WO2023062649A1 - An improved process for the preparation of anhydrous crystalline form-i of boscalid - Google Patents

An improved process for the preparation of anhydrous crystalline form-i of boscalid Download PDF

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WO2023062649A1
WO2023062649A1 PCT/IN2022/050910 IN2022050910W WO2023062649A1 WO 2023062649 A1 WO2023062649 A1 WO 2023062649A1 IN 2022050910 W IN2022050910 W IN 2022050910W WO 2023062649 A1 WO2023062649 A1 WO 2023062649A1
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formula
boscalid
xylene
crystalline form
iii
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PCT/IN2022/050910
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French (fr)
Inventor
Nageswara Rao Bollepalli
Ganapathi SANAKA
Amarnath Jampani
Veeraiah ARUDRA
Radha Rani SAMATHAM
Janaki Rama Rao Ravi
Durga Prasad Konakanchi
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
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Natco Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Definitions

  • the present invention relates to an improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I)
  • 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.
  • SDHI succinate dehydrogenase inhibitor
  • 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- (Ila), followed by condensation with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of pyridine or EtsN to obtain Boscalid of Formula-(I).
  • WO 2015106443 Al 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 CHCI3 to obtain Boscalid of formula-(I).
  • 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).
  • 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).
  • 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).
  • 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 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.
  • 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:
  • 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:
  • step-(iii) combining the solution obtained from step-(iii) with a suitable antisolvent.
  • 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.
  • aromatic hydrocarbons 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 100 C for 60 minutes to 10 hours, preferably 75°C 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 base used in step-(ii) is an organic or inorganic base.
  • the organic base is selected from A,A-diisopropylamine, A,A-diisopropylcthylaminc triethylamine, N,N- dimethylamine, trimethylamine, pyridine, 3- picoline, ;
  • the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof, preferably sodium bicarbonate.
  • 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.
  • aromatic hydrocarbons 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 60°C for —30 minutes to 6 hours, preferably 25°C 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.
  • step (iii) the reaction may be performed from 0°C to 50°C.
  • 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.
  • water or mixture thereof Preferably, water or mixture thereof.
  • step (iv) the reaction may be performed from 0°C to 40°C for 20 minutes 3 hours, preferably 25°C to 35°C for 30 minutes to 2 hours
  • step (v) the reaction may be performed from 0°C to 40 C for 20 minutes 3 hours preferably 25°C to 35°C for - 30 minutes to 2 hours .
  • 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.
  • 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.
  • reaction mass was stirred for 5-10 min at 25-35°C to get suspension.
  • N,N- Dimethylformamide (3.2 ml) was added to the above reaction mass and stirred for 5 min.
  • Thionyl chloride 145.0g, 1.22 moles was added slowly to the reaction mass by maintain the reaction mass temperature not crossing 35°C. Reaction mas was heated to 75-85°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C and kept aside under nitrogen atmosphere and labelled as reaction mass-1.
  • reaction mass was cooled to 5-10°C and then reaction mass-1 was added and heated reaction mixture to 75-85°C and stirred for Ih. After completion of the addition, reaction mass was allowed to 60-65°C. After completion of reaction by TLC, solvent was distilled off under vacuum at 60-65°C to get crude material.
  • reaction mass was stirred for 5-10 min at 25-35°C to get suspension.
  • N,N- Dimethylformamide (1.0 ml) 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C and kept aside under nitrogen atmosphere and labelled as reaction mass-1.
  • Example-3 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 25-35°C. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65°C 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.
  • reaction mass was stirred for 5-10 min at 25-35°C 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C and kept aside under nitrogen atmosphere and labelled as reaction mass-1.
  • Example-5 Preparation of anhydrous crystalline Form-I of Boscalid of Formula-(I)
  • Example-6 Preparation of Boscalid by reverse addition of 2-(4- chlorophenyl)aniline to acid chloride.
  • reaction mass was stirred for 5-10 min at 25-35°C 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 20-25°C.
  • Example-7 Preparation of anhydrous crystalline Form- of Boscalid of Formula-(I):

