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Title:
METHOD OF SYNTHESIS MOLECULES USING CATALYST AND COMPOSITES THEREOF
Document Type and Number:
WIPO Patent Application WO/2014/174397
Kind Code:
A2
Abstract:
A method to synthesis molecules is provided. The method employs a catalyst for a cross- coupling react ion to obtain the molecule. The method comprises coupling boronic acid and halide in presence of the catalyst having graphite oxide supported palladium nanoparticles, a solvent and a base by heating. The heating is performed at a temperature lower than the temperature at which the graphite oxide deforms. The molecule is a biaryl. The method further provides obtaining complexs such as boscalid, telmisartan, valsartan, and SPPARMγ.

Inventors:
MANDAL DR SWADHIN K (IN)
SANTRA SUBHANKAR (IN)
Application Number:
PCT/IB2014/060537
Publication Date:
October 30, 2014
Filing Date:
April 08, 2014
Export Citation:
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Assignee:
MANDAL DR SWADHIN K (IN)
SANTRA SUBHANKAR (IN)
International Classes:
C07C25/24
Attorney, Agent or Firm:
K., Pradeep (101 Tilak Path CMR Point #101,Narayan Bagh Square, Indore 7, IN)
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Claims:
What is claimed is:

1. A method comprising: mixing boronic acid, halide, a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and coupling boronic acid and halide by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms and the coupling is substant ial ly heterogeneous catalyt ic coupling and wherein the coupling provides a biaryl core.

2. The method of claim ι, wherein the catalyst is formed by heat ing graphite oxide and pal lad ium salt at a temperature that alters chemical nature of the pal lad ium salt, while maintaining structural order of the graphite oxide substant ial ly unaltered.

3. The method of claim 2, wherein the catalyst employs graphite oxide and pal lad ium salt in the rat io of 2:1.

it. The method of claim 1, wherein the hal ide is an aryl halide and the boronic acid is phenyl boronic acid.

5. The method of claim 1, wherein the solvent is any one of d ioxane and isopropanol.

6. The method of claim 1, wherein the base is any one of sod ium methoxide and potassium carbonate.

7. The method of claim 1, further comprising subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.

8. The method of claim 1, the halide is a haloaryl amine and the biaryl core has an amine.

9. The method of claim 8, further comprising, subject ing the biaryl core to amine-acid chloride coupling using 2-nicot inyl chloride to obtain boscal id.

10. A molecule obtained by coupl ing boronic acid and halide in presence of a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms, and wherein the coupl ing is substant ial ly heterogeneous catalyt ic coupling, wherein the molecule is a biaryl core.

11. The molecule of claim 10, wherein the hal ide is an aryl hal ide and the boronic acid is phenyl boronic acid.

12. The molecule of claim 10, wherein the solvent is any one of d ioxane and isopropanol.

13. The molecule of claim io, wherein the base is any one of sodium methoxide and potassium carbonate.

14. The molecule of claim io, further comprising subjecting the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule.

15. The molecule of claim 10, the halide is a haloaryl amine and coupling provides a biaryl core having an amine.

16. The molecule of claim 10, further comprising, subjecting the biaryl core to amine-acid chloride coupling using 2-Nicotinyl chloride to obtain boscalid.

Description:
"METHOD OF SYNTHESIS OF MOLECULES USING CATALYST AND COMPOSITES

THEREOF"

CROSS-REFERENCE

[001] The subject matter of the research article Dr. Swadhin Mandal et.al, Palladium Nanoparticles on Graphite Oxide: A Recyclable Catalyst for the Synthesis of Biaryl Cores published in ACS Catal., 2013, 3 (12), pp 2776-2789 is incorporated in this specification by reference. The subject matter of Indian Patent Application Number 464/KOL/2013 and corresponding International Patent Application number PCT/IB2014/060463 are incorporated in this specification by reference.

TECHNICAL FIELD

[002] The present subject matter relates to a method of synthesis of molecules using catalyst. More specif ically the subject matter relates to the method of synthesis of molecules through cross-coupling reaction that employs catalyst. The present subject matter further relates to the molecules and composites thereof.

