HK1134094B - Processes for the preparation of 1,2,4-oxadiazole benzoic acids - Google Patents

Abstract

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

Description

Process for preparing 1,2, 4-oxadiazole benzoic acids

This application claims the benefit of U.S. provisional application No. 60/843,595 filed on 8.9.2006, the entire contents of which are incorporated herein by reference.

1. Field of the invention

The present invention provides methods for preparing compounds useful for treating, preventing or managing diseases associated with nonsense mutations. More specifically, the present invention provides methods for synthesizing 1,2, 4-oxadiazoles. In particular, the present invention provides a process for the preparation of 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid.

2. Background of the invention

1,2, 4-oxadiazole compounds useful in the treatment, prevention or management of diseases ameliorated by the modulation of premature translation termination or nonsense-mediated mRNA degradation are described in U.S. Pat. No. 6,992,096B 2, granted on 31.2006, 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.

A prior liquid phase process for the synthesis of 1,2, 4-oxadiazole benzoic acids is described in U.S. patent No. 6,992,096B 2 (see column 57, line 40, scheme B and example 2), issued on 31.2006. In particular, these methods involve multiple reaction steps, each followed by isolation of the desired intermediate.

While these methods are capable and useful for preparing 1,2, 4-oxadiazole benzoic acids, there are possibilities for changes that may lead to more efficient syntheses. In particular, synthetic methods that have fewer separation steps and that may include the use of less solvent may be more efficient and less costly.

Any reference cited in section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. Summary of the invention

The present invention provides a process for the preparation of 1,2, 4-oxadiazole benzoic acids which is efficient, cost effective and easy to scale up using commercially available reagents.

In one embodiment, the present invention provides a process for preparing 1,2, 4-oxadiazole benzoic acids comprising the steps of: (1) reacting a cyanobenzoate with hydroxylamine; (2) acylation with halobenzoyl chloride; (3) condensation; and (4) hydrolyzing the benzoate ester.

In one embodiment, steps (1) - (3) are performed in the same organic solvent.

In another embodiment, steps (1) - (3) are performed in a single organic solvent.

In another embodiment, steps (1) - (4) are performed in the same organic solvent.

In another embodiment, steps (1) - (4) are performed in a single organic solvent.

In another embodiment, steps (1) - (3) are performed in the same aqueous solvent.

In another embodiment, steps (1) - (3) are performed in a single aqueous solvent.

In another embodiment, steps (1) - (4) are performed in the same aqueous solvent.

In another embodiment, steps (1) - (4) are performed in a single aqueous solvent.

In another embodiment, steps (1) - (3) are performed without isolation of intermediates.

In another embodiment, steps (1) - (4) are performed without isolation of intermediates.

In another embodiment, the micronization step is performed after steps (1) - (4).

In another embodiment, the processes provided herein are used to prepare 1,2, 4-oxadiazole benzoic acids and pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. In another embodiment, the methods provided herein are used to prepare 1,2, 4-oxadiazole benzoic acids and pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, which are useful for treating, preventing, or managing diseases or disorders associated with nonsense mutations. In another embodiment, the processes provided herein are used to prepare 1,2, 4-oxadiazole benzoic acids and pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, which are useful for treating, preventing, or managing genetic diseases and disorders.

4. Detailed description of the invention

4.1 terminology

As used herein, unless otherwise indicated, the terms "halo", "halogen", and the like, refer to-F, -Cl, -Br, or-I.

Unless otherwise indicated, the compounds described herein include intermediates useful in preparing the compounds that include reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties) and also include protected derivatives thereof. "protected derivatives" are those compounds whose reactive sites are protected by one or more protecting groups (also known as blocking groups). For the carboxyl moiety, suitable protecting groups include benzyl, t-butyl, and the like. For amino and amide groups, suitable protecting groups include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For hydroxy, suitable protecting groups include benzyl and the like. Other suitable protecting groups are known to those of ordinary skill in the art. The selection and use of protecting Groups and the reaction conditions for the addition or removal of protecting Groups are described in T.W. Green, "Protective Groups in organic Synthesis", 3 rd edition, Wiley, New York, 1999, the entire contents of which are incorporated herein by reference.

As used herein, unless otherwise indicated, 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.

The term "process" as used herein, unless otherwise specified, refers to the process disclosed herein for the preparation of a 1,2, 4-oxadiazole benzoic acid compound.

As used herein, unless otherwise specified, the term "adding" or the like means contacting one reactant, reagent, solvent, catalyst, or the like, with another reactant, reagent, solvent, catalyst, or the like. The reactants, reagents, solvents, catalysts, etc. may be added independently, simultaneously or separately, and may be added in any order. They may be added with or without heating, and may optionally be added under an inert atmosphere.

As used herein, unless otherwise specified, a reaction that is "substantially complete" or until "substantially complete" means that the reaction comprises 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.

The term "without isolation" as used herein means, unless otherwise specified, that the reaction mixture obtained in one step is subjected to a subsequent step without isolation of the desired product. In certain embodiments, performing multiple reaction steps "without isolation" includes a process comprising transferring the reaction mixture resulting from one step to a new reaction vessel prior to starting a subsequent reaction.

