GB2536979A

GB2536979A - Process for preparing boscalid

Info

Publication number: GB2536979A
Application number: GB1509683.7A
Authority: GB
Inventors: Timothy Bristow James
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Rotam Agrochem International Co Ltd
Priority date: 2015-06-04
Filing date: 2015-06-04
Publication date: 2016-10-05
Anticipated expiration: 2035-06-04
Also published as: GB2536979B; BR102016012785A2; CN106243030B; BR102016012785B1; GB201509683D0; CN106243030A; TW201702227A; TWI756173B

Abstract

A process for preparing the polymorph I of the anhydrate of 2-Chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide (boscalid) of the formula I: is provided, the process comprising the steps of: a) dissolving the polymorph II of the anhydrate of boscalid in a first solvent in an amount and at conditions allowing dissolution of the polymorph II of the anhydrate of boscalid; b) combining the resulting solution with a second solvent at a temperature in the range of from -30 to 30°C, the second solvent being different from the first solvent and selected from the lower alkanes so as to precipitate a solid; and c) recovering the solid to obtain the polymorph I of the anhydrate of boscalid. Preferably, the first solvent is a linear or cyclic ether, a ketone and/or a halogenated alkane. More preferably, the first solvent is either dichloromethane or tetrahydrofuran (THF). The preferred second solvent is n-hexane.

Description

PROCESS FOR PREPARING BOSCALID

The present invention relates to a process for preparing a specific polymorphic form of the anhydrate of 2-Chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide (boscalid). In particular, the present invention relates to a process for preparing polymorph I of the anhydrate of boscalid.

2-Chloro-N-(4'-chlorobipheny1-2-y1)-nicotinamide, having the common name boscalid, is a compound with the structural formula I:

O H

CI

Boscalid is a fungicide of the carboxamide group and acts as a succinate dehydrogenase inhibitor (SDHI), a respiratory inhibitor of mitochondria. It was first registered for commercial use in 2003 and is now registered in over 50 countries including Europe and America.

EP 0545099 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 7,241,896 concerns a process for producing 2-halogen-pyridine-carboxylic acid amides. The preparation of boscalid is disclosed and exemplified. Boscalid is synthesized by the reaction of 2-chloro-3-nicotinyl chloride II with 2-(4-chlorophenyl)aniline in a solvent system. Boscalid was crystallized by cooling an organic solution, after extraction with sodium carbonate solution. Examples of water-immiscible organic solvents indicated in US 7,241,896 include aromatic, aliphatic and cycloaliphatic hydrocarbons, aromatic, aliphatic and cycloaliphatic halogenated hydrocarbons, acyclic ethers, preferably having from 4 to 10 carbon atoms, esters having from 3 to 10 carbon atoms, preferably those of aliphatic or cycloaliphatic alcohols preferably with aliphatic carboxylic acids, for example esters of acetic acid, propionic acid or butyric acid with C3 C8 alkanols, such as methyl, ethyl, n-propyl, n-butyl or isobutyl acetate, propionate, butyrate, and the like, ketones, preferably having from 4 to 10 carbon atoms, such as methyl ethyl ketone, and also aliphatic nitriles preferably having from 4 to 10 carbon atoms, such as butyronitrile, as well as mixtures of the aforementioned organic solvents. Xylene appears to be the preferred solvent of US 7,241,896.

US 8,350,046 discloses a process for preparing arylcarboxamides by reacting an acid chloride with an arylamine in a non-aqueous solvent. Toluene appears to be the preferred solvent of US 8,350,046.

US 7,087,239 concerns crystalline hydrates of nicotinic acid anilide and benzoyl anilide derivatives. The synthesis and recovery of the hydrate of boscalid is specifically exemplified in US 7,087,239. The hydrate is 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]: 343.2 Melting point [°C] (DSC): 145.2 Density [g/mol]: 1.42 X-ray reflection (2e degree): 18; 22.5; 9.5; 6 Cu-Ka IR absorption [cm]: 1650 Water content [%]: <1 US 7,087,239 discloses that the hydrate can be formed by dissolving the anhydrate in tetrahydrofuran (THF) at 40°C and the resulting solution added to water. The precipitate was removed 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 polymorph I of the anhydrate of boscalid.

