A CATALYST FOR ONE POT SYNTHESIS OF NABUMETONE AND PROCESS OF PREPARATION THEREOF FIELD OF INVENTION

The present invention relates to novel catalyst composition for a selective synthesis of Nabumetone. More particularly, the present invention provides a novel catalyst composition for one pot and selective synthesis of Nabumetone and process of preparation of said catalyst. The present invention provides a bifunctional catalyst having condensation and hydrogenation properties for one pot synthesis of Nabumetone comprising of active metals Nickel and Lanthanum-magnesium mixed oxide on support of mesoporous silica.

BACKGROUND OF THE INVENTION

4-(6-Methoxy-2-naphthalenyl)-2-butanone is pharmaceutical active agent, commonly known as Nabumetone (NBM) having below depicted structure formula

(I):

Nabumetone (NBM) is well recognized non-steroidal anti-inflammatory drug (NSAID). NBM is majorly used for its anti-inflammatory, analgesic, and antipyretic effects. Additionally, it has been used in a chronic pain reliever in rheumatoid arthritis and osteoarthritis primarily because of its lower risk of gastrointestinal side effects compared to its analogue Naproxen. Recently, it was also reportedly used as an effective drug for post-operative pain. Conventionally NBM is synthesized by Mizoroki-Heck reaction of methyl vinyl ketone (MVK), 2- halo-6-methoxynaphthalene (2HMN), and olefins using homogeneous Pd-complex catalyst. There are several reports where the use of homogenous base catalyst such as NaOH and KOH is made to convert 2HMN using exotic solvent dimethyl sulfoxide (DMSO). Although these synthesis processes have shown satisfactory yield and selectivity, aryl halides (R-X) as reactants generate halide impurities and undesirable wastes. Therefore, the process is not green.

Thus, to solve the above problem, inventors of the present invention has developed novel heterogeneous multifunctional catalyst, which can be used in aldol condensation of 6-methoxy-2-naphthaldehyde (6MNAL) with acetone followed by hydrogenation in a solvent-free condition to produce NBM in one pot. It would be a green option and hence, environment safe.

A review of prior arts suggests that NBM synthesis (SCHEME I) has been conducted by using two routes, namely, (i) one pot synthesis from 6MNAL and acetone, and (ii) aldol condensation of 6MNAL and acetone to produce 4-(6- methoxy-2-naphthalenyl)-3-buten-2-one (1), isolation of 1 and then hydrogenation of 1 to NBM. Microwave -batch aldol condensation of 6MNAL and acetone was studied at 70 °C for 7.5 min, using NaOH as a base catalyst with 99% conversion of 6MNAL and 97% yield of 1.

6-methoxy-2-naphthaldehyde Acetone 4-(6-methoxy-2-naphthaleny l)-3 -buten-2-one

(6MNAL)

SCHEME I

Hence, there is required to perform a condensation first and followed by hydrogenation to perform the said synthesis in single steps in a single pot. Accordingly, the present invention develop a new multifunctional catalyst which can solely perform both the aldol condensation and hydrogenation steps in a single pot and provide a selective synthesis of Nabumetone and process of preparation of said catalyst.

OBJECTIVES OF THE INVENTION:

• The primary objective of the present invention aims to provide a catalyst for selective synthesis of Nabumetone in single step and process of preparation of said catalyst.

• One more objective of present invention is to provide a bifunctional catalyst that will favours two reactions mainly condensation and hydrogenation in single step.

• Y et one more obj ective of present invention is to provide a bifunctional catalyst that will avoid leaching of any of active metals in reaction mass and provides an effective reusable heterogeneous catalyst. · Another objective of the present invention aims to provide a selective synthesis of Nabumetone in single step.

SUMMARY OF THE INVENTION:

The present invention relates to heterogeneous catalyst for selective synthesis of Nabumetone without using additional solvent in reaction mass as well as in single pot process. More specifically, the present invention provides a bifunctional catalyst that will favours two reactions in selective synthesis of Nabumetone mainly condensation and hydrogenation in single step.

Accordingly, the present invention provides a heterogeneous supported catalyst having bifunctional condensation and hydrogenation properties for one pot synthesis of Nabumetone comprising of: Nickel and Lanthanum-magnesium mixed oxide on support of mesoporous silica; Wherein Lanthanum-magnesium mixed oxide are entrapped in pores and surface of support is coated with Nickel with the result that it prevent the leaching of Lanthanum-magnesium mixed oxide in reaction medium and provides reusability of catalyst.

