FIELD OF THE INVENTION

The present invention relates to a process for preparation of pharmaceutically active compounds paracetamol and bromhexine from 4-nitro phenol and 2-nitro benzyl bromide respectively, via VO-TiO2 catalyzed nitro reduction. Particularly, the present invention provides a one-pot nitro reduction coupled with acetylation of amine for paracetamol, whereas nitro reduction in the case of bromhexine.

Paracetamol Bromhexine

BACKGROUND OF THE INVENTION

Paracetamol (acetaminophen), chemically called '-(4-hydroxy phenyl) belongs to a group of medicines known for analgesics effects. It is used to relieve pain and fever. Paracetamol is a common painkiller and is available in the market in the form of tablets/capsules/syrups containing the only paracetamol and sold in combination with other medicines. Paracetamol was firstly made in 1877 for analgesic and antipyretic action on CNS. The mechanism of the action over CNS was not elucidated yet. Many known processes of synthesis of paracetamol involve the use of expensive and controlled substances like acetic anhydride, which are regulated under the provisions of Narcotic Drugs and Psychotropic Act.

Also, control of iron-iron oxide sludge impurities on a commercial scale is very difficult; further, conventionally available methods involve multiple steps, like, use p-nitro chlorobenzene as starting material, which is further converted to p-nitrophenol, and this in turn is converted to p-aminophenol and then finally to paracetamol thereby involving several steps. Thus, there is a need for a novel and effective process for paracetamol preparation, which avoids the use of costly and harmful chemicals and provides paracetamol with higher purity and better yield. Also, there is a need for an improved process for the synthesis of paracetamol utilizing a heterogeneous metal catalyst, which reduces the metal contamination in the desired product and easy recovery of catalyst from the reaction mixture. The previously reported protocol for the synthesis of paracetamol utilizes a multistep synthetic route and expensive chemical substances. In patent US10286504B2, the synthesis was done by using biomass- derived p-hydroxybenzoate, which was undergoing a sequential chain of the reaction to form paracetamol. US 9,006,488 Bl described the synthetic process, which utilizes acetic anhydride and acetyl chloride to acetylate the p-aminophenol to produce paracetamol. A genetically modified biosynthetic pathway for the synthesis of paracetamol was disclosed in patent WO 2016069155. Another method for the synthesis of paracetamol utilizes multistep reaction, which involves nitration of phenol in the manufacturing of 4-nitrosophenol and optionally reacting the thus formed 4-nitrosophenol further to form paracetamol. WO 2010063276 described the process for the synthesis of paracetamol utilizing Nb catalyst by Beckman rearrangement. Several other processes were also developed for the synthesis of paracetamol like CN1569819, CN108689871A, EP536070, EP2975018, WO2014069875, CN103113254, RU2461543, CN102060729, CN1193982, RO112279, WO2017154024, CN1434026, US20040138509, WO 2006023763, WO 2006023763, WO 2006023763, CN1434026, CN104557592, CN102952032, CN109535010C, Journal of Molecular Catalysis A: Chemical, 355, 96-101; 2012, Synthesis, (19), 3316-3340; 2006, Pharmaceutical Chemistry Journal, 47(11), 610-611; 2014, ACS Catalysis, 7(4), 2698-2708; 2017, ACS Applied Materials & Interfaces, 8(44), 30058-30065; 2016, etc. most of the developed process utilizes multistep synthetic route, acetic anhydride or acetyl chloride for acetylation, expensive metal catalysts, which makes the process expensive.

Bromhexine is a drug used to treat chest congestion and cough. The molecule was patented in 1961 and was came into medicinal practice in 1966. The drug is marketed in both forms; tablet as well as syrup. In this regard CN101817754, CN105461568, IN2006MU00770, DD204913, RO71254, DE19529431, CN109535010, CN109096196 process have been developed. The process described in CN109535010 utilized Raney nickel to reduce the nitro compound into an amine, which is a flammable substance and needs much more precaution during the reaction. Other processes used to prepare the bromhexine required expensive chemicals, precious metal catalysts, pressure reactors, and strong oxidizing and reducing agents.

Present invention report production of paracetamol and bromhexine utilizing a recyclable heterogeneous catalyst system.

OBJECTS OF THE INVENTION

Main object of the present invention is to provide a process to prepare pharmaceutically active compound paracetamol and bromhexine from 4-nitro phenol and 2-nitro benzyl bromide, respectively, via VO-TiO2 catalyzed nitro reduction. Another object of the present invention is to provide a one-pot preparation of paracetamol.

