Description:FIELD OF INVENTION
[0001] The present invention relates to the field of organic and pharmaceutical chemistry, and more particularly to improved synthetic processes for the preparation of 4-fluoro-3-hydroxybenzoic acid and intermediates thereof. The invention specifically pertains to high-yield, scalable, and operationally efficient methods for producing this compound, which serves as a key intermediate in the synthesis of the pharmaceutical agent Acoramidis and potentially other bioactive molecules, including therapeutic and agrochemical products.
BACKGROUND OF THE INVENTION
[0002] 4-Fluoro-3-hydroxybenzoic acid is a valuable intermediate in the synthesis of a variety of bioactive compounds, most notably Acoramidis, a transthyretin (TTR) stabilizer currently under development for the treatment of transthyretin amyloidosis (ATTR). The structural motif of this compound and its precursors is also found in a range of other pharmaceutical agents and agrochemicals, making it a compound of significant synthetic and commercial interest.
[0003] Conventional methods for synthesizing 4-fluoro-3-hydroxybenzoic acid often involve harsh conditions, expensive reagents, or multi-step processes requiring chromatographic purification. These limitations can result in low yields, impure products, or operational inefficiencies that hinder scalability and increase manufacturing costs. In particular, the use of strong acids or bases, prolonged reaction times, and difficult product isolation methods contribute to the challenges associated with existing approaches.
[0004] There remains a need for an improved, high-yielding, and operationally simple process for synthesizing 4-fluoro-3-hydroxybenzoic acid and its intermediates. Ideally, such a process would minimize purification steps, reduce reagent consumption, and be easily scalable for industrial production, while maintaining high chemical selectivity and product purity suitable for downstream pharmaceutical use.
[0005] The present invention addresses these unmet needs by providing two synthetic routes that offer significant synergistic advantages, including enhanced yield, improved purity, simplified work-up, and compatibility with standard crystallization techniques. These improvements facilitate the practical and economical production of this important intermediate for use in the synthesis of Acoramidis and other related bioactive compounds.
[0006] In the CN104447213A patent outlines a two-step synthesis of 3 hydroxy 4 fluorobenzoic acid starting from fluorobenzene: Step-1: 4 fluorophenol formation: Fluorobenzene is hydrolysed with dilute sulfuric acid in water at 80–100 °C, followed by Na₂SO₃ and NaOH treatment under reflux, then sulfonation with SO₂ under N₂ protection, yielding 4 fluorophenol. Step-2: Kolbe–Schmitt carboxylation: The isolated 4 fluorophenol is treated with KOH and CO₂ at 40–60 °C for 2 h, acidified with concentrated H₂SO₄, then refluxed at 110–120 °C for 4 h. post-workup affords 10.96 g of the desired acid (73% yield).
[0007] This route involves prolonged high-temperature reflux (up to 120 °C), handling toxic and corrosive gases (SO₂ and CO₂), and concentrated sulfuric acid—all increasing safety risks and complicating scale-up. The overall moderate yield (~62% combined) and multiple extraction/drying steps lower efficiency and raise environmental and operational concerns.
[0008] However, synthesis of 4-fluoro-3-hydroxybenzoic acid with known processes are associated with several challenges and results in the formation of low quality, low yield, difficulty in operation and high cost.
[0009] Hence, still there is a need to develop an easy, economical process for the synthesis of 4-fluoro-3-hydroxybenzoic acid which can overcome issues related to known synthetic process and can give good quality and high yield of 4-fluoro-3-hydroxybenzoic acid and intermediates thereof.
OBJECT OF INVETNITON
[0010] An object of the present invention is to provide an improved and efficient process for the synthesis of 4-fluoro-3-hydroxybenzoic acid and intermediates thereof, which overcomes the limitations of conventional methods.
[0011] Another object of the invention is to provide synthetic routes that offer high yield, enhanced chemical purity, and reduced formation of by-products, making the process suitable for industrial and pharmaceutical scale-up.
[0012] A further object of the invention is to develop synthetic methodologies that involve simplified reaction work-up, easy isolation of the final product, and minimal need for chromatographic purification, thereby improving cost-effectiveness and operational feasibility.