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

US 7,501,384 describes that the polymorph II of the anhydrate of boscalid may be prepared by a process comprising: a) dissolving the polymorph I of the anhydrate of boscalid in a polar organic solvent or an aromatic hydrocarbon; and b) precipitation of the polymorph II of the anhydrate of boscalid by cooling the solvent.

An alternative process for the preparation of the polymorph II of the anhydrate of boscalid disclosed in US 7,501,384 comprises: a) heating the polymorph I of the anhydrate of boscalid to above 150°C until melted; and b) cooling the melt with the addition of seed crystals of the polymorph II of the anhydrate of boscalid.

US 7,501,384 describes the polymorph II of the anhydrate 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 cell parameters from the crystallographic investigations of the polymorph II of the anhydrate 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 1134.2(4) pm c: 1283.2(5) pm a: 90° 13: 114.52(4)° Y: 90° Volume: 1.5390 nm-3 Z: 4 Density (calculated): 1.481 mg/m-3 R1, wR2: 0.0489; 0.1264 The parameters indicated above have the following meanings: a, b, c = edge lengths of the unit cell; a, 3, y = 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 polymorph II of the anhydrate of boscalid; and Figure 2 is the IR spectrum of the polymorph I of the anhydrate of boscalid.

Conventionally, the polymorph I of the anhydrate of boscalid is prepared from a solution in xylene. Xylene has a high boiling point and a high toxicity.

Hence, there is a need in the art to provide an improved process for preparing the polymorph I of the anhydrate of boscalid, preferably a process that avoids the shortcomings of the prior art processes, in particular the reliance on a solvent such as xylene.

A novel process for the preparation of the polymorph I of the anhydrate of boscalid has now been found.

Accordingly, in a first aspect, the present invention provides a process for preparing the polymorph I of the anhydrate of 2-Chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide (boscalid) of the formula I:

C N H

CI

the process comprising the steps of: a) dissolving the polymorph II of the anhydrate of boscalid in a first solvent in an 10 amount and at conditions allowing dissolution of the polymorph II of the anhydrate of boscalid; b) combining the resulting solution with a second solvent at a temperature in the range of from -30 to 30°C, the second solvent being different from the first solvent and selected from the lower alkanes so as to precipitate a solid; and c) recovering the solid to obtain the polymorph I of the anhydrate of boscalid.

In the first step of the process of the present invention, a solution of boscalid is formed by dissolving in a first organic solvent the polymorph II of the anhydrate of boscalid. The first solvent is an organic solvent. Suitable solvents of boscalid for use as the first solvent include ethers, preferably linear or cyclic lower ethers (that is ethers having from 1 to 12 carbon atoms), more preferably linear or cyclic C2 to C6 ethers, such as tetrahydrofuran, methylether, methylethylether or ethylethylether; ketones, preferably 02 to C6 ketones, such as acetone, propanone, or butanone; halogenated alkanes; and mixtures thereof. Preferred halogenated alkanes are mono-or di-substituted alkanes. Chloride moieties are preferred substituents for the alkanes. The halogenated alkanes are preferably lower alkanes (that is alkanes having from 1 to 12 carbon atoms), more preferably Ci to C6 halogenated alkanes, such as mono-or di-chloromethane, mono-or 1,1-dichloro-or 1,2-di-chloroethane, mono-or 1,1-di-chloro, or 1,2-dichloro-or 1,3 dichloropropane.

Halogenated alkanes are particularly preferred as the first solvent, especially halogenated Ci or 02 alkanes, more especially dichloromethane, or 1,1-dichloro-or 1,2-dichloroethane. Ethers are also preferred as the first solvent, especially tetrahydrofuran.

