PROCESSES FOR THE PREPARATION OF 1,2,4-OXADIAZOLE BENZOIC ACIDS

Abstract

Processes for the preparation of compounds useful for the treatment, prevention, or management of diseases associated with a reverse mutation. More specifically, processes for the synthesis of 1,2,4-oxadiazoles. In particular, processes useful for the preparation of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid.

Description

27093 PROCESSES FOR THE PREPARATION OF 1,2,4-OXADIAZOLE BENZOIC ACIDS 1. FIELD OF THE INVENTION This paper provides processes for the preparation of compounds useful for the treatment, prevention, or management of diseases associated with a reverse mutation. More specifically, this paper provides processes for the synthesis of 1,2,4-oxadiazoles. In particular, this paper provides processes useful for the preparation of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid. 2. BACKGROUND U.S. Patent No. 6,992,096 B2, issued January 31, 2006, describes 1,2,4-oxadiazole compounds useful for the treatment, prevention, or management of diseases that are amended by modulating premature translation termination or reverse-mediated mRNA decay, which is incorporated herein by reference in its entirety. One such compound is 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid. U.S. Patent No. 6,992,096 B2, issued January 31, 2006 (see column 57, line 40, Scheme B and Example 2), describes existing solution-phase methods for synthesizing 1,2,4-oxadiazole benzoic acids. Specifically, these methods comprise multiple reaction steps, each followed by the isolation of the desired intermediate. While these methods are useful and allow the preparation of 1,2,4-oxadiazolebenzoic acids, alterations can be made that may result in a more efficient synthesis. In particular, synthetic processes with fewer isolation steps and that may involve the use of fewer solvents can be more efficient and less expensive. The citation of any reference in Section 2 of this application should not be construed as an acknowledgment that such reference constitutes prior art to this application. 3. SUMMARY This paper provides useful processes for the production of 1,2,4-oxadiazole benzoic acids that are efficient, cost-effective and easily scalable with commercial reagents. 950721 of 26 In one embodiment, useful processes are provided herein for preparing a 1,2,4-oxadiazole benzoic acid comprising the steps of: (1) reacting a cyanobenzoate ester with hydroxylamine; (2) acylation with halobenzoyl chloride; (3) condensation; and (4) hydrolysis of the benzoate ester. In one particular embodiment, steps (1)-(3) are carried out in the same organic solvent. In another particular embodiment, steps (1)-(3) are carried out in a single organic solvent. In another embodiment, steps (1)-(4) are carried out in the same organic solvent. In another embodiment, steps (1)-(4) are carried out in a single organic solvent. In another embodiment, steps (1)-(3) are carried out in the same aqueous solvent. In another embodiment, steps (1)-(3) are carried out in a single aqueous solvent. In another embodiment, steps (1)-(4) are carried out in the same aqueous solvent. In another embodiment, steps (1)-(4) are carried out in a single aqueous solvent. In another embodiment, steps (1)-(3) are carried out without isolating an intermediary. In another embodiment, steps (1)-(4) are carried out without isolating an intermediary. In another embodiment, steps (1)-(4) are followed by a micronization step. In another embodiment, the processes provided herein are useful for preparing pharmaceutically acceptable 1,2,4-oxadiazolebenzoic acids and salts, hydrates, solvates, or polymorphs thereof. In another embodiment, the processes provided herein are useful for preparing pharmaceutically acceptable 1,2,4-oxadiazolebenzoic acids and salts, hydrates, solvates, or polymorphs thereof, useful for the treatment, prevention, or management of diseases or conditions associated with a reverse mutation. In another embodiment, the process provided herein is useful for preparing 1,2,4-oxadiazolebenzoic acids and salts, hydrates, solvates, or polymorphs thereof. 950721 of 26 pharmaceutically acceptable, useful for the treatment, prevention or management of genetic disorders or diseases. 4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Terminology As used herein and unless otherwise indicated, the term “halo”, “halogen” or similar terms mean -F, -Cl, -Br, or -I. Unless otherwise stated, the compounds described herein, including intermediates useful for the preparation of compounds containing reactive functional groups (such as, but not limited to, carboxy, hydroxy, and amino groups), also include protected derivatives thereof. “Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as blocking groups). Suitable protecting groups for carboxy groups include benzyl, tert-butyl, and the like. Suitable protecting groups for amino groups include acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for hydroxy groups include benzyl and the like. Other suitable protecting groups are well known to those skilled in the art.The selection and use of protection groups and the reaction conditions for installing and removing protection groups are described in TW Green, “Protective Groups in Organic Synthesis”, Third Ed., Wiley, New York, 1999, which is incorporated herein by reference in its entirety. As used herein and unless otherwise stated, a composition that is “substantially free” of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound. As used herein and unless