Preparation of Picloram Halogen Analogs

Abstract

A method for preparing 5-fluoro-6-(bromo or chloro)picolinic acid analogs, or derivatives thereof, from picolinic acid, picolinic esters, or nitrile analogs of picolinic acid is provided. The method includes the following chemical process steps: (1) introducing a phthalyl group onto the 4-amino substituent of picolinic acid, picolinic esters, or nitrile analogs of picolinic acid, (2) adding two fluorine atoms at the 5,6-positions of the pyridine ring using a Halex fluorination chemical process, (3) removing the phthalyl group, hydrolyzing the ester or nitrile substituent, and adding chlorine or bromine at the 6-position by treatment with acid and water, and finally, (4) esterifying the 5-fluoro-6-(bromo or chloro)picolinic acid produced in step (3) to 5-fluoro-6-(bromo or chloro)picolinic esters.

Description

[0001] Priority

[0002] This application claims priority to US 62 / 733,285, filed Sep. 19, 2018, which is hereby incorporated by reference in its entirety. Background of the Invention

[0003] Picloram (I; X, Y = Cl), a member of the picolinic acid herbicide family, is an auxin herbicide that provides very good control of broadleaf weeds in pasture, rangeland, forestry, and industrial settings (The Pesticide Manual, 12 th Edition, 2000). Picloram is also used as a starting material for the production of another useful auxin herbicide, known as fluroxypyr (I, X = Cl, Y = H).

[0004] Summary of the Invention

[0005] Methods for preparing 5,6-dihalo analogs of picloram from picloram or its derivatives (esters or nitriles) are described herein. Specifically, 5-fluoro-6-(bromo or chloro) picloram analogs of formula II, or their derivatives (esters or nitriles), can be prepared.

[0006]

[0007] wherein X = Cl or Br, Z is COOR or CN, and R is C1-C 12 alkyl, C6-C 12 arylalkyl, C3-C 12 alkynyl, C1-C3 alkyl substituted with CN, or H.

[0008] As described in WO 2012 / 103044 A1 and WO 2012 / 103041 A2, the compounds of formula II are useful intermediates for the synthesis of herbicides.

[0009] The method involves first combining a compound of formula III with a phthaloyl halide of formula IIIa or phthalic anhydride of formula IIIb, and optionally a base,

[0010]

[0011] Each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4; and W is Cl or Br. Then the compound of formula IV is separated from the first step

[0012]

[0013] and the separated compound of formula IV is combined with a fluorinating compound or a fluorinating mixture of compounds.

[0014] Next, the compound of formula V is separated and combined with HCl or HBr and water.

[0015]

[0016] Finally, the compound of formula II is separated.

[0017] Another aspect of the present disclosure is novel compounds produced by the described method, namely, the following compounds:

[0018]

[0019] where X = Cl or Br, Z is COOR, and R is C2-C 12 alkyl, C6-C 12 arylalkyl, C3-C 12 alkynyl, C1-C3 alkyl substituted with CN, or H; and

[0020]

[0021] where Z is COOR or CN, and R is H, C1-C 12 alkyl, or C6-C 12 arylalkyl; and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4. Detailed Description

[0022] A method for preparing a 5-fluoro-6-(bromo or chloro) picolinic acid analogue of formula II, or a derivative thereof, from picolinic acid ester or nitrile of formula III is provided. As shown in Scheme 1, the method comprises the following chemical process steps: (1) introducing a cyclic imide group (such as phthaloyl) to the 4-amino substituent by reacting a compound of formula III with a diacyl halide (such as phthaloyl chloride) or an acid anhydride (such as phthalic anhydride); (2) placing two fluorine atoms at the 5,6-positions of the pyridine ring by using a fluorination chemical process; and (3) removing the cyclic imide group, hydrolyzing the ester or nitrile substituent, and introducing a halogen atom at the 6-position by treatment with acid HX and water, where X is Cl or Br.

[0023] Scheme 1:

[0024]

[0025] where X is Cl or Br, Z is COOR or CN, R is C1-C 12 alkyl, and R 1 is C2-C 12 alkyl, C6-C 12 arylalkyl, C3-C 12 alkynyl, or C1-C3 alkyl substituted with CN.

[0026] I. Definitions

[0027] A compound of formula IV can be represented by the following chemical structure, where Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, 4, 5, 6, 7, or 8. The phthaloyl structure can be represented by either of two forms of the phthaloyl structure that are considered identical in all respects.

[0028]

[0029] One aspect of the present invention is a compound of formula IV, where Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4.

[0030] One aspect of the present invention is a compound of formula IVa, wherein Z is CO2R or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl.

[0031] One aspect of the present invention is a compound of formula IVb, wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1 or 2.

[0032] One aspect of the present invention is a compound of formula IVc, wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, 4, 5, or 6.

[0033] One aspect of the present invention is a compound of formula IVd, wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, 4, 5, 6, 7, or 8.

[0034] One aspect of the present invention is a compound of formula IVe, wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl.

[0035] One aspect of the present invention is a compound of formula IVf, wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4 and where two Y groups may be bonded to each other to form a ring.

[0036] One aspect of the present invention is a compound of formula IVg, wherein Z is CO2R or CN, R is C1-C 12alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, 4, 5, or 6.

[0037] One aspect of the present invention is a compound of formula IVh, where Z is CO2R or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, 4, 5, 6, 7, or 8.

[0038] As used herein, the term "aryl" and derivative terms such as aryloxy refer to a group of monovalent aromatic carbocyclic groups containing 6 to 14 carbon atoms. The aryl may include a single ring or multiple fused rings. In some embodiments, the aryl includes C6-C 10 aryl. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl may be phenyl, indanyl, or naphthyl. The term "heteroaryl" and derivative terms such as "heteroaryloxy" refer to a 5-membered or 6-membered aromatic ring containing one or more heteroatoms (i.e., N, O, or S); these heteroaromatic rings may be fused to other aromatic systems. In some embodiments, the heteroaryl may be pyridyl, pyrimidinyl, or triazinyl. The aryl or heteroaryl may be unsubstituted or substituted by 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-C 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-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro.

[0039] As used herein, the term "alkyl" refers to a straight-chain alkyl, branched-chain alkyl, or cyclic alkyl. The cyclic alkyl may also include those groups referred to as cycloalkyl or alicyclic groups, such as, for example, cyclohexyl or cyclopentyl.

[0040] As used herein, the term "C6-C 12 arylalkyl" also includes benzyl (i.e., CH2Ph).

[0041] II. Preparation of Phthalimide IV

[0042] The first step of the method for preparing the compound of formula II is shown in Scheme 2 and involves converting the compound of formula III (wherein Z is CO2R or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl) into the corresponding cyclic imide of formula IV by reaction with a diacyl halide such as phthaloyl halide of formula IIIa or an acid anhydride such as phthalic anhydride of formula IIIb (wherein X is Cl or Br, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4).

[0043] Scheme 2:

[0044]

[0045] The process step of manufacturing IV can be carried out in a solvent such as, but not limited to, polar aprotic solvents (such as acetonitrile (ACN), toluene, dimethylformamide (DMF), propionitrile, or benzonitrile), ethers (such as THF, 2-methyl-THF, dioxane, cyclopentyl methyl ether (CPME), monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether or dipropylene glycol ether), or ketones (such as methyl isobutyl ketone (MIBK)), and mixtures thereof. The temperature range for carrying out this process step can be from about 25 °C to about 100 °C, from about 25 °C to about 90 °C, from about 25 °C to about 80 °C, from about 25 °C to about 70 °C, from about 25 °C to about 60 °C, or from about 25 °C to about 55 °C, and the reaction can be carried out over a period of from about 1 hour to about 72 hours, from about 1 hour to about 48 hours, from about 1 hour to about 24 hours, from about 1 hour to about 12 hours, from about 1 hour to about 6 hours, from about 2 hours to about 24 hours, from about 4 hours to about 24 hours, from about 2 hours to about 12 hours, or from about 4 hours to about 12 hours.