Yet another objective of the present invention is to provide bromhexine synthesis under milder and non-hazardous conditions.

SUMMARY OF THE INVENTION

Accordingly, present invention provides a process for the preparation of pharmaceutically active compound of formula I comprising the steps of:

Formula I i. adding para-nitrophenol and reducing agent in a ratio ranging between 1: 1 to 1:5 in an organic solvent in the presence of a 3 to 30% w/w catalyst system to obtain para-aminophenol (PAP); ii. stirring the reduced mixture as obtained in step (i) at a temperature in a range of 30 to 160 °C, preferably between 90 to 150 °C for a period in a range of 0.5-48 hours preferably 1-30 hours to obtain a reaction mixture; iii. adding acetylating agent to the reaction mixture as obtained in step (ii) followed by raising the temperature in a range of 70 to 170 °C for period in a range of 12 to 36 hours to obtain a mixture; iv. cooling the reaction mixture as obtained in step (iii) at temperature in a range of 20 to 35 °C followed by separating and recycling the catalyst to obtain the pharmaceutically active compound of formula I.

In an embodiment of the present invention, the acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, acetic acid, acetamide preferably acetic acid.

In another embodiment of the present invention, the catalyst system comprising of transition metal/metals catalyst.

In yet another embodiment of the present invention, the catalyst system used is VO-TiCh.

In yet another embodiment of the present invention, the reaction results into a product, for example, paracetamol which is > 60 % w/w in the crude mixture as measured by HPLC or NMR. A process of preparing pharmaceutically active compound of formula II comprising the steps of:

Formula II i. adding N-(2-nitrobenzyl)-N-methylcyclohexylamine and reducing agent in a ratio ranging between 1: 1 to 1:5 in a solvent in presence of a 3 to 30% w/w catalyst system at a temperature in a range of 70 to 170°C to obtain N-(2 -amino benzyl)-N -methylcyclohexylamine ; ii. transforming N-(2-amino benzyl)-N-methylcyclohexylamine as obtained in step (i) to bromhexine using brominating agent in an organic solvent at a temperature in a range of 0 to 25 °C to obtain compound of formula II.

In yet another embodiment of the present invention, the catalyst system comprising of transition metal/metals catalyst.

In yet another embodiment of the present invention, the catalyst system used is VO-TiCh.

In yet another embodiment of the present invention, the brominating agent used is N- Bromosuccinimide (NBS) or other brominating agents.

In yet another embodiment of the present invention, the solvent used is selected from the group consisting of ACN, DCM, tertiary butanol, water, toluene, DMF, ethanol, PEG and IPA, preferably ethanol.

In yet another embodiment of the present invention, the reducing reagent used is selected from the group consisting of formic acid, acetic acid, silanes, molecular hydrogen, sodium borohydride, ammonia, and hydrazine hydrate, preferably hydrazine hydrate.

In yet another embodiment of the present invention, the reaction results into a product, for example, bromhexine which is > 40 % w/w in the crude mixture as measured by HPLC or NMR. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of /V-acetyl aminophenol (paracetamol) from p-nitrophenol and bromhexine over heterogeneous recyclable catalyst. This invention provides a clean and economical method for the synthesis of the most prescribed analgesic paracetamol. The method excludes the use of 4-aminophenol and acetic anhydride or acetyl chloride, which is mostly used for the synthesis of paracetamol. The invention was coupled with the use of a heterogeneous metal catalyst, which was reused for the next cycles of the reaction without losing their catalytic activity, and the separation of the catalyst from the mixture was easy.

Present invention provides an economical one-pot method for the preparation of paracetamol from p-nitrophenol. In another aspect of the invention, the process utilizes acetic acid for the acetylation of the p-aminophenol generated in-situ in the reaction mixture. The heterogeneous VO-TiCh catalyst catalyzed the reaction to achieve the target compound in excellent yield. The present invention process comprises subjecting p-nitrophenol to the liquid phase reduction in an organic solvent and the presence of a catalyst system comprising of transition metal/metals catalyst.

