GB2552697A

GB2552697A - Process for the preparation of boscalid

Info

Publication number: GB2552697A
Application number: GB1613458.7A
Authority: GB
Inventors: Timothy Bristow James
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Rotam Agrochem International Co Ltd
Priority date: 2016-08-04
Filing date: 2016-08-04
Publication date: 2018-02-07
Anticipated expiration: 2036-08-04
Also published as: GB2552697B; CN109476604A; WO2018024146A1

Abstract

A process of preparing the crystalline modification II of the anhydrate of boscalid comprising: reacting 2-chloro-nicatinoyl chloride with 4'-chloro-biphenyl-2-ylamine in a solvent system while removing from the reaction mixture hydrogen chloride formed during the reaction; and recovering the crystalline modification II of the anhydrate of boscalid from the reaction mixture. Preferably 4'-chloro-biphenyl-2-ylamine is present in the reaction mixture in excess and the solvent system comprises a polar organic solvent and/or an aromatic solvent. For example the solvent system may comprise iso-propanol, acetonitrile, benzene, toluene or dichloromethane. Preferably the hydrogen chloride produced is removed by adsorption using an adsorbent, preferably activated alumina and an alkali metal promoter. Also preferably the reaction is conducted at a temperature of 20-80°C, and the reaction mixture is subsequently cooled to 5-20°C to allow boscalid to crystallize from the reaction mixture.

Description

(54) Title of the Invention: Process for the preparation of boscalid

Abstract Title: Process of preparing the crystalline modification II of the anhydrate of boscalid (57) A process of preparing the crystalline modification II of the anhydrate of boscalid comprising: reacting 2-chloronicatinoyl chloride with 4'-chloro-biphenyl-2-ylamine in a solvent system while removing from the reaction mixture hydrogen chloride formed during the reaction; and recovering the crystalline modification II of the anhydrate of boscalid from the reaction mixture. Preferably 4'-chloro-biphenyl-2-ylamine is present in the reaction mixture in excess and the solvent system comprises a polar organic solvent and/or an aromatic solvent. For example the solvent system may comprise iso-propanol, acetonitrile, benzene, toluene or dichloromethane. Preferably the hydrogen chloride produced is removed by adsorption using an adsorbent, preferably activated alumina and an alkali metal promoter. Also preferably the reaction is conducted at a temperature of 20-80°C, and the reaction mixture is subsequently cooled to 5-20°C to allow boscalid to crystallize from the reaction mixture.

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PROCESS FOR THE PREPARATION OF BOSCALID

The present invention relates to a process for the preparation of boscalid, in 5 particular to a process for the preparation of crystalline modification II of the anhydrate of boscalid.

The compound 2-chloro-N-(4’chloro[1,1 ’ bi pheny l]-2-y l)-3- py ri di ne carboxamide, having the common name boscalid, has 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. This class of carboximide compounds and the activity of the compounds was first described in US 4,001,416 and US 5,330,995.

Boscalid is active as a fungicide and is now commercially available in a range of formulations for the treatment of fungal infestations and the resulting disorders.

US 7,087,239 concerns the crystalline hydrates of either nicotinic acid anilide 20 and/or benzoyl anilide derivatives. The synthesis and recovery of the hydrate of boscalid is specifically exemplified in US 7,087,239. The hydrate is described as being obtained by first preparing the anhydrate of boscalid, which is obtained at the end of the synthesis procedure as a solution in hot xylene. Upon cooling, boscalid crystallized from the solution and was dried under vacuum in an oven. The anhydrate is indicated to have the following physical properties:

Molecular weight [g/mol]: Melting point [°C] (DSC): Density [g/mol]:

X-ray reflection (2Θ degree) Cu-Ka

IR absorption [cm'¹]:

Water content [%]:

343.2

145.2 1.42

18; 22.5; 9.5; 6

1650 <1

US 7,087,239 discloses that the hydrate can be formed by dissolving the anhydrate in tetrahydrofuran (THF) at 40°C in a solvent and adding the resulting solution to water. The precipitate was isolated from the resulting mixture by filtration and dried, to yield the monohydrate of boscalid. The crystalline modification of the anhydrate of boscalid disclosed in US 7,087,239 is referred to herein as the crystalline modification I of boscalid.

US 7,241,896 concerns a process for producing 2-halogen-pyridinecarboxylic acid amides. The preparation of boscalid is disclosed and exemplified. In the example, boscalid is synthesized by the reaction of 2-chloro-3-nicotinyl chloride II with 2-(4-chlorophenyl)aniline in the presence of water and xylene. After the reaction had been allowed to complete, the aqueous phase was removed. It was then necessary to extract the remaining solution with a hot aqueous solution of sodium carbonate. Boscalid was crystallized by steady cooling of the organic solution, after the extraction with sodium carbonate solution.