[0046] In this process, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1 to about 1.4, about 1 to about 1.3, about 1 to about 1.2, or about 1 to about 1.1 molar equivalents of phthaloyl halide or phthalic anhydride can be used. When phthaloyl halide is used, a base can be used to capture the HX acid released in the process and can be selected from bases such as trialkylamines (such as but not limited to trimethylamine, triethylamine, or tripropylamine), and nitrogen-containing heterocycles (such as pyridine, and alkyl-substituted pyridines such as 2-methylpyridine or 3-methylpyridine). Phthalimide IV can be separated from the process by using standard separation and purification techniques. In the process of manufacturing IV, a base can optionally be used together with phthalic anhydride.

[0047] In one embodiment, the use of an acylation catalyst (such as but not limited to DMAP (4-(dimethylamino)-pyridine) or N-methylimidazole) can be used to prepare IV from IIIa or IIIb.

[0048] In another embodiment of the first step of the method for preparing a compound of formula II as shown in Scheme 2, prior to the first step, it can be one in which formic acid of formula III (where Z is CO2H) is contacted with an alcohol ROH (where R is a C1-C 12 alkyl or C6-C 12 arylalkyl) in the presence of an acid or an acid-forming compound to provide an ester of formula III (where Z is CO2R). Then the ester thus produced can be used to prepare the phthalimide of formula IV as described herein.

[0049] III. Preparation of difluorophthalimide V

[0050] The second step of the method for preparing a compound of formula II involves converting a compound of formula IV (where Z = CO2R or CN, R is a C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4) into the corresponding difluorophthalimide of formula V by treating IV with a fluorinating compound or a fluorinating mixture of compounds in the presence of a solvent, as shown in Scheme 3.

[0051] Scheme 3:

[0052]

[0053] The fluorinated compound or fluorinated mixture of compounds for use in the second step of the method may be selected from the group consisting of KF (potassium fluoride), CsF (cesium fluoride), and TMAF (tetramethylammonium fluoride), and mixtures thereof, or a mixture of tetramethylammonium chloride (TMAC) with KF or CsF.

[0054] Relative to the substrate of formula IV used to prepare the compound of formula V, the amount of the fluorinated compound or fluorinated mixture of compounds used may be about 2 to about 8 molar equivalents of KF, about 2 to about 8 molar equivalents of CsF, or about 2 to about 6 molar equivalents of TMAF. In one embodiment, the fluorinated mixture of compounds comprises about 2 to about 10 molar equivalents of KF or CsF and about 0.01 to about 2.0 molar equivalents of TMAC.

[0055] Solvents that may be suitable for use with the fluorinated compound or fluorinated mixture of compounds to prepare V include, but are not limited to, polar aprotic solvents such as acetonitrile (ACN), propionitrile (PCN), benzonitrile (BCN), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), sulfolane, dimethylacetamide (DMAC), 1,1-dimethyl-2-imidizolidinone (DMI), N,N'-dimethylpropyleneurea (DMP), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyl-THF, dioxane, monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether or dipropylene glycol ether, and mixtures thereof.

[0056] In one embodiment, the fluorination of IV can be carried out with KF or CsF in a DMF solvent. In another embodiment, the fluorination of IV can be carried out with KF or CsF in a DMSO solvent. In another embodiment, the fluorination of IV can be carried out with KF or CsF and TMAC in a DMF solvent. In another embodiment, the fluorination of IV can be carried out with KF or CsF and TMAC in a DMSO solvent. In another embodiment, the fluorination of IV can be carried out with TMAF in a THF solvent.

[0057] Generally, it is preferably carried out under anhydrous or near-anhydrous conditions for the fluorination of IV to prepare V. These anhydrous or near-anhydrous conditions can be obtained by pre-drying the reactants and the solvent. One way to dry the reactants and / or the solvent is to remove a portion of the solvent by distillation prior to carrying out the fluorination reaction.

[0058] The fluorination reaction of the compound of formula V can be carried out at a temperature of at least about 0 °C, at least about 10 °C, at least about 20 °C, at least about 25 °C, at least about 30 °C, at least about 40 °C, at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, or at least about 100 °C. The fluorination reaction of the compound of formula V can be carried out at a temperature of from about 0 °C to about 50 °C, from about 10 °C to about 50 °C, from about 25 °C to about 50 °C, from about 15 °C to about 150 °C, from about 25 °C to about 150 °C, from about 35 °C to about 125 °C, from about 45 °C to about 115 °C, from about 55 °C to about 110 °C, from about 65 °C to about 110 °C, from about 75 °C to about 110 °C, from about 85 °C to about 110 °C, from about 90 °C to about 110 °C, from about 50 °C to about 100 °C, from about 60 °C to about 100 °C, from about 70 °C to about 100 °C, from about 25 °C to about 90 °C, from about 25 °C to about 80 °C, from about 25 °C to about 110 °C, from about 25 °C to about 70 °C, or from about 25 °C to about 60 °C.

[0059] The compound of formula V can be isolated from the fluorination reaction mixture by filtering off the insoluble salts and then adding water to the resulting filtrate to precipitate the desired product, which can be purified using standard purification techniques.

[0060] IV. Preparation of 4-amino-3-chloro-6-(chloro or bromo)-5-fluoropicolinic acid II

[0061] The next step in the process for preparing the compound of formula II involves converting the compound of formula V (wherein Z is CO2R or CN, R is C1-C 12 alkyl or C6-C 12 arylalkyl, and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4) into the compound of formula II, wherein X is Cl or Br. This conversion is shown in Scheme 4 and involves treating the compound V with hydrohalic acid HX and water (where X is Cl or Br) to provide the compound of formula II, wherein X is Cl or Br.

[0062] Scheme 4:

[0063]

[0064] The conversion involves exchanging the 6-fluoro substituent with an HX acid halide to provide a 6-chloro or 6-bromo substituent, hydrolyzing the Z substituent to formic acid, and removing the phthaloyl group by hydrolysis to regenerate the 4-amino substituent. A cosolvent of acetic acid (HOAc) is useful to help facilitate this conversion. The HX salt of compound II (where X is Cl or Br) can also be formed in this reaction.

[0065] This step can be carried out in two stages, where the first stage is carried out at a lower temperature and / or in the absence or limited amount of water to achieve the halide exchange of the 6-fluoro substituent, and the second stage is carried out at a higher temperature and / or in the presence of more water to achieve the hydrolysis of the phthaloyl group and the ester (or cyano) substituent).

[0066] In some instances, the amount of water included in this step, in moles relative to the starting compound of formula V, can be about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 2 to about 5, about 2 to about 4, or about 3 to about 4 molar equivalents of water per mole of compound V.

[0067] In other instances, the amount of acid HCl or HBr included in this step, in moles relative to the starting compound of formula V, can be about 50 to about 1, about 40 to about 1, about 30 to about 1, about 20 to about 1, about 10 to about 1, about 8 to about 1, about 6 to about 1, about 3 to about 1, about 2 to about 1, or about 3 to about 2 molar equivalents of HCl or HBr per mole of compound V.

[0068] In further instances, the reaction of producing the compound of formula II from the compound of formula V can be carried out at a temperature of about 50 °C to about 150 °C, about 60 °C to about 140 °C, about 70 °C to about 130 °C, about 80 °C to about 120 °C, about 90 °C to about 120 °C, or about 100 °C to about 120 °C.

