# Patent

## Title
Process for purifying Mesotrione

## Abstract

A process for reducing the levels of undesirable impurities in a mesotrione sample is disclosed, said process comprising the steps of:

    (i) forming a mesotrione enolate solution in an aqueous solvent,
    (ii) carrying out one or more purification processes, and
    (iii) crystallizing the purified mesotrione out of solution.

## Background
This application is a 371 of International Application No. PCT/EP2004/010960 filed Oct. 1, 2004, which claims priority to GB0323090.1 filed Oct. 2, 2003, and GB0414816.9 filed Jul. 1, 2004, the contents of which are incorporated herein by reference.
The present invention relates to a novel process for reducing the level of impurities in a mesotrione sample.
Mesotrione (2-(2′-nitro-4′-methylsulphonyl benzoyl)-1,3-cyclohexanedione) is a selective corn herbicide and has the structure of formula (I)




Mesotrione is prepared by reacting 2-nitro-4-methylsulphonyl benzoyl chloride with cyclohexanedione to give the enol ester, followed by a rearrangement reaction to give mesotrione, as shown in the following reaction scheme:




2-Nitro-4-methylsulphonyl benzoyl chloride (NMSBC) is prepared from the corresponding 2-nitro-4-methylsulphonyl benzoic acid (NMSBA), which in turn is prepared by oxidation of 2-nitro-4-methylsulphonyl toluene (NMST). More details on the preparative route may be found in U.S. Pat. No. 4,695,673.
However, we have found that this process generally results in undesirable level of impurities being present in the final mesotrione product. One method we have found of reducing the impurities is to subject the NMSBA to a purification process before converting to NMSBC, as described in more detail in WO02/076934. However, purifying the NMSBA does not always guarantee that the final product is free from, or has sufficiently low levels of, these impurities.
It is therefore an object of the present invention to provide an improved process for reducing the level of impurities in a mesotrione sample.
Accordingly, the present invention provides a process for reducing the levels of impurities in a mesotrione sample, said process comprising the steps of:
(i) forming a mesotrione enolate solution in an aqueous solvent,
(ii) carrying out one or more purification processes, and
(iii) crystallising the purified mesotrione out of solution.
Optionally, the process may further comprise a distillation step, which is suitably carried out prior to forming the mesotrione enolate. Generally, the distillation step will only, although not necessarily, be used if the mesotrione product has not been isolated after its preparation.
The enolate solution may be formed by the addition of an appropriate base, for example NaOH, KOH, NH4OH, pyridine or triethylamine; suitably the enolate is formed by the addition of NaOH or KOH. Suitably, the aqueous solvent is water, although in some cases an additional solvent, for example acetonitrile, methanol, ethanol, acetone, dimethylformamide etc, may be required to ensure complete dissolution of the mesotrione enolate. The mesotrione enolate solution is suitably formed at a pH of 6-13.
The one or more purification processes may be selected from the following:
(a) filtration,
(b) adsorption with suitable sorbent, such as carbon, clay etc.,
(c) extraction with an organic solvent, or
(d) decantation.
Any number of the purification processes may be carried out and they may be performed in any order. Suitably, at least two purification processes are carried out and preferably at least three. The purification processes will now be described in further detail.
Filtration is carried out to remove any insoluble impurities that remain in the mesotrione enolate solution. The filtration may be carried out by any suitable method known in the art to a skilled person.
Adsorption treatment adsorbs impurities from the mesotrione enolate solution. A mesotrione enolate solution of suitably 1-30%, and preferably 8-11% is contacted with carbon in a batch or continuous fashion for a period of several hours. Concentration of the adsorbent solution relative to the concentration of mesotrione in the enolate is suitably 2-40% and preferably 10-20%. The pH for adsorption treatment is suitably between pH 5 and 13, and preferably between pH 9 and 11.
Extraction with an organic solvent is carried out to remove any impurities, which are soluble in the organic phase but insoluble in the aqueous phase. An organic solvent is added to the mesotrione enolate aqueous solution and some impurities will preferentially dissolve in the organic phase which is then removed and discarded. The mesotrione enolate aqueous solution may be ‘washed’ a number of times with organic solvent, such as once, twice, three times, four times etc or continuously contacted in a counter current column. It is unlikely that more than four ‘washings’ would be required as all the impurities soluble in the organic solvent are likely to have been removed after this number of ‘washings’. Suitable organic solvents will be known to those skilled in the art, but may include benzonitrile, acetonitrile/xylene, xylene, methylene chloride, MIBK, ethyl ether, n-hexane and 1,2-dichloroethane.
Decantation simply refers to the removal of any organic solvent from the solution. Organic solvent is likely to remain with the mesotrione enolate aqueous solution if the mesotrione product has not been isolated after its preparation and no distillation step is carried out. Removal of the organic solvent will remove any impurities soluble in the organic solvent, but insoluble in the aqueous solution.