Present invention discloses a process for preparation of pharmaceutically active compound of formula I, comprising the steps of: i) adding p-nitrophenol and a reducing agent in a ratio ranging between 1: 1 to 1:5 in an organic solvent in presence of a 3 to 30% w/w catalyst system to obtain para-aminophenol (PAP) in a reduced mixture; ii) stirring the reduced mixture as obtained in step (i) at a temperature in a range of 30 to 160°C, preferably between 90 to 150°C for a period in a range of 0.5-48 hours, preferably 1-30 hours to obtain a reaction mixture; iii) adding acetylating agent to the reaction mixture as obtained in step (ii) followed by raising the temperature in a range of 70 to 170°C for period in a range of 12 to 36 hours to obtain a mixture; iv) cooling the reaction mixture as obtained in step (iii) at temperature in a range of 20 to 35 °C followed by separating and recycling the catalyst to obtain the pharmaceutically active compound of formula I. para -Nitrophenol Paracetamol

Scheme I Present invention also discloses a process of preparing a pharmaceutically active compound of formula II, comprising the steps of: i) adding N-(2-nitrobenzyl)-N-methylcyclohexylamine and a reducing agent in a ratio ranging between 1: 1 to 1:5 in a solvent in presence of a 3 to 30% w/w catalyst system at a temperature in a range of 70 to 170°C to obtain N-(2 -amino benzyl)- N-methylcyclohexylamine; ii) transforming N-(2-amino benzyl)-N-methylcyclohexylamine as obtained in step (i) using a brominating agent in an organic solvent at a temperature in a range of 0 to 25 °C to obtain the pharmaceutically active compound of formula II.

N-(2-amlno benzyi)-N- Bromhexine meihyicyclohexylamine

Scheme II

In a feature of the present invention, the catalyst system comprising of transition metal/metals catalyst.

In a feature of the present invention, the catalyst system used is VO- TiO2.

In a feature of the present invention, the acetylating agent is selected from a group consisting of acetic anhydride, acetyl chloride, acetic acid and acetamide, preferably acetic acid.

In a feature of the present invention, the brominating agent used is N-Bromosuccinimide (NBS) or other brominating agents.

In a feature of the present invention, the solvent is selected from a group consisting of acetonitrile, dichloromethane, tertiary butanol, water, toluene, dimethylformamide, ethanol, polyethylene glycol and isopropyl alcohol, preferably ethanol.

In a feature of the present invention, the reducing reagent is selected from a group consisting of formic acid, acetic acid, silanes, molecular hydrogen, sodium borohydride, ammonia, and hydrazine hydrate, preferably hydrazine hydrate.

The reaction was carried out in the presence of a reductant and a temperature range of 30°C- 170 °C, preferably between 90°C-150°C for a period of 0.5-48 hours, preferably 1-30 hours. The reaction was performed in the solution phase. The solvent used for the reaction is selected from Acetonitrile (ACN), Dichloromethane (DCM), tertiary butanol, water, toluene, Dimethylformamide (DMF), ethanol, Polyethylene glycol (PEG), and Iso-propyl alcohol (IP A). Most preferably, ethanol was used as a solvent for the vanadium catalyzed reaction.

The concentration of catalyst concerning the nitro compound was in the range of 1-30%, preferably 3-30 wt % (w/w) of the nitro compound. The supported heterogeneous vanadium catalysts were prepared according to literature (S. K. Maurya et al. / Journal of Molecular Catalysis A: Chemical 234 (2005) 51-57), which have the strength of the vanadium oxide over titanium oxide was 1-30 wt%. Preferably 20 wt% of the catalyst was used for the excellent yield and better selectivity towards the desired product.

The reducing reagents are selected from the group consisting of formic acid, acetic acid, silanes, molecular hydrogen, sodium borohydride, ammonia, hydrazine hydrate, and preferably hydrazine hydrate was used for better conversion. Their concentration was varying concerning nitro compound and ranged in 1-15 equivalent, most preferably the 3-6 equiv. of the reductant was used.

For acetylation of the amine, the acetylating agent was chosen from acetic anhydride, acetyl chloride, acetic acid, acetamide; most preferably, the acetic acid was used for excellent yield with higher selectivity.

The current invention comprises the studies for recyclability of catalyst. Before separating the catalyst from the reaction mixture, it must ensure the reaction mixture's temperature is optimal to separate the catalyst most preferably; it ranges between 25°C to 35°C. The separated catalyst was washed with a suitable solvent system and dried in an oven at 100-120 °C to reuse the catalyst for the reaction's next cycle . Most preferably, the vanadium -based catalyst was washed with acetone and, after drying, again used for the next cycle.

The reaction products were characterized by using NMR (ID and 2D), IR, GC-MS, UPLC, and other modem characterization techniques. Most preferably, the progress of the reaction was monitored by UPLC-MS.

EXAMPLES

Following examples are given by way of illustration and therefore should not be constmed to limit the scope of the invention.