[0069] The reaction by-products of producing the product of formula II from the compound of formula V are phthalic acid or substituted phthalic acid, which are derived from the hydrolytic cleavage of the phthaloyl group of compound V. The method for separating or removing phthalic acid or substituted phthalic acid from the reaction mixture containing the compound of formula II can include but is not limited to solvent extraction with an organic solvent, an aqueous solvent, or an organic-aqueous solvent, or different water solubilities at certain pH levels or ranges.

[0070] In another instance of this process step, the HBr salt or HCl salt of compound II (where X is Cl or Br) can be formed in a small amount and present in the separated product of formula II. This compound (IIa) can be reduced or removed from product II by solvent extraction of the crude product II with water or an alcohol-water mixture (such as methanol-water).

[0071] V. Preparation of esters of 4-amino-3-chloro-6-(chloro or bromo)-5-fluoropicolinic acid

[0072] The acid of formula II (where X is Cl or Br) can be converted into an ester of formula VI, where X is Cl or Br, and R1 is C1-C 12 alkyl, C6-C 12 arylalkyl, C3-C 12 alkynyl or C1-C3 alkyl substituted with CN. The methods for preparing ester VI from acid II include, but are not limited to

[0073]

[0074] acid-catalyzed esterification of acid II with an alcohol, and alkylation of acid II with an alkyl halide or benzyl halide under basic conditions.

[0075] VI. Isolation / Purification

[0076] After preparing the compound of formula II by the processes described herein, the product can be isolated by using standard separation and purification techniques. For example, the crude product can be separated using standard methods as described herein and purified by crystallization or recrystallization using a single solvent or a mixture of two or more solvents. In addition, the crude product can be purified by washing it with a single-component, two-component, or three-component solvent mixture or by stirring it in a single-component, two-component, or three-component solvent mixture. In one embodiment, the crude product can be purified by stirring it in an aqueous alcohol solvent mixture, which can also be described as an aqueous alcohol slurry treatment.

[0077] The crude product of formula II can also be purified by dissolving it in a solvent to form a solution and then adding a second solvent to the solution to cause the product of formula II to crystallize out of the mixture of the two solvents.

[0078] The following examples are presented to illustrate the methods and compositions described herein.

[0079] Examples

[0080] Example 1a . Preparation of Methyl 4-Amino-3,5,6-trichloropicolinate

[0081]

[0082] Picloram (100 g, 95% purity, 414 mmol, 1.0 eq) was suspended in methanol (800 mL). Sulfuric acid (26 mL, 487 mmol, 1.2 eq) was added slowly at room temperature. The reaction mixture was stirred for 2 days at 75 °C (oil bath with condenser). The mixture was cooled to room temperature. Water (200 mL) was added. The light brown solution was concentrated to remove methanol. The resulting residue was dissolved in water (200 mL) and EtOAc (600 mL), cooled in an ice bath and neutralized to pH = 8 with 4N NaOH and saturated NaHCO3 solution. The EtOAc layer was separated and the aqueous layer was washed with EtOAc. The combined organic layers were dried and concentrated to give compound 2 as a pale yellow solid (71 g, 67% yield). HPLC purity: 99.9%. Mp. 125.8 °C - 126.1 °C; 1 1H NMR (CDCl3) δ 5.38 (br s, 2H), 3.97 (s, 3H).

[0083] Example 1b . Preparation of isopropyl 4-amino-3,5,6-trichloropicolinate

[0084]

[0085] Picloram (4.66 g, 95%, 18.3 mmol, 1 eq) was suspended in isopropanol (30 mL). Concentrated sulfuric acid (0.6 g, 6.1 mmol, 0.33 eq) was added at room temperature. Then the reaction mixture was heated at reflux for 18 h. Then the reaction was cooled to room temperature. 23% aqueous K2CO3 solution (10 mL) was added slowly to the reaction mixture and the mixture was stirred for 30 min. The reaction mixture was extracted with EtOAc (20 mL) and the organic phase was washed with 20 mL of saturated brine. The organic phase was dried, the solvent was evaporated and the residual solid was dried in a vacuum oven to give an off-white solid (4.9 g, 94%; HPLC purity: 96%). Mp 128.5 °C - 131.0 °C; 1 1H-NMR (400 MHz, CDCl3): δ 5.35 (br s, 2H), 5.29 (septet, J = 6.4 Hz, 1H), 1.39 (d, J = 6.4 Hz, 6H) ppm.

[0086] Example 2a . Preparation of phthalimide IV (Z = CO2Me)

[0087]

[0088] Compound III (Z = CO2Me; 86 g, 337 mmol) was dissolved in acetonitrile (600 mL). Triethylamine (TEA, 94 mL, 673 mmol, 2.0 equiv) was then added at room temperature, followed by dropwise addition of phthaloyl chloride (65 mL, 404 mmol, 1.2 equiv). The reaction mixture was stirred at 50 °C overnight. Water (100 mL) was added to the mixture. The suspension was stirred for 1 h and filtered through filter paper. The solid was washed with water and then with hexane, and dried. The dried solid was suspended in toluene (200 mL), and the resulting mixture was concentrated to afford Compound IV as a pale yellow solid (85.1 g, 66% yield). HPLC purity: 97.7%. Mp. 185.3 °C - 185.9 °C; 1 1H NMR (CDCl3) δ 8.02 (m, 2H), 7.88 (d, 2H, m), 4.02 (s, 3H).

[0089] Example 2b . Preparation of phthalimide IV (Z = CN)

[0090]

[0091] Compound III (Z = CN; 64.06 g, 288.0 mmol) was suspended in acetonitrile (960 mL). TEA (90.0 mL, 640.0 mmol, 2.2 equiv) and DMAP (3.52 g, 28.8 mmol, 0.1 equiv) were added at room temperature, followed by slow addition of phthaloyl chloride 2 (51.2 mL, 320 mmol, 1.1 equiv), maintaining the internal temperature of the reaction below 50 °C during addition. The reaction mixture was stirred at room temperature for 4 h. Water (130 mL) was added to the reaction, the suspension was stirred for 30 min and filtered. The collected solid was washed with water (4 × 150 mL), hexane (2 × 100 mL) and dried to give Compound IV (Z = CN; 97.0 g, 96% yield) as a light purple solid, which was dissolved in dichloromethane (DCM) and passed through a silica gel pad to give an off-white solid, with HPLC purity: 99.6%. Mp. 233.7 °C - 234.8 °C; 1 1H NMR (400 mHz, DMSO-d6): δ 8.14 (2H, m), 8.04 (2H, m).

[0092] Example 2c . Preparation of phthalimide IV (Z = CO2Me)

[0093]

[0094] Picloram (105.25 g, 414.9 mmol, 95.2% purity, 1.0 eq) was suspended in MeOH (650 mL) in a 3 L three-necked flask equipped with a mechanical stirrer and a condenser. The mixture was stirred vigorously at room temperature. Thionyl chloride (0.90 mL, 12 mmol, 0.03 eq) was added dropwise. The reaction mixture was stirred at 75 °C (external temperature) for 18 h. After the reaction, the white suspension turned into a light yellow clear solution. A sample was taken for HPLC analysis (96.7% methyl ester, 2.3% picloram). After partially removing methanol to about 150 mL remaining, 500 mL of toluene was added and co-evaporated to dryness under house vacuum at 40 °C - 55 °C. A sample was taken for 1 1H-NMR analysis and no MeOH or toluene residues were present. Then, 690 mL of MeCN was added to form a turbid solution. TEA (134 mL, 959.0 mmol, 2.3 eq) and DMAP (5.33 g, 43.6 mmol, 0.105 eq) were added to this solution, followed by dropwise addition of phthaloyl chloride (77 mL, 479.5 mmol, 90% purity, 1.15 eq) to give an orange reaction mixture (exothermic). In this step, the temperature was controlled below 55 °C by adjusting the addition rate. After the addition was complete, the reaction mixture was stirred for another 2 h. Then water (200 mL) was added to the mixture. The resulting suspension was stirred for 30 min and filtered. The wet cake collected on the funnel was washed with water (2 × 200 mL), hexane (200 mL) and dried under vacuum to give IV as a beige solid (154.4 g, 96% yield over 2 steps, HPLC purity: 98%).

