A new synthesis of tafamidis

Abstract

The present invention relates to a novel method for producing tafamidis with excellent synthesis yield and economical efficiency, more specifically, the present invention relates to a novel method for synthesizing tafamidis with excellent synthesis yield by forming an imine by reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzaldehyde, and synthesizing tafamidis having a benzoxazole skeleton through an oxidative cyclization reaction using a cyanide anion-containing catalyst under basic conditions in air, thereby eliminating the need for separate oxidizing agents such as conventional metal catalysts and / or high-concentration oxygen, and minimizing separation processes.

Description

[Technical field]

[0001] The present invention relates to a novel method for producing tafamidis with excellent synthesis yield and cost efficiency. More specifically, the present invention relates to a novel method for synthesizing tafamidis with a benzoxazole skeleton by reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzaldehyde to form an imine, and then synthesizing the tafamidis with a benzoxazole skeleton through an oxidative cyclization reaction using a cyanide anion-containing catalyst under basic conditions in air, which does not require the use of a separate oxidizing agent such as a conventional metal catalyst and / or high-concentration oxygen, and minimizes the separation process, resulting in an excellent synthesis yield. [Background technology]

[0002] Tafamidis (brand names: Vyndaqel or Vyndamax) is a drug used to slow the progression of certain forms of transthyretin amyloidosis in adults. The drug is used to treat the hereditary forms of familial cardiac amyloidosis and familial amyloidotic fasciculus neuropathy, as well as wild-type transthyretin amyloidosis, formerly known as senile systemic amyloidosis. In people with transthyretin amyloidosis, low levels of transthyretin lead to the formation of (amyloid) clumps that harm tissues, including the nerves and heart. Tafamidis works by stabilizing the quaternary structure of the protein transthyretin, slowing the progression of the disease.

[0003] Tafamidis was first developed in 2003 by Professor Jeffery W. Kelly's team while he was working at Scripps Research Institute. In the same year, Professor Kelly's team and MIT Professor Susan Lindquist established FoldRx, which was acquired by Pfizer in 2010. Tafamidis was approved by the European Medicines Agency (EMA) in 2011 and approved for use in Japan in 2013. In 2019, it was also approved for use in thyretin-related cardiac amyloidosis by the US FDA. It has a high market potential, with global sales reaching 1.5 trillion won (1.29 billion dollars) in 2020, and the related market is expected to grow further in the future considering the increase in prevalence and prescriptions. The substance patent for tafamidis varies by country, but it is set to expire around the end of 2023 or early 2024. As a result, various pharmaceutical companies, including those in Korea, are actively interested in and researching the synthesis of generic versions of the compound.

[0004] [ka]

[0005] Structurally, tafamidis is based on a benzoxazole skeleton with a 3,5-dichlorophenyl group at the 2-position of the benzoxazole and a highly polar carboxyl group at the 5-position. It is currently commercially mass-produced via the route developed by Professor Kelly's team in 2003, as shown below (Scheme 1). [ka]

[0006] In this process, 4-amino-3-hydroxybenzoic acid was first reacted with 3,5-dichlorobenzoyl chloride to form an amide, and then tafamidis with a benzoxazole skeleton was synthesized through a dehydration cyclization reaction under acidic conditions. The carboxylic acid group was then converted to a methyl ester group through a reaction with diazomethane, and the final compound, tafamidis, was synthesized through hydrolysis of the ester group. However, the above synthesis method has an unnecessary process of converting the carboxylic acid functional group into an ester group and then converting it back to a carboxylic acid group through hydrolysis, and diazomethane must be used to perform the esterification reaction. In addition, the overall yield is low, at only about 10%, so many improvements are needed.

[0007] Meanwhile, Ferlin et al. have reported a method of producing benzoxazole after forming an imine in a literature (Francesco Ferlin, et al., Continuous flow / waste-minimized synthesis of benzoxazoles catalyzed by heterogeneous manganese systems, Green Chem., 2019, 21, 5298). However, this method improves the reactivity of the method of producing benzoxazole through an oxidation reaction using a metal catalyst by simultaneously using a different type of catalyst, i.e., heterogeneous mixed valence manganese octahedral molecular sieves (OMSs) and high-concentration oxygen (100% oxygen), which is different from the present invention, which does not use a metal catalyst or high-concentration oxygen.