The catalyst is having surface area in the range of 250 to 300 m ² /g, pore volume in the range of 0.60 to 0.70 cm ³ /g and pore diameter in the range of 7.0 to 9.0 nm.

The percentage of Nickel metal loading is in the range of 3.0 to 5.0% of total weight of catalyst and Lanthanum-magnesium mixed oxide metal loading is in the range of 25 to 30% of total weight of catalyst.

In accordance to one more embodiment, the mole ratio of Lanthanum magnesium in Lanthanum-magnesium mixed oxide metal is 0.005 to 0.015.

The present invention also provides a process for preparation of heterogeneous supported catalyst having bifunctional condensation and hydrogenation properties for one pot synthesis of Nabumetone comprising the steps of;

a) Preparation of mesoporous silica suspension in water,

b) First impregnation by dropwise addition of mixture of aqueous solution of 0.005 mol lanthanum nitrate hexahydrate, 0.015 mol magnesium nitrate hexahydrate under stirring for 5 h,

c) Evaporation of solution by drying at 120 ⁰ C for 12 h,

d) Second impregnation by dropwise addition of aqueous solution of the Nickel nitrate hexahydrate on material of step c) under stirring for 5 h,

e) Evaporation of solution by drying at 120 ⁰ C for 12 h and calcining at temperature between 500 to 650 ⁰ C for 4 h.

BRIEF DESCRIPTION OF DRAWINGS:

For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying Figures and in which: Figure 1 : Illustrate CO2-TPD pattern of different catalysts, A) LMMOHT, B) 40%LMMO/MCF, C) virgin 4%Ni-40%LMMO/MCF _SM , and D) reused 4%Ni- 40%LMMO/MCFSIM.

Figure 2: Illustrate XRD of different catalysts prepared by impregnation method; a) MCF, b) 10%LMMO/MCF, c) 20%LMMO/MCF, d) 30%LMMO/MCF, e) 40%LMMO/MCF, f) 50%LMMO/MCF, g) virgin 4%Ni-40%LMMO/MCF _SiM , h) reused 4%Ni-40%LMMO/MCF _SM and i) 4%Ni-40%LMMO/MCF _Cp (Prepared by Co-precipitation method)

Figure 3: Illustrate XRD of i) MgO, j) LMMOHT, and k) LaiO^

Figure 4: Illustrate SAXS of different catalyst: A) MCF, B) 40%LMMO, C) virgin 4%Ni-40%LMMO/MCF _S M, and D) reused 4%Ni-40%LMMO/MCF _SM .

Figure 5: Illustrate FTIR spectra for a) LMMO, b) MCF, c) 10%LMMO/MCF, d) 20%LMMO/MCF e) 30%LMMO/MCF, f) 40%LMMO/MCF, g) 50% LMMO/MCF, h) virgin 4% Ni-40% LMMO/MCF _S IM, and i) reused 4%-Ni 40%LMMO/MCFSIM.

Figure 6: Illustrate FESEM of MCF (A and B), virgin 4%NI-40%LMMO/MCF _S IM (C and D), and reused 4% Ni-40% LMMO/MCF _S M (E and F).

Figure 7: Illustrate catalyst screening for condensation reaction as depicted in example no. 2.

Figure 8: Illustrate catalyst screening for one pot reaction of condensation followed by hydrogenation as depicted in example 4.

Figure 9: Illustrate effect of catalyst loading on conversion of 6MNAL.

Figure 10: Illustrate reusability study using 4%NI-40%LMMO/MCF _S M catalyst Prepared by sequential impregnation method as per present invention.

Figure 11 : Illustrate reusability study using 4%Ni-40%LMMO/MCFcp catalyst Prepared by Co-precipitation method. DETAILED DESCRIPTION OF THE INVENTION:

This invention relates to a novel catalyst composition for the synthesis of Nabumetone or precursors thereof, and more particularly to novel heterogeneous catalyst for environmentally -friendly process technology suitable for producing Nabumetone on a commercial scale.

In one of its embodiments this invention provides a novel and multifunction catalyst for production of Nabumetone, and method to prepare to said catalyst. The said novel catalyst comprises of Lanthanum, Magnesium, and Nickel particles doped on specific type of silica support, preferably that the support is in amorphous nature.

As the objective of the present invention is to provide a single pot process for synthesis of Nabumetone, as Nabumetone synthesis from 6MNAL and acetone involves cascade reaction (Scheme I), firstly condensation in basic catalyst and hydrogenation in the presence of metal catalyst. Thus, providing a single pot process is major problem for selective synthesis of Nabumetone.

