DESC:FORM 2
THE PATENTS ACT, 1970
(SECTION 39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
1. TITLE OF THE INVENTION

PROCESS FOR THE PREPARATION OF BOSCALID

2. APPLICANT(S)
(a) Name: COROMANDEL INTERNATIONAL LIMITED
(b) Nationality: Indian
(c) Address: Coromandel House, 1-2-10, Sardar Patel Road,
Secunderabad – 500 003, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of boscalid (I) in presence of amide coupling reagents.

BACKGROUND OF THE INVENTION

Boscalid is a new broad spectrum carboximide fungicide used to control a range of plant pathogens in broadacre and horticultural crops. Chemically it is 2-chloro-N-(4’-chlorobiphenyl-2-yl) nicotinamide. It has a low aqueous solubility and is not volatile. It can be very persistent in both soil and aquatic systems depending upon local conditions. It has a low oral mammalian toxicity.

Boscalid is active against different fungal stages both on the plant surface and in the plant tissue. After application to the plant, the active ingredient is taken up via the leaf and then translocated via the transpiration flow. Due its mobility, it shows local systemic and translaminar activity. By that, it can control fungal stages, which have already become established in deeper tissue layers. As a result, Boscalid has preventative and curative activity. Boscalid is active against different fungal stages on and in the plant. When applied protectively, boscalid inhibits spore germination and further development of germinated fungal spores. Boscalid is a pyridine carboxamide fungicide which is effective under preventative and curative conditions. Boscalid mode of action at the molecular level is the inhibition of the enzyme succinate dehydrogenase (SDH), also known as complex II in the mitochondrial electron transport chain.

Boscalid is chemically know as 2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl) pyridine-3-carboxamide and having followed structural formula:

US5589493A discloses synthetic process of boscalid that involves, chlorination of 2-chloronicotinic acid using thionyl chloride followed by coupling reaction of 2-chloronicotinoyl chloride with 4-chloro biphenyl amine in presence of base to form final product. The process is as shown as below in the scheme.

The said process is a two-step reaction and requires high temperature, a large amount of acidic waste gas is generated in the reaction, and the process is not environment friendly. In addition, the chlorinating agents such as thionyl chloride and methane sulfonyl chloride used in step (i), which has strong corrosiveness, equipment is not easy to corrode, and the production cost is increased virtually.

CN113880759B discloses a preparation method of boscalid, which comprises the step of reacting 2-chloronicotinic acid and 4'-chloro-2-aminobiphenyl in the presence of an organic solvent, alkali, and methyl sulfonyl chloride to generate the boscalid.

The present invention relates to an improved process for the preparation of boscalid using alternative method involving amide coupling reagents while maintaining specific reaction conditions that affords better yield and purity. It involves a simple crystallization and filteration method with minimum waste by-products and avoids elimination of hazardous gases and the reaction conditions are milder.

The main objective of the present invention is to provide a simple, economical, commercially, and environmentally feasible process for the preparation of boscalid (I) with high yield and purity.

OBJECT OF THE INVENTION

One object of the present invention is to provide an improved process for the preparation of boscalid (I) in presence of amide coupling reagents, an organic base and in a suitable solvent.

In another object of the present invention, wherein the amide coupling reagent is selected from the group comprising of carbonyl diimidazole (CDI), propane phosphonic acid anhydride (T3P), hydroxy benzotriazole (HOBT), hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 2-1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetra fluoroborate (TBTU), hexafluoro phosphate benzotriazole tetramethyl uranium (HBTU), and ethyl chloroformates.

In another object of the present invention is to provide an improved process for the preparation of boscalid(I) in a more efficient and simple manner which is environment-friendly, industrially scalable, and commercially feasible resulting in high purity and is devoid of any purifications.

Yet another object of the present invention is to provide an improved process for the preparation of boscalid (I) which enables for simple solvent recycle and recovery.

SUMMARY OF THE INVENTION

The present invention is to provide an improved process for the preparation of boscalid compound of formula (I), which comprises,

Boscalid (I)

reacting 2-chloronicotinic acid compound of formula (II)

Formula-(II)
with 4'-chlorobiphenyl-2-amine compound of formula (III),

Formula-(III)
in presence of amide coupling reagent, an organic base, and a suitable solvent.