[0095] Example 2d . Preparation of Phthalimide IV (Z = CO2iPr)

[0096]

[0097] Step 1 : Picloram (100 g, 98.2% pure, 414.1 mmol, 1 eq) and iPrOH (950 mL) were charged into a 3 L three-necked flask equipped with a mechanical stirrer, a condenser and a dropping funnel. SOCl2 (15.1 mL, 207 mmol, 0.5 eq) was added dropwise via the dropping funnel to the slurry at room temperature and then the reaction mixture was heated under reflux for 24 h. The reaction mixture was cooled to room temperature, the solvent was evaporated to dryness and then co-evaporated with MeCN (2 × 100 mL) to give a white solid (117.5 g of crude product). HPLC: 93.6% IV, 2.84% picloram.

[0098] Step 2: Charge the above-separated white solid, MeCN (700 mL), TEA (150 mL, 1076.7 mmol, 2.6 equiv), and DMAP (5.05 g, 41.4 mmol, 0.1 equiv) into a 3 L, 3-necked flask equipped with a mechanical stirrer, thermometer, and addition funnel. Add phthaloyl chloride (90% pure, 73 mL, 455.51 mmol, 1.1 equiv) dropwise via the addition funnel to maintain the temperature below 55 °C. Stir the reaction mixture at room temperature for 3 h. Add water (250 mL) to the mixture. Stir the resulting suspension for 30 min and filter it through filter paper. Wash the solid with water (3 × 100 mL) and hexane (2 × 100 mL) and dry it. Co-evaporate the solid with toluene (2 × 250 mL), dry it, wash it with hexane (2 × 200 mL), and dry it again to give Compound IV as a pale yellow solid (151.5 g, 88% yield). HPLC: 98.8% purity. Mp. 157.0 °C - 157.9 °C; 1 1H-NMR (400 MHz, CDCl3): δ 8.00 - 8.04 (m, 2H), 7.86 - 7.90 (m, 2H), 5.33 (septet, J = 6.4 Hz, 1H), 1.42 (d, J = 6.4 Hz, 6H) ppm.

[0099] Example 2e . Preparation of Phthalimide IV (Z = CO2iPr)

[0100]

[0101] Suspend Compound III (8.1 g, 27.6 mmol, 1.0 equiv) in CH3CN (33 mL) in a 100 mL RBF equipped with a mechanical stirrer and condenser. Add TEA (9.6 mL, 69.0 mmol, 2.5 equiv) and phthalic anhydride (4.9 g, 33.1 mmol, 1.2 equiv) at room temperature, followed by DMAP (0.34 g, 2.76 mmol, 0.1 equiv). Stir the yellow suspension at 80 °C (oil bath temperature) for 2 h. A yellow clear solution was observed after 5 min in an 80 °C oil bath. Add additional phthalic anhydride (4.0 g, 27.0 mmol, 1 equiv) to the reaction mixture at 80 °C. Stir the reaction mixture at 80 °C for another 4.5 h (total reaction time is 6.5 h). Cool the reaction to room temperature and add water (33 mL) to the mixture. Stir the suspension for 30 min and filter it through filter paper. Wash the wet solid with water and hexane and dry it in a vacuum oven at 55 °C to give 3 as a yellow solid (9.8 g, 86% yield). HPLC purity: 99.2%.

[0102] Example 2f . Preparation of Phthalimide IV (Z = CO2iPr)

[0103]

[0104] To a suspension of Compound III (2.5 g, 8.82 mmol, 1.0 eq) in toluene (11 mL) was added triethylamine (2.96 mL, 21.2 mmol, 2.5 eq) and phthalic anhydride (3.26 g, 22.0 mmol, 2.5 eq). The resulting suspension was stirred in an oil bath at 90 °C for 18 h. The clear yellow solution was gradually cooled to room temperature to afford a thick beige slurry. Saturated NaHCO3 solution (5 mL) was added slowly at room temperature and the resulting slurry was stirred in an ice-water bath for 1 h. The solid was collected by vacuum filtration and subsequently washed with water (2 × 5 mL). The wet solid was further dried in a vacuum oven at 55 °C for 5 h to afford Product IV as an off-white powdery solid (3.1 g, 86% yield; HPLC purity: 99.5%).

[0105] Example 2g . Preparation of Phthalimide IV (Z = CO2iPr)

[0106]

[0107] Charge a 2 L flask with picloram (101.8 g, 98.2% purity, 0.414 mol, 1.0 eq) and IPA (918.3 mL). Add SOCl2 (15.6 mL, 97% purity, 0.21 mol, 0.5 eq) and heat the reaction mixture under reflux for 17 h. Then distill out IPA (750 mL) at atmospheric pressure. Add toluene (600 mL) to the resulting solution. Continue distillation and distill out the IPA / toluene mixture (600 mL) at 81 °C - 110 °C after another 2 h.

[0108] Add TEA (144.3 mL, 1.04 mol, 2.5 eq) to the stirred suspension, followed by the batchwise addition of phthalic anhydride (99% purity, 153.3 g, 1.04 mol, 2.5 eq). Heat the reaction mixture at 88 °C - 93 °C for 17 h and cool to room temperature. Add saturated aqueous NaHCO3 solution (400 mL) slowly over 0.5 h while cooling to keep the temperature below 20 °C. After the addition of saturated aqueous NaHCO3 solution is complete, stir the resulting slurry at room temperature for 2 h, filter, wash with water (3 × 100 mL), and dry at 60 °C for 24 h to afford Product IV (144.0 g, 84.2% yield; HPLC purity: 99.03%).

[0109] Example 3a. Preparation of Difluorophthalimide V (Z = CO2Me)

[0110]

[0111] To the compound IV (Z = CO2Me; 5.00 g, 12.97 mmol) in a 250 mL round-bottom flask under nitrogen was added anhydrous THF (100 mL) and tetramethylammonium fluoride (TMAF; 4.83 g, 51.87 mmol, 4 equiv.; Aldrich) in one portion. The reaction mixture was stirred at room temperature for 5 h, cooled to 0 °C, quenched with water (400 mL) and stirred at 0 °C for 1 h. The solid product present was collected by filtration, washed with water (2 × 100 mL) and hexane (3 × 100 mL), and dried to afford compound V as a pale yellow solid (4.0 g, 87% yield). HPLC purity: 92.3% of V; Mp. 180.2 °C - 182.6 °C; 1 1H NMR (d6-DMSO) δ 8.12 (d, 2H), 8.02 (d, 2H), 3.94 (s, 3H). 19F NMR (d6-DMSO) δ -83.30, -133.05. Also contains 6.6% of 3,5,6-trifluoro byproduct.

[0112] Example 3b . Preparation of Difluorophthalimide V (Z = CO2Me)

[0113]

[0114] A mixture of CsF (82.7 g, 545 mmol) in DMSO (1.2 L) was distilled under house vacuum at 90 °C to remove 250 mL of DMSO. After cooling to room temperature with N2, compound IV (60.0 g, 156 mmol) was added in three portions. The mixture was stirred vigorously at 25 °C under N2 for 27 h and then poured into ice water (3.6 L), stirred for 1 h, filtered, and the filtered solid was washed with water (600 mL) and hexane (300 mL), and dried to afford compound V as an off-white solid (55 g, 100% crude product). HPLC purity: 93.6% (containing 1.3% monofluoro byproduct and 2.3% trifluoro byproduct). The off-white solid was refluxed in MeOH (150 mL) for 30 min and filtered to give V as a light beige solid (51.1 g, 92.7% yield): HPLC purity: 95.7%. Also contains 1.3% 6-monofluoro byproduct and 1.7% 3,5,6-trifluoro byproduct.