[0008] In order to solve the problems of the existing methods for producing tafamidis, the present inventors have discovered that synthesis of tafamidis having a benzoxazole skeleton through oxidative cyclization reaction using a cyanide anion-containing catalyst under basic conditions in air, by reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzaldehyde to form an imine, has the advantages of excellent production cost efficiency and yield, and have completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide a novel method for producing tafamidis, which does not require a separate oxidizing agent such as high-concentration oxygen while eliminating the metal catalyst used in the existing methods for producing tafamidis, and therefore does not require a process for removing remaining metals and can be reacted in air. Another object of the present invention is to provide a novel process for the preparation of tafamidis through a single separation process which is economical and yet provides excellent synthetic yield and purity of tafamidis. [Means for solving the problem]

[0010] In order to achieve the above object, in one embodiment of the present invention, (a) reacting compound 2 with compound 3 to obtain compound S1; (b) converting said compound S1 to compound S1′ using one equivalent of a base containing M; (c) converting compound S1' to compound S2 using M'CN as a catalyst under basic conditions; and (d) converting compound S2 into compound 1 by treating with an acid; A method for preparing compound 1, comprising: [ka] Where: M and M' are each independently selected from the group consisting of alkali metals, alkaline earth metals and ammonium, and the preparation method is characterized in that it is carried out in air and does not use a metal catalyst and / or a separate oxidizing agent. Effect of the Invention

[0011] The present invention provides a novel method for producing Tafamidis that does not require a separate oxidizing agent such as high-concentration oxygen while eliminating the metal catalyst used in existing Tafamidis production methods, and does not require a process for removing remaining metals, and can be reacted in air. In addition, the present invention provides a novel method for producing tafamidis, which is economical and can provide tafamidis with excellent synthesis yield and purity through only one separation process. [Brief description of the drawings]

[0012] [Figure 1] NMR spectrum of tafamidis 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In one embodiment of the present invention, the step (a) of obtaining compound S1 is preferably carried out in the presence of a dehydrating agent. The use of such a dehydrating agent can promote the overall reaction by removing water molecules generated during the formation of the imine intermediate. Preferred examples of the dehydrating agent that may be used in the present invention include, but are not limited to, one or more compounds selected from the group consisting of MgSO4 and Na2SO4. In addition, in one embodiment of the present invention, when TiCl4 is used as the dehydrating agent, a base is necessarily used, and a preferred example of the base is Et3N.

[0014] In one embodiment of the present invention, step (a) can be carried out by reacting with molecular sieves or by using azeotropic distillation.

[0015] In one embodiment of the present invention, step (a) may be carried out using a Dean-Stark apparatus.

[0016] The term "alkali metal" as used herein refers to the chemical elements lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), etc., which are group 1 elements in the periodic table.

[0017] The term "alkaline earth metal" as used herein refers to the chemical elements beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), etc., which are group 2 elements of the periodic table.

[0018] The term "base containing M" as used herein refers to an inorganic base containing M selected from the group consisting of alkali metals, alkaline earth metals, and ammonium, which can convert compound S1 to compound S1' through an acid-base reaction. Specifically, the inorganic base refers to a non-organic base, such as a salt containing a proton of M, for example, a hydroxide salt, a carbonate salt, a phosphate salt, a cyanide salt, and an acetate salt, but is not limited thereto.

[0019] In one embodiment of the present invention, M is preferably an alkali metal.

[0020] Preferred examples of the "base containing M" used in one embodiment of the present invention include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, ammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, ammonium carbonate, lithium phosphate, sodium phosphate, potassium phosphate, rubidium phosphate, cesium phosphate, ammonium phosphate, lithium cyanide, sodium cyanide, potassium cyanide, rubidium cyanide, cesium cyanide, ammonium cyanide, lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, ammonium acetate, and the like.

[0021] In one embodiment of the invention, the base is used in the presence of a phase transfer catalyst. In another embodiment, the base is used in the presence of an organic solvent. In another embodiment, the base is used in the presence of one or more of a phase transfer catalyst, water, or an organic solvent.

[0022] The "cyanide anion-containing catalyst" used in the present invention can be represented as M'CN, where M' is selected from the group consisting of alkali metals, alkaline earth metals and ammonium.

[0023] In one embodiment of the present invention, the step (c) forms a benzoxazole ring through an oxidative cyclization reaction using a cyanide anion-containing catalyst under basic conditions in air, so that this step does not require the use of a metal catalyst or a separate oxidizing agent such as high-concentration oxygen. Examples of preferred cyanide anion-containing catalysts used in the present invention include, but are not limited to, sodium cyanide or potassium cyanide.

[0024] In one embodiment of the present invention, a catalyst containing some cyanide anion can be used as both a base and a catalyst. For example, when sodium cyanide is used as both a base and a catalyst, 1.1 equivalents of sodium cyanide are used, through which steps (b) and (c) can all be carried out.

