Claims:WE CLAIM:

1. An improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I), comprising the steps of:

Formula-(I)

(i) reacting a compound of Formula-(II),

Formula-(II)

with thionyl chloride in a suitable solvent to obtain 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa);

Formula-(IIa)
(ii) reacting the compound of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula (III);

Formula-(III)

in presence of 3-picoline in a suitable organic solvent to obtain crude Boscalid of Formula-(I).
(iii) dissolving crude Boscalid in acetone solvent,
(iv) combining the solution obtained from step-(iii) with a suitable anti-solvent,
(v) isolating the anhydrous crystalline Form-I of Boscalid of Formula-(I).

2. The process as claimed in claim 1, wherein the suitable solvent used in step-(i) is selected from hexane, heptane, cyclohexane, cycloheptane, methyl cyclohexane, benzene, toluene, o-xylene, m-xylene and p-xylene mixtures thereof.
3. The process as claimed in claim 1, wherein the suitable solvent used in step-(ii) is selected from hexane, heptane, cyclohexane, cycloheptane, methyl cyclohexane, benzene, toluene, o-xylene, m-xylene and p-xylene or mixtures thereof.
4. The process as claimed in claim 1, wherein the anti-solvent used in step-(iv) is selected from water, aliphatic hydrocarbons, Aromatic hydrocarbons or mixture thereof.
, Description:Field of the Invention
The present invention relates to an improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I)

Background of the Invention
2-Chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide, having the common name Boscalid, is a compound with the structural Formula-(I).

Boscalid is a fungicide of the carboxamide group and acts as a succinate dehydrogenase inhibitor (SDHI) , a respiratory inhibitor of mitochondria.
US 5589493 discloses nicotinamides, anilide derivatives and 2-aminobiphenyl derivatives and their use for controlling Botrytis. The subject compounds are defined by way of a Markush formula.
US ‘493 also discloses a process for the preparation of Boscalid by reaction of 2-chloropyridine-3-carboxylic acid of Formula-(II) with thionyl chloride to obtain 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa), followed by condensation with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of pyridine or Et3N to obtain Boscalid of Formula-(I).
The synthetic procedure is illustrated in Scheme-I as below:

Scheme-I
The process disclosed in US 5589493 suffers from the following disadvantages outlined below:
 The process involves usage of expensive solvent like tetrahydrofuran and chlorinated solvent methylene chloride.
WO 2015106443 A1 discloses a process for the preparation of Boscalid by reaction of 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of triethyl amine in CHCl3 to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-II as below:

Scheme-II
The process disclosed in WO 2015106443 A1 suffers from the following disadvantages outlined below:
 The starting material, 2-chloropyuridine-3-caroxylic acid chloride (IIa) may not stable and convert into corresponding acid and leads to incomplete reaction. And the usage of chlorinated solvent chloroform is not environment friendly.
CN 108997210 discloses a process for the preparation of Boscalid by reaction of 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of sodium carbonate in DCM to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-III as below:

Scheme-III
The process disclosed in CN 108997210 suffers from the following disadvantages outlined below:
 The starting material, 2-chloropyuridine-3-caroxylic acid chloride (IIa) may not stable and convert into corresponding acid and leads to incomplete reaction.
Chemical Science, 2017, 8(5), 3852-3857 reports a process for the preparation of Boscalid by reaction of 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of Et3N in THF to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-IV as below:

Scheme-IV
The process reported in Chemical Science, 2017, 8(5), 3852-3857 suffers from the following disadvantages outlined below:
 The starting material, 2-chloropyuridine-3-caroxylic acid chloride (IIa) may not stable and involves usage of expensive solvent tetrahydrofuran.
CN 104478797 discloses a process for the preparation of Boscalid by reaction of 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of potassium carbonate in DCM to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-V as below:

Scheme-V
The process disclosed in CN 104478797 suffers from the following disadvantages outlined below:
 The starting material, 2-chloropyuridine-3-caroxylic acid chloride (IIa) may not stable and the usage of halogenated solvents not recommended in the process as they are not environment friendly and involves health hazards.

CN 104016915 discloses a process for the preparation of Boscalid by reaction of 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of DIPEA in DCM to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-VI as below:

Scheme-VI

IN 262428 discloses a process for the preparation of Boscalid anhydrous crystalline Form-II from anhydride crystalline Form-I of Boscalid using protic polar solvents.

IN 201817042591 discloses a process for the preparation of Boscalid anhydrous crystalline Form-I from anhydrous crystalline Form-II of Boscalid using Aqueous Acetone solvent.

IN 348869 discloses a process for the preparation of anhydrous crystalline Form-I of Boscalid from mixture of Form-I and Form-II of Boscalid using halogenated hydrocarbon solvents.