The term "condensation", as used herein, unless otherwise indicated, refers to a chemical reaction in which two chemical moieties react and covalently bond to each other while losing a small molecule, such as water.

The term "pharmaceutically acceptable salt" as used herein, unless otherwise specified, refers to salts of the compounds of the present invention that are safe and effective for use in patients. Exemplary pharmaceutically acceptable salts are 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.

The term "hydrate" as used herein, unless otherwise specified, refers to a compound of the invention or salt thereof that also includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

The term "solvate" as used herein, unless otherwise specified, refers to a solvate of a compound of the present invention formed in association with one or more solvent molecules. The term "solvate" includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

The term "polymorph" as used herein, unless otherwise specified, refers to a solid crystalline form 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, unless otherwise indicated, the phrase "a disease or condition associated with a nonsense mutation" refers to a disease or condition that does not occur, is experienced, or causes symptoms if the nonsense mutation is not present.

As used herein, unless otherwise indicated, the terms "treatment," "treating," "treatment," and the like refer to a reduction or amelioration in the development, severity, and/or duration of a disease or disorder, or an improvement in one or more symptoms (preferably one or more discernible symptoms) of a disease or disorder, resulting from the administration of one or more treatments (e.g., one or more therapeutic agents, such as 1,2, 4-oxadiazole benzoic acid).

As used herein, unless otherwise indicated, the terms "prevent", "preventing", "prevention", and the like refer to reducing the risk of developing or developing a particular disease or condition, or reducing or inhibiting the recurrence, onset, or development of one or more symptoms of a particular disease or condition.

If the structure shown in the figure is not consistent with the name given to the structure, the structure shown in the figure is taken as the main structure. Moreover, if the stereochemistry of a structure or a portion thereof is not indicated (e.g., by bold or dashed lines), then the structure or portion thereof is to be interpreted as encompassing all stereoisomers of it.

The embodiments provided by this invention can be more fully understood by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.

4.2 methods

The present invention provides an economical, efficient and effective process for the preparation of 1,2, 4-oxadiazole benzoic acids.

In one embodiment, the method comprises the use of methyl m-cyanobenzoate.

In another embodiment, the method comprises the use of fluorobenzoyl chloride.

In another embodiment, the method comprises the use of o-fluorobenzoyl chloride.

In another embodiment, steps (1) - (3) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps.

In another embodiment, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps (1) - (3).

In another embodiment, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps (1) - (4).

In another embodiment, steps (1) - (3) or steps (1) - (4) are performed in a single aqueous solvent or the same aqueous solvent, and the intermediate is not isolated in steps (1) - (3), or in another embodiment, between steps (1) - (4).

In one embodiment, the solvent used in the process 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 process described herein is an alcoholic solvent such as methanol, ethanol, isopropanol, isobutanol, propanol, butanol and t-amyl alcohol.

In another embodiment, the solvent used in the process described herein is t-butanol.

In one embodiment, the processes described herein are used to prepare a batch of about 500mg or more, about 1kg or more, about 5kg or more, about 10kg or more, about 25kg or more, about 50kg or more, about 75kg or more, about 100kg or more, about 125kg or more, about 150kg or more, about 175kg or more, about 200kg or more, about 225kg or more, about 250kg or more, about 275kg or more, about 300kg or more, about 325kg or more, about 350kg or more, about 375kg or more, about 400kg or more, about 425kg or more, about 450kg or more, about 475kg or more, or about 500kg, or about 600kg, or about 700kg, or about 800 kg, or about 900kg, or about 1000kg or more of 1,2, 4-oxadiazole benzoic acid.

In one embodiment, the 1,2, 4-oxadiazole benzoic acid is prepared in one of the above batches with 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, 85% or more, about 90% or more, or about 95% or more.

In one embodiment, the micronization step is performed after steps (1) - (4). In a particular embodiment, the micronized 1,2, 4-oxadiazole benzoic acid has a particle size distribution of D (v, 0.1): about 0.5 μm to about 1.0 μm; d (v, 0.5): about 1.5 μm to about 5.0 μm; and D (v, 0.9): about 5.5 μm to about 10.0 μm.

In one embodiment, the invention provides a process for preparing a compound of formula I, or a pharmaceutically acceptable salt, hydrate, clathrate, prodrug, polymorph, stereoisomer (including enantiomer, diastereomer, racemate or mixture of stereoisomers) thereof:

wherein:

z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aralkyl;

R¹is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)₂CH₂O)_nR⁶Or any biohydrolyzable group;

R²、R³、R⁴、R⁵and R⁶Independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF₃、OCF₃、OCHF₂、CN、COOH、COOR⁷、SO₂R⁷、NO₂、NH₂Or N (R)⁷)₂；

Each R⁷Independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen or CF₃(ii) a And

n is an integer of 1 to 7,

the method comprises the following steps:

(1) reacting an optionally substituted cyanobenzoate with hydroxylamine;

(2) acylation with an acid chloride;

(3) condensation; and

(4) optionally hydrolyzing the benzoate ester.