[0115] The off-white solid sample (Compound V, 1.0 g) was dissolved in the minimum amount of hot EtOAc (12.5 mL), and the resulting solution was diluted with 25 mL of methanol. The resulting solution was gradually cooled to room temperature with stirring and then cooled in an ice / water bath. The mixture formed was filtered, and the filtered solid was washed twice with 5 mL of MeOH and dried to give Compound V as off-white fine crystals (0.81 g, 81% recovery). HPLC purity: 98.1%. Also contains 6-monofluoro by-product: 0.8% and 3,5,6-trifluoro by-product: 0.9%.

[0116] Example 3c . Preparation of difluorophthalimide V (Z = CO2iPr)

[0117]

[0118] Solid potassium fluoride (12.7 g, 219 mmol; Sigma Aldrich) was added to a 1 L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen purge in the headspace. The reactor was equipped with a 1” diameter plate column distillation column. Then, 353.0 g of dimethyl sulfoxide (DMSO; Fischer Scientific) was added to the reactor. The mixture was stirred at a rate of 350 RPM. A vacuum of approximately 40 mmHg was applied and the temperature of the reactor contents was raised to approximately 108 °C. Approximately 100 mL of material was distilled off through the distillation column and removed from the reactor. The temperature of the reactor contents was lowered to 75 °C, and the water content was determined by Karl-Fischer analysis to be 51 ppm. Then Compound IV (24.9 g, 60.2 mmol) was charged to the reactor and the temperature was raised to 100 °C. The reaction was maintained at 100 °C for approximately 7.5 hours. Then the reactor was cooled to 75 °C and the reaction mixture was passed through a sintered filter to remove the solid salts. The filtered salts were washed with 44 g of DMSO and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 12 °C, the contents were stirred at 250 RPM, and 363 g of water was added continuously to the second vessel over approximately 2 hours. A mixture formed and was stirred at 12 °C for an additional 1 hour, and then the solid present was collected by filtration, washed with approximately 68 g of water, and dried overnight in a vacuum oven at 60 °C and 25 Torr. The resulting dry solid (21.5 g, 94% yield) provided 93.7% of the 5,6-di-F desired product (V) Mp: 115.8 °C - 117.1 °C; 11H NMR (400 MHz, CDCl3): δ 8.00 - 8.06 (2H, m), 7.86 - 7.91 (2H, m), 5.32 (1H, septet, J = 6.0 Hz), 1.42 (6H, d, J = 6.0 Hz). 19 19F NMR (376 MHz, CDCl3): -134.21 (d), -82.76 (d). It also contains 2.6% of the 3,5,6-trifluoro by-product and 2.0% of the 6-monofluoro by-product.

[0119] Example 3d . Preparation of difluorophthalimide V (Z = CO2iPr)

[0120]

[0121] Solid potassium fluoride (7.68 g, 132 mmol; Sigma Aldrich) was added to a 1 L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen purge in the headspace. The reactor was equipped with a 1” diameter column plate distillation column containing 7 plates. Then, 211.7 g of dimethylformamide (DMF; Thermo Fisher Scientific) was added to the reactor, followed by 41.6 g of toluene (Thermo Fisher Scientific). The solution was stirred at a rate of 275 RPM. A vacuum of approximately 350 mmHg was applied and the temperature of the reactor contents was raised to approximately 110 °C. Approximately 75 mL of material was distilled through the distillation column and removed from the reactor by reducing the pressure as the material distilled overhead. Then the temperature of the reactor contents was lowered to 45 °C, and the water content was determined to be 101 ppm by Karl Fischer analysis. Then compound IV (15.2 g, 36.7 mmol) was charged to the reactor and the temperature was raised to 100 °C. The reaction was maintained at 100 °C for approximately 33 hours. Then the reactor was cooled to 40 °C and the reaction mixture was passed through a sintered filter to remove the solid salts. The filtered salts were washed with 36.1 g of DMF and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 10 °C, the contents were stirred at 250 RPM, and 170 g of water was added continuously over approximately 2 hours. A mixture was formed and stirred at 10 °C for an additional 4 hours, and then the solid present was collected by filtration, washed with approximately 44 g of water, and dried overnight in a vacuum oven at 60 °C (25 Torr). The resulting dry solid (12.0 g, 80% yield) provided 82.6% of the 5,6-di-F desired product (V). It also contains 1.1% of the 3,5,6-trifluoro by-product and 16.6% of the 6-monofluoro by-product.

[0122] Example 3e . Preparation of difluorophthalimide V (Z = CO2iPr)

[0123]

[0124] Solid potassium fluoride (11.15 g, 192 mmol; Sigma Aldrich) was added to a 1 L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen purge in the headspace. The reactor was equipped with a 1” diameter column plate distillation column containing 7 plates. Then, 207.2 g of dimethyl sulfoxide (DMSO; Thermo Fisher Scientific) was added to the reactor, followed by the addition of solid tetramethylammonium chloride (5.29 g, 48.3 mmol; TMAC, Sigma Aldrich). The mixture was stirred at a rate of 350 RPM. A vacuum of approximately 100 mmHg was applied and the temperature of the reactor contents was raised to approximately 100 °C. Approximately 35 mL of material was distilled off using the distillation column and removed from the reactor. The temperature of the reactor contents was then lowered to 45 °C and the water content was determined by Karl Fischer analysis to be 102 ppm. Compound IV (19.8 g, 47.9 mmol) was then charged to the reactor and the temperature of the reaction mixture was raised to 60 °C. The reaction was maintained at 60 °C for approximately 3.5 hours and then raised to 70 °C. This temperature was maintained at 70 °C for approximately 8.5 hours and then raised and maintained at 80 °C for 1 hour. The reactor was then cooled to 75 °C and the reaction mixture was passed through a sintered filter to remove the solid salts. The filtered salts were washed with 50 g of DMSO and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 21 °C, the contents were stirred at 250 RPM, and 267 g of water was added continuously over approximately 2 hours. A mixture was formed and stirred at 21 °C for an additional 1 hour, and then the solid present was collected by filtration, washed with approximately 66 g of water, and dried overnight in a vacuum oven at 60 °C (25 Torr). The resulting dry solid (15.5 g, 85% yield) provided 97.5% of the desired 5,6-di-F product (V). It also contained 1.7% of the 3,5,6-trifluoro byproduct and 1.9% of the 6-monofluoro byproduct.

