Title of Invention	PROCESS FOR THE PREPARATION OF UNSYMMETRICALLY SUBSTITUTED BIPHENYL COMPOUNDS
Abstract	A process for the preparation of unsymmetrical biaryl compounds of Formula I wherein, R is alkyl, R’ is cyano, protected or unprotected tetrazole, or –H/C=NR” wherein, R” is alkyl, aryl, aralkyl or alkoxy, said process comprising, reacting Grignard reagent of Formula II wherein, R is alkyl; X is halogen with an aryl halide of Formula III wherein, X is halogen: R’ is a cyano, protected or unprotected tetrazole, or –H/C=NR” wherein, R” is alkyl, aryl, aralkyl or alkoxy in a suitable solvent I the presence of a palladium catalyst and a ligand and Lewis acid as a co catalyst.

Title of Invention

PROCESS FOR THE PREPARATION OF UNSYMMETRICALLY SUBSTITUTED BIPHENYL COMPOUNDS

Abstract

A process for the preparation of unsymmetrical biaryl compounds of Formula I wherein, R is alkyl, R’ is cyano, protected or unprotected tetrazole, or –H/C=NR” wherein, R” is alkyl, aryl, aralkyl or alkoxy, said process comprising, reacting Grignard reagent of Formula II wherein, R is alkyl; X is halogen with an aryl halide of Formula III wherein, X is halogen: R’ is a cyano, protected or unprotected tetrazole, or –H/C=NR” wherein, R” is alkyl, aryl, aralkyl or alkoxy in a suitable solvent I the presence of a palladium catalyst and a ligand and Lewis acid as a co catalyst.