We have found that it is hard to mill the crystalline modification of the anhydrate of boscalid disclosed in US 7,087,239 in water. As a consequence, it is not a straightforward task to directly formulate the crystalline modification of boscalid into desired formulations which require grinding and/or milling processes. Such formulations are, for example, granules, encapsulated granules, tablets, waterdispersible granules, water-dispersible tablets, water-dispersible powders or water dispersible powders for seed treatment, dust formulations, and formulations in which the active compound is present in dispersed form, such as, for example, suspension concentrates, oil-based suspension concentrates, suspoemulsions, or suspension concentrates for seed treatment. Hydration of the crystalline modification of boscalid is needed prior to formulating into a suspension concentrate.

US 7,501,384 discloses an alleged novel crystalline modification of the anhydrate of boscalid. The crystalline modification disclosed in US 7,501,384 is referred to herein as the crystalline modification II of boscalid. It is suggested in US 7,501,384 that the crystalline modification II of boscalid is more suitable for making various formulations, which otherwise require prolonged grinding/milling processes.

US 7,501,384 describes that the crystalline modification II of the anhydrate of boscalid may be prepared by a process comprising:

a) dissolving the anhydrate of the crystalline modification I of boscalid in a polar organic solvent or an aromatic hydrocarbon; and

b) precipitation of the anhydrate of the crystalline modification II of boscalid by cooling the solvent.

An alternative process for the preparation of the crystalline modification II of the anhydrate of boscalid disclosed in US 7,501,384 comprises:

a) heating the crystalline modification I of boscalid to above 150°C until 20 melted; and

b) cooling the melt with the addition of seed crystals of the crystalline modification II of boscalid.

US 7,501,384 describes the crystalline modification II of boscalid as having

the following properties:
Molecular weight [g/mol]:	342
Melting point [°C] (DSC):	147.2
Heat of fusion [J/g] (DSC):	106
Density [g/cm³]:	1.457

Characteristic IR bands [cm^-1]: 868, 917, 1675

The key parameters and the cell matrix obtained from the crystallographic investigations of the crystalline modification II of boscalid using a single crystal diffractometer from Siemens are given in US 7,501,384 as follows:

Class:	Monoclinic
Space group:	P21/C
a:	1162.5(6) pm
b:	1134.2(4) pm
c:	1283.2(5) pm
a:	90°
β:	114.52(4)°
Y:	90°
Volume:	1.5390 nm-³
Z:	4
Density (calculated):	1.481 mg/nr³
R¹, wR²:	0.0489; 0.1264

The parameters indicated above have the following meanings:

a, b, c = edge lengths of the unit cell;

α, β, γ = corresponding angles; and

Z = number of molecules in the unit cell.

FTIR spectrometry may be used to record IR spectra.

Figure 1 is the IR spectrum of the crystalline modification II of the anhydrate 25 of boscalid; and

Figure 2 is the IR spectrum of the crystalline modification I of the anhydrate of boscalid.

It would be of significant advantage if an improved process for the preparation of the crystalline modification II of the anhydrate of boscalid could be provided, in particular a process that is suitable for applying on a commercial scale, with reproducible yields of the modification II product. Preferably, the process would be simple to operate and easy to control.

Accordingly, there is a need for an improved method for preparing boscalid.

In particular, it would be advantageous if the improved method for preparing boscalid could produce the crystalline modification II of the anhydrate in high yields. It would be a further advantage if the process could be simple to operate. Advantageously, the improved process would employ a minimum of components, preferably components that are easy to handle.

There has now been found an improved process for the preparation of boscalid, in particular crystalline modification II of the anhydrate of boscalid. In particular, a novel process involving the reaction of 2-chloro-nicotinoyl chloride with 4'-chloro-biphenyl-2-ylamine in a solvent system has been found.

According to the present invention there is provided a process for the preparing of the crystalline modification II of the anhydrate of boscalid, the process comprising:

(i) reacting 2-chloro-nicotinoyl chloride with 4'-chloro-biphenyl-2-ylamine in a solvent system while removing from the reaction mixture hydrogen chloride formed during the reaction; and (ii) recovering the crystalline modification II of the anhydrate of boscalid from the reaction mixture produced in step (i).

It has been found that the process of the present invention produces the crystalline modification II of the anhydrate of boscalid in yields. The process advantageously may employ a minimum number of components and is simple to operate, in particular on a large or commercial scale.