BACKGROUND

[003] Cross-coupling reactions are used to synthesize molecules. Some cross coupling reactions produce core molecules such as biaryl cores and other core moieties. Pharmaceutical industry is spending tremendous amount of money for developing such core moieties as multiple billions of dollars of business is observed per year around drug candidates such as valsartan, telmisartan, agrochemical agent boscalid and selective PPARy modulator (SPPARMy) that involve such core moieties. Presently the use of noxious phosphine based palladium catalyst is considered as a viable route for preparation of core moieties of a number of drug molecules. However, syntheses of such core moieties with the conventional catalysts have hassles like the contamination of precious metals with the product as well as the "use and throw" nature of the catalyst. Thereby adversely affecting the environment. Therefore, there is a need to obviate the above and other disadvantages. SUMMARY

[004] For the purpose of illustration, following discussion uses a method of synthesis of molecules and composite thereof employing cross-coupling reaction such as Suzuki coupling, only as example. Further, for illustration the discussion uses synthesis of graphite oxide having palladium nanoparticles anchored on it. However, it shall become clear, after reading this specification, that the subject matter may be practiced, without departing from the spirit of the present subject matter, in other cross-coupling reactions.

[005] Cross-coupling reaction that employs a catalyst for synthesizing a molecule is generally homogeneous catalytic reaction that takes place in a reaction mixture. Because, the catalyst is homogeneously mixed in the reaction mixture, separating the catalyst from the reaction mixture is difficult thereby making it difficult to claim and employ the catalyst for further cross-coupling. Furthermore, both the molecules as well as the catalysts used in such reactions often get contaminated during the reactions and therefore, the reaction renders the catalyst unusable for further cross-coupling reactions and produce a poor quality molecule. This is a big disadvantage especially when the catalysts are employed to obtain pharmaceutically important molecules, which require the molecules to be substantially free of any impurities. Furthermore, often the industry observes that employs different catalysts for synthesizing different cross coupled molecules, such as biaryl cores. It may be advantageous and cost effective if a single catalyst enables the synthesis of most varieties of cross-coupled molecules. Further, these methods are often multi-pot, multi-step methods. That is, these method require transfer reaction solution/mixture in many pots and involve a large number of steps. This makes the process of synthesizing these molecules expensive and time consuming.

[006] The present subject matter provides solut ion to the above and other problems. The subject matter provides a method of synthesis of molecules. The method provides a cross-coupling reaction that results into a substantially heterogeneous reaction mixture and therefore, the molecule and the catalyst remain substantially separable and substantially non-contaminated after the synthesis. Therefore, the catalyst claimed after the synthesis of the molecules may be reusably employed in further synthesis.

[007] To achieve above and other objectives, according to one aspect of the present subject matter provides a method for obtaining a catalyst that is substant ial ly free of any surfactants, reagents, and/or reducing agents. The catalyst has carbon derivat ive and anchored nanopart icles on the carbon derivat ive. Accord ing to one aspect, the catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Therefore, undesired effects on the structure and characterist ics of the catalyst caused due to introduct ion of surfactants, reagents and/or reducing agents are substant ial ly avoided. The catalyst has demonstrated its reusability across mult iple the cross-coupling react ions. Accord ing to an aspect of the subject matter, the environment and temperature at which the cross-coupl ing react ion takes place are selected such that the catalyst retains its most of the characterist ics and therefore, renders itself reusable in further cross-coupling react ions.

[008] Accord ing to an aspect of the present subject matter, a method to synthesize a molecule is provided. The method employs a catalyst for a cross-coupling react ion. The catalyst is obtained by d ispersing a carbon derivat ive and a second compound in a solvent to obtain a mixture, wherein the second compound is a salt of a metal; and heat ing the mixture to alter chemical nature of the second compound and to form the catalyst, wherein the catalyst includes nanopart icles of the metal anchored with the carbon derivate. Accord ing to one aspect, the temperature to heat the mixture is selected from a range of temperature, wherein the range has a f irst temperature and a second temperature. The f irst temperature is higher than a temperature at which chemical nature of the second compound is altered begins and the second temperature is lower than the temperature at which the carbon derivat ive begins to deform. The first temperature is lower than the second temperature.