Full Text	FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2006PROVISIONAL SPECIFICATION(See section 10; rule 13) 1 Title of the invention. - PROCESS FOR THE PREPARATION OFUNSYMMETRICALLY SUBSTITUTED BIPHENYL COMPOUNDS 2. Applicant(s)(a) NAME : CALYX CHEMICALS AND PHARMACEUTICALS LTD.(b) NATIONALITY :An India Company(c) ADDRESS : 5, Marwah's Complex, Sakivihar Road, Sakinaka, AndheriMaharashtra, India, hereby declare (E), Mumbai-400 072, 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. FIELD OF INVENTION The present invention relates to the preparation of biaryl compounds of formula I -oh Formula I where R may be alkyl, R' may be a cyano, protected or unprotected tetrazole, or u C=NRM (R" may be alkyl, aryl, aralkyl or alkoxy). In particular the present invention relates to the preparation of the biaryl compound of Formula I in which R is methyl and R' is a cyano group. BACKGROUND OF THE INVENTION Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylphenyl) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) which is a precursor of 2-(tetrazolyl)-4'-methyl biphenyl, can be used as an intermediate in the preparation of various angiotensin II antagonists. A number of coupling approaches have been developed for the construction of the biphenyl systems. As OTBN and related compounds are very important intermediates, various methods have been reported for the preparation of OTBN. Reported methods include the reaction of organo-boron (Suzuki reaction), zinc (Negishi reaction) or tin (Stille coupling) compounds with bromobenzonitriles. Tamao et al., Bull. Chem. Soc. Japan, vol. 49 (1976), pp. 1958-1969, discloses that aryl bromides can be reacted with aryl magnesium halides (aryl Grignard reagents) in the presence of dihalodiphosphinenickel complexes to give biaryl 2 compounds. This reference states that the most serious limitation is that the substituents on the organic halides and on the Grignard reagents are restricted to those, which cannot react with Grignard reagents. The unsymmetrical biaryl coupling reactions require a metal catalyst. Generally these catalysts are selected from palladium, nickel or manganese. The palladium catalyzed coupling of an aryl Grignard compound with an iodo-substituted benzonitrile has been described. US 5288895 discloses a method in which a halobenzonitrile is treated with aryl magnesium haiide in the presence of a manganese salt as catalyst. US 6121480 describes a method for the synthesis of unsymmetrically substituted biphenyls comprising the palladium catalyzed coupling of an aryl magnesium haiide with bromobenzonitrile. The patent claims the concentration of the palladium catalyst to be 1.0 to 2.0mole % based on the bromobenzonitrile. US 6407253 discloses a method for preparing the biphenyl compounds by reacting an aryl haiide with a Grignard reagent using a palladium complex -PdCb/dppp (1 mole %) in the presence of a linear or branched polyether as solvent. According to the invention yield of the desired product is at least 92% and the 4, 4'-dimethylbiphenyl impurity is below 3.5%. However, the said document also states that such results could not be obtained when the solvent was replaced by a cyclic diether. US 6392080 discloses a process for the preparation biphenyl compounds by reacting o-halobenzonitrile with a p-tolylmagnesium haiide in the presence of MnCb / a mixture of 1 mole of MnCb and 2 moles of LiCl and PdCb/dppp complex. The manganous salt is present in the reaction mixture in the proportion of 0.5 to 1.30 molar equivalent of the o-halobenzonitrile and the palladium 3 catalyst is in the concentration. of 0.001 to 2 molar % per mole of the o-halobenzonitrile. US 6194599 describes a process for preparing the biaryl compounds by reacting an aryl group bonded to zinc with an aryl chloride in the presence of palladium or nickel catalyst. US 5922898 mentions reacting aryl magnesium reagents and aryllithium reagents with an aryl halide in the presence of catalysts selected from palladium catalysts and nickel catalysts and a cocatalyst selected from zinc cocatalysts and cadmium cocatalysts. Thus, unsymmetrical biaryl compounds can be prepared by reacting a Grignard reagent with an aryl halide in the presence of transition metal catalysts like palladium catalysts or nickel catalysts in the form of salts or in the form of complexes with ligands with/without any cocatalysts. The reaction is shown schematically below. x R I catalyst Pi AL A y + KJ[ MgX WO97/30970 (equivalent to US 6121480) discloses a process for the said coupling reaction using palladium complex catalyst. The said patent claims the palladium catalyst concentration of 0.1 to 20 molar % based on the bromobenzonitrile. The authors of the patent US 5288895 saw a low yield (22%) of the biaryl compound when 4.2 equivalent of the Grignard reagent (aryl magnesium bromide) 4 and 0.3 equivalent of palladium chloride were used, a yield of 1% was observed when 2.2 equivalent of the Grignard reagent was reacted with 2-bromobenzonitrile in the presence of catalytic amount of tetrakis(tripheny!phosphine)-palladiurn for 6 hours at 65°C. It is also reported in Tetrahedron Letters, 39(1998), 7275-7278 that lower yield (20%) of OTBN was obtained when the coupling of p-tolylmagnesium chloride with o-bromobenzonitrile was carried out using dichloro-bis (tnphenyl) phosphine palladium without any cocatalyst. The present inventors have observed that, when p-tolylmagnesium bromide was reacted with o-bromobenzonitrile using palladium chloride/triphenyl phosphine as catalyst, only 47% conversion to the product (OTBN) was obtained when palladium chloride was in the concentration of 6 mole% with reference to o-bromobenzonitrile. When palladium acetate/triphenyl phosphine catalyst system was used, the conversion to the product was upto 75% when palladium acetate used was 6 mole% with reference to o-bromobenzonitrile. Thus, the processes for the synthesis of unsymmetrical biaryl compounds using palladium catalysts require higher concentration of the catalyst or require special kind of solvent like polyether when used without any cocatalyst. Cocatalyst like manganous chloride is hygroscopic. Hence, there is a need to develop a more economical, a highly selective and simple method for the synthesis of unsymmetrical biphenyls, which are very important intermediates for drugs like angiotensin II antagonists. The present inventors have found that compounds of Formula I can be prepared in good yield and better purity by a process comprising reaction of a Grignard reagent with an aryl halide in a solvent in the presence of a palladium catalyst and a ligand and a cocatalyst selected from