Description:FIELD OF THE INVENTION
The present invention relates to a process for safe and selective hydrogenation of nitriles into primary amines. More specifically, the present invention relates to a continuous flow process for the preparation of primary amines through selective catalytic hydrogenation of nitriles in the presence of a polymer encapsulated transition metal catalyst.

BACKGROUND OF THE INVENTION
Amines are general intermediates and precursors in the preparation of a varied range of products, including natural products, dyes, surfactants, pharmaceuticals, agrochemicals, pigments, polymers, catalysts etc. Among all the amines, primary amines are the most valuable intermediates because of their straightforward functionalization, such as the further derivatization reaction to obtain substituted secondary or tertiary amines.

It is generally known that the catalytic hydrogenation of nitriles in the presence of transition metal catalysts like nickel, platinum, palladium, etc. to produce primary amines is an atom-economical and reliable method. However, the conversion is highly complicated because multiple reactions occur simultaneously, resulting in the formation of undesirable side products that necessitate time-consuming post-synthesis isolation and purification work-up, increasing the cost and duration of the synthesis.

US20050148784A1 describes a process for the preparation of optically active 2-[6-(substituted alkyl)-1,3-dioxane-4-yl]acetic acid derivatives. More particularly, Examples 1-7 of the said document describe a batch process for the preparation of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate starting from (S)-tert-butyl-3,4-epoxybutanoate. The process involves conversion of an intermediate (4R-cis)-1,1-dimethylethyl 6-cyanomethyl 2,2-dimethyl-1,3-dioxane 4-acetate to (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate using Raney Nickel catalyst in the presence of methanol saturated with anhydrous ammonium at a temperature of 40°C and pressure under 3.5 kg/cm2. The said conversion takes 20 hours to complete with a yield of 92%. Moreover, after the conversion, the catalyst needs to be separated by filtration, and the concentrated crude product obtained in the process is subjected to column chromatography to obtain a pure product.

US6452056 describes a batch process for the preparation of fluorine-containing benzylamine derivatives from fluorine-containing benzonitrile derivatives. The process involves a reduction step, wherein a fluorine-containing benzonitrile derivative is converted into a fluorine-containing benzylamine derivative in the presence of a reducing agent consisting essentially of hydrogen in the presence of a Raney nickel catalyst or Raney cobalt catalyst in a non-polar solvent. In particular, Example 1 of the said document describes a batch process for conversion of 2,6-difluorobenzonitrile into 2,6-difluorobenzylamine in the presence of an inflammable solvent, i.e., hexane, and the catalyst at a high temperature of 130°C and a high pressure of 30-40 Kg/cm2. The process requires separation of the catalyst by filtration and distillation under reduced pressure to obtain 2,6-difluorobenzylamine with a yield of 94.6% and purity of 99.2%.

US6649799B2 describes a continuous flow process for the preparation of amines through catalytic hydrogenation of nitriles in the presence of Raney nickel catalyst in the form of hollow bodies of a diameter in the range of 50-20000 microns, which has reduced bulk density. The said document emphasizes choosing the right solvent to achieve the selectivity of the hydrogenation reaction.

CN104803856A describes a process for the synthesis of benzylamine through continuous catalytic hydrogenation of cyano-benzene in the presence of skeletal nickel catalyst, alcohol or ether solvent at a temperature in the range of 80 to 200°C and pressure range of 21 to 81 Kg/m2. In particular, Example 1 describes the conversion of cyano-benzene as only 95.2% and the selectivity of benzylamine as only 96.6%, wherein the conversion has been carried out at a temperature of 160°C, pressure of 6 MPa, and LHSV of 0.6 h -1. The conversion is further reduced to 45.2% and selectivity is reduced to 81.2% when the reaction occurs at a temperature of 80°C while keeping other reaction parameters constant. The said document provides no information about the recyclability or life span of the skeletal nickel catalyst.

This necessitates a careful evaluation of the catalyst system, solvent, operating conditions, and type of reactor used during the process. Most of the known processes for catalytic hydrogenation of nitriles to obtain primary amines in the presence of homogeneous and heterogeneous catalysts have been carried out in batch systems, except gaseous reactions.

Continuous-flow systems have several advantages over batch systems in terms of environmental compatibility, efficiency, and safety. High productivity and saving of energy and space can be attained by using flow systems, and it is possible to adjust the quantity of production by controlling the rate of introduction of starting materials (“just-in-time” production). Furthermore, the separation of catalysts from products is not required when columns packed with suitable heterogeneous catalysts are used.

However, commonly used catalysts for the hydrogenation of nitriles like Raney nickel, palladium, and carbon-based catalysts are well-suited for batch systems only. The small particle size of these catalysts renders them unsuitable for use in column-packed configurations required for continuous-flow systems. Further, metal leaching, low selectivity and pyrophoric nature also limit the application of these catalysts in continuous-flow systems.

Keeping in view of the abovementioned disadvantages associated with the prior art, it is highly desirable to develop an improved continuous-flow catalytic hydrogenation process for the preparation of primary amines from nitriles which can obviate the problems associated with the prior art in terms of selectivity, simplicity, economy, safety, and yield.

OBJECTIVES OF THE INVENTION
It is the primary object of the present invention to provide an improved continuous flow process for the preparation of primary amines through selective catalytic hydrogenation of nitriles.

It is another object of the present invention to provide a process for the preparation of primary amines through catalytic hydrogenation of nitriles, wherein the process has high selectivity for primary amines and enables the complete conversion of a nitrile into a primary amine.

It is another object of the present invention to provide a simple, safe, economic, and eco-friendly process for the preparation of primary amines from nitriles.

It is another object of the present invention to provide a process for the preparation of primary amines through catalytic hydrogenation of nitriles wherein the process conditions like temperature and pressure are milder.

It is another object of the present invention to provide a process for the preparation of primary amines wherein the catalyst used in the process is recyclable and usable multiple times without losing its catalytic activity.

It is another object of the present invention to provide a process for the preparation of primary amines through hydrogenation of nitriles in presence of catalyst which has low metal leaching.

It is another object of the present invention to provide a process for the preparation of primary amines through catalytic hydrogenation of nitriles wherein the downstream processing is simplified.
SUMMARY OF THE INVENTION
This summary is provided to introduce a selection of concepts in a simplified format that are further described in the detailed description of the invention.

In a first aspect of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), comprising the following steps:
(a) mixing a stream containing the nitrile (II) and a stream containing solution of an organic polar solvent and a base to obtain a diluted stream of nitrile (II);
(b) subjecting the diluted stream of nitrile (II) to catalytic hydrogenation in presence of a polymer encapsulated transition metal catalyst at a temperature in a range of 40 ? to 200 ? and at a pressure in a range of 3 bar (300000 pascals) to 20 bar (2000000 pascals) to obtain a reaction mixture;
(c) continuously distilling the reaction mixture to obtain the primary amine (I); and
(d) recycling the organic polar solvent without any purification step.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the primary amine (I) is represented by the structural formula (I):
RCH2NH2 (I),
wherein “R” is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkynyl, heterocycloalkyl, and heterocycloalkenyl.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the nitrile (II) is represented by the structural formula (II):
RCN (II),
wherein “R” is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkynyl, heterocycloalkyl, and heterocycloalkenyl.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the diluted stream of nitrile (II) comprises 14% w/w to 20% w/w of nitrile (II).

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the organic polar solvent is selected from C1 to C4 aliphatic alcohols.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the base is ammonia (NH3).

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the solution of the organic polar solvent is an ammoniacal organic polar solvent comprising 1.5% w/w to 12% w/w of ammonia, and wherein 80% w/w to 86% w/w of the ammoniacal organic polar solvent is mixed with the nitrile (II) to obtain the diluted stream of nitrile (II).

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the catalytic hydrogenation is carried out at a residence time in a range of 60 minutes to 180 minutes, a flow rate of the diluted stream of nitrile (II) in a range of 1.8 ml/min to 2.5 ml/min, reaction temperature in a range of 40 ? to 150 ?, and a flow rate of hydrogen gas in a range of 180 ml/min to 220 ml/min.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the assembly of catalyst beds is selected from moving bed assembly, fixed bed assembly, fluidized bed assembly and a combination thereof.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the conversion % of nitrile (II) to primary amine (I) is about 100 %.

In an embodiment of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), wherein the process has selectivity in the range of 88% to 99% towards the primary amine (I).

BRIEF DESCRIPTION OF THE DRAWING
To further clarify advantages and aspects of the disclosure, a more particular description of the present disclosed process will be rendered by reference to specific embodiments thereof, which is illustrated in the appended drawing(s) and explained hereinafter in the description section. It is appreciated that the drawings provided herein depict only typical embodiments of the process and are therefore not to be considered limiting in its scope.
Figure 1: illustrates a system configuration for the preparation of primary amine (I) through selective catalytic hydrogenation of nitrile (II) using the process provided herein.

DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will be aware that the process provided herein is subject to variations and modifications other than those specifically described. It is to be understood that the process provided herein includes all such variations and modifications. The process provided herein also includes all such steps of the process, features of the system, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such steps or features.

The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred method, and materials are now described.

The process provided herein is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.

In one aspect of the present disclosure, there is provided a continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), comprising the following steps:
(a) mixing a stream containing the nitrile (II) and a stream containing solution of an organic polar solvent and a base to obtain a diluted stream of nitrile (II);
(b) subjecting the diluted stream of nitrile (II) to catalytic hydrogenation in presence of a polymer encapsulated transition metal catalyst at a temperature in a range of 40 ? to 200 ? and at a pressure in a range of 3 bar (300000 pascal) to 20 bar (2000000 pascal) to obtain a reaction mixture;
(c) continuously distilling the reaction mixture to obtain the primary amine (I); and
(d) recycling the organic polar solvent without any purification step.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) from nitrile (II), wherein, the term primary amine (I) denotes an amine represented by the structural formula (I):
RCH2NH2 (I)
wherein “R” is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkynyl, heterocycloalkyl, and heterocycloalkenyl.

In one of the embodiments, the primary amine (I) is selected from amines in which the “R” is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heterocycloalkenyl, wherein the substituent in the substituted “R” is selected from halogen, hydroxyl, cyano, nitro, amino, carbamoyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, and a combination thereof.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) from nitrile (II), wherein the term nitrile (II) denotes a nitrile represented by the structural formula (II):
RCN (II)
wherein “R” is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkynyl, heterocycloalkyl, and heterocycloalkenyl.

In one of the embodiments, the nitrile (II) is selected from nitriles in which the “R” is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heterocycloalkenyl, wherein the substituent in the substituted “R” is selected from halogen, hydroxyl, cyano, nitro, amino, carbamoyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, and a combination thereof.

In one of the embodiments, nitrile (II) is selected from the nitriles, wherein the “R” is a substituted or unsubstituted alkyl group.

In another embodiment, nitrile (II) is selected from the nitriles, wherein the “R” is an alkyl group substituted with a group selected from cycloalkenyl and heterocycloalkyl.

In another embodiment, nitrile (II) is selected from the nitriles, wherein the “R” is a substituted or unsubstituted aryl group.

In another embodiment, nitrile (II) is selected from the nitriles, wherein the “R” is an aryl group substituted with one or more halogens.

In another embodiment, the nitrile (II) is selected from cyclohexenylacetonitrile, 2,4,6-trifluorobenzonitrile, 2,4-dichlorobenzonitrile, 2,4-difluorobenzonitrile, and tert-butyl (4r,6r)-6-cyanomethyl-2,2-dimethyl-1,3 dioxane-4-acetate.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein the process involves dilution of nitrile (II) with an organic polar solvent in the presence of a base before subjecting it to catalytic hydrogenation.
In one of the embodiments, the dilution of nitrile (II) is carried out by mixing 14 % w/w to 20% w/w of the nitrile (II) with an organic polar solvent in presence of a base.

In one of the embodiments, the diluted stream of nitrile (II) comprises 14% w/w to 25 % w/w of the organic polar solvent.

In one of the preferred embodiments, the organic polar solvent is an ammoniacal organic polar solvent and comprises 1.5% w/w to 12% w/w of ammonia.

In one of the embodiments, the dilution of nitrile (II) stream is carried out by mixing around 80% w/w to 86% w/w of ammoniacal organic polar solvent.

In one of the preferred embodiments, the organic polar solvent is a linear or branched C1 to C4 aliphatic alcohol selected from methanol, ethanol, n-propanol, iso-propanol, and 1-butanol.

In the most preferred embodiments, the organic polar solvent is methanol.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through hydrogenation of nitrile (II) in presence of a polymer encapsulated transition metal catalyst, wherein the term “polymer encapsulated transition metal catalyst” denotes a catalyst system comprising a transition metal encapsulated inside a polymer microcapsule.

In one of the embodiments, the polymer encapsulated transition metal catalyst comprises a transition metal selected from a group comprising platinum, palladium, osmium, ruthenium, rhodium, iridium, rhenium, scandium, cerium, samarium, yttrium, ytterbium, lutetium, cobalt, titanium, chromium, copper, iron, nickel, manganese, tin, mercury, silver, gold, and zinc.

In one of the preferred embodiments, the polymer encapsulated transition metal catalyst comprises a transition metal selected from the group comprising platinum, palladium, and nickel.

In the most preferred embodiments, the polymer encapsulated transition metal catalyst comprises nickel as transition metal.

The polymer encapsulated transition metal catalyst used in the process disclosed herein is prepared by the process defined in US9399211 as granted on July 26, 2016.

In one of the embodiments, the polymer encapsulated transition metal catalyst used in the process disclosed herein is prepared by an interfacial polymerization followed by free radical polymerization.

In one of the embodiments, the preparation of polymer encapsulated transition metal catalyst used in the process disclosed herein involves formation of a microcapsule of a ligand around the transition metal followed by free radical polymerization of the ligand in the microcapsule to obtain the polymer encapsulated transition metal catalyst.

In one of the embodiments, the polymer encapsulated transition metal catalyst used in the process disclosed herein is prepared using a ligand represented by the structural formula (III):
PR1R2R3 (III)
where R1, R2, and R3 are each independently an optionally substituted hydrocarbyl group, an optionally substituted hydrocarbyloxy group, or an optionally substituted heterocyclyl group or one or more of R1 and R2, R1 and R3, R2 and R3 optionally being linked in such a way as to form an optionally substituted ring(s); and at least one of R1, R2, and R3 comprises a group polymerizable by free radical polymerization.

In one of the embodiments, the polymer encapsulated transition metal catalyst used in the process disclosed herein is prepared using interfacial polymerization involving condensation of polyisocyanates, tolylene diisocyanates, and a combination thereof.

In one of the embodiments, the polyisocyanates and tolylene diisocyanates used in the preparation of polymer encapsulated transition metal catalyst used in the process disclosed herein are selected from 1-chloro-2,4-phenylene diisocyanate, m-phenylene diisocyanate, p-phenylene diisocyanate, 4,4'-methylenebis(phenyl isocyanate), 2,4-tolylene diisocyanate, tolylene diisocyanate, 2,6-tolylene diisocyanate, 3,3'-dimethyl-4,4'-biphenylene diisocyanate, 4,4'-methylenebis (2-methylphenyl isocyanate), 3,3'-dimethoxy-4,4'-biphenylene diisocyanate, 2,2',5,5'-tetramethyl-4,4'-biphenylene diisocyanate, tolylene diisocyanate, polymethylene polyphenylisocyanate (PMPPI), 1,6-hexamethylene diisocyanate, isophorone diisocyanate, tetramethylxylene diisocyanate, and 1,5-naphthylene diisocyanate.

In one of the embodiments, the polymer encapsulated transition metal catalyst used in the process disclosed herein is in the form of porous beads having average bead size in a range of 60 to 400 microns and metal loading in a range of 21 w/w % to 30 w/w %.

The bead size of polymer encapsulated transition metal catalyst used in the process disclosed herein is favorable for use in a continuous flow process. Use of polymer encapsulated transition metal catalyst with favorable bead size in the process disclosed herein is an advantageous technical feature since commonly used catalysts for hydrogenation of nitriles like Raney nickel, palladium, etc. are well-suited for batch systems only. The small particle size of these catalysts renders them unsuitable for use in column packed configuration required for continuous-flow systems.

The polymer encapsulated transition metal catalyst used in the process disclosed herein is non-pyrophoric in nature rendering the process provided herein safe and non-hazardous. This property of the catalyst used in the process disclosed herein also reduces equipment cost as sophisticated equipment and infrastructure to handle pyrophoric reagents are not required.

The polymer encapsulated transition metal catalyst used in the process disclosed herein is recyclable and usable multiple times without losing its catalytic activity. The leaching of transition metal in the polymer encapsulated transition metal catalyst used in the process disclosed herein is also significantly reduced due to encapsulation inside a polymer shell leading to longer life span of the catalyst.

The beads of polymer encapsulated transition metal catalyst used in the process disclosed herein are highly cross-linked and do not swell significantly in organic solvents which is advantageous for use in the continuous flow process provided herein.

The polymer encapsulated transition metal catalyst used in the process disclosed herein has high selectivity towards primary amines. This leads to reduced undesirable side products leading to enhanced conversion efficiency and yield. It also leads to significant reduction in tedious post-synthesis isolation and purification work-up.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II) in presence of a polymer encapsulated transition metal catalyst inside a continuous flow reactor, wherein the polymer encapsulated transition metal catalyst is packed in multiple catalyst beds forming an assembly of catalyst beds.

The assembly of catalyst beds may have various configurations depending upon the reaction medium, position, movement etc.

In one of the embodiments, the assembly of catalyst beds is selected from a moving bed assembly, a fixed bed assembly, a fluidized bed assembly and a combination thereof.

In one of the embodiments, the process disclosed herein utilizes 35 grams to 250 grams of polymer encapsulated transition metal catalyst in the preparation of 500 grams to 5000 grams of amine (I) from 500 grams to 5000 grams of nitrile (II).

In one of the embodiments, the process disclosed herein involves mixing of nitrile (II) and organic polar solvent containing base inside the feed vessel and pumping the diluted stream of nitrile (II) through the assembly of catalyst beds inside the continuous flow reactor (T1, T2), along with hydrogen gas. The nitrile (II) gets converted into respected primary amine (I) in the continuous flow reactor and collected at the receiver end (R). Finally, the crude primary amine (I) is distilled, or solvent is removed to obtain the pure primary amine (I) and hydrogen gas is recycled into the continuous flow reactor. The polar organic solvent is recovered and recycled to the feed vessel.

The process disclosed herein takes place inside a continuous flow reactor. The continuous flow reactor has arrangements to maintain continuous supply of hydrogen gas and diluted stream of nitrile (II) as feed to facilitate continuous catalytic hydrogenation of nitrile (II). Temperature, pressure, and concentration of diluted stream of nitrile (II) are crucial for product quality, conversion efficiency, and selectivity. The process provided herein involves catalytic hydrogenation of nitrile (II) into primary amine (I) at milder process conditions.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein a stream of nitrile (II) diluted with organic solvent in presence of a base is subjected to catalytic hydrogenation in presence of a polymer encapsulated transition metal catalyst at a temperature in a range of 40 ? to 200 ? and at a pressure in a range of 3 bar (300000 pascal) to 20 bar (2000000 pascal) to obtain a reaction mixture which is further subjected to distillation to obtain the primary amine (I).

In one of the embodiments, the temperature during catalytic hydrogenation is in the range of 40 ? to 150 ?.

In one of the embodiments, the temperature during catalytic hydrogenation is in the range of 50 ? to 70 ?.

In one of the embodiments, the catalytic hydrogenation of nitrile (II) occurs at a pressure in the range of 3 bar (300000 pascal) to 4 bar (400000 pascal).

In one of the embodiments, catalytic hydrogenation of nitrile (II) occurs at a pressure in the range of 4 bar (400000 pascal) to 10 bar (1000000 pascal).

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein the catalytic hydrogenation of nitrile (II) is carried out at a residence time in a range of 60 minutes to 180 minutes, a flow rate of the diluted stream of nitrile (II) in a range of 1.8 ml/min to 2.5 ml/min, reaction temperature in a range of 40 ? to 150 ?, and a flow rate of hydrogen gas in a range of 180 ml/min to 220 ml/min.

In one of the embodiments, the catalytic hydrogenation of nitrile (II) occurs at a residence time in the range of 30 minutes to 240 minutes.

In another embodiment, the catalytic hydrogenation of nitrile (II) occurs at a residence time in the range of 120 minutes to 160 minutes.

In one of the preferred embodiments, the catalytic hydrogenation of nitrile (II) occurs at a residence time in the range of 60 minutes to 180 minutes.

In another aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein the organic polar solvent present in the reaction mixture at the end of the process is distilled and recycled to the feed vessel to mix with nitrile (II) stream.

In an advantageous aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein the process enables conversion of nitrile (II) into primary amine (I) with 100 % conversion efficiency.

In another advantageous aspect of the present disclosure, there is provided a process for preparation of primary amine (I) through catalytic hydrogenation of nitrile (II), wherein the selectivity of the process towards primary amine is in the range of 88% to 99 %.

In one of the embodiments, the selectivity of the process towards the primary amine (I) is in a range of 90 % to 99 %.

In another embodiment, the selectivity of the process towards the primary amine (I) is in a range of 95 % to 99 %.

The present disclosure provides an improved continuous flow process for the preparation of primary amines through selective catalytic hydrogenation of nitriles, wherein the process has high selectivity for primary amines and enables the complete conversion of a nitrile into a primary amine at milder reaction conditions.

EXAMPLES
Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.

Example-1: Preparation of (4R, Cis)-1,1-dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-Acetate

A feedstream for catalytic hydrogenation is prepared by mixing 14% w/w solution of tert-butyl (4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate and 86% w/w of 1.5% w/w to 2% w/w ammoniacal methanol solution. The feedstream is then fed into a continuous flow fixed bed reactor containing polymer encapsulated nickel catalyst beds in continuous supply of hydrogen gas. Catalytic hydrogenation of the feedstream is carried out at a temperature range of 55 °C to 60 °C and at a pressure range of 4 bar to 7 bar to obtain (4R, Cis)-1,1-dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-acetate with 100% conversion efficiency and 99% selectivity. Methanol is then removed by distillation to get the pure product. The recovered methanol is then recycled and reused.

Example-2: Preparation of 2,4-diflurobenzylamine

A feedstream for catalytic hydrogenation is prepared by mixing 17% w/w solution of 2,4-difluorobenzonitrile and 83% w/w of 1.5% w/w to 2% w/w ammoniacal methanol solution. The feedstream is then fed into a continuous flow fixed bed reactor containing polymer encapsulated nickel catalyst beds in continuous supply of hydrogen gas. Catalytic hydrogenation of the feedstream is carried out at a temperature range of 50 °C to 55 °C and at a pressure range of 4 bar to 7 bar to obtain 2,4-Diflurobenzylamine with 100% conversion efficiency and 96%-98% selectivity. Methanol is then removed by distillation to get the pure product. The recovered methanol is then recycled and reused.

Example-3: Preparation of 2, 4-dichlorophenylethyl amine

A feedstream for catalytic hydrogenation is prepared by mixing 17% w/w solution of 2,4-dichlorobenzonitrile and 83% w/w of 1.5% w/w to 2% w/w ammoniacal methanol solution. The feedstream is then fed into a continuous flow fixed bed reactor containing polymer encapsulated nickel catalyst beds in continuous supply of hydrogen gas. The catalytic hydrogenation of the feedstream is carried out at a temperature range of 65 °C to 70 °C and at a pressure range of 7 bar to 10 bar to obtain 2, 4-Dichlorobenzylamine with 100% conversion efficiency and 95%-97% selectivity. Methanol is then removed by distillation to get the pure product. The recovered methanol is then recycled and reused.

Example-4: Preparation of 2,4,6-trifluorobenzyl amine.

A feedstream for catalytic hydrogenation is prepared by mixing 17% w/w solution of 2,4,6-trifluorobenzonitrile and 83% w/w of 1.5% w/w to 2% w/w ammoniacal methanol solution. The feedstream is then fed into a continuous flow fixed bed reactor containing polymer encapsulated nickel catalyst beds in continuous supply of hydrogen gas. The catalytic hydrogenation of the feedstream is carried out at a temperature range of 40 °C to 45 °C and at a pressure range of 3 bar to 4 bar to obtain 2,4,6-trifluorobenzylamine with 100% conversion efficiency and 88%-90% selectivity. Methanol is then removed by distillation to get the pure product. The recovered methanol is then recycled and reused.

Example-5: Preparation of 2-(1-Cyclohexynyl)ethylamine

A feedstream for catalytic hydrogenation is prepared by mixing 15% w/w solution of cyclohexenylacetonitrile and 85% w/w of 10% w/w to 12% w/w ammoniacal methanol solution. The feedstream is then fed into a continuous flow fixed bed reactor containing polymer encapsulated nickel catalyst beds in continuous supply of hydrogen gas. The catalytic hydrogenation of the feedstream is carried out at a temperature of 80 °C and at a pressure of 10 bar to obtain 2-(1-Cyclohexynyl) ethylamine with 100% conversion efficiency and 90%-92% selectivity. Methanol is then removed by distillation to get the pure product. The recovered methanol is then recycled and reused.

Example 6: Preparation of 2,4-diflurobenzylamine using batch process
2,4 Diflurobenzylamine is prepared through catalytic hydrogenation of 2,4-difluorobenzonitrile in 2% w/w ammoniacal methanol using Raney Ni catalyst in a batch process. The conversion is complete with 85% selectivity towards 2,4 Diflurobenzylamine. Undesirable impurities obtained with the product required tedious purification procedures to obtain pure 2,4 Diflurobenzylamine. Example 2 above provides 2,4 Diflurobenzylamine from 2,4-difluorobenzonitrile with 98% selectivity.

The above findings reveal that the present disclosure provides an improved continuous flow process for the preparation of primary amines through selective catalytic hydrogenation of nitriles, wherein the process has high selectivity for primary amines and enables the complete conversion of a nitrile into a primary amine at milder process conditions.

It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained, and since certain changes may be made in the constructions set forth without departing from the spirit and scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense. The invention has been described with reference to preferred and alternate embodiments. Modifications and alterations will become apparent to those skilled in the art upon reading and understanding the detailed discussion of the invention provided herein. This invention is intended to include all such modifications and alterations insofar as they come within the scope of the present invention. These and other modifications of the preferred embodiments as well as other embodiments of the invention will be obvious from the disclosure herein, whereby the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

Finally, to the extent necessary to understand or complete the disclosure of the present invention, all publications, patents, and patent applications mentioned herein are expressly incorporated by reference therein to the same extent as though each were individually so incorporated. , Claims:We claim:

1. A continuous process for the preparation of a primary amine (I) through selective hydrogenation of a nitrile (II), comprising the following steps:
(a) mixing a stream containing the nitrile (II) and a stream containing a solution of an organic polar solvent and a base to obtain a diluted stream of nitrile (II);
(b) subjecting the diluted stream of nitrile (II) to catalytic hydrogenation in presence of a polymer encapsulated transition metal catalyst at a temperature in a range of 40? to 200? and at a pressure in a range of 3 bar to 20 bar to obtain a reaction mixture;
(c) continuously distilling the reaction mixture to obtain the primary amine (I); and
(d) recycling the organic polar solvent without any purification step.

2. The process as claimed in claim 1, wherein the primary amine (I) is represented by the structural formula (I):
RCH2NH2 (I)

and the nitrile (II) is represented by the structural formula (II):
RCN (II),
wherein “R” in the primary amine (I) and the nitrile (II) is selected from the group comprising of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkynyl, heterocycloalkyl, and heterocycloalkenyl.

3. The process as claimed in claim 1, wherein the diluted stream of nitrile (II) comprises 14 w/w % to 20 w/w % of nitrile (II).

4. The process as claimed in claim 1, wherein the organic polar solvent is selected from the group comprising of C1 to C4 aliphatic alcohols or a mixture thereof.

5. The process as claimed in claim 1, wherein the solution of the organic polar solvent in presence of the base is an ammoniacal organic polar solvent comprising 1.5 w/w % to 12 w/w % of ammonia, and wherein 80 w/w % to 86 w/w of the ammoniacal organic polar solvent is mixed with the nitrile (II) to obtain the diluted stream of nitrile (II).

6. The process as claimed in claim 1, wherein the catalytic hydrogenation is carried out at a residence time in a range of 60 minutes to 180 minutes, a flow rate of the diluted stream of nitrile (II) in a range of 1.8 ml/min to 2.5 ml/min, reaction temperature in a range of 40 ? to 150 ?, and a flow rate of hydrogen gas in a range of 180 ml/min to 220 ml/min.

7. The process as claimed in claim 1, wherein the polymer encapsulated transition metal catalyst is embedded in an assembly of catalyst beds, wherein the assembly of catalyst beds has a configuration selected from the group comprising of moving bed assembly, fixed bed assembly, fluidized bed assembly, and a combination thereof.

8. The process as claimed in claim 1, wherein the process has 100 % conversion efficiency for nitrile (II) to primary amine (I) conversion.

9. The process as claimed in claim 1, wherein the process has selectivity in the range of 88% to 99 % towards the primary amine (I).
Dated this the 25th day of July, 2023