The present invention relates to heterogeneous catalyst for selective synthesis of Nabumetone without using additional solvent in reaction mass as well as in single pot process. More specifically, the present invention provides a bifunctional catalyst that will favours two reactions in selective synthesis of Nabumetone mainly condensation and hydrogenation in single step.

The multifunctional catalyst provided in present invention is comprising of metal Nickel (Ni) and Lanthanum-Magnesium mixed oxide (LMMO) doped on mesoporous silica (MCF) support having amorphous structure. Wherein, the single multifunctional catalyst comprising metal Ni, LMMO, and MCF produces the synergistic effect in selectively firstly carry condensation followed by hydrogenation in a single reactor.

Accordingly, the present invention provides a heterogeneous supported catalyst having bifunctional condensation and hydrogenation properties for one pot synthesis of Nabumetone comprising of: Nickel and Lanthanum-magnesium mixed oxide on support of mesoporous silica; Wherein Lanthanum-magnesium mixed oxide are entrapped in pores and surface of support is coated with Nickel with the result that it prevent the leaching of Lanthanum-magnesium mixed oxide in reaction medium and provides reusability of catalyst.

The catalyst is having surface area in the range of 250 to 300 m ² /g, pore volume in the range of 0.60 to 0.70 cm ³ /g and pore diameter in the range of 7.0 to 9.0 nm. The percentage of Nickel metal loading is in the range of 3.0 to 5.0% of total weight of catalyst and Lanthanum-magnesium mixed oxide metal loading is in the range of 25 to 30% of total weight of catalyst.

In accordance to one more embodiment, the mole ratio of Lanthanum magnesium in Lanthanum-magnesium mixed oxide metal is 0.005 to 0.015.

In one aspect, the present invention, Mesoporous cellular foam (MCF) is a silica composed of large, three-dimensional (3D) spherical cells that consist uniform size windows. MCF possesses a very high pore volume and surface area including thermal stability, which can be exploited to support for transition metals and generate more catalytically active sites for reaction. But, simply impregnation of lanthanum-magnesium mixed oxide and transition metals such as Ni, Cu, and Fe on said Mesoporous cellular foam (MCF) disturbed the structure of MCF that affects the actual performance of heterogeneous catalyst. Such as leaching of active metals after single use. Hence, the present invention are based on an efforts for combining the effect of transition metals, mixed oxide, and MCF for one-pot, wherein the heterogeneous catalyst can be separate and reuse for multiple cycle of synthesis batches.

Accordingly, the present invention provides a novel catalyst comprising y%M- x%LMMO/MCF catalyst, wherein M= Ni, Fe, and Cu; y vary between 1 to 10 wt. % and x vary from 10, 20, 30, 40, and 50 wt. %.

In second aspect, the process of preparation of said multifunctional catalyst involve using a specific type of support material, more particularly, suggests that the Structure is amorphous in nature and when doped with Lanthanum, Magnesium, and Nickel particles are dispersed evenly over the surface and inside the pores of MCF, it helping to increase the selectivity of final product instead of side reaction and maintaining the integrity of catalyst after many cycle due to chemical bonding and avoiding leaching of active metals during repetitive use.

The said process includes following process steps:

At first, known quantity of MCF is treated with lanthanum nitrate hexahydrate and magnesium nitrate hexahydrate using sequential impregnation followed by solvent evaporation technique and the drying above 100 ⁰ C for more than 5 h.

The second sequential impregnation with metal (M) such as aqueous solution of the metal nitrate using solvent evaporation technique, and drying material above 100 ⁰ C for more than 5 h. Followed by calcination at above 500 ⁰ C to give y%M- x%LMMO/MCF catalyst.

M= Ni, Fe, and Cu.

The present invention is further described with the help of the following examples, which are given by way of illustration.

EXAMPLES:

Example 1 : Preparation of Catalyst by sequential impregnation method as per present invention composition:

At first a known quantity of MCF was added to a beaker containing 50 ml distilled water. To this suspension, aqueous solution of 0.005 mol lanthanum nitrate hexahydrate and 0.015 mol magnesium nitrate hexahydrate (mole ratio La: Mg = 1 :3) was added dropwise. The solution was stirred vigorously for 5 h. Finally, the solvent was evaporated and the material dried at 120 ⁰ C for 12 h. It was calcined at 600 ⁰ C for 4 h. Different loadings of LMMO such as 10, 20, 30, 40, and 50 wt. % over MCF were prepared to get corresponding wt. % of LMMO/MCF catalyst. The second sequential impregnation with metal (M) such as aqueous solution of the metal nitrate was done. This was followed by stirring for 2 h, evaporation of solvent, and drying at 120 ⁰ C for 12 h. The dried material was calcined in air at 600 ⁰ C for 4 h to give y%M-x%LMMO/MCF catalyst. (i.e y%M-x%LMMO/MCFsM) Wherein, sixi is short form used for sequential impregnation method.

