A sustainable chemical process for reduction of nitro or nitroso compounds into corresponding amino compounds

Abstract

The invention relates to the field of effective and economical conversion of nitro or nitroso compounds in to corresponding amines. More it discloses a reduction processes of nitro or nitroso compounds to corresponding amino compounds, which exhibit differential solubility, exemplified & not restricted to the processes discussed for m-aminoacetophenone, the intermediate of Phenylephrine, ethyl3- [[4-(methylamino)-3-aminobenzoyl](pyridin2yl)amino]propanoate the intermediate of Dabigatran, and 2,4-Difluoroaniline the intermediate of Pantoprazole. Even more particularly, the invention relates to a process involving use of minimal quantity of water or quantity of water required only as the source of hydrogen for generation of sufficient reduction potential to perform the chemical reaction. The process offers a. safer, cost competitive and greener alternative to the conventional process of reduction. A key benefit of the invention is that it avoids side product / s & / or impurity / s resulting from usage of large quantity of water especially when other sensitive / reactive groups are present in the molecule.

Description

[0001] A SUSTAINABLE CHEMICAL PROCESS FOR REDUCTION OF NITRO OR NITROSO COMPOUNDS INTO CORRESPONDING AMINO COMPOUNDS

[0002] Field of Invention:

[0003] The invention relates to the field of effective and economical conversion of nitro or nitroso compounds in to corresponding amines. More particularly the invention relates to reduction processes of nitro or nitroso compounds to corresponding amino compounds, which exhibit differential solubility, exemplified & not restricted to the processes discussed for m-aminoacetophenone, the intermediate of Phenylephrine, ethyl3-[[4-(methylamino)-3- aminobenzoyl](pyridin2yl)amino]propanoate the intermediate of Dabigatran, and 2,4-Difluoroaniline the intermediate of Pantoprazole. Even more particularly, the invention relates to a process involving use of minimal quantity of water or quantity of water required only as the source of hydrogen for generation of sufficient reduction potential to perform the chemical reaction.

[0004] Background of Invention:

[0005] Reduction, classically defined as addition of hydrogen atom / s or removal of oxygen atom / s from any chemical, is one of the important chemical processes extensively applied in the manufacture of many molecules which are important building blocks. Partial or complete reduction of functional groups such as nitro or nitroso, carbonyls, azides, nitriles, azo, and the like yields value added products.

[0006] Reduction of R-NO2 / R-NO compounds into corresponding R-NH2 finds applications in various groups of chemical including pharmaceuticals, dyes and pigments, agrochemicals, specialty chemicals, fine chemicals and explosives. Many pharmaceutical & active pharmaceutical ingredients henceforth called as API, dyes, specialty fine chemicals have R-NH2 as one of the building blocks. In most of the processes this important building block is obtained from the reduction of R-NO2 / R-NO precursor.

[0007] Methods used for reduction of R-N02 / R-N0 into corresponding R-NH2 can be broadly divided into three major categories: (a) chemical reduction (b) catalytic reduction, (c) electrochemical reduction.

[0008] International patent application WO2011 / 048535 Al (2011), US2012 / 0203031 Al (2012), discloses reduction of nitro or nitroso compounds having carboxylic acid or sulphonic acid groups into corresponding amino compounds. The major disadvantage of this patent application is, it is restricted to nitro or nitroso compounds having sulphonic and carboxylic groups only.

[0009] Indian Patent 242146 (2006), discloses the process for reduction of nitro or nitroso compounds using water as a reaction medium at all stages of the process with very high-water factors; the disadvantage being low solubility of organic nitro or nitroso compounds as well as amino compounds in water.

[0010] The catalytic reduction process is one of the widely used processes in the industry where gaseous hydrogen, as hydrogen donor, is used for reduction process along with precious metal catalyst, where precious metal catalyst ensures high conversions. However, this method has major disadvantages. The first disadvantage of catalytic reduction process is that normally it takes place at high pressure of hydrogen and at high temperature, to maintain high reduction potential so as to ensure the complete conversion. However, such high pressure and high temperature reactions at industrial scale need special design of reactor, hydrogen handling systems, etc. Thus, the process lacks inherent safety. The second disadvantage of this process is that during reaction water is generated as a by-product leading to micro / nano level water flooding at the reaction site. Thus, at the nano level site, the reaction conditions are not conducive for selectivity and hence precious metal catalysts are to be used. Thus, the cost of operation at plant scale increases due to the use of precious metal catalyst, risk management systems etc. Also, in this reaction since there is high probability of by-products being generated the mother liquor must be distilled completely for recovery of reaction medium. Pyrolytic catalyst, hydrogen pressure, temperature and solvents mostly excluding water make this mixture very risky and unsafe.

[0011] Thus, these methods are harsh on environment, unsustainable, uneconomical, and have high environmental footprint and so there is a need for reduction methodology which is inherently safe, economically viable and industrially applicable with minimum environmental footprint and with chemo-selectivity.

[0012] Due to these challenges, industry is looking for a safer, cost competitive and greener alternative to this conventional process of reduction.

[0013] Objects and Advantages of Invention:

[0014] In order to overcome various serious drawbacks of the existing methods, the inventors at ‘Newreka Green Synth Technologies Pvt. Ltd.’ have developed a novel process using commercially available materials such as G-Cat and R-Cat for the reduction of R-NO2or R -NO other reducible groups into corresponding R - NH2and the process of the present inventions is to provide a process that uses water in a minimal or stoichiometric quantity; that is required only as a source of hydrogen for sufficient reduction potential, to carry out effective, efficient and economical reduction reaction, that avoids the unwanted use of large quantity of water.

[0015] Another object of the process of the present invention is to use stoichiometric or minimal quantity of water as a source of hydrogen for generating sufficient reduction potential, is to avoid precipitation of organic compounds due to low solubility in water adversely affecting reduction process. Another object of the process of the present invention is to avoid side product / s & / or impurity / s formation which many times is a result of using large quantity of water especially when other sensitive / reactive groups are present in the molecule. Another object of the process of the present invention is recycling of the various streams in reaction sequence and / or isolation sequence.

[0016] An another object of the process of the present invention is to provide a process in which the product isolation processes overcomes the problem of high amine content in solid spent or inorganic by-product formed in the process.

[0017] Yet another object of the process of the present invention is to provide an environmentally friendly and green process that overcomes the problem of generation of liquid wastes resulting from the conventional processes of reduction.

[0018] Another object of the present invention is to provide a process which is inherently safe avoiding use of hydrogen gas, high pressure, pyrophoric and precious metal catalysts.

[0019] Another object of the present invention is to provide a process, wherein undesirable side reactions leading to side products and / or impurities formation are substantially reduced by the virtue of chemo-selectivity and regio-selectivity which results in purer product formation.

[0020] Brief Description of Figures:

[0021] Figure 1 shows a green reaction sequence with the use of minimal quantity of water as source of hydrogen for generation of sufficient reduction potential and recycle of liquid stream generated in the process including mother liquor and / or water miscible or water immiscible solvents, washings. Figure 2, 3 & 4 -shows green isolation sequences Type A, Type B and Type C respectively, depending on the physico-chemical properties and nature of amine product.

[0022] Summary of Invention:

[0023] The present invention uses a proprietary reducing formulation called G-cat, and the treatment & pH adjustment formulation R-Cat, which are commercially available globally from Newreka Green Synth Technologies Pvt Ltd. It also uses, as the reaction medium water-miscible or water-immiscible solvents and minimizes the quantity of water by limiting the use of water purely as a source of hydrogen. Further, it also minimises the use of the solvent by recycling the recovered solvent as well as mother liquor that is generated after isolation of the product back into the process as reaction medium or extraction medium in place of fresh water and fresh solvent. The process does not involve, any pressure or hydrogen gas as the source of hydrogen in this process.