Example 1: Catalyst VO-TiCh preparation at 10-gram scale (Sol-Gel Method)

Example 1-A: Catalyst C-03 [VO-TiCh (3% strength)] preparation at 10-gram scale Preparation of titanium peroxo-complex solution (a): To a beaker charged with 41.33 g of Ti(OBu)4 was added 1000 mL deionized water, and the resulting solution was stirred at 25 °C for 30 min. To this solution was slowly added 200 mL of H2O2 (30% aq.) that resulted in an orange-coloured titanium peroxocomplex solution.

Preparation of peroxovanadic solution (b): 0.3 g of V2O5 was hydrolyzed with 250 mL of deionized water under continuous stirring in a beaker. To this hydrolyzed solution was added 30.0 mL of H2O2 (30% aq.) dropwise to furnish peroxovanadic solution.

Preparation of VzOs/TiCh catalyst (Sol-Gel Method)

Peroxovanadic solution (b) was added to the titanium peroxo-complex solution (a) dropwise via a dropping funnel with continuous stirring to furnish a greenish viscous gel. The resultant gel was dried at 25 °C for 24 hours, followed by drying at 80 °C for 12 hours, and then calcinated at 400 °C for 8 hours.

Example 1-B: Catalyst C-05 [VO-TiCh (5% strength)] preparation at 10-gram scale Preparation of titanium peroxo-complex solution (a): To a beaker charged with 40.4 g of Ti(OBu)4 was added 1000 mL deionized water, and the resulting solution was stirred at 25 °C for 30 min. To this solution was slowly added 200 mL of H2O2 (30% aq.) that resulted in an orange-coloured titanium peroxocomplex solution.

Preparation of peroxovanadic solution (b): 0.5 g of V2O5 was hydrolyzed with 250 mL of deionized water under continuous stirring in a beaker. To this hydrolyzed solution was added 30.0 mL of H2O2 (30% aq.) dropwise to furnish peroxovanadic solution.

Preparation of VzOs/TiCh catalyst (Sol-Gel Method)

Peroxovanadic solution (b) was added to the titanium peroxo-complex solution (a) dropwise via a dropping funnel with continuous stirring to furnish a greenish viscous gel. The resultant gel was dried at 25 °C for 24 hours, followed by drying at 80 °C for 12 hours, and then calcinated at 400 °C for 8 hours.

Example 1-C: Catalyst C-10 [VO-TiCh (10% strength)] preparation at 10-gram scale Preparation of titanium peroxo-complex solution (a): To a beaker charged with 38.35 g of Ti(OBu)4 was added 1000 mL deionized water, and the resulting solution was stirred at 25 °C for 30 minutes. To this solution was slowly added 200 mL of H2O2 (30% aq.) that resulted in an orange -coloured titanium peroxocomplex solution. Preparation of peroxovanadic solution (b): 1.0 g of V2O5 was hydrolyzed with 250 mL of deionized water under continuous stirring in a beaker. To this hydrolyzed solution was added 30.0 mL of H2O2 (30% aq.) dropwise to furnish peroxovanadic solution.

Preparation of VzOs/TiCh catalyst (Sol-Gel Method)

Peroxovanadic solution (b) was added to the titanium peroxo-complex solution (a) dropwise via a dropping funnel with continuous stirring to furnish a greenish viscous gel. The resultant gel was dried at 25 °C for 24 hours, followed by drying at 80 °C for 12 hours, and then calcinated at 400 °C for 8 hours.

Example 1-D: Catalyst C-20 [VO-TiCh (20% strength)] preparation at 10-gram scale Preparation of titanium peroxo-complex solution (a): To a beaker charged with 34.0 g of Ti(OBu)4 was added 1000 mL deionized water, and the resulting solution was stirred at 25 °C for 30 minutes. To this solution was slowly added 200 mL of H2O2 (30% aq.) that resulted in an orange -coloured titanium peroxocomplex solution.

Preparation of peroxovanadic solution (b): 2.0 g of V2O5 was hydrolyzed with 250 mL of deionized water under continuous stirring in a beaker. To this hydrolyzed solution was added 30.0 mL of H2O2 (30% aq.) dropwise to furnish peroxovanadic solution.

Preparation of VzOs/TiCh catalyst (Sol-Gel Method)

Peroxovanadic solution (b) was added to the titanium peroxo-complex solution (a) dropwise via a dropping funnel with continuous stirring to furnish a greenish viscous gel. The resultant gel was dried at 25 °C for 24 hours, followed by drying at 80 °C for 12 hours, and then calcinated at 400 °C for 8 hours.

