Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid

Abstract

The present invention relates to a novel process for nitration of 2-chloro-4-fluorobenzoic acid or alkyl 2-chloro-4-fluorobenzoate, which uses fuming sulfuric acid and nitric acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid or alkyl 2-chloro-4-fluoro-5-nitrobenzoate; purifying the crude reaction product; and recovering the 2-chloro-4-fluoro-5-nitrobenzoic acid or alkyl 2-chloro-4-fluoro-5-nitrobenzoic acid ester in substantially pure form, which can be used in the synthesis of the herbicide saflufenacil.

Description

[0001] Safensulfuron (chemical name: 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]-N-[methyl(propan-2-yl)sulfamoyl]benzamide) is a uracil (amide) herbicide. Safensulfuron is a pre-plant and pre-emergence herbicide that is applied alone or in combination with glyphosate to a wide range of food crops [see PPDB (Pesticide Properties Database created by the University of Hertfordshire) https: / / sitem.herts.ac.uk / aeru / ppdb / en / index.htm )].

[0002] Safensulfuron was first described in WO 01 / 83459. The multi-step synthesis of safensulfuron includes the nitration of 2-chloro-4-fluorobenzoic acid to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. As reported in Example 1 of WO 01 / 83459, the reaction occurs in sulfuric acid by adding nitric acid. The reaction illustrated in WO 01 / 83459 shows 2-chloro-4-fluoro-5-nitrobenzoic acid as the only reaction product:

[0003]

[0004] In fact, the reaction produces a mixture of isomers, i.e., mononitration occurs at the 5- or 3-position of the aromatic ring:

[0005]

[0006] Hereinafter, 2-chloro-4-fluoro-5-nitrobenzoic acid and 2-chloro-4-fluoro-3-nitrobenzoic acid are referred to as the desired isomer and the undesired isomer, respectively. The amount of the undesired isomer is not insignificant, for example, the crude reaction product is usually composed of about 85-90:10-15 isomer mixture. Unfortunately, the undesired isomer is not easy to separate from the crude product. The experimental results reported below indicate that purification of the about 85-90:10-15 isomer mixture by crystallization to recover the desired isomer can only be achieved with unacceptably large proportions of solvent and product. Multi-step crystallization has also encountered difficulties.

[0007] We have found that the conditions for the mononitration of 2-chloro-4-fluorobenzoic acid can be converted to the desired isomer in high yield. That is, by using oleum in the nitration reaction, whether on a substituted benzoic acid or on an ester thereof, the desired isomer is preferably produced in a ratio of 94:6.

[0008] The benefit gained from using oleum in the nitration reaction is due to the selectivity of the induction of the desired isomer.

[0009] Therefore, the present invention mainly relates to a method comprising the following steps:

[0010] reacting 2-chloro-4-fluorobenzoic acid with a nitrating agent prepared from oleum and nitric acid or a salt thereof;

[0011] isolating the crude reaction product; and

[0012] recovering 2-chloro-4-fluoro-5-nitrobenzoic acid in substantially pure form;

[0013] or

[0014] A method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid alkyl ester comprises the following steps:

[0015] reacting an alkyl 2-chloro-4-fluorobenzoate with a nitrating agent prepared from oleum and nitric acid or a salt thereof;

[0016] isolating the crude reaction product; and

[0017] recovering alkyl 2-chloro-4-fluoro-5-nitrobenzoate in substantially pure form;

[0018] wherein the alkyl group contains 1 to 12 carbon atoms.

[0019] The reaction is carried out in high yield under the condition that the mononitration as the main reaction is advanced towards the desired isomer. A group of conditions that can efficiently manage the mononitration reaction include a nitrating agent, reaction temperature and reaction time prepared by oleum and nitric acid or its salt. The ratio (based on HPLC analysis, area %) of the undesirable isomer and the desired isomer lower than 1:9 is usually satisfactory. The undesirable isomer of a larger proportion indicates that, due to both low selectivity and purification process, a productivity loss will occur. Therefore, the above ratio allows the maximum yield of the desired isomer. HPLC conditions are described in the following experimental section.

[0020] The nitration of 2-chloro-4-fluorobenzoic acid or its alkyl ester is preferably carried out with a fuming sulfuric acid / nitric acid combination. The reaction is carried out by feeding more than 1.25 equivalents of nitric acid to a solution of 2-chloro-4-fluorobenzoic acid or its alkyl ester in not less than 2 volumes of fuming sulfuric acid at low temperature.