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to an improved process for the preparation of anhydrous crystalline Form-I of Boscalid.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ANHYDROUS CRYSTALLINE FORM- OF BOSCALID
Figure imgf000003_0001
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).
Figure imgf000003_0002
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- (Ila), followed by condensation with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of pyridine or EtsN to obtain Boscalid of Formula-(I).
The synthetic procedure is illustrated in Scheme-I as below:
Figure imgf000004_0001
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 Al 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 CHCI3 to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-II as below:
Figure imgf000004_0003
2-Chloropyridine-3-carboxylic
Figure imgf000004_0002
acid chloride (Ila)
Scheme-II
The process disclosed in WO 2015106443 Al suffers from the following disadvantages outlined below: The starting material, 2-chloropyuridine-3-caroxylic acid chloride (Ila) 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-Ill as below:
Figure imgf000005_0002
2-Chloropyridine-3-carboxylic
Figure imgf000005_0001
acid chloride (Ha) Scheme-Ill
The process disclosed in CN 108997210 suffers from the following disadvantages outlined below: The starting material, 2-chloropyuridine-3-caroxylic acid chloride (Ila) 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- (Ila) with 2-(4-Chlorophenyl)aniline of Formula-(III) in the presence of EI3N in THF to obtain Boscalid of formula-(I).
The synthetic procedure is illustrated in Scheme-IV as below:
Figure imgf000006_0003
2-Chloropyridine-3-carboxylic
Figure imgf000006_0001
acid chloride (Ila)
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 (Ila) 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:
Figure imgf000006_0004
2-Chloropyridine-3-carboxylic
Figure imgf000006_0002
acid chloride (Ila)
Scheme-V
The process disclosed in CN 104478797 suffers from the following disadvantages outlined below: The starting material, 2-chloropyuridine-3-caroxylic acid chloride (Ila) 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:
Figure imgf000007_0001
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)
Figure imgf000008_0001
(i) reacting a compound of Formula-(II),
Formula-(II)
Figure imgf000008_0002
with thionyl chloride in a suitable solvent to obtain 2-Chloropyridine-3- carboxylic acid chloride of Formula-(IIa)
Formula-(IIa)
Figure imgf000008_0003
(ii) reacting the compound of Formula-(IIa) in-situ with 2-(4- Chlorophenyl) aniline of Formula (III);
Figure imgf000009_0001
Formula-(III) in presence of a base 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 antisolvent;
(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 compound of Formula- II with thionyl chloride in a suitable solvent to obtain 2-chloropyridine-3 -carboxylic acid chloride of Formula-(IIa);
(ii) reacting the compound of Formula-(IIa) in-situ 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 antisolvent.
(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 100 C for 60 minutes to 10 hours, preferably 75°C 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 base used in step-(ii) is an organic or inorganic base. The organic base is selected from A,A-diisopropylamine, A,A-diisopropylcthylaminc triethylamine, N,N- dimethylamine, trimethylamine, pyridine, 3- picoline, ; the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof, preferably sodium bicarbonate.
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 60°C for —30 minutes to 6 hours, preferably 25°C 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 50°C.
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 40°C for 20 minutes 3 hours, preferably 25°C to 35°C for 30 minutes to 2 hours In step (v), the reaction may be performed from 0°C to 40 C for 20 minutes 3 hours preferably 25°C to 35°C 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 (160.0g, 1.015 moles), toluene (480.0 ml) into the 1.0L 4 necked round bottom flask under nitrogen atmosphere. Reaction mass was stirred for 5-10 min at 25-35°C to get suspension. N,N- Dimethylformamide (3.2 ml) was added to the above reaction mass and stirred for 5 min. Thionyl chloride (145.0g, 1.22 moles) was added slowly to the reaction mass by maintain the reaction mass temperature not crossing 35°C. Reaction mas was heated to 75-85°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C and kept aside under nitrogen atmosphere and labelled as reaction mass-1. In another 5.0 L, 4 necked round bottom flask, charged 2-(4-chlorophenyl)amlme (198.5g, 0.974 moles), toluene (320.0 ml) under nitrogen atmosphere and stir for 5- 10 min to get clear solution. Aqueous sodium carbonate solution (dissolved 84.5g sodium carbonate in 800.ml of DM water) was added to the above reaction mass and stirred for 5-10 min. Reaction mass was cooled to 5-10°C and then reaction mass-1 was added and heated reaction mixture to 75-85°C and stirred for Ih. After completion of the addition, reaction mass was allowed to 60-65°C. After completion of reaction by TLC, solvent was distilled off under vacuum at 60-65°C to get crude material.
Example-2: 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 25-35°C to get suspension. N,N- Dimethylformamide (1.0 ml) 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C 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 5-10°C and then reaction mass-1 was added by maintaining the reaction mass temperature not crossing 20°C. After completion of the addition, reaction mass was allowed to 25- 35°C and stirred for l-2h. After completion of reaction by TLC, solvent was distilled off under vacuum at 50-55°C to get crude material.
Example-3: 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 25-35°C. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65°C 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-4: Preparation of Boscalid.
Charged 2-chloropyridine-3 -carboxylic acid (100.0g, 0.634 moles), toluene (300.0 ml) into the IL 4 necked round bottom flask under nitrogen atmosphere. Reaction mass was stirred for 5-10 min at 25-35°C 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 25-30°C and kept aside under nitrogen atmosphere and labelled as reaction mass-1.
In another IL 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 5-10°C and then reaction mass-1 was added by maintaining the reaction mass temperature not crossing 20°C. After completion of the addition, reaction mass was allowed to 25- 35°C and stirred for l-2h. After completion of reaction by TLC, solvent was distilled off under vacuum at 50-55°C to get crude material.
Example-5: 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 25-35°C. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65 C 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-6: 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 25-35°C 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 35°C. Reaction mas was heated to 75-80°C and stirred for 2-3h. After completion of reaction by TLC, reaction mass was cooled to 20-25°C.
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 20-30°C, then stirred for l-2h at 25- 30°C. After completion of the reaction by TLC, solvent was distilled off under vacuum at 50-55°C to get crude material.
Example-7: Preparation of anhydrous crystalline Form- of Boscalid of
Figure imgf000014_0001
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 25-35°C. The resulting suspension was filtered off under suction. Then the solid was dried in vacuum oven at 60-65°C 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.