The process disclosed in IN 348869 suffers from the following disadvantages outlined below:
 Usage of halogenated solvents not recommended in the process, as they are not environment friendly and involves health hazards.
Objective of the Invention

The main objective of the present invention is to provide a simple and cost effective process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-I with high purity and good yield on a commercial scale.

Summary of the Invention
The present invention relates to an improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I), comprising the steps of:

Formula-(I)

(i) reacting a compound of Formula-(II),

Formula-(II)

with thionyl chloride in a suitable solvent to obtain 2-Chloropyridine-3-carboxylic acid chloride of Formula-(IIa)

Formula-(IIa)
(ii) reacting the compound of Formula-(IIa) with 2-(4-Chlorophenyl)aniline of Formula (III);

Formula-(III)

in presence of 3-picoline in a suitable organic solvent to obtain crude Boscalid of Formula-(I).
(iii) dissolving crude Boscalid in acetone solvent;
(iv) combining the solution obtained from step-(iii) with a suitable anti-solvent;
(v) isolating the anhydrous crystalline Form-I of Boscalid of Formula-(I).

Detailed Description of the Invention
The present invention relates to an improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I), comprising the steps of:
(i) reacting a compound of Formula-II with thionyl chloride in a suitable solvent to obtain 2-chloropyridine-3-carboxylic acid chloride of Formula-(IIa);
(ii) Further, reacting the compound of Formula-(IIa) with 2-(4-chlorophenyl)aniline of Formula-(III) in presence of 3-picoline in a suitable organic solvents to obtain crude Boscalid of Formula-(I).
(iii) dissolving crude Boscalid in acetone solvent;
(iv) combining the solution obtained from step-(iii) with a suitable anti-solvent.
(v) isolating the anhydrous crystalline Form-I of Boscalid of Formula-(I).

The suitable solvent used in step-(i) is selected from aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane, methyl cyclohexane and mixtures thereof. Aromatic hydrocarbons like benzene, toluene, o-xylene, m-xylene and p-xylene and mixtures thereof. Preferably, aromatic hydrocarbons.
The mole equivalents of thionyl chloride used in above reaction step are from 1.0 to 2.0, preferably 1.0 to 1.5 mole equivalents and more preferably 1.0 to 1.2 mole equivalents with respective compound of Formula-(II).
The above reaction may be performed from 25°C to 100oC for 60 minutes to 10 hours, preferably 75ºC to 80°C for 2-3 hour. The obtained 2-chloropyridine-3-carboxylic acid chloride of Formula-(IIa) may be used in the next reaction directly without isolation.

The suitable solvent used in step-(ii) is selected from aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane, methyl cyclohexane and mixtures thereof. Aromatic hydrocarbons like benzene, toluene, o-xylene, m-xylene and p-xylene or mixtures thereof. Preferably, aromatic hydrocarbons.
The mole equivalents of 3-picoline used in above reaction step are 1.0 to 2.0, preferably 1.0 to 1.5 mole equivalents and more preferably 1.0 to 1.2 mole equivalents with respective compound of Formula-(IIa).
The above reaction may be performed from 10°C to 60oC for --30 minutes to 6 hours, preferably 25ºC to 35°C for 1 to 2 hours. The obtained crude Boscalid of Formula-(I) may be used in the next reaction directly without isolation.

In step (iii), the reaction may be performed from 0°C to 50oC.
Anti-solvent used in step-(iv) is selected from water and aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane, methyl cyclohexane and mixtures thereof. Aromatic hydrocarbons like benzene, toluene, o-xylene, m-xylene and p-xylene and mixtures thereof. Preferably, water or mixture thereof.
In step (iv), the reaction may be performed from 0°C to 40oC for 20 minutes 3 hours, preferably 25ºC to 35ºC for 30 minutes to 2 hours

In step (v), the reaction may be performed from 0°C to 40oC for 20 minutes 3 hours preferably 25ºC to 35ºC for – 30 minutes to 2 hours .

Further, the Boscalid of Formula-(I) obtained according to the present invention is designated as anhydrous crystalline Form-I and its powder X-ray diffraction pattern having peaks at about 6 ± 0.2°, 9.5 ± 0.2°, 18 ± 0.2° and 22.5 ± 0.2° 2-theta shown in Figure-1. Its DSC thermogram having endotherm at about 143±2°C and shown in Figure-2.
Brief description of the drawings:
Figure- 1: Illustrates the PXRD pattern of anhydrous crystalline Form-I Boscalid of Formula (I) of the present invention.
Figure 2: Illustrates the IR data of anhydrous crystalline Form-I Boscalid of Formula (I) of the present invention.
Figure 3: Illustrates the DSC thermogram of anhydrous crystalline Form-I Boscalid of Formula (I) of the present invention.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES:
Example-1: Preparation of Boscalid
Charged 2-chloropyridine-3-carboxylic acid (50.0g, 0.317 moles), toluene (150.0 ml) into the 500 ml 4 necked round bottom flask under nitrogen atmosphere. Reaction mass was stirred for 5-10 min at 25-35ºC to get suspension. N,N-Dimethylformamide (1.0 m) was added to the above reaction mass and stirred for 5 min. Thionyl chloride (45.2g, 0.380 moles) was added slowly to the reaction mass by maintain the reaction mass temperature not crossing 35ºC. Reaction mas was heated to 75-80ºC and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30ºC and kept aside under nitrogen atmosphere and labelled as reaction mass-1.