In the process of the present invention 2-chloro-nicotinoyl chloride is reacted with 4'-chloro-biphenyl-2-ylamine. The reaction is according to the following general reaction scheme:

O

li

Cl

Cl

2-chloronicotinoyl chloride

4'-chlorobiphenyl-2- boscalid ylamine

Both 2-chloro-nicotinoyl chloride and 4'-chloro-biphenyl-2-ylamine are known compounds and are commercially available.

2-chloro-nicotinoyl chloride and 4'-chloro-biphenyl-2-ylamine may be present in the reaction mixture in any suitable amount. In one preferred embodiment, 4'chloro-biphenyl-2-ylamine is present in a molar excess, to ensure complete reaction of 2-chloro-nicotinoyl chloride. In this embodiment, 4'-chloro-biphenyl-2-ylamine is preferably present in a molar excess of at least 10%, more preferably at least 20%.

A molar excess of up to 50% may be employed, preferably up to 30%. A molar excess of 4'-chloro-biphenyl-2-ylamine of 25% is particularly suitable for many embodiments.

The reaction of 2-chloro-nicotinoyl chloride and 4'-chloro-biphenyl-2-ylamine takes place in the presence of a solvent system. The solvent system is most preferably a single phase solvent system, in particular a single phase organic solvent system. The ability to use a single phase solvent system is a further advantage of the process of the present invention.

The solvent system may comprise one or more suitable solvents. Suitable solvents are organic solvents, including polar organic solvents and aromatic hydrocarbons. Preferred organic solvents include alcohols, including polyols, such as glycols, nitriles, aromatic solvents, halogenated alkanes and mixtures thereof.

Examples of suitable alcohols are Ci to Cs alcohols, preferably Ci to Cs alcohols. The alcohol may be a straight chain or branched aliphatic alcohol, more preferably ethanol, propanol and butanol. The alcohol may be an alicyclic alcohol, for example cyclohexanol. The solvent may comprise a polyol, such as a glycol. Examples of suitable glycols are mono- and polyethylene glycols, preferably ethylene glycol and diethylene glycol. One preferred solvent is iso-propanol.

Examples of suitable nitriles are C3 to Cs nitriles, preferably C3 to Οβ nitriles. Acetonitrile is one preferred nitrile.

Suitable aromatic solvents are benzene, toluene and xylene. Benzene and toluene are two preferred aromatic solvents.

Examples of suitable halogenated alkanes are Ci to Cs halogenated alkanes, preferably Ci to C₅ halogenated alkanes, more preferably Ci to C₃ halogenated alkanes. The alkane may be a straight chain or branched aliphatic alkane, more preferably a halogenated ethane, propane or butane. The alkane may be an alicyclic alkane, for example a halogenated cyclohexane. Suitable halogen moieties include fluorine, chlorine and bromine, with chlorine being preferred. The alkane may comprise a single halogen moiety or two or more halogen moieties. Examples of suitable halogenated alkanes include dichloromethane.

The above indicated solvents are known in the art and are commercially available.

In step (i) of the process of the present invention, 2-chloro-nicotinoyl chloride is reacted with 4'-chloro-biphenyl-2-ylamine to produce boscalid. The reaction of 2chloro-nicotinoyl chloride with 4'-chloro-biphenyl-2-ylamine produces hydrogen chloride as a by-product. In the process of the present invention, hydrogen chloride is removed from the reaction mixture while the reaction of 2-chloro-nicotinoyl chloride with 4'-chloro-biphenyl-2-ylamine is taking place. In this way, the need to take additional steps to neutralise the hydrogen chloride, such as by the addition of significant quantities of a base, are avoided.

Hydrogen chloride is produced and present in the reaction mixture in the form of a gas and may be removed from the reaction mixture in step (i) in any suitable manner. In one preferred embodiment, the hydrogen chloride is removed from the reaction mixture by adsorption. Suitable adsorbents are known in the art. One preferred adsorbent comprises alumina, in particular activated alumina. The adsorbent may further comprise a promoter, for example an alkali metal. One suitable adsorbent is disclosed in US 5,316,998.

The reaction in step (i) of the process may be conducted at any suitable temperature. Step (i) is conducted at a temperature at which the solvent system is a liquid.

The reaction of 2-chloro-nicotinoyl chloride and 4'-chloro-biphenyl-2-ylamine is preferably conducted at a temperature at which solid boscalid will crystallize as a solid from the solvent system once it has been formed in the reaction. In this way, boscalid produced by the reaction of 2-chloro-nicotinoyl chloride and 4'-chlorobiphenyl-2-ylamine is obtained directly as a solid in the reaction mixture.