inexpensive, safe and easy to handle Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid. 5 OBJECT OF THE INVENTION It is an object of the invention to provide a simple process for the synthesis of unsymmetrical biaryl compounds. It is another object of the invention to provide an economically viable process for the synthesis of unsymmetrical biaryl compounds. It is yet another object of the invention to provide a better yielding process for the synthesis of unsymmetrical biaryl compounds. It is a further object of the invention to provide a process for the synthesis of unsymmetrical biaryl compounds with a high purity. It is yet another object of the invention to provide environmentally safe process for the synthesis of unsymmetrical biaryl compounds. SUMMARY OF THE INVENTION According to an aspect of the invention there is provided a novel process for the synthesis of unsymmetrical biaryl compounds of Formula I \ /~A / Formula I where R may be alkyl, R' may be a cyano, protected or unprotected tetrazole, or C^NR" (R" may be alky!, aryl, aralkyl or alkoxy); comprising reaction of a Grignard reagent of Formula II with an aryl halide of Formula III; -MgX 6 Formula II where R may be alky I; X may be halogen with an aryl halide of Formula III Formula III where X may be halogen; R' may be a cyano, protected or unprotected tetrazole, u or C^NR" (R" may be alkyl, aryl, aralkyl or alkoxy); in a suitable solvent in the presence of a palladium catalyst and a cocatalyst selected from inexpensive, safe and easy to handle Lewis acid like boron trifluoride etherate, perchloric acid or salts of perchloric acid. DETAILED DESCRIPTION OF THE PRESENT INVENTION Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylpheny!) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) can be used as an intermediate in the preparation of various angiotensin II antagonists. Formula I where R and R' are same as mentioned earlier. 7 According to an aspect of the invention there is provided a novel process for the synthesis of unsymmetrical biaryl compounds of Formula I Biaryl compounds of Formula I can be prepared by various methods. Suzuki coupling involves reaction of aryl-boron compounds with aryl halides in the presence of palladium catalysts. A Grignard reagent can be reacted with an aryl halide in a suitable solvent in the presence of transition metal catalysts like palladium, nickel and manganese. Formula II where R is same as mentioned earlier The present inventors have found that compounds of Formula I can be conveniently prepared by the reaction of a Grignard reagent of Formula II with aryl halide of Formula III in a solvent in the presence of a palladium catalyst and a Lewis acid cocatalyst. Formula III where R' is same as mentioned earlier. The present inventors have further found that simple, safe, inexpensive and easy to handle Lewis acid can be used in catalytic amounts with palladium catalyst to prepare unsymmetrical biaryl compounds. It is observed that when Lewis acid is added as cocatalyst in the reaction, the amount of palladium catalyst required for the reaction reduces considerably, thus making the process economically viable. According to the present invention, the Grignard reagent is prepared in a suitable solvent and slowly added to the mixture of the aryl halide, palladium complex (prepared in situ from palladium chloride/palladium acetate and ligand) and Lewis acid cocatalyst. 8 The reaction is shown in the scheme beiow: Palladium catalyst \ // \ f^p; perchloric acid/salt of / R, perchloric acid/salt of yS / ^ perchloric acid or " \ / ^— boron trifluoride etherate where R, X and R' are same as mentioned earlier. The molar ratio of the aryl halide to Grignard reagent is preferably 2:1 to 1:2, preferably between 1:1 and 1:1.5, more preferably between 1:1 and 1:1.3. The palladium catalyst is present in the reaction mixture in a concentration of 0.1 mo!e% to 2.5 mole% with reference to the aryl halide. The ligand is in the concentration of 0.1 mole% to 5 mole% with reference to the aryl halide. The Lewis acid catalyst is in the concentration of 0.01 to 10 mole% with reference to the aryl halide. The organic solvent is selected from cyclic ethers, linear or branched chain acyclic ethers, mono- or diether types, N-methylpyrrolidone, alone or in combination. The more preferred solvent is cyclic ether. According to the invention the Grignard reagent is added during 0.5 to 10 hours, preferably during 1 to 8 hours, more preferably during 2 to 6 hours, most preferably during 3 to 6 hours. According to the invention the Grignard reagent is added between 10°C and 100°C, more preferably between 20°C and 85°C, most preferably between 25°C and 75°C. The reaction conditions are to a large extent interchangeable depending upon the reactants. 9 The invention is demonstrated below by non-limiting examples. EXAMPLES Example 1: A solution of o-bromobenzonitrile (100 g, 0.55 mol) and dichloro-bis (triphenyl) phosphine palladium (3.849g, 0.0055 mol, 1 mole %) [prepared in situ from palladium chloride (0.972 g, 0.0055 mol) and triphenylphosphine (2.877 g, 0.011 mole)] and lithium perchiorate (1.46 g, 0.014 mol, 2.5 mol%) in tetrahydrofuran (550 ml) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Tolylmagnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (820 mi) was added slowly over 4 hours while maintaining the temperature 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was monitored by GC. GC analysis of the reaction mixture showed OTBN 91% and 4, 4'-dimethydiphenyl 2.7%. Water (100 ml) was added and THF was distilled off under vacuum. Dichloromethane (300 ml) was added and the organic layer was extracted with 15% HC1 (100 ml). Dichloromethane was distilled off and heptane (300 ml) was added, refluxed for 30 minutes, and cooled to 0°C-5°C. Filtration yielded OTBN (85 g, 80% of theoretical, GC purity 98%). Example 2: A solution of o-bromobenzonitrile (100 g, 0.55 mol) and diacetate-bis (triphenyl) phosphine palladium (8.23g, 0.011 mol, 2 mole %) [prepared in situ from palladium acetate (2.46 g, 0.011 mol) and triphenylphosphine (5.77 g, 0.022 mole)] and boron trifluoride etherate (1.95 g, 0.0138 mol, 2.5 mo!%) in tetrahydrofuran (550 mi) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Toly(magnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (820 ml) was added slowly over 4 hours while maintaining the temperature at 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was 10 monitored by GC. GC analysis of the reaction mixture showed OTBN 77% and 4, 4'-dimethydiphenyI 2%, o-bromobenzonitrile 14%. Dated this 15th day of January 2007. Ashwini Sandu OF S.MAJUMDAR & CO Applicants' Agent. 11