[0024] Disclosed herein is an industrially applicable closed loop process (also refer to Figure 1) for reduction of sparingly soluble or insoluble, slightly miscible or immiscible mono or di- or ploy; nitro or nitroso compounds, in which nitro or nitroso groups can be in any position, in presence of solvent / s, with minimum use of water as a source of hydrogen for generating sufficient reduction potential into corresponding amines exhibiting differential solubility in different organic or inorganic solvents or combination of solvents like that exhibited by process exemplified for and not restricted to the intermediate meta -amino Acetophenone for Phenylephrine, the intermediate ethyl3-[[4-(methylamino)-3- aminobenzoyl](pyridin2yl)amino]propanoate for Dabigatran, and the intermediate 2,4-Difluoro aniline for Pantoprazole. The said processes, as described in the embodiment, are designed and customized by considering generation of reduction potential required, from water as a source of hydrogen for reduction and the physico-chemical properties of nitro or nitroso compounds and amino compounds to make these processes safe, highly energy efficient and environmentally friendly. A key feature of the invention is use of minimal or stoichiometric quantity of water as source of hydrogen for reduction potential. After reduction is over, product amine is isolated by three different methods of isolation (also refer to Figures 2, 3, and 4) depending on nature & physico-chemical properties of amines.; namely Type A, Type B and Type C, wherein, a) Product Isolation Type A - is carried out for the product amines which have solubility, which is temperature sensitive, and are mostly sparingly soluble at low temperature, by chilling of combined isolation mass containing water layer & solvent layer consisting of amine product wherein, product is precipitated or crystallised. Product is then separated by known methods of filtration. The liquid streams comprising of major solvent phase & minor water phase generated in the isolation sequence are stored in storage tanks and recycled back in the green reaction sequence in subsequent cycle. The said isolation process Type - A, is exemplified for and not restricted to m-Amino acetophenone, an intermediate for Phenylephrine and is applicable for isolation of amines of similar nature & physico-chemical properties, like solubility; b) Product Isolation Type B - is carried out for the product amines which are moderately soluble and their solubility is not temperature sensitive, by partial distillation of isolation mass comprising of reaction medium, extraction medium, and wash, followed by chilling of remaining isolation mass retained in the vessel and separation of product amine by known methods of filtration. The liquid streams comprising of solvent phase and water phase generated in the isolation sequence are stored in respective storage tanks and recycled in green reaction sequence in subsequent cycle. This Isolation Sequence - B, is exemplified for and not restricted to Ethyl3-[[4-(methylamino)-3- aminobenzoyl](pyridin2yl)amino]propanoate; an intermediate for Dabigatran and is applicable for isolation of such other amines of similar nature & physicochemical properties. c) Product Isolation Type C - is carried out for the product amines which are highly soluble and their solubility is not temperature sensitive, by complete solvent distillation from the isolation mass followed by chilling of remaining aqueous phase and product separation by filtration. After product is separated by filtration, aqueous filtrate is stored in storage tanks and recycled back in the green reaction sequence & / or green isolation sequence in subsequent cycle. The distilled solvents either miscible or immiscible are stored in storage tanks and recycled back in the green reaction sequence & / or green isolation sequence. This isolation sequence - C is exemplified for 2,4-Difluoro aniline the intermediate of Pantoprazole but not restricted to this molecule and applicable for isolation of all amines of similar nature and physico-chemical properties, like solubility. These methodologies make it possible the recycle of aqueous phase and / or the miscible or immiscible solvent back into the process. Thus, there is no effluent resulting from the process which needs separate treatment and disposal.

[0025] Advantages of the Invention:

[0026] An advantage of the present invention is that due to use of commercially available materials by Newreka Green Synth Technologies Pvt Ltd., and minimal / stoichiometric quantity of water, required only as a source of hydrogen for generating sufficient reduction potential, avoids the use of large quantity of water.

[0027] Another advantage of the present invention is that, due to the use of stoichiometric or minimal quantity of water as a source of hydrogen for generating sufficient reduction potential, it avoids precipitation of organic compounds due to low solubility in water adversely affecting reduction process. Another advantage of the present invention is that it avoids side product / s & / or impurity / s formation which are many times formed as a result of using large quantity of water.

[0028] Another advantage of the present invention is that it recycles all the various streams in the reaction sequence and / or isolation sequence.

[0029] Yet another advantage of the present invention is that it provides a process in which the product isolation processes overcome the problem of high amine content in solid spent or inorganic by-product formation in the process.

[0030] Yet another advantage of the present invention is that it provides an environmentally friendly and green process that overcomes the problem of generation of liquid wastes resulting from the conventional processes of reduction.

[0031] Another advantage of the present invention is that it provides a process which is inherently safe avoiding use of hydrogen gas, high pressure, pyrophoric and precious metal catalysts.

[0032] Another advantage of the present invention is that it provides a process, wherein undesirable side reactions leading to side products and / or impurities formation are substantially reduced by the virtue of chemo-selectivity and regio-selectivity which results in purer product formation.

[0033] Another advantage of the present invention is that, both the number and quantity of organic impurities are comparatively less.

[0034] Another advantage of the invention is that the possibility of build of side products in mother liquor during recycle is less. Another advantage of the present invention is that the method disclosed herein is not only green and sustainable, but also the R-NH2produced by the process is also greener because they have fewer impurities. This makes downstream processing and application that involve this R-NH2highly recyclable.

[0035] A still further advantage of the present invention is that the inorganic by-products of this process are non-sticky, which makes handling easier and simpler than the conventional processes.

[0036] Another advantage of the process of present invention, is, in the Green Isolation sequence, it gives freedom for the use of different industrially applicable & / or viable product isolation process depending on the physico-chemical properties of amino product and economy of the process.

[0037] A further advantage of the invention is that the process described herein does not require large capacity of liquid effluent treatment facility or elaborate solid waste disposal facility.

[0038] A further advantage of the process of the present invention over the conventional processes is that the process does not have any constraints in respect of plant location and does not necessarily have to be carried out in any specific industrial area.

[0039] A further advantage of the present invention wherein, the reaction is carried out at near to neutral conditions and at atmospheric pressure, which makes it safer.

[0040] A still further advantage of the process of the present invention is that its inherent thermodynamic conditions defined in terms of pressure, temperature, pH, concentrations of reaction components and various reagents is close to respective conditions naturally occurring in the nature, thereby making the process of the invention benign and environmentally friendly.

[0041] There are several other key advantages of the process of the present invention, which relate to health and safety, process engineering, process economics and simple material of construction for process equipment.

[0042] The process of the present invention is inherently safe due to the safe levels of the process parameters such as pressure, temperature, pH, concentrations of reaction components, and various reaction materials. This reduces the risk of injuries to the personnel and damage to the process plant.

[0043] Another key advantage of the present process of this invention is that the plant and process breakdowns that could take place due to factors such as power failure, or uncontrolled fluctuations in the process parameters, do not affect the recyclability of the process. This leads to reduction in wastage on account of batch failures. The process therefore is able to avoid sudden shocks to the environment and sudden safety shocks to the plant and the personnel, ultimately leading to sustainable health of plant and personnel.

[0044] The simplicity of the process also makes its engineering design simple.

[0045] Another advantage of the process is that it is carried out at such temperatures values that it saves energy and therefore results in the process economy.

[0046] Detailed Description of the invention:

[0047] In order to facilitate understanding of the process described herein several terms are explicitly defined. • Reaction medium is the solvent phase either water miscible solvent or water immiscible solvent, either high boiling or low boiling or a combination thereof used in the reaction.

[0048] • Fresh reaction medium is the fresh solvent or fresh solvent mixture phase with water miscible or immiscible solvent which is either high boiling or low boiling or a combination thereof used in the reaction.

[0049] • Solvent is any suitable solvent that is water miscible or immiscible, either high boiling or low boiling, aromatic or aliphatic which is linear or branched, either substituted or unsubstituted or mixture thereof. Specific solvent selection to be used in the process is done on the basis of the solubility of Nitro / Nitroso and Amine compounds in the solvent and also the commercial viability of the solvent.

[0050] • Reaction medium factor is the ratio of the weight of fresh reaction medium or reaction medium with weight of R-NO2or R -NO used in the process.

[0051] • Extraction medium factor is the ratio of the weight of fresh extraction medium or extraction medium with weight of R-NO2or R-NO used in the process.

[0052] • Mother liquor (ML) is the liquid stream generated after a product is isolated. Mother liquor has been used as the reaction medium (RM) at various stages of the process of the invention in its cycles following the first cycle.

[0053] • Nitro or nitroso compound can be aromatic either mono or poly or aliphatic linear or branched, substituted or un- substituted where substitution can be alkyl, hydroxyl, halogen, carboxylic acid, carbonyl, nitro or nitroso, amino, amide, thio, sulphonic acid group, diazo group, etc and all similar groups either mono substituted or poly substituted.

[0054] • QRT is total quantity of reducing agent in typical cycle • (Weight Ratio)RA, is the ratio of the weight of the reducing agent required in a single cycle

[0055] • QRMT is total quantity of reaction medium

[0056] • (Weight Ratio)RM is weight ratio of fresh reaction medium or the reaction medium

[0057] • Optional use of water in creating startup is defined by the use of solvent (water miscible or water immiscible) in the process. Water is used in creating startup when water miscible solvent is used in the process and water is not used in creating startup when water immiscible solvent is used in the process.

[0058] • G-Cat - is the reducing formulation developed by Newreka Green Synth Technologies Pvt Ltd., and is commercially available

[0059] • R-Cat - is the treatment and pH adjustment formulation developed by Newreka Green Synth Technologies Pvt Ltd., and is commercially available.