otherwise indicated, the term “process(es)” refers to the methods disclosed herein that are useful for preparing a 1,2,4-oxadiazole benzoic acid compound. As used herein and unless otherwise indicated, the terms “add” or “add” or similar terms mean bringing one reactant, reagent, solvent, catalyst, or the like into contact with another reactant, reagent, solvent, catalyst, or the like. Reactants, reagents, solvents, catalysts, or the like may be added individually, simultaneously, or separately, and 950721 of 26 can be added in any order. They can be added in the presence or absence of heat and can optionally be added in an inert atmosphere. As used herein and unless otherwise stated, a reaction that is “substantially complete” or carried to be “substantially complete” means that the reaction contains more than about 80% percent yield, more than about 90% percent yield, more than about 95% percent yield, or more than about 97% percent yield of the desired product. As used herein and unless otherwise stated, the term “without isolation” means that the reaction mixture resulting from one step is carried to a subsequent step without isolating the desired product. In certain embodiments, carrying out multiple reaction steps “without isolation” includes processes comprising transferring the reaction mixture resulting from one step to a new reaction vessel before commencing the next reaction. As used herein and unless otherwise stated, the term “condensation” means a chemical reaction in which two chemical parts react and covalently bond to each other with the consequent loss of a small molecule, e.g., water. As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is safe and effective for use in a patient. By way of example, pharmaceutically acceptable salts are those prepared using metals, inorganic bases, or organic bases. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, and zinc salts. A suitable organic base salt is triethylamine. As used herein and unless otherwise indicated, the term “hydrate” means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein and unless otherwise indicated, the term “solvate” means a solvate formed from the association of one or more solvent molecules with a compound of the present invention. The term “solvate” includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like). As used herein and unless otherwise indicated, the 950721 of 26 The term “polymorph” means solid crystalline forms of a compound of the present invention or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and / or spectroscopic properties. As used herein and unless otherwise indicated, the phrase “diseases or disorders associated with a backswing mutation” means diseases or disorders that would not produce, prolong, or cause symptoms if the backswing mutation were not present. As used herein and unless otherwise indicated, the terms “treat”, “treatment”, “treating”, or similar terms refer to the reduction or improvement of the progression, severity and / or duration of a disease or disorder, or the improvement of one or more symptoms (preferably one or more discernible symptoms) of a disease or condition resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as 1,2,4-oxadiazolebenzoic acid). As used herein and unless otherwise indicated, the term “prevent”, “prevention”, “preventing”, or the like refers to the reduction of the risk of contracting or developing a particular disease or disorder, or the reduction or inhibition of the recurrence, onset, or development of one or more symptoms of a particular disease or disorder. If there is a discrepancy between a represented structure and a name given to that structure, the represented structure should take precedence. Furthermore, if the stoichiometry of a structure or a portion thereof is not indicated, for example, in bold or dotted lines, it should be understood that the structure or portion thereof encompasses all of its stereoisomers. The embodiments provided herein will be more fully understood after the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments. 4.2 Processes This paper provides cost-effective and efficient processes useful for the production of 1,2,4-oxadiazole benzoic acids. In one embodiment, the processes comprise the use of m-cyanobenzoic acid methyl ester. In another embodiment, the processes involve the use of fluorobenzoyl chloride. In another embodiment, the processes involve the use of chloride or 950721 of 26 fluorobenzoyl. In another embodiment, steps (1)-(3) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between the steps. In another embodiment, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(3). In another embodiment, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(4). In another embodiment, steps (1)-(3) or steps (1)-(4) are carried out in a single aqueous solvent or in the same aqueous solvent and without the isolation of an intermediate between steps (1)-(3) or, in another embodiment, between steps (1)-(4). In one embodiment, the solvent used in the processes described herein is a polar solvent such as tetrahydrofuran, dioxane, isobutyl acetate, isopropyl acetate, and ethyl acetate. In another embodiment, the solvent used in the processes described herein is an alcoholic solvent, such as methanol, ethanol, isopropanol, isobutanol, propanol, butanol, and tert-amyl alcohol. In another embodiment, the solvent used in the processes described herein is tert-butanol. In one embodiment, the processes described herein are useful for producing a batch size of 1,2,4-oxadiazole