[0013] Yet another object of the invention is to offer alternative synthetic routes that provide flexibility in reagent selection and reaction conditions, making the process robust and reproducible.
[0014] It is also an object of the invention to enable the production of 4-fluoro-3-hydroxybenzoic acid as a key intermediate for the preparation of Acoramidis and potentially for other therapeutic or agrochemical compounds that utilize similar structural scaffolds.
SUMMARY OF THE INVENTION
[0015] The present invention provides improved and industrially viable synthetic routes for the preparation of 4-fluoro-3-hydroxybenzoic acid and intermediates thereof, which serve as key building blocks in the synthesis of Acoramidis and other bioactive molecules.
[0016] In one embodiment, the invention involves a first synthetic route wherein 4-bromo-1-fluoro-2-methoxybenzene undergoes direct cyanation using copper(I) cyanide in a polar aprotic solvent to yield 4-fluoro-3-methoxybenzonitrile. This intermediate is then subjected to in situ hydrolysis and demethylation using an inorganic acid or base, resulting in the formation of 4-fluoro-3-hydroxybenzoic acid with high purity and yield.
[0017] In an alternative embodiment, the invention provides a second synthetic route wherein the starting material, 4-bromo-1-fluoro-2-methoxybenzene, undergoes amination in the presence of ammonia and a copper salt catalyst to form 4-fluoro-3-methoxyaniline. This intermediate is then converted to 4-fluoro-3-methoxybenzonitrile via a Sandmeyer reaction, followed by hydrolysis and demethylation to obtain the final product.
[0018] Both synthetic routes are operationally simple, require minimal purification steps, and are readily scalable, making them suitable for commercial manufacturing. The synergistic advantages of the invention include high reaction yields, enhanced product purity, reduced use of harsh reagents, and simplified work-up and isolation procedures. These attributes make the invention particularly advantageous for pharmaceutical production settings where efficiency, consistency, and regulatory compliance are critical.
DETAILS OF ACCOMPANYING DRAWINGS:
Figure-1: Illustrate a reaction scheme of two synthetic routes for the preparation of 4-fluoro-3-hydroxybenzoic acid from 4-bromo-1-fluoro-2-methoxybenzene.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features.
Definitions
[0020] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0021] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
[0022] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
[0023] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of elements or steps but not the exclusion of any other element or step or group of element or steps.
[0024] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
[0025] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, the process is carried out at a temperature in a range of -20 to 50°C should be interpreted to include not only the explicitly recited limits of -20 to 50°C but also to include sub-ranges, such as -15 to 30°C, -19 to 24°C, 40 to 50°C and so forth, as well as individual amounts, including fractional amounts, within the specified ranges, such as -18.5°C, -14.9°C, -10.6°C, -5.6°C, 40°C, 45°C and 48°C.
[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
[0027] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products, compositions, formulations, and methods are clearly within the scope of the disclosure, as described herein.
[0028] As discussed in the background of present disclosure, the present invention provides improved synthetic processes for the preparation of 4-fluoro-3-hydroxybenzoic acid and intermediates thereof, particularly useful in the synthesis of Acoramidis and other related bioactive compounds. The invention is based on two alternative synthetic routes starting from a common precursor, 4-bromo-1-fluoro-2-methoxybenzene.
Route 1: Cyanation Pathway
[0029] In the first embodiment, 4-bromo-1-fluoro-2-methoxybenzene is reacted with copper(I) cyanide (CuCN) in a polar aprotic solvent such as N,N-dimethylformamide (DMF). The reaction mixture is heated under reflux conditions for approximately 24 hours. Upon completion, copper salts (e.g., CuBr) are removed by filtration, and the solvent is distilled off under reduced pressure. The resulting crude 4-fluoro-3-methoxybenzonitrile is then subjected to hydrolysis and demethylation in situ using an inorganic acid (e.g., hydrobromic acid) or base. The reaction mass is heated to 80–100 °C under reflux to convert the cyano group to a carboxylic acid and the methoxy group to a hydroxyl group. The final product, 4-fluoro-3-hydroxybenzoic acid, is isolated via standard filtration, crystallization, and drying procedures, yielding a high-purity compound suitable for pharmaceutical use.