The polymorph II of the anhydrate of boscalid is dissolved in an amount of the first solvent under conditions allowing complete dissolution of the polymorph I of the anhydrate of boscalid. The dissolution in step a) may be carried out at any suitable temperature. If an elevated temperature is employed in step a), the temperature is below the boiling point of the first solvent. Optionally, for example depending on the type and the amount of the solvent used, dissolution of the polymorph II of the anhydrate of boscalid may be carried out by heating the solvent to elevated temperatures, such as to a temperature of from 20 to 90°C, preferably from 30 to 90°C, more preferably from 30 to 80°C, even more preferably from 40 to 70°C, more preferably still to a temperature of from 40 to 65°C.

The dissolution of the polymorph II of the anhydrate of boscalid in the first solvent may be carried out with agitation, preferably with stirring and/or shaking.

Once the polymorph II of the anhydrate of boscalid has been fully dissolved in the first solvent, a second solvent comprising one or more lower alkanes is added in step b) of the process. In this respect, the term 'lower alkane' is a reference to an alkane that is a liquid under standard conditions of temperature and pressure and having 12 carbon atoms or less. The lower alkane may be linear, branched or cyclic. Preferred lower alkanes are C4 to 010 alkanes, more preferably C5 to C9 alkanes. Examples of preferred lower alkanes are pentane, especially n-pentane or isopentane, hexane, especially n-hexane or cyclohexane, heptane, especially n-heptane, octane, especially n-octane, nonane, especially n-nonane, or a mixture thereof. Particularly preferred solvents are n-pentane, isopentane, n-hexane, cyclohexane or mixtures thereof. Preferred solvents are n-hexane and a mixture of n-hexane with another lower alkane, especially one or more of n-pentane, isopentane and cyclohexane.

The combination of the lower alkane to the solution of boscalid is preferably effected in a slow manner, such as dropwise. The lower alkane is preferably combined with the boscalid solution with agitation, for example stirring, to avoid a local high concentration of the lower alkane solvent or the boscalid solution. The lower alkane may be added to the solution of boscalid. More preferably, the solution of boscalid is added to the lower alkane.

The second solvent is employed in step b) in an amount until precipitation of a solid commences and is preferably continued to achieve full precipitation of the solid from the solution.

The second solvent may be employed in any suitable amount to effect precipitation of boscalid from the solution. Preferably, the second solvent is employed in step b) in an amount sufficient to cause substantially complete precipitation of solid boscalid from the solution. For example, the second solvent may be used in an amount by weight equal to the amount by weight of the first solvent used in step a).

The second solvent is combined with the solution prepared in step a) at a temperature in the range of from -30 to 30°C. Preferably, step b) is conducted at a temperature in the range of from -20 to 25°C, more preferably from -15 to 20°C, still more preferably from -15 to 15°C, more preferably still from -15 to 10°C, especially from -15 to 5°C.

Adjusting the temperature of the solution of the polymorph II of the anhydrate of boscalid in the first solvent is required to the extent that the temperature of step b) of the process is above or below the temperature of the solution resulting in step a). Preferably, the temperature in step a) of the process at which dissolution is effected is above the temperature in step b), in which case the solution resulting in step a) is cooled.

This may be achieved in a number of ways. For example, the temperature of the solution resulting from step a) may be adjusted, as required, during step b) to a temperature in a range of from about -30 to 30°C.

The solution of the polymorph II of the anhydrate of boscalid produced in step a) may be cooled at any suitable rate. Preferably cooling in step b) is carried out at a rate of from about 1 to 20°C/minute, more preferably from 1 to 10°C/minute, still more preferably from about 5 to 10°C/minute. Preferably cooling is carried out while agitating the solution, for example by stirring.

After the solution has reached the desired temperature in step b), this temperature is preferably maintained at the selected level for a time period sufficient to ensure a uniform temperature throughout the cooled solution.

Alternatively, the solution resulting from step a) may be adjusted by first cooling the second solvent to an appropriate temperature, before it is combined with the solution. For example, the second solvent may be at a temperature lower than the temperature of the solution produced in step a) and thereby cool the solution when added thereto.

Preferably, both the temperature of the boscalid solution resulting from step a) is adjusted, in particular cooled, as required to be within the temperature range in step b) of from about -30 to 30°C and the temperature of the second solvent is adjusted to be within the aforementioned range. In this way, both the boscalid solution and the second solvent are at a temperature in the range of from about -30 to 30°C when combined in step b) of the process. Preferably, the temperature of the boscalid solution and the temperature of the second solvent are substantially the same when being combined.