benzoic acid of about 500 mg or more, about 1 kg or more, about 5 kg or more, about 10 kg or more, about 25 kg or more, about 50 kg or more, about 75 kg or more, about 100 kg or more, about 125 kg or more, about 150 kg. or more, around 175 Kg. or more, around 200 Kg. or more, around 225 Kg. or more, around 250 kg. or more, around 275 kg. or more, around 300 kg. or more, around 325 kg. or more, around 350 kg. or more, around 375 kg. or more, around 400 Kg. or more, around 425 Kg. or more, around 450 Kg. or more, around 475 Kg. or more, or around 500 Kg., or around 600 Kg., or around 700 Kg., or around 800 Kg., or around 900 Kg., or around 1000 Kg. or more. In one embodiment, 1,2,4-oxadiazolebenzoic acid is produced 950721 of 26 in one of the above-described batch sizes in an overall yield of about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, or about 95% or more. In one embodiment, steps (1)-(4) are followed by a micronization step. In a particular embodiment, 1,2,4-oxadiazolebenzoic acid has a particle size distribution of D(v, 0.1): about 0.5 pm to about 1.0 pm; D(v, 0.5): about 1.5 pm to about 5.0 pm; and D(v, 0.9): about 5.5 pm to about 10.0 pm. In one embodiment, useful processes are provided herein for preparing a compound of formula I: or pharmaceutically acceptable salts, hydrates, clathrates, prodrugs, polymorphs, stereoisomers thereof, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, wherein: Z is a substituted or unsubstituted ring, a substituted or unsubstituted heteroring ring, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted ring alkyl; R1 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted ring, a substituted or unsubstituted heteroring ring, -(CH2CH2O)nR6 or any biohydrolyzable group; R2R3R4R5 and R6 are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted anyl group, a substituted or unsubstituted heteroanyl group, alkoxy, anyloxy, heteroalyloxy, halogen, CF3, OCF3, OCHF2, CN, COOH, COOR7, SO2R7, NO2, NH2oN(R7)2; 950721 of 26 each case of R7 is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an alkoxy, aryloxy, heteroaryloxy, halogen or CF3; and n is an integer from 1 to 7, comprising the steps of: (1) reacting an optionally substituted cyanobenzoate ester with hydroxylamine; (2) acylation with a chloride acid; (3) condensation; and (4) optional hydrolysis of benzoate ester. In one embodiment, steps (1)-(3) are carried out in a single organic solvent. In another embodiment, steps (1)-(3) are carried out in the same organic solvent. In another embodiment, steps (1)-(4) are carried out in a single organic solvent. In another embodiment, steps (1)-(4) are carried out in the same organic solvent. In another embodiment, steps (1)-(3) are carried out without the isolation of an intermediary. In another embodiment, steps (1)-(4) are carried out without the isolation of an intermediary. In another embodiment, steps (1)-(3) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between the steps. In another embodiment, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(3). In another embodiment, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(4). In one embodiment, the solvent used in the processes described herein is tert-butanol. 950721 of 26 In one embodiment, the processes provided herein are useful for preparing a compound of formula I having the structure of formula II: or pharmaceutically acceptable salts, hydrates, clathrates, prodrugs, polymorphs, stereoisomers thereof, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, wherein: R1 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -(CH2CH2O)nR6 or any biohydrolyzable group; X is in each case independently F, Cl, Br or I; ym is an integer from 1 to 5, comprising the stages of: (1) react a methyl ester of cyanobenzoic acid with hydroxylamine; (2) acylation with a chloride acid; (3) condensation; and (4) methyl ester hydrolysis. In one form of realization, X is F. In another realization, m is 1. In another realization, X is F and m is 1. In another embodiment, m is 1 and X is F in the ortho position In another realization, m is 1 and X is F in the goal position. In another embodiment, m is 1 and X is F in the position for. In another embodiment, R1 is H. In one embodiment, processes are provided herein for preparing compounds of formula I, including compounds having the structure of formulas II and IIa, comprising the steps described in Scheme 1: 950721 of 26 Scheme 1 wherein R1 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -(CH2CH2O)nR6, any biohydrolyzable group or any suitable blocking group known to a person skilled in the art, wherein step (4) is an optional hydrolysis step when R1 is different from H; X is in each case independently F, Cl, Br or I; ym is an integer from 1 to 5, In one embodiment of Scheme 1, X is F. In another embodiment of Scheme 1, m is 1. In another embodiment of Scheme 1, X is F and m is 1. In another embodiment, m is 1 and X is F in the ortho position In another realization, m is 1 and X is F in the goal position. In another embodiment, m is 1 and X is F in the position for. In another embodiment of Scheme 1, R1 is methyl. In another embodiment of Scheme 1, steps (1)-(3) are carried out in a single organic solvent. In another embodiment of Scheme 1, steps (1)-(3) are carried out in the same organic solvent. In another embodiment of Scheme 1, steps (1)-(4) are carried out in a single organic solvent. In another form of implementation of Scheme 1, steps (1)-(4) are carried out 950721 of 26 in the same organic solvent. In another