Full Text

FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2006PROVISIONAL SPECIFICATION(See section 10; rule 13)
1 Title of the invention. - PROCESS FOR THE PREPARATION OFUNSYMMETRICALLY SUBSTITUTED BIPHENYL COMPOUNDS
2. Applicant(s)(a) NAME : CALYX CHEMICALS AND PHARMACEUTICALS LTD.(b) NATIONALITY :An India Company(c) ADDRESS : 5, Marwah's Complex, Sakivihar Road, Sakinaka, AndheriMaharashtra, India, hereby declare (E), Mumbai-400 072,
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF INVENTION
The present invention relates to the preparation of biaryl compounds of formula I
-oh
Formula I where R may be alkyl, R' may be a cyano, protected or unprotected tetrazole, or
u
C=NRM (R" may be alkyl, aryl, aralkyl or alkoxy).
In particular the present invention relates to the preparation of the biaryl compound of Formula I in which R is methyl and R' is a cyano group.
BACKGROUND OF THE INVENTION
Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylphenyl) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) which is a precursor of 2-(tetrazolyl)-4'-methyl biphenyl, can be used as an intermediate in the preparation of various angiotensin II antagonists.
A number of coupling approaches have been developed for the construction of the biphenyl systems. As OTBN and related compounds are very important intermediates, various methods have been reported for the preparation of OTBN. Reported methods include the reaction of organo-boron (Suzuki reaction), zinc (Negishi reaction) or tin (Stille coupling) compounds with bromobenzonitriles.
Tamao et al., Bull. Chem. Soc. Japan, vol. 49 (1976), pp. 1958-1969, discloses that aryl bromides can be reacted with aryl magnesium halides (aryl Grignard reagents) in the presence of dihalodiphosphinenickel complexes to give biaryl
2

compounds. This reference states that the most serious limitation is that the substituents on the organic halides and on the Grignard reagents are restricted to those, which cannot react with Grignard reagents.
The unsymmetrical biaryl coupling reactions require a metal catalyst. Generally these catalysts are selected from palladium, nickel or manganese. The palladium catalyzed coupling of an aryl Grignard compound with an iodo-substituted benzonitrile has been described.
US 5288895 discloses a method in which a halobenzonitrile is treated with aryl magnesium haiide in the presence of a manganese salt as catalyst.
US 6121480 describes a method for the synthesis of unsymmetrically substituted biphenyls comprising the palladium catalyzed coupling of an aryl magnesium haiide with bromobenzonitrile. The patent claims the concentration of the palladium catalyst to be 1.0 to 2.0mole % based on the bromobenzonitrile.
US 6407253 discloses a method for preparing the biphenyl compounds by reacting an aryl haiide with a Grignard reagent using a palladium complex -PdCb/dppp (1 mole %) in the presence of a linear or branched polyether as solvent. According to the invention yield of the desired product is at least 92% and the 4, 4'-dimethylbiphenyl impurity is below 3.5%. However, the said document also states that such results could not be obtained when the solvent was replaced by a cyclic diether.
US 6392080 discloses a process for the preparation biphenyl compounds by reacting o-halobenzonitrile with a p-tolylmagnesium haiide in the presence of MnCb / a mixture of 1 mole of MnCb and 2 moles of LiCl and PdCb/dppp complex. The manganous salt is present in the reaction mixture in the proportion of 0.5 to 1.30 molar equivalent of the o-halobenzonitrile and the palladium
3