The optional distillation step is suitably carried out prior to forming the mesotrione enolate solution and will remove any organic solvent remaining after the condensation/rearrangement reaction described above.
The crystallisation step may be carried out by any method known to those skilled in the art. For example, the process may be a batch method, a semi-batch method or a continuous crystallisation method. The crystallisation is suitably effected by reducing the pH of the mesotrione enolate solution, for example by the controlled addition of acid such as hydrochloric acid. Seed crystals of mesotrione may be used to assist the crystallisation process. Optionally, a water-soluble solvent may be added, since the presence of a water soluble solvent such as acetonitrile aids in reducing the amount of impurities present at this point.
In one specific embodiment of the invention, the process comprises: a distillation step; formation of a mesotrione enolate solution, preferably the potassium enolate; one or more purification steps; and crystallisation of mesotrione.
In a second specific embodiment of the invention, the process comprises: formation of a mesotrione enolate solution, preferably the potassium enolate; decantation, filtration and adsorption treatment, carried out in any order (although preferably the decantation process is carried out first); and crystallisation of mesotrione.
By carrying out the process according to the invention, the level of impurities in the final mesotrione product is reduced to an acceptable level.
A further advantage of the process of the present invention is that is can be integrated into the mesotrione manufacturing process, thus eliminating the need for isolation of crude mesotrione followed by purification. Accordingly, a further aspect of the invention provides an integrated manufacturing/purification process for mesotrione, said process comprising the steps of:
(i) reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione;
(ii) formation of mesotrione enolate in aqueous solution;
(iii) carrying out one or more purification processes, and
(iv) crystallising the purified mesotrione out of solution.
Optionally, the process may further comprise a distillation step, which is suitably carried out prior to forming the mesotrione enolate.
Optionally, the NMSBC is first subjected to a carbon purification treatment.
Thus, one specific embodiment of this aspect of the invention provides an integrated manufacturing/purification process for mesotrione, said process comprising: reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; a distillation step; formation of potassium enolate mesotrione solution; one or more purification steps; and crystallisation of mesotrione.
A second specific embodiment of this aspect of the invention provides an integrated manufacturing/purification process for mesotrione, said process comprising reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; formation of a mesotrione enolate solution, preferably the potassium enolate; decantation, filtration and adsorption treatment, carried out in any order (although preferably the decantation process is carried out first); and crystallisation of mesotrione.
Previously, in order to attempt to obtain a final mesotrione product with an acceptable level of impurities, it was necessary to subject the crude NMSBA (prepared by oxidation of NMST) to a purification process, as described in WO02/076934. However, as mentioned above, this did not always give sufficiently low levels of impurities in the final mesotrione product to be acceptable. Surprisingly, we have now found that if the process of the invention is followed, the purification of NMSBA is not essential or at most only ‘partial’ purification, such as one step as opposed to the two or three disclosed in WO02/076934, is required; that is acceptable levels of impurities can be obtained in the final mesotrione product when less purified or even crude NMSBA is used. Accordingly, a yet further aspect of the invention provides a process for preparing mesotrione, said method comprising:
(i) Oxidation of NMST to give crude NMSBA;
(ii) conversion of NMSBA to NMSBC;
(iii) reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione;
(iv) formation of mesotrione enolate in aqueous solution;
(v) carrying out one or more purification processes, and
(vi) crystallising the purified mesotrione out of solution.
Optionally, the process may further comprise partial purification of crude NMSBA.
Optionally, the process may further comprise a distillation step, which is suitably carried out prior to forming the mesotrione enolate.
Thus one specific embodiment of this aspect of the invention provides a process for preparing mesotrione, said process comprising: oxidation of NMST to give crude NMSBA; optional partial purification of crude NMSBA; conversion of NMSBA to NMSBC; reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; a distillation step; formation of mesotrione enolate solution, preferably the potassium enolate; one or more purification steps; and crystallisation of mesotrione.
A second embodiment of this aspect of the invention provides a process for preparing mesotrione, said process comprising: oxidation of NMST to give crude NMSBA; optional partial purification of crude NMSBA; conversion of NMSBA to NMSBC; reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; formation of a mesotrione enolate solution; decantation, filtration and adsorption treatment carried out in any order; and crystallisation of mesotrione.
The present invention will now be described further by way of example only.