embodiment of Scheme 1, steps (1)-(3) are carried out without the isolation of an intermediary. In another embodiment of Scheme 1, steps (1)-(4) are carried out without the isolation of an intermediary. In another embodiment of Scheme 1, steps (1)-(3) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between the steps. In another embodiment of Scheme 1, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(3). In another embodiment, steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between steps (1)-(4). In one embodiment of Scheme 1, the solvent used is tetrahydrofuran, dioxane, isobutyl acetate, isopropyl acetate, ethyl acetate, methanol, ethanol, isopropanol, isobutanol, propanol, butanol, or tert-amyl alcohol. In one particular embodiment of Scheme 1, the solvent used is tert-butanol. In one embodiment of Scheme 1, step (1) comprises reacting 3-methyl cyanobenzoic acid ester with aqueous hydroxylamine in tert-butanol. In one particular embodiment, 50% aqueous hydroxylamine is used in step (1). In another embodiment, molten tert-butanol is used in step (1). In another embodiment, aqueous hydroxylamine is added to the 3-methyl cyanobenzoic acid ester and tert-butanol at a temperature of approximately 40-45°C. In another embodiment, the reaction mixture of step (1) is stirred for 2 hours. In another embodiment of Scheme 1, step (2) comprises reacting the product of step (1) with a halobenzoyl chloride in triethylamine and tert-butanol. In one particular embodiment, the halobenzoyl chloride is fluorobenzoyl chloride, more particularly, 2-fluorobenzoyl chloride. In another embodiment, the reaction mixture of step (2) is further diluted with molten tert-butanol. In another embodiment, the reaction of step (2) is carried out at a temperature below 40°C, and in one particular embodiment, at approximately 30-35°C. In another embodiment, the reaction mixture of step (2) is stirred for at least 2 hours. In certain embodiments, it is 950721 of 26 may add additional triethylamine or halobenzoyl chloride to the reaction mixture of step (2) to complete the reaction. In another embodiment of Scheme 1, step (3) comprises refluxing the product of step (2) in tert-butanol. In one particular embodiment, step (3) comprises refluxing the product of step (2) in tert-butanol at a temperature of approximately 82°C. In another embodiment, step (3) comprises crystallizing the product from a closed ring by adding water at approximately 60-65°C. In another embodiment, the resulting slurry is cooled to room temperature, filtered, rinsed with tert-butanol / water (50 / 50 v / v), and vacuum dried. In another embodiment of Scheme 1, step (4) comprises hydrolyzing the methyl ester of the product of step (3) into the corresponding sodium salt by adding aqueous sodium hydroxide to tert-butanol. In another embodiment, the hydrolysis of the methyl ester of the product of step (3) is carried out in aqueous sodium hydroxide and tert-butanol at a temperature of approximately 68-72°C. In a further embodiment, step (4) comprises converting the sodium salt to the free acid by filtering a hot sodium salt solution through an in-line filter (e.g., a 5-micron in-line filter) and acidifying it with sulfuric acid to approximately pH 1-3.In yet another embodiment, step (4) comprises converting the sodium salt into free acid by filtering a hot sodium salt solution through an in-line filter (e.g., a 1-micron in-line filter) and acidifying it with hydrochloric acid to approximately pH 1–3, then stirring at 70°C for about 1 hour. In a further embodiment, the free acid is isolated using a Rosenmund filter and rinsed with aqueous tert-butanol and water, followed by drying (e.g., with a paddle dryer or a double-cone dryer) or centrifugation. The progress of the reactions described herein can be controlled by any method known to those skilled in the art, including, but not limited to, thin layer chromatography (TLC), high performance liquid chromatography (HPLC), spectroscopic methods (e.g., 1H-NMR, 13C-NMR, IR, Raman, MS). In one embodiment, processes are provided herein for preparing 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid, comprising the steps described in Scheme 2: 950721 of 26 Scheme 2 In one embodiment, useful processes are provided herein for preparing a compound of formula II, comprising performing the following steps: (1) react a methyl ester of cyanobenzoic acid: CO2Me with hydroxylamine to obtain: followed by (2) acylation with a halobenzoyl chloride, to obtain: 950721 of 26 CO2Me followed by (3) condensation to obtain: CO£Mé In another embodiment, the processes provided herein further comprise (4) hydrolysis of the methyl ester, to obtain: CO2 In one form of realization, X is F. In another realization, m is 1. In another realization, X is F and m is 1. In another embodiment, m is 1 and X is F in the ortho position In another realization, m is 1 and X is F in the goal position. In another embodiment, m is 1 and X is F in the position for. In one embodiment, steps (1)-(3) are carried out in a single organic solvent. In another embodiment, steps (1)-(3) are carried out in the same 950721 of 26 organic solvent. In another embodiment, steps (1)-(4) are carried out in a single organic solvent. In another embodiment, steps (1)-(4) are carried out in the same organic solvent. In another embodiment, steps (1)-(3) or steps (1)-(4) are carried out in tert-butanol. In another embodiment, steps (1)-(3) are carried out without the isolation of an intermediary. In another embodiment, steps (1)-(4) are