Once the reaction of 2-chloro-nicotinoyl chloride with 4'-chloro-biphenyl-2ylamine has been completed, the reaction mixture may be cooled to further crystallize any boscalid remaining in solution in the solvent system. For example, the reaction mixture may be cooled to a temperature at or about room temperature, such as from 10 to 20°C.

In many embodiments, the reaction of 2-chloro-nicotinoyl chloride and 4'chloro-biphenyl-2-ylamine in step (i) is performed at a temperature of greater than 10 °C, more preferably at least 15 °C, still more preferably at least 20°C. In some preferred embodiments, the reaction in step (i) is performed at a temperature of at least 30 °C, more preferably at least 40 °C, still more preferably at least 50 °C, with temperatures above 60 °C being suitable in many embodiments. The reaction temperature in step (i) is below the boiling point of the reaction mixture. Preferably, the temperature is less than 80 °C, still more preferably below 75 °C, more preferably still below 70 °C. A reaction temperature of 65 °C has been found to be suitable in many embodiments.

Once the reaction of 2-chloro-nicotinoyl chloride and 4'-chloro-biphenyl-2ylamine in step (i) of the process has been completed, the boscalid product is recovered from the reaction mixture. For example, boscalid may be recovered from the reaction mixture by crystallization. Solid boscalid produced in step (i) may be recovered by filtration, either before or after crystallization of boscalid from solution. Boscalid may be crystallized from the reaction mixture produced in step (i) using any suitable technique. In one preferred embodiment, boscalid is crystallised from the reaction mixture by reducing the temperature of the reaction mixture sufficiently to cause solid boscalid to crystallize. The temperature at which boscalid will crystallize from the reaction mixture will depend upon the solvent system employed. Typical temperatures for crystallizing boscalid are from 5 to 20 °C. Alternative techniques for recovering boscalid from solution in the reaction mixture are known in the art and include removing solvent from the reaction mixture, for example by use of a vacuum or compressed air, and/or by introducing seeding crystals into the reaction mixture. If seed crystals are employed, they are preferably crystals of crystalline modification II of boscalid.

Once the solid boscalid product has been obtained in the reaction mixture, the solid boscalid product may be recovered. The solid recovered is the crystalline modification II of boscalid. The crystalline modification II of the anhydrate of boscalid may be recovered using any suitable technique, for example by one or a combination of removing the solvent and filtration. The recovered crystalline modification II of boscalid is preferably dried following recovery from the reaction mixture.

As noted above, a particular advantage of the process of the present invention lies in the removal of hydrogen chloride from the reaction mixture as it is produced in step (i). As also noted above, this avoids the need to employ a significant amount of a further component, such as a base, to neutralise the hydrogen chloride. By operating step (i) of the process with an excess of 4'-chloro10 biphenyl-2-ylamine, traces of hydrogen chloride remaining in the reaction mixture are removed by reaction with 4'-chloro-biphenyl-2-ylamine, further improving the efficiency and advantage of the process of the present invention.

Embodiments of the present invention will now be described, for illustration purposes only, by way of the following examples.

In the following examples, the percentages indicated are percentage by weight, unless otherwise stated.

EXAMPLES

Example 1

Boscalid was prepared using the following general reaction sequence:

'N Cl

/

2-chloronicotinoyl 4'-chlorochloride biphenyl-2ylamine

O

A rj '-γ ί·ϊ

II J Η

N Cl boscalid

Cl

3.5 g of 2-chloro-nicotinoyl chloride was dripped into a solution of 5.0 g of 4'chloro-biphenyl-2-ylamine in 30 ml methylene chloride contained in a reaction flask at 20°C. The reaction flask was connected to an external HCL adsorber containing an adsorbent comprising activated alumina and an alkali metal promoter. The mixture the reaction flask was maintained at 20°C for 2 hours with stirring.

The resulting mixture was then cooled with stirring to 10°C and boscalid solid allowed to crystallize out of solution. The boscalid solid was recovered in an amount equivalent to a yield of 90% based on the 2-chloro-nicotinoyl chloride used.

The form of the boscalid in the resulting solid material was confirmed as being the crystalline modification II of the anhydrate of boscalid by melting point analysis (DSC), infrared (IR) spectrometry and X-ray diffraction (XRD).

Example 2

Boscalid was prepared following the same general reaction sequence as in Example 1 above.