Route 2: Amination–Sandmeyer Pathway
[0030] In the second embodiment, 4-bromo-1-fluoro-2-methoxybenzene is subjected to amination using aqueous ammonia in the presence of a catalytic amount of a copper salt, such as copper(I) chloride or copper(II) sulfate. The reaction mixture is heated until formation of 4-fluoro-3-methoxyaniline is confirmed. After standard work-up and isolation, the aniline intermediate is dissolved in hydrobromic acid and cooled to 0–5 °C. A solution of sodium nitrite is added slowly to generate the diazonium salt. This is then added to a refluxing solution of CuCN in acetic acid, facilitating the Sandmeyer reaction and forming 4-fluoro-3-methoxybenzonitrile. The intermediate is subsequently hydrolysed and demethylated as described above to afford the desired 4-fluoro-3-hydroxybenzoic acid.
Applications
[0031] The final product, 4-fluoro-3-hydroxybenzoic acid, is a known intermediate in the synthesis of Acoramidis, a transthyretin stabilizer under development for the treatment of transthyretin amyloidosis. The compound and its nitrile and aniline intermediates may also be used in the synthesis of other pharmaceuticals, such as potassium channel inhibitors and enzyme modulators, as well as in agrochemical co-crystallization platforms.
[0032] Although the subject matter has been described in considerable detail with reference to certain examples and implementations thereof, other implementations are possible.
EXAMPLES
[0033] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices, and materials are described herein. It is to be understood that this disclosure is not limited to particular composition, methods, and experimental conditions described, as such methods and conditions may apply. The present invention will be described in a more detailed manner by way of examples. However, these examples should not be construed as limiting the scope of the present invention.
EXAMPLE 1: Synthesis of 4-Fluoro-3-hydroxybenzoic Acid via Direct Cyanation (Route 1)
Step 1: Cyanation Reaction
[0034] To a 500 mL round-bottom flask equipped with a reflux condenser, 25 g (0.105 mol) of 4-bromo-1-fluoro-2-methoxybenzene was dissolved in 150 mL of anhydrous N, N-dimethylformamide (DMF). To this, 12 g (0.13 mol) of copper(I) cyanide (CuCN) was added. The reaction mixture was stirred and heated at reflux (approximately 155 °C) for 24 hours under a nitrogen atmosphere.
[0035] After completion (monitored by TLC), the reaction mixture was cooled, diluted with water, and filtered to remove copper salts. The filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to yield 4-fluoro-3-methoxybenzonitrile.
Step 2: Hydrolysis and Demethylation
[0036] The crude nitrile (obtained above) was taken in 150 mL of 48% hydrobromic acid and heated at 90 °C under reflux for 6 hours. After completion, the mixture was cooled and neutralized with aqueous sodium bicarbonate. The precipitated solid was filtered, washed with cold water, and recrystallized from ethanol-water to yield pure 4-fluoro-3-hydroxybenzoic acid as a white solid.
Yield: 18.6 g (overall 71%)
Purity (HPLC): >98%
Melting Point: 214-218 °C
EXAMPLE 2: Synthesis via Amination and Sandmeyer Route (Route 2)
Step 1: Amination
[0037] To a 250 mL round-bottom flask, 10 g (0.042 mol) of 4-bromo-1-fluoro-2-methoxybenzene was dissolved in 100 mL of concentrated aqueous ammonia. Copper(I) chloride (1.2 g, 0.012 mol) was added as a catalyst. The mixture was heated in a sealed tube at 120 °C for 8 hours. After cooling, the mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated to yield 4-fluoro-3-methoxyaniline.
Step 2: Sandmeyer Reaction
[0038] The crude aniline was dissolved in 60 mL of 48% HBr and cooled to 0–5 °C. A cold aqueous solution of sodium nitrite (3.1 g, 0.045 mol) was added dropwise with stirring, maintaining the temperature below 5 °C. After diazotization, the cold diazonium solution was added slowly to a refluxing solution of CuCN (5.5 g, 0.06 mol) in 50 mL of acetic acid. The mixture was refluxed for 2 hours. After completion, the reaction was cooled, diluted with water, and worked up as in Example 1 to isolate the nitrile intermediate.