[0021] The nitration of 2-chloro-4-fluorobenzoic acid or its alkyl ester is preferably carried out with an oleum / nitric acid combination. The reaction vessel is charged with 23% oleum solution and then the starting material 2-chloro-4-fluorobenzoic acid or its alkyl ester is added at low temperature.

[0022] The addition of nitric acid to the mixture of 23% oleum and starting materials is carried out gradually under cooling, maintaining the temperature during the addition at about -10°C to +15°C. Preferably, between -5°C and +5°C. Still more preferably, between 0°C and 5°C (this addition is accompanied by the release of heat).

[0023] Nitric acid can be supplied to the reaction in commercially available grades ranging from 70% to 98%. 23% oleum solution is a clear to off-white liquid of H2S2O7, which is a combination of sulfur trioxide in sulfuric acid. Also known as fumingsulfuric acid.

[0024] The order of addition may be reversed and the nitric acid may be added first, e.g. dropwise, to the oleum and then the starting material 2-chloro-4-fluorobenzoic acid or its alkyl ester is added dropwise, preferably at low temperature, e.g. about -10°C to +15°C. Preferably, between -5°C and +5°C. Still more preferably, between 0°C and 5°C.

[0025] After the addition of nitric acid is complete, the reaction mixture can be kept under stirring for about 2 hours. The reaction temperature is generally in the range of 0° C. to 5° C. Typically, the reaction time is not less than 1 hour, such as not less than 2 hours, such as 1 to 3 hours (e.g., about 1 to 2 hours).

[0026] For example, one variation of the process comprises dissolving 2-chloro-4-fluorobenzoic acid or an alkyl ester thereof in 23% oleum, adding nitric acid in a molar excess of at least 25% (e.g., 40% to 80% (about 50%)) HNO3, while cooling the reaction mixture, stirring appropriately, and maintaining the reaction mixture at said temperature for about 2 hours.

[0027] Alternatively, after the above time period, additional acid, such as sulfuric acid, may be added. In this way, the undesirable isomer becomes dinitrated, and the separation process becomes more efficient (see Example 3). Preferably, the reaction is diluted with an acid (e.g. sulfuric acid). Typically, the acid is diluted, e.g., 30-80% v / v, e.g., 35-70% v / v of the acid in water.

[0028] At the end of the reaction, in the case of esters, the crude product is extracted 5 times from the aqueous phase with an organic solvent. After combining the organic phases, the one combined organic phase is washed twice again with water and then evaporated to receive the crude product.

[0029] Next, the crude product is purified by recrystallization from an organic solvent (i.e., a mixture of a solvent or a plurality of solvents). The purification by recrystallization is not limited to crystallization by cooling or evaporative crystallization from a single solvent, and also includes the use of solvent pairs. For example, from a 5-15 / 85-95 by volume ethyl acetate / heptane solvent mixture.

[0030] Aliphatic hydrocarbons (e.g., heptane) are generally inefficient when used alone, but mixtures of aliphatic hydrocarbons with moderately polar solvents (such as ethyl acetate or isopropanol) can achieve separation of products with high purity levels. However, in general, higher recoveries can be achieved by cooling crystallization from alkylated aromatics, and this technique is generally preferred.

[0031] The ratio of the aromatic solvent and crude product required for efficient recrystallization is realized in the range of 3 / 1 to 10 / 1, for example 4 / 1 to 9 / 1, for example 5 / 1 to 8 / 1 (expressed as the dry crude product of solvent / unit weight per unit volume, for example mL / g). Typical crude product is composed of the desired isomer and the undesirable isomer of about 85-95:5-15 (HPLC, area %) respectively. Efficient purification means to realize industrially acceptable yield (>75%, for example>80%) and low amount of undesirable isomer impurities (<0.5%, for example, <0.3%). The ratio between solvent and crude product is expected to change according to solvent type, target purity level and desired recovery rate, and will be adjusted accordingly. For example, toluene (5V to 7V) is proved to be an efficient solvent for recrystallization.

[0032] Drying of the recrystallized material can be carried out at 45°C-50°C in vacuum for several hours to reach a moisture level of no more than 4%. It is not necessary to reduce the moisture level to, say, 1%. 2-Chloro-4-fluoro-5-nitrobenzoic acid appears to exhibit some degree of hygroscopicity, as it tends to absorb water and return to a level of about 4% water.