3.5 g of 2-chloro-nicotinoyl chloride was dripped into a solution of 5.0 g of 4'chloro-biphenyl-2-ylamine in 30 ml benzene contained in a reaction flask at room temperature. The reaction flask was connected to an external HCL adsorber containing an adsorbent comprising activated alumina and an alkali metal promoter. The mixture was then heated to 40 °C and maintained at this temperature for 2 hours with stirring.

The resulting mixture was then cooled with stirring to room temperature and boscalid solid allowed to crystallize out of solution. The boscalid solid was recovered from the reaction mixture in an amount equivalent to a yield of 92% based on the 2chloro-nicotinoyl chloride used.

Example 3

Boscalid was prepared following the same general reaction sequence as in

Example 1 above.

3.5 g of 2-chloro-nicotinoyl chloride was dripped into a solution of 5.0 g of 4'chloro-biphenyl-2-ylamine in 30 ml iso-propanol held in a reaction flask at 40 °C. The reaction flask was connected to an external HCL adsorber containing an adsorbent comprising activated alumina and an alkali metal promoter. The mixture was then heated to 65 °C and maintained at this temperature for 2 hours with stirring.

The resulting mixture was then cooled with stirring to room temperature and boscalid solid allowed to crystallize out of solution. The boscalid solid was recovered in an amount equivalent to a yield of 95% based on the 2-chloro-nicotinoyl chloride used.

Example 4

3.5 g of 2-chloro-nicotinoyl chloride was dripped into a solution of 5.0 g of 4'chloro-biphenyl-2-ylamine in 30 ml acetonitrile held in a reaction flask at 40 °C. The reaction flask was connected to an external HCL adsorber containing an adsorbent comprising activated alumina and an alkali metal promoter. The mixture was then heated to 65 °C and maintained at this temperature for 2 hours with stirring.

Example 5

3.5 g of 2-chloro-nicotinoyl chloride was dripped into a solution of 5.0 g of 4'chloro-biphenyl-2-ylamine in 30 ml toluene held in at room temperature. The reaction flask was connected to an external HCL adsorber containing an adsorbent comprising activated alumina and an alkali metal promoter. The mixture was then heated to 65 °C and maintained at this temperature for 2 hours with stirring.

The resulting mixture was then cooled with stirring to room temperature and boscalid solid allowed to crystallize out of solution. The boscalid solid was recovered in an amount equivalent to a yield of 92% based on the 2-chloro-nicotinoyl chloride used.

Claims

1. A process for the preparing of the crystalline modification 11 of the anhydrate of boscalid, the process comprising:

2. The process according to claim 1, wherein 4'-chloro-biphenyl-2-ylamine is present in the reaction mixture of step (i) in excess.

3. The process according to claim 2, wherein 4'-chloro-biphenyl-2-ylamine is present in a molar excess of at least 10%.

4. The process according to claim 3, wherein 4'-chloro-biphenyl-2-ylamine is present in a molar excess of at least 20%.

5. The process according to claim 4, wherein 4'-chloro-biphenyl-2-ylamine is present in a molar excess of about 25%.

6. The process according to any preceding claim, wherein the solvent system is a single phase organic solvent system.

7. The process according to any preceding claim, wherein the solvent system comprises a polar organic solvent and/or an aromatic solvent.

8. The process according to claim 7, wherein the solvent system comprises an alcohol, a nitrile, an aromatic solvent, a halogenated alkane, or a mixture thereof.

9. The process according to claim 8, wherein the solvent system comprises isopropanol, acetonitrile, benzene, toluene, dichloromethane, or a mixture thereof.

10. The process according to any preceding claim, wherein hydrogen chloride produced in step (i) is removed by adsorption using an adsorbent.

11. The process according to claim 10, wherein the adsorbent comprises activated alumina.

12. The process according to either of claims 10 or 11, wherein the adsorbent comprises an alkali metal promoter.

13. The process according to any preceding claim, wherein step (i) is conducted at a temperature at which solid boscalid will crystallize from the reaction mixture.

14. The process according to any preceding claim, wherein step (i) is conducted at a temperature of at least 20°C.

15. The process according to any preceding claim, wherein step (i) is conducted at a temperature of up to 80°C.

16. The process according to any preceding claim, wherein step (ii) comprises cooling the reaction mixture produced in step (i) to allow boscalid to crystallize from the reaction mixture.

17. The process according to claim 16, wherein the reaction mixture is cooled to a temperature of from 5 to 20°C.

18. A process for the preparation of the crystalline modification II of the anhydrate of boscalid substantially as hereinbefore described.

Intellectual

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Office

Application No: GB1613458.7 Examiner: Helen Yard