catalyst is in the concentration. of 0.001 to 2 molar % per mole of the o-halobenzonitrile.
US 6194599 describes a process for preparing the biaryl compounds by reacting an aryl group bonded to zinc with an aryl chloride in the presence of palladium or nickel catalyst.
US 5922898 mentions reacting aryl magnesium reagents and aryllithium reagents with an aryl halide in the presence of catalysts selected from palladium catalysts and nickel catalysts and a cocatalyst selected from zinc cocatalysts and cadmium cocatalysts.
Thus, unsymmetrical biaryl compounds can be prepared by reacting a Grignard reagent with an aryl halide in the presence of transition metal catalysts like palladium catalysts or nickel catalysts in the form of salts or in the form of complexes with ligands with/without any cocatalysts. The reaction is shown schematically below.
x
R I
catalyst
Pi AL
A
y + KJ[
MgX
WO97/30970 (equivalent to US 6121480) discloses a process for the said coupling reaction using palladium complex catalyst. The said patent claims the palladium catalyst concentration of 0.1 to 20 molar % based on the bromobenzonitrile.
The authors of the patent US 5288895 saw a low yield (22%) of the biaryl compound when 4.2 equivalent of the Grignard reagent (aryl magnesium bromide)
4

and 0.3 equivalent of palladium chloride were used, a yield of 1% was observed when 2.2 equivalent of the Grignard reagent was reacted with 2-bromobenzonitrile in the presence of catalytic amount of tetrakis(tripheny!phosphine)-palladiurn for 6 hours at 65°C. It is also reported in Tetrahedron Letters, 39(1998), 7275-7278 that lower yield (20%) of OTBN was obtained when the coupling of p-tolylmagnesium chloride with o-bromobenzonitrile was carried out using dichloro-bis (tnphenyl) phosphine palladium without any cocatalyst.
The present inventors have observed that, when p-tolylmagnesium bromide was reacted with o-bromobenzonitrile using palladium chloride/triphenyl phosphine as catalyst, only 47% conversion to the product (OTBN) was obtained when palladium chloride was in the concentration of 6 mole% with reference to o-bromobenzonitrile. When palladium acetate/triphenyl phosphine catalyst system was used, the conversion to the product was upto 75% when palladium acetate used was 6 mole% with reference to o-bromobenzonitrile.
Thus, the processes for the synthesis of unsymmetrical biaryl compounds using palladium catalysts require higher concentration of the catalyst or require special kind of solvent like polyether when used without any cocatalyst. Cocatalyst like manganous chloride is hygroscopic.
Hence, there is a need to develop a more economical, a highly selective and simple method for the synthesis of unsymmetrical biphenyls, which are very important intermediates for drugs like angiotensin II antagonists.
The present inventors have found that compounds of Formula I can be prepared in good yield and better purity by a process comprising reaction of a Grignard reagent with an aryl halide in a solvent in the presence of a palladium catalyst and a ligand and a cocatalyst selected from inexpensive, safe and easy to handle Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid.
5

OBJECT OF THE INVENTION
It is an object of the invention to provide a simple process for the synthesis of
unsymmetrical biaryl compounds.
It is another object of the invention to provide an economically viable process for
the synthesis of unsymmetrical biaryl compounds.
It is yet another object of the invention to provide a better yielding process for the
synthesis of unsymmetrical biaryl compounds.
It is a further object of the invention to provide a process for the synthesis of
unsymmetrical biaryl compounds with a high purity.
It is yet another object of the invention to provide environmentally safe process
for the synthesis of unsymmetrical biaryl compounds.
SUMMARY OF THE INVENTION
According to an aspect of the invention there is provided a novel process for the synthesis of unsymmetrical biaryl compounds of Formula I

\ /~A /

Formula I where R may be alkyl,
R' may be a cyano, protected or unprotected tetrazole,
or C^NR" (R" may be alky!, aryl, aralkyl or alkoxy);
comprising reaction of a Grignard reagent of Formula II with an aryl halide of Formula III;
-MgX
6

Formula II where R may be alky I; X may be halogen with an aryl halide of Formula III
Formula III where X may be halogen; R' may be a cyano, protected or unprotected tetrazole,
u
or C^NR" (R" may be alkyl, aryl, aralkyl or alkoxy);
in a suitable solvent in the presence of a palladium catalyst and a cocatalyst selected from inexpensive, safe and easy to handle Lewis acid like boron trifluoride etherate, perchloric acid or salts of perchloric acid.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylpheny!) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) can be used as an intermediate in the preparation of various angiotensin II antagonists.