Step 3: Hydrolysis and Demethylation
[0039] Same as described in Example 1. Final product was isolated and purified.
Yield: 15.4 g (overall 65%)
Purity (HPLC): >96%
Melting Point: 214-218 °C
KEY OBSERVATIONS:
Both routes yielded high-purity product suitable for downstream pharmaceutical synthesis.
Route 1 offers greater yield and simplicity for scale-up.
Route 2 provides a useful alternative when cyanation reagents are not preferred.
ADVANTAGES OF THE PRESENT INVENTION
[0040] Both routes exhibit several synergistic advantages over conventional methods:
High Yields: Each route provides excellent conversion efficiency, reducing material loss during intermediate handling.
High Purity: Minimal side-product formation allows isolation of final product with >98% purity via simple crystallization.
Simplified Work-Up: Filtration and standard solvent removal suffice; no chromatographic purification is required.
Scalability: The reactions use readily available reagents and standard lab equipment, making them easily scalable for industrial manufacturing.
Flexibility: The invention allows flexibility in route selection based on reagent availability or regulatory constraints.
, C , Claims:1. A process for the preparation of 4-fluoro-3-hydroxybenzoic acid, comprising:
(a) converting 4-bromo-1-fluoro-2-methoxybenzene to 4-fluoro-3-methoxybenzonitrile via either:
(i) direct cyanation using copper(I) cyanide in a polar aprotic solvent under reflux conditions; or
(ii) amination with ammonia in the presence of a copper catalyst to form 4-fluoro-3-methoxyaniline, followed by a Sandmeyer reaction using sodium nitrite and copper(I) cyanide; and
(b) subjecting the 4-fluoro-3-methoxybenzonitrile to hydrolysis and demethylation using an inorganic acid or base to obtain 4-fluoro-3-hydroxybenzoic acid.
2. The process as claimed in claim 1, wherein the polar aprotic solvents are dimethylformamide (DMF), dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO), Sulfolane and N-methylpyrrolidone (NMP).
3. The process as claimed in claim 1, wherein the hydrolysis and demethylation are carried out in hydrobromic acid at a temperature between 80°C and 100°C.
4. The process as claimed in claim 1, wherein the amination step uses aqueous ammonia and a copper (I) or copper (II) salt.
5. The process as claimed in claim 1, wherein the Sandmeyer reaction is carried out by generating a diazonium salt at 0°C to 5°C and reacting it with copper(I) cyanide in acetic acid under reflux.
6. The process as claimed in claim 1, wherein the final product is isolated by filtration and purified by crystallization without requiring chromatographic purification.
7. The process as claimed in claim 1, wherein the 4-fluoro-3-hydroxybenzoic acid is obtained with a purity of at least 98% as measured by HPLC.
8. The process as claimed in claim 1, wherein the 4-fluoro-3-hydroxybenzoic acid is used as an intermediate in the synthesis of Acoramidis.
9. An intermediate compound selected from 4-fluoro-3-methoxybenzonitrile and 4-fluoro-3-methoxyaniline, when prepared according to the process of any one of claims 1 to 5, for use in the synthesis of 4-fluoro-3-hydroxybenzoic acid.
10. 4-fluoro-3-hydroxybenzoic acid, whenever prepared by a process comprising:
(a) reacting 4-bromo-1-fluoro-2-methoxybenzene with copper(I) cyanide under reflux in a polar aprotic solvent to yield 4-fluoro-3-methoxybenzonitrile; and
(b) converting the 4-fluoro-3-methoxybenzonitrile to 4-fluoro-3-hydroxybenzoic acid by hydrolysis and demethylation using an inorganic acid or base.
11. 4-fluoro-3-hydroxybenzoic acid, whenever prepared by a process comprising:
(a) aminating 4-bromo-1-fluoro-2-methoxybenzene with ammonia in the presence of a copper catalyst to yield 4-fluoro-3-methoxyaniline;
(b) converting the aniline intermediate to 4-fluoro-3-methoxybenzonitrile via Sandmeyer reaction; and
(c) hydrolysing and demethylating the nitrile to obtain 4-fluoro-3-hydroxybenzoic acid

Dated this 3rd day of July 2025

Alimamad Malani
(IN/PA 5631)