[0033] 2-Chloro-4-fluoro-5-nitrobenzoic acid or its alkyl ester is recovered in substantially pure form, i.e., free of undesired isomers, with a purity level (by HPLC, area %) of not less than 97.0%, e.g., >98.0%, >99.0%, >99.5%.

[0034] The following embodiments and aspects of the present invention will be described:

[0035] In one aspect, the present invention provides a method comprising the steps of:

[0036] reacting 2-chloro-4-fluorobenzoic acid with a nitrating agent prepared from oleum and nitric acid or a salt thereof;

[0037] isolating the crude reaction product; and

[0038] 2-Chloro-4-fluoro-5-nitrobenzoic acid is recovered in substantially pure form.

[0039] In certain embodiments, in the method, the ratio between the volume of oleum and the mass of 2-chloro-4-fluorobenzoic acid is greater than 2.

[0040] In certain embodiments, in the method, at least about 25% molar excess of nitric acid or a salt thereof is used relative to 2-chloro-4-fluorobenzoic acid.

[0041] In certain embodiments, the method comprises dissolving 2-chloro-4-fluorobenzoic acid in oleum, adding nitric acid or a salt thereof while keeping the reaction mixture cool, and maintaining the reaction mixture at low temperature until complete conversion.

[0042] In certain embodiments, in the method, the crude product is isolated by precipitation upon addition of the reaction mixture to cold water and / or ice, followed by separation of the crude solid product from the aqueous medium.

[0043] In certain embodiments, in this method, the isolated crude product contains about 85% to about 95% 2-chloro-4-fluoro-5-nitrobenzoic acid (HPLC, area %).

[0044] In certain embodiments, in this method, the crude product is purified by recrystallization from one or more solvents.

[0045] In certain embodiments, in the method, the one or more solvents are selected from the group consisting of a hydrocarbon solvent, a halogenated solvent, an ester solvent, and a ketone solvent, or a mixture thereof.

[0046] In certain embodiments, in the process, the ratio between the solvent and the crude product is in the range of 2 / 1 to 9 / 1.

[0047] In yet another aspect, the present invention provides a method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid alkyl ester, the method comprising the steps of:

[0048] reacting an alkyl 2-chloro-4-fluorobenzoate with a nitrating agent prepared from oleum and nitric acid or a salt thereof;

[0049] isolating the crude reaction product; and

[0050] The alkyl 2-chloro-4-fluoro-5-nitrobenzoate is recovered in substantially pure form.

[0051] In certain embodiments, in the method, the ratio between the volume of oleum and the mass of alkyl 2-chloro-4-fluorobenzoate is greater than 2.

[0052] In certain embodiments, in the method, at least about 25% molar excess of nitric acid or a salt thereof is used relative to the alkyl 2-chloro-4-fluorobenzoate.

[0053] In certain embodiments, the method comprises dissolving the alkyl 2-chloro-4-fluorobenzoate in oleum, adding nitric acid or a salt thereof while keeping the reaction mixture cool, and maintaining the reaction mixture at low temperature until complete conversion.

[0054] In certain embodiments, in the process, the crude product is isolated by extraction from the reaction mixture with a chlorinated solvent inert to oleum or by precipitation after adding the reaction mixture to cold water and / or ice, followed by separation of the crude solid product from the aqueous medium.

[0055] In certain embodiments, in this method, the isolated crude product contains about 85% to about 95% alkyl 2-chloro-4-fluoro-5-nitrobenzoate (HPLC, area %).

[0056] In certain embodiments, in this method, the crude product is purified by recrystallization from one or more solvents.

[0057] In certain embodiments, in the method, the one or more solvents are selected from the group consisting of a hydrocarbon solvent, a halogenated solvent, an ester solvent, and a ketone solvent, or a mixture thereof.

[0058] In certain embodiments, in the process, the ratio between the solvent and the crude product is in the range of 2 / 1 to 9 / 1.

[0059] In certain embodiments, in the method, the concentration of oleum is about 20% to about 70% and is liquid under the reaction conditions.

[0060] In certain embodiments, the method further comprises converting 2-chloro-4-fluoro-5-nitrobenzoic acid or an alkyl ester thereof into a compound having herbicidal activity.