[0060] • R-Cat treatment with pH adjustment RM - is the solvent phase or system which is neutralized.

[0061] • Separation RM is the mixture of neutralized immiscible or immiscible solvent ready for phase separation.

[0062] • Washing medium - is the fresh solvent and / or fresh water used for product washing

[0063] • Settling RM is the mixture of miscible or mimmiscible solvent which is settled for phase separation.

[0064] • Isolation Type A - is used for isolation of amines which have solubility, which is sensitive to temperature and which are mostly sparingly soluble at low temperature

[0065] • Isolation Type B - is used for isolation of amines which are moderately soluble and their solubility is not temperature sensitive • Isolation Type C - is used for isolation of amines which are highly soluble and their solubility is not temperature sensitive

[0066] • Cooling curve (CC) is profile of temperature verses time.

[0067] The process of the present invention uses a proprietary reducing agent G-Cat which is a multifunctional, chemical reduction formulation mainly comprising of high surface area and activated Iron (Fe), Oxides of Silica (SiO2), and Alumina (A12O3) and Carbon as inert materials for catalyst support, minor percentage of Fe2O3 / FeO, and is commercially made available.

[0068] The other chemical formulation namely R-Cat is used in the process of the present invention. R-Cat is a multifunctional pH adjustment with recycle treatment formulation mainly comprising very high surface area and super activated Iron (Fe), Oxides, Hydroxides and Sulphites of Sodium, Magnesium and Calcium; Oxides of Silica (SiO2), Alumina (A12O3) and Carbon as inert materials for catalyst support, minor percentage of Fe2O3 / FeO, commercially made available.

[0069] The chemical process of the present invention basically comprises effective and economical reduction with use of minimal quantity of water as a source of hydrogen for generating sufficient reduction potential and inherent recycle of the mother liquor streams and solvent streams generated during any of the cycles. Each cycle further comprises two sequences. The first sequence of typical cycle is represented in Figure 1 and is termed as the green reaction sequence. The second sequence of the cycle is termed as the green isolation sequence, performed by three different methods of isolation, represented in Figure 2 - Type A, Figure 3 - Type B & Figure 4 - Type C of isolation respectively.

[0070] One of the novel features of the process of present invention is the use of very minimal quantity of water as a source of hydrogen for generating sufficient reduction potential. Referring to Figure 1, in the very first cycle of the process, of the present invention fresh reaction medium is used as the reaction medium in the start-up (Step 1.1) and minimal quantity of water as a source of hydrogen for generating reduction potential in reduction Step 1.1 & / or (Step 1.2) step, and fresh reaction medium for steps involving extraction (Step 1.5, 1.6) and washings (Step 1.7). As a key feature of the present invention, in the subsequent cycles, the liquid streams generated in various steps of the previous cycle are used as the reaction & / or extraction and washing medium in the subsequent cycles with addition of required makeup quantity to compensate process losses.

[0071] 1. Streams generated at various stages of the green reaction sequence of the invention are now defined as -

[0072] As shown the reaction sequence in Figure 1, streams of settling & decantation in step 1.4, extraction & filtration stream in Step 1.5 & inorganic by-product water washing step in Step 1.6 & 1.7 are generated after performing respective process. All the stream optionally except wash stream of step 1.7, are collected as a combined isolation mass containing water layer & solvent layer consisting of amine product, in a vessel as input for next process. The collective stream is then transferred to a separate vessel for further process of Green Isolation Sequence (Refer to fig. 2 or 3 or 4) respectively. The spent wash stream generated in step 1.7 is stored separately for recycle in the spent washing step in step 1.6 in subsequent cycle.

[0073] Another embodiment in the process of present invention is, the Green Isolation Sequence of amine can be performed in three types depending on the physico-chemical properties of the amine as well as considering the economy and industrial applicability of the process and discussed below are the various streams generated in respective type of isolation process followed. . Streams generated at various stages in respective green isolation sequence of the invention are now defined in detail as -

[0074] Isolation Type A: As shown in Figure 2 of the green isolation sequence, in step 2.1, chilling of combined isolation mass containing water layer and solvent layer consisting of amine product from step 1.7 is carried out followed by product separation by known methods of filtration in step 2.2, the mother liquor and the liquid streams are generated after layer separation in step 2.3 after performing respective process. The mother liquor stream is collected in a respective storage tank for recycle in green reaction sequence in subsequent cycle as reaction, extraction and washing medium in subsequent cycle.

[0075] Isolation Type B: As shown in Figure 3 of the green isolation sequence, from the combined isolation mass containing water layer and solvent layer containing of amine product in step 1.7, solvent stream and water stream obtained in step 2.1 after layer separation, partial distillation of solvent in step 2.2, stream of solvent recovered after product filtration in step 2.4 are generated. The liquid streams, solvent stream and water stream generated in the isolation sequence are stored in respective storage tank and recycled back in the green reaction sequence in subsequent cycle as reaction, extraction and washing medium or combination thereof.

[0076] Isolation Type C: As shown in Figure 4 of the green isolation sequence, the combined isolation mass containing water layer and solvent layer containing of amine product in step 1.7, solvent stream generated after complete distillation in step 2.1 and liquid stream after product filtration in step 2.3 are collected in respective storage tank for recycled back in the green reaction sequence as reaction, extraction and washing medium or combination thereof in the subsequent cycle.

[0077] Some quantity of fresh reaction medium or any other appropriate liquid streams, 5 or a combination thereof are used as make-up liquid and / or miscible or immiscible solvent either high boiling or low boiling in various steps to compensate for the various liquid losses through handling, evaporation, and so on.

[0078] Details of the steps involved in the two sequences that form a typical cycle of the 10 process of the present invention are described below, with reference to figures 1- 2, 1-3 and 1-4.

[0079] The preferred embodiment of the present invention and various other embodiments are now described.

[0080] 15

[0081] In the process of the present invention, the green reaction sequence comprising solvent or mixture of fresh miscible or immiscible solvent and minimal quantity of water as a source of hydrogen for generation of sufficient reduction potential required to complete the reaction, followed by the green isolation sequence in 20 three different ways for economic isolation of amines generated, having industrial applicability with recycle of all liquid streams - water & / or miscible or immiscible solvent are exemplified for but not restricted to following examples and can be applied to all similar molecules. ropanoate 2y )am no]propanoate

[0082] The process of present invention is exemplified for above molecules and is not restricted only to these examples; it can be applied to all similar nitro or nitroso to amine reduction processes with minimal use of water as source of hydrogen for 5 generation of sufficient reduction potential to complete the reaction.

[0083] Sequence 1.0 - Green reaction sequence: As shown in Figure 1, this sequence comprises seven steps, namely the start-up, reduction, R-Cat treatment with pH adjustment, decantation, extraction, filtration and washing. Each of these steps is described below. One of the key features of this sequence is the various materials like G-Cat the reducing formulation & R- Cat - the R-Cat treatment with pH adjustment formulation, developed and commercially made available by Newreka Green Synth Technologies Pvt Ltd., and minimal or stoichiometric quantity of water are used in various steps. A predetermined quantity of these materials is added as and when required. These materials along with specific reaction conditions generated as defined by the temperature, pressure, pH, rate and type of agitation, and other such parameters lead to the unique inherent reduction along with recyclability of the liquid streams in the process of the present invention.

[0084] The total quantity of the reducing agent G-Cat required in this sequence for a typical cycle (referred to hereafter as QRT) is dictated by the requirement of the reduction potential of R-NO2or R-NO to be reduced. QRTis determined by a reducing agent’s weight ratio, (Weight Ratio)RA, that is the ratio of the weight of the reducing agent required in a single cycle, WRA of the process of this invention to the weight of total amount of R-NO2or R-NO to be reduced in that single cycle, WN. That is for a single cycle:

[0085] (Weight Ratio)RA = WRA / WN Equation 1

[0086] The QRT is such that its weight is equal to WRA which is determined from Equation 1.

[0087] In the preferred embodiment of the present invention, (Weight Ratio) RA is preferably in the range of 0.5 to 5.0. Step 1.1 - Start-up: This step is carried out in a reaction vessel that is equipped with an agitator and necessary attachments known to a person skilled in the art. As shown in figure 1, at the beginning of the first cycle of process of the present invention a reaction medium is charged to the reaction vessel in suitable quantities.