Claims

WE CLAIM:
1. An improved process for the preparation of anhydrous crystalline Form-I of Boscalid of Formula- (I), comprising the steps of:
Figure imgf000015_0003
(i) reacting compound of Formula-(II),
Formula-(II)
Figure imgf000015_0001
with thionyl chloride in a suitable solvent to obtain 2-Chloropyridine-3- carboxylic acid chloride of Formula- (Ila), )
Figure imgf000015_0004
(ii) reacting the compound of Formula-(IIa) in-situ with 2-(4- Chlorophenyl) aniline of Formula (III),
Figure imgf000015_0002
Formula-(III) in presence of a base 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 base used in step-(ii) is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, potassium carbonate, A,A-diisopropylaminc, A,A/-diisopropylethylamine, triethylamine, N,N- dimethylamine, trimethylamine, pyridine, 3- picoline, sodium hydride or mixture thereof.
4. 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.
5. 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.
PCT/IN2022/050910 2021-10-14 2022-10-11 An improved process for the preparation of anhydrous crystalline form-i of boscalid WO2023062649A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018024145A1 (en) * 2016-08-04 2018-02-08 Jiangsu Rotam Chemistry Co., Ltd Process for preparing boscalid
US20190144392A1 (en) * 2016-05-09 2019-05-16 Jiangsu Rotam Chemistry Co., Ltd Process for preparing boscalid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190144392A1 (en) * 2016-05-09 2019-05-16 Jiangsu Rotam Chemistry Co., Ltd Process for preparing boscalid
WO2018024145A1 (en) * 2016-08-04 2018-02-08 Jiangsu Rotam Chemistry Co., Ltd Process for preparing boscalid

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