In one embodiment, steps (1) - (3) are performed in a single organic solvent.

In another embodiment, steps (1) - (3) are performed in the same organic solvent.

In another embodiment, steps (1) - (4) are performed in a single organic solvent.

In another embodiment, steps (1) - (4) are performed in the same organic solvent.

In another embodiment, steps (1) - (3) are performed without isolation of intermediates.

In another embodiment, steps (1) - (4) are performed without isolation of intermediates.

In another embodiment, steps (1) - (3) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps.

In another embodiment, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps (1) - (3).

In another embodiment, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps (1) - (4).

In one embodiment, the solvent used in the process described herein is t-butanol.

In one embodiment, the present invention provides a process for preparing a compound of formula I having the structure of formula II:

or a pharmaceutically acceptable salt, hydrate, clathrate, prodrug, polymorph, stereoisomer (including enantiomer, diastereomer, racemate or mixture of stereoisomers) thereof, wherein:

R¹is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)₂CH₂O)_nR⁶Or any biohydrolyzable group;

each X is independently F, Cl, Br or I; and

m is an integer of 1 to 5,

the method comprises the following steps:

(1) reacting methyl cyanobenzoate with hydroxylamine;

(2) acylation with halobenzoyl chloride;

(3) condensation; and

(4) hydrolyzing the methyl ester.

In one embodiment, X is F.

In another embodiment, m is 1.

In another embodiment, X is F and m is 1.

In another embodiment, m is 1 and X is F in the ortho position.

In another embodiment, m is 1 and X is F in the meta position.

In another implementationIn the scheme, m is 1 and X is F in para position. In another embodiment, R₁Is H.

In one embodiment, the present invention provides a process for preparing compounds of formula I, including compounds having the structures of formulae II and IIa, comprising the steps listed in scheme 1:

scheme 1

Wherein R is₁Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)₂CH₂O)_nR⁶Any biohydrolyzable group or any suitable blocking group known to those skilled in the art, wherein R is when₁When not H, step (4) is an optional hydrolysis step;

each X is independently F, Cl, Br or I; and

m is an integer of 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 embodiment, m is 1 and X is F in the meta position.

In another embodiment, m is 1 and X is F in the para position.

In another embodiment of scheme 1, R₁Is methyl.

In another embodiment of scheme 1, steps (1) - (3) are performed in a single organic solvent.

In another embodiment of scheme 1, steps (1) - (3) are performed in the same organic solvent.

In another embodiment of scheme 1, steps (1) - (4) are performed in a single organic solvent.

In another embodiment of scheme 1, steps (1) - (4) are performed in the same organic solvent.

In another embodiment of scheme 1, steps (1) - (3) are performed without isolation of intermediates.

In another embodiment of scheme 1, steps (1) - (4) are performed without isolation of intermediates.

In another embodiment of scheme 1, steps (1) - (3) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps.

In another embodiment of scheme 1, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the intermediate between steps (1) - (3).

In another embodiment, steps (1) - (4) are performed in a single organic solvent or the same organic solvent, and there is no need to isolate the 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 a specific embodiment of scheme 1, the solvent used is t-butanol.

In one embodiment of scheme 1, step (1) comprises reacting methyl 3-cyanobenzoate with aqueous hydroxylamine in t-butanol. In a specific embodiment, a 50% aqueous solution of hydroxylamine is used in step (1). In another embodiment, molten tert-butanol is used in step (1). In another embodiment, an aqueous solution of hydroxylamine is added to methyl 3-cyanobenzoate and t-butanol at about 40-45 ℃. In another embodiment, the reaction mixture of step (1) is stirred for about 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 a 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 t-butanol. In another embodiment, the reaction of step (2) is carried out at a temperature of less than 40 ℃, and in a specific embodiment, the reaction of step (2) is carried out at a temperature of about 30-35 ℃. In another embodiment, the reaction mixture of step (2) is stirred for at least about 2 hours. In certain embodiments, additional triethylamine or halobenzoyl chloride may be added to the reaction mixture of step (2) to facilitate completion of the reaction.

In another embodiment of scheme 1, step (3) comprises refluxing the product of step (2) in t-butanol. In particular embodiments, step (3) comprises refluxing the product of step (2) in t-butanol at about 82 ℃. In another embodiment, step (3) comprises crystallizing the ring-closed product at about 60-65 ℃ by adding water. In another embodiment, the resulting slurry is cooled to room temperature, filtered, washed with tert-butanol/water (50/50v/v) and dried in vacuo.