[009] Accord ing to one aspect, a method provides: mixing boronic acid, hal ide, a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and coupling boronic acid and halide by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms and the coupling is substant ial ly heterogeneous catalyt ic coupl ing and wherein the coupl ing provides a biaryl core. Accord ing to a further aspect, the catalyst is formed by heat ing graphite oxide and pal lad ium salt at a temperature that alters chemical nature of the pal lad ium salt, while maintaining structural order of the graphite oxide substant ial ly unaltered. Accord ing to yet a further aspect, the catalyst employs graphite oxide and pal lad ium salt in the rat io of 2:1. Accord ing to another aspect, the halide is an aryl hal ide and the boronic acid is phenyl boronic acid. Accord ing to yet another aspect, the solvent is any one of d ioxane and isopropanol. Accord ing to a further aspect, the base is any one of sod ium methoxide and potassium carbonate. Accord ing to yet a further aspect, the method comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule. Accord ing to yet another further aspect, the hal ide is a haloaryl amine and the biaryl core has an amine group. Accord ing to further aspect, the method further comprises, subject ing the biaryl core with amine to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.

[0010] In another embod iment, the present subject matter provides a molecule obtained by coupl ing boronic acid and hal ide in presence of a catalyst having graphite oxide supported pal lad ium nanopart icles, a solvent and a base and by heat ing, wherein, heat ing includes heat ing at a temperature lower than the temperature at which the graphite oxide deforms, and wherein the coupl ing is substant ial ly heterogeneous catalyt ic coupling, wherein the molecule is a biaryl core. In an aspect, the hal ide is an aryl halide and the boronic acid is phenyl boronic acid. In yet an aspect, the solvent is any one of d ioxane and isopropanol. In another aspect, the base is any one of sod ium methoxide and potassium carbonate. In yet another aspect, the method further comprises subject ing the biaryl core to further coupling to obtain any one of boscalid, telmisartan, valsartan, and SPPARMy molecule. Accord ing to a further aspect, the halide is a haloaryl amine and coupling provides a biaryl core having an amine group. Accord ing to further aspect, the method further comprises, subject ing the biaryl core to amine-acid chloride coupl ing using 2-nicot inyl chloride to obtain boscalid.

[0011] Accord ing to the method, the catalyst and a substrate are combined. In another example, the substrate may include more than one compound. In one opt ion, the catalyst and the substrates are further provided with a base. The combinat ion is then suppl ied with a solvent to obtain a first mixture. The first mixture is then heated. Heat ing the first mixture init iates the cross-coupl ing react ion. The heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross- coupling react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms. The environment for the cross-coupling react ion is selected in such a way that the molecule is synthesized without adversely affect ing the catalyst and therefore, the catalyst retains most of its characterist ics and therefore may be reused in further cross- coupling react ions as catalyst. In one possibil ity the environment has nitrogen, in some other examples, the environment has inert environment, and in some further examples, the environment has air.

[0012] Cross-coupled molecule and the catalyst may be then separated. In one example, the catalyst may be separated through a membrane paper. The separated catalyst may be used for further cross-coupling react ions.

BRIEF DESCRIPTION OF DRAWINGS

[0013] The subject matter shal l now be described with reference to the accompanying f igures, wherein:

[001 ] FIG. 1 shows a schemat ic d iagram of a graphite oxide structure;

[0015] FIG. 2 shows representat ive core molecules and drug complexes thereof;

[0016] FIG. 3a and FIG. 3b show a TABLE 1 and TABLE 2 respect ively;

[0017] FIG. ^ shows a schemat ic d iagram accord ing an embod iment of a method of the present subject matter;

[0018] FIG. a and FIG. b shows more detailed d iagrams of the method of the present subject matter;

[0019] FIG. 5 shows a l ist of solvents, bases, environment cond it ions and temperatures accord ing to an aspect of the present subject matter;

[0020] FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter;

[0021] FIG. 7a and FIG. 7b show TABLE 6 and TABLE 7 respect ively that l ist various combinat ions of molecules that may be obtained by the method of present subject matter.