[0061] In some embodiments, the method comprises the following steps:

[0062] Reducing or hydrogenating 2-chloro-4-fluoro-5-nitrobenzoic acid or an alkyl ester thereof to obtain 5-amino-2-chloro-4-fluorobenzoic acid or an alkyl ester thereof;

[0063] These compounds are converted into ester compounds having the formula A1:

[0064]

[0065] Where Alk is C 1-12 alkyl;

[0066] The ester of formula A1 is cleaved to the corresponding benzoic acid of formula A2:

[0067] as well as

[0068] The benzoic acid A2 is reacted with NH2-SO2-N[(CH3)(CH(CH3)2)] to provide saflufenacil.

[0069] In some embodiments, the method comprises the following steps:

[0070] a) condensing 2-chloro-4-fluoro-5-nitrobenzoic acid with N-methyl-N-isopropylaminosulfonamide to give nitrobenzoylsulfonamide, followed by reduction or hydrogenation of the nitro group to form an amine compound having formula B1;

[0071]

[0072] b) preparing a compound of formula B2 from the compound of formula B1 by:

[0073]

[0074] b1) coupling a compound of formula B1 with 2-dimethylamino-4-(trifluoromethyl)-6H,1,3-oxazin-6-one; or

[0075] b2) converting the compound of formula B1 into the corresponding isocyanate and reacting the isocyanate with an enamine; or

[0076] b3) reacting the compound of formula B1 with ethyl chloroformate and subsequently coupling with an enamine; and

[0077] c) methylating the compound of formula B2 to provide saflufenacil.

[0078] As indicated above, 2-chloro-4-fluoro-5-nitrobenzoic acid is useful as an intermediate in the synthesis of compounds having herbicidal activity, such as saflufenacil shown below:

[0079]

[0080] A process comprising converting the 2-chloro-4-fluoro-5-nitrobenzoic acid thus formed into a compound having herbicidal activity constitutes a further aspect of the invention.

[0081] Several synthetic pathways can be used to obtain benzenesulfuronamide.For example, 2-chloro-4-fluoro-5-nitrobenzoic acid is reduced or hydrogenated to the corresponding amino compound 2-chloro-4-fluoro-5-aminobenzoic acid by means of a metal reducing agent such as iron or zinc, in an organic solvent, in the presence of acid.For example, the reaction can occur in acetic acid as a solvent using iron powder.Then 2-chloro-4-fluoro-5-aminobenzoic acid is coupled with 2-dimethylamino-4-(trifluoromethyl)-6H,1,3-oxazine-6-one in acetic acid, then alkylated in the presence of a base, for example, to realize methylation (for example, with iodomethane and potassium carbonate in a polar aprotic solvent such as dimethylformamide) at free nitrogen uracil ring and acid group, and converted into an intermediate with formula A1 as shown below, as shown in Examples 3 and 4 of WO 01 / 83459:

[0082]

[0083] For example, using BBr3 as a deprotecting agent, the ester intermediate of formula A1 is cleaved to obtain the corresponding benzoic acid. The deprotection reaction occurs in, for example, dichloromethane. The corresponding benzoic acid (chemical name 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluorobenzoic acid, CAS No.: 120890-57-5) thus formed is collected as a white solid (here identified as a compound of formula A2):

[0084]

[0085] The acid is reacted with, for example, NH2-SO2-N[(CH3)(CH(CH3)2)] to provide benzsulfamide. The acid can be activated by conversion to the acid chloride. However, it is more convenient to react the acid with N,N-carbonyldiimidazole (CDI) in tetrahydrofuran at reflux temperature in the presence of diazabicycloundecane (DBU).

[0086] Another important intermediate compound used in the synthesis of saflufenacil is aminobenzoylsulfonamide having the formula B1:

[0087]

[0088] The preparation of the intermediate with formula B1 includes the condensation of 2-chloro-4-fluoro-5-nitrobenzoic acid and N-methyl-N-isopropylaminosulfonamide (CAS No. 372136-76-0). As shown in Example 54 of WO 01 / 83459, the reaction can be carried out in tetrahydrofuran (THF) as solvent in the presence of N, N'-carbonyldiimidazole (CDI) and diazabicycloundecane (DBU) to obtain the corresponding nitrobenzoyl sulfonamide. As in the previously described synthetic route, in acetic acid and THF as a co-solvent, iron powder is used to reduce the nitro to obtain the aminobenzoyl sulfonamide with formula B1. It is also possible to hydrogenate the nitro in methanol with Raney nickel (see the hydrogenation procedure in Example 31 of US 7,820,846). Intermediate B1 is prepared by acid by the reaction scheme diagram shown below:

[0089]

[0090] a) CDI, DBU, THF, R = NO2; b) AcOH, Fe powder, THF, or Raney nickel, H2, MeOH, R = NH2.