[0125] Example 3f . Preparation of difluorophthalimide V (Z = CO2iPr)

[0126]

[0127] Solid potassium fluoride (12.7 g, 219 mmol; Sigma Aldrich) was added to a 1 L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen purge in the headspace. The reactor was equipped with a 1” diameter tray-type distillation column containing 7 trays. Then, 408.9 g of dimethyl sulfoxide (DMSO; Thermo Fisher Scientific) was added to the reactor, followed by addition of a solution of 34.6 g (110 mmol) of 35% tetramethylammonium chloride (TMAC) in methanol (SAChem). The mixture was stirred at a rate of 350 RPM. A vacuum of approximately 60 mmHg was applied and the temperature of the reactor contents was raised to approximately 100 °C. Approximately 115 mL of material was distilled off using the distillation column and removed from the reactor. The temperature of the reactor contents was lowered to 70 °C and an additional 54 g of DMSO was added to the pot before restarting the distillation and collecting an additional 35 mL of distillate. The temperature of the reactor contents was lowered to 75 °C and the water content was determined by Karl Fischer analysis to be 179 ppm. Then compound IV (24.9 g, 60.2 mmol) was charged to the reactor and the temperature was raised to 100 °C. The reaction was maintained at 100 °C for approximately 2.25 hours. The reactor was cooled to 75 °C and the reaction mixture was passed through a sintered filter to remove the solid salts. The filtered salts were washed with 116 g of DMSO and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 14 °C, the contents were stirred at 250 RPM, and 283 g of water was added continuously over approximately 2 hours. A mixture was formed and stirred at 14 °C for an additional 1 hour, and then the solid present was collected by filtration, washed with approximately 64 g of water, and dried overnight in a vacuum oven at 60 °C (25 Torr). The resulting dry solid (22.5 g, 98% yield) provided 98.3% of the desired product (V) of 5,6-di-F. It also contained 3.8% of the 3,5,6-trifluoro byproduct and 0.5% of the 6-monofluoro byproduct.

[0128] Example 3g . Preparation of difluorophthalimide V (Z = CO2Et)

[0129]

[0130] Solid potassium fluoride (5.9 g, 102 mmol; Sigma Aldrich) was added to a 1 L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen purge in the headspace. The reactor was equipped with a 1” diameter column plate distillation column containing 7 plates. Then, 139.5 g of dimethylformamide (DMF; Thermo Fisher Scientific) was added to the reactor, followed by addition of a solution of 15.8 g (50.4 mmol) of 35% tetramethylammonium chloride (TMAC) in methanol (SAChem). The solution was stirred at a rate of 350 RPM. A vacuum of approximately 90 mmHg was applied and the temperature of the reactor contents was raised to approximately 90 °C. Approximately 75 mL of material was distilled off using the distillation column and removed from the reactor. The temperature of the reactor contents was lowered to 45 °C and the water content was determined by Karl Fischer analysis to be 105 ppm. Then compound IV (10.05 g, 25.1 mmol) was charged to the reactor and the temperature was raised to 100 °C. The reaction was maintained at 100 °C for approximately 4 hours. The reactor was cooled to 50 °C and the reaction mixture was passed through a sintered filter to remove the solid salts. The filtered salts were washed with 73 g of DMF and the filtrate and washings were added to a second container for crystallization. The second container was cooled to 2 °C, the contents were stirred at 250 RPM, and 172.3 g of water was added continuously to the reaction mixture over approximately 2 hours to keep the mixture temperature below 10 °C. A mixture was formed and stirred at approximately 10 °C for an additional 1 hour, and then the solid present was collected by filtration, washed with approximately 35 g of water, and dried overnight in a vacuum oven at 60 °C (25 Torr). The resulting dry solid (6.44 g, 70% yield) provided 97.3% of the desired 5,6-di-F product (V). Mp: 111.2 °C - 116.7 °C; 1 H NMR (400 MHz, CDCl3): δ 8.00 - 8.04 (2H, m), 7.88 - 7.90 (2H, m), 4.47 (2H, q, J = 6.8 Hz), 1.43 (3H, d, J = 6.8 Hz); 19 F NMR (376 MHz, CDCl3): -133.57 (d), -82.54 (d). Also contains 2.4% of the 3,5,6-trifluoro byproduct and 3.8% of the 6-monofluoro byproduct.

[0131] Example 3h . Preparation of difluorophthalimide V (Z = CO2 cyclohexyl)

[0132]

[0133] CsF (1.17 g, 7.70 mmol) was added to a 50 mL RBF equipped with a stir bar and a distillation apparatus. Then 25 mL of dimethyl sulfoxide (DMSO) was added. The flask was immersed halfway into an oil bath. A vacuum (ca. 1 mm Hg) was connected to the distillation apparatus. Approximately 10 mL of DMSO was distilled off. The distillation apparatus was removed and the system was cooled with an N2 balloon. When the oil bath reached 25 °C, compound 1 (1.0 g, 2.17 mmol) was added to the flask in one portion and the flask was capped with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 24 h, poured into 50 mL of ice water, stirred for 30 min and the product was collected. The wet cake was washed with water (2 × 10 mL) and hexane (10 mL) and dried in a vacuum oven at 55 °C to give V as a yellow solid (0.89 g, 95% yield, HPLC purity 92.9%). 19 19F NMR (376 MHz, DMSO-d6): δ -83.3 (d, J = 26.7 Hz), -133.7 (d, J = 26.7 Hz). Also contains 2.1% of the 3,5,6-trifluoro byproduct.

[0134] Example 3i . Preparation of difluorophthalimide V (Z = CO2CH2Ph)

[0135]

[0136] CsF (1.15 g, 7.58 mmol) was added to a 50 mL RBF equipped with a stir bar and a distillation apparatus. Then 25 mL of dimethyl sulfoxide (DMSO) was added. The flask was immersed halfway into an oil bath. A vacuum (ca. 1 mm Hg) was connected to the distillation apparatus. Approximately 10 mL of DMSO was distilled off. The distillation apparatus was removed and the system was cooled with a nitrogen balloon. Compound IV (1.0 g, 2.17 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 24 h, poured into 50 mL of ice water, stirred for 30 min and the product was collected. The wet cake was washed with water (2 × 10 mL) and hexane (10 mL) and dried in a vacuum oven at 55 °C to afford compound V as a beige solid (0.86 g, 93% yield, HPLC purity 88.4%). 1 1H NMR (400 MHz, DMSO-d6): δ 8.10 - 8.18 (2H, m), 8.00 - 8.06 (2H, m), 7.45 (2H, m), 7.30 - 7.42 (3H, m), 5.42 (2H, s). 1919F NMR (376 MHz, DMSO-d6): δ -83.2 (d, J = 26.7 Hz), -133.0 (d, J = 26.7 Hz). It also contains 0.7% of the 6-monofluoro by-product and 7.6% of the 3,5,6-trifluoro by-product.

[0137] Example 4a . Preparation of 4-amino-3,6-dichloro-5-fluoropicolinic acid

[0138]

[0139] Compound V (Z = CO2Me; 5.0 g, 14.2 mmol) was suspended in a solution of HCl in acetic acid (2 M, 35.5 mL, 71 mmol, 5.0 eq) in a 450 mL sealed flask. The mixture was stirred overnight at 110 °C (oil bath) and then cooled to 5 °C. Aqueous HCl solution (12 N, 10 mL) was slowly added to the flask, the flask was sealed again, and placed in an 110 °C oil bath overnight. The resulting mixture was cooled to 5 °C and filtered. The collected solid was suspended in 100 mL of 2 N aqueous HCl solution, stirred at 110 °C for 60 min, and filtered. The filtered solid was washed with hexane and dried to afford Compound II-Cl as an off-white solid (1.88 g, 51% yield). HPLC purity: 97.1%. Mp: 211.0 °C - 212.7 °C; 1 1H NMR (d6-DMSO) δ 13.81 (broad s, 1H), 7.21 (broad s, 2H). 19 19F NMR (d6-DMSO) δ -137.05.

[0140] Example 4b . Preparation of 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid

[0141]

[0142] A mixture of Compound V (3.92 g, 11.11 mmol), water (2 mL, 111.0 mmol, 10 eq), and anhydrous HBr in AcOH (5.7 M, 78 mL, 444.6 mmol, 40 eq) in a 500 mL sealed flask was heated at 110 °C for 18 h. Then the reaction mixture was cooled to 0 °C and quenched with water (400 mL). The resulting suspension was stirred at 0 °C for 30 min, filtered, and the collected solid was washed with water (2 × 100 mL) and hexane (3 × 100 mL) to afford Compound II-Br as a beige solid (2.08 g, 54% yield). HPLC purity: 96.5%. Mp: 211.3 °C - 212.5 °C; 11H NMR (d6-DMSO) δ 13.72 (broad s, 1H), 7.16 (broad s, 2H). 19 19F NMR (d6-DMSO) δ -130.28.