carried out without the isolation of an intermediary. In another embodiment, steps (1)-(3) or steps (1)-(4) are carried out in a single organic solvent or in the same organic solvent and without the isolation of an intermediate between the steps. In another embodiment, the solvent used is tetrahydrofuran, dioxane, isobutyl acetate, isopropyl acetate, ethyl acetate, methanol, ethanol, isopropanol, isobutanol, propanol, butanol, or tert-amyl alcohol. In one particular embodiment, the solvent used is tert-butanol. In one embodiment, the compound of formula II is 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid. In another embodiment, the synthesis is carried out in a single reaction vessel (i.e., “single pot” synthesis). In one embodiment, useful processes are provided herein for preparing a compound of formula II, comprising carrying out the following steps in a single reaction vessel: react with cyanobenzoic acid: with hydroxylamine, to obtain: 950721 of 26 followed by acylation with halobenzoyl chloride, to obtain: followed by reflux, to obtain: In one embodiment, the compound is 3-[5-(2-fluorophenyl)[1,2,4]oxadiazol-3-yl]benzoic acid. The embodiments described herein are further illustrated by the examples set forth below, which should not be interpreted as limiting the scope of the embodiments described herein. The starting materials and reagents useful in the processes described herein may be obtained from commercial sources or may be prepared using methods known to persons skilled in the art. 5. EXAMPLES Methyl 3-r5-(2-fluorophenyl)-ri,2,4)oxadiazol-3-yl1-benzoate Lot 1 950721 of 26 3-Methyl cyanobenzoate (105 kg) and molten tert-butanol were loaded into a dry reactor. 50% aqueous hydroxylamine (43 L, 47.4 kg) was added to the clear solution of 3-Methyl cyanobenzoate in molten tert-butanol under an inert atmosphere for 2 hours and 48 minutes. The maximum batch temperature during the addition of the 50% aqueous hydroxylamine was approximately 43°C. The addition rate of the 50% aqueous hydroxylamine varied from approximately 9 L per hour at the beginning of the addition to approximately 30 L per hour. The batch temperature was maintained by altering the reactor liner's setpoint. Specifically, the setpoint was changed from approximately 40.5°C at the beginning of the addition to approximately 29.6°C as the addition rate increased. The reaction was considered complete (i.e., less than 0.5% ester) after stirring for about 4 hours at about 40-45°C. The batch was transferred to a dry reactor and pushed with approximately 10 L of molten tert-butanol. The liner setpoint was lowered from approximately 33°C when the batch entered the dry reactor to approximately 27°C after the transfer was completed. Partial crystallization of the batch was observed, but it did not negatively affect batch stirring. The batch was then cooled to approximately 34.4°C, and triethylamine (72.6 kg, 100 L) was charged into the reactor. The liner temperature setpoint was raised from approximately 20.4°C to approximately 31.0°C to maintain the batch temperature within a range of approximately 30–35°C. After an in-line rinse with molten tert-butanol (10 L), the batch was charged with 2-fluorobenzoyl chloride (113.7 kg, 86.0 L). The addition rate during the first third of the charge was approximately 25 L per hour.During this period, the lining inlet temperature was lowered to approximately 15°C, and the batch temperature remained at approximately 34.6°C. The addition was completed after approximately 5.5 hours. The maximum batch temperature during the addition was approximately 38.8°C. The addition rate was reduced toward the end of the addition, such that the last 27 liters of 2-fluorobenzoyl were added at approximately 11 L per hour. The reaction was considered complete (i.e., less than approximately 0.5% methyl 3-amidinobenzoate) after stirring for approximately 2 hours at 30–35°C. The batch was then heated to reflux temperature (around 82°C) for approximately 1 hour and 42 minutes and stirred for a further 18 hours. During stirring, some of the product crystallized into a slurry. The slurry was cooled to around 40°C to allow for sampling, and complete crystallization occurred during this period. The batch was then heated again to 17 The slurry was heated to reflux temperature 950721 and stirred for approximately 1 hour and 50 minutes. The batch was then cooled for 2 hours to approximately 69°C, and 630 L of purified water was slowly added over approximately 4 hours and 15 minutes while maintaining the batch temperature between 66 and 69°C. The slurry was cooled to approximately 22.4°C for approximately 3 hours and 14 minutes and transferred to two 200 L ceramic filters lined with 25-30 μm polypropylene filter cloths. The transfer of the material from the vessel to the filters was completed after 55 minutes. The filter cakes were rinsed with 210 L of aqueous 50% tert-butanol, allowing the cakes to soak in the bath for approximately 10 minutes. The cakes were then dried in a vacuum for about 5-10 minutes.Purified water was applied to the filter cakes as a second rinse (158 L per cake) to remove residual tert-butanol and triethylammonium chloride salt. Liquors were removed after vacuum drying for approximately 5 minutes. The cakes were then vacuum dried for approximately 2 additional hours and subsequently sampled using liquid chromatography. The purity of the cakes was determined to be approximately 99.6% by liquid chromatography. After drying the cakes in a vacuum for approximately 8 hours and 25 minutes, the wet cake (207.4 kg) was transferred to an air oven. The wet cake was dried in the air oven at approximately 50–55°C for 52 hours. The overall yield of the insulated product was approximately 89.9% (174.65 kg), which can be adjusted to approximately 90.7% taking into account the material consumed during sampling. Lot 2 105 kg of methyl 3-cyanobenzoate and molten tert-butanol were loaded into a dry reactor. 