EXAMPLE 1
This is an example of the solid adsorption treatment (using carbon as adsorbent) of previously isolated mesotrione which had high levels of impurities. The additional purification option of pre-filtration was used in these examples.











TABLE 1








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















1A
Already isolated mesotrione was dissolved
7900
2800
65%



into a 10% enolate solution at pH 9.5 with



KOH. The mixture was pre-filtered and



contacted with 15% carbon for 2.5 hours



before being filtered and batch crystallized



following standard lab procedures.


1B
Already isolated mesotrione was dissolved
7400
4500
39%



into a 10% enolate solution at pH 9.5 with



KOH. The mixture was pre-filtered and



contacted with 15% carbon for 2.5 hours



before being filtered and batch crystallized



following standard lab procedures.


1C
Already isolated mesotrione was dissolved
7400
2300
69%



into a 10% enolate solution at pH 9.5 with



NaOH/acetonitrile. The enolate was pre-



filtered and contacted with 15% carbon for



2.5 hours before being filtered and batch



crystallized following standard lab



procedures.


1D
Already isolated mesotrione was dissolved
8800
1900
78%



into a 10% enolate solution at pH 9.5 with



NaOH/acetonitrile. The enolate was pre-



filtered and batch carbon treated with 9%



carbon for 3 hours. The carbon was filtered



and the enolate was crystallized in a



continuous reactor following standard lab



procedures.


1E
Already isolated mesotrione was dissolved
8800
3100
65%



into a 10% enolate solution at pH 9.5 with



triethylamine. The enolate was pre-filtered



and batch carbon treated with 9% carbon



for 3 hours. The carbon was filtered and



the enolate was crystallized in a continuous



reactor following standard lab procedures.


1F
Already isolated mesotrione was dissolved
7900
4600
42%



into a 10% enolate solution at pH 9.5 with



NaOH/acetonitrile. The mixture was pre-



filtered and contacted with 15% carbon for



2.5 hours before being filtered and batch



crystallized following standard lab



procedures.


1G
Already isolated mesotrione was dissolved
7400
4600
38%



into a 10% enolate solution at pH 9.5 with



NaOH. The mixture was pre-filtered and



contacted with 15% carbon for 2.5 hours



before being filtered and batch crystallized



following standard lab procedures.









EXAMPLE 2
This is an example of a solvent extraction treatment of previously isolated mesotrione which had high levels of impurities.











TABLE 2








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content







2A
Already isolated mesotrione was dissolved
8000
4100
49%



into a 10% enolate solution at pH 12.5



with KOH. The mixture was contacted



with 1,2-dichloroethane, the 1,2-



dichloroethane was extracted, and the



remaining aqueous layer was batch



crystallized following standard lab



procedures.


2B
Already isolated mesotrione was dissolved
8000
4300
46%



into a 10% enolate solution at pH 12.5



with KOH. The mixture was contacted



with benzonitrile, the benzonitrile was



extracted, and the remaining aqueous layer



was batch crystallized following standard



lab procedures.









EXAMPLE 3
This is an example of an integrated adsorption treatment of in-process mesotrione enolate. NMSBA purified by standard procedures was used as the starting material. The mixture was distilled before the enolate treatments and the purification element of pre-filtration was included. Different adsorbent loadings are shown in the examples in this table.











TABLE 3








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















3A
Mesotrione was made using the standard
13800
11100
20%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 13% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


3B
Mesotrione was made using the standard
13800
5100
63%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 27% carbon for 3.5 hours



before being filtered and batch crystallized



following standard lab procedures.


3C
Mesotrione was made using the standard
13800
5700
59%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 40% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


3D
Mesotrione was made using the standard
13800
5800
58%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 53% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


3E
Mesotrione was made using the standard
17900
15900
11%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 5% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


3F
Mesotrione was made using the standard
17900
15000
16%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 10% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


3G
Mesotrione was made using the standard
17900
12300
31%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 20% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.









EXAMPLE 4
This is an example of an integrated adsorption treatment of in process mesotrione enolate. NMSBA purified by standard procedures was used as the starting material. The mixture was distilled before the enolate treatment, and the purification element of pre-filtration was included. Different filtration conditions are used in the examples in this table.