Example 1-E: Catalyst C-30 [VO-TiCh (30% strength)] preparation at 10 gram scale Preparation of titanium peroxo-complex solution (a): To a beaker charged with 29.8 g of Ti(OBu)4 was added 1000 mL deionized water, and the resulting solution was stirred at 25 °C for 30 minutes. To this solution was slowly added 200 mL of H2O2 (30% aq.) that resulted in an orange -coloured titanium peroxocomplex solution.

Preparation of peroxovanadic solution (b): 3.0 g of V2O5 was hydrolyzed with 250 mL of deionized water under continuous stirring in a beaker. To this hydrolyzed solution was added 30.0 mL of H2O2 (30% aq.) dropwise to furnish peroxovanadic solution.

Preparation of VzOs/TiCh catalyst (Sol-Gel Method)

Peroxovanadic solution (b) was added to the titanium peroxo-complex solution (a) dropwise via a dropping funnel with continuous stirring to furnish a greenish viscous gel. The resultant gel was dried at 25 °C for 24 hours, followed by drying at 80 °C for 12 hours, and then calcinated at 400 °C for 8 hours.

Example 2: Procedure for the synthesis of p-amino phenol (PAP) from the reduction of p-nitrophenol

Example 2-A: Reduction of p-nitrophenol with C-03 Catalyst (3 % VO-TiCh)

To a glass vessel placed 1.0 g of p-nitrophenol (1.0 equivalent) and was added 100 mg of C- 03 catalyst (10 wt % of nitro compound), 10 mL of ethanol (10.0 V), and 1.08 mL ofhydrazine hydrate (3.0 equivalent), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or filtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 5% yield (55 mg).

Example 2-B: Reduction of p-nitrophenol with C-05 Catalyst (5 % VO-TiOz)

To a glass vessel placed 1.0 g of p-nitrophenol (1.0 equiv.) and was added 100 mg of C-05 catalyst (10 wt % of nitro compound), 10 mL of ethanol (10.0 V), and 1.08 mL of hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or filtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 8 % yield (87 mg).

Example 2-C: Reduction of p-nitrophenol with C-10 Catalyst (10 % VO-TiOz)

To a glass vessel placed 1.0 g of p-nitrophenol (1.0 equiv.) and was added 100 mg of C-10 catalyst (10 wt % of nitro compound), 10 mL of ethanol (10.0 V), and 1.08 mL of hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or fdtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 35% yield (380 mg).

Example 2-D: Reduction of p-nitrophenol with C-20 Catalyst (20 % VO-TiOz) To a glass vessel placed 1.0 g of p-nitrophenol (1.0 equiv.) and was added 100 mg of C-20 catalyst (10 wt % of nitro compound), 10 mL of ethanol (10.0 V), and 1.08 mL of hydrazine hydrate (1.08 mL, 3.0 equiv.), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or filtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 96% yield (1.04 g).

Example 2-E: Reduction of p-nitrophenol with C-30 Catalyst (30 % VO-TiCh)

To a glass vessel placed 1.0 g of p-nitrophenol (1.0 equiv.) and was added 100 mg of C-30 catalyst (10 wt % of nitro compound), 10 mL of ethanol (10 mL, 10.0 V), and 1.08 mL of hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or filtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 95% yield (978 mg).

Example 3

Example 3-A: Synthesis of paracetamol at 10 g scale with C-20 Catalyst (20% VO-TiCh) All reactions were conducted in a sealed vertical glass vial having a rounded and closed bottom or round bottom flask equipped with a condenser. The tube or flask portion of the reaction apparatus was immersed in an oil bath.

To a glass vessel placed 10.0 g of para-nitrophenol (1.0 equiv.) and was added 1.0 g of C-20 catalyst (10 wt % of nitro compound), 100 mL of ethanol (10.0 V), and 10.8 mL of hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90°C for 3 hours. After complete conversion of the nitro to amine, 43.1 mL acetic acid (10.0 equiv.) was added to the reaction mixture, and the temperature was raised to 150 °C and stirred for 24 hours. After complete conversion of amine to their respective acetyl derivative (monitored by UPLC-MS), the reaction mixture was cooled to 30 °C; and the catalyst was separated by filtration or by centrifugation methods. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 93% yield (10.1 g). 'H NMR (600 MHz, Chloroform-d): 3 9.67 (s, 1H), 9.17 (s, 1H), 7.35 (d, J = 9.0 Hz, 2H), 6.69 (d, J= 9.0 Hz, 2H), 1.98 (s, 3H). ¹³ C NMR (151 MHz, Chlor oform-d): 3 167.6, 153.2, 131.1, 120.9, 115.1, 23.8.