50% aqueous hydroxylamide (47.85 kg) was then added to the dry reactor under an inert atmosphere for 3 hours and 29 minutes, while the temperature was maintained at approximately 40–45°C. The reaction was considered complete (i.e., less than 0.5% ester) after stirring for approximately 3 hours and 16 minutes at approximately 40–45°C. The batch was transferred to a dry reactor as described for Batch 1. The batch was then cooled to approximately 34.4°C, and triethylamine (72.6 kg, 100 L) was charged into the reactor. The addition was carried out over a period of approximately 45 minutes while maintaining the batch temperature at approximately 30–35°C. The inlet temperature of the liner rose from approximately 31.4°C to approximately 32.6°C during the addition. After in-line rinsing with molten tert-butanol, the batch was charged with 950721 of 26 2-fluorobenzoyl chloride (113.7 kg, 86.0 L). Chloric acid was added for approximately 3 hours and 27 minutes. After stirring for approximately 8 hours at 35°C, the reaction was deemed incomplete (i.e., more than 0.5% methyl 3-amidinobenzoate was present). Then, 1.5 wt% of the original triethylamine and 2-fluorobenzoyl chloride charges were added to the batch. Each additional charge was accompanied by an in-line rinse of tert-butanol (10 L). No additional cooling was performed during the addition of the chloride acid. The batch temperature was maintained at approximately 30–35°C, and the lining inlet temperature was maintained in the range of approximately 30.3 to approximately 33.0°C. The reaction was considered complete (i.e., less than 0.5% methyl amidinobenzoate) after stirring for about 2 hours at 30-35°C: The batch was heated to reflux temperature (approximately 83°C) for about 1 hour and 44 minutes and stirred for 18 hours. As with Batch 1, when the batch was cooled for sampling, the solids crystallized completely. The batch was heated again to reflux temperature and stirred for 1 hour and 2 minutes. It was then cooled for 2 hours and 20 minutes to approximately 69.2°C, and 630 L of purified water were slowly added over about 4 hours and 30 minutes while maintaining the batch temperature between 65.6 and 69.2°C. The slurry was cooled to around 23.4°C for about 3 hours and 30 minutes and the contents were transferred to ceramic filters as described in the case of Batch 1. The transfer of the material was completed after about 5 hours and 6 minutes.The filter cakes were rinsed with 50% aqueous tert-butanol (2 volumes per cake), allowing the cakes to soak in the bath for approximately 10 minutes before vacuum drying. Filtration was completed after about 1 hour and 40 minutes. Purified water was used for the final rinse of the cakes. Liquors were removed by vacuum drying for about 10 minutes. The cakes were then vacuum dried for an additional 2 hours and 5 minutes, and subsequently sampled using liquid chromatography. The purity of the cakes was determined by liquid chromatography to be approximately 99.5% and 99.6%, respectively. After drying the cakes in a vacuum for an additional 2 hours and 5 minutes, the wet cake (191.5 kg) was transferred to an air oven. Drying was carried out in the air oven at approximately 50–55°C for about 48 hours. The overall yield of isolated product was approximately 92.5% (179.7 kg) in Batch 3. 950721 of 26 A reaction vessel was charged with 3-cyanobenzoic acid methyl ester (52.5 kg) and molten tert-butanol (228 kg). The vessel was sealed, the batch temperature was set to 40–45°C, and the stirrer was started. The reactor was charged with 50% aqueous hydroxylamine (24 kg) in an inert atmosphere for 2 hours and 40 minutes. During the addition, the temperature was maintained at approximately 40–45°C. The reaction was completed after stirring for an additional 5 hours at approximately 42°C. The batch was cooled to 30–35°C and charged with triethylamine (36 kg) for 15 minutes. 2-Fluorobenzoyl chloride was added over a period of 2 hours and 44 minutes. During the addition, the batch temperature was maintained at approximately 30–35°C. The reaction was completed after stirring the batch for an additional 2 hours and 10 minutes at 32°C. The batch was reheated to reflux temperature (83–86°C) for approximately 50 minutes and stirred for approximately 18 hours at approximately 81°C. The batch was then cooled for 2 hours to approximately 65–70°C, and 315 L of purified water was slowly added over approximately 6 hours and 25 minutes while the batch temperature remained between 65–70°C. The slurry was cooled to approximately 22°C for approximately 2 hours and 15 minutes, and the contents were transferred to a centrifuge filter (2 batches). Filtration was completed after approximately 1 hour and 40 minutes. The filter cakes were rinsed with approximately 50% tert-butanol (90 kg per cake) for approximately 20 minutes. For the final rinse, purified water was applied to the cakes (79 kg per cake). The cakes were dried at approximately 900 rpm for about 1 hour and 5 minutes and then discharged into a drum.Using liquid chromatography, it was determined that the purity of the wet cake (91.5 Kg., LOD= 5% by