[0091] Saflufenacil can be obtained via various routes from the intermediate having formula B1.

[0092] For example, based on WO 01 / 83459, an intermediate having formula B1 is coupled with 2-dimethylamino-4-(trifluoromethyl)-6H,1,3-oxazin-6-one in acetic acid to give toluenesulfonamide having formula B2:

[0093]

[0094] Other methods involve a cyclization step to form the uracil ring system.

[0095] A synthetic route is based on converting the amine group of the intermediate of formula B1 into isocyanate and coupling it with 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester. The preparation of phenyl isocyanate is described in US 7,820,846. The aminobenzoyl sulfonamide with formula B1 is treated with a phosgenating agent to provide the corresponding phenyl isocyanate. US 7,737,275 describes the preparation of the benzene flumetin precursor (i.e., demethyl benzene flumetin) with formula B2 by coupling it with an enamine from an isocyanate. The synthetic route is shown below:

[0096]

[0097] The coupling of phenyl isocyanate with enamine is carried out under inert atmosphere (water is removed from the reaction vessel by azeotropic drying before adding the isocyanatobenzoyl group). Different types of bases can be used, such as sodium hydride, potassium methoxide and potassium tert-butoxide and potassium carbonate, such as MeOK in Example 2 of US 7,737,275.

[0098] Another synthetic route is found in US 8,252,925, which involves a cyclization step for forming a uracil ring system. The aminobenzoyl sulfonamide intermediate with formula B1 is treated with a solution of ethyl chloroformate (e.g., in dichloromethane in the presence of pyridine) to obtain the corresponding ethanolate (see Example 1.2 of US 8,252,925). The ethanolate is reacted with 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester (e.g., in DMF) to form a uracil ring to complete the closed loop (see Example 3.1.a of US 8,252,925). The obtained demethylbenzenesulfonamide with formula B2 is alkylated with dimethyl sulfate (e.g., in toluene / THF) as a phase transfer catalyst in the presence of an aqueous base to provide the target active ingredient (see Example 3.3 of US 8,252,925). An exemplary synthetic route is shown below:

[0099]

[0100] a) Ethyl chloroformate, pyridine, DCM; b) MeOK / MeOH, DMF, Δ; c) (MeO)2SO2, TBAB, NaOH / H2O, toluene / THF

[0101] Accordingly, the 2-chloro-4-fluoro-5-nitrobenzoic acid prepared according to the present invention can be used to produce saflufenacil by a method comprising the following steps:

[0102] a) condensing 2-chloro-4-fluoro-5-nitrobenzoic acid with N-methyl-N-isopropylaminosulfonamide to give nitrobenzoylsulfonamide, followed by reduction or hydrogenation of the nitro group to form an amine compound having formula B1;

[0103]

[0104] b) preparing a compound of formula B2 from the compound of formula B1 by:

[0105]

[0106] b1) coupling a compound of formula B1 with 2-dimethylamino-4-(trifluoromethyl)-6H,1,3-oxazin-6-one; or

[0107] b2) converting the compound of the formula B1 into an isocyanate, for example by means of a phosgenating agent, and reacting the isocyanate with an enamine; or

[0108] b3) reacting the compound of formula B1 with ethyl chloroformate and subsequently coupling with an enamine; and

[0109] c) methylating the compound of formula B2 to provide saflufenacil.

[0110] Examples

[0111] HPLC method conditions: Column: XBridge C18 (4.6 × 150) mm, 3.5 μm;

[0112] Mobile phase A: 10% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; gradient (T / %B): 0 / 10, 10 / 90, 15 / 90, 16 / 10, 20 / 10; flow rate: 1 mL / min; diluent: acetonitrile / water (1:1 v / v); injection volume: 5 μL; running time: 20 minutes.

[0113] [RRT for the undesired isomer is 1.22, RRT for the dinitro isomer is 1.45].