A. Characterisation of Catalyst

1) CO2-TPD: The basic strength of all the synthesized catalyst was calculated using

CO2-TPD. As per Table 1, the total basic strength of MgO is the highest, i.e., 0.56 and that of La203 was 0.31 mmol/g _cat, respectively. LMMOHT having total basicity 0.42 mmol/g _cat , which is in between that for MgO and La203. A sharp peak at -154 and 330 °C (Figure 1) confirms the presence of higher number of weak basic sites and moderate to strong basic sites over LMMOHT catalyst. A small hump at 540 confirms the strong basic sites. The basic strength was found to be increase with increasing LMMO loading (10-50 wt. %) over MCF (Table 1). In the case of 40%LMMO/MCF catalyst, peaks at -190 and 380 °C, respectively, confirm the presence of weak and moderate to strong basic sites on the catalyst. Furthermore, the addition of 4 wt. % of Ni causes slight decrease in basicity of virgin and reused 4%NI-40%LMMO/MCF _S IM catalyst. The basicity of both virgin and reused 4%Ni- 40%LMMO/MCF _S M catalyst were found to be almost similar.

Table 1 CO2-TPD of various synthesized catalyst

CO2-TPD Basicity (mmol/g _cat )

# Catalyst Weak Moderate/ Total

Strong

1 LMMOHT 0.14 0.28 0.42

2 La2C>3 0.03 0.28 0.31

3 MgO 0.25 0.31 0.56

4 10%LMMO/MCF 0.17 0.045 0.215

5 20%LMMO/MCF 0.18 0.047 0.227

6 30%LMMO/MCF 0.19 0.064 0.254

7 40%LMMO/MCF 0.21 0.07 0.28

8 50%LMMO/MCF 0.24 0.064 0.304

9 virgin 4%Ni-40%LMMO/MCFsiM 0.15 0.085 0.235

10 reused 4%Ni-40%LMMO/MCFsM 0.15 0.073 0.223 2) XRD: XRD patterns of all MCF supported catalysts are shown in Figure 2. A broad signature peak of MCF at 20 value 23.15° confirms the amorphous nature of the material (JCPDS no. 01-082-1560 (C)). Increase in loading of lanthanum and magnesium mixed oxide from 10-50% over MCF (Figure 2. b-f), leads to shifts of the peak at higher 20 value (29.5°). It also indicates that lanthanum and magnesium oxide might have been incorporated into the pores of MCF which was responsible for the shift. Additionally, the absence of peak for lanthanum- magnesium mixed oxide represents high dispersion of these oxides. No additional peaks in Figure 2 (b-f) also suggest that the amorphous nature and structural integrity of MCF was well-maintained which was also independently confirmed by FESEM and HRTEM analysis. The diffraction peaks of NiO for virgin and reused 4%NI-40%LMMO/MCF _S IM catalyst (Figure 2 g and h) at 2Q value 37.29, 44.3, 62.61, 76.08, and 79.18 are assigned to (111), (200), (220), (311), and (222) planes, respectively. As explained earlier, in the case of 4%Ni- 40%LMMO/MCF _C P catalyst (Figure 2h) the peak at 29.5° represents amorphous nature of catalyst. The small diffraction peak at 44.3(200) was assigned to NiO. All the peaks of NiO are found to be in good agreement with that of JCPDS # 47- 1049.

The XRD for MgO, La ₂ 03, and LMMOHiare shown in Figure 3. All the diffraction peaks were present for MgO at 36.8(111), 42.61(200), 61.9(220), 74.5(311), and 78.46° (222) which were identical to those reported in JCPDS # 01-089-7746. Similarly, La ₂ 0 ₃ diffraction peaks were observed at 20 value of 15.8(100), 28.03(2-10), 30.04 (201), 39.5 (221) and 55.6 (203) and La ₂ 0 ₂ C0 ₃ at 25.8(101), 44.4°(2-10), respectively [JCPDS # 03-065-1871 (I)]. In the case of LMMOHT, along with La ₂ 03 and La ₂ 0 ₂ C03, additional MgO peaks at 42.61(200) and 61.9 °(220) were observed. This confirms that both lanthanum and magnesium species are present in LMMOHT catalyst (Figure 3.j).