weight) was 99.75% of the area. 3-[5-(2-fluorophenyl)-ri,2,4-1-oxadiazol-3-yl-1-benzoic acid] Lot 1 The reaction vessel was charged with 3-[5-(2-fluorophenyl)[1,2,4]oxadiazol-3-yl]benzoate (74.0 kg), sealed, evacuated, and purged. The setpoint of the coating was set at approximately 35°C, and the stirrer in the vessel was started. Molten tert-butanol (222 L, 3 vol.) and purified water (355 L; 4.8 vol.) were charged into the vessel. These charges were followed by the addition of 25.1 wt% aqueous sodium hydroxide solution (43.5 kg, 1.1 mol equivalent) and an in-line rinse with additional purified water (100 L, 1.35 mol). The batch temperature decreased from approximately 39.0°C to approximately 38.8°C during the addition. The batch temperature was raised to approximately 63–67°C for 1 hour and 54 minutes and then adjusted to approximately 68–72°C for approximately 30 minutes. The mixture was stirred for 20 minutes. 950721 of 26 for about 3 hours at about 68-72°C. The solution was then cooled to about 40-45°C for about 5 hours and 11 minutes. The solution was then heated again to about 68-72°C following the above procedure for 3 hours and 33 minutes. The temperature of the reaction vessel lining was set at approximately 60°C, the stirrer was started, and the hot liquor was transferred through a 1-micron filter at approximately 70°C under slight positive nitrogen pressure (1.5 to 5.6 psig). The product temperature dropped to approximately 64.3°C during the transfer, which was completed in about 45 minutes. The vessel was then charged with purified water (61 L, 0.82 vol) and its contents heated to approximately 68–72°C. The batch temperature was adjusted to approximately 69.4 °C and treated with 13.9 wt% sulfuric acid (100.7 kg, 1.15 mol equivalent) for approximately 4 hours and 18 minutes. The batch temperature was maintained at approximately 68.0–70.8 °C during the addition. Following the acid addition, an online rinse was performed with purified water (50 L, 0.68 vol.), and stirring continued at approximately 68–72 °C for an additional approximately 13 minutes. The batch was cooled linearly from approximately 69.2°C to approximately 41.2°C over approximately 4 hours and 10 minutes. The stirrer in a Rosenmund filter / dryer was raised to its highest position, and the coating point was set at approximately 40°C. The slurry was transferred into the filter / dryer in two parts. Constant nitrogen pressure (less than approximately 15 psig) was applied to the first part. The pressure was found to be in the range of approximately 23.9 to approximately 28.8 psi during the transfer, which was completed in approximately 1 hour and 5 minutes. The second part of the slurry was transferred to the top of the filter cake, and the mixture was briefly stirred to homogenize the batch. The second part was filtered using nitrogen pressure between about 26.1 and about 29.1 psi and the liquor was removed from the cake after about 3 hours.The cake was washed with hot aqueous tert-butanol solution (352kg, 5 vol) at around 38-42°C and hot 3X purified water (370L, 5 vol.) at around 65-70°C. The filter / dryer lining temperature was set at 43°C, and the product was dried under vacuum with periodic stirring for approximately 26 hours. The purity was determined to be 99.7%. The total yield of the isolated product was approximately 74.4% (52.45 kg). Lot 2 A reactor vessel was loaded with methyl 3-[5-2-fluorophenyl)-[1,2,4]oxadiazole 950721 of 26 3-yl]-benzoate (47 kg wet cake) and molten tert-butanol (111.4 kg) were mixed into the vessel. The vessel was sealed, the batch temperature was set at 30–40°C, and the stirrer was started. Purified water (51.6 kg) was then added to the vessel. Following this addition, 3.47 wt% aqueous sodium hydroxide solution (202.4 kg) was added. The batch temperature was raised to approximately 67–73°C for about 1 hour, and then the mixture was stirred for approximately 3 hours at approximately 70°C. The batch was filtered using a 1-micron polypropylene filter bag under slight positive nitrogen pressure and then transferred to a new reactor. The vessel was charged with purified water (146 kg) and the batch was heated to approximately 68–72°C. The batch was charged with 10.7% aqueous hydrochloric acid for approximately 4 hours. The batch temperature was maintained at approximately 68–72°C during the addition. The batch pH was determined to be approximately 2.2 per pH meter, and stirring was continued at approximately 70°C for approximately 1 additional hour. The batch was cooled linearly from approximately 70°C to approximately 60°C for about 2 hours. The batch at approximately 60°C was then cooled linearly from approximately 60°C to approximately 40°C for about 2 hours. The batch was stirred for a further 2 hours at 40°C, and the slurry was transferred to a centrifuge filter. Filtration was completed after about 30 minutes. The filter cakes were washed with approximately 42 wt% aqueous tert-butanol (165 kg) for about 30 minutes. Purified water (118 kg, 40°C) was applied to the cakes as a final wash. The cakes were dried at approximately 900 rpm for about 1 hour and then discarded in a drum. The moist cakes were transferred to a paddle dryer (a double-cone dryer is also suitable for this stage), and the coating temperature was set at approximately 70°C. The product was vacuum-dried at approximately 70°C with periodic stirring for about 48 hours. The purity was determined to be 99.8%. The overall yield of the isolated product was approximately 74% (68.5 kg). Lot 3 A reactor vessel was charged with methyl 3-[5,2-fluorophenyl]-[1,2,4]oxadiazol-3-yl]benzoate (10 g) and molten tert-butanol (128 mL). The batch temperature was set at 30–40°C and the stirrer was started. 