Formula I where R and R' are same as mentioned earlier.
7
According to an aspect of the invention there is provided a novel process for the synthesis of unsymmetrical biaryl compounds of Formula I

Biaryl compounds of Formula I can be prepared by various methods. Suzuki coupling involves reaction of aryl-boron compounds with aryl halides in the presence of palladium catalysts. A Grignard reagent can be reacted with an aryl halide in a suitable solvent in the presence of transition metal catalysts like palladium, nickel and manganese.

Formula II
where R is same as mentioned earlier

The present inventors have found that compounds of Formula I can be conveniently prepared by the reaction of a Grignard reagent of Formula II with aryl halide of Formula III in a solvent in the presence of a palladium catalyst and a Lewis acid cocatalyst.
Formula III
where R' is same as mentioned earlier.
The present inventors have further found that simple, safe, inexpensive and easy to handle Lewis acid can be used in catalytic amounts with palladium catalyst to prepare unsymmetrical biaryl compounds. It is observed that when Lewis acid is added as cocatalyst in the reaction, the amount of palladium catalyst required for the reaction reduces considerably, thus making the process economically viable.
According to the present invention, the Grignard reagent is prepared in a suitable solvent and slowly added to the mixture of the aryl halide, palladium complex (prepared in situ from palladium chloride/palladium acetate and ligand) and Lewis acid cocatalyst.
8

The reaction is shown in the scheme beiow:
Palladium catalyst
\ // \ f^p; perchloric acid/salt of / R, perchloric acid/salt of yS / ^
perchloric acid or " \ / ^—
boron trifluoride etherate
where R, X and R' are same as mentioned earlier.
The molar ratio of the aryl halide to Grignard reagent is preferably 2:1 to 1:2, preferably between 1:1 and 1:1.5, more preferably between 1:1 and 1:1.3.
The palladium catalyst is present in the reaction mixture in a concentration of 0.1 mo!e% to 2.5 mole% with reference to the aryl halide.
The ligand is in the concentration of 0.1 mole% to 5 mole% with reference to the aryl halide.
The Lewis acid catalyst is in the concentration of 0.01 to 10 mole% with reference to the aryl halide.
The organic solvent is selected from cyclic ethers, linear or branched chain acyclic
ethers, mono- or diether types, N-methylpyrrolidone, alone or in combination. The
more preferred solvent is cyclic ether.
According to the invention the Grignard reagent is added during 0.5 to 10 hours,
preferably during 1 to 8 hours, more preferably during 2 to 6 hours, most
preferably during 3 to 6 hours.
According to the invention the Grignard reagent is added between 10°C and
100°C, more preferably between 20°C and 85°C, most preferably between 25°C
and 75°C.
The reaction conditions are to a large extent interchangeable depending upon the
reactants.
9

The invention is demonstrated below by non-limiting examples. EXAMPLES
Example 1:
A solution of o-bromobenzonitrile (100 g, 0.55 mol) and dichloro-bis (triphenyl) phosphine palladium (3.849g, 0.0055 mol, 1 mole %) [prepared in situ from palladium chloride (0.972 g, 0.0055 mol) and triphenylphosphine (2.877 g, 0.011 mole)] and lithium perchiorate (1.46 g, 0.014 mol, 2.5 mol%) in tetrahydrofuran (550 ml) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Tolylmagnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (820 mi) was added slowly over 4 hours while maintaining the temperature 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was monitored by GC. GC analysis of the reaction mixture showed OTBN 91% and 4, 4'-dimethydiphenyl 2.7%. Water (100 ml) was added and THF was distilled off under vacuum. Dichloromethane (300 ml) was added and the organic layer was extracted with 15% HC1 (100 ml). Dichloromethane was distilled off and heptane (300 ml) was added, refluxed for 30 minutes, and cooled to 0°C-5°C. Filtration yielded OTBN (85 g, 80% of theoretical, GC purity 98%).
Example 2:
A solution of o-bromobenzonitrile (100 g, 0.55 mol) and diacetate-bis (triphenyl) phosphine palladium (8.23g, 0.011 mol, 2 mole %) [prepared in situ from palladium acetate (2.46 g, 0.011 mol) and triphenylphosphine (5.77 g, 0.022 mole)] and boron trifluoride etherate (1.95 g, 0.0138 mol, 2.5 mo!%) in tetrahydrofuran (550 mi) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Toly(magnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (820 ml) was added slowly over 4 hours while maintaining the temperature at 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was
10