In another embodiment of scheme 1, step (4) comprises hydrolyzing the methyl ester of the product of step (3) to the corresponding sodium salt by adding aqueous sodium hydroxide solution to t-butanol. In one embodiment, the hydrolysis of the methyl ester of the product of step (3) is carried out in aqueous sodium hydroxide and t-butanol at about 68-72 ℃. In a further embodiment, step (4) comprises converting the sodium salt to the free acid by: the hot sodium salt solution is filtered through an in-line filter (e.g., a 5 micron in-line filter) and acidified with sulfuric acid to about pH 1-3. In a still further embodiment, step (4) comprises converting the sodium salt to the free acid by: the hot sodium salt solution is filtered through an in-line filter (e.g., a 1 micron in-line filter), acidified to about pH 1-3 with about 10-15% hydrochloric acid, and then stirred at about 70 ℃ for about 1 hour. In further embodiments, the free acid is isolated using a Rosenmund filter and washed with aqueous t-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 monitored by any method known to those skilled in the art, including, but not limited to, Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), or spectroscopic methods (e.g., HPLC)¹H-NMR、¹³C-NMR、IR、Raman、MS)。

In one embodiment, the present invention provides a process for preparing 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid comprising the steps listed in scheme 2:

scheme 2

In one embodiment, the present invention provides a process for preparing a compound of formula II, comprising performing the steps of:

(1) preparing methyl cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with a halobenzoyl chloride to yield:

and, thereafter performing (3) condensation to produce:

in another embodiment, the process provided herein further comprises (4) hydrolyzing the methyl ester to produce:

in one embodiment, X is F.

In another embodiment, m is 1.

In another embodiment, X is F and m is 1.

In another embodiment, m is 1 and X is F in the ortho position.

In another embodiment, m is 1 and X is F in the meta position.

In another embodiment, m is 1 and X is F in the para position.

In another embodiment, steps (1) - (3) are performed in a single organic solvent.

In another embodiment, steps (1) - (3) are performed in the same organic solvent.

In another embodiment, steps (1) - (4) are performed in a single organic solvent.

In another embodiment, steps (1) - (4) are performed in the same organic solvent.

In another embodiment, steps (1) - (3) or steps (1) - (4) are performed in t-butanol.

In another embodiment, steps (1) - (3) are performed without isolation of intermediates.

In another embodiment, steps (1) - (4) are performed without isolation of intermediates.

In another embodiment, steps (1) - (3) or steps (1) - (4) are performed in a single organic solvent or the same organic solvent without isolation of the intermediate.

In one embodiment, the solvent used is tetrahydrofuran, dioxane, isobutyl acetate, isopropyl acetate, ethyl acetate, methanol, ethanol, isopropanol, isobutanol, propanol, butanol or tert-amyl alcohol.

In a 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 performed in a single reaction vessel (i.e., a "one-pot" synthesis).

In one embodiment, the present invention provides a process for preparing a compound of formula II comprising performing the following steps in a single reaction vessel:

and (2) preparing cyanobenzoic acid:

reacting with hydroxylamine to form:

followed by acylation with a halobenzoyl chloride to yield:

then refluxing was performed to generate:

in one embodiment, the compound is 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid.

The described embodiments of the invention are further illustrated by the following examples, which should not be construed as limiting the scope of the described embodiments of the invention.

Starting materials and reagents useful in the methods described herein can be obtained from commercial sources or prepared using methods known to those skilled in the art.

5. Examples of the embodiments

3- [5- (2-fluorophenyl) - [1, 2, 4]]Oxadiazol-3-yl]-benzoic acid methyl ester

Batch 1

Methyl 3-cyanobenzoate (105kg) and molten t-butanol were charged to a drying reactor. A50% aqueous hydroxylamine solution (43L, 47.4kg) was added to a clear solution of methyl 3-cyanobenzoate in molten t-butanol under an inert atmosphere over about 2 hours 48 minutes. The maximum temperature of the batch during the addition of the 50% aqueous hydroxylamine solution was about 43 ℃. The rate of addition of the 50% aqueous hydroxylamine solution was varied from about 9L/hr at the start of the addition to about 30L/hr. The temperature of the batch was maintained by changing the jacket set point of the reactor. In particular, the set point is about 40.5 ℃ at the beginning of the addition and changes to about 29.6 ℃ as the rate of addition increases. After stirring at about 40-45 ℃ for about 4 hours, the reaction was considered complete (i.e., less than about 0.5% ester).

The batch was transferred to a drying reactor and about 10L of molten t-butanol was added (chased through). The jacket set point was reduced from about 33 ℃ when the batch was received by the drying reactor to about 27 ℃ after the transfer was complete. Partial crystallization of the batch was observed, which did not adversely affect stirring. The batch was cooled to about 34.4 ℃ and triethylamine (72.6kg, 100L) was added to the reactor. The jacket temperature setpoint is increased from about 20.4 ℃ to about 31.0 ℃ to maintain the batch temperature in the range of about 30-35 ℃. After a linear wash (line rose) with molten t-butanol (10L), 2-fluorobenzoyl chloride (113.7kg, 86.0L) was added to the batch. The first third of the charge was added at a rate of about 25L/hour. During this time, the jacket inlet temperature was reduced to about 15 ℃, and the batch temperature was maintained at about 34.6 ℃. After about 5.5 hours, the addition was complete. The maximum temperature of the batch during the addition was about 38.8 ℃. Towards the end of the addition, the rate of addition was slowed and the last 27 liters of 2-fluorobenzoyl chloride was added at about 11L/hr. After stirring at 30-35 ℃ for about 2 hours, the reaction is considered complete (i.e., less than about 0.5% methyl-3-amidinobenzoate).