The solid precipitated from the solution in step b) of the process is the polymorph I of the anhydrate of boscalid. The polymorph I of the anhydrate of boscalid may then be recovered in any suitable manner, such as by one or more of decanting the solvent, filtration, and/or evaporation of the solvent.

The polymorph I of the anhydrate of boscalid recovered in step c) is preferably dried, for example under reduced pressure, preferably under a vacuum. Suitable drying techniques are known in the art.

During the process of preparing the polymorph I of the anhydrate of boscalid, the conversion rate from polymorph II to polymorph I can be monitored using appropriate analysis methods and based on the chemical and physical properties of the two polymorphic forms, some of which are listed in Table 1 below.

Tablel

Physical properties of anhydrous boscalid polymorph I and polymorph II Properties Anhydrous boscalid, Anhydrous boscalid, polymorph I polymorph II Molecular weight [g/mol] 342 342 Melting point [°C] (DSC) 144.8 147.2 Heat of fusion [J/g] (DSC) 85 106 Density [g/cm3] 1.399 1.457 IR characteristic band [cm-1] 924,1310,1650 868,917,1675 Any suitable analysis method may be employed. One suitable analysis technique is IR spectroscopy, which also allows for quantification of the conversion, for example by the shifting of a characteristic band, such as the 0=0 stretching vibration. For example, the C=0 stretching vibration shifts from 1675cm-1 to 1650cm-1 when polymorph II of anhydrous boscalid is converted to polymorph I. The disappearance from the IR spectrograph of a band at 1675cm-1 indicates complete conversion from polymorph II to polymorph I. Alternatively, single-crystal X-ray diffraction may be used for monitoring the conversion. Table 2 below lists cell parameters of the two polymorphic forms.

Table 2

Table cell parameters from the crystallographic investigations using a single crystal diffractometer Parameters Anhydrous boscalid, polymorph I Anhydrous boscalid, polymorph II Space group P21/c P21/c a 1479.2(3)pm 1163.2(8)pm b 1157.67(19)pm 1136.3(5)pm c 1872.1(3)pm 1287.3(8)pm a 90° 90° R 91.993(17) ° 114.57(1) ° y 90° 90° Melting point 144-145°C 147-148°C where the symbols have the following meaning: a, b, c = edge length of unit cell; a, 13, y = corresponding angles; and Z = number of molecular in unit cell.

The process of the present invention has the advantage of being easy to carry out and is suitable for use on an industrial scale. The process of the present invention also provides the advantage that a reduction in the use of toxic solvents can be obtained, thereby diminishing harm to the environment.

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

Unless otherwise indicated, percentages are percent by weight.

EXAM PLES

Example 1

Anhydrous boscalid polymorph II (200 g, 0.583 mol, 1.0 eq) was added to a reaction bottle with the addition of dichloromethane (1600 mL). The mixture was heated to a temperature of from 30 to 40°C while stirring until the boscalid had dissolved completely. The resulting solution was cooled to a temperature of from -15 to 5°C and transferred to a dropping funnel for further use.

N-hexane (800 mL) was added to a reaction bottle and cooled to below room temperature, to a temperature of from -15 to 5°C.

The boscalid solution was added dropwise from the dropping funnel to the reaction bottle and combined with the n-hexane. Gradually, solid was seen to precipitate from the solution. After the addition of the boscalid solution had been completed, the resulting mixture was held at a temperature of from -15 to 5°C for 1 to 2 hours, after which the solid was recovered by filtering and drying in a vacuum for 6 hours. 168g of white powder with yield of 84% was obtained.

Single-crystal X-ray diffraction and IR spectroscopy were used to identify the solid product as the polymorph I of the anhydrate of boscalid.

Example 2

Anhydrous boscalid polymorph II (200 g, 0.583 mol, 1.0 eq) was added to a reaction bottle with the addition of tetrahydrofuran (THF) (1600 mL). The mixture was heated to a temperature of from 30 to 66°C while stirring until the boscalid had dissolved completely. The resulting solution was cooled to a temperature of from -15 to 5°C and then transferred to a dropping funnel for further use.