3) SAXS: Small-angle X-ray scattering (SAXS) patterns for MCF, 40%LMMO/MCF, virgin 4%Ni-40%LMMO/MCF _SiM , and reused 4%Ni- 40%LMMO/MCF _S M are shown in Figure 4. All the prepared catalyst samples showed a single sharp peak at 2Q of 0-0.5°. This signature peak indicates mesoporous nature of the samples. In the case of 40%LMMO/MCF, virgin 4%Ni- 40%LMMO/MCFSM, and reused 4%NI-40%LMMO/MCFSIM, it was observed that there was a slight shift in the 2Q to lower scattering angle as well as decrease in peak intensity. This might have occurred due to incorporation of lanthanum, magnesium, as well as nickel into the pores or expansion of the framework upon incorporation. However, the structural integrity of mesoporous form was well maintained. 4) BET surface area analysis: N2 adsorption desorption data indicate type IV isotherm which confirms the well-mesoporous and highly porous MCF. LaiCf and MgO have very low surface area (19.8 and 86 m ² /g, respectively) compared to MCF. Additionally, LMMOHT shows surface area of ~40 m ² /g. In comparison to individual oxides or mixed oxides, metal oxides supported on MCF provide enormous surface area, pore volume and pore diameter. The MCF support possesses surface area (549 m ² /g). With increasing loading of lanthanum magnesium mixed oxides of x% (x= 10-50%) the surface area of x% LMMO/MCF further decreases indicating the pores were occupied by LMMO (Table 2). Table 2 Textural properties of various prepared catalysts

Catalyst BET Total Avg. pore surface Pore diameter area volume (nm)

..(. ^m ..’/a).. (THL./S.) .

LaiCb 19.8 0.55 5.61

MgO 86 0.208 4.84

LMMOHT 40 0.095 4.8

MCF 549 1.33 12.5

10%LMMO/MCF 370 0.97 9.6

20%LMMO/MCF 351 0.83 8.89

30%LMMO/MCF 326 0.51 8.7

40%LMMO/MCF 298 0.62 8.43

50%LMMO/MCF 278 0.55 8.6 virgin 4%Ni-40%LMMO/MCF _SiM 285 0.71 8.4 reused 4%Ni-40%LMMO/MCF _SiM 275.4 0.66 7.9 Moreover, in the case of virgin 4%NI-40%LMMO/MCF _S M catalyst the surface area was found to be 285 m ² /g with pore volume 0.71 cm ³ /g, and average pore diameter of 8.4 nm. The reused 4%NI-40%LMMO/MCF _S M catalyst showed minor decrease (~3%) in surface area and pore volume as a result of blockage of some of the pores of MCF.

5) FTIR: FTIR spectra of all the catalysts are shown in Figure 5. Lattice vibration due to La-0 bond was observed for LMMOHT at 652 cm ¹ (Figure 5a). As shown in Figure 5(c-i), for (10-50%) LMMO/MCF and 4%Ni-40%LMMO/MCF _SiM (virgin and reused) there is a shift in band to slightly higher value of -658 cm ¹ which might be due to dispersion of lanthanum and magnesium over MCF. The weak band at -1085 cm ¹ signifies symmetric carbonate species (Figure 5 a). The adsorption band at 3610 cm ¹ shows the existence of-OH species of adsorbed FLO molecules. The characteristic bands at 1464 and 1511 cm ¹ are due to carbonate species. The characteristic MCF broad stretching and bending band of Si-O-Si were observed at 1082 and 810 cm ¹ (Figure 5 b-i). MCF shows band at 970 cm ¹ for Si-OH linkage (Figure 6a). All the samples of MCF supported catalyst (Figure 5b-i) show -OH vibration band of medium intensity at 1630 cm ¹ which is assigned to probable H-O-H bending. The broad band of-OH stretching vibration at 3441 cm ¹ due to silanols was observed as presented in Figure 5 (b-i).