monitored by GC. GC analysis of the reaction mixture showed OTBN 77% and 4, 4'-dimethydiphenyI 2%, o-bromobenzonitrile 14%.
Dated this 15th day of January 2007.

Ashwini Sandu OF S.MAJUMDAR & CO
Applicants' Agent.
11

Documents:

76-mum-2007-abstract(14-1-2008).pdf

76-mum-2007-annexure to form 3(14-2-2008).pdf

76-mum-2007-claims(14-1-2008).pdf

76-MUM-2007-CLAIMS(AMENDED)-(18-2-2014).pdf

76-MUM-2007-CLAIMS(AMENDED)-(28-2-2013).pdf

76-MUM-2007-CLAIMS(MARKED COPY)-(18-2-2014).pdf

76-MUM-2007-CLAIMS(MARKED COPY)-(28-2-2013).pdf

76-MUM-2007-CORRESPONDENCE(11-9-2013).pdf

76-mum-2007-correspondence(14-2-2008).pdf

76-MUM-2007-CORRESPONDENCE(17-1-2014).pdf

76-MUM-2007-CORRESPONDENCE(7-12-2010).pdf

76-mum-2007-correspondence-received.pdf

76-mum-2007-description (provisional).pdf

76-mum-2007-description(complete)-(14-1-2008).pdf

76-mum-2007-form 1(24-1-2007).pdf

76-MUM-2007-FORM 18(7-12-2010).pdf

76-mum-2007-form 2(24-1-2008).pdf

76-mum-2007-form 2(title page)-(14-1-2008).pdf

76-mum-2007-form 2(title page)-(provisional)-(15-1-2007).pdf

76-mum-2007-form 5(14-2-2008).pdf

76-mum-2007-form-1.pdf

76-mum-2007-form-2.doc

76-mum-2007-form-2.pdf

76-mum-2007-form-26.pdf

76-mum-2007-form-3.pdf

76-mum-2007-general power of attorney(27-9-2006).pdf

76-MUM-2007-REPLY TO EXAMINATION REPORT(28-2-2013).pdf

76-MUM-2007-REPLY TO HEARING(18-2-2014).pdf

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Patent Number

259679

Indian Patent Application Number

76/MUM/2007

PG Journal Number

13/2014

Publication Date

28-Mar-2014

Grant Date

22-Mar-2014

Date of Filing

15-Jan-2007

Name of Patentee

CALYX CHEMICALS AND PHARMACEUTICALS LTD.

Applicant Address

5, MARWAH'S COMPLEX, SAKIVIHAR ROAD, SAKINAKA, ANDHERI (E), MUMBAI 400 072.

Inventors:

#	Inventor's Name	Inventor's Address
1	BAPAT, CHINTAMANI	FLAT NO 2, BLDG NO 16, OSWAL PARK, POKHRAN ROAD 2, THANE (WEST)- 400 601.
2	CHATURVEDI, ROHIT	C-10. SAIDHAM CO-OP HSG SOCIETY, PREMIER ROAD, KURLA, MUMBAI 400 070.
3	MULLA, DILAWAR	C/O MR.HEMANT P.KHAMKAR, 202, DEEPEN JYOT CHS, SHIVAJI UDYOG NAGAR, MANPADA ROAD, DOMBIVLI (E), THANE 421 201.
4	NARKHEDE, NISHIKANT	B-306, PARVATI DEVI CHS, VADAVALI SECTOR, AMBARNATH (E), THANE 421 705.
5	LAL, BANSI	1005 MARATHON GALAXY II L.B.S. MARG, MULUND (W) MUMBAI 400 080.
6	TADE, KAILASH	MAHADEV, D 6/503, MADHAV SRISHTI, NEAR GODREG HILL KHADAKPADA, KALYAN (W), THANE 421 301.

PCT International Classification Number

C07D251/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA