Method for preparing 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) benzyl picolinate

Abstract

The invention relates to a process for the preparation of benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinate (I) from benzyl 4, 5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinate (II), and to a method for the preparation of benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinate (I) from benzyl 4, 5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinate (II). The method comprises the steps of amination and chlorination to obtain the compound as shown in the formula I.

Description

[0001] The present application is a divisional application of the Chinese patent application No. 2017800764657 (application date: 2017 / 12 / 6, invention name: Method for preparing benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 433,415 filed on December 12, 2016, the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0004] Current methods for preparing (benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate; I) are described in US Pat. Nos. 8,609,855 and 8,871,943.

[0005] Summary of the invention

[0006] The present invention provides a method for preparing clofopyralid (i.e., a compound of formula I). ​​Specifically, the method comprises converting 4,5-difluoro-6-arylpicolinate (compound of formula II) into clofopyralid (formula I). ​​The method comprises the following steps:

[0007] a) combining a compound of formula II with anhydrous ammonia;

[0008]

[0009] b) isolating the compound of formula III from the combination of step a);

[0010]

[0011] c) combining the compound of formula III isolated from step b) with anhydrous HCl to form the HCl salt of formula IV;

[0012]

[0013] d) isolating the compound of formula IV from step c) and combining the isolated compound of formula IV with a base to form the compound of formula III;

[0014] e) adding a chlorinating agent to the combination of step d); and

[0015] f) isolating the compound of formula I.

[0016] The process may alternatively comprise isolating the compound of formula III after step d) and then adding the chlorinating agent in step e). DETAILED DESCRIPTION

[0017] The present invention provides a method for preparing chlorofluanilide (Formula I) from 4,5-difluoro-6-arylpicolinate of Formula II. As shown in Scheme 1, the method includes a chemical treatment step for introducing the following groups: (1) a 4-amino group obtained by amination reaction of the compound of Formula II with ammonia, and (2) a 3-chloro group obtained by chlorination reaction with an N-chloro compound.

[0018] Scenario 1:

[0019]

[0020] I. Definitions

[0021] As used herein, the term "aryl" and derivative terms such as aryloxy refer to groups including monovalent aromatic carbocyclic groups having 6 to 14 carbon atoms. Aryl groups may include a single ring or multiple condensed rings. In some embodiments, aryl groups include C6-C 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group can be a phenyl, indanyl, or naphthyl group. The term "heteroaryl" and derivative terms such as "heteroaryloxy" refer to a 5- or 6-membered aromatic ring containing one or more heteroatoms, i.e., N, O, or S; these heteroaromatic rings can be fused to other aromatic systems. In some embodiments, the heteroaryl group can be a pyridyl, pyrimidyl, or triazinyl group. Aryl or heteroaryl substituents can be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, amino, halogen, hydroxy, nitro, cyano, formyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl ... 10 Alkoxycarbonyl, C1-C6 carbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include halogen, C1-C2 alkyl, C1-C 10 Alkoxycarbonyl and C1-C2 haloalkyl.

[0022] As used herein, the term "Bn" used in a chemical structure diagram (ie, a compound of Formula I, II, III, IIIa, IIIb, or IV) refers to a benzyl group, which may also be represented as PhCH2.

[0023] As described herein, the compound of formula III is

[0024]

[0025] The compound of formula III can be prepared in different ways. For the sake of clarity, the compound formed in different ways can be represented as a compound of formula IIIa or a compound of formula IIIb, depending on how it is prepared. When the compound of formula III is prepared by amination of a difluoropicolinate compound of formula II with ammonia, it is referred to as a compound of formula IIIa. When the compound of formula III is prepared by neutralizing the HCl salt of a compound of formula IV with a base, it is referred to as a compound of formula IIIb.

[0026] II. Amination of difluoropicolinate II

[0027] The first step of the process for preparing compounds of formula I involves converting the difluoropicolinate of formula II to the hydrochloric acid (HCl) salt of formula IV by amination with ammonia followed by treatment with anhydrous HCl (Scheme 3).

[0028] Solution 3:

[0029]

[0030] The difluoropicolinate can first be reacted with anhydrous ammonia under pressure to obtain 4-aminopyridine of formula IIIa and byproduct NH4F (Scheme 4). After removing NH4F and excess ammonia, the 4-aminopyridine of formula IIIa is then treated with anhydrous HCl to obtain 4-amino-3-fluoropicolinate HCl salt of formula IV (Scheme 3). The formation of the HCl salt of formula IV allows for convenient product isolation.

[0031] Solution 4:

[0032]

[0033] Suitable solvents for the amination reaction include, but are not limited to, aprotic solvents such as acetonitrile, propionitrile, benzonitrile, toluene, xylenes, xylene mixtures, ethers such as THF, dioxane, mono- and diethylene glycol ethers, mono- and dipropylene glycol ethers, and mixtures thereof.

[0034] It has been found that the use of acetonitrile (CH3CN) as a reaction solvent for the amination reaction to prepare the compound of formula IIIa provides a beneficial effect superior to other solvents such as highly polar solvents such as DMSO and NMP. Even though these highly polar solvents provide rapid amination of the compound of formula II at low temperatures, the water treatment process required for separating the product is very inefficient. In addition, in these highly polar solvents, the formation and separation of the HCl salt of formula IV is not feasible. Therefore, the use of these highly polar solvents cannot provide an effective and scalable amination method for preparing the HCl salt of formula IIIa or formula IV.

[0035] Under high pressure of anhydrous ammonia and elevated reaction temperature, the amination of difluoropicolinate of formula II in acetonitrile solvent provides acceptable reaction cycle time, excellent product yield and lower impurity formation. Table 1 shows the results of amination of compound of formula II at various temperatures, pressures and reaction times. As shown in Table 1, it was surprisingly found that the best conditions for amination of compound of formula II were a temperature of about 100° C., an ammonia pressure of about 100 psig and a reaction time of about 2 hours to provide 4-aminopicolinate of formula IIIa with a yield of 85% (97% conversion).

[0036] Table 1 . Reaction of difluoropicolinate II with ammonia in CH3CN in a 300 mL Parr reactor.

[0037]

[0038] 1 The Parr reactor is heated to the specified temperature and then pressurized with anhydrous ammonia to the specified pressure.

[0039] Surprisingly, lowering the reaction temperature to 50°C while maintaining the ammonia pressure at 100 psig (entry 5) resulted in a decrease in the yield of the compound of Formula IIIa, even though the conversion was 99%.

[0040] The amination reaction to prepare the compound of formula IIIa can be carried out in acetonitrile solvent in a pressure reactor with anhydrous ammonia at a temperature of at least about 60°C, at least about 65°C, at least about 70°C, at least about 75°C, at least about 80°C, at least about 85°C, at least about 90°C, at least about 95°C, at least about 100°C, at least about 105°C, at least about 110°C, or at least about 115°C. Alternatively, the amination reaction to prepare the compound of formula IIIa can be carried out in acetonitrile at a temperature between about 60°C and about 130°C or between about 80°C and about 120°C. In another example, the amination reaction to prepare the compound of formula IIIa can be carried out in acetonitrile at a temperature between about 90°C and about 110°C.

[0041] The amination reaction to prepare the compound of formula IIIa can be carried out in an acetonitrile solvent in a pressure reactor with anhydrous ammonia, wherein the pressure in the reactor is maintained between about 40 and about 150 pounds per square inch gauge (psig), between about 50 and about 140 psig, between about 50 and about 120 psig, between about 50 and about 100 psig, between about 60 and about 130 psig, between about 70 and about 120 psig, between about 80 and about 110 psig, or between about 90 and about 110 psig by adding anhydrous ammonia to the reactor. During the amination reaction, the pressure in the reactor may vary slightly from these pressure ranges due to the periodic addition and consumption of anhydrous ammonia in the reactor.

[0042] After completing the amination of the compound of formula II to prepare the compound of formula IIIa, the pressure reactor is cooled, the pressure is discharged, and the reaction mixture is filtered or centrifuged to remove the by-product ammonium fluoride to obtain a filtrate. The filtrate is then distilled (i.e., atmospheric pressure or reduced pressure distillation) to remove substantially all residual ammonia, and the solution containing the crude compound of formula IIIa is concentrated to a concentration of not more than about 20% by weight, not more than about 15% by weight, not more than about 10% by weight, or not more than about 5% by weight of the compound of formula IIIa. The filtrate can also be sprayed with an inert gas (e.g., nitrogen) stream to remove or reduce the amount of residual ammonia.

[0043] As used herein, the phrase "removing substantially all residual ammonia" means removing enough ammonia from the filtrate to make the final ammonia concentration in the filtrate less than about 500 ppm. In addition, the final ammonia concentration can be less than about 250 ppm, less than about 125 ppm, less than about 63 ppm, less than about 32 ppm, or less than about 16 ppm.

[0044] After removing the byproduct NH4F by filtration or centrifugation and removing substantially all residual ammonia by distillation or sparging with nitrogen, the amination reaction mixture containing the crude compound of Formula IIIa is treated with anhydrous HCl. The resulting mixture is then filtered or centrifuged to provide the HCl salt of Formula IV. In some examples, the HCl salt of Formula IV can be prepared using about 1.0 to about 5.0, about 1.0 to about 2.0, about 1.0 to about 1.5, or about 1.0 to about 1.2 molar equivalents of anhydrous HCl relative to the compound of Formula IIIa.

[0045] The preparation of the HCl salt of Formula IV can be carried out at a temperature between about 25° C. to about 75° C., between about 25° C. to about 65° C., between about 35° C. to about 65° C., between about 45° C. to about 65° C., between about 45° C. to about 55° C., between about 45° C. to about 75° C., or between about 55° C. to about 75° C. Alternatively, the formation of the HCl salt of Formula IV can be carried out at a temperature between about 40° C. to about 60° C.

[0046] The purity of the isolated HCl salt of Formula IV can be at least about 75 weight percent (wt %), at least about 80 wt %, at least about 85 wt %, at least about 87 wt %, at least about 89 wt %, at least about 90 wt %, at least about 91 wt %, at least about 92 wt %, at least about 93 wt %, at least about 94 wt %, or at least about 95 wt %.

[0047] Other acids that may be suitable for use in preparing acid-derived salts of compounds of Formula IIIa include, but are not limited to, HBr, MeSO3H, H2SO4, H3PO4, HNO3, and HBF4.

[0048] III. Chlorination of 4-aminopicolinate IIIb

[0049] The next step in the process for preparing the compound of formula I comprises converting the HCl salt of formula IV to cloflupyridinyl ester (formula I). ​​This conversion is shown in Scheme 5 and comprises neutralizing the HCl salt of formula IV with a base to provide a 4-aminopicolinate of formula IIIb, and then converting the compound of formula IIIb to the compound of formula I by using an N-chloro compound chlorinating agent.

[0050] Solution 5:

[0051]

[0052] A. Two-phase solvent system for neutralization of IV and separation of IIIb

[0053] A two-phase solvent system can be used to neutralize the HCl salt of formula IV with a base and separate the 4-aminopicolinate of formula IIIb again. The two-phase solvent system can include water (i.e., aqueous liquid phase) and an organic solvent (i.e., water-immiscible liquid phase) selected from aromatic hydrocarbons such as toluene, xylene, a mixture of xylenes, benzonitrile, esters such as ethyl acetate, ethers such as tert-amyl methyl ether (TAME) and methyl tert-butyl ether (MTBE), chlorinated hydrocarbons such as methylene chloride and 1,2-dichloroethane and mixtures thereof. When a two-phase solvent system is used, the base suitable for neutralizing the HCl salt of formula IV to prepare the 4-aminopicolinate of formula IIIb can include but is not limited to trialkylamines such as triethylamine, dialkylamines, monoalkylamines, ammonia and heterocyclic amines such as pyridine and N-methylimidazole. When a two-phase solvent system is used, other bases that can be used for neutralizing the HCl salt of formula IV can include inorganic bases (such as but not limited to NaOH and KOH) and carbonates (such as Na2CO3 and K2CO3).

[0054] The water portion of the two-phase solvent system can be added to the neutralization reaction before or after the addition of the base. Water is used to easily remove the salts (i.e., Et3N.HCl, NaCl or KCl) generated during the neutralization reaction by elution, thereby allowing the 4-aminopicolinate of Formula IIIb to be re-isolated as a solution in a water-immiscible solvent.

[0055] The two-phase solvent system neutralization reaction can be carried out at a temperature between about 25°C to about 100°C, between about 25°C to about 90°C, between about 35°C to about 90°C, between about 45°C to about 90°C, between about 55°C to about 90°C, between about 60°C to about 90°C, or between about 70°C to about 90°C.

[0056] After removal of the aqueous phase from the two-phase neutralization reaction mixture (and subsequent isolation of IIIb), the remaining organic solution containing the 4-aminopicolinate of formula IIIb may be distilled to remove any water and / or residual base and to concentrate the solution.

[0057] B. Chlorination of Reisolated IIIb

[0058] The concentrated solution containing the 4-aminopicolinate of formula IIIb prepared as described herein can then be treated with a chlorinating agent to introduce a chloro group onto the pyridine ring of the 4-aminopicolinate of formula IIIb to provide the final product of formula I.

[0059] The chlorination reaction to prepare the final product of Formula I can be carried out at a temperature between about 25°C and about 120°C, between about 40°C and about 120°C, between about 50°C and about 120°C, between about 60°C and about 110°C, between about 70°C and about 110°C, between about 70°C and about 100°C, between about 70°C and about 90°C, or between about 75°C and about 85°C.

[0060] The chlorinating agent for preparing the compound of formula I by the 4-aminopicolinate of formula IIIb can be an N-chloro compound. Suitable N-chloro compounds that can be used to prepare I include but are not limited to 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide, 1,3,5-trichloro-2,4,6-triazinetrione, N-chloro-o-sulfonylbenzoimide and N-chlorophthalimide. The available chlorinating agent for preparing the compound of formula I is 1,3-dichloro-5,5-dimethylhydantoin.

[0061] B. Single-phase solvent system for neutralization of IV and chlorination of IIIb

[0062] A single-phase solvent system (i.e., a single organic liquid phase and a liquid-free second phase) can be used to neutralize the HCl salt of formula IV with a base to obtain a 4-aminopicolinate of formula IIIb. The single-phase solvent system can include organic solvents such as, but not limited to, aromatic hydrocarbons, such as toluene, xylene and xylene mixtures, acetonitrile, benzonitrile, esters such as ethyl acetate, ethers such as THF, dioxane, tert-amyl methyl ether (TAME) and methyl tert-butyl ether (MTBE), chlorinated hydrocarbons such as dichloromethane and 1,2-dichloroethane, and mixtures thereof. When a single-phase solvent system is used, the base suitable for neutralizing the HCl salt of formula IV to prepare the 4-aminopicolinate of formula IIIb can include, but is not limited to, trialkylamines such as triethylamine, dialkylamines, monoalkylamines, ammonia, and heterocyclic amines such as pyridine and N-methylimidazole.

[0063] The single-phase solvent system neutralization reaction can be carried out at a temperature between about 25°C to about 100°C, between about 25°C to about 90°C, between about 35°C to about 90°C, between about 45°C to about 90°C, between about 55°C to about 90°C, between about 60°C to about 90°C, or between about 70°C to about 90°C.

[0064] After neutralizing the HCl salt of Formula IV with a base to prepare the 4-aminopicolinate of Formula IIIb using a single-phase solvent system, the resulting mixture can be treated with a chlorinating agent to introduce a chloro group onto the pyridine ring of the 4-aminopicolinate IIIb to obtain the final product of Formula I. For example, the chlorinating agent used to prepare the compound of Formula I from the 4-aminopicolinate of Formula IIIb using a single-phase solvent system can be an N-chloro compound. Suitable N-chloro compounds that can be used to prepare I include those described herein.

[0065] The chlorination reaction using a single-phase solvent system to prepare the final product of Formula I can be carried out at a temperature between about 25°C and about 120°C, between about 40°C and about 120°C, between about 50°C and about 120°C, between about 60°C and about 110°C, between about 70°C and about 110°C, between about 70°C and about 100°C, between about 70°C and about 90°C, or between about 75°C and about 85°C.

[0066] III. Isolation / Purification

[0067] After preparing the compound of formula I by the methods described herein, the product can be isolated by using standard separation and purification techniques. For example, the crude product can be isolated using standard methods as described herein and purified by crystallization using a single solvent or a mixture of two or more solvents. The one or more solvents used in the crystallization may include one or more of an aliphatic hydrocarbon, an aromatic hydrocarbon, and an alcohol.

[0068] The crude product of formula I can be obtained by12 The single solvent of alcohol such as toluene, dimethylbenzene, dimethylbenzene mixture, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-2-butanol, 1-hexanol, 2-hexanol, 3-methyl-1-pentanol, cyclohexanol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 2-propyl-1-heptanol, 1-nonanol, 1-decanol, 1-undecanol and 1-dodecanol crystallization are purified. In one embodiment, the crude product of formula I can be purified by crystallization from 2-ethyl-1-hexanol. In another embodiment, the crude product of formula I can be purified by solvent exchange (that is, removing a solvent and replacing with a second solvent) and crystallization by a second solvent. For example, the solution of the crude product of formula I in toluene can be distilled to remove toluene, and toluene is replaced with the second solvent (2-ethyl-1-hexanol).

[0069] The crude product of formula I can also be prepared by reacting two or more hydrocarbons selected from aliphatic hydrocarbons, aromatic hydrocarbons and C4-C 12 For example, the crude product of Formula I can be crystallized with a combination of an aliphatic hydrocarbon such as hexane or a hexane mixture and an aromatic hydrocarbon such as toluene. In addition, the crude product of Formula I can be recrystallized with an aromatic hydrocarbon and a C4-C 12 In addition, the recrystallization of the crude product of Formula I can be carried out with aliphatic hydrocarbons and C4-C 12 Alcohol combination.

[0070] The crude product of Formula I can also be purified by dissolving it in one solvent to form a solution and then adding a second solvent to the solution to cause crystallization of the product of Formula I from the mixture of the two solvents. For example, a solution of the crude product of Formula I in an aromatic hydrocarbon solvent such as toluene can be treated with an aliphatic hydrocarbon solvent such as hexane or a mixture of hexanes to cause crystallization of the product of Formula I from the mixture of the two solvents.

[0071] The following examples are provided to illustrate the methods and compositions described herein.

[0072] Example

[0073] Example 1 .Preparation of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid benzyl ester hydrochloride

[0074] A. 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinic acid benzyl ester (15 grams, 78.9 weight percent, 29.1 mmol) and 125 grams of acetonitrile were added to a 300 mL Parr reactor. The reactor was pressurized and then vented three times with 350 psi nitrogen to ensure the removal of oxygen. Stirring was started and the solution was heated to 100° C. After reaching temperature, ammonia was added to the reactor over 6 minutes to bring the reactor to a final pressure of 80 psi. The reaction mixture was stirred for 5 hours, during which the reactor pressure was maintained at 80 psi by adding additional ammonia as necessary. After the reaction was determined to be complete by HPLC, the solution was cooled and vented to remove excess ammonia. The crude solution was filtered to remove the ammonium fluoride byproduct, and the resulting reactor solution was analyzed by HPLC, indicating that the in-pot yield of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinic acid benzyl ester intermediate was 85% as measured by using a quantitative internal standard method. The solution was briefly heated to 82 ° C and distilled at ambient pressure to remove any residual ammonia and the solution was concentrated to about 20% by weight solid loading. The solution was then cooled to 50 ° C and treated by dropwise addition of 12.3% by weight HCl in acetonitrile (26.4 mmol) over 3 minutes. The resulting slurry was stirred for 1 hour and then filtered at 50 ° C. The wet cake was washed with room temperature acetonitrile and dried overnight in a vacuum oven to obtain the desired 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate hydrochloride (91.7% by weight, 70% yield) as a brown solid.

[0075] B. 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)benzyl picolinate (325 grams, 81.3 weight percent, 0.65 mol) and 2395 grams of acetonitrile were added to a 5-liter Hastelloy C jacketed reactor. The reactor was pressurized to 175 psig with nitrogen and vented three times to ensure oxygen removal. Stirring was initiated and the solution was heated to 100°C. After reaching temperature, ammonia was added to the reactor over 30 minutes to bring the reactor to a final pressure of 80 psig. The reaction mixture was stirred for 4 hours, during which time the reactor pressure was maintained at 80 psig by adding additional ammonia as necessary. After the reaction was determined to be complete by HPLC, the solution was cooled and vented to remove excess ammonia. The crude solution was filtered to remove the ammonium fluoride byproduct and transferred to a 5-liter glass jacketed reactor. The ammonium fluoride wet cake was washed with 415 g of additional acetonitrile. The wash filtrate was combined with the initial reactor solution in a 5-liter glass reactor. The solution merged by HPLC analysis shows that as measured by using quantitative internal standard method, the yield in the kettle of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinic acid benzyl ester intermediate is 83%. The solution is briefly heated to 60 ° C and distilled under vacuum (365mmHg) to remove any residual ammonia and the solution is concentrated to the required product load of about 14 weight %. Then the solution is cooled to 50 ° C and sprayed with HCl (24.8g, anhydrous, 0.68mol) in 50 minutes. The gained slurries are stirred for 30 minutes and then filtered at 50 ° C. The wet cake is washed with room temperature acetonitrile (321g) and dried overnight in a vacuum oven to obtain 238g of required 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) picolinate hydrochloride (93.2 weight %, 77% yield) in the form of a brown solid.

[0076] Example 2 .Preparation of 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid benzyl ester

[0077] A. A mixture of 200.0 g of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate hydrochloride (93.2 weight %, 0.42 mol) and 1440 g of toluene was placed in a 5-liter jacketed reactor equipped with a condenser and an overhead stirring device. The solution was placed under a nitrogen atmosphere and treated with triethylamine (44.9 g, 0.44 mol). The mixture was then heated to 80° C. and stirred for another 0.5 hour. The resulting solution was washed twice with 1780 g of water. The aqueous wash was discarded and the reactor solution was heated to 80° C. and distilled under vacuum (300 mmHg) to remove any residual water and triethylamine. The solution was then treated with DCDMH (1,3-dichloro-5,5-dimethylhydantoin, 51.0 g, 0.25 mol) and stirred at 75° C. for 2.5 hours. After the reaction was determined to be complete by HPLC analysis, the cooled solution was washed with 1290 g of sodium bisulfite aqueous solution (0.7 weight %, 0.08 mol) and then washed with 1500 g of water. The combined aqueous washes were discarded, and the organic solution was then heated to 80 ° C and distilled again under vacuum (300 mmHg) to concentrate the solution and remove any residual water. The solution was concentrated to about 17 weight % of the product, cooled to 70 ° C, and then about 790 g of hexane was added dropwise to the solution over 90 minutes, which was then cooled back to room temperature. The resulting mixture was filtered and the resulting wet cake was washed with a mixture consisting of 300 g of toluene and 300 g of hexane. The wet cake was then dried overnight in a vacuum oven at 70 ° C to obtain the desired product in 84% yield as a yellow solid (166 g, 92.2 weight %).

[0078] B. A mixture consisting of 200.4 g of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate hydrochloride (80.2% purity), 38.9 g of TEA, and 2038 g of toluene was placed in a 4.5 L jacketed reactor. The resulting slurry was placed under a nitrogen atmosphere and heated to 80°C. The solution was then washed with 1511 g of water, followed by a second wash with 1302 g of water. The resulting organic layer was vacuum transferred to a 3.5 L jacketed reactor along with a 124 g toluene rinse. The solution was then distilled under vacuum to remove excess water. After the water was removed, about 43.9 g of 1,3-dichloro-5,5-dimethylhydantoin (0.6 eq.) was added to the reactor over 12 minutes. The solution was stirred at 75°C for 4 hours, and an additional 1.35 g of 1,3-dichloro-5,5-dimethylhydantoin (0.02 eq.) was added to complete the reaction. After 90 minutes, a mixture consisting of 19g of a 40 wt% aqueous sodium bisulfite solution and 1000g of warm tap water was added to the reactor. The reactor was heated to 80°C and the water layer was decanted. Another 1000g of warm tap water was added for a second water extraction. As previously described, the mixture was heated to 80°C and the water layer was decanted. At this point, toluene was vacuum distilled at 80°C for solvent exchange. After removing most of the toluene, 595g of 2-ethyl-1-hexanol was poured into the reactor. Restart distillation for 80 minutes until the final pressure in the reactor was 53mmHg and the final temperature was 91.6°C (about 60mL was collected at the top). At this point, another 563g of 2-ethyl-1-hexanol was poured into the reactor, the solution was heated to 82°C, and then cooled to 20°C. The resulting slurry was filtered, the collected wet cake solids were washed with 207 g of 2-ethyl-1-hexanol, then washed with 192 g of hexane, and partially dried in a vacuum oven. The partially dried wet cake solids were re-slurried with hexane and finally fully dried overnight in a vacuum oven. The output of the final isolated 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester was 142.0 g (84% yield) with a purity of 95.2% by weight.

[0079] C. A mixture of 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate hydrochloride (50.0 g, 88.6 wt %, 100.3 mmol) and 253 g of toluene was added to a 1 liter jacketed reactor. The resulting slurry was placed under a nitrogen atmosphere and heated to 83°C. The solution was then treated with a 50 wt % triethylamine solution in toluene (23.3 g, 115.5 mmol). The solution was then cooled to 40°C and subsequently treated with 1,3-dichloro-5,5-dimethylhydantoin (13.5 g, 67.8 mmol). The solution was reheated to 80°C over 1 hour and then washed twice with 248 g of water. At this point, toluene was vacuum distilled at 80°C for solvent exchange. After removing most of the toluene, 148 g of 2-ethyl-1-hexanol was poured into the reactor. Distillation was restarted to remove the remaining toluene until the final pressure in the reactor was 75 mmHg and the final temperature was 87° C. Next, an additional 153 g of 2-ethyl-1-hexanol was poured into the reactor and the solution was slowly cooled to 6° C. The slurry was filtered and the resulting wet cake was washed with 145 g of heptane. The washed wet cake was dried in a vacuum oven overnight to give 39.9 g of the desired 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester product (yield 84%) with a purity of 92.9 wt %.

[0080] D. Purification: A 74.18 g sample of a toluene solution containing 13.0 wt % 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester was added to a 250 mL jacketed reactor along with an additional 14.5 grams of toluene. The slurry was heated to 80° C. and distilled under vacuum to remove a portion of the toluene. When the liquid level in the reactor was low enough, 18.1 g of 2-ethyl-1-hexanol (2EH) was added to the reactor and the solution was further distilled to remove more toluene. When the distillation conditions reached 84 mm Hg vacuum and 88° C., the distillation was stopped, 17.2 g of 2EH was added to the reactor, and the solution was sampled by LC and GC to determine the 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester assay and solvent composition. Based on these results, 26.69g 2EH, 17.58g heptane and 4.47g toluene were added to the reactor. The mixture was heated to 81°C and then cooled to 20°C in 6 hours. The resulting slurries were filtered and washed with 40g hexane to obtain 16.33g 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester wet cake. The solid was dried overnight in a vacuum oven to obtain 9.08g 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester (87% yield), with a purity of 93.8 % by weight.

[0081] The compositions and methods of the claims are not limited in scope by the specific compositions and methods described herein, which are intended to be illustrations of some aspects of the claims, and any functionally equivalent compositions and methods are intended to fall within the scope of the claims. Various modifications to the compositions and methods other than those shown and described herein are intended to fall within the scope of the appended claims. In addition, although only certain representative composition materials and method steps disclosed herein are specifically described, other combinations of composition materials and method steps are intended to fall within the scope of the appended claims even if they are not specifically listed. Therefore, a combination of steps, elements, components or ingredients may be explicitly mentioned herein, however, even if not explicitly stated, other combinations of steps, elements, components and ingredients are included. As used herein, the term "comprising" and its variants are used synonymously with the term "including" and its variants, and are open, non-restrictive terms. Although the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" may be used instead of "comprising" and "including" to provide more specific embodiments of the present invention, and these terms are also disclosed.

[0082] In summary, the present invention includes but is not limited to the following items:

[0083] 1. A method for preparing a compound of formula I:

[0084]

[0085] The following steps are involved:

[0086] a) combining a compound of formula II with anhydrous ammonia;

[0087]

[0088] b) isolating the compound of formula III from said combination of step a);

[0089]

[0090] c) combining the isolated compound of formula III from step b) with anhydrous HCl to form the HCl salt of formula IV;

[0091]

[0092] d) isolating the compound of formula IV from step c), and combining the isolated compound of formula IV with a base to re-form the compound of formula III;

[0093] e) adding a chlorinating agent to the combination of step d); and

[0094] f) isolating the compound of formula I.

[0095] 2. The method according to item 1 further comprises isolating the compound of formula III after step d) and then adding the chlorinating agent in step e).

[0096] 3. The method according to item 1 or 2, wherein step a) further comprises a solvent selected from acetonitrile, propionitrile, benzonitrile, toluene, xylene, a xylene mixture, THF, dioxane, monoethylene glycol ether and diethylene glycol ether and monopropylene glycol ether and dipropylene glycol ether.

[0097] 4. A method according to claim 3, wherein the solvent is acetonitrile.

[0098] 5. The process according to any one of clauses 1 to 4, wherein the combined anhydrous ammonia of step a) is maintained at a pressure of about 40 to about 150 pounds per square inch gauge (psig).

[0099] 6. The process according to any one of clauses 1 to 4, wherein the combined anhydrous ammonia of step a) is maintained at a pressure of about 70 to about 100 pounds per square inch gauge (psig).

[0100] 7. The process according to any one of items 1 to 4, wherein the combination of step a) is maintained at a temperature of about 60 to about 130°C.

[0101] 8. The process of any one of items 1 to 4, wherein the combination of step a) is maintained at a temperature of about 80 to about 120°C.

[0102] 9. The process according to any one of items 1 to 8, wherein step b) comprises removing ammonium fluoride and substantially all residual ammonia from the combination of step a).

[0103] 10. A process according to claim 9, wherein the ammonium fluoride is removed by filtration or centrifugation.