According to the present invention, an improved process for the preparation of boscalid (I) involves, reacting 2-chloronicotinic acid of formula (II) with 4'-chlorobiphenyl-2-amine of formula (III) in presence of an amide coupling reagent, an organic base, and in a suitable solvent at a temperature of 50oC to 100oC for 4 to 15 hours. After completion of the reaction, the resulting mixture is cooled and filtered. Distilled off the filtrate to get desired boscalid of formula (I) with more than 95% of yield and purity.

According to the present invention, the amide coupling reagent is selected from the group comprising of Carbonyl diimidazole (CDI), Propane phosphonic acid anhydride(T3P), Hydroxy benzotriazole (HOBT), Hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (TBTU), Hexafluoro phosphate benzotriazole tetramethyl uranium (HBTU), and Ethyl chloroformate.

According to the present invention, the base is selected from organic base and inorganic base. The organic base is selected from the group comprising of triethylamine (TEA), N, N-diisopropylethylamine (DIPEA), N.N-dimethyl amino pyridine (N, N-DMAP), N-methyl morpholine (NMP), pyridine, dimethyl aniline, 1,4-dimethyl piperazine, and triethanolamine. The preferred organic base is triethylamine.

The inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate and lithium carbonate.

According to the present invention, the solvent is selected from the group comprising of toluene, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, N, N-dimethylformamide (DMF), 1,2-dimethoxyethane, dimethylacetamide (DMA), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), 1,4-dioxane, acetonitrile (ACN), acetone, methyl ethyl ketone (MEK) and methyl isobutyl ketone, xylene, mono chlorobenzene (MCB), dichlorobenzene, 1,2-dichloromethane (DCM) and 1,2-dichloroethane (EDC). The preferred solvent is toluene.

In another aspect of the present invention, an improved process for the preparation of boscalid (I) which involves, reacting 2-chloronicotinic acid of formula (II) with 4'-chlorobiphenyl-2-amine of formula (III) in presence of Propane phosphonic acid anhydride (T3P), triethylamine (TEA) and toluene at a temperature of 60oC to 70oC for 4 to 6 hours. After completion of the reaction, the resulting mixture is cooled and filtered. Distilled off the filtrate to get desired boscalid of formula (I) with more than 95% of yield and purity.

In another aspect of the present invention is to provide an improved process for the preparation of boscalid (I) in a more efficient and simple manner which is environment-friendly, industrially scalable, and commercially feasible resulting in high purity and is devoid of any purifications.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

It is to be noted that, as used in the specification, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

In one embodiment of the present invention provides an improved process for the preparation of boscalid compound of formula (I), which comprises,

Boscalid (I)
reacting 2-chloronicotinic acid compound of formula (II)

Formula-(II)
with 4'-chlorobiphenyl-2-amine compound of formula (III),

Formula-(III)
in presence of amide coupling reagent, an organic base, and a suitable solvent.

According to the present embodiment, reacting 2-chloronicotinic acid of formula (II) with 4'-chlorobiphenyl-2-amine of formula (III) in presence of an amide coupling reagent, an organic base, and in a suitable solvent at a temperature of 50oC to 100oC for 4 to 15 hours. After completion of the reaction, the resulting mixture is cooled and filtered. Distilled off the filtrate to get desired boscalid of formula (I) with more than 95% of yield and purity.

According to the present embodiment, the amide coupling reagent is selected from the group comprising of Carbonyl diimidazole (CDI), Propane phosphonic acid anhydride (T3P), Hydroxy benzotriazole (HOBT), Hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (TBTU), Hexafluoro phosphate benzotriazole tetramethyl uranium (HBTU), and Ethyl chloroformate.

According to the present embodiment, the base is selected from organic base and inorganic base. The organic base is selected from the group comprising of triethylamine (TEA), N, N-diisopropylethylamine (DIPEA), N.N-dimethyl amino pyridine (N, N-DMAP), N-methyl morpholine (NMP), pyridine, dimethyl aniline, 1,4-dimethyl piperazine, and triethanolamine. The preferred organic base is triethylamine.

The inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate and lithium carbonate.

According to the present embodiment, the solvent is selected from the group comprising of toluene, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, N, N-dimethylformamide (DMF), 1,2-dimethoxyethane, dimethylacetamide (DMA), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), 1,4-dioxane, acetonitrile (ACN), acetone, methyl ethyl ketone (MEK) and methyl isobutyl ketone, xylene, mono chlorobenzene (MCB), dichlorobenzene, 1,2-dichloromethane (DCM) and 1,2-dichloroethane (EDC). The preferred solvent is toluene.

In another embodiment of the present invention, an improved process for the preparation of boscalid (I) involves, reacting 2-chloronicotinic acid of formula (II) with 4'-chlorobiphenyl-2-amine of formula (III) in presence of Propane phosphonic acid anhydride (T3P), triethylamine (TEA) and toluene at a temperature of 60oC to 70oC for 4 to 6 hours. After completion of the reaction, the resulting mixture is cooled and filtered. Distilled off the filtrate to get desired boscalid of formula (I) with more than 95% of yield and purity.

In yet another embodiment of the present invention, the process for the preparation of boscalid of formula (I) using amide coupling reagents provides commercially feasible with high yield without further purification.

The further embodiment of the present invention is illustrated by the following examples, which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Boscalid(I) synthesis using amide coupling reagents:
Example-1:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). Triethylamine (1.5 eq.) and CDI (1.3 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 4-6 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 6-10 hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 70-80%; HPLC Purity: 94%.

Example-2:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in ethyl acetate (3 vol.) at room temperature (25-30 oC). Diisopropyl ethyl amine (DIPEA) (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 50-80°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 40%-50%; HPLC Purity: 96%.

Example-3:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in toluene (3 vol.) at room temperature (25-30 oC). Triethylamine (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 4-6 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 96-97%; HPLC Purity: 98%.

Example-4:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in toluene (3 vol.) at room temperature (25-30 oC). DIPEA (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 4-6 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 94-96%; HPLC Purity: 98%.

Example-5:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in toluene (3 vol.) at room temperature (25-30 oC). N, N-Dimethyl amino pyridine (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 4-6 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 96-97%; HPLC Purity: 98%.

Example-6:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in toluene (3 vol.) at room temperature (25-30 oC). Sodium Carbonate (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 60-70%; HPLC Purity: 98%.

Example-7:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in toluene (3 vol.) at room temperature (25-30 oC). Potassium Carbonate (1.5 eq.) and T3P (1.3 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 60-70%; HPLC Purity: 98%.

Example-8:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). N, N-Dimethyl amino pyridine (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 50-60°C and maintained for 8-10 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-9:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). TEA (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-10:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). DIPEA (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-11:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). N, N-Dimethyl amino pyridine (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-12:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). Sodium carbonate (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-13:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in THF (3 vol.) at room temperature (25-30 oC). Potassium Carbonate (1.2 eq.) and HOBT (1.0 eq.) were added. The reaction mixture was slowly heated to 60-70°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-14:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in 1,4-dioxane (3 vol.) at room temperature (25-30 oC). Sodium carbonate (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 10-20%

Example-15:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). TEA (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 30-40%

Example-16:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). DIPEA (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 30-40%

Example-17:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). N, N-Dimethyl amino pyridine (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 30-40%

Example-18:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). Sodium carbonate (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 10-20%

Example-19:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in DMF (3 vol.) at room temperature (25-30 oC). Potassium carbonate (1.2 eq.) and HATU (1.0 eq.) were added. The reaction mixture was slowly heated to 80-100°C and maintained for 10-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 10-20%

Example-20:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). Potassium carbonate (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 50-60°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-21:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). TEA (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 40-50°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-22:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). DIPEA (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 40-50°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-23:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). N, N-Dimethyl amino pyridine (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 40-50°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 20-30%

Example-24:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). Sodium carbonate (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 40-50°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 10-20%