In another 500 ml 4 necked round bottom flask, charged 2-(4-chlorophenyl)aniline (64.8g, 0.318 moles), toluene (100.0 ml) under nitrogen atmosphere and stir for 5-10 min to get clear solution. 3-Picoline (35.4g, 0.380 moles) was added to the above reaction mass and stirred for 5-10 min. Reaction mass was cooled to 5-10ºC and then reaction mass-1 was added by maintaining the reaction mass temperature not crossing 20ºC. After completion of the addition, reaction mass was allowed to 25-35ºC and stirred for 1-2h. After completion of reaction by TLC, solvent was distilled off under vacuum at 50-55ºC to get crude material.

Example-2: Preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I)
Acetone (250.0 ml) was added to the above crude, stirred for 5-10 min to get clear solution. Water (500.0 ml) was added to the above solution and stirred for 45-60 min at 25-35ºC. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65ºC for 10-12h to get Boscalid as off-white to cream coloured solid (97.6g, 89.6% by theory). Purity of the compound > 98.0% by HPLC.

Example-3: Preparation of Boscalid.
Charged 2-chloropyridine-3-carboxylic acid (100.0g, 0.634 moles), toluene (300.0 ml) into the 1L 4 necked round bottom flask under nitrogen atmosphere. Reaction mass was stirred for 5-10 min at 25-35ºC to get suspension. N,N-Dimethylformamide (2.0 ml) was added to the above reaction mass and stirred for 5 min. Thionyl chloride (90.4g, 0.76 moles) was added slowly to the reaction mass by maintain the reaction mass temperature not crossing 35ºC. Reaction mas was heated to 75-80ºC and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30ºC and kept aside under nitrogen atmosphere and labelled as reaction mass-1.

In another 1L 4 necked round bottom flask, charged 2-(4-chlorophenyl)aniline (129.6g, 0.636 moles), toluene (200.0 ml) under nitrogen atmosphere and stir for 5-10 min to get clear solution. 3-Picoline (70.8g, 0.76 moles) was added to the above reaction mass and stirred for 5-10 min. Reaction mass was cooled to 5-10ºC and then reaction mass-1 was added by maintaining the reaction mass temperature not crossing 20ºC. After completion of the addition, reaction mass was allowed to 25-35ºC and stirred for 1-2h. After completion of reaction by TLC, solvent was distilled off under vacuum at 50-55ºC to get crude material.

Example-4: Preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I)
Acetone (500.0 ml) was added to the above crude, stirred for 5-10 min to get clear solution. Water (1000.0 ml) was added to the above solution and stirred for 45-60 min at 25-35ºC. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65ºC for 10-12h to get Boscalid as off-white to cream coloured solid (200.43g, 89.6% by theory). Purity of the compound > 98.0% by HPLC.

Example-5: Preparation of boscalid by reverse addition of 2-(4-chlorophenyl)aniline to acid chloride.
Charged 2-chloropyridine-3-carboxylic acid (50.0g, 0.317 moles), toluene (150.0 ml) into the 500 ml 4 necked round bottom flask under nitrogen atmosphere. Reaction mass was stirred for 5-10 min at 25-35ºC to get suspension. N,N-Dimethylformamide (1.0 m) was added to the above reaction mass and stirred for 5 min. Thionyl chloride (45.2g, 0.380 moles) was added slowly to the reaction mass by maintain the reaction mass temperature not crossing 35ºC. Reaction mas was heated to 75-80ºC and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 20-25ºC.

Prepared a solution from 2-(4-chlorophenyl)aniline (58.7g, 0.288 moles), toluene (100.0 ml) and 3-Picoline (38.74g, 0.416 moles) in a beaker. The resulting solution was added slowly to the above reaction mass at 20-30ºC, then stirred for 1-2h at 25-30ºC. After completion of the reaction by TLC, solvent was distilled off under vacuum at 50-55ºC to get crude material.

Example-6: Preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I):
Acetone (250.0 ml) was added to the above crude, stirred for 5-10 min to get clear solution. Water (500.0 ml) was added to the above solution and stirred for 45-60 min at 25-35ºC. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65ºC for 10-12h to get Boscalid as off-white to cream coloured solid (85.6g, 86.64 by theory). Purity of the compound > 98.0% by HPLC.