[0022] . FIG. 8a, FIG. 8b and FIG. 8c show graphs of percentage isolated yield obtained upon employing the catalyst recyclably accord ing to the present subject matter;

[0023] FIG. 9 shows a TABLE 8 that lists a number of examples accord ing to which intermed iate molecules of some top sel l ing drug cand idates may be obtained accord ing to present subject matter; and

[002 ] FIG. 10 shows a route normal ly adapted by the industry for synthesizing boscalid and the route accord ing to the present subject matter.

DETAILED DESCRIPTION

[0025] Before the present subject matter is described in further detail, it is to be understood that the subject matter is not l imited to the part icular embod iments described, and may vary as such. It is also to be understood that the terminology used throughout the preced ing and forthcoming d iscussion is for the purpose of describing part icular embod iments only, and is not intended to be l imit ing. It must be noted that as used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly d ictates otherwise.

[0026] FIG. 1 shows a schemat ic d iagram of structure of a graphite oxide. FIG. 1 shows representat ive funct ion groups 101, 103, 105, 107 and 109. The funct ional groups 103 and 107 demonstrate somewhat similar behavior.

[0027] FIG. 2 shows some core molecules and drug complexes thereof. The core molecule 2'-(4,4-d imethyl-4,5-d i hydrooxazol-2-yl)biphenyl-4-carbaldehyde is used to form drug complex telmisartan. The core molecule (S)-methyl 2-((2'-(iH-tetrazol-5-yl)biphenyl-4- yl)methylamino)-3-methyl butanoate may be used to form drug complex valsartan. The core molecule 4'-chloro-2-nitrobiphenyl may be used to form the drug complex boscalid. The core molecule ethyl 3-(4-tert-butylphenyl)-iH-indole-2-carboxylate may be used to form the drug complex SPPARMy etc. The drug complex telmisartan is being developed by a company Boehringer under brand name Micard is. The drug complex valsartan is developed by company Novart is under brand name Diovan. The drug complex boscalid is developed by company BASF. The drug complex SPPARMy is being developed by company GlaxoSmithKl ine etc.

[0028] FIG. 3a and FIG. 3b show TABLE 1 and TABLE 2, respect ively. The TABLE 1 and

TABLE 2 l ist some of the synthesis processes of molecules and catalysts, synthet ic procedures adapted for synthesizing the respect ive molecules. However the issue of reusabil ity of the catalysts in these examples has not been appropriately addressed. [0029] FIG. ^ shows a schematic diagram according an embodiment of a method 400 of the present subject matter. According to one aspect, at block 401, the method 400 provides obtaining a catalyst substantially free of surfactants, reagents and/or reducing agents. According to a further aspect of the present subject matter at block 403, the method 400 provides synthesizing a molecule using the catalyst.

[0030] FIG a shows the block 401 of the method 400 in more details. According to one aspect of the block 401, at block 91, the carbon derivative and a second compound is dispersed in a solventto obtain a mixture. The second compound is a salt of the metal. Forthe purpose of this discussion, the carbon derivative is graphite oxide and second compound is palladium acetate. In some embodiments, the block 91 is performed in the substantially inert environment. The block 91, may include a block 411, a block 421, a block 31, and a block 93. At block 411, the graphite oxide and palladium acetate are mixed in a substantially inert environment. Subjecting the mixed carbon derivative and the second compound to the substantially inert environment removes active or reactive elements. In some examples, elements such as oxygen and moisture are removed from the substantially inert environment. In some other examples, the substantially inert environment comprises any one or more of vacuum, nitrogen, argon, xenon and a substantially inert gas. Atthe block 21 graphite oxide and palladium acetate are dispersed in a solvent to obtain the mixture.

Forthe purpose of this discussion, the solvent is toluene. At block 31, the mixture is exposed to ultrasonic exposure to substantially uniformly distribute the graphite oxide and palladium acetate. At block 31, some part of the palladium acetate may get dissolved in the toluene.