[0088] In the preferred embodiment of the present invention fresh reaction medium is used as the reaction medium. The total quantity of the reaction medium required for a typical cycle (referred to hereafter QRMT) is dictated by the solubility of R- NH2. This quantity is determined by weight ratio of fresh reaction medium or the reaction medium, denoted as (Weight Ratio)RM, that is the ratio of the weight of the fresh reaction medium or the reaction medium required in a single cycle, WRM, to the weight of total amount of R-NO2or R-NO to be reduced in that single cycle, WN. That is

[0089] (Weight Ratio)RM = WRM / WNEquation 2

[0090] The QRMT is such that its weight is equal to WRM which is determined from Equation 2.

[0091] The quantity of the fresh reaction medium or the reaction medium used in Step 1.1, denoted as QRMI.I, is variable.

[0092] In the preferred embodiment, (Weight Ratio)RM is preferably in the range of 0.25 to 20, and QRMI.I is in the range of 0% (w / w) to 100% (w / w) of QRMT used in this cycle.

[0093] In the preferred embodiment, the nitro or nitroso compound (respectively R-N02or R-NO) to be reduced is added as is or in the form of solution or mixture in solvent at once or in any number of lots or continuous addition to the reaction vessel. The total amount of R-NO2or R-NO to be reduced is added at once or over a duration of 0.5 hours to 12 hours, at a suitable interval or continuously that depends on the molecule to be reduced, in the temperature range of the mixture during the agitation in the range between 20° to reflux temperature wherein starting nitro or nitroso compound remains soluble in the respective solvent.

[0094] In the preferred embodiment of the invention, G-Cat is used as the reducing formulation and (Weight Ratio) RA is preferably in the range of 0.5 to 5.0 w / w of nitro / nitroso compounds. The quantity of the reducing formulation used in Step 1.1, QRI.I is variable in the range of 0% (w / w) to 100% (w / w) QRT.

[0095] In the preferred embodiment of the invention, optionally water in the range being 0.25 to 4.0 w / w of nitro / nitroso compounds is added at once, or over a duration of 0.5 hrs to 20 hrs in the reaction vessel under agitation, as a source of hydrogen for generating sufficient reduction potential.

[0096] The mixture is agitated with predetermined rpm for a predetermined time that is in the range between 0.5 hours to 5 hours. In the agitation stage, the pH of the reaction mixture is maintained throughout at a predetermined level that is in the range of 3 to 9.

[0097] After predetermined duration of agitation, agitation is continued, and a reducing formulation, G-Cat, developed and commercially made available by Newreka Green Synth Technologies Pvt Ltd., is charged in suitable quantity. It is added either in its full required quantity or in any number of lots of any size, or continuously, or any combination thereof. The reducing formulation is added over a predetermined period, at a predetermined temperature, and a predetermined pH. The period over which the reducing agent is added at once or over 20 hours or continuously. The temperature at which the reducing agent is added is in the range of 20° to reflux temperature. The pH at which the reducing agent is added is in the range of 3 to 9. In another embodiment of the present invention, the temperature at which the reducing formulation is charged is in the range of 20° to reflux temperature. G-Cat developed & commercially made available by Newreka Green Synth Technologies Pvt Ltd., or any other commercially available reducing material is used as the reducing agent in this embodiment.

[0098] In another embodiment of the present invention, the reaction medium or a combination thereof, and the reducing agent developed and commercially made available by Newreka Green Synth Technologies Pvt Ltd., are added in any sequence.

[0099] In the subsequent cycles of the process of the present invention, mother liquor & / or solvent stream is used as a reaction medium instead of fresh reaction medium in the start-up (step 1.1).

[0100] Step 1.2 - Reduction: This step is carried out in the same reaction vessel of startup in step 1.1, equipped with an agitator and necessary attachments known to a person skilled in the art. In the preferred embodiment of the invention according to this step as shown in figure 1, at the beginning of the first cycle of process of the present invention G-Cat is charged at once or lot wise or continuously followed by addition of minimal quantity of water at the predetermined temperature, during the predetermined time, and at a predetermined range pH. step 1.2a. in the preferred embodiment of the invention, G-Cat is charged in the Weight Ratio <RA) is preferably in the range of 0.5 to 5.0 w / w of nitro / nitroso compounds. The quantity of the reducing agent used in Step 1.2, QRI.2 is variable in the range of 0% (w / w) to 100% (w / w) QRT. step 1.2b. in another embodiment of the invention, water in the range 0.25 to 4.0, w / w of nitro / nitroso compounds is added in the reaction vessel maintaining the reaction at predetermined temperature range of 20° to reflux temperature , for a predetermined range of maintaining time preferably between 0.5 hours to 20 hours, depending on the physico-chemical properties of nitro or nitroso compound to be reduced. step 1.2c. in another embodiment of the invention, the pH of reduction mass is maintained in the range of 3 to 9, and temperature between 20° to reflux temperature .

[0101] In the preferred embodiment of the present invention, water is used as the source of hydrogen for generating sufficient reduction potential in this step 1.2 in all the cycles of the process.

[0102] In the preferred embodiment of the present invention, wherein nitro or nitroso compound is reduced at the predetermined temperature in the range of 20° to reflux temperature; at the predetermined pH in the range between 3 to 9; at the pressure in the range of 0.5 to 5.0 Kg / cm2, most preferably atmospheric pressure.

[0103] In another embodiment of the present invention, wherein fresh reaction medium is used in the first cycle, and in the subsequent cycles subject to the process of this invention liquid streams generated in earlier cycles are used.

[0104] Step 1.3 - R-Cat treatment with pH adjustment: After completion of the reduction at the end of Step 1.2, optionally a suitable reaction medium is charged in suitable quantity to the reaction vessel. The decision to add the reaction medium depends on the consistency of the solids in the reaction mixture. The quantity of the reaction medium used in Step 1.3, denoted as QRM1.3, is variable in the range of 0% (w / w) or minimum required for proper agitation of the reaction mixture of the total quantity QRMT used in this cycle. R-Cat treatment with pH adjustment agent R-Cat, developed and commercially made available by Newreka Green Synth Technologies Pvt Ltd., is added to the reaction mixture over a predetermined period and at a predetermined temperature. The fundamental role of the R-Cat is to provide a strong reduction potential for low concentration R-NO2or R-NO towards the end step 1.2 and also providing necessary filterability to spent and also providing necessary pH adjustment for the reaction mixture, and also providing required purity and the quality of amine in terms of color and impurity profile obtained at the end of step 1.2.

[0105] The period over which R-Cat the pH adjustment cum recycling treatment formulation is added at once or in lots or in 3 hours. The temperature at which the R-Cat treatment with pH adjustment agent is added, is in the range of 20° to reflux temperature. The pH at which the R-Cat treatment with pH adjustment agent is added, is in the range of 3 to 9.

[0106] The R-Cat treatment with pH adjustment process wherein, the R-Cat is allowed to react with unreacted R-N02or R-NO at a R-Cat treatment with pH adjustment process temperature is continued for a R-Cat treatment with pH adjustment process time. The R-Cat treatment with pH adjustment process temperature is maintained in the range of 20° to reflux temperature and the pH of the R-Cat treatment with pH adjustment process is maintained between 6 to 12. The R-Cat treatment with pH adjustment process time is in the range of 30 minutes to 3 hours.

[0107] In the preferred embodiment of the process of the invention the R-Cat treatment with pH adjustment formulation is done with R-Cat. The quantity of the R-Cat, QNAT is determined by its weight ratio, denoted as (Weight RatiojNA, that is the ratio of the weight of the R-Cat required in a single cycle, WNA, to the weight of total amount of R-N02 or R-NO to be reduced in that single cycle. That is, (Weight Ratio)NA = WNA / WNEquation 4

[0108] The QNAT is such that its weight is equal to WNA which is determined from Equation 4. step 1.3a. In the preferred embodiment the (Weigh Ratio)NA of R-Cat treatment with pH adjustment formulation is charged preferably in the range between 0.05 to 0.5 w / w of nitro / nitroso compounds. step 1.3b. In the preferred embodiment of the invention, fresh reaction medium is optionally charged at once or during 10 minutes to 3 hours at pH in the range between 3 to 9, as the reaction medium in the first cycle of this sequence, and for the subsequent cycles subject to the process of this invention, fresh reaction medium is replaced by liquid streams, mother liquor stream & / or solvent streams in respective type of isolation sequence performed after completing the reaction sequence as mentioned in Fig. 1 and Isolation in Fig. 2 or 3 or 4 respectively.

[0109] The inventors, Newreka Green Synth Technologies Pvt Ltd., have surprisingly found that the action of its commercially available materials G-Cat and R-Cat used in the steps 1.1 to 1.3 collectively favors very high degree of chemoselectivity and regio-selectivity for R-N02or R-NO to R-NH2green reduction reaction.