[0143] Example 4c . Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinic Acid

[0144]

[0145] In a 1 L Hastelloy C276 reactor, compound V (50 g, 0.142 mol, 1.0 mol equivalent) was suspended in water (8.93 g, 0.496 mol, 3.5 mol equivalent), and then HBr (57.45 g, 0.71 mol, 5 mol equivalent) in acetic acid (116.6 g) was added. The reactor was heated to 110 °C with stirring and maintained at 110 °C for 8 h. Then the reactor was cooled to 60 °C and filtered. The wet filter cake was washed with water (2 × 150 mL) and dried to afford compound II-Br as an off-white solid (42.6 g, 90% yield, 90% purity).

[0146] Example 4d . Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinic Acid

[0147]

[0148] In a 1 L Hastelloy C276 reactor, compound V (Z = CO2-i-Pr; 50 g, 0.13 mol, 1.0 mol equivalent) was suspended in water (8.25 g, 0.46 mol, 3.5 mol equivalent), and then a solution of HBr (53.0 g, 0.65 mol, 5 mol equivalent) in acetic acid (107.6 g) was added. The reactor was heated to 110 °C with stirring and maintained at 110 °C for 8 h. Then the reactor was cooled to 60 °C and filtered. The wet filter cake was washed with water (2 × 150 mL) and dried to afford compound II-Br as an off-white solid (39.3 g, 90% yield). HPLC purity was determined to be 90%.

[0149] Example 4e . Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinic Acid

[0150]

[0151] In a 1 L Hastelloy C276 reactor, compound V (Z = CO2Me, Y = H; 50 g, 0.142 mol, 1.0 mol equivalent) was suspended in a mixture of water (8.93 g, 0.496 mol, 3.5 mol equivalents) and a solution of HBr (57.45 g, 0.71 mol, 5 mol equivalents) in acetic acid (116.6 g). The reactor was heated to 110 °C with stirring, maintained at this temperature for 8 h, and then cooled to 60 °C and filtered. The filtered wet cake was reslurried in 50 wt% aqueous methanol (150 g) at 60 °C for 1 h and filtered. The wet cake was dried to afford compound II-Br as an off-white solid (33.72 g, 87.6% yield). The HPLC purity of the isolated product was determined to be 99.1%.

[0152] Example 4f . Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinic Acid

[0153]

[0154] In a 1 L Hastelloy C276 reactor, compound V (Z = CO2iPr, Y = H; 50 g, 0.13 mol, 1.0 mol equivalent) was suspended in a mixture of water (8.25 g, 0.46 mol, 3.5 mol equivalents) and a solution of HBr (53.0 g, 0.65 mol, 5 mol equivalents) in acetic acid (107.6 g). The reactor was heated to 110 °C with stirring, maintained at this temperature for 8 h, and then cooled to 60 °C and filtered. The filtered wet cake was reslurried in 50 wt% aqueous methanol (150 g) at 60 °C for 1 h and filtered. The wet cake was dried to afford compound II-Br as an off-white solid (31.42 g, 88.2% yield). The HPLC purity of the isolated product was determined to be 99.0%.

[0155] Example 4g . Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinic Acid

[0156]

[0157] Step 1:

[0158] Compound V (5.0 g, 14.18 mmol, 1 equiv) and HBr in AcOH (5.7 M, 25 mL, 141.8 mmol, 10 equiv) were charged into a Chemglass pressure vessel (75 mL) equipped with a magnetic stirrer. The flask was sealed with a PTFE cap and heated at 50 °C for 24 h. The reaction mixture was cooled to 0 °C and quenched with water (50 mL). The suspension was stirred at room temperature for 30 min, filtered, and the solid was washed with water (2 × 30 mL) and dried.

[0159] Step 2:

[0160] 40 mL of H2SO4 / H2O (2:1 v / v) was added to the crude mixture. The mixture was stirred at 110 °C for 24 h, cooled to 0 °C, and quenched with water (200 mL). The suspension was stirred at room temperature for 30 min and filtered. The solid was suspended in 200 mL of water, heated at 110 °C for 1 h, the hot suspension was filtered, and dried to obtain Compound II-Br (2.67 g, 70% yield, 2 steps). HPLC purity: 90.3%.

[0161] Example 4h . Preparation of 4-Amino-3,6-dichloro-5-fluoropicolinic Acid

[0162]

[0163] Step 1:

[0164] Compound V (2.5 g, 7.1 mmol, 1.0 equiv) was suspended in HCl in HAc (2 M, freshly made in the laboratory and bubbled with dry HCl, 17.5 mL, 35 mmol, 5.0 equiv) in a 75 mL glass-sealed flask. The mixture was stirred in an oil bath at 90 °C for 19 h. The reaction mixture was cooled to 5 °C, the flask was carefully opened, poured into 60 mL of ice water, stirred for 30 min, and filtered. The white solid was 4.5 g (wet) and used without further purification in the next reaction.

[0165] Step 2:

[0166] 20 mL of H2SO4 / H2O (2:1 v / v) was added to the crude mixture. The mixture was stirred at 110 °C for 24 h, cooled to 0 °C, and quenched with water (100 mL). The suspension was stirred at room temperature for 30 min and filtered. The solid was suspended in 100 mL of water, heated at 110 °C for 1 h, the hot suspension was filtered, and dried to obtain Compound II-Cl (1.10 g, 60% yield, 2 steps). HPLC purity: 91.4%.

[0167] Example 5a. Preparation of Benzyl 4-Amino-6-bromo-3-chloro-5-fluoropicolinate

[0168]

[0169] Charge a 125 mL three-necked flask equipped with a magnetic stirrer, a cold water condenser, a thermocouple, and a nitrogen blanket with 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid (5.0 g, 18.56 mmol) and dimethyl sulfoxide (20 mL). Stir the mixture and add powdered K2CO3 (2.82 g, 20.41 mmol, 1.1 eq) in portions over 10 min (a slight exotherm was observed with the temperature rising from 20 °C to 22.5 °C). After stirring the mixture at ambient temperature for 30 min, add benzyl chloride (2.59 g, 20.41 mmol, 1.1 eq) in one portion. Stir the resulting mixture at ambient temperature for 15 min, at 40 °C for 5 h, and at 50 °C for 2 h. Then, cool the reaction mixture to ambient temperature, add water (75 mL) and stir the resulting mixture for 30 min. Filter the solid present, wash with water (20 mL), suction dry, and dry overnight in a vacuum oven at 50 °C to give the benzyl ester, 6.5 g (97% yield). 1 1H-NMR (500 HMz / CDCl3) δ 7.44 (m, 2H), 7.35 (m, 3H), 5.40 (s, 2H), 4.98 (s, br, 2H). 19 19F-NMR δ -129.16.