The block 401 includes a block 93. In some examples, the block 93 may be included with the block 91. At block 93 the mixture is heated to alter the chemical nature of the palladium acetate. Generally, the alteration is performed by introducing reagents and/or reducing agents, however, according to the method 401 the alteration is performed by heating the mixture. This ensures that structure and the characteristics of the catalyst are not adversely affected by the reagents and/or reducing agents, which often degrade the quality of the catalyst by affecting adversely the functional groups (101, 103, 105, 107 and 109 shown in

FIG.1) of the graphite oxide. Further, a temperature for heating the mixture is selected from a range of temperature, wherein the temperature is between a first temperature and the second temperature. The first temperature is higher than the temperature at which the chemical alteration of the second compound takes place and the second temperature is lower than the temperature at which the carbon derivat ive deforms. The catalyst is formed by heat ing the mixture for a predetermined t ime, the t ime is determined based on the volume of the mixture. The catalyst, which may be Graphite Oxide having anchored Pal lad ium Nanopart icles GO-PdNPs, at block 95, is extracted from the mixture.

[0031] FIG. shows block 403 of FIG. in more details. The block 03 comprises a block 13, at block 13 the catalyst and a substrate are combined to obtain a combinat ion. In another example, the substrate may include more than one compound or component. In one opt ion, the catalyst and the substrates are further provided with a base to obtain a combinat ion. At block 23 the combinat ion is suppl ied to a solvent to obtain a f irst mixture. At block 33 the f irst mixture is then heated. Heat ing the first mixture init iates the cross- coupling react ion. The heat ing of the first mixture is control led such that the temperature of the first mixture is raised high enough to begin the cross-coupl ing react ion, but is kept lower than a temperature at which the carbon derivat ive of the catalyst deforms. Heat ing is performed for a predetermined t ime, the t ime is determined based on the volume of the mixture at the above selected temperature. At block 3, the cross-coupled molecule and the catalyst are separated from the first mixture. The separated catalyst may be employed in synthesis of further molecules. In some embod iments, the method 400 or a part thereof is performed in a vacuum or nitrogenous environment, or a substant ial ly inert environment to remove oxygen and moisture and other react ive elements from the combinat ion.

[0032] Accord ing to one aspect of the present subject matter, the catalyst is reusably employed in the cross-coupling react ion. Accord ing to a further aspect, the method 400 is performed in a control led environment. In one example, the controlled environment is nitrogenous. In a further example, the control led environment has an inert gas. In some other example, the control led environment has air.

[0033] Accord ing to a further aspect, the substrate is aryl halide. In one example, the substrate is bromobenzene. Accord ing to a further aspect, the other substrate is a boronic acid. In one example, the other substrate is phenyl boronic acid. In one example, the base is sod ium methoxide. In some other example, the substrate is a combinat ion of aryl halide, phenyl boronic acid. In an example, the base is potassium carbonate, K 2 C0 3 . In one example, the solvent is isopropanol. In some other example, the solvent is d ioxane. FIG. 5 shows TABLE 3 which l ists a number of solvents and bases with respect ive environment cond it ions and temperature that may be employed for cross coupling react ion accord ing to an aspect of the present subject matter.

[003 ] Accord ing to one aspect of the present subject matter, the catalyst may be resuably employed for many cycles for obtaining the molecule using cross-coupling react ions. The catalyst is developed without introducing any surfactants, reagents and/or reducing agents. Should the surfactants, reagents and/or reducing agents be introduced during the synthesis of the catalyst, a number of funct ional groups of the graphite oxide gets consumed by the surfactants, reagents and/or reducing agents therefore, reducing the number of funct ional groups available for anchoring the pal lad ium nanopart icles. The present subject matter provides that the object ive of introducing surfactants, reagents and/or reducing agents may be achieved without introducing them by control l ing the environment and the temperature during the synthesis of the catalyst. Thereby obtaining a higher quality catalyst.

[0035] During the cross-coupl ing react ion, the quality of the catalyst remains substant ial ly unaffected because of availabil ity of a large number of funct ional groups. That is during the cross-coupling react ions, a number of bond that anchor the pal lad ium nanopart icles to the graphite oxide may break, however, because a large number of funct ional groups are available, new bonds may form to anchor the pal lad ium nanopart icles and therefore creat ing a macro-cycl ic effect and leaving the catalyst substant ial ly unaffected in terms of quality beyond the cross-coupl ing react ion and hence enabling reuse of the catalyst for further react ions. Furthermore, because the catalyst of the present subject matter does not get d issolved in the solvent during the cross-coupling react ion, it becomes relat ively easy to extract the catalyst after the react ion is complete and the molecule is formed.

[0036] The method of the present subject matter shal l be described in more details. Accord ing to one aspect of the present subject matter, the method may be employed to obtain a molecule of biaryl using aryl hal ide and phenyl boronic acid as substrates, sod ium methoxide as base and d ioxane as solvent and GO-PdNPs as catalyst. The fol lowing equat ion shows the react ion. aryl haiide biaryl

[0037] Accord ing to one aspect, the method may be performed in a Schlenk flask. Accord ing to the method to obtain the biaryl molecule, GO-PdNPs catalyst of about 10 mg is taken. The GO-PdNPs is obtained by the method described above. Accord ing to an aspect, the GO-PdNPs is mixed with substrates, aryl haiide (1 mmol) and phenyl boronic acid (1.5 mmol); and base NaOMe (2 mmol). The mixture is subjected to high vacuum. The vacuum removes oxygen, moisture and other volat ile react ive elements from the mixture. In one embod iment, the mixture may be subjected to vacuum for about one hour; the t ime however may be decided based on the quant ity of the mixture. Accord ing to a further aspect, the dry d ioxane (5 mL) is added to the mixture under N2 atmosphere fol lowed by the add it ion of l iquid substrates (if any) in the requisite amounts. The d ioxane d issolves aryl haiide, phenyl boronic acid and part ial ly d issolves sod ium methoxide. Nitrogen creates substant ial ly inert environment. Further, subject ing the mixture to high vacuum could result into vaporizat ion of l iquid aryl hal ides; therefore, l iquid substrates (aryl hal ides) may be added to the mixture after a nitrogenous environment is created. The mixture is then heated at about 100 degree Celsius for about 24 hours under nitrogenous environment. In some embod iments, the t ime for heat ing the mixture may be determined based on quant ity of the mixture. Furthermore, the temperature at which the mixture is heated is determined based on the temperature at which cross-coupl ing react ion starts but the temperature is kept below the temperature at which the structure of the catalyst deforms. The catalyst and biaryl molecule are extracted, by cooling the mixture at room temperature, filtrat ion using a membrane paper and washing of the react ion mixture and the desired biaryl molecule is then purified employing vaporizat ion under reduced pressure and short column chromatography (silica gel 100-200 mesh) etc.

[0038] FIG. 6a and FIG. 6b show TABLE and TABLE 5 respect ively. The TABLE and

TABLE 5 l ist various combinat ions of molecules that may be obtained by the method of present subject matter.

[0039] Accord ing to one aspect of the present subject matter, the method may be employed to obtain a molecule of biaryl using aryl haiide and phenyl boronic acid as substrates, potassium carbonate as base, isopropanol as solvent and GO-PdNPs as cata The following equation shows the reaction.

a

carbonate

[00 0] According to a further embodiment, the catalyst (GO-PdNPs) (10 mg), aryl halide (1 mmol), boronic acid (1.5 mmol), K2CO3 (2 mmol) and isopropanol (5 mL) are combined to obtain a mixture and refluxed at about 90 °C for 24 hour. As discussed above the time for boiling may be determined based on the quantity of the mixture. At about 90 degree Celsius, isopropanol boils and initiates the catalytic reaction. The mixture is then cooled at room temperature. The catalyst may be extracted employing filtration through a membrane paper and washing of the reaction mixture and the desired biaryl molecule may be then purified employing vaporization under reduced pressure and short column chromatography (silica gel 100-200 mesh).

[00 1] FIG.7a and FIG.7b show TABLE 6 and TABLE 7, respectively. The TABLE 6 and TABLE 7 list various combinations of molecules that may be obtained by the method of present subject matter.