[0110] Step 1.4 - Decantation: After completion of the R-Cat treatment with pH adjustment process in step 1.3, the mixture thus formed, termed as the decantation mixture, settled for predetermined time and predetermined pH. The clear layer is decanted and filtered through a filtration unit at a predetermined decantation temperature and at predetermined decantation pH. In the preferred embodiment of the present invention, the decantation temperature is in the range of 20°C to below reflux temperature and the decantation pH is in the range of 6 to 9.

[0111] The pH and temperature conditions are maintained at this level of pH and temperature for predetermined time that is in the range of 0.5 hours to 3 hours.

[0112] Optionally a reaction medium is added to the decantation mixture after or along with the addition of the agent R-Cat. It is added at a predetermined temperature which is preferably in the range of 20° to reflux temperature and pH that is in the range of 6 to 9.

[0113] Liquid layer that forms as a result of the decantation process, is decanted & filtered at a first decantation temperature, first decantation pH and first decantation time and charged as 1stdecanted stream as the input to Step 2.1 of same cycle or any of the following cycles.

[0114] In the preferred embodiment of the invention, the first decanting temperature is in the range between 20° to below reflux temperature at first decanting pH in the range between 6 to 9.

[0115] For the subsequent cycles subject to the process of this invention, fresh reaction medium is replaced by the mother liquor & / or solvent streams generated in previous cycle of the process of invention.

[0116] Step 1.5: Extraction and Filtration: As shown in Figure 1, a reaction medium, referred to as the first extraction RM, is optionally charged to the mixture obtained at the end of Step 1.4 in the reaction vessel in a suitable quantity and at suitable temperature and pH, the temperature being in the range of 20°C to reflux temperature and the pH being in the range of 6 to 9. The mixture thus formed is allowed to settle at a first extraction pH, by maintaining it at a first extraction temperature for a first settling time.

[0117] In the preferred embodiment of the invention the first extraction pH is in the range of 6 to 9; the first filtration temperature is in the range between 20°C to below reflux temperature; and the first decantation filtration time is for 5 minute to 8 hours depending on filtration equipment used and the nature of the mixture to be filtered.

[0118] Liquid layer that forms as a result of the extraction process is filtered at a first filtration temperature, first filtration pH and first filtration time and charged as input to Step 2.1 of same cycle or any of the following cycles.

[0119] Step 1.6: Extraction and Filtration: As shown in Figure 1, a reaction medium, referred to as the second extraction RM, is optionally charged to the mixture obtained at the end of Step 1.5 in the reaction vessel in a suitable quantity and at suitable temperature and pH, the temperature being in the range of 20°C to reflux temperature and the pH being in the range of 6 to 9. The mixture thus formed is allowed to settle at a second extraction pH, by maintaining it at a second extraction temperature for a second settling time.

[0120] In the preferred embodiment of the invention the second extraction pH is in the range of 6 to 9; the second filtration temperature is in the range of 20° to below reflux temperature; and the second filtration time is for 5 minute to 8 hours depending on the filtration equipment used and the nature of the mixture to be filtered.

[0121] Liquid layer that forms as a result of the second extraction process is filtered at a second filtration temperature, second filtration pH and second filtration time and charged to Step 2.1 as input of same cycle or any of the following cycles. Step 1.7: Washing & Filtration: As shown in Figure 1, a fresh separation RM, is charged, to the G-Cat spent and optionally mixed with R-Cat spent, under agitation obtained at the end of Step 1.6 in the reaction vessel in a suitable quantity and at suitable temperature and pH, the temperature being in the range of 10° to reflux temperature and the pH being in the range of 6 to 9 and the second filtration time is for 30 minute to 5 hours depending on the filtration equipment used and the nature of the mixture to be filtered.

[0122] Liquid layer that forms as a result of the washing & filtration process above, is filtered at a washing filtration temperature, second filtration pH and second filtration time and collected separately in a storage tank; and optionally charged as washing medium in step 1.6, in subsequent cycle.

[0123] In the preferred embodiment of the invention in Step No. 1.7, fresh washing medium is used in the all cycles subject to the process of this invention.

[0124] In another embodiment of the present invention, fresh washing medium is used in all cycles of the invention subject to the requirements of process of this invention.

[0125] In another embodiment of the present invention, the filtration temperature is preferably between 10° to below reflux temperature.

[0126] The reaction mixture at all stages of this step is optionally stirred with agitators rotating at a rate between 20 to 200 RPM.

[0127] In another embodiment of the present invention, the washing of in-organic byproduct or spent ensures that the by-product formed in the process of the present invention has surprisingly low level of amine content and are thus green in nature.

[0128] A single cycle of the green reaction sequence is complete at the end of step 1.7.

[0129] T1 Sequence 2.0 - Green isolation sequence:

[0130] The green isolation sequence can be performed in three different types as shown in Figure 2, Figure 3 and Figure 4 respectively and this sequence comprises different steps, depending on the preferred Type of Isolation process.

[0131] The isolation process of types A, B & C are discussed in detail as follows -

[0132] 1. Type A Isolation: The type A isolation process in the present invention is exemplified herein for and not restricted to reduction of meta- Nitro acetophenone to meta-Amino acetophenone the intermediate of Phenylephrine, and can be applied to all similar nitro or nitroso to amine reduction and isolation of amine with Type A isolation process as shown in Fig.2.

[0133] Brief description of Process: Isolation of amine in this process is done by cooling and / or chilling of entire isolation mass obtained after completing step 1.7 in green reaction sequence consisting of amine product, wherein; the product is precipitated or crystallized and then separated by filtration. Cooling or chilling of isolation mass is done following predetermined cooling curve with predetermined temperature and predetermined time, and at predetermined rpm of agitator, wherein product falls out or precipitates or crystallizes from the combined isolation mass. At the end, the resulting mass is filtered through the suitable filtration equipment to obtain the wet cake of the product. The wet cake is washed optionally by a suitable solvent and / or water. The mother liquor stream thus generated is then collected in the respective storage tanks for use in reaction sequence as reaction, extraction and washing medium in next cycle. The filtration stream generated is stored in storage tank and is optionally used in subsequent cycle.

[0134] Detailed description of Type A Isolation Sequence -

[0135] Green Isolation Sequence (Type A) - Chilling of combined isolation mass for product isolation followed by product filtration and the storage of liquid stream generated. Each of these steps of Type A Isolation sequence is described in detail as follows.

[0136] Step 2.1A - Chilling & Separation: As shown in Figure 2, the combined isolation mass obtained at the end of Step 1.7 in the Green Reaction Sequence, containing amine product, is charged to the isolation vessel equipped with agitator & other attachments known to a person skilled in the art, in a suitable quantity, at a suitable temperature and pH, the temperature being the range of 20° to reflux temperature and the pH being in the range of 6 to 9. The mixture thus formed is allowed to cool or chill following a predetermined cooling curve & maintained to a predetermined temperature range -5° to 40°C and for a predetermined time in the range of 30 min to 10 hours at a suitable pH and at a suitable RPM.

[0137] In the preferred embodiment of the invention, the organic mass is maintained at a chilling & isolation temperature and pH by ensuring product precipitation or crystallization and then subjected to product filtration and washing if required.

[0138] Step 2.2A - Product Filtration - As shown in Figure 2, the isolation mass in the form of product slurry, obtained at the end of Step 2.1 A, is charged to the filtration unit for product separation by known methods of filtration at a predetermined temperature in the range of -5° to 40°C for a product filtration time in the time range of 30 minutes to 3 hours. The wet product obtained after filtration is then washed with solvent and / or water, as & when required, and the wet cake of product is forwarded to further processing. The mother liquor stream and washing stream thus generated, are collected in respective storage tanks.

[0139] Step 2.3A - Layer Separation - As shown in Figure 2, the combined mother liquor stream generated, the mixture of water layer and solvent layer obtained at the end of Step 2.2A, is charged to the layer separation vessel in a suitable quantity, at suitable temperature and pH, the temperature being in the range of -5° to 40°C and the pH being in the range of 6 to 9. The mixture thus formed is allowed to settle at a separation pH, by maintaining it at a separation temperature for a first separation time.

[0140] In the preferred embodiment of the invention the layer separation pH is in the range of 6 to 9; the temperature is in the range of -5°C to 40°C; and the time in the range of 30 minutes to 8 hours.

[0141] Once the layers are separated, the separated aqueous layer is collected at a predetermined separation temperature, a predetermined separation pH and at a predetermined separation time and charged to mother liquor storage tank.

[0142] The separated solvent layer is collected at a predetermined separation temperature, a predetermined separation pH and at a predetermined separation time and is charged to a solvent storage tank.

[0143] In the preferred embodiment of the invention, in the first fresh cycle, fresh reaction medium is used for reduction, extraction, washing & filtration medium respectively in Step 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 & 1.7 and in subsequent cycles subject to the process of this invention, fresh reaction medium is replaced by water and / or solvent stream except step 1.7.