[0025] In one embodiment of the present invention, any suitable solvent may be used in steps (b) and (c). In particular, it is preferred to use a polar aprotic solvent in steps (b) and (c). Examples of polar aprotic solvents that may be used in the present invention include, but are not limited to, acetone, acetonitrile, tetrahydrofuran, dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoric acid triamide (HMPA), etc. In one embodiment of the present invention, it is preferred to use a polar aprotic solvent in steps (b) and (c) that is DMF or DMSO.

[0026] In one embodiment of the present invention, the step (c) is preferably carried out under basic conditions.

[0027] In one embodiment of the invention, step (c) may be performed at any suitable temperature, for example, a suitable performance temperature for step (c) is a temperature above room temperature, such as 25° C. to 100° C., or 25° C. to 80° C., or 50° C. to 80° C.

[0028] In one embodiment of the present invention, the compound S1 obtained in step (a) may be separated through a separation process as determined by those skilled in the art, or may be used directly in step (b) without a separate separation process. For example, in the present invention, it is preferred to use the compound S1 obtained in step (a) directly in step (b) without a separation process, thereby making it possible to obtain tafamidis economically and with excellent synthesis yield and purity.

[0029] In one embodiment of the present invention, step (d) is a step of finally treating the compound S2 obtained under basic conditions with an acid to obtain tafamidis. The type of acid used in the present invention is not limited, but sulfuric acid or hydrochloric acid is preferably used.

[0030] The term "air" as used in this invention refers to the colorless, transparent gas that constitutes the lower part of the atmosphere surrounding the earth, and contains small amounts of carbon dioxide, argon, etc. in addition to the main components nitrogen and oxygen.

[0031] The reaction mixture in each step of the present invention may be at any suitable pressure. Such pressure generally affects the reaction rate of a chemical reaction, the state of reactants, etc. For example, the reaction mixture of the present invention is preferably carried out under normal pressure (1 atm) without applying pressure, but is not limited thereto. For example, the reaction mixture of each step of the present invention may be carried out under relatively lower or higher pressure conditions than normal pressure conditions, as long as it does not affect the overall reaction yield. However, although compressed air, etc. may be used in the present invention, high-concentration oxygen (100% oxygen), etc. is not used separately. EXAMPLES

[0032] The present invention will be described in more detail with reference to the following examples, which are provided to aid in the understanding of the present invention and are not intended to limit the scope of the present invention.

[0033] General Procedure All reactions were carried out in oven-dried glassware under an argon atmosphere unless otherwise noted. All reactions were self-stirred and monitored by analytical thin layer chromatography (TLC) using silica gel glass plates (0.25 mm) pre-coated with F254 indicator and visualized with UV light (254 nm) unless otherwise indicated. Flash column chromatography was performed using silica gel 60 (230-400 mesh) with the indicated eluents. Commercial grade reagents were used without further purification. Yields refer to chromatographically and spectroscopically pure compounds unless otherwise noted. 1 H NMR and 13 C NMR spectra were recorded on 500 MHz and 125 MHz spectrometers, respectively. Tetramethylsilane (δ TMS : 0.0 ppm) and residual NMR solvent (CDCl3(δ H: 7.26 ppm, δ C : 77.16 ppm) or (CD3)2SO(δ H : 2.50 ppm, δ C :39.52ppm) respectively 1 H NMR and 13 It was used as an internal standard for the C NMR spectra. Proton spectra were denoted as δ (position of proton, multiplicity, coupling constant J, number of protons). Multiplicities were denoted as s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), m (multiplet) and br (broad). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer (QTOF-MS) using electrospray ionization (ESI) as the ionization method. The main reagents used included NaCN, toluene, and DMF.

[0034] Synthesis Example 1: Tafamidis 1 [ka]

[0035] Aniline compound 2 (153 mg, 1.0 mmol) and aldehyde compound 3 (175 mg, 1.0 mmol) were placed in a two-neck flask equipped with a Dean-Stark apparatus, toluene (10 mL) was added, and the reaction was stirred at 140 °C while monitoring the progress of the reaction by TLC. 1 H NMR was used to observe. After the compounds 2 and 3 were completely consumed, the reaction mixture was concentrated to obtain a mixture of imine compounds S1, which was used in the next reaction without further separation.