TABLE 4








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















4A
Mesotrione was made using the standard
15800
7400
53%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 7 was formed with



KOH. The mixture was pre-filtered and



contacted with 10% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


4B
Mesotrione was made using the standard
15800
7700
51%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 7 was formed with



KOH. The mixture was pre-filtered and



contacted with 10% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


4C
Mesotrione was made using the standard
15800
10400
34%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 10% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.


4D
Mesotrione was made using the standard
15800
8600
46%



process from NMSBA purified by standard



procedures. After the distillation, an



enolate solution at pH 9.5 was formed with



KOH. The mixture was pre-filtered and



contacted with 10% carbon for 2 hours



before being filtered and batch crystallized



following standard lab procedures.









EXAMPLE 5
This is an example of an integrated solvent extraction treatment of in process mesotrione enolate. Crude NMSBA was used as the starting material. The mixture was distilled before the enolate treatment.











TABLE 5








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content







5A
Mesotrione was made using the standard
11000
7800
29%



process from crude NMSBA. After the



distillation, an enolate solution at pH 13



was formed with KOH. The mixture was



contacted with 1,2-dichloroethane, the 1,2-



dichloroethane was extracted, and the



remaining aqueous layer was batch



crystallized following standard lab



procedures.









EXAMPLE 6
This is an example of an integrated adsorption treatment of in process mesotrione enolate. Partially purified NMSBA was used as the starting material. The mixture was distilled before the enolate treatment.











TABLE 6








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















6A
Mesotrione was made using the standard
13300
6300
53%



process from partially purified NMSBA.



After the distillation, an enolate solution at



pH 5 was formed with NaOH and ACN.



The mixture was contacted with 20%



carbon for 2 hours before being filtered and



batch crystallized following standard lab



procedures.


6B
Mesotrione was made using the standard
8500
4900
42%



process from partially purified NMSBA(.



After the distillation, an enolate solution at



pH 9 was formed with NaOH and ACN.



The mixture was contacted with 20%



carbon for 2 hours before being filtered and



batch crystallized following standard lab



procedures.









EXAMPLE 7
This is an example of an integrated column adsorption treatment of in process mesotrione enolate. Crude NMSBA was used as the starting material. The mixture was distilled before the enolate treatment.











TABLE 7








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















7A
Mesotrione was made from crude NMSBA
11400
10500
8%



following standard lab procedures. After



the distillation, an enolate solution at pH



9.5 was formed with KOH. The mixture



was pre-filtered and sent through a carbon



column such that there was 14.9% carbon



usage. Samples were batch crystallized



following standard lab procedures.


7B
Mesotrione was made from crude NMSBA
11400
10100
11%



following standard lab procedures. After



the distillation, an enolate solution at pH



9.5 was formed with KOH. The mixture



was pre-filtered and sent through a carbon



column such that there was 5.08% carbon



usage. Samples were batch crystallized



following standard lab procedures.


7C
Mesotrione was made from crude NMSBA
11400
6600
42%



following standard lab procedures. After



the distillation, an enolate solution at pH



9.5 was formed with KOH. The mixture



was pre-filtered and sent through a carbon



column such that there was 2.93% carbon



usage. Samples were batch crystallized



following standard lab procedures.









EXAMPLE 8
This is an example of an integrated adsorption treatment of in process mesotrione enolate. Purified or crude NMSBA was used as the starting material. TEA decantation is included as a purification element. The mixture was distilled before the enolate treatment.











TABLE 8








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















8A
Mesotrione was made from crude NMSBA
11400
5600
51%



by the standard process. An enolate



solution at pH 13 was formed with KOH.



The TEA was decanted, and the enolate



was contacted with 20% carbon for 2



hours at pH 9.5 before being filtered and



batch crystallized following standard lab



procedures.


8B
Mesotrione was made from crude NMSBA
20600
8900
57%



by the standard process. After the



distillation, an enolate solution at pH 13



was formed with KOH. The TEA was



decanted, and the enolate was contacted



with 20% carbon for 2 hours at pH 9.5



before being filtered and batch crystallized



following standard lab procedures.


8C
Mesotrione was made from crude NMSBA
15000
6300
58%



by the standard process. After the



distillation, an enolate solution at pH 13



was formed with KOH. The TEA was



decanted, and the enolate was contacted



with 20% carbon for 2 hours at pH 9.5



before being filtered and batch crystallized



following standard lab procedures.