The batch was then heated to reflux temperature (about 82 ℃) for about 1 hour 42 minutes and stirred for about 18 hours. During stirring, some of the product partially crystallized to form a slurry. The slurry was cooled to about 40 ℃ so that sampling could be performed, during which time complete crystallization occurred. The batch was heated to reflux temperature again and stirred for about 1 hour 50 minutes. The batch was then cooled to about 69 ℃ over about 2 hours and 630L of purified water was slowly added over about 4 hours and 15 minutes while maintaining the batch temperature at about 66-69 ℃. The slurry was cooled to about 22.4 ℃ over about 3 hours and 14 minutes and transferred to a 2X 200L ceramic filter fitted with 25-30 μmesh polypropylene filter cloth. After about 55 minutes, the transfer of material from the container to the filter was completed. The filter cakes were washed with 50% aqueous tert-butanol (210L) for about 10 minutes to allow the wash liquor to penetrate into each filter cake. The filter cake was then dried in vacuo for about 5-10 minutes. Purified water was applied to the cake as a second wash (158L/cake) to remove residual t-butanol and triethylammonium chloride salts. After drying in vacuo for about 5 minutes, the solution was removed. The filter cake was dried in vacuo for an additional 2 hours and then sampled using liquid chromatography. The purity of the filter cake as determined by liquid chromatography was about 99.6%.

After drying the filter cake in vacuo for about 8 hours and 25 minutes, the wet filter cake (207.4kg) was transferred to an air oven. Drying is carried out in an air oven at about 50-55 c for about 52 hours. The overall yield of isolated product was about 89.9% (174.65kg), which could be adjusted to about 90.7% after calculating the material consumed for sampling.

Batch 2

Methyl 3-cyanobenzoate (105kg) and molten t-butanol were charged to a drying reactor. Under an inert atmosphere, 50% aqueous hydroxylamine solution (47.85kg) was added to the reactor over about 3 hours and 29 minutes. During the addition, the temperature was maintained at about 40-45 ℃. After stirring at about 40-45 ℃ for about 3 hours 16 minutes, the reaction is considered complete (i.e., less than about 0.5% ester).

As described for batch 1, the batch was transferred to the drying reactor. The batch was cooled to about 34.4 ℃ and triethylamine (72.6kg, 100L) was added. The addition was made during about 45 minutes while maintaining the batch temperature at about 30-35 ℃. During the addition, the jacket inlet temperature increased from about 31.4 ℃ to about 32.6 ℃. After linear washing with molten t-butanol, 2-fluorobenzoyl chloride (113.7kg, 86.0L) was added to the batch. Over about 3 hours 27 minutes, the acid chloride was added. After stirring for about 8 hours at 35 deg.C, the reaction was deemed to be incomplete (i.e., more than about 0.5% of the methyl 3-amidinobenzoate remained). Then, 1.5% by weight of the original charge of triethylamine and 2-fluorobenzoyl chloride was added to the batch. Each additional charge was accompanied by a linear wash of t-butanol (10L). During the addition of the acid chloride, no additional cooling was performed. The batch temperature was maintained at about 30-35 ℃ and the jacket inlet temperature was maintained in the range of about 30.3 ℃ to about 33.0 ℃. After stirring at 30-35 ℃ for about 2 hours, the reaction was considered complete (i.e., less than 0.5% methyl 3-amidinobenzoate).

The batch was heated to reflux temperature (about 83 ℃) over about 1 hour 44 minutes and stirred for about 18 hours. As with batch 1, during the cooling sampling the solid was completely crystallized. The batch was heated to reflux temperature again and stirred for about 1 hour 2 minutes. The batch was then cooled to about 69.2 ℃ over about 2 hours and 20 minutes and 630L of purified water was slowly added over about 4 hours and 30 minutes while maintaining the batch at a temperature of about 65.6-69.2 ℃. The slurry was cooled to about 23.4 ℃ over about 3 hours and 30 minutes and the contents were transferred to a double ceramic filter as described for batch 1. After about 5 hours 6 minutes, the transfer of the material was completed. The filter cakes were washed with about 50% t-butanol (2 volumes per filter cake) for 10 minutes to allow the wash solution to penetrate into each filter cake, followed by drying in vacuo. After about 1 hour and 40 minutes, the filtration was complete. Purified water was added to the filter cake as the final wash. The liquid was removed by drying in vacuo for about 10 minutes. The filter cake was dried in vacuo for an additional 2 hours and 5 minutes before sampling using liquid chromatography. The purity of the filter cake as determined by liquid chromatography was about 99.5% and 99.6%, respectively.

After the filter cake was dried in vacuo for about 2 hours and 5 minutes, the wet filter cake (191.5kg) was transferred to an air oven. Dried in an air oven at about 50-55 c for about 48 hours. The overall yield of isolated products was about 92.5% (179.7 kg).