[0036] The mixture of imine compound S1 was dissolved in dimethylformamide (2 mL), and potassium carbonate (138 mg, 1.0 mmol) and sodium cyanide (4.9 mg, 0.1 mmol) were added to the mixture, and the reaction was monitored by TLC while stirring at 80°C. After compound S1 was completely consumed, distilled water (5 mL) was added dropwise and stirred for 30 minutes. Then, 1N HCl aqueous solution was added dropwise to the reaction mixture until the pH reached 1, causing an ivory-colored precipitate to form. The resulting precipitate was filtered and washed with distilled water to obtain tafamidis 1 (270 mg, 0.87 mmol, 87%) as an ivory-colored solid.

[0037] 1 H NMR(500 MHz,CD3OD)δ13.29(br,1H), 8.29(d,J=1.1Hz,1H), 8.18(d,J=2.0Hz,2H), 8.05(dd,J=8.4,1.5Hz,1H), 7.98(t,J=1.9Hz,1H), 7.94(d,J=8.4Hz,1H)

[0038] Synthesis Example 2: Tafamidis 1 [ka]

[0039] Aniline compound 2 (153 mg, 1.0 mmol) and aldehyde compound 3 (175 mg, 1.0 mmol) were placed in a two-neck flask equipped with a Dean-Stark apparatus, toluene (10 mL) was added, and the reaction was stirred at 140 °C while monitoring the progress of the reaction by TLC. 1 After the complete consumption of compound 2 and compound 3, the reaction mixture was concentrated to obtain a mixture of imine compound S1, which was used in the next reaction without further separation.

[0040] The mixture of imine compound S1 was dissolved in dimethylformamide (2 mL), sodium cyanide (54 mg, 1.1 mmol) was added to the mixture, and the reaction was monitored by TLC while stirring at 80°C. After compound S1 was completely consumed, distilled water (5 mL) was added dropwise and stirred for 30 minutes. 1 N HCl aqueous solution was added dropwise until the pH reached 1, resulting in the formation of an ivory-colored precipitate. The precipitate was filtered and washed with distilled water to obtain tafamidis 1 (270 mg, 0.87 mmol, 87%) as an ivory-colored solid.

[0041] 1 H NMR (500MHz, DMSO‐d6) δ13.29(br,1H), 8.29(d,J=1.1Hz,1H), 8.18(d,J=2.0Hz ,2H), 8.05(dd,J=8.4,1.5Hz,1H), 7.98(t,J=1.9Hz,1H), 7.94(d,J=8.4Hz,1H)

Claims

1. (a) reacting compound 2 with compound 3 to obtain compound S1; (b) converting said compound S1 to compound S1′ using one equivalent of a base containing M; (c) converting compound S1' to compound S2 using M'CN as a catalyst under basic conditions; and (d) converting compound S2 to compound 1 by treating with an acid; A method for preparing Compound 1, comprising: 【Chemistry 1】 Where: M and M' are each independently selected from the group consisting of alkali metals, alkaline earth metals and ammonium, and the method is characterized in that it is carried out in air and does not use a metal catalyst and / or a separate oxidizing agent.

2. The process of claim 1 , wherein step (a) is carried out in the presence of a dehydrating agent.

3. The dehydrating agent is MgSO 4 and Na 2 SO 4 3. The method of claim 2, wherein the compound is one or more compounds selected from the group consisting of:

4. The step (a) is carried out using TiCl 4 The method according to claim 1 , wherein the method is carried out in the presence of a base.

5. The base is Et 3 The method according to claim 4, wherein N is N.

6. 2. The method of claim 1, wherein the step (a) is carried out using azeotropic distillation.

7. 2. The method of claim 1, wherein step (a) is carried out using a Dean-Stark apparatus.

8. The method of claim 1 , wherein M is an alkali metal.

9. 2. The method of claim 1, wherein the base containing M is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, ammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, ammonium carbonate, lithium phosphate, sodium phosphate, potassium phosphate, rubidium phosphate, cesium phosphate, ammonium phosphate, lithium cyanide, sodium cyanide, potassium cyanide, rubidium cyanide, cesium cyanide, ammonium cyanide, lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, and ammonium acetate.

10. The process according to claim 9, wherein the base is sodium cyanide.

11. The method of claim 1, wherein the M'CN is NaCN or KCN.

12. The method according to claim 1, wherein steps (b) and (c) are carried out in a polar aprotic solvent.

13. The process according to claim 12, wherein the polar aprotic solvent is DMF or DMSO.

14. 2. The method of claim 1, wherein step (c) is performed at a temperature of 25 to 100°C.

15. The method according to claim 1, wherein the compound S1 obtained in step (a) is used in step (b) directly without a separate separation process.

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