8D
Mesotrione was made from purified
6300
3400
46%



NMSBA by the standard process. An



enolate solution at pH 13 was formed with



KOH. The TEA was decanted, and the



enolate was contacted with 20% carbon for



2 hours at pH 9.5 before being filtered and



batch crystallized following standard lab



procedures.


8E
Mesotrione was made from purified
7300
2900
60%



NMSBA by the standard process. An



enolate solution at pH 13 was formed with



KOH after the completion of the solvent



distillation. The TEA was decanted, and



the enolate was contacted with 20% carbon



for 2 hours at pH 9.5 before being filtered



and batch crystallized following standard



lab procedures.


8F
Mesotrione was made from purified
6600
3300
50%



NMSBA by the standard process. An



enolate solution at pH 13 was formed with



KOH after the completion of the solvent



distillation. The TEA was decanted, and



the enolate was contacted with 20% carbon



for 2 hours at pH 9.5 before being filtered



and batch crystallized following standard



lab procedures.









EXAMPLE 9
This is an example of the effect of the presence of acetonitrile during crystallization on the impurity content of mesotrione. An integrated purification was done which used the purification elements of TEA decant and the presence of acetonitrile during the crystallization. The mixture was distilled before the enolate treatment. Crude NMSBA was used as the starting material.











TABLE 9








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















9A
Mesotrione was made from crude NMSBA
21800
12800
41%



using the standard process. After solvent



distillation, a potassium enolate solution at



pH 13 was made and the TEA was



decanted. The enolate was batch



crystallized following standard lab



procedures except that acetonitrile was



present during the crystallization.


9B
Mesotrione was made from crude NMSBA
21800
12800
41%



using the standard process. After solvent



distillation, a potassium enolate solution at



pH 13 was made and the TEA was



decanted. The enolate was batch



crystallized following standard lab



procedures except that acetonitrile was



present during the crystallization.


9C
Mesotrione was made from crude NMSBA
30900
9000
71%



using the standard process. After solvent



distillation, a potassium enolate solution at



pH 13 was made and the TEA was



decanted. The enolate was batch



crystallized following standard lab



procedures except that acetonitrile was



present during the crystallization.









EXAMPLE 10
This is an example of the integrated process starting with crude NMSBA in which a partial NMSBA purification is incorporated directly into the process. The purification elements of decantation and adsorption treatment are used in these examples.











TABLE 10








Impurities
%




Original
Content
Reduction




Impurities
after
in


Example

Content
Treatment
Impurities


No.
Treatment
(PPM)
(PPM)
Content



















10A
Mesotrione was made from the integrated
2900
2500
53%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make a NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.


10B
Mesotrione was made from the integrated
2900
1100
62%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make a NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.


10C
Mesotrione was made from the integrated
2900
2100
28%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make a NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.


10D
Mesotrione was made from the integrated
2900
1600
45%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make a NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.


10E
Mesotrione was made from the integrated
2900
1900
34%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile



was added to make a NMSBA solution



and the remaining water was distilled.



Inorganic salts were filtered from the acid



chloride after excess phosgene removal.



The C/R proceeded by normal reaction



conditions. An enolate solution at pH 13



was formed with KOH. The TEA and



benzonitrile were decanted and the enolate



was contacted with 20% carbon for 2



hours at pH 9.5 before being filtered and



batch crystallized following standard lab



procedures.


10F
Mesotrione was made from the integrated
2900
1500
48%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water at pH 0.8.



Benzonitrile was added to make a 20%



NMSBA solution and the remaining water



was distilled. Inorganic salts were filtered



from the acid chloride after excess



phosgene removal. The C/R proceeded by



normal reaction conditions. An enolate



solution at pH 13 was formed with KOH.



The TEA and benzonitrile were decanted



and the enolate was contacted with 20%



carbon for 2 hours at pH 13 before being



filtered and batch crystallized following



standard lab procedures.


10G
Mesotrione was made from the integrated
4900
3100
37%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile



was added to make a NMSBA solution



and the remaining water was distilled.



Inorganic salts were filtered from the acid



chloride after excess phosgene removal.



The C/R proceeded by normal reaction



conditions. An enolate solution at pH 13



was formed with KOH. The TEA and



benzonitrile were decanted and the enolate



was contacted with 20% carbon for 2



hours at pH 9.5 before being filtered and



batch crystallized following standard lab



procedures.


