulphite(as shown in first stage as represented herein below ) with aqueous solution of SO2 in requisite proportions (as shown in second stage as represented earlier) in a substantially constant temperature+ pH environment mentioned above through the arrangement of a loop type reactor with a large recycle of reacted mass simultaneously permitting the distribution of the heat generated during the exothermic mixing of the aqueous solutions of alkali metal nitrite and alkali metal bisulphite as well as due to the exothermic reaction between SO2 and the aqueous mixture/ solution comprising alkali metal nitrite and alkali metal apart from the large recycle also acting as a pH buffer restricting variation of pH to any significant degree. The next stage comprises alkylation(methylation) of the compound of formula III using alkylating agent (dimethyl sulphate) in presence of sodium hydroxide at a temperature about (55 – 60 0 C) and pH ( 7.0 to 9.5) thereby resulting in generation of the desired product “as a base”of formula I followed by its conversion into corresponding salt thereof of formula I.

In accordance with one of the specific embodiment, in the present invention for the preparation of methoxy amine and salts thereof of formula IA comprising reacting the pre-cooled aqueous mixture /solution comprising NaNO2 and NaHSO3(as shown in first stage as represented herein above) with aqueous solution of SO2 in requisite proportions (as shown in second stageas represented herein below) in a substantially constant temperature and pH environment, in a loop type reactor arrangement with a large recycle of reacted mass simultaneously permitting the distribution of the heat generated during the exothermic mixing of the aqueous solutions of sodium nitrite and sodium bisulphite as well as due to the exothermic reaction between SO2 and the aqueous mixture/ solution comprising sodium nitrite and sodium bisulphite or sodium acetate over a very large mass thus restricting the temperature rise thereby restricting the formation of undesirable by product of the reaction. This loop reactor arrangement also ensures that the pH of the reaction mass stays substantially unchanged, the massive recycle steam acting as a “mass” buffering agent. The next stage comprises methylation of the compound of formula III using dimethyl sulphate in presence of sodium hydroxide at a temperature (50 - 600 C) and pH of 7.0 to 9.5 thereby resulting in the production of the desired product“as a base” of formula IA followed by its conversion into salt thereof of formula IA.

The present invention can be best understood from the following examples.
1] Example no-1
Aqueous sodium bisulphite 35% solution and Aqueous sodium nitrite 20% solution are fed simultaneously in loop 1 (wherein there is already reacted mass loaded) in such a way so that temperature of = 40 C remains maintained with continuous feeding of sulfur dioxide aqueous solution of 9.2% strength in loop 2 maintaining pH of solution at 3.5 to 4.2. The said pH if needed is maintained by using aq. Solution of NaOH.The sampling was carried out to determine the formation of disulfonate salt. The formation of disulfonate salt after steady state to the extent of 85% of solution was observed with unreacted nitrite ions. The disulfonate salt was then methylated using dimethyl sulphate at a temperature of 50-600 C and pH of 6.5 to 8.0. The methylation reaction is observed to go to 80% completion. After hydrolysis and distillation, the methoxyamine was obtained in 72% yield with 98.2% purity. Base thus obtained is converted into its hydrochloride salt.