Batch 3

Methyl 3-cyanobenzoate (52.5kg) and molten t-butanol (228kg) were charged to a reaction vessel. The vessel was sealed, the batch temperature was set at about 40-45 ℃, and the stirrer was started. Under an inert atmosphere, 50% aqueous hydroxylamine solution (24kg) was added to the reactor over 2 hours and 40 minutes. During the addition, the temperature was maintained at about 40-45 ℃. After stirring at about 42 ℃ for about 5 more hours, the reaction was complete.

The batch was cooled to 30-35 ℃ and over 15 minutes triethylamine (36kg) was added. 2-fluorobenzoyl chloride (57kg) was added over about 2 hours and 44 minutes. During the addition, the batch temperature was maintained at about 30-35 ℃. The batch was stirred for an additional 2 hours and 10 minutes at 32 ℃ to complete the reaction.

The batch was heated to reflux temperature (about 83-86 ℃) over about 50 minutes, and stirred at about 81 ℃ for about 18 hours. The batch was then cooled to about 65-70 ℃ over about 2 hours and purified water (315L) was slowly added over about 6 hours and 25 minutes while maintaining the batch temperature at about 65-70 ℃. Over about 2 hours and 15 minutes, the slurry was cooled to about 22 ℃, and the contents were transferred to a centrifugal filter (2 batches). After about 1 hour and 40 minutes, the filtration was complete. Over about 20 minutes, the filter cake was washed with about 50% aqueous tert-butanol (90 kg/filter cake). Purified water (79 kg/filter cake) was added to the filter cake as the final wash. The filter cake was dried at about 900rpm for about 1 hour 5 minutes and then charged into a cylinder. The wet cake (91.5kg, LOD 5% w/w) was about 99.75 area% pure as determined by liquid chromatography.

3- [5- (2-fluorophenyl) - [1, 2, 4]]Oxadiazol-3-yl]-benzoic acid

Batch 1

Methyl 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoate (74.0kg) was charged to a reaction vessel, which was sealed, evacuated and purged. The jacket setting was about 35 ℃ and the stirrer was started in the vessel. Molten t-butanol (222L, 3 vol) and purified water (355L, 4.8 vol) were added to the vessel. An additional 25.1% w/w aqueous sodium hydroxide solution (43.5kg, 1.1 molar equivalents) was added after these additions and washed linearly with additional purified water (100L, 1.35 moles). During the addition, the batch temperature was reduced from about 39.0 ℃ to about 38.8 ℃. The batch temperature was raised to about 63-67 ℃ over about 1 hour and 54 minutes, and then adjusted to about 68-72 ℃ over about 30 minutes. The mixture was stirred at about 68-72 ℃ for about 3 hours. The solution was then cooled to about 40-45 ℃ over about 5 hours and 11 minutes. Then, after the above process, the solution was heated to about 68-72 ℃ over about 3 hours and 33 minutes.

The jacket temperature on the reaction vessel was set to about 60 ℃, the stirrer was started, and the hot liquid was transferred through a 1 micron filter at about 70 ℃ under a slight positive pressure of nitrogen (1.5 to 5.6 psig). During the transfer, the product temperature was reduced to about 64.3 ℃, and the transfer was completed in about 45 minutes. Purified water (61L, 0.82 vol) was added to the vessel and the contents were heated to about 68-72 ℃.

The batch was temperature adjusted to about 69.4 ℃ and treated with 13.9% w/w sulfuric acid (100.7kg, 1.15 molar equivalents) over about 4 hours and 18 minutes. During the addition, the batch temperature was maintained at about 68.0-70.8 ℃. After addition of the acid, the column was washed linearly with purified water (50L, 0.68 vol.) and stirred at about 68-72 ℃ for an additional 31 minutes.

The batch was cooled in a linear fashion from about 69.2 ℃ to about 41.2 ℃ over about 4 hours and 10 minutes. The stirrer on the Rosenmund filter/dryer was raised to the highest position and the jacket setting was set at about 40 ℃. The slurry was transferred in two portions to the filter/dryer. A constant nitrogen pressure (less than about 15psig) was applied to the first section. During the transfer, the pressure is about 23.9 to about 28.8psi, and the transfer is complete in about 1 hour and 5 minutes. A second portion of the slurry was transferred onto the filter cake and the composite was simply stirred to homogenize the batch. The second portion was filtered using about 26.1 to about 29.1psi of nitrogen pressure and after about 3 hours, the filter cake was pressed free of liquid. The filter cake was washed with hot aqueous t-butanol at about 38-42 deg.C (352kg, 5 volumes) and 3 × hot purified water at about 65-70 deg.C (370L, 5 volumes).

The filter/dryer jacket temperature was set to about 43 ℃, and the product was dried in vacuo for about 26 hours with periodic stirring. The purity was determined to be about 99.7%. The overall yield of isolated products was about 74.4% (52.45 kg).