[00 2] According to an aspect, catalyst may be recyclably employed to obtain the molecule. FIG.8a, FIG.8b and FIG.8c show graphs of the percentage isolated yield obtained upon employing the catalyst recyclably in the cross-coupling reaction. The graphs demonstrate that the catalyst remains active for a number of cycles.

[00 3] FIG.8a corresponds to the following catalytic reaction.

[ooi f i f FIG.8b corresponds to the following catalytic reaction.

O

[00 5] FIG.8c corresponds to the following catalytic reaction.

[00 6] According to an aspect of the present subject matter, the subject matter may be employed for obtaining active intermediate molecules.

ary a e p eny oronc ac

[00 7] FIG. 9 shows TABLE 8 that lists a number of examples according to which intermediate molecules may be obtained according to present subject matter.

[00 8] According to a further aspect, the subject matter provides a method of synthesis of boscalid. The method according to this aspect, takes advantage of the robustness of the catalysts and provides a cost effective and safe solution for synthesis of boscalid. FIG.10 shows a route normally adapted by the industry for synthesizing boscalid and the route according to the present subject matter.

[00 9] Conventional industrial route for synthesis of boscalid does not employ haloaryl amine for the synthesis of the corresponding biaryl core. This is because, the amine group in haloaryl amine substrate tend to poison the catalyst in the cross-coupling reaction and therefore resulting an inactive catalyst. Therefore, in this process the catalyst is often becomes unusable for further catalytic purposes. This is because of the fact that the amine group of the haloaryl amine substrate preferably coordinates with the active palladium catalyst molecule and thereby rendering the catalyst unstable and also unusable for further re-process. Therefore, instead of using haloaryl amine, the industry employs mult i step processes for synthesis of molecules such as boscal id avoid ing haloaryl amine as substrate for the cross-coupl ing. In this process, the haloaryl nitrobenzene is used instead of haloaryl amine for the Suzuki coupl ing react ion to obtain nitrobiphenyl. The nitrobiphenyl is then hydrogenated to obtain the respect ive biaryl that has an amine group as shown above. The hydrogenat ion process is expensive and environmental ly unfriend ly. To get the resultant boscalid, the biaryl containing the amine group is subjected to amine-acid chloride coupl ing react ion with 2-nicot inyl chloride. Further this process is cumbersome, mult i-step and mult i- pot process.

[0050] On the other hand, the catalyst of the present subject matter shows robustness even with haloaryl amine and therefore may produce the boscalid d irectly by employing the haloaryl amine in the Suzuki coupling react ion removing the requirement of the expensive and hazardous step of hydrogenat ion as shown in the above react ion. The catalyst of the present subject matter, not only remains substant ial ly unaltered during the coupling process even with aryls such as haloaryl amines but also shows reusabil ity. The one-pot synthesis of boscalid may be accomplished by introducing 2-nicot inyl chloride after the cross-coupling react ion is complete. Accord ing to an aspect, the method may yield about 67% of isolated boscalid. The GO-PdNPs may be used for number of consecut ive cycles in cross-coupling react ion of haloaryl amine and boronic acid to achieve quant itat ive yield of 4'- chlorobiphenyl-2-amine. The result of which are shown in FIG. 8c.

[0051] Further, the below table shows a comparison of yields obtained accord ing to present subject matter and convent ional methods.

[0052] The yield -I represent yield from reaction condition: Pd(OAc)2 (2.2 mg), aryl halide (1 mmol), boronic acid (1.5 mmol) and base (2 mmol) reacted in 5 mL of solvent under appropriate condition. And yield -II show yields according to present subject matter. It clears from the above table that the present subject matter results in better yields.

[0053] While the subject matter may be susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and have been described herein. Alternate embodiments or modifications may be practiced without departing from the spirit of the subject matter. The drawings shown are schematic drawings and may not be to the scale. While the drawings show some features of the subject matter, some features may be omitted. In some other cases, some features may be emphasized while others are not. Further, the methods disclosed herein may be performed in manner and/or order in which the methods are explained. Alternatively, the methods may be performed in manner or order different than what is explained without departing from the spirit of the present subject matter. It should be understood that the subject matter is not intended to be limited to the particular forms disclosed. Rather, the subject matter is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the subject matter as described above.