[0144] A key advantageous feature of the present invention is that a part of the stored liquid, in suitable quantity is recycled into various steps 1.1 to 1.6, except 1.7 of the following cycles of the process of the invention.

[0145] The present process of invention is exemplified for and not restricted to amine intermediates for Phenylephrine, Imatinib, Flubendazole and Itraconazole and can be applied to all other similar intermediates for various molecules. A key feature of the present isolation sequence of this invention is that all steps of a typical cycle are carried out at atmospheric pressure. (Refer figure 2 for isolation Type-A).

[0146] A typical cycle of the process of the present invention, that is a cycle consisting of a green reaction sequence and a green isolation sequence Type - A, ends here.

[0147] The second type of isolation process is described in detail as follows.

[0148] 2. Type B Isolation: The type B isolation process in the present invention is exemplified for and not restricted to the reduction of Ethyl -3- [[4-(m ethyl amine)- 3-nitrobenzoly](pyridine2yl)amino]propanoate to Ethyl3-[[4-(methylamino)-3- aminobenzoyl](pyridin2yl)amino]propanoate, the intermediate of Dabigatran, can be applied to all other similar nitro or nitroso to amine reduction and isolation of amine with Type B process as shown in Fig. 3.

[0149] Brief description of Type B isolation process: Isolation of product amine in this process is done by charging the combined isolation mass containing product amine in a separation vessel, separation of water layer and solvent layer followed by partial distillation of the solvent layer. The entire isolation mass after partial distillation is chilled or cooled so that product is precipitated or crystallized, and then filtration of product is done by known methods of product filtration.

[0150] Detailed description of Type-B Isolation Sequence -

[0151] Each of the steps of Type B Isolation sequence is described in detail as follows.

[0152] Step 2.1B - Layer Separation: As shown in Figure 3, the combined isolation mass, obtained at the end of Step 1.7, containing product amine, is charged to the separation vessel, at suitable temperature and pH, the temperature being in the range between 20° to reflux temperature and the pH in the range of 6 to 9. The mixture is then allowed to settle at a first separation pH, by maintaining it at a first separation temperature for a first separation time.

[0153] In the preferred embodiment of the invention the first layer separation pH is in the range of 6 to 9; the first layer separation temperature is in the range between 20° to reflux; and the first layer separation time is for 30 minute to 8 hours.

[0154] The separated solvent layer is transferred to a distillation vessel equipped with agitator & other necessary attachments at a predetermined temperature, pH and at a predetermined time, as input to Step 2.2B of the same cycle or any of the following cycles.

[0155] The separated mother liquor layer is collected at a predetermined separation temperature, a predetermined separation pH and at a predetermined separation time. The mother liquor layer is then transferred to mother liquor storage tank and stored for recycling in subsequent batches.

[0156] In the preferred embodiment of the invention, in the first fresh cycle fresh reaction medium is used for reduction, extraction, washing & filtration medium respectively in Step 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 & 1.7 and for the subsequent cycles subject to the process of this invention, fresh reaction medium is replaced by mother liquor stream and / or solvent stream except step 1.7.

[0157] In the preferred embodiment of the invention, fresh reaction medium is used in all the cycles of the invention in step 1.7 to compensate for the various liquid losses through handling, evaporation, and so on.

[0158] In the preferred embodiment of the invention, the layer separation is done in a predetermined temperature range and pH between 6 to 9. Step 2.2B - Solvent Distillation: The solvent layer obtained in layer separation in Step 2. IB is charged into distillation vessel equipped with agitator & other attachments known to a person skilled in the art.

[0159] In the preferred embodiment, the solvent layer containing amine is concentrated by partial distillation at predetermined vacuum in the range of 10 to 40 mm Hg and predetermined pH in the range of 6 to 9, in the predetermined time in the range of 30 minutes to 8 hrs.

[0160] The saturation points of organic mass, solubility of amine, distillation temperature and time of solvent distillation dictates the volume of partially distilled out solvent.

[0161] In the preferred embodiment of the invention, the volume of partial solvent distillation to saturate organic mass is in preferable range 50% to 90% of the total input volume of solvent layer, at a predetermined vacuum in the range of 10 to 40 mmHg and predetermined pH in the range of 6.0 to 9.0 & predetermined time of distillation 30 minutes to 8 hrs.

[0162] In the preferred embodiment, the solvent recovered after distillation at predetermined distillation temperature and predetermined pH in step 2.2B is collected in solvent storage tank for recycling in subsequent cycle.

[0163] In the preferred embodiment, the saturated organic mass retained in the vessel after distillation is processed further in the same vessel for the product isolation.

[0164] Step 2.3B: Chilling: The saturated organic mass obtained after completing partial solvent distillation in step 2.2B, is chilled or cooled following a predetermined cooling curve to effect precipitation or crystallization with stirring at product isolation temperature in the preferable range -5° to 30°C. Furthermore, the isolation mass is maintained at a temperature in the range of -5° to 30°C for isolation time in the range of 30 minutes to 8 hours at the predetermined pH of isolation in the range of 6 to 9.

[0165] Step 2.4B: Filtration: After maintaining at the predetermined temperature and isolation time in step 2.3B, the isolation mass is then filtered by known methods of product filtration at the product filtration temperature preferably at -5° to 30°C, preferably in 30 minutes to 3 hours.

[0166] The wet product obtained after filtration is then washed with solvent and / or water, as & when required, and the wet cake of product is forwarded to further processing.

[0167] The recovered solvent stream, mother liquor stream and washing stream thus generated, are collected in respective storage tanks.

[0168] A key advantageous feature of the present invention is that, fresh reaction medium is used as the reaction, extraction, washing medium in first cycle of the invention & for the subsequent cycle subject to the process of this invention, fresh reaction medium is replaced by mother liquor and / or solvent stream in subsequent cycle of the sequence respectively, in suitable quantity into various steps (Step 1.1 to 1.6) of the following cycles of the process of the invention except step 1.7.

[0169] The process of present invention is exemplified for and not restricted to amine intermediates for Dabigatran, Domperidone, and can be applied for intermediates for all other similar molecules.

[0170] A key feature of the present invention is that all steps of a typical cycle are preferably carried out at atmospheric pressure. A typical cycle of the process of the present invention, that is a cycle consisting of a green reaction sequence and a green isolation sequence, Type - B ends here.

[0171] The third type of isolation process is described in detail as follows.

[0172] 3. Type C Isolation: The type C isolation process in the present invention is exemplified for and not restricted to reduction of 2,4-Difluoro nitrobenzene to 2,4- Difluoro aniline; the intermediate of Pantoprazole, and can be applied to all other similar nitro or nitroso to amine reduction and isolation of amine with Type C process.

[0173] Brief description of Type C isolation process: Isolation of amine in this process is done by charging the combined isolation mass containing product amine to a distillation vessel equipped with agitator & other necessary attachments followed by complete distillation of solvent. In some cases, additional solvent is added to the aqueous mass retained in the vessel after distillation is followed by chilling or cooling for product isolation by the crystallization or precipitation or any other known method for separation of the product and to achieve maximum separation. The chilled mass is then filtered through the suitable filtration equipment to obtain the wet cake of product as shown in Fig.4.

[0174] Detailed description of Type C- Isolation Sequence-

[0175] C) Green Isolation Sequence (Type C) -

[0176] Each of the steps of Type C Isolation sequence is described in detail as follows.

[0177] Step 2.1C - Solvent Distillation: The combined isolation mass obtained in Step 1.7 is charged to a distillation vessel equipped with agitator & other attachments known to a person skilled in the art. Charging of the combined isolation mass, and distilling complete solvent optionally along with water, optionally at vacuum in the range of 10 mm to 40 mm of mercury and pH in the range of 6 to 9, and over a period in the range of 30 minutes to 10 hours

[0178] In the preferred embodiment, the combined isolation mass, containing amine product is concentrated by complete solvent distillation optionally along with water, optionally at vacuum in the range of 10 mm to 40 mm of mercury, at a predetermined pH in the range of 6.0 to 9.0, in the predetermined time in the range of 30 minutes to 10 hrs.

[0179] In the preferred embodiment of the invention, the volume of solvent is completely distilled out to saturate organic mass in the aqueous layer itself, at a predetermined vacuum in the range of 10 to 40 mmHg and predetermined pH in the range of 6.0 to 9.0 & predetermined time of distillation 30 minutes to 10 hrs.

[0180] In the preferred embodiment, the recovered solvent after the solvent distillation at predetermined distillation temperature and predetermined pH in Step 2.1C is collected in solvent storage tank for recycling in subsequent cycles.