6) FESEM: Field emission scanning electron microscopy (FESEM) was used to study the morphology, size and shape of the synthesized mesoporous materials. As indicated in Figure 6, MCF, virgin 4%NI-40%LMMO/MCF _S IM, and reused 4%NI-40%LMMO/MCFSM catalyst show the characteristic mesoporous nature. The MCF spherical particles are even and well dispersed as clearly seen from Figure 6A and B. These particles have average size range 5-7 pm. The metal such as Nickel and lanthanum magnesium mixed oxide were dispersed evenly over the surface of MCF (Figure 6 C and D). Moreover, the contents in MCF were confirmed by EDX and elemental mapping. Reused 4%NI-40%LMMO/MCF _S IM shows that the fidelity of catalyst morphology as well as metal particles was well retained over MCF support.

7) EDS: Energy dispersive spectroscopy (EDS) was used for elemental analysis of 4%NI-40%LMMO/MCF _S M catalyst. The atomic weight percentage for all the elements are presented in Table 3 and found to be the same as the as-synthesized amount.

Table 3 EDS data of 4%Ni-40%LMMO/MCF _SM catalyst

Atomic weight percentage (%)

Catalyst Si O Ni La Mg C

4%Ni-40%LMMO/MCF SIM 19.7 40.1 3.8 12.6 4.8 19 8) H2 pulse chemisorption: The chemisorption of 4%NI-40%LMMO/MCF _S IM catalyst was performed to study the Ni dispersion over MCF as well as metallic surface area (Table 4). Ni dispersion was found to be 4.2% for stoichiometry of 1. The values of Ft uptake and metallic surface area were 13.1 pmol/g and 25.5 m ² /g, respectively.

Table 4 Eh pulse chemisorption analysis

Catalyst Metallic Metal Eh uptake

surface area dispersion pmol/g

(m ² /g of metal) (%)

4%Ni-40%LMMO/MCF SIM 25.5 4.2 13.1

Example 2: Studies For cross aldol condensation of 6MNAL and acetone:

Various catalysts were screened for the cross aldol condensation of 6MNAL and acetone. (Scheme 1) by following reaction condition:

Parameter: 6MNAL:acetone (mol ratio 1:30), speed of agitation 900 rpm, catalyst wt. 0.3 g, temperature, 140 °C, reaction time 6 h, total volume 33 cm ³ . The conversion of 6MNAL and selectivity to (1) was in the following order:

50% LMMO/MCF (max) > 40% LMMO/MCF > 30% LMMO/MCF > 20%LMMO/MCF > 10% LMMO/MCF > LMMOHT.

Among all 40%LMMO/MCF was found to give the best conversion of >99 % and selectivity to (1) of 94% (Figure 7).

As acetone self-condensation produces DAA and mesityl oxide in a small quantity (5-6%) over 40%LMMO/MCF catalyst. This optimized combination of support (MCF) and mixed oxide (lanthanum-magnesium) was further modified with different metals for one pot synthesis step.

Example 3: Catalyst performance studies on synthesis ofNabumetone:

Catalyst activity tests were performed in 50 ml stainless steel autoclave (Autoclave Engineers, USA). The required amount of catalyst (x%LMMO/MCF) was put into the reactor along with acetone, 6MNAL and «-Decane (50 pi) as an internal standard. It was heated to the desired temperature to carry out aldol condensation step. In the case of one pot synthesis, prior to reaction the required amount of catalyst (y%M-x%LMMO/MCF) was freshly reduced by EL pressure of 20 atm, at 200 °C for 2 h and charged into the reactor along with 6MNAL and acetone (with mole ratio 1 :30) to make a total volume of 33 ml. «-Decane (50 mΐ) was used as an internal standard. After achieving the desired temperature, condensation reaction was carried out until complete conversion of 6MNAL. For hydrogenation step, the reactor was cooled, purged three times with hydrogen and set to desired temperature and hydrogen pressure. The reaction was then carried out for next 2 h, samples collected periodically and analyzed by GC.

Different y%M-x%LMMO/MCF catalysts were screened for one-pot synthesis of NBM. The selectivity to NBM was found in the order of:

4%Ni-40%LMMO/MCF SM (max) > 4%Fe-40%LMMO/MCF _SiM > 4%Cu- 40%LMMO/MCF _S M.

In the case of 4%Fe-40%LMMO/MCFsM and 4%CU-40%LMMO/MCF _S IM catalysts the selectivity towards the by-product MIBK was more (Table 5) than NBM. While 4%NI-40%FMMO/MCF _S IM catalyst was found to give complete conversion and highest selectivity to NBM (93%, Table 5).

Table 5 Efficacy of different catalyst for one-pot synthesis of NBM

Catalyst La/Mg Conversion Selectivity Selectivity ratio of 6MNAL of NBM of MIBK 4%Fe-40%LMMO/MCF _SiM ^a 1 :3 63.2 84 16

4%Cu-40%FMMO/MCF SIM 1 :3 79 75 25

4%Ni-40%FMMO/MCF SIM 1 :3 100 93 7

³ reaction condition 6MNAF: acetone mole ratio 1:30, catalyst weight 0.3 g, speed of agitation 900 rpm, temperature 140 °C, hydrogen pressure 15 atm, reaction time 8 h, reaction volume 33 cm ³ , hydrogen was introduced after 6 h.

Example 4: Effect of different metals

Different metals like Ni, Cu, and Fe were screened to find out the best for one-pot synthesis.

Reaction Parameter: 6MNAL:acetone (mol ratio 1:30), speed of agitation 900 rpm, catalyst wt. 0.3 g, temperature, 140 °C, reaction time 8 h, hydrogen was introduced after 6 h, total volume 33 cm ³ .

Figure 8 indicates that among all tested catalyst 4%Ni-40%LMMO/MCFsM stands out to be the best because of good conversion and selectivity over other two catalyst namely 4%Fe-40%LMMO/MCF _SM and 4%CU-40%LMMO/MCF _S IM catalyst, respectively. In the case of 4%Fe-40%LMMO/MCFsiM and 4%Cu- 40%LMMO/MCF _S M catalyst, the selectivity of MIBK was 16 and 25%, respectively. The Ni doping was found to favoring selective synthesis of NBM over Fe and Cu. This is consonance with some reports where Ni was found to the most active for C=C hydrogenation with higher selectivity. Hence all further reaction were studied on 4%NI-40%FMMO/MCF _S M catalyst.

A) Effect of metal loading: Nickel loading of 2, 4, and 6 wt. % were studied for hydrogenation of 1 to NBM in one pot synthesis keeping all other parameters constant. As shown in Table 6 increase in Ni loading increases both conversion of 1 as well as selectivity to NBM. At 4 and 6% loadings, conversion of 1 and the selectivity of NBM were practically constant. Hence 4%Ni loading was selected for further optimization. The values of conversion of 1 and selectivity to NBM were found to be 94 and 93%.

Table 6 Effect of metal loading on the activity of one pot synthesis of NBM.

Ni Conversion Conversion Selectivity Selectivity Selectivity loading of 6MNAL of (1) (%) of NBM of MIBK of DAA

(wt.%) (%) (%) (%) and MO

(%)

2 ^a 99 85.5 91 9 10-12

4 ^a 100 94 93 7 7-9

6 ^a 100 95.1 93 7 8-9 ^a Reaction condition: Effect of different catalyst on the conversion of 6MNAL; catalyst wt. 0.3 g,

6MNAL: acetone 1:30, speed of agitation 900 rpm, hydrogen pressure 15 atm, temperature 140 °C, total reaction time 8 h, total volume 33 cm ³ , hydrogen was introduced after 6 h.

B) Effect of percentage of catalyst in reaction mass: To study the effect of catalyst loading, the quantity of catalyst was varied from 0.009 to 0.013 %w/w.

Wherein an effect of catalyst loading on the conversion of 6MNAL; Reaction parameter 6MNAL:acetone 1 :30, speed of agitation 900 rpm, 4%Ni- 40%LMMO/MCF _S IM catalyst, wt. 0.3 g, hydrogen pressure 15 atm, temperature 140 °C, reaction time 8 h, total volume 33 cm ³ , hydrogen was introduced after 6 h. As depicted in Figure 9, as catalyst loading increases conversion increases because the number of active sites are proportional to surface area which in turn is proportional to catalyst loading. There was no substantial change in the conversion after 0.011 %w/w catalyst loading. Therefore, all further experiments of optimization were carried out at 0.011 %w/w loading.

C) Effect of mole ratio of substrate: 6MNAF to acetone mole ratio was varied from 1: 10 to 1:40 by keeping the volume constant. In other words, the effect of concentration of the reactants on rate of reaction and conversion was studied. Both increased with concentration of 6MNAF but beyond 1 :30 mole ratio the rate of reaction was practically the same. However, the selectivity to by-product MIBK was increased. At mole ratio 1 : 10 the selectivity to NBM increased substantially (99%) however, conversion dropped to 71.5%. Therefore, at 1 :30 mole ratio, was chosen as the optimized mole ratio.