Example 3-B: Synthesis of paracetamol at 10 g scale with C-30 Catalyst (30% VO-TiCh) To a glass vessel placed 10.0 g para-nitrophenol (1.0 equiv.) and was added 1.0 g of C-30 catalyst ( 10 wt % of nitro compound), 100 mL ethanol ( 10.0 V), and 10.8 mL hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90°C for 3 hours. After complete conversion of the nitro to amine, 43.1 mL acetic acid (10.0 equiv.) was added to the reaction mixture, and the temperature was raised to 150 °C and stirred for 24 hours. After complete conversion of amine to their respective acetyl derivative (monitored by UPLC-MS), the reaction mixture was cooled to 30 °C; and the catalyst was separated by filtration or by centrifugation methods. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 90% yield (9.8 g).

Example 4: Synthesis of Bromhexine (B)

Step 1: To a glass vessel, placed 1.57 g A-mcthyl cyclohexylamine (1.1 equiv.) and was added 50 mL DCM (20.0 V of 2-nitrobenzyl bromide), cooled the resulting mixture to 0°C, and added 8.1 mL triethylamine (5.0 equiv.) and stirred for 5 minutes. A solution of 2.5 g of 2-nitrobenzyl bromide (1.0 equiv.) in 25 mL DCM (10.0 V) was added dropwise and resulting mixture was stirred for 2 hours at room temperature. Upon completion, the reaction mixture was washed with saturated brine solution (100 mL) and extracted with DCM (3 x 100 mL), filtered over sodium sulfate, and dried under reduced pressure to obtain the compound in 88% yield (2.53 g)-

Step 2: The 2.53 g of obtained compound from step 1 was taken in a glass vessel and to this was added 253 mg of C-20 catalyst (10 wt % of nitro compound), 25.3 mL of ethanol (10.0 V), and 1.53 mL of hydrazine hydrate (3.0 equiv.), the resulting mixture was then stirred at 90 °C for 3 hours. On completion of the reaction, the catalyst was separated by centrifugation or filtration method. The resulting solution was then evaporated to dryness and then diluted with ethyl acetate and washed with water and bicarbonate solution. The organic phase was dried over a rotatory evaporator, furnished desired product in 91% yield (2.0 g).

Step 3: The 2.0 g of obtained compound from step 2 was dissolved in 8.3 mL DCM (4.16 V) and cooled at 0 °C, to this solution, a solution of 3.58 g of NBS in 223.7 mL DCM (62.5 V) was added dropwise and stirred the resulting mixture for 30 minutes at the same temperature. On completion of the reaction, the resulting mixture was washed with water (100 mL) and extracted with DCM (3 x 100 mL). Organic layers evaporated to dryness under reduced pressure and purified by using silica gel chromatography to obtained desired compound in 54% yield (1.88 g).

'H NMR (600 MHz, Chlor of orm-d): 37.48 (d, J= 2.4 Hz, 1H), 7.06 (d, J= 1.8 Hz, 1H), 5.51 (s, 2H), 3.61 (s, 2H), 2.40-2.45 (m, 1H), 2.13 (s, 3H), 1.82 (d, J= 10.4 Hz, 4H), 1.66 (d, J = 12.5 Hz, 1H), 1.34 - 1.23 (m, 4H), 1.16 - 1.08 (m, 1H). ¹³ C NMR (151 MHz, Chloroform- d): 3 144.1, 132.9, 131.7, 126.2, 110.0, 108.0, 61.9, 36.4, 28.2, 26.3, 25.9.

Example 5: General procedure for catalyst recyclability

On completion of the reaction, the reaction mixture was cooled to 25 °C and diluted with ethyl acetate. The catalyst was then recycled via fdtration or centrifugation method. The catalyst was then washed with the acetone and dried in the oven at 100 °C for 2 hours, and again used for the next cycle of the reaction.

ADVANTAGES OF THE INVENTION

The present invention has following advantages:

(1) One -pot synthetic protocol for the preparation of paracetamol.

(2) The developed system utilizes heterogeneous recyclable VO-TiO2 catalyst, that can be recycled and reused for the multiple times.

(3) The synthetic protocol of bromhexine synthesis utilized less hazardous chemicals and reagents.

(4) The present invention avoids the use of controlled chemical substances such as acetic anhydride.