4.48 wt% aqueous sodium hydroxide solution (32.5 g) was charged into the vessel for approximately 30 minutes. The batch temperature was maintained at approximately 40–50°C. The batch temperature was then raised to approximately 78–82°C for approximately 1 hour, and the mixture was stirred for an additional approximately 1 hour at approximately 78–82°C. The batch was filtered using a filter. 950721 of 26 polyethylene of 5 pm under slight positive nitrogen pressure and then transferred to a new reactor. The batch temperature was maintained at around 78-82°C. A new container was filled with 37% aqueous hydrochloric acid (4 mL) and molten tert-butanol (8 mL). The temperature was maintained at around 30-40°C and the mixture was stirred for about 30 minutes. The batch was charged with hydrochloric acid in tert-butanol for approximately 4 hours using a metering pump. The first half of the charge was added over approximately 20–30 minutes. The stirrer speed was set at approximately 200 rpm. The remaining charge was added over approximately 3.5 hours. The stirrer speed was set at approximately 100 rpm. The batch temperature was maintained at approximately 78–82°C during the addition. The pH of the final batch was adjusted to approximately 1.2 per pH meter, and stirring was continued at approximately 78–82°C for an additional 1 hour. The batch was cooled linearly from approximately 78-82°C to approximately 70°C for about 1 hour. The batch at approximately 70°C was then cooled linearly from approximately 70°C to approximately 50°C for about 4 hours, with the stirrer speed set at approximately 80 rpm. The batch at approximately 50°C was then cooled linearly from approximately 50°C to approximately 40°C for about 4 hours, with the stirrer speed set at approximately 60 rpm. This batch was then stirred for a further 4 hours at 40°C. The filter temperature was set at approximately 40–45°C. The slurry was transferred to a filter. Filtration was complete after about 1 minute. The filter cakes were washed with tert-butanol (50 mL, 50°C) for about 2 minutes. Purified water (100 mL, 2, 60°C) was applied to the cakes as a final wash. The cakes were dried at approximately 60–70°C under vacuum for about 12 hours and then disposed of in a container. HPLC purity was determined in approximately 99.9% of the area. The yield of the isolated product was approximately 94% (9.0 g). 950721 of 26 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid: Single pot process A reactor vessel was charged with 3-cyanobenzoic acid (7.35 g) and molten tert-butanol (100 mL). The vessel was sealed, the batch temperature was set to 60°C, and the stirrer was started. The suspension was stirred for 1 hour, then the batch temperature was set to 40°C. 50% aqueous hydroxylamine (3.63 g) was charged into the reactor under an inert atmosphere for 3 hours. The batch temperature was maintained at 38–41°C during the addition. The reaction was completed after stirring for 18 hours at 40°C. The batch was cooled to 27°C and charged with triethylamine (5.56 g) for 2 minutes. 2-Fluorobenzoyl chloride (7.82 g) was added over 3 hours. The batch temperature was maintained at 24–27°C during the addition. The batch was stirred for a further 4 hours at 40°C. The batch was heated to 79°C for 30 minutes and stirred for 16 hours at approximately 79°C. Water (100 mL) was added to the white suspension over 3 hours while maintaining the batch temperature at 70°C. The batch was charged with 37% aqueous hydrochloric acid for 20 minutes. The pH of the batch was determined to be approximately 2.2, and stirring was continued at approximately 70°C for approximately 1 additional hour. The batch was cooled linearly between 70°C and 30°C for 3 hours, and the slurry was transferred to a filter. Filtration was completed after 5 minutes. The filter cakes were washed with tert-butanol (50 mL, 40°C) for 5 minutes. 24 Purified water (100 mL, 60°C) was applied to the cakes as a final wash in batch 950721 of 26. The cakes were dried in a vacuum oven at 70°C for 18 hours and then discarded. Purity was determined to be approximately 98.68%. The overall yield of the isolated product was approximately 76% (10.8 g). Simply through routine experimentation, those skilled in the art will recognize, or be able to ascertain, various equivalents of the specific embodiments of the invention described herein. Such equivalents are intended to be included in the following claims. All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually stated to be incorporated herein by reference. 950721 of 26 Federico Aulmann - 20219535830 Digitally signed by PORTALTRAM ITES - INPI Date: 2020.05.12 16:57:52 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 950721

Claims

1. A process for preparing a compound of formula FORMULA 01 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is an unsubstituted C1-6 alkyl or -(CH2CH2O)nH; X is in each case independently F, Cl, Br, or I; n is an integer from 1 to 7, and m is an integer from 1 to 5, comprising performing the following steps in tert-butanol: (1) reacting the cyanobenzoic acid ester FORMULA 02 with hydroxylamine to produce FORMULA 03 followed by (2) acylation with a halobenzoyl chloride to produce FORMULA 04 followed by (3) condensation, and wherein steps (1) - (3) are carried out without the isolation of an intermediate. Nine claims follow.