Example-25:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in acetonitrile (3 vol.) at room temperature (25-30 oC). Potassium carbonate (1.2 eq.) and TBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 40-50°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 10-20%

Example-26:
2-chloronicotinic acid (1 eq.) and 4’-chlorobiphenyl-2-amine (1 eq.) were dissolved in EDC (3 vol.) at room temperature (25-30 oC). DIPEA (1.2 eq.) and HBTU (1.0 eq.) were added. The reaction mixture was slowly heated to 50-75°C and maintained for 8-15 hrs. After the completion of reaction, toluene was distilled out completely. To the residue 10% bicarbonate solution was added to get the precipitate and filtered the obtained solid. To this crude product, methanol was added and refluxed the mixture for 2-3hr to get clear solution. The reaction solution was slowly cooled to 5-10oC and stirred for 1 hr. The obtained solid was filtered under vacuum to afford pure boscalid. Yield: 30-40%.

Table 1: Comparison of yield using amide coupling reagents:
Example No’s Base Coupling reagent Solvent Reaction temp (°C) Reaction time (hrs) % Yield
1. TEA CDI DMF 80-100 6-10 70-80
2. DIPEA T3P EA 50-80 8-15 40-50
3. TEA T3P Toluene 60-70 4-6 96-97
4. DIPEA T3P Toluene 60-70 4-6 94-96
5. N, N-DMAP T3P Toluene 60-70 4-6 96-97
6. Na2CO3 T3P Toluene 60-70 10-15 60-70
7. K2CO3 T3P Toluene 60-70 10-15 60-70
8. N, N-DMAP HOBT THF 50-60 8-10 20-30
9. TEA HOBT THF 60-70 10-15 20-30
10. DIPEA HOBT THF 60-70 10-15 20-30
11. N, N-DMAP HOBT THF 60-70 10-15 20-30
12. Na2CO3 HOBT THF 60-70 10-15 20-30
13. K2CO3 HOBT THF 60-70 10-15 95-96
14. Na2CO3 HATU Dioxane 80-100 10-15 10-20
15. TEA HATU DMF 80-100 10-15 30-40
16. DIPEA HATU DMF 80-100 10-15 30-40
17. N, N-DMAP HATU DMF 80-100 10-15 30-40
18. Na2CO3 HATU DMF 80-100 10-15 10-20
19. K2CO3 HATU DMF 80-100 10-15 10-20
20. K2CO3 TBTU ACN 50-60 8-15 20-30
21. TEA TBTU ACN 40-50 8-15 20-30
22. DIPEA TBTU ACN 40-50 8-15 20-30
23. N, N-DMAP TBTU ACN 40-50 8-15 20-30
24. Na2CO3 TBTU ACN 40-50 8-15 10-20
25. K2CO3 TBTU ACN 40-50 8-15 10-20
26. DIPEA HBTU EDC 50-75 8-15 30-40

Advantages of the present invention using amide coupling reagents:
1. It is a single step process and is classified under green chemistry.
2. It produces better yield and purity.
3. It has simple crystallization and filtration method.
4. It is an industrially and economically feasible process with safe operations.
5. It enables for easy solvent recycle and recovery.
6. It minimizes or eliminates waste by-products, and avoids elimination of hazardous gases, and reaction conditions are milder.
,CLAIMS:We claim:

1. An improved process for the preparation of boscalid (I) which comprises,

Boscalid (I)
reacting 2-chloronicotinic acid compound of formula (II),

Formula-(II)
with 4'-chlorobiphenyl-2-amine compound of formula (III),

Formula-(III)
in presence of an amide coupling agent, an organic base, and in a suitable solvent.
Wherein the amide coupling reagent is propane phosphonic acid anhydride (T3P).

2. The process as claimed in claim 1, wherein the organic base is triethylamine (TEA).

3. The process as claimed in claim 1, wherein the solvent is toluene.

4. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 60oC to 70oC.

Dated this Twenty Ninth (29th) day of April 2024

Mr. Sahadev Katam,
General Manager, Legal-IPR,
Coromandel International Limited,
Registered Indian Patent Agent (IN/PA/5560)