[0181] Step 2.2C- Product Isolation: The concentrated organic mass obtained after complete solvent distillation in step 2.1C, is chilled or cooled to a predetermined temperature, for a predetermined time at a predetermined pH in an isolation vessel following a predetermined cooling curve to effect precipitation in the product separation vessel equipped with agitator & other attachments known to a person skilled in the art.

[0182] In other embodiment of invention, the concentrated organic mass is chilled or cooled with stirring to effect product crystallization or precipitation at the product isolation temperature following a predetermined cooling curve, in the preferable range -5° to 30°C. Furthermore, the isolation mass is maintained at the temperature in the more preferable range of -5° to 30°C for isolation time in the range of 30 minutes to 10 hours at the predetermined pH of isolation in the range of 6.0 to 9.0.

[0183] In another embodiment of the invention, additional solvent is added to the concentrated organic mass and total mass is chilled following a predetermined cooling curve in the temperature range -5 to 30°C and time in the range of 30 minutes to 10 hours at the predetermined pH of isolation in the range of 6.0 to 9.0.

[0184] Step 2.3C - Product Filtration: The product isolation mass after maintaining at the crystallization or product precipitation temperature and for the predetermined time is then filtered by known methods of product filtration at the product filtration temperature preferably at -5° to 30°C in predetermined time 30 minutes to 3 hours.

[0185] The wet cake of product obtained after filtration is then washed with solvent and / or water, as & when required, and the wet cake of product is forwarded to further processing.

[0186] The recovered mother liquor, recovered solvent and washing stream obtained after product filtration are collected in respective storage tanks for recycling in subsequent cycle of the invention.

[0187] A key advantageous feature of the present invention is that, fresh reaction medium is used as the reaction, extraction, washing medium in first cycle of the invention & for the subsequent cycle subject to the process of this invention, fresh reaction medium is replaced by mother liquor and / or solvent stream in subsequent cycle of the sequence respectively, in suitable quantity into various steps (Step 1.1 to 1.6) of the following cycles of the process of the invention except in step 1.7. A key feature of the present invention is that all steps of a typical cycle are carried out at atmospheric pressure.

[0188] A typical cycle of the process of the present invention, that is a cycle consisting of a green reaction sequence and a green isolation sequence - Type - C, ends here.

[0189] In another embodiment of the present invention subject to the requirement of the process, process economy, viability and ease of operation, after step 1.7, the combined isolation mass containing the product amine except the spent wash layer of step 1.7, is directly forwarded to the next reaction, without isolation of amine product by performing the Green Isolation Sequence.

[0190] In step 1.7 fresh reaction medium is used in all cycles to make up the losses of previous cycles in the process of this invention.

[0191] The process of present invention is exemplified for and not restricted to amine intermediates for Pantoprazole, Telmisartan, Bendamustine, Albendazole, Flurbiprofen, etc and can be applied to all other similar molecules.

[0192] Newreka Green Synth Technologies Pvt Ltd., inventors of the present invention have found that the purity of product amine after drying in any cycle varies in the range of 95% to 99.9%.

[0193] The mother liquor and washings comprising water or solvent or combination thereof obtained during various steps described above are stored for use in further cycles.

[0194] Furthermore, the inventors have surprisingly found that the reduction of R-NO2 or R-NO to R-NH2carried out with the process described above, generates inorganic by-product in any cycle in the ratio of weight in the range of 0.25 to 25 to the weight of R-NO2or R-NO to be reduced of the above sequence is crystalline and non-sticky in nature. Colour of these by-product ranges from brown to jet-black normally jet-black. The pH of the inorganic by-product is in the range of 4.0 to 8.0. The moisture content of the inorganic by-product is in the range of 5% to 50%.

[0195] The inventors have found that the process of the present invention is applicable to the R-NO2 or R-NO compounds having one or more nitro or nitroso groups including aromatic R-N02or R-NO compounds like nitrobenzene, nitronaphthalenes, nitro anthracenes, nitrophenanthrenes, heterocyclic nitro or nitroso compounds with one or more hetero atoms either same or different, aliphatic nitro or nitroso compounds and all such other nitro or nitroso compounds.

[0196] Examples:

[0197] Examples of the reduction process described herein are now provided. The examples illustrate the conditions under which the reduction process is carried out in a minimal / stoichiometric quantity of water which is one of the key features of the present invention along with different Types of isolation methods i.e., Type A, Type B and Type C in respective Isolation Sequence.

[0198] Examples 1 : Phenylephrine Intermediate

[0199] Solvent : Toluene

[0200] Intermediate : 3-Aminoacetophenone from 3-Nitroacetophenone

[0201] Isolation : Type A

[0202] Fresh cycle (RO): In a round bottom flask equipped with stirrer, condenser, thermometer, addition port arranged in suitable heating / cooling system was charged 150ml Toluene, 25g 3 -Nitroacetophenone and 35g G-Cat at room temperature and then heated to 85°C. 45ml water was charged slowly during Ihr maintaining temperature at 85°C. The reaction mass was maintained at 85°C till all nitro compound was consumed in the reaction. Completion of reaction was 5 checked by TLC for disappearance of 3 -Nitroacetophenone. After reduction was over, pH was checked and then 2.5g R-CAT was slowly added in reaction mass at 85°C during 15mins. Reaction mass was maintained at 85°C for 30mins. Reaction mass was then filtered, the spent G-Cat collected and was washed with 50ml toluene of 65 °C temperature twice. The spent G-Cat was further washed 10 three times with 50ml water of 65 °C temperature. Total filtrate of toluene and water were collected and transferred in another round bottom flask equipped with stirrer, thermometer in suitable cooling / chilling system for isolation. The isolation mass was then chilled to 10°C and maintained for 3 hours at 10°C. The product was then filtered and was dried art room temperature to obtain 14.3gm 15 yellow colored product having melting point 96 - 98°C. The filtrate was settled for 30 minutes in separation flask to separate 202ml toluene and 122ml water layer and recycled in the next batch in place of toluene and water respectively.

[0203] Example 2 : Dabigatran Intermediate

[0204] 20 Solvent : Ethyl acetate

[0205] Intermediate : Ethyl-3-[[4-(methylamino)-3- aminobenzoyl](pyridin2yl)amino]propanoate from

[0206] Ethyl-3- [[4-(methylamino)-3- nitrobenzoyl](pyridine2yl)amino]propanoate

[0207] Isolation : Type B

[0208] Fresh cycle (RO): In a round bottom flask equipped with stirrer, condenser, thermometer, addition port arranged in suitable heating / cooling system was charged 144 ml Ethyl acetate, 20 g nitro compound and 25 g G-Cat at room temperature and then heated to 70 - 72°C. 12ml Water was charged slowly for 2 hours maintaining temperature at 70 - 72°C. The reaction mass was maintained at 70 - 74°C till all nitro compound was consumed in the reaction. Completion of reaction was checked by TLC for disappearance of nitro compound. After reduction was over, pH was checked and then 5.0 g R-Cat was slowly added in reaction mass at 70°C during 15mins. Reaction mass was maintained at 70 - 72°C for 30mins. Reaction mass was settled for 30 mins and the reaction mass was then decanted through Buchner funnel in filtration flask. 60 ml Ethyl acetate was charged in the RBF for Spent G-Cat extraction, and the reaction mass was heated to reflux temperature at 70 - 74°C. The reaction mass was maintained for 30 mins at 70 - 72°C and then filtered, the spent G -Cat collected and was washed with 15 ml Ethyl acetate of 65°C temperature twice. The spent G -Cat was further washed with 40 ml water of 65°C temperature for one time. Total filtrate of ethyl acetate and water were collected and transferred in separation funnel and settled for 30 mins. The ethyl acetate layer containing the product and water layer were then separated. The water layer was kept aside, and the Ethyl acetate layer was transferred to another round bottom flask equipped with stirrer, thermometer in suitable heating system for distillation. 60% of the total Ethyl acetate layer was distilled out which kept 105 ml Ethyl acetate in the RBF. The isolation mass was then chilled to 10°C and maintained for 2 hours at 10°C. The product was then filtered and was dried at room temperature to obtain 13.18 g m cream color product. The 99 ml filtrate generated after the product filtration was recycled in the next batch during distillation along with the Ethyl acetate layer of the next batch.

[0209] Example 3 : Pantoprazole Stage-1 Intermediate

[0210] Solvent : Methanol

[0211] Intermediate : 2.4-Difluoro aniline from 2,4-Difluoro nitrobenzene

[0212] Isolation : Type C

[0213] Fresh cycle (RO): In a round bottom flask equipped with stirrer, condenser, thermometer, addition port arranged in suitable heating / cooling system was charged 60 ml Methanol, 31.25 ml water, 43.75 gm G-Cat. 25 gm nitro was dissolved in 75 ml Methanol and this nitro solution was charged in the reaction mass and heated to reflux temperature of 70 - 75°C. The reaction mass was maintained for reaction for reaction completion for 1 hours at reflux temperature for reaction completion. Completion of reaction was checked by TLC for disappearance of nitro compound. After reduction was over, pH was checked and then 4.0 g R-Cat was slowly added in reaction mass at reflux temperature of 70 - 75°C in 15mins. Reaction mass was maintained at reflux temperature of 70 - 75°C for 30mins and then filtered, the spent G -Cat was washed with 50 ml hot methanol twice and then with 15 ml water of 65°C temperature for one time. 250 ml Total filtrate of methanol and water were collected and forwarded to distillation. Complete Methanol was distilled out at 10 - 15°C under vacuum to get 14.22 gm of the product.

[0214] Fresh cycle (RO): In a round bottom flask equipped with stirrer, condenser, thermometer, addition port arranged in suitable heating / cooling system was charged 60 ml Methanol, 31.25 ml water, 43.75 gm G-Cat. 25 gm nitro was dissolved in 75 ml Methanol and this nitro solution was charged in the reaction mass and heated to reflux temperature of 70 - 75°C. The reaction mass was maintained for reaction for reaction completion for 1 hours at reflux temperature for reaction completion. Completion of reaction was checked by TLC for disappearance of nitro compound. After reduction was over, pH was checked and then 4.0 g R-Cat was slowly added in reaction mass at reflux temperature of 70 - 75°C in 15mins. Reaction mass was maintained at reflux temperature of 70 - 75°C for 30mins and then filtered, the spent G -Cat was washed with 50 ml hot methanol twice and then with 15 ml water of 65°C temperature for one time. 250 ml Total filtrate of methanol and water were collected and forwarded to distillation. Complete Methanol was distilled out at 10 - 15°C under vacuum to get 14.98 gm of the product.

Claims

Claims1. A sustainable chemical process for reduction of nitro or nitroso compounds into corresponding amino compounds characterised in that said process has a number of cycles comprising a reaction sequence followed by an isolation sequence wherein said reaction sequence uses water as source of hydrogen for generation of sufficient reduction potential.

2. A process as claimed in claim 1 wherein liquid streams generated including mother liquor and / or water-miscible or water-immiscible solvents, and washings are recycled inherently in all of said cycles.

3. The process as claimed in claim 1, wherein the first cycle of said reaction sequence of said cycles has the following steps in the sequence :- step 1.1, a start-up step of charging a fresh reaction medium to a reaction vessel at once along with a predetermined quantity of said nitro or nitroso compound as is or in the form solution or mixture in solvent at once or over a duration of 0.5 hrs to 12 hrs, and an optional amount of water at once, or over a duration of 0.5 hrs to 20 hrs under agitating the mixture, by maintaining the pH of said mixture between 3 and 9 at a temperature between 20°C to reflux temperature, followed by adding a reducing formulation G-cat at once, or lot wise, or continuously over a duration of 0.5 to 20 hours ;- step 1.2a. a reduction step of charging said reducing formulation G-Cat at once or lot wise or continuously in a weight ratio in the range of 0.5 to 5.0;- step 1.2b. a reduction step of charging water continuously or in lots in a range between 0.25 and 4.0 w / w of nitro / nitroso compounds, and in the time range between 0.5 hrs to 20 hrs;- step 1.2c - a reduction step of maintaining the pH between 3 and 9 and a temperature between 20° and reflux temperature;- step 1.3a. a R-Cat treatment with pH adjustment step of charging a R-Cat treatment with pH adjustment formulation R-Cat between 0.05 to 0.5 w / w;- step 1.3b. R-Cat treatment with pH adjustment step of R-Cat treatment with pH adjustment by optionally adding a reaction medium; and a R-Cat at once or over a period of 10 minutes to 3 hours to maintain the pH between 3 and 9, at a temperature between 20° and reflux temperature; step 1.

4. decantation step wherein a settling and decantation step of forming layers, wherein the decantation mixture formed at the end of step 1.3, is settled for a predetermined period and at a predetermined pH, whereafter a clear layer formed is decanted and filtered through a filtration unit at a predetermined decantation temperature and a predetermined decantation pH;- step 1.

5. extraction and filtration step wherein the first extraction RM is charged and agitated at a suitable temperature in the range of 20° to reflux temperature and pH in the range of 6 to 9. The mixture thus formed is settled, decanted and filtered at a temperature being in the range of 20° to below reflux temperature and pH in the range of 6 to 9 and time in the range of 5 minutes to 8 hours; and charged as input to step 2.1;- step 1.

6. extraction and filtration step wherein the second extraction RM is charged and agitated at a suitable temperature in the range of 20° to reflux temperature and pH in the range of 6 to 9. The mixture thusformed is settled, decanted and filtered at a temperature being in the range of 20° to below reflux temperature and pH in the range of 6 to 9 and time in the range of 5 minutes to 8 hours; and charged as the input to step 2.1;- step 1.

7. washing and filtration step wherein a fresh RM is charged to the G-Cat spent & optionally mixed with R-Cat spent under agitation at the temperature in the range of 10° to reflux temperature and pH in the range of 6 to 9 and the filtration time is for 30 minutes to 5 hours at temperature range of 10° to below reflux temperature, the filtrate is then collected separately in a storage tank; and optionally charged as washing medium in step 1.7, in subsequent cycle; whereby a single cycle of said reaction sequence is completed, and whereafter a cycle of isolation sequence is carried out.

4. A process as claimed in claim 1, wherein in the case where said amines are the ones having sensitivity to temperature and are sparingly soluble at low temperatures, said isolation sequence comprises the following steps: step 2.1 A of charging the reaction mixture obtained at the end of step 1.7 of said reaction sequence containing amine product to the isolation vessel at a temperature between 20° C and reflux temperature and at a pH in the range of 6 to 9 followed by cooling or chilling the mixture thus formed to a temperature between -5° C and 40°C over a period between 30 min to 10 hours at a suitable pH and RPM; step 2.2A of charging the isolation mass obtained at the end of step 2.1 A to the filtration unit at a temperature between -5° C to 40°C for filtration in the time range of 30 minutes to 3 hours optionally followed by washing the wet product obtained with solvent and / or water;step 2.3A of charging the combined mother liquor stream generated, i.e. the mixture of water layer and solvent layer obtained at the end of step 2.2Ato a layer separation vessel at a temperature in the range between - 5° C and 40°C and pH in the range of 6 to 9, followed by allowing the mixture to settle at a temperature between -5° C to 40° C and pH in the range between of 6 to 9 over a period between 30 minutes to 8 hours.

5. A process as claimed in claim 1, wherein in the case said amines are moderately soluble and whose solubility is not temperature sensitive, said isolation sequence comprises the steps of: step 2.1B of charging the combined isolation mass obtained at the end of step 1.7 to the layer separation vessel at the temperature between 20° C and reflux temperature and at a pH in the range of 6 to 9, followed by allowing the mixture to settle at a pH in the range of 6 to 9, temperature between 20° to reflux temperature over a separation period between 30 minutes to 8 hours; step 2.2B of charging the solvent layer obtained at the end of layer separation in step 2. IB to a distillation vessel and is then concentrating it by partial distillation optionally at the vacuum in the range between 10 and 40 mm of mercury and at a pH in the range of 6 to 9 and time in the range of 30 minutes to 8 hours wherein the volume of partial solvent distillation is in the range of 50% to 90% of total input volume; step 2.3B of cooling / maintaining the saturated organic mass obtained after partial solvent distillation in step 2.2B to a temperature between -5° C to 30° C over a period in the range of 30 minutes to 8 hours and pH in the range of 6 to 9; step 2.4B. of filtering the isolation mass obtained at the end of step 2.3B at temperature in the range of -5° C to 30°C, and over a period in the range of 30 minutes to 3 hours.

6. A process as claimed in claim 1, wherein in the case said amines are highly soluble and their solubility is not temperature sensitive, said isolation sequence comprises the steps of:- step 2.1C of charging of the combined isolation mass, and distilling complete solvent optionally along with water, optionally at vacuum in the range of 10 mm to 40 mm of mercury and pH in the range of 6 to 9, and over a period in the range of 30 minutes to 10 hours;- step 2.2C of cooling or chilling / or maintaining of the organic mass obtained at the end of step 2.2B to a temperature in the range of -5° C to 30° C and pH in the range of 6 to 9;- step 2.3C of filtering the mass obtained at the end of step 2.2C at a temperature in the range of -5° C to 30°C and in the time range of 30 minutes to 3 hours.

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