[0114] Example 1

[0115] Preparation and Purification of 2-Chloro-4-fluoro-5-nitrobenzoic Acid

[0116] 8.9g of 2-chloro-4-fluorobenzoic acid (0.05mol) is dissolved in 27mL of 23% oleum, and the mixture is cooled to 0 ℃.In this mixture, 98% nitric acid of feeding 4g is maintained at 0 ℃ to 5 ℃ under good stirring simultaneously.Reaction mixture is kept 2 hours under these conditions, and quenched in 300g crushed ice.Aqueous mixture is stirred under the situation of not cooling until ice melts completely, and crude product is filtered.The purity of 2-chloro-4-fluoro-5-nitrobenzoic acid is 87 area %, wherein 12.5 area % is undesirable isomer.The crude compound is recrystallized from toluene to obtain the product that purity is 98 area %.

[0117] Example 2

[0118] Preparation and Purification of Ethyl 2-Chloro-4-fluoro-5-nitrobenzoate

[0119] 10.3g of 2-chloro-4-fluorobenzoic acid ethyl ester (0.05mol) was dissolved in 30mL of 23% oleum, and the mixture was cooled to 0°C. 4g of 98% nitric acid was fed into the mixture, while the temperature was maintained between 0°C and 5°C under good stirring. The reaction mixture was kept under these conditions for 2 hours and extracted with 1,2-dichloroethane (5×70mL). The organic phases were combined, washed with water (2×50mL), and evaporated to give 2-chloro-4-fluoro-5-nitrobenzoic acid ethyl ester with a purity of 89.7 area % and 9.1 area % of undesirable isomers. The crude compound was recrystallized from ethyl acetate / heptane to give a product with a purity of 98.9 area %.

[0120] Example 3

[0121] Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid followed by dinitration of the undesired isomer and further purification

[0122] A 1 L four-necked glass RBF equipped with an overhead stirrer, temperature probe and condenser was charged with 300 ml of 25% oleum and cooled to 0° C.-5° C. 98% nitric acid (45.1 g, 0.715 mol, 1.25 eq) was added dropwise at 0° C.-5° C. and the mixture was stirred at 5° C.-10° C. for 10-15 min. A solution of 2-chloro-4-fluorobenzoic acid (100 g, 0.5728 mol, 1.0 eq) in 25% oleum (200 ml) was added dropwise at 10° C.-15° C. over 3-4 hours and stirred at 10° C.-15° C. for another hour.

[0123] At this point, the mononitration was complete. Sulfuric acid (50%, 200 ml) was added dropwise to the reaction mixture. The addition was exothermic and the temperature rose to 55-60° C. The mixture was heated to 80-85° C. and maintained at this temperature for 3-5 hours.

[0124] The progress of the reaction was monitored by HPLC analysis based on area %.

[0125] After completion of the reaction, the reaction mass was cooled to 30 °C and quenched by slowly adding into ice+water (1500 ml) while maintaining the temperature below 30 °C.

[0126] The reaction mass was stirred at 25°C-30°C for 1-2 hours, filtered and the solid was washed with water (100 ml) to provide a wet cake (228 g) and a filtrate MLR (2765 g). The wet cake was 2-chloro-4-fluoro-5-nitrobenzoic acid with a purity of 91%, and the content of 2-chloro-4-fluoro-3-nitrobenzoic acid was 3.3% and the content of 2-chloro-4-fluoro-3,5-dinitrobenzoic acid was 4.3%.

[0127] A 500 mL four-necked RFB equipped with an overhead stirrer, temperature probe and condenser was charged with xylene (500 ml) and wet cake (228 g). The contents were gradually heated to 85°C-90°C until the solids were completely dissolved, and the aqueous phase (91 g) was separated from the organic layer (548 g).

[0128] The organic layer was cooled to 25-30°C and stirred at 25-30°C for 1-2 hours. The solid was filtered and the wet cake (160 g) was dried at 40-45°C for 6-8 hours. The yield of 2-chloro-4-fluoro-5-nitrobenzoic acid was 112 g, 89%, and the purity was 99.1%.

Claims

1. A method comprising the following steps: reacting 2-chloro-4-fluorobenzoic acid with a nitrating agent prepared from oleum and nitric acid or a salt thereof; isolating the crude reaction product; and 2-Chloro-4-fluoro-5-nitrobenzoic acid is recovered in substantially pure form.

2. The method according to claim 1, wherein: The ratio between the volume of oleum and 2-chloro-4-fluorobenzoic acid is greater than 2.

3. The method according to claim 1 or 2, wherein: At least about 25% molar excess of nitric acid or a salt thereof relative to 2-chloro-4-fluorobenzoic acid.