Batch 2

To the reactor vessel was added 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid methyl ester (47kg, wet cake) and molten t-butanol (111.4 kg). The vessel was sealed and the batch temperature was set to 30-40 ℃ and the stirrer was started. Purified water (51.6kg) was added to the vessel. After the addition, 3.47% w/w aqueous sodium hydroxide (202.4kg) was added. The batch was raised to a temperature of about 67-73 ℃ over about 1 hour, and then stirred at about 70 ℃ for about 3 hours.

The batch was filtered under nitrogen at slightly positive pressure with a 1 micron polypropylene filter bag and then transferred to a new reactor. Purified water (146kg) was added to the vessel and the batch was heated to about 68-72 ℃.

Over about 4 hours, a 10.7% aqueous hydrochloric acid solution was added to the batch. During the addition, the batch temperature was maintained at about 68-72 ℃. The batch had a pH of about 2.2 as measured by a pH meter and continued stirring at about 70 ℃ for about 1 hour.

Over about 2 hours, the batch was cooled in a linear fashion from about 70 ℃ to about 60 ℃. Over about 2 hours, the batch at about 60 ℃ was cooled in a linear fashion from about 60 ℃ to about 40 ℃. The batch was stirred for a further 2 hours at 40 ℃ and the slurry was transferred to a centrifugal filter. After about 30 minutes, filtration was complete. The filter cake was washed over about 30 minutes with about 42% w/w aqueous tert-butanol (165 kg). Purified water (118kg, 40 ℃) was added to the filter cake as the final wash. The filter cake was dried at about 900rpm for about 1 hour and then charged into a cylinder.

The wet cake was transferred to a paddle dryer (a double cone dryer is also suitable for this step) and the jacket temperature was set to about 70 ℃. The product was dried in vacuo at about 70 ℃ for about 48 hours while stirring periodically. The purity was determined to be about 99.8%. The overall yield of isolated products was about 74% (68.5 kg).

Batch 3

To the reaction vessel was added 3- [5- (2-fluorophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid methyl ester (10g) and molten t-butanol (128 mL). The batch temperature was set to 30-40 ℃ and the stirrer was started. Over about 30 minutes, 4.48% w/w aqueous sodium hydroxide (32.5g) was added to the vessel. The batch temperature was maintained at about 40-50 ℃. The batch was raised to a temperature of about 78-82 ℃ over about 1 hour, and then stirred at about 78-82 ℃ for an additional about 1 hour. The batch was filtered under nitrogen at slightly positive pressure with a 5 micron polyethylene filter bag and then transferred to a new reactor. The batch temperature was maintained at about 78-82 ℃.

To a fresh vessel were added 37% aqueous hydrochloric acid (4mL) and molten t-butanol (8 mL). The temperature was maintained at about 30-40 ℃ and the mixture was stirred for about 30 minutes.

Hydrochloric acid in t-butanol was added to the batch over about 4 hours using a metering pump. The first half of the charge was added over about 20-30 minutes. The speed of the stirrer was set to about 200 rpm. The remaining charge was added over about 3.5 hours. The stirrer speed was set to about 100 rpm. During the addition, the batch temperature was maintained at about 78-82 ℃. The final batch was adjusted to a pH of about 1.2 using a pH meter and stirring was continued for an additional about 1 hour at about 78-82 deg.C.

Over about 1 hour, the batch was cooled in a linear fashion from about 78-82 ℃ to about 70 ℃. Over about 4 hours, the batch at about 70 ℃ was cooled in a linear fashion from 70 ℃ to about 50 ℃ and the speed of the stirrer was set to about 80 rpm. Over about 4 hours, the batch at about 50 ℃ was cooled in a linear fashion from 50 ℃ to about 40 ℃ and the speed of the stirrer was set to about 60 rpm. The batch was stirred at 40 ℃ for a further 4 hours.

The temperature of the filter was set to about 40-45 ℃. The slurry was transferred to a filter. After about 1 minute, filtration was complete. The filter cake was washed with t-butanol (50mL, 50 deg.C) over about 2 minutes. Purified water (100 mL. times.2, 60 ℃) was added to the filter cake as a final wash. The filter cake was dried under vacuum at about 60-70 c for about 12 hours and then charged to a vessel.

The HPLC purity was determined to be about 99.9% area. The isolated product was obtained in a yield of about 94% (9.0 g).

3- [5- (2-fluorophenyl) - [1, 2, 4]]Oxadiazol-3-yl]-benzoic acid: one-pot method

Methyl 3-cyanobenzoate (7.35g) and molten t-butanol (100mL) were added to the reactor vessel. The vessel was sealed, the batch temperature was set to 60 ℃, and the stirrer was started. The suspension was stirred for 1 hour, then the batch temperature was set to 40 ℃. Under an inert atmosphere, over 3 hours, a 50% aqueous hydroxylamine solution (3.63g) was added to the reactor. During the addition, the batch temperature was maintained at 38-41 ℃. After stirring at 40 ℃ for 18 hours, the reaction was completed.

The batch was cooled to 27 ℃ and over 2 minutes triethylamine (5.56g) was added. Over 3 hours, 2-fluorobenzoyl chloride (7.82g) was added. During the addition, the batch temperature was maintained at 24-27 ℃. The batch was stirred at 40 ℃ for a further 4 hours.