[0170] Example 5b . Preparation of Benzyl 4-Amino-6-bromo-3-chloro-5-fluoropicolinate

[0171]

[0172] In a 250-mL three-necked flask equipped with a magnetic stirrer, a cold water condenser, a thermocouple, and a nitrogen blanket, a sample of 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid (12.87 g, as determined by 182 wt% purity estimated by \(^1\)H NMR, 39.17 mmol, containing 18 wt% (13.94 mmol) of phthalic acid) was dissolved in DMSO (100 mL). Powdery K\(_2\)CO\(_3\) (9.95 g, 72 mmol) was added in portions over 10 min, resulting in a slightly exothermic reaction with the temperature rising from 20 °C to 25 °C. The mixture was stirred at ambient temperature for 30 min, then benzyl bromide (8.00 g, 46.8 mmol) was added slowly over 10 min while maintaining the temperature below 25 °C with a cold water bath. The resulting mixture was stirred at ambient temperature for 4 h, then poured into 300 mL of cold water. The resulting slurry was stirred for 15 min, filtered and washed with 100 mL of water. After suction drying, the crude product was washed with hexane (100 mL) and dried in vacuo at 45 °C overnight to afford 13.40 g (95% yield) of the benzyl ester.

[0173] Example 5c . Preparation of benzyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate

[0174]

[0175] 4-Amino-6-bromo-3-chloro-5-fluoropicolinic acid (3.00 g, 11.13 mmol), benzyl alcohol (11.48 g, 10 equiv), toluene, and p-toluenesulfonic acid monohydrate (p-TSA, 212 mg, 0.1 equiv) were added to a three-necked flask equipped with a stir bar, heating mantle, and a Dean-Stark trap with condenser. The mixture was heated at 80 °C and slowly brought to a vacuum of 30 mmHg to remove the water generated in situ. After heating at 80 °C for 10 h, the reaction mixture was cooled to ambient temperature. Cyclohexane (50 mL) was added dropwise and the resulting slurry was stirred for 2 h, cooled to 10 °C, filtered and the wet cake was washed with cyclohexane (10 mL). The wet cake was then washed with water (20 mL), suction dried, rinsed with cyclohexane (5 mL), and dried under reduced pressure in a vacuum oven at 45 °C to afford 3.29 g (82.3% yield) of the benzyl ester.

[0176] Example 5d . Preparation of cyanomethyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate

[0177]

[0178] 4-Amino-6-bromo-3-chloro-5-fluoropicolinic acid (2.0 g, 7.42 mmol) and acetone (30 mL) were charged into a 125 mL round-bottom flask equipped with a magnetic stir bar. Bromoacetonitrile (1.034 mL, 14.84 mmol) was added, followed by dropwise addition of triethylamine (4.14 mL, 29.7 mmol). A white precipitate formed and additional acetone (10 mL) was added. After 25.5 h, additional triethylamine (1.035 mL, 7.42 mmol), bromoacetonitrile (0.517 mL, 7.42 mmol) and acetone (10 mL) were added. The reaction mixture was stirred for an additional 22.5 h and then the volatiles were removed under reduced pressure. The crude material was resuspended in EtOAc and washed with water. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid cyanomethyl ester (1.365 g, 4.42 mmol) as an off-white solid in 60% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.34 (s, 2H), 5.27 (s, 2H). 19 19F NMR (564 MHz, DMSO-d6): δ -127.73.

[0179] The compositions and methods of the claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of several aspects of the claims, and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods, in addition to those shown and described herein, are also intended to fall within the scope of the appended claims. Further, although only certain representative composition materials and method steps are specifically described herein, other combinations of the composition materials and method steps are also intended to fall within the scope of the appended claims even if not specifically recited. Accordingly, combinations of steps, elements, components, or ingredients may be expressly recited herein; however, other combinations of steps, elements, components, and ingredients are included even if not expressly stated. The term "comprising," and variations thereof, as used herein, is used synonymously with the term "including," and variations thereof, and is an open-ended, non-limiting term. Although the terms "comprising" and "including" have been used to describe various embodiments herein, the terms "consisting essentially of" and "consisting of" may be used in place of "comprising" and "including" to provide more specific embodiments of the invention and are also disclosed.

Claims

1. A compound of the following formula: wherein Z is COOR or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl; and each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4.

2. A method for preparing a compound of formula II, or its HCl salt or HBr salt: wherein X is Cl or Br; The method comprises the following steps: a) reacting a compound of formula III with a phthaloyl halide of formula IIIa or phthalic anhydride of formula IIIb, and optionally a base; wherein Z is COOR or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl, and wherein each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, wherein n is 1, 2, 3, or 4; and W is Cl or Br; b) separating the compound of formula IV from step a); wherein Z is COOR or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl, and wherein each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4; c) reacting the separated compound of formula IV from step b) with a fluorinated compound or a fluorinated mixture of compounds; d) separating the compound of formula V from step c); where Z is COOR or CN, and R is C1-C 12 alkyl or C6-C 12 arylalkyl, and wherein each Y substituent is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or nitro, where n is 1, 2, 3, or 4; e) reacting the separated compound of formula V from step d) with HCl or HBr and water; and f) separating the compound of formula II from step e).

3. The method according to claim 2, wherein Before step a), there is step a'), wherein step a') comprises preparing a compound of formula III where R is H by reacting a compound of formula III where R is H with a C1-C 12 alkyl or C6-C 12 arylalkyl alcohol and an acid, where Z is COOR and R is C1-C 12 alkyl or C6-C 12 arylalkyl.

4. The method according to claim 2, wherein, Step a) further comprises a solvent selected from: acetonitrile, toluene, N,N-dimethylformamide, propionitrile, benzonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, cyclopentyl methyl ether, monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether, dipropylene glycol ether, or methyl isobutyl ketone, or a mixture thereof.

5. The method according to claim 2, wherein, Step a) further comprises a solvent selected from: acetonitrile, toluene, N,N-dimethylformamide, cyclopentyl methyl ether, or methyl isobutyl ketone, or a mixture thereof.

6. The method according to claim 2, wherein, Step a) further comprises the solvent toluene.

7. The method according to claim 2, wherein The base in step a) is a trialkylamine compound.

8. The method according to claim 2, wherein The base in step a) is triethylamine.

9. The method according to claim 2, wherein, The reaction of step a) is maintained at a temperature of 25°C to 100°C.

10. The method according to claim 2, wherein, The reaction of step a) is maintained at a temperature of 25°C to 70°C.

11. The method according to claim 2, wherein, The fluorinated compound or the fluorinated mixture of compounds in step c) is potassium fluoride, cesium fluoride, tetramethylammonium fluoride, potassium fluoride / tetramethylammonium chloride, cesium fluoride / tetramethylammonium chloride, or a mixture thereof.

12. The method according to claim 2, wherein The fluorinated compound in step c) is potassium fluoride.

13. The method according to claim 2, wherein, Step c) further comprises an aprotic solvent.

14. The method according to claim 13, wherein, The aprotic solvent is selected from: acetonitrile, propionitrile, benzonitrile, dimethyl sulfoxide, N,N-dimethylformamide, sulfolane, dimethylacetamide, 1,1-dimethyl-2-imidazolidinone, N,N'-dimethylpropyleneurea, N-methylpyrrolidone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether, or dipropylene glycol ether, or a mixture thereof.

15. The method according to claim 2, wherein, The reaction of step c) is maintained at a temperature of 15°C to 150°C.

16. The method according to claim 2, wherein, The reaction of step c) is maintained at a temperature of 25°C to 110°C.

17. The method according to claim 2, wherein The reaction of step e) further comprises acetic acid.

18. The method according to claim 2, wherein, Step b) includes separating the compound of formula IV by filtration or centrifugation, and / or step d) includes separating the compound of formula V by filtration or centrifugation, and / or step f) includes separating the compound of formula II by filtration or centrifugation.

19. The method according to claim 2, which further comprises esterifying the compound of formula II by combining the compound of formula II from step f) with an alcohol and an acid, or with an alkylating agent and a base to provide a compound of formula VI, where X = Cl or Br, and R 1 is C1-C 12 alkyl, C6-C 12 arylalkyl, C3-C 12 alkynyl or C1-C3 alkyl substituted with CN.

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