Table 7 Effect of mole ratio on the conversion of 6MNAL

Sr. Mole ratio Conversion of Selectivity of Selectivity of

No (6MNAL: 6MNAL (%) NBM (%) MIBK (%)

Acetone)

1 1 : 10 71.5 99 1

2 1 :20 82 95 5-6

3. 1 :30 100 93 7

4. 1 :40 100 86.5 15-16

Reaction condition: 4%NI-40%LMMO/MCF _S M catalyst, wt. 0.3 g, speed of agitation, 900 rpm, hydrogen pressure, 15 atm, temperature 140 °C, reaction time 8h, total volume 33 cm ³ , hydrogen was introduced after 6 h.

Example 5: Preparation of Catalyst by Co-precipitation method.

Firstly, a known quantity of MCF was added to a beaker containing 50 ml distilled water. An aqueous containing 0.005 mol of magnesium nitrate hexahydrate and 0.015 mol of lanthanum nitrate hexahydrate was prepared separately by dissolving it in 50 ml of distilled water to form solution A. An aqueous solution of 35 mmol sodium hydroxide and 9.43 mmol sodium carbonate was prepared by dissolving it in 20 ml of distilled water to form solution B. Similarly solution C was prepared by dissolving required Metal (Ni) precursor in 50ml distilled water. All solution A, B and C were then co-precipitated by means of adding them simultaneously and dropwise with vigorous stirring at 30 °C for 5 h. During the addition the pH of the solution was maintained at 9-10. The slurry was then kept at 65°C for next 5 h. It was then washed several times with distilled water until neutral pH, filtered and dried at 100 °C for 12 h. The obtained mass was then calcined at 600 °C for 4 h. The final catalyst labelled as y%M-x%LMMO/MCFcp Example 6: Effect of Support and method of loading of metals in catalyst preparation on one pot synthesis of Nabumetone:

Table 8: BET analysis of different catalysts:

Sr NO. 1* to 5* catalysts were prepared by Sequential impregnation method (sixi) as per present invention and Sr NO. 6# catalyst was prepared by Co-precipitation method (CP).

Conclusion: 4%Ni-40%La ₂ O ₃ /MCF catalyst has surface area of 203.8 m ² /g, as the La ₂ 03 particles are larger in size, which distributed over MCF resulting in decreased surface area. On the other hand, in case of 4%Ni-40%MgO/MCF catalyst, MgO has small particle size which gives higher surface area.

Table 9: Activity of different catalyst

Sr NO. 1* to 5* catalysts were prepared by Sequential impregnation method (sixi) as per present invention and Sr NO. 6# catalyst was prepared by Co-precipitation method (CP).

Table 9 shows that of all the tested catalysts, the activity of 4%Ni- 40%LMMO/MCF _S IM (entry 5, prepared by impregnation) was found to be the best. Additionally, the activity of 4%Ni-40%LMMO/MCFcp (entry 6, prepared by co precipitation) was almost similar to that of entry 5; however, as studied in following example no. 7, the reusability of 4%Ni-40%LMMO/MCFcp was not as significant as that of 4%NI-40%LMMO/MCFSIM catalyst as illustrated in Figure no. 11.

Example 7 : Reusability of catalysts prepared by different methods of impregnation of metals and test for checking leaching of active metals in reaction mass:

A Reusability study for 4%Ni-40%LMMQ/MCF(sTM) Catalyst prepared by sequential impregnation method prepared as per example no. 1 :

The catalyst reusability was studied for four cycles (Fig. 10). The catalyst was recovered after each use by means of centrifugation, washing with methanol, and drying at 100 °C for 12 h. The minor loss of catalyst in these steps was covered by adding fresh catalyst to maintain catalyst loading constant in all experiments. There was a marginal change in the conversion of 6MNAL. However, no change in the selectivity was observed which indicated that the catalyst was active up to 4th reuse. The CO2-TPD and FE-SEM data also confirmed the insignificant change in basicity and morphology, respectively showing stability of the catalyst.

B Reusability study for 4%Ni-40%LMMQ/MCFcp Catalyst Prepared by Co precipitation method prepared as per example no. 5:

The catalyst reusability was repeated for 4%Ni-40%LMMO/MCFcp to four cycles (Fig. 11), unlike 4%NI-40%LMMO/MCF _S IM both conversion of MNAL and selectivity of NBM were dropped significantly with each reuse cycle. After 4 ^th reuse conversion of MNAL was 60% and selectivity of NBM was 51%. The decrease in activity might occurred due to leaching of LMMO and Ni from the surface of MCF.