Over 30 minutes, the batch was heated to 79 ℃ and stirred at about 79 ℃ for 16 hours. Over 3 hours, water (100mL) was added to the white suspension while maintaining the batch temperature at 70 ℃. Over 20 minutes, 37% aqueous hydrochloric acid was added to the batch. The batch had a pH of about 2.2 as measured by a pH meter and stirring was continued at about 70 ℃ for an additional 1 hour.

Over 3 hours, the batch was cooled in a linear fashion from 70 ℃ to 30 ℃ and the slurry was transferred to a filter. After 5 minutes, filtration was complete. The filter cake was washed with t-butanol (50mL, 40 ℃) over 5 minutes. Purified water (100mL, 60 ℃) was added to the filter cake as the final wash. The filter cake was dried in a vacuum oven at 70 ℃ for 18 hours and then removed. The purity was determined to be about 98.68%. The overall yield of isolated products was about 76% (10.8 g).

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims (23)

1. A process for preparing 3- [5- (halophenyl) - [1, 2, 4] oxadiazol-3-yl ] -benzoic acid, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) reacting methyl cyanobenzoate with hydroxylamine;

(2) acylation with halobenzoyl chloride;

(3) condensation; and

(4) the methyl ester is hydrolyzed by the reaction of the acid,

wherein each reaction step is carried out in the same alcoholic organic solvent.

2. The method of claim 1, wherein the alcoholic organic solvent is methanol, ethanol, isopropanol, isobutanol, propanol, butanol, or tert-amyl alcohol.

3. The process of claim 1, wherein the alcoholic organic solvent is t-butanol.

4. The method of claim 1, wherein steps (1) - (3) are performed without isolation of an intermediate.

5. A process for preparing a compound of the formula:

wherein:

R₁is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)₂CH₂O)_nR⁶Or any biohydrolyzable group, R⁶Is hydrogen, substituted or unsubstituted alkyl, n is an integer from 1 to 7;

each X is independently F, Cl, Br or I; and

m is an integer of 1 to 5,

the method comprises the following steps carried out in the same alcoholic organic solvent:

(1) reacting a cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with a halobenzoyl chloride to yield:

followed by (3) condensation.

6. The method of claim 5, wherein X is F.

7. The method of claim 5, wherein m is 1.

8. The method of claim 5, wherein X is F and m is 1.

9. The method of claim 5, wherein R1 is methyl.

10. The method of claim 5, wherein steps (1) - (3) are performed without isolation of an intermediate.

11. The process of claim 10 wherein the alcoholic organic solvent is t-butanol.

12. The process of claim 5, wherein the halobenzoyl chloride is 2-fluorobenzoyl chloride.

13. A process for preparing a compound of the formula or a pharmaceutically acceptable salt thereof,

wherein:

R₁is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substitutedOr unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)₂CH₂O)_nR⁶Or any group that is biohydrolyzable,

R⁶is hydrogen, substituted or unsubstituted alkyl, n is an integer from 1 to 7;

each X is independently F, Cl, Br or I; and m is an integer of 1 to 5,

the method comprises the following steps carried out in the same alcoholic organic solvent:

(1) reacting a cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with a halobenzoyl chloride to yield:

followed by (3) condensation to form:

followed by (4) hydrolysis

To generate:

or a pharmaceutically acceptable salt thereof.

14. The process of claim 13, wherein the hydrolysis is carried out in t-butanol.

15. The method of claim 14, wherein R1 is methyl.

16. A process for preparing a compound having the formula:

comprising carrying out the following steps without isolation of intermediates:

(1) preparing methyl cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with 2-fluorobenzoyl chloride to give:

followed by (3) condensation.

17. The process of claim 16, wherein steps (1) - (3) are performed in the same alcoholic organic solvent.

18. The process of claim 17, wherein the alcoholic organic solvent is t-butanol.

19. A process for preparing a compound having the formula or a pharmaceutically acceptable salt thereof,

which comprises carrying out the following steps without isolation of intermediates:

(1) preparing methyl cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with 2-fluorobenzoyl chloride to give:

followed by (3) condensation to form:

followed by (4) hydrolysis

To generate:

or a pharmaceutically acceptable salt thereof.

20. A process for preparing a compound having the formula:

comprising the following steps carried out in the same alcoholic organic solvent:

(1) preparing methyl cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with 2-fluorobenzoyl chloride to give:

followed by (3) condensation.

21. The process of claim 20, wherein the alcoholic organic solvent is t-butanol.

22. A process for preparing a compound having the formula:

comprising the following steps carried out in the same alcoholic organic solvent:

(1) preparing methyl cyanobenzoate:

reacting with hydroxylamine to form:

followed by (2) acylation with 2-fluorobenzoyl chloride to give:

followed by (3) condensation to form:

followed by (4) hydrolysis

To generate:

or a pharmaceutically acceptable salt thereof.

23. The process of claim 22, wherein the hydrolysis is carried out in t-butanol.