The boscalid solution was added dropwise from the dropping funnel to the reaction bottle and combined with the n-hexane. Gradually, solid was seen to precipitate from the solution. After the addition of the boscalid solution had been completed, the resulting mixture was held at a temperature of from -15 to 5°C for 1 to 2 hours, after which the solid was recovered by filtering and drying in a vacuum for 6 hours. 174g of white powder with yield of 87% was obtained.

Claims

CLAIMS1. A process for preparing the polymorph I of the anhydrate of 2-Chloro-N-(4'-chlorobipheny1-2-y1)-nicotinamide (boscalid) of the formula I: 0 N HCIthe process comprising the steps of: a) dissolving the polymorph II of the anhydrate of boscalid in a first solvent in an amount and at conditions allowing dissolution of the polymorph II of the anhydrate of boscalid; b) combining the resulting solution with a second solvent at a temperature in the range of from -30 to 30°C, the second solvent being different from the first solvent and selected from the lower alkanes so as to precipitate a solid; and c) recovering the solid to obtain the polymorph I of the anhydrate of boscalid.
2. The process according to claim 1, wherein the first solvent is selected from a linear or cyclic lower ether, a ketone, a halogenated alkane, and mixtures thereof
3. The process according to claim 2, wherein the first solvent is selected from a linear or cyclic C2 to C6 ether, a C2 to C6 ketone. a C1 to C6 halogenated alkane, or a mixture thereof.
4. The process according to claim 3, wherein the first solvent is selected from tetrahydrofuran, methylether, methylethylether, ethylethylether, acetone, propanone, butanone, mono-or di-chloromethane, mono-or 1,1-dichloro-or 1,2-di-chloroethane, mono-or 1,1-di-chloro, or 1,2-dichloro-or 1,3 di-chloropropane, or mixtures thereof.
5. The process according to any preceding claim, wherein step a) is conducted at an elevated temperature.
6. The process according to claim 5, wherein step a) is conducted at a temperature of from 20 to 90°C
7. The process according to claim 6, wherein step a) is conducted at a temperature of from 30 to 90°C.
8. The process according to claim 7, wherein step a) is conducted at a temperature of from 30 to 80°C.
9. The process according to claim 8, wherein step a) is conducted at a temperature of from 40 to 70°C.
10. The process according to any preceding claim, wherein the second solvent comprises a C4 to C10 alkane.
11. The process according to claim 10, wherein the second solvent comprises a C6 to C9 alkane.
12. The process according to claim 11, wherein the second solvent comprises pentane, hexane, heptane, octane, nonane, or a mixture thereof.
13. The process according to claim 12, wherein the second solvent comprises n-pentane, isopentane, n-hexane, cyclohexane or mixtures thereof.
14. The process according to claim 13, wherein the second solvent is n-hexane, or a mixture of n-hexane with another lower alkane selected from one or more of n-pentane, isopentane and cyclohexane.
15. The process according to any preceding claim, wherein in step b) the solution resulting from step a) is added to the second solvent.
16. The process according to any preceding claim, wherein step b) is conducted at a temperature of from -20 to 25°C.
17. The process according to claim 16, wherein step b) is conducted at a temperature of from -15 to 20°C.
18. The process according to claim 17, wherein step b) is conducted at a temperature of from -15 to 15°C.
19. The process according to claim 18, wherein step b) is conducted at a temperature of from -15 to 10°C.
20. The process according to claim 19, wherein step b) is conducted at a temperature of from -15 to 5 °C.
21. The process according to any preceding claim, wherein the temperature of both the solution produced in step a) and the second solvent is adjusted to the temperature required in step b), before being combined.
22. The process according to any preceding claim, wherein recovering the solid comprises drying the precipitate.
23. The process according to claim 22, wherein drying is conducted under vacuum at an elevated temperature.
24. A process for preparing the polymorph I of the anhydrate of 2-Chloro-N-(4'-chlorobipheny1-2-y1)-nicotinamide (boscalid) substantially as hereinbefore described having reference to the accompanying figures.