10H
Mesotrione was made from the integrated
3200
2500
22%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.


10I
Mesotrione was made from the integrated
3200
2000
38%



process starting with crude NMSBA in



water which was partially purified and



distilled to remove water. Benzonitrile was



added to make a NMSBA solution and the



remaining water was distilled. Inorganic



salts were filtered from the acid chloride



after excess phosgene removal. The C/R



proceeded by normal reaction conditions.



An enolate solution at pH 13 was formed



with KOH. The TEA and benzonitrile



were decanted and the enolate was



contacted with 20% carbon for 2 hours at



pH 9.5 before being filtered and batch



crystallized following standard lab



procedures.









EXAMPLE 11
Previously isolated mesotrione, made from crude NMSBA, was dissolved by addition of dilute potassium hydroxide to form a 9.1% w/w solution of potassium enolate at pHs 7, 9.5 and 11, respectively. The very small amount of residual solid was removed by filtration.
Extraction
The aqueous solution of potassium enolate of mesotrione (183 g) was extracted with solvent (150 ml) four times. The phases were separated after each extraction and the solvent phase was discarded. After the fourth extraction, the mesotrione was recovered from the aqueous phase by continuous crystallisation according to standard procedure. Analysis showed reduction of the impurities (Table 11A). The figures in parenthesis are the percentage of the impurities remaining after treatment.









TABLE 11A









Sum of impurities in mesotrione sample (%)











Solvent
Before
After pH 7
After pH 9.5
After pH 11





MIBK
3.419
0.258 (7.55%)
1.305 (38.2%)
1.308 (38.3%)


Ethyl acetate
3.419
1.997 (58.4%)
1.941 (56.8%)
2.098 (61.4%)


Benzonitrile
3.419
1.991 (58.2%)
1.018 (29.8%)
1.652 (48.3%)


2-
5.627
0.182 (3.2%) 
1.361 (24.2%)
1.217 (21.6%)


ethylhexanol









Adsorption
The aqueous solution of potassium enolate of mesotrione (183 g) was stirred with 5 g adsorbent at ambient temperature ( ̃25° C.) for 30 minutes. The adsorbent was removed by filtration and the mesotrione was recovered from the aqueous phase by continuous crystallisation according to standard procedure. Analysis showed reduction of the impurities (Table 11B). The figures in parenthesis are the percentage of the impurities remaining after treatment.









TABLE 11B









Sum of impurities in mesotrione sample (%)











Adsorbent
Before
After pH 7
After pH 9.5
After pH 11





Ambersorb
5.627
0.383 (6.81%)
0.680 (12.1%)
0.171 (3.04%)


348F


Amberlite
5.627
0.892 (15.9%)
1.692 (30.1%)


XAD4


Amberlite
3.419
0.245 (7.17%)
0.063 (1.84%)
0.145 (4.24%)


XAD16


Molecular
5.627
1.414 (25.1%)

1.792 (31.8%)


sieves 5A

## Claims

1. A process for preparing mesotrione, said process comprising:
(i) Oxidation of 2-nitro-4-methylsulphonyl toluene (NMST) to give crude 2-nitro-4-methylsulphonyl benzoic acid (NMSBA);
(ii) conversion of NMSBA to 2-nitro-4-methylsulphonyl benzoyl chloride- (NMSBC);
(iii) reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione;
(iv) formation of mesotrione enolate in aqueous solution;
(v) carrying out one or more purification processes on the mesotrione enolate formed in iv, and
(vi) crystallizing the purified mesotrione enolate out of solution.

2. The process of claim 1, wherein the process further comprises partial purification of the crude NMSBA.

3. The process of claim 1, wherein the process further comprises a distillation step.

4. A process for preparing mesotrione, said process comprising: oxidation of NMST to give crude NMSBA; optional partial purification of crude NMSBA; conversion of NMSBA to NMSBC; reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; a distillation step; formation of potassium enolate mesotrione solution; one or more purification steps; and crystallisation of mesotrione.

5. A process for preparing mesotrione, said process comprising: oxidation of NMST to give crude NMSBA; optional partial purification of crude NMSBA; conversion of NMSBA to NMSBC; reacting cyclohexanedione with 2-nitro-4-methylsulphonyl benzoyl chloride (NMSBC) to form an enol ester followed by a rearrangement process to give mesotrione; formation of a mesotrione enolate solution; decantation, filtration and adsorption treatment carried out in any order; and crystallisation of mesotrione.