[0104] 11. A method according to item 9, wherein the residual ammonia is removed by distillation or by sparging with an inert gas.

[0105] 12. The method according to any one of items 1 to 11, wherein isolating the compound of formula IV in step d) comprises isolating the compound of formula IV by filtration or centrifugation.

[0106] 1 3. The method according to item 2, wherein isolating the compound of formula III further comprises a solvent that is immiscible with water.

[0107] 14. A process according to claim 13, wherein the water-immiscible solvent is an aromatic hydrocarbon.

[0108] 15. The process according to item 14, wherein the aromatic hydrocarbon is toluene, xylene, a xylene mixture or benzonitrile.

[0109] 16. The process according to any one of items 1 to 15, wherein the base in step d) is a trialkylamine compound.

[0110] 17. A method according to item 16, wherein the trialkylamine compound is triethylamine.

[0111] 18. The method according to item 2, wherein the further separation of the compound of formula III comprises using water

[0112] washing.

[0113] 19. A method according to any one of items 1 to 18, wherein the chlorinating agent in step e) is an N-chloro compound.

[0114] 20. A process according to item 19, wherein the N-chloro compound is 1,3-dichloro-5,5-dimethylhydantoin.

[0115] 21. The process according to any one of items 1 to 20, wherein the combination in step d) comprises a single-phase solvent system.

[0116] 22. A method according to claim 21, wherein the single-phase solvent system comprises one or more solvents selected from toluene, xylene, xylene mixtures, acetonitrile, benzonitrile, ethyl acetate, THF, dioxane, tert-amyl methyl ether (TAME), methyl tert-butyl ether (MTBE) and chlorinated hydrocarbons.

[0117] 23. The process according to any one of items 1 to 22, wherein after separation in step f), the compound of formula I is purified by crystallization from a solvent comprising a C4-C12 alcohol, an aliphatic hydrocarbon, an aromatic hydrocarbon or a mixture thereof.

[0118] 24. A method according to item 23, wherein the C4-C 12 Alcohols include 2-ethyl-1-hexanol.

[0119] 25. The process according to any one of items 1 to 22, wherein after separation in step f), the compound of formula I is purified by crystallization from a solvent mixture comprising aliphatic hydrocarbons as hexane or a hexane mixture and aromatic hydrocarbons as toluene.

[0120] 26. The process according to items 23-24, wherein after separation in step f), the compound of formula I is purified by crystallization from a solvent mixture comprising 2-ethyl-1-hexanol, heptane and toluene.

Claims

1. A method for preparing a compound of formula I: The following steps are involved: a) combining a compound of formula II with anhydrous ammonia and acetonitrile; and maintaining a pressure of 40 to 150 pounds per square inch gauge (psig) and a temperature of 60° C. to 130° C. with anhydrous ammonia; b) filtering or centrifuging to form an acetonitrile solution of the combined compound of formula III from step a); c) combining the resulting compound of formula III from step b) with anhydrous HCl to form the HCl salt of formula IV; d) isolating the compound of formula IV from step c) in solid form and combining the isolated compound of formula IV with a base to re-form the compound of formula III; e) adding a chlorinating agent to the combination of step d); and f) isolating the compound of formula I.

2. The method of claim 1, further comprising isolating the compound of formula III after step d) and before adding the chlorinating agent in step e).

3. The process of claim 1 or 2, wherein the combination of step a) is maintained at a pressure of 70 to 100 pounds per square inch gauge (psig) and a temperature of 80°C to 120°C with anhydrous ammonia.

4. The process of any one of claims 1 to 3, wherein step b) comprises removing ammonium fluoride and residual ammonia from the combination of step a) such that the combination of step a) contains less than 500 ppm of residual ammonia.

5. The process of claim 4, wherein the ammonium fluoride is removed by filtration, and wherein the residual ammonia is removed by distillation or by purging with an inert gas.

6. The method according to any one of claims 1 to 5, wherein isolating the compound of formula IV in step d) comprises isolating the compound of formula IV by filtration or centrifugation.

7. The method according to claim 2, wherein isolating the compound of formula III further comprises a solvent that is immiscible with water.

8. The process according to claim 7, wherein the water-immiscible solvent is an aromatic hydrocarbon selected from toluene, xylene, a xylene mixture or benzonitrile.

9. The process according to any one of claims 1 to 8, wherein the base in step d) comprises triethylamine.

10. The process according to claim 2, wherein re-isolating the compound of formula III comprises washing with water.

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