4. The process according to claim 1, comprising dissolving 2-chloro-4-fluorobenzoic acid in oleum, adding nitric acid or a salt thereof while keeping the reaction mixture cool, and maintaining the reaction mixture at low temperature until complete conversion.

5. The method according to any one of claims 1 to 4, wherein: The crude product is isolated by precipitation upon addition of the reaction mixture to cold water and / or ice followed by separation of the crude solid product from the aqueous medium.

6. The method according to claim 5, wherein: The isolated crude product contained about 85% to about 95% 2-chloro-4-fluoro-5-nitrobenzoic acid (HPLC, area %).

7. The method according to any one of claims 1 to 6, wherein: The crude product is purified by recrystallization from one or more solvents.

8. The method according to claim 7, wherein: The one or more solvents are selected from the group consisting of hydrocarbon solvents, halogenated solvents, ester solvents and ketone solvents or mixtures thereof.

9. The method according to claim 8, wherein: The ratio between the solvent and the crude product ranges from 2 / 1 to 9 / 1.

10. A method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid alkyl ester, the method comprising the following steps: reacting an alkyl 2-chloro-4-fluorobenzoate with a nitrating agent prepared from oleum and nitric acid or a salt thereof; isolating the crude reaction product; and The alkyl 2-chloro-4-fluoro-5-nitrobenzoate is recovered in substantially pure form.

11. The method according to claim 10, wherein: The ratio between the volume of oleum and the mass of 2-chloro-4-fluorobenzoic acid is greater than 2.

12. The method according to claim 10 or 11, wherein: At least about 25% molar excess of nitric acid or a salt thereof relative to the alkyl 2-chloro-4-fluorobenzoate.

13. The process according to claim 12, comprising dissolving the alkyl 2-chloro-4-fluorobenzoate in oleum, adding nitric acid or a salt thereof while keeping the reaction mixture cool, and maintaining the reaction mixture at low temperature until complete conversion.

14. The method according to any one of claims 10 to 13, wherein: The crude product is isolated by extraction from the reaction mixture with a chlorinated solvent inert to oleum or by precipitation after adding the reaction mixture to cold water and / or ice, followed by separation of the crude solid product from the aqueous medium.

15. The method according to claim 14, wherein: The isolated crude product contained about 85% to about 95% alkyl 2-chloro-4-fluoro-5-nitrobenzoate (HPLC, area %).

16. The method according to any one of claims 10 to 15, wherein: The crude product is purified by recrystallization from one or more solvents.

17. The method according to claim 16, wherein: The one or more solvents are selected from the group consisting of hydrocarbon solvents, halogenated solvents, ester solvents and ketone solvents or mixtures thereof.

18. The method according to claim 17, wherein: The ratio between the solvent and the crude product ranges from 2 / 1 to 9 / 1.

19. The method according to claim 1 or 10, wherein: The oleum has a concentration of about 20% to about 70% and is liquid under the reaction conditions.

20. The method according to any one of the preceding claims, further comprising converting 2-chloro-4-fluoro-5-nitrobenzoic acid or an alkyl ester thereof into a compound having herbicidal activity.

21. The method according to claim 20, comprising the steps of: Reducing or hydrogenating 2-chloro-4-fluoro-5-nitrobenzoic acid or an alkyl ester thereof to obtain 5-amino-2-chloro-4-fluorobenzoic acid or an alkyl ester thereof; These compounds are converted into ester compounds having the formula A1: Where Alk is C 1-12 alkyl; The ester of formula A1 is cleaved to the corresponding benzoic acid of formula A2: as well as The benzoic acid A2 is reacted with NH2-SO2-N[(CH3)(CH(CH3)2)] to provide saflufenacil.

22. The method according to claim 20, comprising the steps of: a) condensing 2-chloro-4-fluoro-5-nitrobenzoic acid with N-methyl-N-isopropylaminosulfonamide to give nitrobenzoylsulfonamide, followed by reduction or hydrogenation of the nitro group to form an amine compound having formula B1; b) preparing a compound of formula B2 from the compound of formula B1 by: b1) coupling the compound of formula B1 with 2-dimethylamino-4-(trifluoromethyl)-6H,1,3-oxazin-6-one; or b2) converting the compound of formula B1 into the corresponding isocyanate and reacting the isocyanate with an enamine; or b3) reacting the compound of formula B1 with ethyl chloroformate and subsequently coupling with an enamine; and c) methylating the compound of formula B2 to provide saflufenacil.

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